Distinct Molecular Profiles of Sporadic Early-Onset Colorectal Cancer: A Population-Based Cohort and Systematic Review.

Background and Aims: The observed increase in the incidence of early-onset colorectal cancer (EOCRC) is being driven by sporadic cases, but the molecular characteristics of these tumors are not fully understood. Our objective was to investigate the prevalence of microsatellite instability (MSI) and selected mutations in sporadic EOCRC, and their association with survival. Methods: Firstly, we compared the prevalence of molecular characteristics and survival within a population-based cohort study of 652 stage II and III colon cancer patients in Northern Ireland, comparing sporadic early-onset (<50 years, n = 35) with older (60-69 years, n = 179) patients. Secondly, a systematic review for studies reporting the prevalence of MSI, mismatch repair deficiency (dMMR), or BRAF, KRAS, NRAS, PIK3CA, and TP53 mutations in sporadic EOCRC was conducted. A meta-analysis was performed to calculate pooled estimates of the prevalence of molecular features in sporadic EOCRC. Results: Firstly, within the cohort study, EOCRC patients did not have a significantly increased risk of colorectal cancer-specific death (adjusted hazard ratio 1.20; 95% confidence interval [CI] 0.61-2.39) compared with 60- to 69-year-olds. Second, 32 studies were included in the systematic review. The pooled analysis estimated a prevalence of 10% (95% CI 7%-14%) for MSI high/dMMR in sporadic EOCRC. BRAF and KRAS mutations had a prevalence of 1% (95% CI 0%-3%) and 32% (95% CI 23%-40%), respectively. Conclusion: The molecular characteristics of sporadic EOCRC differ from those of cancers in older adults, particularly regarding reduced prevalence of BRAF mutations. Ten percent of sporadic EOCRC display MSI high/dMMR. Further studies are needed to address survival in sporadic EOCRC cases and whether molecular profiles influence EOCRC outcomes in this patient group.

Capturing the clinical decision-making processes of expert and novice diabetic retinal graders using a 'think-aloud' approach.

BACKGROUND: Diabetic eye screening programmes have been developed worldwide based on evidence that early detection and treatment of diabetic retinopathy are crucial to preventing sight loss. However, little is known about the decision-making processes and training needs of diabetic retinal graders, particularly in low- and middle-income countries. OBJECTIVES: To provide data for improving evidence-based diabetic retinopathy training to help novice graders process fundus images more like experts. SUBJECTS/METHODS: This is a mixed-methods qualitative study conducted in southern Vietnam and Northern Ireland. Novice diabetic retinal graders in Vietnam (n = 18) and expert graders in Northern Ireland (n = 5) were selected through a purposive sampling technique. Data were collected from 21st February to 3rd September 2019. The interviewer used neutral prompts during think-aloud sessions to encourage participants to verbalise their thought processes while grading fundus images from anonymised patients, followed by semi-structured interviews. Thematic framework analysis was used to identify themes, supported by illustrative quotes from interviews. Mann-Whitney U tests were used to compare graders' performance. RESULTS: Expert graders used a more systematic approach when grading images, considered all four images per patient and used available software tools such as red-free filters prior to making a decision on management. The most challenging features for novice graders were intra-retinal microvascular abnormalities and new vessels, which were more accurately identified by experts. CONCLUSION: Taking more time to grade fundus images and adopting a protocol-driven "checklist" approach may help novice graders to function more like experts.

Surgical under-treatment of older adult patients with cancer: A systematic review and meta-analysis.

