Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Complex differences in infection rates between ethnic groups in Scotland: a retrospective, national census-linked cohort study of 1.65 million cases.

BACKGROUND: Ethnicity can influence susceptibility to infection, as COVID-19 has shown. Few countries have systematically investigated ethnic variations in infection. METHODS: We linked the Scotland 2001 Census, including ethnic group, to national databases of hospitalizations/deaths and serological diagnoses of bloodborne viruses for 2001-2013. We calculated age-adjusted rate ratios (RRs) in 12 ethnic groups for all infections combined, 15 infection categories, and human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) viruses. RESULTS: We analysed over 1.65 million infection-related hospitalisations/deaths. Compared with White Scottish, RRs for all infections combined were 0.8 or lower for Other White British, Other White and Chinese males and females, and 1.2-1.4 for Pakistani and African males and females. Adjustment for socioeconomic status or birthplace had little effect. RRs for specific infection categories followed similar patterns with striking exceptions. For HIV, RRs were 136 in African females and 14 in males; for HBV, 125 in Chinese females and 59 in males, 55 in African females and 24 in males; and for HCV, 2.3-3.1 in Pakistanis and Africans. CONCLUSIONS: Ethnic differences were found in overall rates and many infection categories, suggesting multiple causative pathways. We recommend census linkage as a powerful method for studying the disproportionate impact of COVID-19.

The challenge of using routinely collected data to compare hospital admission rates by ethnic group: a demonstration project in Scotland.

BACKGROUND: Recording patients' ethnic group supports efforts to achieve equity in health care provision. Before the Equality Act (2010), recording ethnic group at hospital admission was poor in Scotland but has improved subsequently. We describe the first analysis of the utility of such data nationally for monitoring ethnic variation. METHODS: We analysed all in-patient or day case hospital admissions in 2013. We imputed missing data using the most recent ethnic group recorded for a patient from 2009 to 2015. For episodes lacking an ethnic code, we attributed known ethnic codes proportionately. Using the 2011 Census population, we calculated rates and rate ratios for all-cause admissions and ischaemic heart diseases (IHDs) directly standardized for age. RESULTS: Imputation reduced missing ethnic group codes from 24 to 15% and proportionate redistribution to zero. While some rates for both all-cause and IHD admissions appeared plausible, unexpectedly low or high rates were observed for several ethnic groups particularly amongst White groups and newly coded groups. CONCLUSIONS: Completeness of ethnicity recoding on hospital admission records has improved markedly since 2010. However the validity of admission rates based on these data is variable across ethnic groups and further improvements are required to support monitoring of inequality.

Ethnic variations in falls and road traffic injuries resulting in hospitalisation or death in Scotland: the Scottish Health and Ethnicity Linkage Study.

OBJECTIVES: To investigate ethnic differences in falls and road traffic injuries (RTIs) in Scotland. STUDY DESIGN: A retrospective cohort of 4.62 million people, linking the Scottish Census 2001, with self-reported ethnicity, to hospitalisation and death records for 2001-2013. METHODS: We selected cases with International Classification of Diseases-10 diagnostic codes for falls and RTIs. Using Poisson regression, age-adjusted risk ratios (RRs, multiplied by 100 as percentages) and 95% confidence intervals (CIs) were calculated by sex for 10 ethnic groups with the White Scottish as reference. We further adjusted for country of birth and socio-economic status (SES). RESULTS: During about 49 million person-years, there were 275,995 hospitalisations or deaths from fall-related injuries and 43,875 from RTIs. Compared with the White Scottish, RRs for falls were higher in most White and Mixed groups, e.g., White Irish males (RR: 131; 95% CI: 122-140) and Mixed females (126; 112-143), but lower in Pakistani males (72; 64-81) and females (72; 63-82) and African females (79; 63-99). For RTIs, RRs were higher in other White British males (161; 147-176) and females (156; 138-176) and other White males (119; 104-137) and females (143; 121-169) and lower in Pakistani females (74; 57-98). The ethnic variations differed by road user type, with few cases among non-White motorcyclists and non-White female cyclists. The RRs were minimally altered by adjustment for country of birth or SES. CONCLUSION: We found important ethnic variations in injuries owing to falls and RTIs, with generally lower risks in non-White groups. Culturally related differences in behaviour offer the most plausible explanation, including variations in alcohol use. The findings do not point to the need for new interventions in Scotland at present. However, as the ethnic mix of each country is unique, other countries could benefit from similar data linkage-based research.

