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Introduction Malignant mesothelioma is a deadly disease that is strongly associated with asbestos exposure. Peritoneal mesotheliomas account for 10% of all the cases. BRCA1 associated protein 1 (BAP1) is a deubiquitinating hydrolase that plays a key role in various cellular processes. Germline and somatic inactivation of BRCA1 associated protein 1 gene ( BAP1 ) is frequent in pleural mesothelioma; however, little is known about its status in peritoneal mesothelioma. Methods Taking advantage of the extensive French National Network for the Diagnosis of Malignant Pleural Mesothelioma and Rare Peritoneal Tumors and the French National Network for the Treatment of Rare Peritoneal Surface Malignancies, we collected biological material and clinical and epidemiological data for 46 patients with peritoneal mesothelioma. The status of BAP1 was evaluated at the mutational and protein expression levels and combined with our previous data on copy number alterations assessed in the same samples. Results We detected mutations in 32% of the malignant peritoneal mesotheliomas analyzed. In addition, we have previously reported that copy number losses occurred in 42% of the samples included in this series. Overall, 73% of the malignant peritoneal mesotheliomas analyzed carried at least one inactivated BAP1 allele, but only 57% had a complete loss of its protein nuclear expression. Better overall survival was observed for patients with BAP1 mutations ( p = 0.04), protein expression loss ( p = 0.016), or at least one of these alterations ( p = 0.007) independently of tumor histological subtype, age, and sex. Conclusions As in pleural mesothelioma, inactivation of BAP1 is frequent in peritoneal mesotheliomas. We found that BAP1 protein nuclear expression is a good prognostic factor and a more reliable marker for the complete loss of BAP1 activity than mutation or copy number loss.

Accepted manuscript version, licensed CC BY-NC-ND 4.0. Published version available in European Journal of Cancer, 75, 299-307. Aim of the study: A vast majority of human malignancies are associated with ageing, and age is a strong predictor of cancer risk. Recently, DNA methylation-based marker of ageing, known as ‘epigenetic clock’, has been linked with cancer risk factors. This study aimed to evaluate whether the epigenetic clock is associated with breast cancer risk susceptibility and to identify potential epigenetics-based biomarkers for risk stratification. Methods: Here, we profiled DNA methylation changes in a nested caseecontrol study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (n Z 960) using the Illumina HumanMethylation 450K BeadChip arrays and used the Horvath age estimation method to calculate epigenetic age for these samples. Intrinsic epigenetic age acceleration (IEAA) was estimated as the residuals by regressing epigenetic age on chronological age. Results: We observed an association between IEAA and breast cancer risk (OR, 1.04; 95% CI, 1.007e1.076, P Z 0.016). One unit increase in IEAA was associated with a 4% increased odds of developing breast cancer (OR, 1.04; 95% CI, 1.007e1.076). Stratified analysis based on menopausal status revealed that IEAA was associated with development of postmenopausal breast cancers (OR, 1.07; 95% CI, 1.020e1.11, P Z 0.003). In addition, methylome-wide analyses revealed that a higher mean DNA methylation at cytosine-phosphate-guanine (CpG) islands was associated with increased risk of breast cancer development (OR per 1 SD Z 1.20; 95 %CI: 1.03e1.40, P Z 0.02) whereas mean methylation levels at non-island CpGs were indistinguishable between cancer cases and controls. Conclusion: Epigenetic age acceleration and CpG island methylation have a weak, but statistically significant, association with breast cancer susceptibility.

Scientific Reports 4: Article number: 4482; published online: 27 March 2014 updated: 16 January 2017. In this Article, an additional affiliation for Hana Huskova was omitted. The correct affiliations for this Author are listed below: Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, 69008 Lyon, France.

Differentiated thyroid carcinoma (TC) is threefold more common in women than in men and, therefore, a role of female hormones in the etiology of differentiated TC has been suggested. We assessed these hypotheses in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Among 345,157 women (mean age 51) followed for an average of 11 years, 508 differentiated TC cases were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. No significant associations were observed between differentiated TC risk and number of pregnancies, breast feeding, menopausal status, and age at menarche and at menopause. Significant associations were found with history of infertility problems (HR 1.70; 95% CI 1.12-2.60), a recent pregnancy (HR for 5 vs. >5 years before recruitment 3.87; 95% CI 1.43-10.46), menopause type (HR for surgical vs. natural menopause: 2.16; 95% CI 1.41-3.31), oral contraceptive (OC) use at recruitment (HR: 0.48; 95% CI 0.25-0.92) and duration of OC use (HR for 9 vs. 1 year: 0.66; 95% CI: 0.50-0.89). An increased risk was also found with hormone replacement therapy use at recruitment (HR=1.30, 95% CI 1.02-1.67), but this was not significant after adjustment for type of menopause (HR=1.22, 95% CI 0.95-1.57). Overall, our findings do not support a strong role of reproductive and menstrual factors, and female hormone use in the etiology of differentiated TC. The few observed associations may be real or accounted for by increased surveillance in women who had infertility problems, recent pregnancies or underwent surgical menopause.

IntroductionA retrospective cohort study of 35 840 employees is currently being conducted in a chrysotile mine and its processing facilities in Asbest, the Russian Federation. The primary aim is to quantify exposure-response relationships for cancers potentially associated with chrysotile exposure. Some of those cancers are also tobacco-related; however individual-level information on tobacco use is not available for the full cohort. To address this gap, a cross-sectional study of current and retired workers from JSC Uralasbest was conducted to assess the relationship between smoking status and workers’ exposure to chrysotile.MethodsSelf-administered questionnaires were completed by current workers during meetings organized by occupational safety specialists. Retired workers filled in questionnaires during Veterans’ meetings or were interviewed via telephone or at home. Estimates of exposure to chrysotile were available for 999 current and 3795 retired workers who were linked to the cohort study.ResultsAmong the 7451 respondents (n=3698 men and n=3753 women), 66% of men and 9% of women were ever-smokers. Smoking prevalence was stable across birth decades in men, but increased from ConclusionWhile no adjustments for smoking among men appear necessary in the future analyses, including smoking propensity by birth cohort for women may be useful.

Ductal carcinoma {\em in situ} (DCIS) lesions are non-invasive tumours of the breast which are thought to precede most invasive breast cancers (IBC). As individual DCIS lesions are initiated, grow and invade (i.e. become IBC) the size distribution of the DCIS lesions present in a given human population will evolve. We derive a differential equation governing this evolution and show, for given assumptions about growth and invasion, that there is a unique distribution which does not vary with time. Further, we show that any initial distribution converges to this stationary distribution exponentially quickly. It is therefore reasonable to assume that the stationary distribution is equal to the true DCIS size distribution, at least for human populations which are relatively stable with respect to the determinants of breast cancer. Based on this assumption and the size data of 110 DCIS lesions detected in a mammographic screening program between 1993 and 2000, we produce maximum likelihood estimates for certain growth and invasion parameters. Assuming that DCIS size is proportional to a positive power $p$ of the time since tumour initiation we estimate $p$ to be 0.50 with a 95% confidence interval of $(0.35, 0.71)$. Therefore we estimate that DCIS lesions follow a square-root growth law and hence that they grow rapidly when small and relatively slowly when large. Our approach and results should be useful for other mathematical studies of cancer, especially those investigating biological mechanisms of invasion., 12 pages, 2 figures and 1 table. To appear in Mathematical Medicine and Biology