BACKGROUND: Older patients with cancer often have lower surgery rates and survival than younger patients, but this may reflect surgical contraindications of advanced disease, comorbidities, and frailty - and not necessarily under-treatment. OBJECTIVES: This review aims to describe variations in surgery rates and observed or net survival among younger (<75) and older (≥75) patients with breast, lung and colorectal cancer, while taking account of pre-existing health factors, in order to understand how under-treatment is defined and estimated in the literature. METHOD: MEDLINE, EMBASE, Web of Science and PubMed databases were searched for studies reporting surgery rates and observed or net survival among younger and older patients with breast, lung, and colorectal cancer. Study quality was assessed using the Newcastle Ottawa Scale, and random effects meta-analyses were used to combine study results. The I-squared statistic and subgroup analyses were used to assess heterogeneity. RESULTS: Thirty relatively high-quality studies of patients with breast (230,200; 71.9%), lung (77,573; 24.2%), and colorectal (12,407; 3.9%) cancers were identified. Compared to younger patients, older patients were less likely to receive surgical treatment for 1) breast cancer after adjusting for comorbidity, performance status (PS), functional status and patient choice, 2) lung cancer after accounting for stage, comorbidity, PS, and 3) colorectal cancer after adjusting for stage, comorbidity, and gender. The pooled unadjusted analyses showed lower surgery receipt in older patients with breast (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.13-0.78), lung (OR 0.54, 95% CI 0.39-0.75), and colorectal (OR 0.59, 95% CI 0.51-0.68) cancer. In separate analyses, older patients with breast, lung and colorectal cancer had lower observed and net survival, compared to younger patients. CONCLUSIONS: Lower surgery rates in older patients may contribute to their poorer survival compared to younger patients. Future research quantifying under-treatment should include necessary clinical factors, patient choice, patient's quality of life and a statistically-robust approach, which will demonstrate how much of the survival deficit in older patients is due to their receiving lower surgery rates.

Insights into the factors associated with achieving the preference of home death in terminal cancer: A national population-based study.

ABSTRACTObjectives:Most terminally ill cancer patients prefer to die at home, yet only a minority are able to achieve this. Our aim was to investigate the factors associated with cancer patients achieving their preference to die at home. METHODS: This study took the form of a mortality followback, population-based, observational survey of the relatives of deceased cancer patients in Northern Ireland. Individuals who registered the death of a friend or relative (aged ≥ 18 years) between 1 December 2011 and 31 May 2012, where the primary cause of death was cancer (ICD10: C00-D48), who were invited to take part. Preferred and actual place of death, and patient, service, and clinical data were collected using the QUALYCARE postal questionnaire. Multivariable logistic regression was employed to investigate the factors associated with achieving a home death when preferred. RESULTS: Some 467 of 1,493 invited informants completed the survey. The 362 (77.5%) who expressed a preference for dying at home and spent time at home in their final 3 months were included in our analysis. Of these, 53.4% achieved their preference of a home death. Factors positively associated with achieving a home death were: living in an affluent area, receipt of good and satisfactory district nurse care, discussing place of death with health professionals, and the caregiver's preference for a home death. Being older than 80 years of age, being a Presbyterian, and being unconscious most of the time during their final week were negatively associated with achieving a home death. SIGNIFICANCE OF RESULTS: Communication, care satisfaction, and caregiver preferences were all associated with home death. Our findings will help inform the design of future interventions aimed at increasing the proportion of patients achieving their preferred place of death at home, for example, by targeting interventions toward older patients and those from the most deprived communities.

Life tables for global surveillance of cancer survival (the CONCORD programme): data sources and methods.

BACKGROUND: We set out to estimate net survival trends for 10 common cancers in 279 cancer registry populations in 67 countries around the world, as part of the CONCORD-2 study. Net survival can be interpreted as the proportion of cancer patients who survive up to a given time, after eliminating the impact of mortality from other causes (background mortality). Background mortality varies widely between populations and over time. It was therefore necessary to construct robust life tables that accurately reflected the background mortality in each of the registry populations. METHODS: Life tables of all-cause mortality rates by single year of age and sex were constructed by calendar year for each population and, when possible, by racial or ethnic sub-groups. We used three different approaches, based on the type of mortality data available from each registry. With death and population counts, we adopted a flexible multivariable modelling approach. With unsmoothed mortality rates, we used the Ewbank relational method. Where no data were available from the registry or a national statistical office, we used the abridged UN Population Division life tables and interpolated these using the Elandt-Johnson method. We also investigated the impact of using state- and race-specific life tables versus national race-specific life tables on estimates of net survival from four adult cancers in the United States (US). RESULTS: We constructed 6,514 life tables covering 327 populations. Wide variations in life expectancy at birth and mortality by age were observed, even within countries. During 1995-99, life expectancy was lowest in Nigeria and highest in Japan, ranging from 47 to 84 years among females and 46 to 78 years among males. During 2005-09, life expectancy was lowest in Lesotho and again highest in Japan, ranging from 45 to 86 years among females and 45 to 80 years among males. For the US, estimates of net survival differed by up to 4% if background mortality was fully controlled with state- and race-specific life tables, rather than with national race-specific life tables. CONCLUSIONS: Background mortality varies worldwide. This emphasises the importance of using population-specific life tables for geographic and international comparisons of net survival.

