Excess Cancer Risk Research Articles

Abstract 30: A pedigree-based approach to ovarian cancer risk variant discovery in the Utah Population Database

Abstract Introduction: Genetic risk variants are critical to risk prediction for invasive epithelial ovarian cancer (EOC), yet an estimated 50-55% of EOC heritability remains missing. Novel approaches to risk variant discovery are needed to detect variants that have not been uncovered by linkage analysis or genome-wide association studies (GWAS). We approach risk variant discovery using Shared Genomic Segment analysis (SGS), a novel statistical genetics method that enables risk variant discovery in extended high-risk pedigrees. Methods: The Utah Population Database (UPDB) is a population-based resource of over ten million individuals connected to the state of Utah, five million of whom are linked to a minimum of three generations of genealogy data. By linking this genealogy data with cancer data from the Utah Cancer Registry, we identified pedigrees with an excess risk of EOC. We generated germline genotyping data from cases (diagnosed 1983-2018) in a subset of these high-risk pedigrees, focusing on pedigrees well-suited for SGS (i.e., at least 3 cases separated by a total of at least 12 meioses). SGS identifies all runs of consecutive alleles that are shared identical-by-state by cases in a pedigree and determines which of these genomic segments are longer than would be expected by chance. These long segments are likely to be identical-by-descent, inherited from a common founder, and may harbor risk variants. Results: We successfully linked UPDB genealogy data to information from the Utah Cancer Registry to identify approximately 2,000 extended high-risk pedigrees with ≥5 ovarian cancer cases, an average of 7-10 meioses between pairs cases, and a statistically significant excess risk of ovarian cancer (α=0.05). We obtained biospecimens for 141 cases in 36 of the most promising pedigrees (i.e., high familial standardized incidence ratio, p-value<0.005, not attributable to known risk variants in BRCA1 or BRCA2 as observed in first-, second- or third-degree relatives of EOC cases). We genotyped 96 out of the 141 cases in these pedigrees (68%). SGS analyses to identify genomic regions that may harbor risk variants are currently underway. Conclusions: Using pedigrees identified in the UPBD, SGS has identified risk loci and novel risk variants for a number of diseases, including breast and hematologic cancers. We have identified a set of EOC high-risk pedigrees for SGS analysis and will leverage SGS to identify genomic regions that may harbor EOC risk variants. Citation Format: Mollie E. Barnard, Robert Sargent, G. Bryce Christensen, Bonita A. Mahaffey, James Albro, Elke A. Jarboe, Terence Rhodes, Nicola J. Camp, Jennifer A. Doherty. A pedigree-based approach to ovarian cancer risk variant discovery in the Utah Population Database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 30.

Sex disparity of lung cancer risk in non-smokers: a multicenter population-based prospective study based on China National Lung Cancer Screening Program.

Background:Non-smokers account for a large proportion of lung cancer patients, especially in Asia, but the attention paid to them is limited compared with smokers. In non-smokers, males display a risk for lung cancer incidence distinct from the females—even after excluding the influence of smoking; but the knowledge regarding the factors causing the difference is sparse. Based on a large multicenter prospective cancer screening cohort in China, we aimed to elucidate the interpretable sex differences caused by known factors and provide clues for primary and secondary prevention.Methods:Risk factors including demographic characteristics, lifestyle factors, family history of cancer, and baseline comorbidity were obtained from 796,283 Chinese non-smoking participants by the baseline risk assessment completed in 2013 to 2018. Cox regression analysis was performed to assess the sex difference in the risk of lung cancer, and the hazard ratios (HRs) that were adjusted for different known factors were calculated and compared to determine the proportion of excess risk and to explain the existing risk factors.Results:With a median follow-up of 4.80 years, 3351 subjects who were diagnosed with lung cancer were selected in the analysis. The lung cancer risk of males was significantly higher than that of females; the HRs in all male non-smokers were 1.29 (95% confidence interval [CI]: 1.20–1.38) after adjusting for the age and 1.38 (95% CI: 1.28–1.50) after adjusting for all factors, which suggested that known factors could not explain the sex difference in the risk of lung cancer in non-smokers. Known factors were 7% (|1.29–1.38|/1.29) more harmful in women than in men. For adenocarcinoma, women showed excess risk higher than men, contrary to squamous cell carcinoma; after adjusting for all factors, 47% ([1.30–1.16]/[1.30–1]) and 4% ([7.02–6.75]/[7.02–1])) of the excess risk was explainable in adenocarcinoma and squamous cell carcinoma. The main causes of gender differences in lung cancer risk were lifestyle factors, baseline comorbidity, and family history.Conclusions:Significant gender differences in the risk of lung cancer were discovered in China non-smokers. Existing risk factors did not explain the excess lung cancer risk of all non-smoking men, and the internal causes for the excess risk still need to be explored; most known risk factors were more harmful to non-smoking women; further exploring the causes of the sex difference would help to improve the prevention and screening programs and protect the non-smoking males from lung cancers.

