New onset sarcoid-like granulomatosis developing during anti-TNF therapy: an under-recognised complication.

Tumour necrosis factor-alpha (TNF-a) antagonists have advanced the treatment of inflammatory arthropathies, and are even considered for use in refractory sarcoidosis with some success. Paradoxically, cases of new onset sarcoidosis-like diseases are increasingly reported in patients receiving TNF-a antagonists. Here, we report three cases of sarcoid-like granulomatosis that developed during treatment with TNF-a antagonists. Review of the Biologics clinic data base at Westmead, Sydney, Australia identified three patients whom, during anti-TNF therapy, developed non-caseating granulomas consistent with sarcoidosis. These three cases are described with review of the literature from 2000 to 2009 using PubMed. One hundred and sixty-nine patients within our data base were reviewed for the period 2003­2009. Sarcoidosis-like granulomas developed in three patients within a period of 3 to 36 months of treatment with etanercept and/or adalimumab. All cases demonstrated non-infective, non-caseating granulomas on renal or lymph node biopsy. Improvement was seen in two cases upon cessation of TNF-a antagonist and steroid therapy. Interestingly, clinical deterioration was noted upon re-challenge with the same TNF-a antagonist in one patient. To date, a total of 37 cases of sarcoid-like granuloma development after anti-TNF therapy have been reported in the literature. Development of sarcoidosis-like granulomatosis in patients treated with TNF-a antagonists is a phenomenon previously under-recognised. All three anti-TNF agents have been observed to cause this phenomenon, suggesting a 'class effect' rather than being drug specific.

99mTc-labelled glucosamine in the assessment of systemic sclerosis inflammatory lung disease: a novel inexpensive investigative tool with predictive value.

OBJECTIVE: To evaluate the role of 99mTc-labelled glucosamine [99mTc-ECDG] as a clinical biomarker for the early detection of interstitial lung disease (ILD) in systemic sclerosis (SSc). METHODS: In this prospective pilot study, glucosamine scanning (GS) was performed in 15 SSc patients, with and without ILD. Collected data included patient disease characteristics, autoantibody profile, GS results, high-resolution computerised tomography [HRCT], pulmonary function tests [PFT], and transthoracic echocardiogram [TTE]. Glucosamine results were correlated with patient clinical profile, HRCT, and PFT's findings. RESULTS: Lung uptake of 99mTc-ECDG was high in 4 patients, moderate in 3, mild in 5, and normal in 3 with SSc, respectively. Of the patients with high and moderate uptake there was a 100% correlation between 99mTc-ECDG uptake and HRCT showing ILD. Of the 5 patients with mild 99mTc-ECDG uptake, 4 patients had aspiration pneumonia, and 1 had early ILD using HRCT. Of the 3 patients with normal 99mTc-ECDG, 2 had normal HRCTs; the third had severe pulmonary arterial hypertension with minimal HRCT changes of ILD. High and moderate 99mTc-ECDG lung uptake predicted abnormal PFT's in 100% of cases. In 3 patients, there was less extensive disease depicted on the 99mTc-ECDG scans than on the HRCT. These patients demonstrated a more favourable outcome than would have been expected from the HRCT scans alone. Mild 99mTc-ECDG lung uptake correlated with abnormal PFT's in 60% of cases. The pattern of 99mTc-ECDG uptake was excellent (100%) at distinguishing metabolically active ILD from aspiration pneumonia. Diffuse uptake was noted in the former and patchy uptake in the latter disease entity. CONCLUSION: Increased 99mTc-ECDG uptake in scleroderma lung correlated positively with both structural and functional changes. 99mTc-ECDG is a useful adjunct helping elucidate inflammation secondary to aspiration pneumonia and/or other causes of abnormal PFT's.

Methotrexate: long-term safety and efficacy in an Australian consultant rheumatology practice.

