Tumour diploidy and survival in breast cancer patients with BRCA2 mutations

It is not well known to what extent carrying a BRCA2 mutation affects the survival of women with breast cancer and prognostic factors among BRCA2-positive women warrant investigation. Using a record linkage approach we compared the long-term survival in carriers and noncarriers of an inherited BRCA2 founder mutation (999del5), and sought to identify prognostic factors among the BRCA2 mutation-positive subset, including markers of genetic instability (aneuploidy) and mitotic activity (S-phase fraction). We established the genetic status of 2,967 Icelandic breast cancer patients (215 mutation carriers and 2,752 noncarriers) diagnosed from 1955 to 2004, representing 72 % of all cases diagnosed in the country during this period. Tumour ploidy and S-phase fraction were assessed on tumour cells by DNA flow cytometry. Prognostic factors were assessed blindly with respect to mutation status. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival by BRCA2 status, using Cox regression. After a median follow-up of 9.5 years, BRCA2 mutation carriers had a higher risk of death from breast cancer than noncarriers (HR 1.64, 95 % CI 1.24–2.16, p < 0.001). The risk increase was restricted to women with diploid tumours (HR 3.03, 95 % CI 1.91–4.79, p < 0.001). Among breast cancer patients with aneuploid tumours, survival of carriers was similar to that of noncarriers (HR 0.76, 95 % CI 0.41–1.41, p = 0.38). Increased tumour size and a positive nodal status predicted worse prognosis in all patients, whereas the highly correlated prognostic factors diploidy, low proliferative activity and a positive estrogen receptor status had reverse effects in mutation carriers and noncarriers. Breast cancer patients who carry the Icelandic founder BRCA2 mutation have inferior long-term survival than noncarriers, but the adverse prognosis is restricted to mutation carriers with diploid, slowly proliferating tumours.     

Segregation analysis of 389 Icelandic pedigrees with Breast and prostate cancer

Breast cancer and prostate cancer are the most commonly occurring cancers in females and males, respectively. The objective of this project was to test the hypothesis that breast cancer in females and prostate cancer in males represent homologous cancers that may be controlled by one or more common unidentified genes that may explain some of the observed familial aggregation. We modeled the transmission of a breast-prostate cancer phenotype in 389 pedigrees ascertained through a breast cancer proband drawn from the Icelandic Cancer Registry. Assuming that age at diagnosis of this combined phenotype followed a logistic distribution, segregation analyses were performed to evaluate residual parental effects, a sibship covariate, and a dichotomous cohort effect. The most parsimonious model was a Mendelian codominant model, which could partly explain the familial aggregation of both cancers. Inheritance of a putative high-risk allele (A) predicted gender-specific mean ages of onset for females as 53.8 years, 59.7 years, and 65.6 years for the putative AA, AB, and BB genotypes, respectively. Similarly, the predicted means were 73.7 years, 75.6 years, and 78.3 years, respectively, among males. Under this codominant model, the lifetime risk of a woman being affected was 19% by age 80 years. This implies that when prostate cancer among male relatives of breast cancer probands (unselected for family history or early-onset disease) is considered a pleiotrophic effect of the same gene that increases the risk for breast cancer, women are predicted to have a less than 1 in 5 risk of developing breast cancer when they carry the putative high-risk allele. However, this is a higher risk than in the general Icelandic population. Our results suggest that BRCA2 mutations alone are inadequate to explain all of the excess clustering of prostate cancer cases in families of breast cancer probands, and that additional genes conferring excess risk to both breast and prostate cancer may exist in this population.     

Cancer incidence among priests: 45?years of follow-up in four Nordic countries

Previously published studies on the risk of cancer among male priests have been based on cancer mortality with the exception of one case–control study. The aim of this study was to present estimates of cancer incidence among Nordic male priests. The study cohort for our analyses consisted of 6.5 million men aged 30–64 years old who had participated in any computerised population census in four Nordic countries in 1990 or earlier. Follow-up was done by drawing linkages with the national population and cancer registries. 13,491 priests were identified by their job title codes. We estimated the standardised incidence ratio (SIR) and 95% confidence intervals (95% CI) for the priests using the male population as a reference. Priests had a lower cancer incidence than the general population (overall SIR 0.85, 95% CI: 0.82–0.88). The majority of smoking- and alcohol-related cancers were associated with decreased SIR estimates. Increased risks were observed for skin melanoma (SIR 1.34, 95% CI: 1.11–1.62), acute myeloid leukemia (SIR 1.75, 95% CI: 1.20–2.47) and thyroid cancer (SIR 1.86, 95% CI: 1.22–2.73). This is the first cohort study regarding the incidence of cancer among priests. The lower incidence of smoking and alcohol-related cancers among Nordic male priests can be explained by their lower exposure to cigarettes and alcohol when compared to the general population. A greater risk of melanoma is typical of highly-educated people, but it is unclear why priests should have an increased risk of acute myeloid leukemia or thyroid cancer.     