The prognostic impact of consensus molecular subtypes (CMS) and its predictive effects for bevacizumab benefit in metastatic colorectal cancer: molecular analysis of the AGITG MAX clinical trial.

Background: The consensus molecular subtypes (CMS) is a transcriptome-based classification of colorectal cancer (CRC) initially described in early-stage cohorts, but the associations of CMS with treatment outcomes in the metastatic setting are yet to be established. This study aimed to evaluate the prognostic impact of CMS classification and its predictive effects for bevacizumab benefit in metastatic CRC by correlative analysis of the AGITG MAX trial. Patients and methods: The MAX trial previously reported improved progression-free survival (PFS) for the addition of bevacizumab (B) to chemotherapy [capecitabine (C)±mitomycin (M)]. Archival primary tumours from 237 patients (50% of trial population) underwent gene expression profiling and classification into CMS groups. CMS groups were correlated to PFS and overall survival (OS). The interaction of CMS with treatment was assessed by proportional hazards model. Results: The distribution of CMS in MAX were CMS1 18%, CMS2 47%, CMS3 12%, CMS4 23%. CMS1 was the predominant subtype in right-sided primary tumours, while CMS2 was the predominant subtype in left-sided. CMS was prognostic of OS (P = 0.008), with CMS2 associated with the best outcome and CMS1 the worst. CMS remained an independent prognostic factor in a multivariate analysis. There was a significant interaction between CMS and treatment (P-interaction = 0.03), for PFS, with hazard ratios (95% CI) for CB+CBM versus C arms in CMS1, 2, 3 and 4: 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25), respectively. Conclusions: This exploratory study found that CMS stratified OS outcomes in metastatic CRC regardless of first-line treatment, with prognostic effects of CMS groups distinct from those previously reported in early-stage cohorts. In CMS associations with treatment, CMS2 and possibly CMS3 tumours may preferentially benefit from the addition of bevacizumab to first-line capecitabine-based chemotherapy, compared with other CMS groups. Validation of these findings in additional cohorts is warranted. Clinical trial number: This is a molecular sub-study of MAX clinical trial (NCT00294359).

Novel associations between blood DNA methylation and body mass index in middle-aged and older adults.

BACKGROUND/OBJECTIVES: There is increasing evidence of a relationship between blood DNA methylation and body mass index (BMI). We aimed to assess associations of BMI with individual methylation measures (CpGs) through a cross-sectional genome-wide DNA methylation association study and a longitudinal analysis of repeated measurements over time. SUBJECTS/METHODS: Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined in baseline peripheral blood samples from 5361 adults recruited to the Melbourne Collaborative Cohort Study (MCCS) and selected for nested case-control studies, 2586 because they were subsequently diagnosed with cancer (cases) and 2775 as controls. For a subset of 1088 controls, these measures were repeated using blood samples collected at wave 2 follow-up, a median of 11 years later; weight was measured at both time points. Associations between BMI and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. These were applied to cases and controls separately, with results combined through fixed-effects meta-analysis. RESULTS: Cross-sectional analysis identified 310 CpGs associated with BMI with P<1.0 × 10-7, 225 of which had not been reported previously. Of these 225 novel associations, 172 were replicated (P<0.05) using the Atherosclerosis Risk in Communities (ARIC) study. We also replicated using MCCS data (P<0.05) 335 of 392 associations previously reported with P<1.0 × 10-7, including 60 that had not been replicated before. Associations between change in BMI and change in methylation were observed for 34 of the 310 strongest signals in our cross-sectional analysis, including 7 that had not been replicated using the ARIC study. CONCLUSIONS: Together, these findings suggest that BMI is associated with blood DNA methylation at a large number of CpGs across the genome, several of which are located in or near genes involved in ATP-binding cassette transportation, tumour necrosis factor signalling, insulin resistance and lipid metabolism.