BACKGROUND: The aim of this study was to evaluate the rate and cause of methotrexate (MTX) termination in clinical practice, describe the types of toxicities noted, assess the incidence of achieving remission in rheumatoid arthritis (RA) patients and review the appropriateness of current clinical guidelines for monitoring MTX treatment. METHODS: A retrospective, case review of patients seen in a private rheumatology practice attached to a major Sydney Teaching Hospital was undertaken over an 18-year period. The primary outcome was time to cessation of MTX. RESULTS: Seven hundred and ninety patients satisfied the inclusion criteria. MTX was terminated in 272 patients (34.4%). Toxicity-related discontinuation occurred in 93 patients (11.8%) and due to non-adverse reactions in 179 patients. The median duration of therapy in these two groups was 2.0 and 2.9 years, respectively. There was no difference in the average maximum weekly dose of MTX. Of patients with RA, 47.5% were in remission at last follow up. Cox proportional hazards analyses showed that those of the female sex remained on treatment significantly longer than the male sex (hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.57-0.96; P = 0.014); patients with RA remained on treatment significantly longer than patients with seronegative arthritis (HR 0.56, 95%CI 0.42-0.74; P < 0.001). Being of the male sex aged more than 60 years and having a non-RA diagnosis predisposed to stopping MTX earlier. CONCLUSION: MTX is a safe and effective medication. Notable remission rates are achievable in patients with RA with current conventional treatment protocols. MTX has a low toxicity profile and this study stresses the need to re-evaluate and revise the current monitoring guidelines.

The Ukrainian-American study of leukemia and related disorders among Chornobyl cleanup workers from Ukraine: I. Study methods.

There are relatively few data on the risk of leukemia among those exposed to external radiation during cleanup operations after the Chornobyl nuclear accident, and results have not been consistent. To investigate this further, we assembled a cohort of 110,645 male cleanup workers from Ukraine and identified cases of leukemia occurring during the period 1986 to 2000. Detailed interviews were conducted and individual bone marrow doses estimated using a new time-and-motion method known as RADRUE described in companion paper II. For the initial analyses we used a nested case-control approach with a minimum of five controls per case, matched for year of birth, oblast (region) of registration, and residence. All identified cases were reviewed by an international panel of experts; 87 of 111 were confirmed. The dose-response analysis and results are given in companion paper III. As background, we describe herein the design, procedures, outcome of case finding and confirmation, control selection, dose estimation and interviewing of subjects.

Mortality from diseases other than cancer following low doses of ionizing radiation: results from the 15-Country Study of nuclear industry workers.

BACKGROUND: Ionizing radiation at very high (radio-therapeutic) dose levels can cause diseases other than cancer, particularly heart diseases. There is increasing evidence that doses of the order of a few sievert (Sv) may also increase the risk of non-cancer diseases. It is not known, however, whether such effects also occur following the lower doses and dose rates of public health concern. METHODS: We used data from an international (15-country) nuclear workers cohort study to evaluate whether mortality from diseases other than cancer is related to low doses of external ionizing radiation. Analyses included 275 312 workers with adequate information on socioeconomic status, over 4 million person-years of follow-up and an average cumulative radiation dose of 20.7 mSv; 11 255 workers had died of non-cancer diseases. RESULTS: The excess relative risk (ERR) per Sv was 0.24 [95% CI (confidence intervals) -0.23, 0.78] for mortality from all non-cancer diseases and 0.09 (95% CI -0.43, 0.70) for circulatory diseases. Higher risk estimates were observed for mortality from respiratory and digestive diseases, but confidence intervals included zero. Increased risks were observed among the younger workers (attained age <50 years, identified post hoc) for all groupings of non-cancer causes of death, including external causes. It is unclear therefore whether these findings reflect real effects of radiation, random variation or residual confounding. CONCLUSIONS: The most informative low-dose radiation study to date provides little evidence for a relationship between mortality from non-malignant diseases and radiation dose. However, we cannot rule out risks per unit dose of the same order of magnitude as found in studies at higher doses.

The 15-Country Collaborative Study of Cancer Risk Among Radiation Workers in the Nuclear Industry: design, epidemiological methods and descriptive results.