Oesophageal adenocarcinoma and prior diagnosis of Barrett's oesophagus: a population-based study.

OBJECTIVE: Endoscopic surveillance of Barrett's oesophagus (BO) provides an opportunity to detect early stage oesophageal adenocarcinoma (OAC). We sought to determine the proportion of OAC patients with a prior diagnosis of BO on a population basis and to evaluate the influence of a prior diagnosis of BO on survival, taking into account lead and length time biases. DESIGN: A retrospective population-based study of all OAC patients in Northern Ireland between 2003 and 2008. A prior BO diagnosis was determined by linkage to the Northern Ireland BO register. Stage distribution at diagnosis and histological grade were compared between patients with and without a prior BO diagnosis. Overall survival, using Cox models, was compared between patients with and without a prior BO diagnosis. The effect of adjusting the survival differences for histological grade and estimates of lead and length time bias was assessed. RESULTS: There were 716 OAC cases, 52 (7.3%) of whom had a prior BO diagnosis. Patients with a prior BO diagnosis had significantly lower tumour stage (44.2% vs. 11.1% had stage 1 or 2 disease; p<0.001), a higher rate of surgical resection (50.0% vs. 25.5%; p<0.001) and had a higher proportion of low/intermediate grade tumours (46.2% vs. 26.5%; p=0.011). A prior BO diagnosis was associated with significantly better survival (HR for death 0.39; 95% CI 0.27 to 0.58), which was minimally influenced by adjustment for age, sex and tumour grade (adjusted HR 0.44; 95% CI 0.30 to 0.64). Correction for lead time bias attenuated but did not abolish the survival benefit (HR 0.65; 95% CI 0.45 to 0.95) and further adjustment for length time bias had little effect. CONCLUSIONS: The proportion of OAC patients with a prior diagnosis of BO is low; however, prior identification of BO is associated with an improvement in survival in OAC patients.

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2).

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems. FUNDING: Canadian Partnership Against Cancer (Toronto, Canada), Cancer Focus Northern Ireland (Belfast, UK), Cancer Institute New South Wales (Sydney, Australia), Cancer Research UK (London, UK), Centers for Disease Control and Prevention (Atlanta, GA, USA), Swiss Re (London, UK), Swiss Cancer Research foundation (Bern, Switzerland), Swiss Cancer League (Bern, Switzerland), and University of Kentucky (Lexington, KY, USA).

Surveillance of nonmelanoma skin cancer incidence rates in kidney transplant recipients in Ireland.

BACKGROUND: The incidence of nonmelanomatous skin cancer (NMSC) is substantially higher among renal transplant recipients (RTRs) than in the general population. With a growing RTR population, a robust method for monitoring skin cancer rates in this population is required. METHODS: A modeling approach was used to estimate the trends in NMSC rates that adjusted for changes in the RTR population (sex and age), calendar time, the duration of posttransplant follow-up, and background population NMSC incidence rates. RTR databases in both Northern Ireland (NI) and the Republic of Ireland (ROI) were linked to their respective cancer registries for diagnosis of NMSC, mainly squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). RESULTS: RTRs in the ROI had three times the incidence (P<0.001) of NMSC compared with NI. There was a decline (P<0.001) in NMSC 10-year cumulative incidence rate in RTRs over the period 1994-2009, which was driven by reductions in both SCC and BCC incidence rates. Nevertheless, there was an increase in the incidence of NMSC with time since transplantation. The observed graft survival was higher in ROI than NI (P<0.05) from 1994-2004. The overall patient survival of RTRs was similar in NI and ROI. CONCLUSION: Appropriate modeling of incidence trends in NMSC among RTRs is a valuable surveillance exercise for assessing the impact of change in clinical practices over time on the incidence rates of skin cancer in RTRs. It can form the basis of further research into unexplained regional variations in NMSC incidence.

