Rheumatoid arthritis and cancer risk in the Million Women Study.

BACKGROUND: Most previous studies of rheumatoid arthritis (RA) and cancer risk have lacked information on potential confounding factors. We investigated RA-associated cancer risks in a large cohort of women in the UK, taking account of shared risk factors. METHODS: In 1996-2001, women aged 50-64, who were invited for routine breast screening at 66 National Health Service (NHS) screening centres in England and Scotland, were also invited to take part in the Million Women Study. Participants provided information on sociodemographic, lifestyle and health-related factors, including RA, and were followed up for cancers and deaths. Cox regression yielded RA-associated hazard ratios (HRs) of 20 cancers, adjusted for 10 characteristics including smoking status and adiposity. RESULTS: Around 1.3 million women (half of those invited) were recruited into the study. In minimally adjusted analyses, RA was associated with the risk of 13 of the 20 cancers. After additional adjustment for lifestyle factors, many of these associations were attenuated but there remained robust evidence of RA-associated increases in the risk of lung (HR 1.21, 95% confidence interval 1.15-1.26), lymphoid (1.25, 1.18-1.33), myeloid (1.12, 1.01-1.25), cervical (1.39, 1.11-1.75) and oropharyngeal (1.40, 1.21-1.61) cancers, and decreases in the risk of endometrial (0.84, 0.77-0.91) and colorectal (0.82, 0.77-0.87) cancers. CONCLUSIONS: After taking account of shared risk factors, RA is positively associated with lung and certain blood and infection-related cancers, and inversely associated with colorectal cancer. These findings are consistent with existing hypotheses around immune response, susceptibility to infections, and chronic inflammation. The inverse association observed for endometrial cancer merits further investigation.

Body size in early life and the risk of postmenopausal breast cancer.

BACKGROUND: Greater early life adiposity has been reported to reduce postmenopausal breast cancer risk but it is unclear whether this association varies by tumour characteristics. We aimed to assess associations of early life body size with postmenopausal breast cancer and its subtypes, allowing for body size at other ages. METHODS: A total of 342,079 postmenopausal UK women who reported their body size at age 10, clothes size at age 20, and body mass index (BMI) at baseline (around age 60) were followed by record linkage to national databases for cancers and deaths. Cox regression yielded adjusted relative risks (RRs) of breast cancer, overall and by tumour subtype, in relation to body size at different ages. RESULTS: During an average follow-up of 14 years, 15,506 breast cancers were diagnosed. After adjustment for 15 potential confounders, greater BMI at age 60 was associated with an increased risk of postmenopausal breast cancer (RR per 5 kg/m2=1.20, 95%CI 1.18-1.22) whereas greater adiposity in childhood and, to a lesser extent, early adulthood, was associated with a reduced risk (0.70, 0.66-0.74, and 0.92, 0.89-0.96, respectively). Additional adjustment for midlife BMI strengthened associations with BMI at both age 10 (0.63, 0.60-0.68) and at age 20 (0.78, 0.75-0.81). The association with midlife adiposity was confined to hormone sensitive subtypes but early life adiposity had a similar impact on the risk of all subtypes. CONCLUSION: Early life and midlife adiposity have opposite effects on postmenopausal breast cancer risk and the biological mechanisms underlying these associations are likely to differ.

Time-dependent associations between presentation-based infections and subsequent risk of childhood immune cell malignancies.