BACKGROUND: Much of the current literature on diet-colorectal cancer (CRC) associations focused on studies of single foods/nutrients, whereas less is known about nutrient patterns. We investigated the association between major nutrient patterns and CRC risk in participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) study.METHODS: Among 477 312 participants, intakes of 23 nutrients were estimated from validated dietary questionnaires. Using results from a previous principal component (PC) analysis, four major nutrient patterns were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed for the association of each of the four patterns and CRC incidence using multivariate Cox proportional hazards models with adjustment for established CRC risk factors.RESULTS: During an average of 11 years of follow-up, 4517 incident cases of CRC were documented. A nutrient pattern characterised by high intakes of vitamins and minerals was inversely associated with CRC (HR per 1 s.d.=0.94, 95% CI: 0.92-0.98) as was a pattern characterised by total protein, riboflavin, phosphorus and calcium (HR (1 s.d.)=0.96, 95% CI: 0.93-0.99). The remaining two patterns were not significantly associated with CRC risk.CONCLUSIONS: Analysing nutrient patterns may improve our understanding of how groups of nutrients relate to CRC.British Journal of Cancer advance online publication 20 October 2016; doi:10.1038/bjc.2016.334 www.bjcancer.com.

Background Head and neck squamous cell carcinomas (HNSCCs) represent a heterogeneous group of cancers for which human papilloma virus (HPV) infection is an emerging risk factor. Previous studies showed promoter hypermethylation in HPV(+) oropharyngeal cancers, but only few consistent target genes have been so far described, and the evidence of a functional impact on gene expression is still limited. Methods We performed global and stratified pooled analyses of epigenome-wide data in HNSCCs based on the Illumina HumanMethylation450 bead-array data in order to identify tissue-specific components and common viral epigenetic targets in HPV-associated tumours. Results We identified novel differentially methylated CpGs and regions associated with viral infection that are independent of the anatomic site. In particular, most hypomethylated regions were characterized by a marked loss of CpG island boundaries, which showed significant correlations with expression of neighbouring genes. Moreover, a subset of only five CpGs in a few hypomethylated regions predicted HPV status with a high level of specificity in different cohorts. Finally, this signature was a better predictor of survival compared with HPV status determined by viral gene expression by RNA sequencing in The Cancer Genome Atlas cohort. Conclusions We identified a novel epigenetic signature of HPV infection in HNSCCs which is independent of the anatomic site, is functionally correlated with gene expression and may be leveraged for improved stratification of prognosis in HNSCCs. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0419-z) contains supplementary material, which is available to authorized users.

Circulating miRNAs have shown great promises as noninvasive diagnostic and predictive biomarkers in several solid tumors. While the miRNA profiles of renal tumors have been extensively explored, knowledge of their circulating counterparts is limited. Our study aimed to provide a large-scale genome-wide profiling of plasma circulating miRNA in clear-cell renal cell carcinoma (ccRCC). Plasma samples from 94 ccRCC cases and 100 controls were screened for 754 circulating micro-RNAs (miRNA) by TaqMan arrays. Analyses including known risk factors for renal cancer-namely, age, sex, hypertension, obesity, diabetes, tobacco smoking and alcohol consumption-highlighted that circulating miRNA profiles were tightly correlated with the stage of the disease. Advanced tumors, characterized as stage III and IV, were associated with specific miRNA signatures that significantly differ from both controls and earlier stage ccRCC cases. Molecular pathway enrichment analyses of their gene targets showed high similarities with alterations observed in renal tumors. Plasma circulating levels of miR-150 were significantly associated with RCC-specific survival and could marginally improve the predictive accuracy of clinical parameters in our series, including age at diagnosis, sex and conventional staging. In summary, our results suggest that circulating miRNAs may provide insights into renal cell carcinoma progression.

To examine the diversity of somatic alterations and clonal evolution according to aggressiveness of disease, nineteen tumor-blood pairs of 'formerly bronchiolo-alveolar carcinoma (BAC)' which had been reclassified into preinvasive lesion (adenocarcinoma in situ; AIS), focal invasive lesion (minimally invasive adenocarcinoma; MIA), and invasive lesion (lepidic predominant adenocarcinoma; LPA and non-lepidic predominant adenocarcinoma; non-LPA) according to IASLC/ATS/ERS 2011 classification were explored by whole exome sequencing. Several distinct somatic alterations were observed compare to the lung adenocarcinoma study from the Cancer Genome Atlas (TCGA). There were higher numbers of tumors with significant APOBEC mutation fold enrichment (73% vs. 58% TCGA). The frequency of KRAS mutations was lower in our study (5% vs. 32% TCGA), while a higher number of mutations of RNA-splicing genes, RBM10 and U2AF1, were found (37% vs. 11% TCGA). We found neither mutational pattern nor somatic copy number alterations that were specific to AIS/MIA. We demonstrated that clonal cell fraction was the only distinctive feature that discriminated LPA/non-LPA from AIS/MIA. The broad range of clonal frequency signified a more branched clonal evolution at the time of diagnosis. Assessment of tumor clonal cell fraction might provide critical information for individualized therapy as a prognostic factor, however this needs further study.

Purpose Human papillomavirus type 16 (HPV16) infection is causing an increasing number of oropharyngeal cancers in the United States and Europe. The aim of our study was to investigate whether HPV antibodies are associated with head and neck cancer risk when measured in prediagnostic sera. Methods We identified 638 participants with incident head and neck cancers (patients; 180 oral cancers, 135 oropharynx cancers, and 247 hypopharynx/larynx cancers) and 300 patients with esophageal cancers as well as 1,599 comparable controls from within the European Prospective Investigation Into Cancer and Nutrition cohort. Prediagnostic plasma samples from patients (collected, on average, 6 years before diagnosis) and control participants were analyzed for antibodies against multiple proteins of HPV16 as well as HPV6, HPV11, HPV18, HPV31, HPV33, HPV45, and HPV52. Odds ratios (ORs) of cancer and 95% CIs were calculated, adjusting for potential confounders. All-cause mortality was evaluated among patients using Cox proportional hazards regression. Results HPV16 E6 seropositivity was present in prediagnostic samples for 34.8% of patients with oropharyngeal cancer and 0.6% of controls (OR, 274; 95% CI, 110 to 681) but was not associated with other cancer sites. The increased risk of oropharyngeal cancer among HPV16 E6 seropositive participants was independent of time between blood collection and diagnosis and was observed more than 10 years before diagnosis. The all-cause mortality ratio among patients with oropharyngeal cancer was 0.30 (95% CI, 0.13 to 0.67), for patients who were HPV16 E6 seropositive compared with seronegative. Conclusion HPV16 E6 seropositivity was present more than 10 years before diagnosis of oropharyngeal cancers.

