Risk factors for Clostridium difficile toxin-positive diarrhea: a population-based prospective case-control study.

Increased incidence and severity of Clostridium difficile infections (CDIs) is of major concern. However, by minimizing known risk factors, the incidence can be decreased. The aim of this investigation was to calculate the incidence and assess risk factors for CDI in our population. A 1-year prospective population-based nationwide study in Iceland of CDIs was carried out. For risk factor evaluation, each case was matched with two age- and sex-matched controls that tested negative for C. difficile toxin. A total of 128 CDIs were identified. The crude incidence was 54 cases annually per 100,000 population >18 years of age. Incidence increased exponentially with older age (319 per 100,000 population >86 years of age). Community-acquired origin was 27 %. Independent risk factors included: dicloxacillin (odds ratio [OR]: 7.55, 95 % confidence interval [CI]: 1.89-30.1), clindamycin (OR: 6.09, 95 % CI: 2.23-16.61), ceftriaxone (OR: 4.28, 95 % CI: 1.59-11.49), living in a retirement home (OR: 3.9, 95 % CI: 1.69-9.16), recent hospital stay (OR: 2.3, 95 % CI: 1.37-3.87). Proton pump inhibitors (PPIs) were used by 60/111 (54 %) versus 91/222 (41 %) (p = 0.026) and ciprofloxacin 19/111 (17 %) versus 19/222 (9 %) (p = 0.027) for cases and controls, respectively. In all, 75 % of primary CDIs treated with metronidazole recovered from one course of treatment. CDI was mostly found among elderly patients. The most commonly identified risk factors were broad-spectrum antibiotics and recent contact with health care institutions. PPI use was significantly more prevalent among CDI patients.

The effect of a single BRCA2 mutation on cancer in Iceland.

OBJECTIVE: To estimate the risk of malignant diseases in families of probands with the same mutation in the BRCA2 gene. DESIGN: A cohort study using record linkage of a breast cancer family resource and the Icelandic Cancer Registry. SETTING: Iceland. SUBJECTS: Families of 995 breast cancer patients, from which 887 were tested for a single founder 999del5 mutation; 90 had the mutation and 797 did not. RESULTS: Relatives of probands with the mutation had significantly increased relative risk (RR) of breast cancer. For first degree relatives, the RR was 7.55 (95% CI 6.04 to 9.03) but was 1.72 (95% CI 1.49 to 1.96) in first degree relatives of probands without the mutation. For prostate and ovarian cancer, the first and second degree relatives of probands with the mutation had a significantly increased RR, but in families of probands without the mutation no significant familial risk was found. CONCLUSIONS: The 999del5 mutation in the BRCA2 gene explains a substantial proportion of familial risk of breast cancer in Iceland, but significant familial risk remains in relatives of probands without the mutation. For prostate and ovarian cancer, the mutation accounts for most of the familiality observed in families of breast cancer patients.

A majority of patients with Barrett's oesophagus are unlikely to benefit from endoscopic cancer surveillance.

BACKGROUND: Endoscopic cancer surveillance has been advocated for patients with Barrett's oesophagus. However, only a small minority of patients dies from adenocarcinoma in Barrett's oesophagus. It has been calculated that endoscopic cancer surveillance will only add to the quality of life of individuals in whom the incidence of adenocarcinoma in Barrett's oesophagus is greater than 1/200 patient-years. OBJECTIVE: To determine the proportion of a consecutive cohort of patients, in whom Barrett's oesophagus was diagnosed over a 5-year period, likely to benefit from endoscopic cancer surveillance. METHODS: All patients who had died during the observation period or were over 75 years old and those with diseases likely to impair survival were excluded. Next, all patients in whom the risk of developing adenocarcinoma in Barrett's oesophagus fell below 1/200 patient-years were excluded (including all women, all men under the age of 60 and all men with Barrett's oesophagus of < 3 cm in length). Patients with dysplasia of any degree and/or presence of an ulcer or stricture in Barrett's oesophagus were reinstated. RESULTS: Of 335 adult patients diagnosed with Barrett's oesophagus but without adenocarcinoma or high-grade dysplasia, 75 had died from unrelated causes, 47 had other diseases limiting survival and 59 were over 75 years old. After exclusion of all women, all men with Barrett's oesophagus of < 3 cm in length and all men under 60 years old, 15 patients were left. However, 32 were reinstated because of risk factors and another five because of insufficient data, resulting in 52 of the original 335 patients (15.5%) being eligible for endoscopic cancer surveillance. CONCLUSION: This study suggests that less than 20% of patients identified with Barrett's oesophagus at routine endoscopy would benefit from endoscopic cancer surveillance. Prospective surveillance programmes should be limited to patients with an increased cancer risk and a good health profile.