Evaluation of Cancer Risks Associated with Radon Concentration Measured in the Science Faculty Building Complex Basement of a Tertiary Institution in South West, Nigeria

In this study, radon concentration was measured with an active detector (RAD 7) in the Science Faculty building complex basement of a tertiary institution in South West (SW), Nigeria. The attendant risk descriptors were determined with the help of mathematical models. The range of mean detectable radon concentration in the basement is 26.5 ±12.3 – 242 ± 50.7 Bq m-3 and the mean for all the rooms examined is 61.74 ± 58.48 Bq m-3. The overall mean is less than the global mean of 100 Bq m-3. The mean annual dose rate is found to be 0.97 ± 0.92 mSv y-1. The mean annual effective doses for different subjects examined are 0.412 ± 0.391 mSv y-1 (worker), 0.0221 ± 0.0209 mSv y-1 (student in lab session), 0.515 ± 0.488 mSv y-1 (student who lives in the hostel) and 2.149 ± 2.036 mSv y-1 (home owner). Students and workers in the basement are not likely to develop serious health effects, however, if the basement is used as a living room, the radon concentration in Room I-R might lead to health effects. The range of calculated excess life cancer risks (ELCRs) are (0.64-5.82) x 10-3 and (1.16 -10.58) x 10-3 for student and homeowner respectively. The mean values for the two subjects examined fall below the maximum risk of 3.5 x 10-3.

Risk of cancer in young and older patients with congenital heart disease and the excess risk of cancer by syndromes, organ transplantation and cardiac surgery: Swedish health registry study (1930-2017).

SummaryBackgroundIncreasing survival of patients with congenital heart disease (CHD) will result in an increased risk of age-dependent acquired diseases later in life. We aimed to investigate the risk of cancer in young and older patients with CHD and to evaluate the excess risk of cancer by syndromes, organ transplantation and cardiac surgery.MethodsPatients with CHD born between 1930 and 2017 were identified using Swedish Health Registers. Each patient with CHD (n = 89,542) was matched by sex and birth year with ten controls without CHD (n = 890,472) from the Swedish Total Population Register.Findings4012 patients with CHD (4·5%) and 35,218 controls (4·0%) developed cancer. The median follow-up time was 58·8 (IQR 42·4–69·0) years. The overall cancer risk was 1·23 times higher (95% confidence interval (CI) 1·19–1·27) in patients with CHD compared with matched controls, and remained significant when patients with syndromes and organ transplant recipients were excluded. The risk of cancer was higher in all CHD age groups, and in patients that underwent cardiac surgery during the first year after birth (Hazard Ratio 1·83; 95% CI 1·32–2·54). The highest risk was found in children (0–17 years), HR 3·21 (95% CI 2·90–3·56).InterpretationThe cancer risk in patients with CHD was 23% higher than in matched controls without CHD. The highest risk was found in children and in the latest birth cohort (1990–2017).FundingFunding by the Swedish state (Grant Number: 236611), the Swedish Research Council (Grant Number: 2019-00193), the Swedish Childhood Cancer Fund (Grant Number: SP2017-0012) and the Swedish Heart-Lung Foundation (Grant Number: 20190724).