Radiation protection standards are based mainly on risk estimates from studies of atomic bomb survivors in Japan. The validity of extrapolations from the relatively high-dose acute exposures in this population to the low-dose, protracted or fractionated environmental and occupational exposures of primary public health concern has long been the subject of controversy. A collaborative retrospective cohort study was conducted to provide direct estimates of cancer risk after low-dose protracted exposures. The study included nearly 600,000 workers employed in 154 facilities in 15 countries. This paper describes the design, methods and results of descriptive analyses of the study. The main analyses included 407,391 nuclear industry workers employed for at least 1 year in a participating facility who were monitored individually for external radiation exposure and whose doses resulted predominantly from exposure to higher-energy photon radiation. The total duration of follow-up was 5,192,710 person-years. There were 24,158 deaths from all causes, including 6,734 deaths from cancer. The total collective dose was 7,892 Sv. The overall average cumulative recorded dose was 19.4 mSv. A strong healthy worker effect was observed in most countries. This study provides the largest body of direct evidence to date on the effects of low-dose protracted exposures to external photon radiation.

The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: estimates of radiation-related cancer risks.

A 15-Country collaborative cohort study was conducted to provide direct estimates of cancer risk following protracted low doses of ionizing radiation. Analyses included 407,391 nuclear industry workers monitored individually for external radiation and 5.2 million person-years of follow-up. A significant association was seen between radiation dose and all-cause mortality [excess relative risk (ERR) 0.42 per Sv, 90% CI 0.07, 0.79; 18,993 deaths]. This was mainly attributable to a dose-related increase in all cancer mortality (ERR/Sv 0.97, 90% CI 0.28, 1.77; 5233 deaths). Among 31 specific types of malignancies studied, a significant association was found for lung cancer (ERR/Sv 1.86, 90% CI 0.49, 3.63; 1457 deaths) and a borderline significant (P = 0.06) association for multiple myeloma (ERR/Sv 6.15, 90% CI <0, 20.6; 83 deaths) and ill-defined and secondary cancers (ERR/Sv 1.96, 90% CI -0.26, 5.90; 328 deaths). Stratification on duration of employment had a large effect on the ERR/Sv, reflecting a strong healthy worker survivor effect in these cohorts. This is the largest analytical epidemiological study of the effects of low-dose protracted exposures to ionizing radiation to date. Further studies will be important to better assess the role of tobacco and other occupational exposures in our risk estimates.

Autoimmune thyroiditis and exposure to iodine 131 in the Ukrainian cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident: results from the first screening cycle (1998-2000).

CONTEXT: Due to the Chornobyl accident, millions were exposed to radioactive isotopes of iodine and some received appreciable iodine 131 (131I) doses. A subsequent increase in thyroid cancer has been largely attributed to this exposure, but evidence concerning autoimmune thyroiditis (AIT) remains inconclusive. OBJECTIVE: The objective of the study was to quantify risk of AIT after 131I exposure. DESIGN/SETTING/PARTICIPANTS: Baseline data were collected from the first screening cycle (1998-2000) of a large cohort of radiation-exposed individuals (n = 12,240), residents of contaminated, iodine-deficient territories of Ukraine. Study individuals were under the age of 18 yr on April 26, 1986, and had thyroid radioactivity measurements made shortly after the accident. OUTCOMES: AIT was defined a priori based on various combinations of elevated antibodies to thyroid peroxidase (ATPO), TSH, and clinical findings; elevated ATPO were considered to be an indicator of thyroid autoimmunity. RESULTS: No significant association was found between 131I thyroid dose estimates and AIT, but prevalence of elevated ATPO demonstrated a modest, significant association with 131I that was well described by several concave models. This relationship was apparent in individuals with moderately elevated ATPO and euthyroid, thyroid disease-free individuals. CONCLUSIONS: Twelve to 14 yr after the Chornobyl accident, no radiation-related increase in prevalence of AIT was found in a large cohort study, the first in which 131I thyroid doses were estimated using individual radioactivity measurements. However, a dose-response relationship with ATPO prevalence raises the possibility that clinically important changes may occur over time. Thus, further follow-up and analysis of prospective data in this cohort are necessary.

Post-Chernobyl thyroid cancers in Ukraine. Report 2: risk analysis.