Differences in all-cause hospitalisation by ethnic group: a data linkage cohort study of 4.62 million people in Scotland, 2001-2013.

OBJECTIVES: Immigration into Europe has raised contrasting concerns about increased pressure on health services and equitable provision of health care to immigrants or ethnic minorities. Our objective was to find out if there were important differences in hospital use between the main ethnic groups in Scotland. STUDY DESIGN: A census-based data linkage cohort study. METHODS: We anonymously linked Scotland's Census 2001 records for 4.62 million people, including their ethnic group, to National Health Service general hospitalisation records for 2001-2013. We used Poisson regression to calculate hospitalisation rate ratios (RRs) in 14 ethnic groups, presented as percentages of the White Scottish reference group (RR = 100), for males and females separately. We adjusted for age and socio-economic status and compared those born in the United Kingdom or the Republic of Ireland (UK/RoI) with elsewhere. We calculated mean lengths of hospital stay. RESULTS: 9.79 million hospital admissions were analysed. Compared with the White Scottish, unadjusted RRs for both males and females in most groups were about 50-90, e.g. Chinese males 49 (95% confidence interval [CI] = 45-53) and Indian females 76 (95% CI 71-81). The exceptions were White Irish, males 120 (95% CI 117-124) and females 115 (95% CI 112-119) and Caribbean females, 103 (95% CI 85-126). Adjusting for age increased the RRs for most groups towards or above the reference. Socio-economic status had little effect. In many groups, those born outside the UK/RoI had lower admission rates. Unadjusted mean lengths of stay were substantially lower in most ethnic minorities. CONCLUSIONS: Use of hospital beds in Scotland by most ethnic minorities was lower than by the White Scottish majority, largely explained by their younger average age. Other countries should use similar methods to assess their own experience.

The role of intramedullary fixation in ankle fractures - A systematic review.

BACKGROUND: Ankle fractures are one of the most commonly occurring fractures in the elderly population. The overall incidence has been reported to be up to 184 fractures per 100,000 persons per year, of which 20-30% occur in the elderly. Medical co-morbidities, osteoporosis, suboptimal skin quality and poor toleration of non-weight bearing status all contribute to difficulties in managing these injuries in this population. Intramedullary implants are advantageous as they utilise smaller incisions, minimise soft tissue disruption and may allow early weight bearing. This systematic review aims to analyse the use of both fibula nails and talo-tibial-calcaneal (TTC) implants in the management of fragility ankle fractures. METHODS: We conducted a systematic review of the literature using the online databases Medline and EMBASE on 26th December 2015. Only studies assessing ankle fractures that were treated with either an intramedullary fibula nail or TTC implant were included. Studies must have reported complications, patient mobility status or a functional outcome measure. Studies were excluded if the intramedullary device utilised was an adjunct to plate fixation or where a variety of surgical treatments were included in the study. The included studies were appraised with respect to a validated quality assessment scale. RESULTS: Our search strategy produced 350 studies although only 17 studies met inclusion criteria; ten assessed a fibula nail and seven assessed a standard hindfoot nail, a TTC implant. 15 studies were case series, the overall quality of the studies was low and only one randomised controlled trial was reviewed. The mean Olerud and Molander Ankle Score for fibula nail studies ranged from 58 to 97 and the complication rate from 0 to 22%. Two comparative studies reported a statistically significant increase in complication rate with plate fixation but similar functional outcomes. Studies assessing TTC implants reported a mean Olerud and Molander Ankle Score of 50-62 and complication rate from 18 to 22.6%. CONCLUSION: The studies reviewed suggest that fibula nails may be capable of producing similar functional outcomes with lower rates of complications to plate fixation. TTC implants produce lower functional outcomes but this may be acceptable in a subgroup of patients at high risk or with reduced pre-injury mobility. However, the low quality of evidence reviewed, the variation in patients included, implant used and outcome scores measured restricts the ability to draw definitive conclusions. Further comparative studies are required to explore the role of these implants further.

Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study.

Background: TNM staging alone does not accurately predict outcome in colon cancer (CC) patients who may be eligible for adjuvant chemotherapy. It is unknown to what extent the molecular markers microsatellite instability (MSI) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathological annotation. Patients and methods: After imputation of missing at random data, a subset of patients accrued in phase 3 trials with adjuvant chemotherapy (n = 3016)-N0147 (NCT00079274) and PETACC3 (NCT00026273)-was aggregated to construct multivariable Cox models for 5-year overall survival that were subsequently validated internally in the remaining clinical trial samples (n = 1499), and also externally in different population cohorts of chemotherapy-treated (n = 949) or -untreated (n = 1080) CC patients, and an additional series without treatment annotation (n = 782). Results: TNM staging, MSI and BRAFV600E mutation status remained independent prognostic factors in multivariable models across clinical trials cohorts and observational studies. Concordance indices increased from 0.61-0.68 in the TNM alone model to 0.63-0.71 in models with added molecular markers, 0.65-0.73 with clinicopathological features and 0.66-0.74 with all covariates. In validation cohorts with complete annotation, the integrated time-dependent AUC rose from 0.64 for the TNM alone model to 0.67 for models that included clinicopathological features, with or without molecular markers. In patient cohorts that received adjuvant chemotherapy, the relative proportion of variance explained (R2) by TNM, clinicopathological features and molecular markers was on an average 65%, 25% and 10%, respectively. Conclusions: Incorporation of MSI, BRAFV600E and KRAS mutation status to overall survival models with TNM staging improves the ability to precisely prognosticate in stage II and III CC patients, but only modestly increases prediction accuracy in multivariable models that include clinicopathological features, particularly in chemotherapy-treated patients.

Tumour MLH1 promoter region methylation testing is an effective prescreen for Lynch Syndrome (HNPCC).

BACKGROUND AND AIMS: Lynch syndrome (LS) patients have DNA mismatch repair deficiency and up to 80% lifetime risk of colorectal cancer (CRC). Screening of mutation carriers reduces CRC incidence and mortality. Selection for constitutional mutation testing relies on family history (Amsterdam and Bethesda Guidelines) and tumour-derived biomarkers. Initial biomarker analysis uses mismatch repair protein immunohistochemistry and microsatellite instability. Abnormalities in either identify mismatch repair deficiency but do not differentiate sporadic epigenetic defects, due to MLH1 promoter region methylation (13% of CRCs) from LS (4% of CRCs). A diagnostic biomarker capable of making this distinction would be valuable. This study compared two biomarkers in tumours with mismatch repair deficiency; quantification of methylation of the MLH1 promoter region using a novel assay and BRAF c.1799T>A, p.(Val600Glu) mutation status in the identification of constitutional mutations. METHODS: Tumour DNA was extracted (formalin fixed, paraffin embedded, FFPE tissue) and pyrosequencing used to test for MLH1 promoter methylation and presence of the BRAF c.1799T>A, p.(Val600Glu) mutation 71 CRCs from individuals with pathogenic MLH1 mutations and 73 CRCs with sporadic MLH1 loss. Specificity and sensitivity was compared. FINDINGSS: Unmethylated MLH1 promoter: sensitivity 94.4% (95% CI 86.2% to 98.4%), specificity 87.7% (95% CI 77.9% to 94.2%), Wild-type BRAF (codon 600): sensitivity 65.8% (95% CI 53.7% to 76.5%), specificity 98.6% (95% CI 92.4% to 100.0%) for the identification of those with pathogenic MLH1 mutations. CONCLUSIONS: Quantitative MLH1 promoter region methylation using pyrosequencing is superior to BRAF codon 600 mutation status in identifying constitutional mutations in mismatch repair deficient tumours.

Comparing levels of social capital in three northern post-industrial UK cities.