BACKGROUND: Infection is hypothesised as a contributory cause of childhood immune cell malignancies. Although some have reported associations between individual infections and immune cell malignancies, some could be spurious due to infections caused by malignancies that were already active prior to diagnosis. METHODS: Identified from Taiwan Cancer Registry, ∼3000 children with four commonest immune cell malignancies diagnosed during 2001-2015 at age 1-20 years were identified and matched with 1:10 controls. Using logistic regression, we estimated the time-specific case-versus-control odds ratios of seven common infection presentations in their health records. We also compared recorded unexplained lymph nodes between cases and controls to explore for how long malignancy may be active prior to diagnosis. RESULTS: Unexplained lymph nodes were increasingly recorded months before the diagnosis of childhood leukaemias and years before the diagnosis of childhood lymphomas. When using p < 0.01 as a guide, large case-control differences in infection records were found mostly within 0-2 months prior to the diagnosis (15 out of 28 comparisons). Changes in odds ratios within 3-35 months (2 out of 28 comparisons) and case-control differences beyond 36+ months prior to diagnosis (7 out of 28 comparisons) was relatively small (∼10 % difference in leukaemias). Statistical power varied according to incidence of malignancy, incidence of infection records, and the age distribution. CONCLUSION: Immune cell malignancies were likely to be active some time before the diagnosis. Previous studies using conventional population-based methods may not be able to distinguish any small causal link between infection and immune cell malignancies from spurious associations.

Adult cancer risk in women who were breastfed as infants: large UK prospective study.

There are known short-term benefits in breastfed infants versus bottle-fed infants in terms of lower risks of infection and obesity in infancy and childhood, but the long-term effect on the risk of adult cancers is unclear. In a cohort of 1 in 4 UK women born in 1935-1950 we report the incidence of adult cancers in relation to having been breastfed in infancy. In median year 2001 (interquartile range 2000-2003) 548,741 women without prior cancer reported whether they had been breastfed. There was 81% agreement between women's report of having been breastfed and information on breastfeeding recorded when they were 2 years old. Participants were followed by record-linkage to national cancer registration, hospital admission and death databases. Cox regression yielded adjusted relative risks (RRs) and 95% confidence intervals (CI) by having been breastfed or not for eight cancer sites with > 2000 incident cases and for related conditions, where appropriate. Of the eight cancers examined here one association was highly statistically significant: an increase in colorectal cancer incidence among women who had been breastfed versus not (RR 1.18, 95% CI 1.12-1.24, n = 8651). To investigate further the findings for colorectal cancer, we studied eight other gastro-intestinal conditions, and found increased risks in women who had been breastfed versus not for benign colorectal polyps (RR 1.09, 95% CI 1.05-1.13, n = 17,677) and for appendicitis (RR 1.19, 95% CI 1.07-1.31, n = 2108). The greater risks of adult colorectal cancer, colorectal polyps and appendicitis associated with having been breastfed in infancy suggest possible long-term effects of infant feeding practices on the gastrointestinal tract. Further studies are required to clarify this novel association.

Coffee and pancreatic cancer risk among never-smokers in the UK prospective Million Women Study.

Reported associations between coffee consumption and an increased risk of pancreatic cancer could be due to residual confounding by smoking and/or biased recall of coffee consumption in retrospective studies. Studying associations prospectively in never smokers should minimize these problems, but thus far such studies have included relatively small numbers of cases. In our study, 309,797 never-smoking women self-reported typical daily coffee consumption at a mean age of 59.5 years (SD 5.0 years) and were followed up for a median of 13.7 years (IQR: 12.2-14.9) through record linkage to national health cancer and death registries. During this period, 962 incident cases of pancreatic cancers were registered. Cox regression was used to calculate adjusted relative risks [RRs] of incident pancreatic cancer with 95% confidence intervals [CIs] in relation to coffee consumption at baseline. After adjustment for potential confounding factors, including body mass index and alcohol consumption, RRs of pancreatic cancer in never-smokers who reported usually consuming 1-2, 3-4, and ≥ 5 cups of coffee daily, compared to nondrinkers of coffee, were 1.02 (CI 0.83-1.26), 0.96 (0.76-1.22), and 0.87 (0.64-1.18), respectively (trend p = 0.2). A meta-analysis of results from this cohort and 3 smaller prospective studies found little or no statistically significant association between coffee consumption and pancreatic cancer risk in never smokers (summary RR = 1.00, CI 0.86-1.17 for ≥2 vs. zero cups of coffee per day).

Sex differences in common childhood infections in Taiwan.