P148 CANCER INCIDENCE AND MORTALITY ACCORDING TO PRE–EXISTING HEART FAILURE IN A COMMUNITY–BASED COHORT

Abstract Background Studies assessing whether heart failure (HF) is associated with an excess risk of cancer and cancer–related mortality yielded conflicting results. Here, we assessed the incidence and mortality of cancer according to the presence of HF in a community–based cohort. Methods By reviewing the health care records of the Puglia region in Italy, we first selected the individuals ≥50–year–old, with no history of cancer within 3 years before the baseline evaluation and ≥5 years of follow–up, during the period from January 1st, 2005 to December 31st, 2013. Next, we matched 1:1 104,020 subjects with HF at baseline and 104,020 controls based on age, sex, Drug–Derived Complexity Index, and follow–up duration. Cancer incidence and mortality were analyzed by Kaplan–Meier method and Cox regression models. Fine and Grey’s regression model was also used to compare cancer–specific mortality while taking into account the competing risk of non–cancer death. Results Overall, the mean age of the study population was 76±10 years and the mean follow–up was 5.7 years. The incidence rate of cancer in HF patients and controls was 21.36 (95%CI, 20.98–21.74) and 12.42 (95%CI, 12.14–12.72) per 1000 person/years, respectively, corresponding to a 76% higher risk of incident cancer in HF patients (HR, 1.76; 95%CI, 1.71–1.81). HF patients also died from cancer more frequently than controls (HR 4.11; 95%CI, 3.86–4.38; Figure 1). This excess mortality was highest when age was <70 years (HR 7.54, 95%CI 6.33–8.98), and declined in subjects aged 70–79 years (HR 3.80, 95%CI 3.44–4.19) and ≥80 years (HR 3.10, 95%CI 2.81–3.43). The association of HF with cancer mortality was confirmed in the competing risk analysis (subdistribution HR 3.48, 95%CI 3.27–3.72), as well as the interaction with age: <70 years of age: SHR 6.65, 95%CI 5.60–7.94; 70–80 years: SHR 3.14, 95%CI 2.84–3.48; and ≥80 years: SHR 2.81, 95%CI 2.55–3.10. The HF–related risk applied to the majority of cancer types. Interestingly, among HF patients a high consumption of loop diuretic (≥80 mg/d of furosemide equivalents for ≥30 days in the year before the index date) was associated with a higher mortality for cancer (HR 1.35, 95%CI 1.19–1.53 vs. ≤37.5 mg/d). Conclusions The analysis of this large community–based sample suggests that HF does portend an increased risk of cancer and cancer–related mortality, which is blunted, yet remains substantial, with increasing age and competing risk of dying from other causes.

Cancer Risk and Diesel Exhaust Exposure Among Railroad Workers

Inhalation exposure to diesel exhaust in the railroad work environment causes significant and quantifiable cancer risks to many railroad workers. Diesel exhaust has been identified as a known human carcinogen by the International Agency for Research on Cancer (“IARC”) and as a potential carcinogen by the United States Environmental Protection Agency (“USEPA”), the California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (“OEHHA”), and the National Institute for Occupational Safety & Health (“NIOSH”). Peer-reviewed literature defines the ambient air concentrations of diesel exhaust for several railroad occupations as being above environmental background levels. This study uses diesel exhaust concentrations in the railroad work environment in conjunction with the USEPA’s Integrated Risk Information System (“IRIS”) risk assessment methodology to quantify the cancer risk posed to railroad workers due to occupational inhalation exposure to diesel exhaust. NIOSH Bulletin 68 (2017) states that there is “no known safe level” of exposure to carcinogens and recommends an evaluation of the USEPA’s IRIS guidance to evaluate quantitative risk assessment of human exposure to occupational carcinogens. This is the first study to utilize USEPA methodology to calculate the excess lung cancer risk caused by railroad workers’ cumulative exposure to diesel exhaust.