On April 26, 1986, the worst nuclear reactor accident to date occurred at the Chornobyl (Chernobyl) power plant in Ukraine. Millions of people in Ukraine, Belarus and Russia were exposed to radioactive nuclides, especially (131)I. Since then, research has been conducted on various subgroups of the exposed population, and it has been demonstrated that the large increase in thyroid cancer is related to the (131)I exposure. However, because of study limitations, quantified risk estimates are limited, and there remains a need for additional information. We conducted an ecological study to investigate the relationship between (131)I thyroid dose and the diagnosis of thyroid cancer in three highly contaminated oblasts in Northern Ukraine. The study population is comprised of 301,907 persons who were between the ages of 1 and 18 at the time of the Chornobyl accident and were living in 1,293 rural settlements in the three study oblasts. Twenty-four percent of the study population had individual thyroid dose estimates and the other 76% had "individualized" estimates of thyroid dose based on direct thyroid measurements taken from a person of the same age and gender living in the same or nearby settlement. Cases include 232 thyroid cancers diagnosed from January 1990 through December 2001, and all were confirmed histologically. Dose-response analyses took into account differences in the rate of ultrasound examinations conducted in the three study oblasts. The estimated excess relative risk per gray was 8.0 (95% CI = 4.6-15) and the excess absolute risk per 10,000 person-year gray was estimated to be 1.5 (95% CI = 1.2-1.9). In broad terms, these estimates are compatible with results of other studies from the contaminated areas, as well as studies of external radiation exposure.

A follow-up study of a ten-percent sample of the Canadian labor force. I. Cancer mortality in males, 1965-73.

A system is described for monitoring the mortality experience of an approximately 10% sample of the Canadian Labor Force with the use of computerized record linkage to the Canadian mortality data base. Results are presented for the 4,203 cancer deaths that occurred between 1965 and 1973 in 415,201 males with known occupational histories from 1965 to 1969. A number of previously suggested associations between certain occupations and cancers have been confirmed in these results, and a number of new associations also have been observed. The system provides a powerful tool for both generating and testing hypotheses, and this power will increase as further mortality experience is accumulated by the cohort.

Age at first pregnancy and risk of colorectal cancer: a case-control study.

Results from a case-control study of colorectal cancer conducted in Toronto and Calgary, Canada, are reported with respect to pregnancy-related variables. A total of 158 female "ever-married" colon cancer cases, 71 rectum cancer cases, 242 neighborhood controls, and 257 hospital controls were interviewed to obtain a complete pregnancy history. The results indicate a strong protective effect of early age at first pregnancy for both colon and rectum cancers, with little or no effect noted for the total number of pregnancies. There is a suggestion that age at first pregnancy may have a greater effect on right colon cancer than on left colon cancer. In addition, there also is a suggestion that non-live-birth outcomes may be a risk factor for both colon and rectum cancer. The similarity of these results to those of other studies on large bowel cancer and on breast cancer support the hypothesis that carcinogenesis in the large bowel may be at least partly mediated by female sex hormones.

Correlations between cancer incidence rates from the Canadian National Cancer Incidence Reporting System, 1969-78.

Incidence rates for 19 cancers in females and 16 cancers in males have been computed from data reported by 8 Canadian provinces to the National Cancer Incidence Reporting System between 1969 and 1978. The rates, very similar in absolute and relative magnitude to those reported by the U.S. Third National Cancer Survey, have been used to examine patterns of correlation between various cancers within the 8 provinces. There is strong evidence of positive associations between a number of cancers, including a number of associations that have been reported in other similar correlational studies. Correlations that may be of particular interest in suggesting etiologic factors in common include clusters of smoking-related cancers (buccal cavity with pharynx, larynx, lung, and bladder), female sexual cancers (breast, corpus uteri, and ovary), and a group of cancers that have shown correlation in other studies (i.e., cancers of the pancreas and kidney, leukemias, lymphomas, and cancer of the prostate gland). Organs in the gastrointestinal tract (esophagus, stomach, colon, and rectum) anatomically close to each other show a high positive correlation in both females and males, but the further apart the organs are the lower is the correlation; these observations are consistent with other evidence of varying dietary etiologies. Two individual correlations of particular interest are those between female brain tumors and female bladder cancer (two cancers for which little is known of the etiology for a large percentage of them) and those between female breast cancer and female lung cancer. This study, the largest correlational study of incidence data reported to date, demonstrates the utility of such simple correlational analyses.