Sex differences in childhood infections are commonly reported in case-only studies. In this population-based study of 278000 Taiwanese children followed from 3 months to 18 years of age during the period 2000-2012, age-trajectories of monthly numbers of all-cause healthcare visits and monthly rates of infection-specific healthcare visits were compared between boys and girls. For all-cause healthcare visits and for healthcare visits related to conjunctivitis, respiratory tract infections, enteritis, hand, foot, and mouth disease, and herpangina, there was good resemblance of age trajectories between boys and girls. Despite this resemblance, there was evidence of a slightly higher rate in boys than in girls under age 6 years (i.e., a male tendency, or male-to-female ratio >1.0) across all diagnoses except herpangina. For urinary tract infection, where an age-specific sex difference is well reported in case-only studies, this population-based study confirmed that there was a much higher rate of kidney infection among boys than among girls during infancy, and a higher rate of kidney and bladder infection among girls than among boys after this period. The age-specific sex difference in urinary tract infections was so strong that the age trajectories in boys and girls were qualitatively different. This report confirms previously reported sex differences in other countries, whilst placing this in the context of age dynamics in childhood infection.

Differences in risk factors for 3 types of stroke: UK prospective study and meta-analyses.

OBJECTIVE: To compare associations of behavioral and related factors for incident subarachnoid hemorrhage and intracerebral hemorrhage and ischemic stroke. METHODS: A total of 712,433 Million Women Study participants without prior stroke, heart disease, or cancer reported behavioral and related factors at baseline (1999-2007) and were followed up by record linkage to national hospital admission and death databases. Cox regression yielded adjusted relative risks (RRs) by type of stroke. Heterogeneity was assessed with χ2 tests. When appropriate, meta-analyses were done of published prospective studies. RESULTS: After 12.9 (SD 2.6) years of follow-up, 8,128 women had an incident ischemic stroke, 2,032 had intracerebral hemorrhage, and 1,536 had subarachnoid hemorrhage. In women with diabetes mellitus, the risk of ischemic stroke was substantially increased (RR 2.01, 95% confidence interval [CI] 1.84-2.20), risk of intracerebral hemorrhage was increased slightly (RR 1.31, 95% CI 1.04-1.65), but risk of subarachnoid hemorrhage was reduced (RR 0.43, 95% CI 0.26-0.69) (heterogeneity by stroke type, p < 0.0001). Stroke incidence was greater in women who rated their health as poor/fair compared to those who rated their health as excellent/good (RR 1.36, 95% CI 1.30-1.42). Among 565,850 women who rated their heath as excellent/good, current smokers were at an increased risk of all 3 stroke types, (although greater for subarachnoid hemorrhage [≥15 cigarettes/d vs never smoker, RR 4.75, 95% CI 4.12-5.47] than for intracerebral hemorrhage [RR 2.30, 95% CI 1.94-2.72] or ischemic stroke [RR 2.50, 95% CI 2.29-2.72]; heterogeneity p < 0.0001). Obesity was associated with an increased risk of ischemic stroke and a decreased risk of hemorrhagic stroke (heterogeneity p < 0.0001). Meta-analyses confirmed the associations and the heterogeneity across the 3 types of stroke. CONCLUSION: Classic risk factors for stroke have considerably different effects on the 3 main pathologic types of stroke.

Specific and Non-specific Clinical Presentations in the Year Before the Diagnosis of Childhood Leukaemia.

INTRODUCTION: Clinical presentations of childhood leukaemia have been reported in case-only studies. The timing when these presentations start to occur prior to diagnosis is less clear. METHODS: In this nested case-control study, 1,025 and 334 children with lymphoid and myeloid leukaemia, respectively, were matched (1:30) to population-based controls by sex, region and year of birth. An index date was assigned for each control when the matched case was diagnosed. Healthcare access records of cases and controls in the year before the index date were extracted. RESULTS: Children with lymphoid leukaemia started to visit doctors more often at least 2 months before leukaemia diagnosis (P < 0.05). Various presentations were recorded in these visits: rates of haematological presentations, musculoskeletal presentations, and injuries started to increase significantly at least 3 months before diagnosis; rates of respiratory, gastrointestinal and urinary tract presentations did not increase significantly until the last month. The findings for myeloid lymphoma were less clear, but children appeared to visit doctors more often at least 4 months before diagnosis, and the rate of haematological presentations also started to increase at least 4 months before leukaemia diagnosis. Although haematological presentations were most strongly associated with undiagnosed leukaemia (odds ratio > 290 in the last month), the majority (>96%) of children with haematological presentations did not have leukaemia if they had not been diagnosed in their first visit. CONCLUSIONS: We described a clinical picture in the year before leukaemia diagnosis. These findings revealed ongoing difficulties in early diagnosis of childhood leukaemia in healthcare settings.