Likely uptake of a future lung cancer screening programme in Hodgkin lymphoma survivors: a questionnaire study

BackgroundMany Hodgkin lymphoma (HL) survivors are at increased risk of subsequent malignant neoplasms (SMN), including lung cancer, due to previous treatment for HL. Lung cancer screening (LCS) detects early-stage lung cancers in ever smokers but HL survivors without a heavy smoking history are ineligible for screening. There is a rationale to develop a targeted LCS. The aim of this study was to investigate levels of willingness to undergo LCS in HL survivors, and to identify the psycho-social factors associated with screening hesitancy.MethodsA postal questionnaire was sent to 281 HL survivors registered in a long-term follow-up database and at increased risk of SMNs. Demographic, lung cancer risk factors, psycho-social and LCS belief variables were measured. Multivariable logistic regression analysis was performed to determine the factors associated with lung cancer screening hesitancy, defined as those who would ‘probably’ or ‘probably not’ participate.ResultsThe response rate to the questionnaire was 58% (n = 165). Participants were more likely to be female, older and living in a less deprived area than non-participants. Uptake (at any time) of breast and bowel cancer screening among those previously invited was 99% and 77% respectively. 159 participants were at excess risk of lung cancer. The following results refer to these 159. Around half perceived themselves to be at greater risk of lung cancer than their peers. Only 6% were eligible for lung cancer screening pilots aimed at ever smokers in the UK. 98% indicated they would probably or definitely participate in LCS were it available. Psycho-social variables associated with LCS hesitancy on multivariable analysis were male gender (OR 5.94 CI 1.64–21.44, p < 0.01), living in an area with a high index of multiple deprivation decile (deciles 6–10) (OR 8.22 CI 1.59–42.58, p < 0.05) and lower levels of self-efficacy (OR 1.64 CI 1.30–2.08 p < 0.01).ConclusionHL survivors responding to this survey were willing to participate in a future LCS programme but there was some hesitancy. A future LCS trial for HL survivors should consider the factors associated with screening hesitancy in order to minimise barriers to participation.

Occurrence, Distribution and Risk Assessment of PAHs in Road Dust Sediment in Daejeon Metropolitan City, South Korea

In this study, the occurrence and distribution of polycyclic aromatic hydrocarbons (PAHs) in road dust sediment(RDS) deposited from main traffic roads as well as residential and industrial areas were examined with a total of 144 samples in seasons. Based on the results, the concentrations of PAHs were found to be higher in winter and ranged between 0.15 and 1.94 mg/kg with an average of 0.65 mg/kg. The results indicate that pyrene, fluoranthene, phenanthrene, and benzo(ghi)perylene were commonly found in RDS, likely originated from vehicle exhaust emissions and fuel combustion by the diagnostic ratio study. Non-cancer risk from PAHs for humans exposed to RSD was found to be low (HI 1.2E-05). The estimated excess cancer risks by PAHs in RDS was also much less than the regulatory guideline for cancer risk (1×10-6). Thus, current concentrations of PAHs in RDS are expected to be pose no threat to humans under the assumed exposure scenarios with applied exposure factors. However, more extensive and long-term sample analysis for gaseous and particulate PAHs is still warranted to determine potential risks to humans and the fate in the environment, since their concentration and distribution can be influenced by micro-metrological conditions, traffic volumes, or road clean-up conditions.

222Rn Activity Concentration Measurement and its Radiological Risks in the Environment of Barserin Village, Erbil-Iraq

222Rn Activity Concentration Measurement and its Radiological Risks in the Environment of Barserin Village, Erbil-Iraq

Radiological Health Risk from Gamma Radiation of Coastal Communities in Okrika Local Government Area of Rivers State, Nigeria