OBJECTIVES: A high level of 'excess' mortality (i.e. that seemingly not explained by deprivation) has been shown for Scotland compared to England & Wales and, in particular, for its largest city, Glasgow, compared to the similarly deprived postindustrial English cities of Liverpool and Manchester. The excess has been observed across all social classes, but, for premature mortality, has been shown to be highest in comparison of those of lowest socio-economic status (SES). Many theories have been proposed to explain this phenomenon. One such suggestion relates to potential differences in social capital between the cities, given the previously evidenced links between social capital and mortality. The aim of this study was to ascertain whether any aspects of social capital differed between the cities and whether, therefore, this might be a plausible explanation for some of the excess mortality observed in Glasgow. STUDY DESIGN: Cross-sectional study. METHODS: A representative survey of Glasgow, Liverpool and Manchester was undertaken in 2011. Social capital was measured using an expanded version of the Office for National Statistics (ONS) core 'Social Capital Harmonised Question Set'. Differences between the cities in five sets of social capital topics (views about the local area, civic participation, social networks and support, social participation, and reciprocity and trust) were explored by means of a series of multivariate regression models, while controlling for differences in the characteristics (age, gender, SES, ethnicity etc.) of the samples. RESULTS: Some, but not all, aspects of social capital were lower among the Glasgow sample compared to those in Liverpool and Manchester. A number of these differences were greatest among those of higher, rather than lower, SES. Levels of social participation, trust and (some measures of) reciprocity were lower in Glasgow, particularly in comparison with Liverpool. However, assessment of any potential impact of these differences is limited by the cross-sectional nature of the data. CONCLUSIONS: The analyses suggest it is at least possible that differences in some aspects of social capital could play some part in explaining Glasgow's excess mortality, especially among particular sections of its population (e.g. those of higher SES). However, in the absence of more detailed longitudinal data, this remains speculative.

Characterisation of familial colorectal cancer Type X, Lynch syndrome, and non-familial colorectal cancer.

BACKGROUND: Familial Colorectal Cancer Type X (FCCTX) is defined as individuals with colorectal cancer (CRC) who families meet Amsterdam Criteria-1 (AC1), but whose tumours are DNA-mismatch-repair-proficient, unlike Lynch syndrome (LS). FCCTX does not have an increased risk of extra-colonic cancers. This analysis compares epidemiologic and clinicopathologic features among FCCTX, LS, and 'non-familial' (non-AC1) CRC cases. METHODS: From the Colon Cancer Family Registry, FCCTX (n=173), LS (n=303), and non-AC1 (n=9603) CRC cases were identified. Questionnaire-based epidemiologic information and CRC pathologic features were compared across case groups using polytomous logistic regression. RESULTS: Compared with LS, FCCTX cases were less likely to be current (vs never) smokers; have a proximal subsite (vs rectal) tumour; or have mucinous histology, poor differentiation, or tumour-infiltrating lymphocytes. There were no observed differences in co-morbidities or medication usage. CONCLUSIONS: FCCTX were less likely to be current tobacco users; other exposures were similar between these groups. Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX.

KRAS-mutation status in relation to colorectal cancer survival: the joint impact of correlated tumour markers.

BACKGROUND: Mutations in the Kirsten Ras (KRAS) oncogene are common in colorectal cancer (CRC). The role of KRAS-mutation status as a prognostic factor, however, is unclear. We evaluated the relationship between KRAS-mutation status and CRC survival, considering heterogeneity in this association by tumour and patient characteristics. METHODS: The population-based study included individuals diagnosed with CRC between 1998-2007 in Western Washington State. Tumour specimens were tested for KRAS exon 2 mutations, the BRAF p.V600E mutation, and microsatellite instability (MSI). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between KRAS-mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumour site, stage, and MSI. We conducted additional analyses combining KRAS-mutation, BRAF-mutation, and MSI status. RESULTS: Among 1989 cases, 31% had KRAS-mutated CRC. Kirsten Ras (KRAS)-mutated CRC was associated with poorer disease-specific survival (HR=1.37, 95% CI: 1.13-1.66). This association was not evident in cases who presented with distant-stage CRC. Cases with KRAS-wild-type/BRAF-wild-type/MSI-high CRC had the most favourable prognosis; those with CRC exhibiting a KRAS- or BRAF-mutation and no MSI had the poorest prognosis. Patterns were similar for overall survival. CONCLUSION: Kirsten Ras (KRAS)-mutated CRC was associated with statistically significantly poorer survival after diagnosis than KRAS-wild-type CRC.