P53 mutations analysis in benign and malignant breast lesions: using needle rinses from fine-needle aspirations.

The fine-needle aspiration (FNA) technique is a widely used method for diagnostic assessment of breast diseases. In the current study we investigated the feasibility of sampling material for genetic studies from the same FNA samples as would be used for breast cytology. After making smears for cytological examination, the needle was rinsed into phosphate-buffered saline (PBS) solution. The material gained was sufficient for a polymerase chain reaction (PCR)-based study. As the FNA samples reflect a broad range of breast diseases, it is possible to study genetic changes at various stages of the neoplastic process. We looked for mutations in the p53 tumor suppressor gene in 198 FNA needle rinses, 42 from carcinomas and 156 from cytologically benign lesions. In the malignant samples, 22% carried mutations in the p53 gene. We also looked for p53 mutations in matching tissue sections from tumors and found the FNA needle rinses to represent the tumor well. In addition, three mutations in cytologically benign lesions were found, but none of these 3 patients were diagnosed with malignant tumors in the time frame of the study. The clinical significance of p53 mutations in benign breast tissue remains to be determined.

Loss of heterozygosity at 11q23.1 and survival in breast cancer: results of a large European study. Breast Cancer Somatic Genetics Consortium.

Among the chromosomal regions commonly undergoing deletions in breast tumors is 11q23.1. The genes that are targets for loss of heterozygosity (LOH) in this region is not yet established. One of the candidate genes located in this region is ATM, responsible for the rare autosomal recessive disorder ataxia-telangiectasia (A-T). Interestingly, A-T heterozygotes may have an increased risk of cancer, in particular breast cancer, although this is still controversial. A common assumption has been that the target for the LOH at 11q23.1 in breast carcinoma is the ATM gene, but the area studied has been too large, the density of markers too low, and the number of tumors studied has been too small to draw any firm conclusions. The present study is a multicenter study including 918 breast cancer patients with clinical information and survival data available for most of them. Primary breast tumors were investigated for LOH using a high density of microsatellite markers spanning approximately 6 Mb around the ATM gene. Survival analyses showed that there are most likely one or more candidate genes in a 3-4 Mb region between the markers D11S1819 and D11S927 including the ATM gene. Cancer-specific survival was significantly reduced in patients whose tumors exhibited LOH of markers D11S2179 (within the ATM gene), D11S1778, D11S1294, and D11S1818. The highest survival hazard ratios were 1.8(C11.2-2.8, P = 0.010) and 2.1 (C11.4-3.0, P = 0.0004) for markers D11S2179 and D11S1818, respectively. One or more of these markers are therefore most likely to be located close to or within genes associated with breast cancer survival.

BRCA2 and p53 mutations in primary breast cancer in relation to genetic instability.

The products of the BRCA breast cancer susceptibility genes have been implicated in cell cycle control and DNA repair. It has been suggested that mutations in the p53 gene are a necessary step in tumorigenesis in BRCA tumors. We tested samples from 402 breast cancer patients for germ-line BRCA2 and p53 mutations in tumors. p53 mutations are more frequent in BRCA2 mutation carriers than they are in controls. Tumors with mutations in either gene had multiple chromosomal abnormalities, as shown by cytogenetic analysis.