In-situ measurement of background ionization radiation was carried out in coastal communities of Okrika Local Government Area. This field work was achieved with the use of Digilert 200 to record the background ionization radiation and global positioning system in taking the coordinates of the sampled Locations. The exposure rate ranged from 0.010 to 0.017 with a mean value of 0.0122+ 0.03, which is quite lower than the acceptable limit of 0.0133 . The absorbed dose varied from 85.70 nGy/h to 140.9 nGy/h with a mean value of 108.3+23.34 nGy/h. The mean value was a little higher than the world average of 89.0 nGy/h. The annual effective dose ranged from 0.13 mSv/y to 0.23 mSv/y with an overall mean of 0.1611+0.04 mSv/y. The overall mean value obtained was found to be lesser that the acceptable limit of 1.0 ms/y . The excess life cancer risk ranged from 0.47 x to 0.79 x with overall mean of 0.57+ 0.12 which is higher than the world average of 0.29 x . The study area is free from radiological hazards, even though there is no visible adverse effect on the populace, it is strongly recommended that companies and oil activities within the study area should be properly monitored to ensure that the populace and environment are free from radiological hazards, by ensuring that all forms of radiation exposure to both man and the environment should be kept as low as reasonably achievable.

Low-dose ionizing radiation and cancer mortality among enlisted men stationed on nuclear-powered submarines in the United States Navy

Background Men stationed on nuclear-powered submarines are occupationally exposed to external ionizing radiation at very low levels and radiation dose for each individual is closely monitored. Little is known about ionizing radiation (IR) risks of cancer mortality for populations with levels of cumulative ionizing radiation exposure this low. Materials and methods This historical cohort study followed 85,033 enlisted men who had served on a nuclear-powered submarine in the U.S. Navy between 1969 and 1982 to determine patterns of cancer mortality. Occupational radiation doses were measured by badge dosimeters for each individual for all periods of Navy service potentially involving radiation exposure. Deaths were ascertained through 1995 by searches of multiple national mortality databases. Within-cohort dose-response relationships for cancer mortality were estimated using linear Poisson regression models. Individual-level smoking status was not available so cancer risks were estimated separately for cancers with and without previously published evidence of consistently moderate or strong associations with smoking. Results A total of 584 cancer deaths occurred during a follow-up period of up to 27 years. The mean and median cumulative occupational radiation doses received while in the Navy were 5.7 and 1.1 milliSieverts (mSv), respectively, range 0–242 mSv. Mortality Excess Relative Risks (ERRs) per 10 mSv and 95% confidence intervals (CI) were 0.053 (CI −0.03, 0.17) for all cancers, 0.052 (CI −0.03, 0.18) for all solid cancers, and 0.003 (CI −0.29, 0.30) for leukemias excluding chronic lymphocytic leukemia. The ERRs per 10 mSv were 0.052 (CI −0.07, 0.17) for cancers previously associated with smoking and 0.012 (CI −0.10, 0.12) for cancers that were not. Conclusions The ERR point estimates for solid cancers and leukemia were statistically compatible with those reported in previously published studies of other ionizing radiation-exposed and monitored cohorts, albeit with wide confidence intervals. This study, with high-quality measurements of in-Navy occupational external IR doses, high follow-up proportion, and detailed IR dose-response analyses, is consistent with the premise of small excess cancer risks from low-dose IR.

Investigation and mapping of natural and artificial radioactivity in sediment samples from Borçka Black Lake, Artvin-Turkey

ABSTRACT All living creatures in nature are constantly exposed to ionising radiation, which is emitted from natural and artificial radiation sources. For this reason, it is important to monitor the levels of radioactivity in living spaces and visited areas. In this study, natural (238U, 232Th, 40K) and artificial (137Cs) radioactivity concentrations in sediment samples taken from Borçka Black Lake located on the Nature Park in Artvin province were determined using a high purity germanium detector (HPGe). It was determined that 238U, 232Th, 40K and 137Cs radioisotope concentrations in the sediment samples varied between 8.73 and 26.45, 7.01 and 22.98, 289.92 and 578.98, and 6.26 and 70.96 Bq kg−1, respectively. Mean radioactivity concentrations were found to be 14.99 ± 0.89 Bq kg−1 for 238U, 13.85 ± 1.10 Bq kg−1 for 232Th, 473.67 ± 14.21 Bq kg−1 for 40K and 35.06 ± 0.96 Bq kg−1 for 137Cs. In order to evaluate the radiological hazards, radium equivalent activity, external hazard index, absorbed dose rate in the air, the annual effective dose rate and excess life time cancer risk were calculated and compared with the values recommended by international organisations. As a result, it has been shown with this study that the radioactivity caused by the examined radioisotopes will not pose any health risk for the visitors of Borçka Black Lake.