Udgivelsesdato: 2010-Nov-2 Background:Oral contraceptive use and reproductive factors may initiate long-term changes to the hormonal milieu and thereby, possibly influence colorectal cancer risk.Methods:We examined the association of hormonal and reproductive factors with risk of colorectal cancer among 337 802 women in the European Prospective Investigation into Cancer and Nutrition, of whom 1878 developed colorectal cancer.Results:After stratification for center and age, and adjustment for body mass index, smoking, diabetes mellitus, physical activity and alcohol consumption, ever use of oral contraceptives was marginally inversely associated with colorectal cancer risk (hazard ratio (HR), 0.92; 95% confidence interval (CI), 0.83-1.02), although this association was stronger among post-menopausal women (HR, 0.84; 95% CI: 0.74-0.95). Duration of oral contraceptive use and reproductive factors, including age at menarche, age at menopause, type of menopause, ever having an abortion, parity, age at first full-term pregnancy and breastfeeding, were not associated with colorectal cancer risk.Conclusion:Our findings provide limited support for a potential inverse association between oral contraceptives and colorectal cancer risk.British Journal of Cancer advance online publication, 2 November 2010; doi:10.1038/sj.bjc.6605965 www.bjcancer.com.

TP53 gene mutations are one of the most frequent somatic events in cancer. The IARC TP53 Database (http://p53.iarc.fr) is a popular resource that compiles occurrence and phenotype data on TP53 germline and somatic variations linked to human cancer. The deluge of data coming from cancer genomic studies generates new data on TP53 variations and attracts a growing number of database users for the interpretation of TP53 variants. Here, we present the current contents and functionalities of the IARC TP53 Database and perform a systematic analysis of TP53 somatic mutation data extracted from this database and from genomic data repositories. This analysis showed that IARC has more TP53 somatic mutation data than genomic repositories (29,000 vs. 4,000). However, the more complete screening achieved by genomic studies highlighted some overlooked facts about TP53 mutations, such as the presence of a significant number of mutations occurring outside the DNA-binding domain in specific cancer types. We also provide an update on TP53 inherited variants including the ones that should be considered as neutral frequent variations. We thus provide an update of current knowledge on TP53 variations in human cancer as well as inform users on the efficient use of the IARC TP53 Database.

BACKGROUND: Inter-women and intra-women comparisons of mammographic density (MD) are needed in research, clinical and screening applications; however, MD measurements are influenced by mammography modality (screen film/digital) and digital image format (raw/processed). We aimed to examine differences in MD assessed on these image types. METHODS: We obtained 1294 pairs of images saved in both raw and processed formats from Hologic and General Electric (GE) direct digital systems and a Fuji computed radiography (CR) system, and 128 screen-film and processed CR-digital pairs from consecutive screening rounds. Four readers performed Cumulus-based MD measurements (n = 3441), with each image pair read by the same reader. Multi-level models of square-root percent MD were fitted, with a random intercept for woman, to estimate processed-raw MD differences. RESULTS: Breast area did not differ in processed images compared with that in raw images, but the percent MD was higher, due to a larger dense area (median 28.5 and 25.4 cm2 respectively, mean √dense area difference 0.44 cm (95% CI: 0.36, 0.52)). This difference in √dense area was significant for direct digital systems (Hologic 0.50 cm (95% CI: 0.39, 0.61), GE 0.56 cm (95% CI: 0.42, 0.69)) but not for Fuji CR (0.06 cm (95% CI: -0.10, 0.23)). Additionally, within each system, reader-specific differences varied in magnitude and direction (p, published_or_final_version

Background Concerns have been raised about the quality of reporting in nutritional epidemiology. Research reporting guidelines such as the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement can improve quality of reporting in observational studies. Herein, we propose recommendations for reporting nutritional epidemiology and dietary assessment research by extending the STROBE statement into Strengthening the Reporting of Observational Studies in Epidemiology—Nutritional Epidemiology (STROBE-nut). Methods and Findings Recommendations for the reporting of nutritional epidemiology and dietary assessment research were developed following a systematic and consultative process, coordinated by a multidisciplinary group of 21 experts. Consensus on reporting guidelines was reached through a three-round Delphi consultation process with 53 external experts. In total, 24 recommendations for nutritional epidemiology were added to the STROBE checklist. Conclusion When used appropriately, reporting guidelines for nutritional epidemiology can contribute to improve reporting of observational studies with a focus on diet and health., Carl Lachat and colleagues describe the STROBE-nut reporting guideline extension to improve reporting of observational studies that focus on diet and health.

Background Few studies have examined common childhood infections and adult asthma. We examined associations between childhood infectious diseases, childhood pneumonia, and current, persisting, and incident asthma to middle age. Methods We analyzed data from the Tasmanian Longitudinal Health Study (TAHS). A history of pneumonia was ascertained from their parents when the TAHS participants were 7 years old. Measles, rubella, mumps, chickenpox, diphtheria, and pertussis were identified from school medical records. Associations with current, persisting, or incident asthma were examined using regression techniques. Results Greater infectious diseases load was negatively associated with persisting asthma at all ages. Individually, pertussis (adjusted OR [aOR], 0.53; 95% CI, 0.28–1.00) was negatively associated with asthma persisting to age 13 years, chickenpox (aOR, 0.58; 95% CI, 0.38–0.88) was negatively associated with asthma persisting to age 32 years, and rubella was negatively associated with asthma persisting to ages 32 (aOR, 0.61; 95% CI, 0.31–0.96) and 44 years (aOR 0.53; 95% CI, 0.35–0.82). Pertussis was associated with preadolescent incident asthma (adjusted hazard ratio [aHR], 1.80; 95% CI, 1.10–2.96), whereas measles was associated with adolescent incident asthma (aHR, 1.66; 1.06–2.56). Childhood pneumonia was associated with current asthma at ages 7 (aOR, 3.12; 95% CI, 2.61–3.75) and 13 years (aOR, 1.32; 95% CI, 1.00–1.75), an association stronger in those without than those with eczema (aOR, 3.46; 95% CI, 2.83–4.24 vs aOR, 2.08; 95% CI, 1.38–3.12). Conclusions Overall, childhood infectious diseases protected against asthma persisting in later life, but pertussis and measles were associated with new-onset asthma after childhood. Measles and pertussis immunization might lead to a reduction in incident asthma in later life.

Results from case-control and prospective studies suggest a moderate positive association between obesity and height and differentiated thyroid carcinoma (TC). Little is known on the relationship between other measures of adiposity and differentiated TC risk. Here, we present the results of a study on body size and risk of differentiated TC based on a large European prospective study (EPIC). During follow-up, 508 incident cases of differentiated TC were identified in women, and 58 in men. 78% of cases were papillary TC. Cox proportional hazard models were used to estimate hazard ratios (HRs). In women, differentiated TC risk was significantly associated with body mass index (BMI, kg/m(2) ) (HR highest vs lowest quintile = 1.41, 95% CI: 1.03-1.94); height (HR = 1.61; 95% CI: 1.18-2.20); HR highest vs lowest tertile waist (HR = 1.34, 95% CI: 1.00-1.79) and waist-to-hip ratio (HR = 1.42, 95% CI: 1.05-1.91). The association with BMI was somewhat stronger in women below age 50. Corresponding associations for papillary TC were similar to those for all differentiated TC. In men the only body size factors significantly associated with differentiated TC were height (non linear), and leg length (HR highest vs. lowest tertile = 3.03, 95% CI: 1.30-7.07). Our study lends further support to the presence of a moderate positive association between differentiated TC risk and overweight and obesity in women. The risk increase among taller individuals of both sexes suggests that some genetic characteristics or early environmental exposures may also be implicated in the etiology of differentiated TC.

