Asbestos-associated diseases in a cohort of cigarette-filter workers

To estimate the effects on health of occupational exposure to crocidolite, a highly toxic form of asbestos, we studied a cohort of 33 men who worked in 1953 in a Massachusetts factory that manufactured cigarette filters containing crocidolite fibers from 1951 to 1957. Twenty-eight of the men have died, as compared with 8.3 deaths expected. This increased mortality was attributable to asbestos-associated diseases. Fifteen deaths were caused by cancer, as compared with 1.8 expected (relative risk, 8.2; 95 percent confidence interval, 4.6 to 13.4), including eight from lung cancer, five from malignant mesothelioma, and two from other types of cancer. There were seven deaths from nonmalignant respiratory disease, as compared with 0.5 expected (relative risk, 14.7; 95 percent confidence interval, 5.9 to 30.3), of which five were due primarily to asbestosis. In contrast, the mortality rates from cardiovascular diseases and all other causes were not increased. Four of the five living workers have pulmonary asbestosis; three of them have recently diagnosed cancers, including two additional lung cancers. We conclude that the extremely high morbidity and mortality in these workers were caused by intense exposure to crocidolite asbestos fibers.     

Mortality from breast cancer after irradiation during fluoroscopic examinations in patients being treated for tuberculosis

The increasing use of mammography to screen asymptomatic women makes it important to know the risk of breast cancer associated with exposure to low levels of ionizing radiation. We examined the mortality from breast cancer in a cohort of 31,710 women who had been treated for tuberculosis at Canadian sanatoriums between 1930 and 1952. A substantial proportion (26.4 percent) had received radiation doses to the breast of 10 cGy or more from repeated fluoroscopic examinations during therapeutic pneumothoraxes. Women exposed to greater than or equal to 10 cGy of radiation had a relative risk of death from breast cancer of 1.36, as compared with those exposed to less than 10 cGy (95 percent confidence interval, 1.11 to 1.67; P = 0.001). The data were most consistent with a linear dose-response relation. The risk was greatest among women who had been exposed to radiation when they were between 10 and 14 years of age; they had a relative risk of 4.5 per gray, and an additive risk of 6.1 per 10(4) person-years per gray. With increasing age at first exposure, there was substantially less excess risk, and the radiation effect appeared to peak approximately 25 to 34 years after the first exposure. Our additive model for lifetime risk predicts that exposure to 1 cGy at the age of 40 increases the number of deaths from breast cancer by 42 per million women. We conclude that the risk of breast cancer associated with radiation decreases sharply with increasing age at exposure and that even a small benefit to women of screening mammography would outweigh any possible risk of radiation-induced breast cancer.     

The observation and analysis of cancer deaths among classified radiation workers.

The extent to which occupational radiation exposure contributes to cancer mortality is an influence on future world energy policy. It is also a factor in deciding the level of expenditure to reduce radiation levels experienced by workers. Here we discuss some of the difficulties in analysing the situation and present the results of some calculations which estimate the expected age-specific radiation mortalities from all inducible cancers and also from leukaemia separately. Using a high value for the average occupational exposure and a conservative estimate of the associated risk, we find that a survey of mortality among radiation workers must run over many years before sufficient data would be accumulated to resolve the effects of radiation-induced neoplasms from those arising from other causes. We show the advisability of determining the cause of death both of persons who remain employed in the industry and all for only a short time. Our estimates are based on maintenance of an occupationally exposed dose of one rad per person per year during the period of the survey which may extend over several decades. However, scaling of the estimates to any other exposure rates is easily performed. We also give estimates of the lowest risk coefficients detectable in a given observation time. Since for a work force of 3000 these lowest detectable values are an order of magnitude larger than those expected, it is clear that only a national or international survey can produce data adequate for even modest objectives.     

Depression and cancer: a follow-up study

Thirty-nine male and 90 female patients aged 40 and over, who had been given a primary diagnosis of depression, were followed up for 2 1/3-4 years. During this period 9 male and 9 female patients died. Five male patients and 1 female died from cancer that had not been diagnosed at the time of their psychiatric admissions. The male cancer deaths are significantly higher than expected. The possible relationships of malignant neoplasm to affective disorder are discussed.     

Mortality in a cohort of IVF patients.