Probabilistic health risk assessment and monetization based on benzene series exposure in newly renovated teaching buildings

To meet the needs of the rapid development of education, there have been growing investments in the issue of university infrastructures. However, few studies have paid attention to the assessment and monetization of health risks in newly renovated teaching buildings. In this study, concentrations of the benzene series (BTEX) group were measured in five areas of three newly renovated teaching buildings. A total of 135 BTEX samples were collected using passive diffusion monitors and analyzed by GC–FID. Human health risk assessments were conducted by using probabilistic methods for four types of population exposure to BTEX. The results showed that the cancer risk of benzene accounted for most of the total in each group. There was over 90% probability of excess cancer risks in the areas within the tested buildings; and the non-cancer risks were all within the acceptable level. The health risks of men were greater than those of women, and those of teachers were higher than those of students. The model calculation results of Disability-Adjusted Life Year (DALY) and Willingness to Pay (WTP) indicated that the average price that society was willing to pay to offset the health damage caused in these newly renovated teaching buildings was 381.35 yuan/year. For the first time, this study highlights the health risks of newly built teaching buildings in universities, points out the urgent need to improve the control of BTEX sources in this type of indoor environment; moreover, it provides theoretical support for the society and occupational protection departments to compensate for the health damage to professionals.

Atmospheric levels, distribution, sources, correlation with meteorological parameters and other pollutants and health risk of PAHs bound in PM2.5 and PM10 in Burgas, Bulgaria – a case study

The quality of atmospheric air of Burgas city, Bulgaria was analyzed in relation to PAHs in two particulate matter fractions – 2.5 μm and 10 μm. It was found that PAHs registered in PM10 represent entirely the ones registered in PM2.5 – an indication that the particulate PAHs in ambient air of Burgas for the sampling period are associated with the fine PM fraction. The PAH compounds with highest concentrations are mainly associated with coal combustion, diesel and gasoline vehicle and biomass burning, which is further confirmed by the calculated diagnostic ratios. The combustion-derived PAHs represent on average 86.6 ± 2.8% of total PAHs concentration. The linear regression analysis showed strong and statistically meaningful correlations between PM fractions and PAHs indicating the influence of similar local events and emission sources of pollution. PM2.5 or PM10 relationships with PAHs were significant but lower correlation coefficients were observed for low-molecular weight (LMW) PAHs in comparison to middle-molecular weight (MMW) and higher-molecular weight (HMW) PAHs, due to their lower presence in particulates and higher partition in gaseous atmospheric phase. Further significant correlations were found with wind speed, solar radiation and atmospheric pressure as well as NO2 and O3 ambient concentration. The calculated excess cancer risks are twice as much as acceptable limit.

CD4/CD8 Ratio and Cancer Risk Among Adults With HIV.