International audience; Metabolomics is a potentially powerful tool for identification of biomarkers associated with lifestyle exposures and risk of various diseases. This is the rationale of the 'meeting-in-the-middle' concept, for which an analytical framework was developed in this study. In a nested case-control study on hepatocellular carcinoma (HCC) within the European Prospective Investigation into Cancer and nutrition (EPIC), serum 1H nuclear magnetic resonance (NMR) spectra (800 MHz) were acquired for 114 cases and 222 matched controls. Through partial least square (PLS) analysis, 21 lifestyle variables (the 'predictors', including information on diet, anthropometry and clinical characteristics) were linked to a set of 285 metabolic variables (the 'responses'). The three resulting scores were related to HCC risk by means of conditional logistic regressions. The first PLS factor was not associated with HCC risk. The second PLS metabolomic factor was positively associated with tyrosine and glucose, and was related to a significantly increased HCC risk with OR = 1.11 (95% CI: 1.02, 1.22, P = 0.02) for a 1SD change in the responses score, and a similar association was found for the corresponding lifestyle component of the factor. The third PLS lifestyle factor was associated with lifetime alcohol consumption, hepatitis and smoking, and had negative loadings on vegetables intake. Its metabolomic counterpart displayed positive loadings on ethanol, glutamate and phenylalanine. These factors were positively and statistically significantly associated with HCC risk, with 1.37 (1.05, 1.79, P = 0.02) and 1.22 (1.04, 1.44, P = 0.01), respectively. Evidence of mediation was found in both the second and third PLS factors, where the metabolomic signals mediated the relation between the lifestyle component and HCC outcome. This study devised a way to bridge lifestyle variables to HCC risk through NMR metabolomics data. This implementation of the 'meeting-in-the-middle' approach finds natural applications in settings characterised by high-dimensional data, increasingly frequent in the omics generation.

Elaidic acid is the main unnatural trans fatty acid isomer occurring during partial hydrogenation of vegetable oils used as ingredients for the formulation of processed foods. The main objective is to assess associations between processed food intakes and plasma phospholipid elaidic acid concentrations within the European Prospective Investigation into Cancer and Nutrition study. A cross-sectional study was used to determine fatty acid profiles in 3,003 subjects from 16 centers. Single 24-h dietary recalls (24-HDR) were collected using a standardized computerized interview program. Food intakes were computed according to their degree of processing (moderately/nonprocessed foods, processed staple foods, highly processed foods). Adjusted ecological and individual correlations were calculated between processed food intakes and plasma elaidic acid levels. At the population level, mean intakes of highly processed foods were strongly correlated with mean levels of plasma elaidic acid in men (P = 0.0016) and in women (P = 0.0012). At the individual level, these associations remained but at a much lower level in men (r = 0.08, P = 0.006) and in women (r = 0.09, P = 0.0001). The use of an averaged 24-HDR measure of highly processed food intakes is adequate for predicting mean levels of plasma elaidic acid among European populations.

BACKGROUND: Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data. METHODS: We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation. RESULTS: The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (Po0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6-47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7-25.7) for mitotic index over 50 mitoses per 10 high-powered field (P 0.0003); and 2.7 (1.3-5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P 0.01). The area under the ROC curve was 0.87 (0.83-0.90). CONCLUSION: Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history. British Journal of Cancer (2011) 104, 903-909. doi: 10.1038/ bjc. 2011.41 www. bjcancer. com

Haplotype-based association studies have been proposed as a powerful comprehensive approach to identify causal genetic variation underlying complex diseases. Data comparisons within families offer the additional advantage of dealing naturally with complex sources of noise, confounding and population stratification. Two problems encountered when investigating associations between haplotypes and a continuous trait using data from sibships are (i) the need to define within-sibship comparisons for sibships of size greater than two and (ii) the difficulty of resolving the joint distribution of haplotype pairs within sibships in the absence of parental genotypes. We therefore propose first a method of orthogonal transformation of both outcomes and exposures that allow the decomposition of between- and within-sibship regression effects when sibship size is greater than two. We conducted a simulation study, which confirmed analysis using all members of a sibship is statistically more powerful than methods based on cross-sectional analysis or using subsets of sib-pairs. Second, we propose a simple permutation approach to avoid errors of inference due to the within-sibship correlation of any errors in haplotype assignment. These methods were applied to investigate the association between mammographic density (MD), a continuously distributed and heritable risk factor for breast cancer, and single nucleotide polymorphisms (SNPs) and haplotypes from the VDR gene using data from a study of 430 twins and sisters. We found evidence of association between MD and a 4-SNP VDR haplotype. In conclusion, our proposed method retains the benefits of the between- and within-pair analysis for pairs of siblings and can be implemented in standard software.

Contains fulltext : 88547.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To examine the association between fruit and vegetable consumption and risk of different histological subtypes of lung cancer among participants of the European Prospective Investigation into Cancer and Nutrition study. METHODS: Multivariable Cox proportional hazard models were used to analyze the data. A calibration study in a subsample was used to reduce dietary measurement errors. RESULTS: During a mean follow-up of 8.7 years, 1,830 incident cases of lung cancer (574 adenocarcinoma, 286 small cell, 137 large cell, 363 squamous cell, 470 other histologies) were identified. In line with our previous conclusions, we found that after calibration a 100 g/day increase in fruit and vegetables consumption was associated with a reduced lung cancer risk (HR 0.94; 95% CI 0.89-0.99). This was also seen among current smokers (HR 0.93; 95% CI 0.90-0.97). Risks of squamous cell carcinomas in current smokers were reduced for an increase of 100 g/day of fruit and vegetables combined (HR 0.85; 95% CI 0.76-0.94), while no clear effects were seen for the other histological subtypes. CONCLUSION: We observed inverse associations between the consumption of vegetables and fruits and risk of lung cancer without a clear effect on specific histological subtypes of lung cancer. In current smokers, consumption of vegetables and fruits may reduce lung cancer risk, in particular the risk of squamous cell carcinomas. 01 maart 2010

Understanding which factors influence mammographically dense and nondense areas is important because percent mammographic density adjusted for age is a strong, continuously distributed risk factor for breast cancer, especially when adjusted for weight or body mass index. Using computer-assisted methods, we measured mammographically dense areas for 571 monozygotic and 380 dizygotic Australian and North American twin pairs ages 40 to 70 years. We used a novel regression modeling approach in which each twin's measure of dense and nondense area was regressed against one or both of the twin's and co-twin's covariates. The nature of changes to regression estimates with the inclusion of the twin and/or co-twin's covariates can be evaluated for consistency with causal and/or other models. By causal, we mean that if it were possible to vary a covariate experimentally then the expected value of the outcome measure would change. After adjusting for the individual's weight, the co-twin associations with weight were attenuated, consistent with a causal effect of weight on mammographic measures, which in absolute log cm2/kg was thrice stronger for nondense than dense area. After adjusting for weight, later age at menarche, and greater height were associated with greater dense and lesser nondense areas in a manner inconsistent with causality. The associations of dense and nondense areas with parity are consistent with a causal effect and/or within-person confounding. The associations between mammographic density measures and height are consistent with shared early life environmental factors that predispose to both height and percent mammographic density and possibly breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3474–81)