A cohort study of fat intake and risk of breast cancer.

Between 1982 and 1987, 519 newly incident, histologically confirmed cases of breast cancer were identified in a cohort of 56,837 women enrolled in the Canadian National Breast Screening Study. These women had completed a dietary questionnaire before the occurrence of their breast cancer, and this has been used to estimate their intake of dietary fat and several other nutrients. There is evidence of a positive association between breast cancer and total fat intake, with a relative risk of 1.35 (95% confidence interval, 1.00-1.82) per 77 g per day, and some evidence of a dose-response relationship (P = .052).

Tobacco, alcohol, asbestos, and nickel in the etiology of cancer of the larynx: a case-control study.

A case-control study of laryngeal cancer was conducted in southern Ontario between 1977 and 1979 with 204 subjects with newly diagnosed cancer and 204 controls, individually matched by sex, age, and residence. Tobacco products and alcohol showed strong associations with cancer of the larynx for males, with relative risks (RR) for users of cigarettes, cigars or cigarillos, pipes, and alcohol of 6.1, 2.9, 1.6, and 5.2, respectively. The population attributable risk percent for males using tobacco products and alcohol together was estimated to be 94%. Cigarette smoking was also an important risk factor for females, although the small number of female pairs (20) precluded any meaningful detailed analysis of other possible risk factors. The RR for males for exposure to asbestos after the effects of cigarette smoking were controlled was 2.3, and the effects seemed restricted to cigarette smokers. The findings on asbestos were based on small numbers of cases and controls exposed and consequently were subject to large sampling errors. The estimate was consistent, however, with that from other studies and supported a causal role for asbestos exposure and cancer of the larynx. The RR for males for exposure to nickel was 0.9.

Dietary fat intake and risk of epithelial ovarian cancer.

BACKGROUND: Evidence exists that dietary fat may be a contributory factor in the development of hormone-related cancers such as ovarian cancer. Previous studies have demonstrated significantly higher circulating-estrogen levels among nonvegetarian women than among vegetarian women; the increase correlated directly with consumption of saturated fat. However, the contribution that dietary fat plays in the development of hormone-related cancers remains unresolved. PURPOSE: Our purpose was to evaluate whether saturated fat intake increases the risk of ovarian cancer development. METHODS: Population-based sampling was used to acquire cases and controls over a 3-year period from the study area, which included the highly populated region surrounding the western end of Lake Ontario, Canada. From the Ontario Cancer Registry, all histologically confirmed, primary malignant or borderline malignant epithelial ovarian tumors first diagnosed from November 1989 through October 1992 among study-area residents aged 35-79 years were determined. In total, 631 eligible case subjects were identified, of whom 450 (71.3%) were interviewed concerning reproduction and diet; 564 randomly selected population control subjects were similarly interviewed. From the quantitative diet-history information, average daily intakes of macronutrients and micronutrients were calculated. Unconditional continuous logistic regression methods were used for analysis, with adjustment for age at interview, number of full-term pregnancies, years of oral contraceptive use, and total daily caloric intake. RESULTS: Saturated fat consumption was associated with increasing risk of ovarian cancer (odds ratio [OR] = 1.20 for each 10 g/day of intake; 95% confidence interval [CI] = 1.03-1.40; one-sided P = .0082). No relationship was seen with intake of unsaturated fats. Egg consumption also appeared related to increased risk (OR = 1.42 for each 100 mg of egg cholesterol per day; 95% CI = 1.18-1.72; two-sided P = .0002), though this association may have resulted from disease-related changes in the dietary practices of case subjects prior to diagnosis. Consumption of vegetable fiber (but not fruit or cereal fiber) was associated with decreased risk (OR = 0.63 for each 10 g/day; 95% CI = 0.49-0.80; two-sided P = .0001). All three nutrients (saturated fat, egg cholesterol, and vegetable fiber) remained statistically significant when included in the same regression model. CONCLUSION: Diet may contribute to risk of ovarian cancer development. IMPLICATION: If confirmed in further studies, this association may allow women to appreciably lower their risk of ovarian cancer through dietary modifications: reducing the intake of saturated fats and eating more vegetables.