BACKGROUND: Risks associated with IVF and related assisted reproduction technologies include complications of ovarian stimulation, surgical procedures and pregnancy itself. Serious complications are uncommon but may be potentially life threatening. The aims of this study were to compare the mortality rates of women who received IVF treatment, as well as those who were referred but were not treated, with the mortality rate in the general female population, to determine the maternal mortality rate following IVF conception and to establish whether any deaths had occurred as a result of treatment complications. METHODS: Deaths were identified in a cohort of 29 700 Australian IVF patients by record-linkage with the National Death Index and a cancer registry. RESULTS: The all-cause mortality rates in IVF patients (treated and untreated) were significantly lower than in the general female population of the same age. In treated women, 72 deaths were observed and 125 deaths were expected giving an age-standardized mortality ratio of 0.58 (95% confidence interval 0.48-0.69). Two maternal deaths were identified in the 42 days of the puerperium. Complications of ovarian hyperstimulation syndrome could not be directly related to any of the deaths identified in this cohort. CONCLUSIONS: As well as providing some reassurance about the safety of IVF treatments, the findings point to the existence of a 'healthy patient effect' whereby the unhealthiest women in the population are deterred from pregnancy and infertility treatment.     

Tissue doses from radiotherapy of cancer of the uterine cervix

For use in an epidemiologic study of subsequent tumors, absorbed doses from brachytherapy and external beam radiotherapy were measured and calculated for various tissues of patients treated for cancer of the uterine cervix. External beams included orthovoltage x rays (1.9 and 3.0 mm Cu half-value layer), cobalt-60 gamma rays, 2 MV x rays, and 25 MV X rays. The brachytherapy sources were encapsulated radium. Measurements were made in an Alderson anthropomorphic phantom and a water phantom; calculations were made using a Monte Carlo technique or standard radiotherapy methods. Depending upon stage of disease and radiation energy, the absorbed doses (cGy) from typical treatment regimes to tissues of interest were: ovaries, 1400-5200; stomach, 130-320; kidneys, 120-310; pancreas, 100-260; lungs 22-48; breasts, 19-52; thyroid, 6-17; salivary glands, 4-11; brain, 2-7, and total active bone marrow, 320-1100. The lower values of each range were for stage I of the disease.     

Comparison of genotoxic potency of styrene 7,8-oxide with gamma radiation and human cancer risk estimation of styrene using the rad-equivalence approach

Styrene is suspected to cause lympho-hematopoietic malignancies through the formation of styrene 7,8-oxide. However, we are still unable to calculate the cancer risk for workers exposed to styrene using epidemiological data. The aims of this study were to determine the blood dose after styrene exposure and to compare the genotoxic potency of styrene 7,8-oxide and gamma radiation in order to calculate the cancer risk by means of the rad-equivalence approach. Leucocytes of 20 individuals were exposed to 0, 0.1, 0.2 or 0.3 mM styrene 7,8-oxide (1 h) or 1, 2 or 3 gray (=100, 200, 300 rad) gamma radiation. Genotoxicity was evaluated with the cytokinesis-block micronucleus assay. Comparison of the two slopes of the regression lines between micronuclei and dose revealed a genotoxic potency for styrene 7,8-oxide of 37 rad/mMh, corresponding with a median value derived from mutagenicity studies (1, 37, 208 rad/mMh). At exposure levels of 1 ppm styrene, a blood styrene 7,8-oxide concentration between 0.03 x 10(-)(6) and 0.42 x 10(-)(6) mM is to be expected using data of toxicokinetic models and human exposure studies. With the cancer risk per unit dose of gamma radiation as benchmark, we calculated a lifetime risk of acquiring a fatal lympho-hematopoietic cancer of 0.17 in 10(3) workers (between 0.037 x 10(-)(3) and 5.0 x 10(-)(3)) exposed to 20 ppm styrene during 40 years.     

Mortality among children with Kawasaki disease in Japan.

BACKGROUND AND METHODS. It is not certain whether patients with Kawasaki disease have a higher death rate than the age-matched healthy population. We therefore undertook a study to investigate this question. Between July 1982 and December 1988, 53 collaborating treatment centers collected data on all patients who had an unequivocal new diagnosis of Kawasaki disease; patients who had recurrent disease or whose first visit to the treatment center occurred more than 14 days after the onset of symptoms were excluded. Patients were followed from the time of the first visit to the treatment center until December 31, 1989, or until death, whichever occurred first. The expected number of deaths was calculated from Japanese vital-statistics data and compared with the number observed. RESULTS. Of 4676 patients who met the eligibility criteria, 4608 (98.5 percent) were followed through either the end of the study or the date of death. Thirteen patients (10 boys and 3 girls) died during the study period. The number of deaths expected was 7.61 (ratio of observed to expected deaths, 1.71; 95 percent confidence interval, 0.91 to 2.92). The ratio was 2.04 (95 percent confidence interval, 0.98 to 3.76) for boys and 1.11 (95 percent confidence interval, 0.23 to 3.23) for girls. During the acute phase of the disease (the first two months after onset), the ratios of observed to expected deaths were higher: 9.86 overall (95 percent confidence interval, 3.95 to 20.31), 13.33 for boys (95 percent confidence interval, 4.89 to 29.07), and 3.85 for girls (95 percent confidence interval, 0.10 to 21.42). After the acute phase, however, both sexes had ratios of observed to expected deaths that were lower than 1, and the difference from the control population was not statistically significant. CONCLUSIONS. The mortality rate among boys with Kawasaki disease in Japan is twice that among healthy boys of the same age, and most deaths occur within two months of diagnosis. The mortality rate among girls with the disease appears similar to that among healthy girls, although the numbers are very small.     