Standardised classification system for bespoke thermoplastic ankle foot orthoses.

PURPOSE: To validate a new classification system for bespoke thermoplastic ankle foot orthoses (AFOs). METHODS: Inter- and intra-observer reliability study. A classification system based on the design and function of AFOs was created. Sixty-three independent observers classified thirty-six photographs of different AFOs, according to the proposed classification system via an online questionnaire. Approximately two weeks later, the same AFOs were classified again by fifty-three of the same participants. All participants were health care professionals, researchers, or technicians with experience in referring for, prescribing, fitting, reviewing, researching or manufacturing AFOs. RESULTS: The mean inter- and intra-observer agreement Fleiss' kappa was 0.932 and 0.944, respectively. 98.3% of participants reported that the classification system was very easy or moderately easy to use, with 85.7% reporting they would use the classification system. 90.5% of participants reported that the proposed AFO classification system was clear, with 84% stating it was useful. CONCLUSION: The proposed classification system for bespoke thermoplastic AFOs, has an excellent inter- and intra-observer agreement. It will reduce the ambiguity of the description of the type of AFOs used in clinical practice and research. Furthermore, it makes reproducible comparisons between groups possible, which are essential for future evaluations of evidence-based orthotic care.

Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients.

BACKGROUND: In colorectal cancer (CRC), tumour microsatellite instability (MSI) status and CpG island methylator phenotype (CIMP) status are indicators of patient outcome, but the molecular events that give rise to these outcomes remain largely unknown. Wnt5a is a critical regulator of non-canonical Wnt activity and promoter hypermethylation of this gene has emerging prognostic roles in CRC; however the frequency and prognostic significance of this epigenetic event have not been explored in the context of colorectal tumour subtype. Consequently, we investigated the frequency and prognostic significance of Wnt5a methylation in a large cohort of MSI-stratified CRCs. METHODS: Methylation was quantified in a large cohort of 1232 colorectal carcinomas from two clinically distinct populations from Canada. Associations were examined between methylation status and clinicopathlogical features, including tumour MSI status, BRAF V600E mutation, and patient survival. RESULTS: In Ontario, Wnt5a methylation was strongly associated with MSI tumours after adjustment for age, sex, and tumour location (odds ratio (OR)=4.2, 95% confidence interval (CI)=2.4-7.4, P<10(-6)) and with BRAF V600E mutation, a marker of CIMP (OR=12.3, 95% CI=6.9-21.7, P<10(-17)), but was not associated with patient survival. Concordant results were obtained in Newfoundland. CONCLUSION: Methylation of Wnt5a is associated with distinct tumour subtypes, strengthening the evidence of an epigenetic-mediated Wnt bias in CRC.

Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes.

BACKGROUND: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers. METHODS: A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry. RESULTS: During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56). CONCLUSION: Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers.

Three-dimensional ultrasound of carotid atherosclerosis: semiautomated segmentation using a level set-based method.