Although large-scale prospective cohort studies have related hyperglycemia to increased risk of cancer overall, studies specifically on colorectal cancer have been generally small. We investigated the association between prediagnostic levels of glycosylated hemoglobin (HbA1c), a marker for average glucose level in blood, and colorectal cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort. One thousand and twenty-six incident colorectal cancer cases (561 men and 465 women) and 1,026 matched controls were eligible for the study. Multivariate conditional logistic regression was used to estimate odds ratios (ORS) adjusted for possible confounders. Increasing HbA1c percentages were statistically significantly associated with a mild increase in colorectal cancer risk in the whole population [OR, 1.10; 95% confidence interval (CI), 1.01,1.19 for a 10% increase in HbA1c]. In women, increasing HbA1c percentages were associated with a statistically significant increase in colorectal cancer risk (OR, 1.16; 95% CI, 1.01, 1.32 for a 10% increase in HbA1c) and with a borderline statistically significant increase in rectum cancer (OR, 1.22; 95% CI, 0.99,1.50 for a 10% increase in HbA1c). No significant association with cancer risk was observed in men. The results of the current study suggest a mild implication of hyperglycemia in colorectal cancer, which seems more important in women than in men, and more for cancer of the rectum than of the colon. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3108–15)

Many individually rare missense substitutions are encountered during deep resequencing of candidate susceptibility genes and clinical mutation screening of known susceptibility genes. BRCA1 and BRCA2 are among the most resequenced of all genes, and clinical mutation screening of these genes provides an extensive data set for analysis of rare missense substitutions. Align-GVGD is a mathematically simple missense substitution analysis algorithm, based on the Grantham difference, which has already contributed to classification of missense substitutions in BRCA1, BRCA2, and CHEK2. However, the distribution of genetic risk as a function of Align-GVGD's output variables Grantham variation (GV) and Grantham deviation (GD) has not been well characterized. Here, we used data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests plus two risk estimates, one approximating the odds ratio and the other reflecting strength of selection, to display the distribution of risk in the GV-GD plane as a series of surfaces. We abstracted contours from the surfaces and used the contours to define a sequence of missense substitution grades ordered from greatest risk to least risk. The grades were validated internally using a third, personal and family history-based, measure of risk. The Align-GVGD grades defined here are applicable to both the genetic epidemiology problem of classifying rare missense substitutions observed in known susceptibility genes and the molecular epidemiology problem of analyzing rare missense substitutions observed during case-control mutation screening studies of candidate susceptibility genes.

Summary Background Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3–6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). Methods We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3–6 h after onset of ischaemic stroke. PWI and DWI were done before and 3–5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537. Findings We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71·6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1·24 with alteplase and 1·78 with placebo (ratio 0·69, 95% CI 0·38–1·28; Student's t test p=0·239); the median relative infarct growth was 1·18 with alteplase and 1·79 with placebo (ratio 0·66, 0·36–0·92; Wilcoxon's test p=0·054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0·001), better neurological outcome (p Interpretation Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted. Funding National Health and Medical Research Council, Australia; National Stroke Foundation, Australia; Heart Foundation of Australia.

We used data from a prospective cohort study of twins to investigate the influence of unmeasured genetic and measured and unmeasured environmental factors on the smoking behaviour of adolescents and young adults. Twins were surveyed in 1988 (aged 11–18 years), 1991, 1996 and 2004 with data from 1409, 1121, 732 and 758 pairs analysed from each survey wave, respectively. Questionnaires assessed the smoking behaviour of twins and the perceived smoking behaviour of friends and parents. Using a novel logistic regression analysis, we simultaneously modelled individual risk and excess concordance for current smoking as a function of zygosity, survey wave, parental smoking and peer smoking. Being concordant for having peers who smoked was a predictor of concordance for current smoking (P

RAD51D is a homolog of the RAD51 protein, which is known to be an important component of the DNA repair pathway. A rare missense variant in the RAD51D gene, E233G (c.A > G), has been reported to be more prevalent in breast cancer cases from specific multiple-case breast cancer families, with an odds ratio of 2.6 (95% confidence interval (CI): 1.12-6.03). We assessed whether this variant was associated with breast cancer risk using two studies: a population-based case-control-family study based on 1,110 cases and 629 controls, and a clinic-based study based on 390 cases from multiple-case breast cancer families. We conducted case-control analyses and modified segregation analyses of carrier families. The carrier frequencies (95% CI) of the RAD51D variant were 4.1% (2.4-6.6) for clinic-based cases, 3.9% (2.8-5.2) for population-based cases, and 3.7% (2.3-5.4) for population-based controls, and were not significantly higher in case groups than controls (P = 0.7 and P = 0.8, respectively). After genotyping the relatives of cases who carried the variant, modified segregation analyses of these families were conducted, and the estimated hazard ratio for breast cancer corresponding to the E233G variant was 1.30 (95% CI: 0.66-2.58; P = 0.4) for familial breast cancer families and 1.28 (95% CI: 0.47-3.43; P = 0.6) for families unselected for family history. Therefore, despite being well powered to detect moderate risks, no evidence for an association between the E233G variant and breast cancer risk was observed in any setting. Larger studies would be required to determine if this variant is associated with a smaller risk of breast cancer.

Background The association between allergic rhinitis and asthma is well documented, but the temporal sequence of this association has not been closely examined. Objective We sought to assess the associations between childhood allergic rhinitis and (1) asthma incidence from preadolescence to middle age and (2) asthma persistence to middle age. Methods Data were gathered from the 1968, 1974, and 2004 surveys of the Tasmanian Asthma Study. Cox regression was used to examine the association between childhood allergic rhinitis and asthma incidence in preadolescence, adolescence, and adult life. Binomial regression was used to examine the association between childhood allergic rhinitis and asthma beginning before the age of 7 years and persisting at age 44 years. Results Childhood allergic rhinitis was associated with a significant 2- to 7-fold increased risk of incident asthma in preadolescence, adolescence, or adult life. Childhood allergic rhinitis was associated with a 3-fold increased risk of childhood asthma persisting compared with remitting by middle age. Conclusions Childhood allergic rhinitis increased the likelihood of new-onset asthma after childhood and the likelihood of having persisting asthma from childhood into middle age. Clinical implications Asthma burden in later life might be reduced by more aggressive treatment of allergic rhinitis in early life.

Ambulance bypass occurs when the emergency department (ED) of a hospital becomes so busy that ambulances are requested to take their patients elsewhere, except in life-threatening cases. It is a major concern for hospitals in Victoria, Australia, and throughout most of the western world, not only from the point of view of patient safety but also financially - hospitals lose substantial performance bonuses if they go on ambulance bypass too often in a given period. We show that the main cause of ambulance bypass is the inability to move patients from the ED to a ward. In order to predict the onset of ambulance bypass, the ED is modelled as a queue for treatment followed by a queue for a ward bed. The queues are assumed to behave as inhomogeneous Poisson arrival processes. We calculate the probability of reaching some designated capacity C within time t, given the current time and number of patients waiting.