Cancer mortality (1965-77) in relation to diesel fume and coal exposure in a cohort of retired railway workers.

A cohort study of 43,826 male pensioners of the Canadian National Railway Company was conducted. The cause of death of 17,838 pensioners who died between 1965 and 1977 was ascertained by computerized record linkage to the Canadian national mortality data base. The main finding was an elevated risk of lung cancer for those employed in occupations involving exposure to diesel fumes and coal dust, with highly significant dose-response relationships observed. That such association may be due in part to smoking cannot be excluded; but in view of the widespread exposure to diesel fumes, the finding warrants further investigation. The present study also demonstrated the utility and feasibility of large-scale occupational cohort studies conducted with the use of computerized record linkage to national mortality records.

Lung cancer mortality (1950-80) in relation to radon daughter exposure in a cohort of workers at the Eldorado Beaverlodge uranium mine.

A cohort study of 8,487 workers employed between 1948 and 1980 at a uranium mine in Saskatchewan, Canada, has been conducted. A total of 65 lung cancer deaths was observed (34.24 expected, P less than 10(-5)). There was a highly significant linear relationship between dose and increased risk of lung cancer giving estimates for the relative and attributable risk coefficients of 3.28% per working level month (WLM) and 20.8 per WLM per 10(6) person-years. Age at first exposure had a significant modifying effect on risk. The interaction of exposure with age at observation fits a relative risk model well. The similarity of these results to a recent study of Swedish iron miners with similar levels of relatively low exposure suggests that exposure to radon daughter products may be a major contributory factor to lung cancer occurring among nonsmokers in the general population. The results also reinforce concerns as to the appropriateness of present occupational exposure standards.

Tobacco use, occupation, coffee, various nutrients, and bladder cancer.

In a Canadian population-based case-control study of 480 males and 152 female case-control pairs, the relative risk for development of bladder cancer for ever used versus never used cigarettes was 3.9 for males and 2.4 for females, with a dose-response relationship in both sexes. A reduced risk was associated with the use of filter cigarettes compared to nonfilter cigarettes. After control for cigarette usage, a significant risk was noted for male pipe smokers. For male ex-smokers the risk after 15 years of no smoking was less than one-half that of current male smokers. Bladder cancer risk was found for workers in the chemical, rubber, photographic, petroleum, medical, and food processing industries among males and for workers occupationally exposed to dust or fumes among both sexes. Bladder cancer risk was elevated for males consuming all types of coffee, regular coffee, and instant coffee and for females consuming instant coffee, but no dose-response relationship was found. Risk was found for males consuming water from nonpublic supples but not for females. No risk was observed in males or females consuming nitrate-containing foods, beverages other than coffee, or fiddlehead greens. Hair dye usage in females and phenacetin usage in males and females carried no risk. Divergent findings by area for aspirin suggested that an overall association was not causal. Reevaluation of the data on artificial sweeteners confirmed a significant bladder cancer risk in males and a dose-response relationship. The cumulated population attributable risk for bladder cancer was 90% for males from cigarette smoking, industrial exposure, and exposure to nonpublic water supplies and 29% for females from cigarette smoking, industrial exposure, and instant coffee consumption.

Radon and cancers other than lung cancer in underground miners: a collaborative analysis of 11 studies.