Independent of CD4 cell count, a low CD4/CD8 ratioin people with HIV (PWH) is associated with deleterious immune senescence, activation, and inflammation, which may contribute to carcinogenesis and excess cancer risk. We examined whether low CD4/CD8 ratios predicted cancer among PWH in the United States and Canada. We examined all cancer-free PWH with 1 or more CD4/CD8 values from North American AIDS Cohort Collaboration on Research and Design observational cohorts with validated cancer diagnoses between 1998 and 2016. We evaluated the association between time-lagged CD4/CD8 ratio and risk of specific cancers in multivariable, time-updated Cox proportional hazard models using restricted cubic spines. Models were adjusted for age, sex, race and ethnicity, hepatitis C virus, and time-updated CD4 cell count, HIV RNA, and history of AIDS-defining illness. Among 83 893 PWH, there were 5628 incident cancers, including lung cancer (n = 755), Kaposi sarcoma (n = 501), non-Hodgkin lymphoma (n = 497), and anal cancer (n = 439). The median age at cohort entry was 43 years. The overall median 6-month lagged CD4/CD8 ratio was 0.52 (interquartile range = 0.30-0.82). Compared with a 6-month lagged CD4/CD8 of 0.80, a CD4/CD8 of 0.30 was associated with increased risk of any incident cancer (adjusted hazard ratio = 1.24 [95% confidence interval = 1.14 to 1.35]). The CD4/CD8 ratio was also inversely associated with non-Hodgkin lymphoma, Kaposi sarcoma, lung cancer, anal cancer, and colorectal cancer in adjusted analyses (all 2-sided P < .05). Results were similar using 12-, 18-, and 24-month lagged CD4/CD8 values. A low CD4/CD8 ratio up to 24 months before cancer diagnosis was independently associated with increased cancer risk in PWH and may serve as a clinical biomarker.

Inflammatory bowel disease and risk of adenocarcinoma and neuroendocrine tumors in the small bowel

Uncertainty prevails about the magnitude of excess risk of small bowel cancer in patients with inflammatory bowel disease (IBD). To quantify the risk of small bowel adenocarcinoma and neuroendocrine tumors in patients with ulcerative colitis (UC) and Crohn's disease (CD), we undertook a population-based cohort study of all patients with IBD diagnosed in Norway and Sweden from 1987 to 2016. Patients were followed through linkage to national registers. We calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) of small bowel adenocarcinomas and neuroendocrine tumors for patients with CD and UC. We excluded the first year of follow-up to reduce reverse causality. Among 142008 patients with a median follow-up of 10.0 years, we identified 66 adenocarcinomas and 57 neuroendocrine tumors in the small bowel. The SIR of small bowel adenocarcinoma was 8.3 (95% CI 5.9-11.3) in CD and 2.0 (95% CI 1.2-3.1) in UC. The incidence rates of adenocarcinomas were highest in CD with stricturing disease and extent limited to the small bowel, at 14.7 (95% CI 8.2-24.2) and 15.8 (95% CI 8.4-27.0) per 100000 person-years, respectively. The SIR of neuroendocrine tumors was 2.5 (95% CI 1.5-3.9) in CD and 2.0 (95% CI 1.4-2.8) in UC. Patients with CD experienced an eightfold increased risk of small bowel adenocarcinomas, patients with both UC and CD experienced an about twofold increased risk of neuroendocrine tumors, and patients with UC experienced a twofold increased risk of small bowel adenocarcinoma. The small absolute excess cancer risk suggests that active surveillance to diagnose small intestinal cancer early is unlikely to be cost-effective.

Biological and cellular responses of humans to high-level natural radiation: A clarion call for a fresh perspective on the linear no-threshold paradigm

There remains considerable uncertainty in obtaining risk estimates of adverse health outcomes of chronic low-dose radiation. In the absence of reliable direct data, extrapolation through the linear no-threshold (LNT) hypothesis forms the cardinal tenet of all risk assessments for low doses (≤ 100 mGy) and for the radiation protection principle of As Low As Reasonably Achievable (ALARA). However, as recent evidences demonstrate, LNT assumptions do not appropriately reflect the biology of the cell at the low-dose end of the dose-response curve. In this regard, human populations living in high-level natural radiation areas (HLNRA) of the world can provide valuable insights into the biological and cellular effects of chronic radiation to facilitate improved precision of the dose-response relationship at low doses. Here, data obtained over decades of epidemiological and radiobiological studies on HLNRA populations is summarized. These studies do not show any evidence of unfavourable health effects or adverse cellular effects that can be correlated with high-level natural radiation. Contrary to the assumptions of LNT, no excess cancer risks or untoward pregnancy outcomes have been found to be associated with cumulative radiation dose or in-utero exposures. Molecular biology-driven studies demonstrate that chronic low-dose activates several cellular defence mechanisms that help cells to sense, recover, survive, and adapt to radiation stress. These mechanisms include stress-response signaling, DNA repair, immune alterations and most importantly, the radiation-induced adaptive response. The HLNRA data is consistent with the new evolving paradigms of low-dose radiobiology and can help develop the theoretical framework of an alternate dose-response model. A rational integration of radiobiology with epidemiology data is imperative to reduce uncertainties in predicting the potential health risks of chronic low doses of radiation.