Background: Mammographic density, the light/white radiographic appearance on a mammogram that represents connective and epithelial tissue, is a strong risk factor for breast cancer which seems to be highly heritable. Little is known about its genetic determinants.Methods: We studied 457 women from 207 sisterhoods (104 monozygotic twins, 182 dizygotic twins, and 171 singletons). Percentage mammographic density (PMD) as well as dense area and nondense area were calculated using a computer-assisted method. We measured six single nucleotide polymorphisms from six candidate genes (COMT, HSD3B1, IGFBP3, HER2, XPD, and XRCC3). Associations between genotypes and mammographic measures were tested (a) cross-sectionally using a multivariate normal model fitted using FISHER that allowed separate correlations for monozygotic, dizygotic, and nontwin pairs and (b) within sister pairs using paired t tests.Results: Cross-sectionally, each additional copy of the HSD3B1 Asn367Thr variant allele was associated with lower PMD (−3.47% per allele; SE = 1.65; P = 0.035). Within-pair regression estimates confirmed this association. There was no evidence for an association between the mammographic density measures and any of the other variants studied.Conclusion: We have replicated an association between a variant in the HSD3B1 gene and PMD, which suggests that HSD3B1 may be genetic determinant of mammographic density. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1479–84)

This study examines missed opportunities for recommended influenza vaccine and 23-valent pneumococcal vaccine (23vPPV) among hospitalised elderly persons. 4772 inpatients agedor = 65 years (cases of pneumonia and frequency-matched randomly selected cohort subjects) participated from two large tertiary Australian hospitals. For subjects unvaccinated with influenza vaccine (past year), 1110/1115 (99.6%) had visited either a doctor (99.4%, mean 11.2 visits) or the same hospital (52.0%, mean 1.5 visits). For those unvaccinated with 23vPPV (past 5 years), 1809/1813 (99.8%) had visited either a doctor (99.7%, mean 11.2 visits) or the same hospital (51.5%, mean 1.5 times) in the past year; 71% had been admitted to the same hospital in the past 5 years (mean 3.4 times). 2.3% of all subjects had vaccination status recorded. No unvaccinated subject was vaccinated during admission, despite approximately 40% reporting acceptability of vaccination if offered. Previous hospitalisation was a risk factor for being unvaccinated. Barriers to implementation of current vaccination policy in the hospital setting require formal evaluation in Australia.

Few data exist on associations between childhood adiposity and incident asthma in later life. The present authors examined the relationship between childhood body mass index (BMI) and incident asthma beginning in adolescence or in adult life. All subjects included in the study were participants in the Tasmanian Asthma Survey, a large population-based cohort study, and were asthma free at 7 yrs of age. Weight, height and lung function were measured at 7 yrs of age. Asthma status at 7 and 32 yrs of age was ascertained by questionnaire. Odds ratios were calculated for the association between childhood adiposity, expressed as "overweight" or as BMI z-score quartiles at 7 yrs of age, and asthma development after that age. In females, but not in males, there was a significant association between adiposity at 7 yrs of age and current asthma at 32 yrs of age that developed after the age of 21 yrs. The association was not explained by childhood lung function or age at menarche. There was no association between adiposity at 7 yrs of age and asthma that developed after that age and remitted at 32 yrs of age in either sex. Higher body mass index in nonasthmatic young females at 7 yrs of age predicts risk of current asthma developing in adult life.

Background The nature of somatic mutations observed in human tumors at single gene or genome-wide levels can reveal information on past carcinogenic exposures and mutational processes contributing to tumor development. While large amounts of sequencing data are being generated, the associated analysis and interpretation of mutation patterns that may reveal clues about the natural history of cancer present complex and challenging tasks that require advanced bioinformatics skills. To make such analyses accessible to a wider community of researchers with no programming expertise, we have developed within the web-based user-friendly platform Galaxy a first-of-its-kind package called MutSpec. Results MutSpec includes a set of tools that perform variant annotation and use advanced statistics for the identification of mutation signatures present in cancer genomes and for comparing the obtained signatures with those published in the COSMIC database and other sources. MutSpec offers an accessible framework for building reproducible analysis pipelines, integrating existing methods and scripts developed in-house with publicly available R packages. MutSpec may be used to analyse data from whole-exome, whole-genome or targeted sequencing experiments performed on human or mouse genomes. Results are provided in various formats including rich graphical outputs. An example is presented to illustrate the package functionalities, the straightforward workflow analysis and the richness of the statistics and publication-grade graphics produced by the tool. Conclusions MutSpec offers an easy-to-use graphical interface embedded in the popular Galaxy platform that can be used by researchers with limited programming or bioinformatics expertise to analyse mutation signatures present in cancer genomes. MutSpec can thus effectively assist in the discovery of complex mutational processes resulting from exogenous and endogenous carcinogenic insults. Electronic supplementary material The online version of this article (doi:10.1186/s12859-016-1011-z) contains supplementary material, which is available to authorized users.

Incidence rates of differentiated thyroid carcinoma (TC) have increased in many countries. Adiposity and dietary risk factors may play a role, but little is known on the influence of energy intake and macronutrient composition. The aim of this study was to investigate the associations between TC and the intake of energy, macronutrients, glycemic index (GI) and glycemic load in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The study included 477,274 middle-age participants (70.2% women) from ten European countries. Dietary data were collected using country-specific validated dietary questionnaires. Total carbohydrates, proteins, fats, saturated, monounsaturated and polyunsaturated fats (PUFA), starch, sugar, and fiber were computed as g/1,000 kcal. Multivariable Cox regression was used to calculate multivariable adjusted hazard ratios (HR) and 95% confidence interval (CI) by intake quartile (Q). After a mean follow-up time of 11 years, differentiated TC was diagnosed in 556 participants (90% women). Overall, we found significant associations only with total energy (HRQ4 vs .Q1, 1.29; 95% CI, 1.00-1.68) and PUFA intakes (HRQ4 vs .Q1, 0.74; 95% CI, 0.57-0.95). However, the associations with starch and sugar intake and GI were significantly heterogeneous across body mass index (BMI) groups, i.e., positive associations with starch and GI were found in participants with a BMI≥25 and with sugar intake in those with BMI

Recent advances in laboratory sciences hold a promise for a 'leap forward' in understanding the aetiology of complex human diseases, notably cancer, potentially providing an evidence base for prevention. For example, remarkable advances in epigenomics have an important impact on our understanding of biological phenomena and importance of environmental stressors in complex diseases. Environmental and lifestyle factors are thought to be implicated in the development of a wide range of human cancers by eliciting changes in the epigenome. These changes, thus, represent attractive targets for biomarker discovery intended for the improvement of exposure and risk assessment, diagnosis and prognosis and provision of short-term outcomes in intervention studies. The epigenome can be viewed as an interface between the genome and the environment; therefore, aberrant epigenetic events associated with environmental exposures are likely to play an important role in the onset and progression of different human diseases. The advent of powerful technologies for analysing epigenetic patterns in both cancer tissues and normal cells holds promise that the next few years will be fundamental for the identification of critical cancer- and exposure-associated epigenetic changes and for their evaluation as new generation of biomarkers. Here, we discuss new opportunities in the current age of 'omics' technologies for studies with prospective design and associated biospecimens that represent exciting potential for characterising the epigenome as a key component of the fetal exposome and for understanding causal pathways and robust predictors of cancer risk and associated environmental determinants during in utero life. Such studies should improve our knowledge concerning the aetiology of childhood cancer and identify both novel biomarkers and clues to causation, thus, providing an evidence base for cancer prevention.