PURPOSE: Three-dimensional ultrasound (3D US) of the carotid artery provides measurements of arterial wall and plaque [vessel wall volume (VWV)] that are complementary to the one-dimensional measurement of the carotid artery intima-media thickness. 3D US VWV requires an observer to delineate the media-adventitia boundary (MAB) and lumen-intima boundary (LIB) of the carotid artery. The main purpose of this work was to develop and evaluate a semiautomated segmentation algorithm for delineating the MAB and LIB of the carotid artery from 3D US images. METHODS: To segment the MAB and LIB, the authors used a level set method and combined several low-level image cues with high-level domain knowledge and limited user interaction. First, the operator initialized the algorithm by choosing anchor points on the boundaries, identified in the images. The MAB was segmented using local region- and edge-based energies and an energy that encourages the boundary to pass through anchor points from the preprocessed images. For the LIB segmentation, the authors used local and global region-based energies, the anchor point-based energy, as well as a constraint promoting a boundary separation between the MAB and LIB. The data set consisted of 231 2D images (11 2D images per each of 21 subjects) extracted from 3D US images. The image slices were segmented five times each by a single observer using the algorithm and the manual method. Volume-based, region-based, and boundary distance-based metrics were used to evaluate accuracy. Moreover, repeated measures analysis was used to evaluate precision. RESULTS: The algorithm yielded an absolute VWV difference of 5.0% +/- 4.3% with a segmentation bias of -0.9% +/- 6.6%. For the MAB and LIB segmentations, the method gave absolute volume differences of 2.5% +/- 1.8% and 5.6% +/- 3.0%, Dice coefficients of 95.4% +/- 1.6% and 93.1% +/- 3.1%, mean absolute distances of 0.2 +/- 0.1 and 0.2 +/- 0.1 mm, and maximum absolute distances of 0.6 +/- 0.3 and 0.7 +/- 0.6 mm, respectively. The coefficients of variation of the algorithm (5.1%) and manual methods (3.9%) were not significantly different, but the average time saved using the algorithm (2.8 min versus 8.3 min) was substantial. CONCLUSIONS: The authors generated and tested a semiautomated carotid artery VWV measurement tool to provide measurements with reduced operator time and interaction, with high Dice coefficients, and with necessary required precision.

A role for intravenous lidocaine in severe cancer-related neuropathic pain at the end-of-life.

BACKGROUND: Systemic administration of lidocaine has been widely reported to provide effective analgesia in both cancer and non-malignant pain. CASE REPORT: We report the use of intravenous lidocaine in the management of cancer-related neuropathic pain and its pivotal role in restoring function and facilitating end-of-life care at home.

Perceptions of anxiety in lung cancer patients and their support network.

INTRODUCTION: Lung cancer is a disease of high symptom burden, major psychosocial impact and poor prognosis. Although diagnosis is individual, each patient operates within a social context. Patient perception of family's or friends' concern may affirm the presence of support or may drive personal anxiety. Perceived worry may impact on freedom to discuss illness or symptoms within the support network. The validated palliative outcome scale quantifies physical and psychosocial needs. It also evaluates anxiety felt and anxiety perceived in the support network. This study examined lung cancer patients' symptoms, performance status, their supportive care needs and their perception of family's/friends' anxiety. GOALS OF WORK: The aim of this study was to evaluate lung cancer patients' anxiety, physical symptoms, performance status and their perception of anxiety within their support network. PATIENTS AND METHODS: The study was a prospective observational evaluation of 170 lung cancer out-patients using an adapted palliative outcome scale questionnaire. Comparison was made between patients perceiving high anxiety within their support network and those who perceiving low anxiety. MAIN RESULTS: Perceived familial and self-rated personal anxiety both increased as function declined (p < 0.001; p = 0.001). Increased perceived worry was associated with increased physical symptoms [dyspnoea (p < 0.001), cough (p = 0.001), haemoptysis (p = 0.009)], low self-esteem (p = 0.004) and feeling lack of worth (p = 0.035). Perception of increased worry did not influence whether patients felt able to share their feelings (p = 0.362). CONCLUSIONS: As physical function declines and symptoms increase, patients are more worried themselves and perceive increased anxiety within their support network. However, this circle of anxiety did not impair the perception that feelings could be shared within the support network.

Charge Donation by Calcium into the t1g Band of C60.

Photoemission spectra of compounds prepared by the reaction of C(60) films with calcium show two distinct metallic phases, whereas alkali-doped C(60) films have only one. In the first phase the bulk t(1u) band, derived from the lowest unoccupied molecular orbital of C(60), is partially occupied. This is followed by an insulating phase that has the composition Ca(3)C(60) in which the t(1u) band is filled and has properties analogous to those of K(6)C(60). Continued exposure to calcium produces a second metallic phase in which electrons are donated into the t(1g) band. The superconductivity of Ca(5)C(60) is associated with the t(1g) band.