Maternal mortality in Dar es Salaam,Tanzania: Socio-economic,obstetric history and accessibility of health care factors

A community-based incident case-referent study was performed in Ilala district, Dar es Salaam, Tanzania to estimate the social, obstetric history and accessibility of health care factors for maternal death. From February 1991 to January 1993 all female deaths in the reproductive ages were identified through the existing administrative information system. For every maternal death three live mothers was selected as referents matched for age. In cases a relative to the deceased mother and in referents the live mother herself was interviewed using a pre-tested questionnaire. Socio-economic factors were strongly related to the risk of maternal death. Single and divorced women were at an increased risk (odds ratio (OR) equals5.1; 95% confidence interval (CI): 2.8-9.3 and OR equals28; 95% CI: 6.5- 118). Women with less than 3 years' education had a 3 fold higher risk than women with more than 7 years' schooling. Also women who were peasants and unskilled workers were at higher risk when compared with professionals and peasants and unskilled workers were at higher risk when compared with professionals and skilled workers (OR equals20, 95% CI:7.4-51 and OR equals6.2; 95% CI:2.5-15). An obstetric history with no previous live births (OR equals 36; 95% CI: 8.239), more than one induced abortion (OR=36; 95% CI; 9.7-132) or stillbirth (OR equals4.8; 95% CI:1.6-14) and unwanted pregnancy (OR equals4.0; 95% CI:2.2-7.3) were, as expected, statistically significant risk factors for maternal death. Factors reflecting living standards such as type of housing, access to tap- water and electricity, availability of a toilet and the living standard as estimated by the interviewer were all statistically significant for the risk of maternal death (OR equals7.2, 2.7, 2.1, 8.3 and 6.2, respectively). Increased distance in meters from the house to a road and increased time in minutes taken to reach the nearest transport, clinic and hospital in minutes increased the risk for a maternal death significantly. The preventive activities require efforts from the whole community. The health care system can contribute by early identification of risk cases. e.g. women with previous stillbirths and miscarriages in the antenatal care.     

Relation between effective radiation dose and outcome of radioiodine therapy for thyroid cancer

We used a combination of radioiodine scanning and quantitative radiation dosimetry to evaluate responses to therapeutic irradiation with 131I in 76 patients with thyroid adenocarcinoma. Fifty patients received 131I treatment for ablation of residual thyroid tissue after surgical thyroidectomy, and 26 had 131I treatment for metastatic thyroid cancer. Successful ablation was observed in patients receiving higher radiation doses to the thyroid--about 4.4 times those in patients whose lesions were not ablated--largely because of a longer effective half-life of 131I in residual thyroid tissue in the patients with ablated lesions. Patients with metastases that persisted after 131I therapy tended to have more advanced disease and received significantly lower radiation doses per millicurie of administered 131I than did persons whose lesions responded to treatment. Initial 131I treatment resulting in radiation doses of at least 30,000 rad to thyroid remnants and 8000 rad to metastases was associated with a significant increase in the rate of response to therapy.     