Lung cancer resection rates have increased significantly in females during a 15-year period.

OBJECTIVE: The aim was to carry out a comparative study of lung cancer incidence and resection rates following the introduction of positron emission tomography-computed tomography (PET-CT) and the reorganisation of Cancer Services in Northern Ireland. METHODS: Data were retrieved from the Regional Thoracic Service Database and Northern Ireland Cancer Registry (NICR) covering the period 1994-2008. The two databases are maintained independently. A total of 13288 lung cancer cases and 1575 lung resections were identified. Secondary tumours were excluded. The incidence of lung tumours and procedures performed was available for each individual year. The incidence of lung cancer was taken from the NICR. The NICR confirmed the diagnosis of lung cancer using international guidelines and cancer was confirmed by histology, cytology, radiological investigations and post-mortem examinations. Poisson regression was used to model the incidence and resections per year; logistic regression was used to model the yearly rate of resections per incidence case. The 15-year period was divided into three periods to assess trends in surgical resection, but the surgical resection rate (SRR) was calculated on a yearly basis. RESULTS: The regional incidence of lung cancer in Northern Ireland (NI) females has increased (1.7% per annum P<0.01, Poisson regression), but this increase has not been seen in males. The incidence of lung cancer patients, who underwent resection at the regional Thoracic Surgery Unit, increased for females (4.4% per annum, P<0.01, Poisson regression), but not for males. The proportional rate of resection (number of resections in a given year/incidence in that year) has changed significantly over the study period for females but not males (the odds ratio per unit year was 1.029, P<0.01, logistic regression). The average age of females increased by 0.2 year (P<0.01) annually; there was no significant increase in the age of males over this period. There was no significant overall rise in the number of patients diagnosed with non-small-cell lung cancer (NSCLC). The percentage of all lung cancer patients who were discussed at multidisciplinary team (MDT) meetings rose from 19% in 1996 to 64% in 2006. The percentage of patients aged over 75 years discussed at an MDT increased from 12% in 1996 to 58% in 2006. The number of females presenting with NSCLC and the number of people presenting with stage I and II disease did not change over the time frame. More patients aged above 70 years had an operation in group III. These accounted for over 50% of the increase in operations between the first and last group. The number of females in this group rose by 92% compared with group I. Significantly, more patients aged over 80 years had an operation in group III than in group I; however, there was significantly more males treated surgically aged over 80 years than females; P=0.001. CONCLUSIONS: The resection rate is currently higher in females than males, and has significantly increased during the study period. The incidence in female lung cancer has risen but it is still below male incidence rates. It seems unlikely that one single factor has brought about this increase. With better education among medical practitioners and the public, more lung cancer cases have been considered for surgery by surgeons. There has been an overall increase in patients presented at MDTs involving thoracic surgeons. For whatever reason, it appears that many lung cancer cases in females had previously not been presented to surgeons prior to the introduction of MDT meetings practice guidelines. The development of MDT meetings throughout NI along with the close involvement of the Thoracic Surgical Unit from the inception of all MDTs seems the most likely factor leading to a change in lung cancer resection rates.

Greater gains from smoke-free legislation for non-smoking bar staff in Belfast.