Delahaye-Sourdeix, Manon Anantharaman, Devasena Timofeeva, Maria N Gaborieau, Valerie Chabrier, Amelie Vallee, Maxime P Lagiou, Pagona Holcatova, Ivana Richiardi, Lorenzo Kjaerheim, Kristina Agudo, Antonio Castellsague, Xavier Macfarlane, Tatiana V Barzan, Luigi Canova, Cristina Thakker, Nalin S Conway, David I Znaor, Ariana Healy, Claire M Ahrens, Wolfgang Zaridze, David Szeszenia-Dabrowska, Neonilia Lissowska, Jolanta Fabianova, Eleonora Mates, Ioan Nicolae Bencko, Vladimir Foretova, Lenka Janout, Vladimir Curado, Maria Paula Koifman, Sergio Menezes, Ana Wunsch-Filho, Victor Eluf-Neto, Jose Boffetta, Paolo Fernandez Garrote, Leticia Polesel, Jerry Lener, Marcin Jaworowska, Ewa Lubinski, Jan Boccia, Stefania Rajkumar, Thangarajan Samant, Tanuja A Mahimkar, Manoj B Matsuo, Keitaro Franceschi, Silvia Byrnes, Graham Brennan, Paul McKay, James D eng 1R03DE020116/DE/NIDCR NIH HHS/ R01CA092039 05/05S1/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural 2015/04/04 06:00 J Natl Cancer Inst. 2015 Apr 2;107(5). pii: djv037. doi: 10.1093/jnci/djv037. Print 2015 May.; International audience; Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10(-10)) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust association between a truncating BRCA2 variant and UADT cancer risk suggests that treatment strategies orientated towards BRCA2 mutations may warrant further investigation in UADT tumors.

International audience; The MYD88 L265P is a recurrent somatic mutation in neoplastic cells from patients with Waldenström Macroglobulinemia (WM). We identified the MYD88 L265P mutation in three individuals from unrelated families, but its presence did not explain the disease segregation within these WM pedigrees. We observed the mutation in these three individuals at high allele fractions in DNA extracted from EBV-immortalized Lymphoblastoid cell lines established from peripheral blood (LCL), but at much lower allele fractions in DNA extracted directly from peripheral blood, suggesting that this mutation is present in a clonal cell subpopulation rather than of germ-line origin. Furthermore, we observed that the MYD88 L265P mutation is enriched in WM families, detected in 40.5% of patients with familial WM or MGUS (10/22 WM, 5/15 MGUS), compared to 3.5% of patients with familial MM or MGUS (0/72 MM, 4/41 MGUS) (p = 10−7). The mutant allele frequency increased with passages in vitro after immortalization with Epstein-Barr virus (EBV) consistent with the MYD88 L265P described gain-of-function proposed for this mutation. The MYD88 L265P mutation appears to be frequently present in circulating cells in patients with WM, and MGUS, and these cells are amenable to immortalization by EBV.

There have been a number of genome-wide linkage studies for adult height in recent years. These studies have yielded few well-replicated loci, and none have been further confirmed by the identification of associated gene variants. The inconsistent results may be attributable to the fact that few studies have combined accurate phenotype measures with informative statistical modelling in healthy populations. We have performed a multi-stage genome-wide linkage analysis for height in 275 adult sibling pairs drawn randomly from the Victorian Family Heart Study (VFHS), a healthy population-based Caucasian cohort. Height was carefully measured in a standardised fashion on regularly calibrated equipment. Following genome-wide identification of a peak Z-score of 3.14 on chromosome 3 at 69 cM, we performed a fine-mapping analysis of this region in an extended sample of 392 two-generation families. We used a number of variance components models that incorporated assortative mating and shared environment effects, and we observed a peak LOD score of approximately 3.5 at 78 cM in four of the five models tested. We also demonstrated that the most prevalent model in the literature gave the worst fit, and the lowest LOD score (2.9) demonstrating the importance of appropriate modelling. The region identified in this study replicates the results of other genome-wide scans of height and bone-related phenotypes, strongly suggesting the presence of a gene important in bone growth on chromosome 3p. Association analyses of relevant candidate genes should identify the genetic variants responsible for the chromosome 3p linkage signal in our population.

Background and Purpose— Since the failure of a number of phase III trials of neuroprotection in ischemic stroke, the need for smaller phase II studies with MRI surrogates has emerged. There is, however, little information available about sample size requirements for such phase II trials and rarely enough patients in single studies to make robust estimates. We have formed an international collaborative group to assemble larger datasets and from these have generated sample size tables for MRI-based infarct expansion as the outcome measure. Methods— Twelve centers from Australia, Europe, and North America contributed data from patients with hemispheric ischemic stroke. Infarct expansion was defined from initial diffusion-weighted images and later fluid-attenuated inversion recover or T 2 images. Sample size estimates were calculated from data on infarct expansion ratios treated as dichotomous or continuous variables. A nonparametric approach was used because the distribution of infarct expansion was resistant to all forms of transformation. Results— As an example, a 20% absolute reduction in infarct expansion ratio (≤1), 80% power, and α=0.05 requires 99 patients in each arm. To achieve an equivalent effect size with a continuous approach requires 61 patients. Conclusions— These tables will be useful in planning phase II trials of therapy with the use of MRI outcome measures. For positive studies, biologically plausible surrogates such as these may provide a rationale for proceeding to phase III trials.

Background: Surgery is considered the treatment of choice for patients with resectable stage I and II (and some patients with stage IIIA) non-small cell lung cancer (NSCLC), but there have been no previously published systematic reviews. Methods: A systematic review and meta-analysis of randomised controlled trials was conducted to determine whether surgical resection improves disease specific mortality in patients with stages I–IIIA NSCLC compared with non-surgical treatment, and to compare the efficacy of different surgical approaches. Results: Eleven trials were included. No studies had untreated control groups. In a pooled analysis of three trials, 4 year survival was superior in patients undergoing resection with stage I–IIIA NSCLC who had complete mediastinal lymph node dissection compared with lymph node sampling (hazard ratio estimated at 0.78 (95% CI 0.65 to 0.93)). Another trial reported an increased rate of local recurrence in patients with stage I NSCLC treated with limited resection compared with lobectomy. One small study reported a survival advantage among patients with stage IIIA NSCLC treated with chemotherapy followed by surgery compared with chemotherapy followed by radiotherapy. No other trials reported significant improvements in survival after surgery compared with non-surgical treatment. Conclusion: It is difficult to draw conclusions about the efficacy of surgery for locoregional NSCLC because of the small number of participants studied and methodological weaknesses of the trials. However, current evidence suggests that complete mediastinal lymph node dissection is associated with improved survival compared with node sampling in patients with stage I–IIIA NSCLC undergoing resection.

Purpose: To assess misclassification in adults reporting childhood asthma. Methods: The Tasmanian Asthma Survey commenced in 1968 when 8,583 7-year-old children attending school in Tasmania (participants) were studied. In 1991–1993, a stratified sample of 1,494 participants was studied. Their recall of childhood asthma was compared to their parents' prospectively gathered report. Results: Where participants had childhood asthma, those with current asthma, severe eczema, or hay fever were less likely to misclassify while females were more likely to misclassify. Where participants had no childhood asthma, misclassification was associated with current asthma, hay fever, or allergies. Conclusions: Retrospective self-assessment of childhood asthma is unreliable.