Body size in early life and risk of lymphoid malignancies and histological subtypes in adulthood.

Risk of adult lymphoid malignancy is associated with recent adiposity. Some have reported apparent associations with adiposity in childhood or early adulthood, but whether these associations are independent of recent adiposity is unknown. Birth weight, body size at age 10 years, clothes size at age 20 years, and recent body mass index (BMI) were recorded in 745,273 UK women, mean age 60.1 (SD 4.9) at baseline, without prior cancer. They were followed for 11 years, during which time 5,765 lymphoid malignancies occurred. Using Cox regression, a higher risk of lymphoid malignancy was strongly associated with higher recent BMI (RR=1.33, 95%CI 1.17-1.51, for BMI 35+ vs <22.5 kg/m(2)), and this association remained essentially unchanged after adjustment for birth weight and body size at 10. Higher lymphoid malignancy risk was also associated with large size at birth, at age 10, and at age 20 years, but after adjustment for recent BMI, the significance of the associations with large size at birth and at age 10 years was sufficiently reduced that residual confounding by adult BMI could not be excluded; a weak association with large size at 20 years remained (adjusted RR =1.17, 95%CI 1.10-1.24 for large size at age 20 vs. medium or small size). We found no strong evidence of histological specificity in any of these associations. In conclusion, our findings suggest a possible role of adiposity throughout adulthood in the risk of lymphoid malignancy, but the independent contribution of body size at birth and during childhood appears to be small.

Obesity in children: bariatric surgery.

INTRODUCTION: The prevalence of childhood obesity in the UK and in many countries worldwide remains high. Behavioural interventions to modify lifestyle, such as diet and physical activity, usually form part of weight management strategies for obese children. Whether or not surgical interventions are effective and safe in treating childhood obesity is unclear. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of surgical interventions for the treatment of childhood obesity? We searched Medline, Embase, The Cochrane Library, and other important databases up to August 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, after deduplication and removal of conference abstracts, 67 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 19 studies and the further review of 48 full publications. Of the 48 full articles evaluated, two systematic reviews were included at this update. CONCLUSIONS: In this systematic overview, we categorised the efficacy for two comparisons based on information about the effectiveness and safety of bariatric surgery versus no intervention and different types of bariatric surgery versus each other.

Tea and coffee and risk of endometrial cancer: cohort study and meta-analysis.

BACKGROUND: Previous reports, mostly from retrospective studies, suggested possible protective effects of both tea and coffee against endometrial cancer, but recent reports from prospective studies generally showed weaker or null associations. OBJECTIVES: We investigated endometrial cancer risk in relation to tea and coffee consumption in a large prospective study and did a meta-analysis of published results. DESIGN: Daily consumption of tea and coffee was recorded in 560,356 participants (without a hysterectomy) in the UK Million Women Study of whom 4067 women developed endometrial cancer during 5.2 million person-years of follow up (average: 9.3 y per woman). RESULTS: With the use of Cox proportional hazards regression, we showed no significant association between endometrial cancer risk and consumption of either tea (multivariate adjusted RR per cup daily: 1.00; 95% CI: 0.98, 1.02) or coffee (RR per cup daily: 0.98; 95% CI: 0.96, 1.01). Our meta-analyses showed no significant association between endometrial cancer risk and tea consumption and a weak association for coffee consumption in prospective studies, but there may have been selective publication of only part of the evidence. CONCLUSIONS: There is little or no association between tea consumption and endometrial cancer risk. If there is any association with coffee consumption, it appears to be weak.