Risk of cancer with angiotensin-receptor blockers increases with increasing cumulative exposure: Meta-regression analysis of randomized trials.

Angiotensin-receptor blockers (ARBs) are a class of drugs approved for the treatment of several common conditions, such as hypertension and heart failure. Recently, regulatory agencies have started to identify possibly carcinogenic nitrosamines and azido compounds in a multitude of formulations of several ARBs, resulting in progressive recalls. Furthermore, data from several randomized controlled trials suggested that there is also a clinically increased risk of cancer and specifically lung cancer with ARBs; whereas other trials suggested no increased risk. The purpose of this analysis was to provide additional insight into the ARB-cancer link by examining whether there is a relationship between degree of cumulative exposure to ARBs and risk of cancer in randomized trials. Trial-level data from ARB Trialists Collaboration including 15 randomized controlled trials was extracted and entered into meta-regression analyses. The two co-primary outcomes were the relationship between cumulative exposure to ARBs and risk of all cancers combined and the relationship between cumulative exposure and risk of lung cancer. A total of 74,021 patients were randomized to an ARB resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent). 61,197 patients were randomized to control. There was a highly significant correlation between the degree of cumulative exposure to ARBs and risk of all cancers combined (slope = 0.07 [95% CI 0.03 to 0.11], p<0.001), and also lung cancer (slope = 0.16 [95% CI 0.05 to 0.27], p = 0.003). Accordingly, in trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk of all cancers combined (I2 = 31.4%, RR 1.11 [95% CI 1.03 to 1.19], p = 0.006). There was a statistically significant increase in risk of lung cancers in trials where the cumulative exposure was greater than 2.5 years (I2 = 0%, RR 1.21 [95% CI 1.02 to 1.44], p = 0.03). In trials with lower cumulative exposure to ARBs, there was no increased risk of all cancers combined or lung cancer. Cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme inhibitor treatment or the type of control (i.e. placebo or non-placebo control). Since this is a trial-level analysis. the effects of patient characteristics such as age and smoking status could not be examined due to lack of patient-level data. In conclusion, this analysis, for the first time, reveals that risk of cancer with ARBs (and specifically lung cancer) increases with increasing cumulative exposure to these drugs. The excess risk of cancer with long-term ARB use has public health implications.

De Novo Malignancies after Kidney Transplantation.

Cancer is an important outcome after kidney transplantation because it is the second leading cause of death in most Western countries. The excess risk of cancer after transplantation is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers. Once cancer develops, outcomes are generally poor, particularly for those with melanoma, renal cell carcinoma, and post-transplant lymphoproliferative disease. More importantly, effective screening and treatment strategies are limited in this high-risk population. In this review, we begin with a patient's journey that maps the experience of living with a kidney transplant and understand the patient's knowledge, education, and experience of cancer in the context of transplantation. The epidemiology and burden of cancer in recipients of kidney transplants, along with the up-to-date screening and treatment strategies, are discussed. We also focus on the current understanding of optimal care for recipients of kidney transplants who are living with cancer from the patients' perspectives.

Excess morbidity and mortality among survivors of childhood acute lymphoblastic leukaemia: 25 years of follow-up from the United Kingdom Childhood Cancer Study (UKCCS) population-based matched cohort

ObjectivesTo examine morbidity and mortality among teenagers and young adults (TYAs) previously diagnosed with acute lymphoblastic leukaemia (ALL) in childhood, and compare to the general TYA population.DesignNational population-based sex-matched and...