Summary Introduction: Low dose spiral computed tomography (CT) is a sensitive screening tool for lung cancer that is currently being evaluated in both non-randomised studies and randomised controlled trials. Methods: We conducted a quantitative decision analysis using a Markov model to determine whether, in the Australian setting, offering spiral CT screening for lung cancer to high risk individuals would be cost-effective compared with current practice. This exploratory analysis was undertaken predominantly from the perspective of the government as third-party funder. In the base-case analysis, the costs and health outcomes (life-years saved and quality-adjusted life years) were calculated in a hypothetical cohort of 10,000 male current smokers for two alternatives: (1) screen for lung cancer with annual CT for 5 years starting at age 60 year and treat those diagnosed with cancer or (2) no screening and treat only those who present with symptomatic cancer. Results: For male smokers aged 60–64 years, with an annual incidence of lung cancer of 552 per 100,000, the incremental cost-effectiveness ratio was $57,325 per life-year saved and $105,090 per QALY saved. For females aged 60–64 years with the same annual incidence of lung cancer, the cost-effectiveness ratio was $51,001 per life-year saved and $88,583 per QALY saved. The model was used to examine the relationship between efficacy in terms of the expected reduction in lung cancer mortality at 7 years and cost-effectiveness. In the base-case analysis lung cancer mortality was reduced by 27% and all cause mortality by 2.1%. Changes in the estimated proportion of stage I cancers detected by screening had the greatest impact on the efficacy of the intervention and the cost-effectiveness. The results were also sensitive to assumptions about the test performance characteristics of CT scanning, the proportion of lung cancer cases overdiagnosed by screening, intervention rates for benign disease, the discount rate, the cost of CT, the quality of life in individuals with early stage screen-detected cancer and disutility associated with false positive diagnoses. Given current knowledge and practice, even under favourable assumptions, reductions in lung cancer mortality of less than 20% are unlikely to be cost-effective, using a value of $50,000 per life-year saved as the threshold to define a “cost-effective” intervention. Conclusion: The most feasible scenario under which CT screening for lung cancer could be cost-effective would be if very high-risk individuals are targeted and screening is either highly effective or CT screening costs fall substantially.

Objective: We examine to what extent the lower mammographic sensitivity found in hormone replacement therapy (HRT) users can be explained by any association of HRT use with higher mammographic density and more difficult to detect cancers. Methods: We used logistic regression to estimate the odds of a false-negative screen (a breast cancer diagnosed in the 24 months after a negative screening examination) for HRT users and to estimate, and adjust for, mammographic density (measured on a continuous scale, blinded, using a reliable, computer-assisted method), tumor characteristics (size, grade, and morphology), and potential confounders (age, symptom status, family history, and prior screening) among women ages ≥55 years who attended BreastScreen Victoria for first round screening mammography in 1994 and 1995 (1,086 breast cancers) and for subsequent round screening (471 breast cancers) in 1995 and 1996. Results: After adjusting for confounders, HRT users were more likely to have a false-negative screen [first round: odds ratio (OR), 1.99; 95% confidence interval (95% CI), 1.4-2.9; subsequent round: OR, 2.29; 95% CI, 1.4-3.8]. This effect was modestly attenuated by adjusting for mammographic density (first round: OR, 1.54; 95% CI, 1.0-2.3; subsequent round: OR, 1.97; 95% CI, 1.2-3.3). Adjusting for tumor characteristics resulted in a modest increase in the odds of a false negative at first round but had no effect at subsequent round. Conclusions: Mammographic density only partly explains the effect of HRT on sensitivity. Further research needs to clarify whether hyperemic breast tissue changes affect cancer detectability in HRT users as well as the possibility that the quality of mammography may be poor in some HRT users.

SummaryBackground: The extent to which overdiagnosis occurs in lung cancer screening programmes has been debated. Overdiagnosis refers to the detection by screening of cancers that would not have become clinically apparent or symptomatic before that individual died of other causes.Methods: A retrospective review of coronial autopsies performed in Victoria between April 1991 and February 2002 was conducted to determine the rate of incidental lung cancer in individuals who died of natural causes.Results: A total of 24,708 autopsy reports were searched electronically. We estimated that in 56% of these death was from natural causes. Amongst individuals who died naturally there were 167 cases of lung cancer, 47 of these were incidental including five carcinoid tumours, three small cell tumours, 11 cases of carcinoma in situ and 28 invasive nonsmall cell lung cancers. Of the incidental invasive nonsmall cell lung cancers, 86% were stage I.Conclusions: Although incidental lung cancer is uncommon, there are some lung cancers that remain undetected during life and do not contribute to death. These findings support the hypothesis that some lung cancers detected by screening may never progress to cause symptoms or death in that individual's lifetime and therefore may be overdiagnosed by screening.

Objectives: To determine the prevalence of and assess risk factors associated with head lice infections (pediculosis) in children from government primary schools in Victoria, Australia. Methods: Between May and October 2001, children were selected by clustered random sampling of schools and classes, then examined for head lice using hair conditioner and a fine-toothed head lice comb. There were 1838 children screened from 16 primary schools. Risk factors evaluated included metropolitan or rural residence, school class, gender and hair length. Results: Thirteen percent of children (239/1838) had an active infection (95% CI, 10.9−15.1) and 3.3% (61/1838) had an inactive infection (95% CI, 2.0−4.6). Prevalence of active pediculosis varied between schools from 0 to 28%. Our screening identified no more than one case per class in the majority of classes screened (58.5%). Females were 2.2 times more likely to have active infection than males (95% CI [1.7,2.9]) and there was no significant difference for the other risk factors investigated. Conclusions: Our study demonstrated the prevalence of head lice varied across Victoria and showed that risk factors commonly attributed to head lice infections did not hold true. Our findings support the premise that traditional ad hoc mass school-based screening may not be the best use of resources when controlling head lice. We suggest a more pragmatic community-based approach.

The majority of invasive aspergillosis (IA) in allogeneic stem cell transplantation (SCT) occurs during the post-engraftment period. We used Cox proportional hazards regression to evaluate post-engraftment IA risk in a cohort of 217 allogeneic SCT recipients from 1991 to 1998. The aim was to quantify the effects of dose-intensity and duration of corticosteroids and other risk factors. Median duration of follow-up was 330 days. There were 19 cases of IA (overall 8.8%) with 14 post-engraftment infections. In the final model, the risk of IA was greatest within 2 weeks of high-dose corticosteroids (HR 8.5, P=0.003), with risk extending to 4 weeks with doses of 0.25-1 mg/kg/day (HR 3.1, P=0.08). Ganciclovir was associated with greatest risk (HR 13.6). Grade 3 or 4 acute GVHD (HR 5.7) and secondary neutropenia (HR=1.3) were also additive risks. In the univariate analysis, corticosteroid doses of 0.25-1.0 mg/kg/day for any duration between 2 and 10 weeks demonstrated prolonged risk for IA. Moderate doses of corticosteroids can confer an increased risk for IA for extended periods which is almost as marked as that conferred by higher doses. Knowledge of these risks may facilitate the development of targeted surveillance and prophylaxis strategies for prevention of IA.