BACKGROUND: In April 2007, smoke-free legislation was enacted in workplaces throughout N. Ireland. The effects of this legislation on bar workers' health and their exposure to second-hand smoke at home, work and social environment, and their attitudes to the legislation before and after its implementation remain to be documented. METHODS: A self-completed questionnaire of bar staff in 35 Belfast bars, before (March 2007, n = 110) and after the legislation (July 2007, n = 110). RESULTS: Smokers (excluding 'social smokers') made up 41.6% of respondents. After the introduction of the smoke-free legislation, the reductions in the proportion of bar workers reporting various respiratory symptoms ranged from 1.3% to 18.6% for smokers and from 21.9% to 33.2% for non-smokers. Likewise, the reductions for various sensory symptoms ranged from 7.3% to 17.7% for smokers and from 29.6% to 46.8% for non-smokers. Reduction in wheeze, cough and throat symptoms after the legislation were much greater for non-smokers than smokers. The proportion of bar staff who reported satisfaction with the legislation remained unchanged across the surveys. Decreases in perceived exposure to second-hand smoke occurred at work, home and in social settings. After the legislation's enactment, a majority of bar workers felt the workplace was healthier (98%). CONCLUSION: These first findings show reduced reported symptoms among bar workers, both smokers and non-smokers, after the introduction of smoke-free legislation in N. Ireland, though greater among non-smokers. There was also a reported fall in the hours of second-hand smoke exposure in the home for this group of workers which has a high prevalence of smokers.

Testosterone: from initiating change to modulating social organisation in domestic fowl (Gallus gallus domesticus).

Testosterone (T) concentrations in many species are sensitive to seasonal changes and to changes in social conditions. However, the effect of the natural or endogenous T increase in the juvenile on their social behaviour is not well understood. In this study, T and behaviour were measured from the pro-social juvenile to the adult stage in semi-feral domestic fowl. During the pro-social phase T levels and the distance chicks maintained between each other, i.e. inter-individual distance (IID) were low. Then, as T increased, a corresponding increase in IID occurred and continued in males until dispersal to individual adult male territories. In the new and initially stable adult social structure, T declined and IID remained high, indicating a new behavioural mechanism was in place. Males first mated as T levels were declining. They were then challenged; then T increased, and then IID increased again. Adult male T levels fluctuate, being low or declining in a socially stable environment and increasing following a challenge, suggesting a regulatory or modulating role for T. The results are consistent with T having an endogenous role: in the juvenile, driving behavioural change towards adulthood, and in adulthood, a modulating role regulating social organisation.

Observations of veterinary medicine students' approaches to study in pre-clinical years.

RATIONALE FOR THIS STUDY: This study has two purposes. The first is to explore an instrument of evaluation of the approaches to study (deep, strategic, and surface) adopted by students in the pre-clinical years of their veterinary degree program. The second is to examine relationships between these approaches and a broad range of further factors deemed relevant to the veterinary medicine context. We envisage that a greater knowledge of how these students learn will aid curriculum reform in a way that will enrich the learning experience of veterinary students. METHODOLOGY: A questionnaire consisting of the 52-question Approaches to Study Inventory (ASI) and an additional 49 questions relating mainly to teaching, assessment, and study skills was distributed to 215 veterinary medicine (MVB) students in their pre-clinical years of study. Factor analysis was used to ensure that the ASI section of the questionnaire maintained previously reported structure. The internal reliability of the approaches measured was tested using Cronbach alpha analysis. The approaches were described as frequency distributions. Associations between the parameters (deep, strategic, and surface) and 49 additional context-specific factors were investigated using loglinear analysis. RESULTS: (1) Factor analysis revealed that the integrity and structure of the instrument in this context was generally comparable to previous studies. (2) The impact of a high workload was evident in the surface approach, with fear of failure becoming a strong motivating factor and syllabus boundness a widely used strategy. (3) Associations made between the approaches and 49 context-specific factors showed strong associations between both workload and lack of prior knowledge with the surface approach. (4) Grades were associated positively with both the deep and strategic approaches but negatively with the surface approach. (5) A range of learning and study skills were associated positively with the deep and strategic approaches and negatively with the surface approach. CONCLUSION: The ASI proved to be a reliable and insightful instrument, highlighting specific surface learning tendencies present in the group as well as a deep learning approach, the pattern of which deviates from previous studies on this subject. This study also confirms the value of some teaching practices as a means of supporting deep learning and perhaps challenging surface learning strategies. The prevalent perception of a high workload is notable, as is its positive association with surface learning.