Altered expression of CA-125 in breast carcinomas.

CA-125 is a high molecular weight glycoprotein that is best known as a tumour marker for ovarian carcinoma but has been found to be present on various epithelial surfaces including normal tissues. Elevated serum levels of CA-125 have been described in malignancies other than ovarian carcinoma as well as in inflammatory conditions. The expression of CA-125 was studied in paraffin-embedded tissue from 48 mammary carcinomas and 11 samples of normal mammary gland using two monoclonal antibodies, M2 and M11. CA-125 was detected in all normal tissue samples and 64% of the breast carcinomas. Eight of the thirty CA-125-positive carcinomas reacted with only one of the antibodies, indicating molecular change. In normal mammary tissue, CA-125 was seen on apical surfaces and in ductal contents, whilst the majority of the carcinomas (90%) expressed CA-125 in cytoplasmic granules, often showing membranous staining as well. In 16 samples of lymph node metastases CA-125 expression was similar to that seen in the primary tumour. Elevated serum levels of CA-125 were detected in only 3 out of 41 samples available from this patient group. No significant associations were detected with various clinical parameters. We conclude that CA-125 is normally expressed in the mammary gland and that the expression is frequently altered and sometimes absent in mammary carcinoma, possibly reflecting the loss of cellular polarity. Measuring serum levels of CA-125 is not relevant in breast carcinoma patients since one third of breast carcinomas were CA-125 negative and even patients with strongly CA-125-positive tumors had undetectable CA-125 serum levels.

[DNA flow cytometry is a useful prognostic guide in the treatment of breast cancer.].

It is widely agreed that the presence or absence of axillary lymph-node involvement (N) is the most reliable predictor of relapse or survival in breast cancer, together with tumor size (T) and the presence or absence of distant metastasis (M). These prognostic factors are the cornerstones of the TNM staging system. The aim of the present study was to ascertain, in all patients diagnosed with invasive primary breast cancer in Iceland during the years 1981-84 (n=347), whether flow cytometric DNA analysis of ploidy status and fraction of cells in the S-phase contribute prognostic information, addi nottional to that obtained with TNM staging variables. Paraffin fixed tumor material was available from 340 patients (98%) and DNA ploidy and S-phase fraction was assessed with flow cytometry. DNA ploidy could be analysed in 98% of tumor samples (n=334), of which 114 (34%) were diploid and 220 (66%) non-diploid. S-phase fraction could be analysed in 97% of the tumor samples (n=329), the median S-phase value was 7.0%, and was higher in non-diploid than diploid tumors (p<0.0001, 9.3% vs. 2.7%). Median duration of patient follow-up was 7.5 years. The disease-free survival at that point of time was 15% higher in patients with diploid tumors than non-diploid ones (p=0.004, 69% vs 54%). Similar survival comparison in relation to S-phase fraction was 30% when the median S-phase value was used as cut-off point (p<0.0001, S-phase<7.0% being 74% vs. S-phase ;7.0% being 44%). Multivariate analyses with regard to breast cancer survival and disease-free survival, which included both ploidy status and S-phase categories adjusting for age, tumor size and lymph node involvement, showed the S-phase value categories to be independent prognostic variables (p<0.0001). Patients with high S-phase tumors had a three-fold higher risk of recurrence than patients with low S-phase tumors. Ploidy status was not an independent prognostic variable, if however the S-phase categories were excluded from analysis, ploidy status was on the borderline of being an independent variable (p=0.09). In node-negative patients the S-phase fraction was the only useful variable in determining prognosis. We conclude that the S-phase value is a useful prognostic guide for the clinician and will be used for this purpose in the treatment of breast cancer in Iceland.