Vitamin D Intake and Status in 6-Year-Old Icelandic Children Followed up from Infancy

High serum 25-hydroxyvitamin D (25(OH)D) levels have been observed in infants in Nordic countries, likely due to vitamin D supplement use. Internationally, little is known about tracking vitamin D status from infancy to childhood. Following up 1-year-old infants in our national longitudinal cohort, our aims were to study vitamin D intake and status in healthy 6-year-old Icelandic children (n = 139) and to track vitamin D status from one year of age. At six years, the mean 25(OH)D level was 56.5 nmol/L (SD 17.9) and 64% of children were vitamin D sufficient (25(OH)D ≥ 50 nmol/L). A logistic regression model adjusted for gender and breastfeeding showed that higher total vitamin D intake (Odds ratio (OR) = 1.27, 95% confidence interval (CI) = 1.08–1.49), blood samples collected in summer (OR = 8.88, 95% CI = 1.83–43.23) or autumn (OR = 5.64, 95% CI = 1.16–27.32) compared to winter/spring, and 25(OH)D at age one (OR = 1.02, 95% CI = 1.002–1.04) were independently associated with vitamin D sufficiency at age six. The correlation between 25(OH)D at age one and six was 0.34 (p = 0.003). Our findings suggest that vitamin D status in infancy, current vitamin D intake and season are predictors of vitamin D status in early school age children. Our finding of vitamin D status tracking from infancy to childhood provides motivation for further studies on tracking and its clinical significance.     

Testicular germ cell tumours in Iceland: a nationwide clinicopathological study

The purpose of this study was to examine the pathology of all germ cell tumours of the testis diagnosed in Iceland 1955-2002. A total of 214 patients were included in the study. The current age-standardized incidence was found to be 6.1 per 100,000 and had increased almost fourfold during the study period. Seminoma was diagnosed in 55% of cases. Non-seminomas were diagnosed in 45%, and these were further classified as mixed germ cell tumours (33%), embryonal carcinoma (8%), teratoma (3%), and yolk sac tumour (n=1). The mean age at diagnosis was significantly higher for the seminomas than the non-seminomas (38 years versus 29 years) (p<0.001) and the non-seminomas were diagnosed at a significantly higher stage than the seminomas (p<0.001). Thus, in seminoma patients the tumour was localized to the testis (stage I) in 81% of cases, in 17% of patients the tumour had spread to the lymph nodes (stage II or III), and only 2% had extranodal metastasis at diagnosis (stage IV). In contrast, in the non-seminoma patients, the tumours were found to be stage I in 56%, stage II or III in 24%, and stage IV in 20% of cases. No significant difference in staging was found between non-seminoma subtypes. Identification of necrosis or vascular invasion was significantly associated with metastatic disease at diagnosis (p=0.002). During the study period a significant increase in stage I tumours was found as well as a decrease in the size of the tumours.     

Acute isovolemic hemodilution triggers proinflammatory and procoagulatory endothelial activation in vital organs: role of erythrocyte aggregation

OBJECTIVES: The essential role of erythrocytes as oxygen carriers is historically well established, but their function to aggregate and the consequences on the microcirculation is under debate. The pathogenic potential of low erythrocyte aggregation could be important for patients undergoing on-pump cardipopulmonary bypass. These patients are severely hemodiluted due to preoperative isovolemic hemodilution (IHD), circuit priming, and large fluid infusions perioperatively. Considering the vascular endothelium sensitivity to variations in blood rheology, the authors hypothesize that low erythrocyte aggregation will be responsible for activation of vascular endothelium during acute IHD. METHODS: Acute IHD (30 mL/kg exchange transfusion with colloid solutions) was induced in an "aggregating species"(pigs, n = 15). The hypoxic oxidative stress (plasma malondialdehyde, ex vivo oxygen radicals production in heart, lung, kidney, liver, and ileum tissue biopsies), erythrocyte aggregation (LORCA), and endothelial activation (real-time quantitative RT-PCR on von Willebrand factor (vWF), E- and P-selectins, endothelial nitric oxide synthase gene-expression in tissue biopsies) were investigated. RESULTS: The production of superoxide and hydroxyl radicals, measured as H2O2 generation, was similar at all times in sham-operated and hemodiluted animals, proving a maintained oxygen delivery to tissues. Acute IHD was followed by a dramatic drop in erythrocyte aggregation and immediate prothrombotic (significant vWF mRNA upregulation in heart, lungs, kidney, liver, ileum) and proinflammatory (significant E- and P-selectins mRNA upregulation in lungs and ileum) endothelial activation. Low erythrocyte aggregation was significantly correlated with increased mRNA-expression of vWF (heart, liver, ileum) and P-selectin (lungs, ileum, and heart). CONCLUSIONS: These results suggest that low erythrocyte aggregation might trigger endothelium-dependent thrombogenic and proinflammatory response during acute isovolemic hemodilution.     

Spread of a methicillin-resistant Staphylococcus aureus ST80-IV clone in a Danish community.

OBJECTIVE: We report a community cluster of methicillin-resistant Staphylococcus aureus (MRSA) in Denmark with emphasis on routes of transmission and infection control measures. The objective is to extend knowledge of MRSA in a community setting where a nosocomial link could effectively be ruled out. DESIGN: Population-based observational study from November 1997 until June 2003. SETTING: North Jutland County, with approximately 495,000 inhabitants. SUBJECTS: The cluster encompassed 46 individuals and 26 households. INTERVENTIONS: Infection control measures included repeated visits to affected households by an infection control nurse who undertook screening for carriage among all household members and provided a program for decolonization. RESULTS: The causal strain was identical to a newly described international clone, ST80; SSCmec type IV; and Panton-Valentine leukocidin positive. Plausible routes of transmission included household contact and contact at work, kindergarten, and school. We did not detect a nosocomial source or any secondary cases in hospitals. Transmission by healthcare contact outside the hospital was plausible for three cases. We found evidence that the clone was introduced on more than one occasion to immigrant families from the Middle East. A 5-day decolonization program was successful at first attempt in 15 of 16 households that could be evaluated. CONCLUSIONS: Despite the described infection control measures, we continued to see new cases, underlining a need for a national policy to contain MRSA in the community.