BACKGROUND: Exposure to the radioactive gas radon and its progeny (222Rn and its radioactive decay products) has recently been linked to a variety of cancers other than lung cancer in geographic correlation studies of domestic radon exposure and in individual cohorts of occupationally exposed miners. PURPOSE: This study was designed to characterize further the risks for cancers other than lung cancer (i.e., non-lung cancers) from atmospheric radon. METHODS: Mortality from non-lung cancer was examined in a collaborative analysis of data from 11 cohorts of underground miners in which radon-related excesses of lung cancer had been established. The study included 64,209 men who were employed in the mines for 6.4 years on average, received average cumulative exposures of 155 working-level months (WLM), and were followed for 16.9 years on average. RESULTS: For all non-lung cancers combined, mortality was close to that expected from mortality rates in the areas surrounding the mines (ratio of observed to expected deaths [O/E] = 1.01; 95% confidence interval [CI] = 0.95-1.07, based on 1179 deaths), and mortality did not increase with increasing cumulative exposure. Among 28 individual cancer categories, statistically significant increases in mortality for cancers of the stomach (O/E = 1.33; 95% CI = 1.16-1.52) and liver (O/E = 1.73; 95% CI = 1.29-2.28) and statistically significant decreases for cancers of the tongue and mouth (O/E = 0.52; 95% CI = 0.26-0.93), pharynx (O/E = 0.35; 95% CI = 0.16-0.66), and colon (O/E = 0.77; 95% CI = 0.63-0.95) were observed. For leukemia, mortality was increased in the period less than 10 years since starting work (O/E = 1.93; 95% CI = 1.19-2.95) but not subsequently. For none of these diseases was mortality significantly related to cumulative exposure. Among the remaining individual categories of non-lung cancer, mortality was related to cumulative exposure only for cancer of the pancreas (excess relative risk per WLM = 0.07%; 95% CI = 0.01-0.12) and, in the period less than 10 years since the start of employment, for other and unspecified cancers (excess relative risk per WLM = 0.22%; 95% CI = 0.08-0.37). CONCLUSIONS: The increases in mortality from stomach and liver cancers and leukemia are unlikely to have been caused by radon, since they are unrelated to cumulative exposure. The association between cumulative exposure and pancreatic cancer seems likely to be a chance finding, while the association between cumulative exposure and other and unspecified cancers was caused by deaths certified as due to carcinomatosis (widespread disseminated cancer throughout the body) that were likely to have been due to lung cancers. This study, therefore, provides considerable evidence that high concentrations of radon in air do not cause a material risk of mortality from cancers other than lung cancer. IMPLICATIONS: Protection standards for radon should continue to be based on consideration of the lung cancer risk alone.

Dietary intake of fiber and decreased risk of cancers of the colon and rectum: evidence from the combined analysis of 13 case-control studies.

BACKGROUND: Colorectal cancer is a major public health problem in both North America and western Europe, and incidence and mortality rates are rapidly increasing in many previously low-risk countries. It has been hypothesized that increased intakes of fiber, vitamin C, and beta carotene could decrease the risk of colorectal cancer. PURPOSE: The objective of this study was to examine the effects of fiber, vitamin C, and beta-carotene intakes on colorectal cancer risk in a combined analysis of data from 13 case-control studies previously conducted in populations with differing colorectal cancer rates and dietary practices. The study was designed to estimate risks in the pooled data, to test the consistency of the associations across the studies, and to examine interactions of the effects of the nutrients with cancer site, sex, and age. METHODS: Original data records for 5287 case subjects with colorectal cancer and 10,470 control subjects without disease were combined. Logistic regression analysis was used to estimate relative risks and confidence intervals for intakes of fiber, vitamin C, and beta carotene, with the effects of study, sex, and age group being adjusted by stratification. RESULTS: Risk decreased as fiber intake increased; relative risks were 0.79, 0.69, 0.63, and 0.53 for the four highest quintiles of intake compared with the lowest quintile (trend, P < .0001). The inverse association with fiber is seen in 12 of the 13 studies and is similar in magnitude for left- and right-sided colon and rectal cancers, for men and for women, and for different age groups. In contrast, after adjustment for fiber intake, only weak inverse associations are seen for the intakes of vitamin C and beta carotene. CONCLUSION: This analysis provides substantive evidence that intake of fiber-rich foods is inversely related to risk of cancers of both the colon and rectum. IMPLICATIONS: If causality is assumed, we estimate that risk of colorectal cancer in the U.S. population could be reduced about 31% (50,000 cases annually) by an average increase in fiber intake from food sources of about 13 g/d, corresponding to an average increase of about 70%.