Thyroid diseases after treatment of Hodgkin's disease

BACKGROUND AND METHODS. Thyroid disease, especially hypothyroidism, is common in patients with Hodgkin's disease who have been treated with irradiation. We reviewed the records of 1787 patients (740 women and 1047 men) with Hodgkin's disease who were treated with radiation therapy alone (810 patients), radiation and chemotherapy (920 patients), or chemotherapy alone (57 patients) at Stanford University between 1961 and 1989. Among these patients, 1533 were alive at the last follow-up, and 254 had died of causes other than Hodgkin's disease. (Four other patients were excluded from the analysis because they had undergone thyroidectomy before treatment for Hodgkin's disease. The thyroid was irradiated in 1677 patients. Follow-up averaged 9.9 years. RESULTS. A total of 573 patients had clinical or biochemical evidence of thyroid disease. Among the 1677 patients whose thyroid was irradiated, the actuarial risk of thyroid disease 20 years after treatment was 52 percent, and it was 67 percent at 26 years. Hypothyroidism was found in 513 patients. A total of 486 patients received thyroxine therapy for elevated serum thyrotropin concentrations and either low free thyroxine (208 patients) or normal free thyroxine values (278 patients); 27 had transient elevations of the serum thyrotropin level that were not treated. Graves' hyperthyroidism developed in 30 patients (2 of whom had not undergone thyroid irradiation), and ophthalmopathy developed in 17 of these patients. Ophthalmopathy developed in four other patients with Graves' disease during a period of hypothyroidism (n = 3) or euthyroidism (n = 1). The risk of Graves' disease was 7.2 to 20.4 times that for normal subjects. Silent thyroiditis with thyrotoxicosis developed in six patients. Forty-four patients were found to have single or multiple thyroid nodules, 26 of whom underwent thyroidectomy. Six of the 44 had papillary or follicular cancers. Among the patients who did not undergo operation, 12 had small functioning nodules, 4 had cysts, and 2 had multinodular goiters. The actuarial risk of thyroid cancer was 1.7 percent. The risk of thyroid cancer was 15.6 times the expected risk. CONCLUSIONS. High risks of thyroid disease persist more than 25 years after patients have received radiation therapy for Hodgkin's disease, reinforcing the need for continued clinical and biochemical evaluation. Prolonged follow-up confirms an elevated risk of thyroid cancer and Graves' disease as well as hypothyroidism in these patients.     

An analysis of lung cancer risk from exposure to hexavalent chromium

Lung cancer risk in relation to airborne levels of hexavalent chromium was analyzed for chromium chemical production workers studied by Hayes, Lilienfeld, and Snell. Hayes et al [18] had observed statistically significant increases in lung cancer mortality among chromium chemical production workers hired during 1945-1959 and followed to mid-1977. A dose-response was observed by Hayes et al. in that long-term workers had a higher lung cancer risk than short-term workers. Concurrent exposure data for the study plant were abstracted from the records of a local health department. The usual air concentration of hexavalent chromium was estimated as 413 micrograms per cubic meter (micrograms/m3) during 1945-1949. Cumulative exposure estimates for individual workers could not be developed with available information. Instead, cumulative exposures in terms of micrograms/m3-years were estimated for groups of short-term workers and long-term workers (cumulative exposure = usual exposure level in micrograms/m3 X average length of exposure). For workers hired during 1945-1949, cumulative exposures were estimated as 670 and 3,647 micrograms/m3-years for short-term and long-term workers, respectively. Like most estimates based on historical data, these exposure estimates are subject to uncertainty. Nevertheless, these results suggest a potential excess risk of death from lung cancer among U.S. workers exposed to the current permissible exposure limit (PEL) for hexavalent chromium of 52 micrograms/m3 because such workers could accumulate exposures (micrograms/m3-years) similar to those associated with excess risk in Hayes et al's cohort. Moreover, many current workers are estimated to be exposed to levels above the PEL. Further exploration of the dose-response relationship for chromium carcinogenesis is indicated.     

基于颈椎退行性变患者颈部MR影像的甲状腺异常的检出率及影响因素分析

目的 探讨颈椎退行性变患者甲状腺异常的MRI检出率及相关影响因素。方法 回顾性研究。纳入2014年10月—2018年4月徐州医科大学附属医院骨科963例颈椎退行性变患者的临床资料,其中男515例、女448例,年龄28~91 （56.0±11.1）岁。统计甲状腺异常患者的检出率、类型。根据是否合并甲状腺异常将患者分为合并甲状腺异常和无甲状腺异常2组,比较2组患者的性别、年龄、体质量指数（BMI）、颈部放射史及甲状腺疾病家族史等临床资料,采用多因素logistic回归分析甲状腺异常发生的影响因素。结果 963例患者中,发现甲状腺异常63例,检出率6.5%。63例甲状腺异常患者中,甲状腺结节47例,甲状腺肿10例,桥本甲状腺炎3例,甲状腺部分切除术术后2例,甲状腺癌1例。900例无甲状腺异常者和63例合并甲状腺异常者2组颈椎退行性变患者比较,在吸烟史方面差异无统计学意义（P>0.05）;在年龄、性别、BMI、颈部放射史及甲状腺疾病家族史等方面差异均有统计学意义（P值均<0.05）。进一步多因素logistic回归分析显示,女性[比值比（OR）=4.640、95%可信区间（CI）2.470~8.719]是甲状腺异常的危险因素,年龄（OR=0.968、95% CI 0.946~0.991）及BMI（OR=0.918、95% CI 0.848~0.993）是甲状腺异常的保护因素（P值均<0.05）。结论 颈椎退行性变患者在颈椎MRI中检出甲状腺异常并不少见,性别、年龄、BMI是甲状腺异常的独立影响因素。临床应重视颈椎MRI中甲状腺区域的判读、评估,尤其是对女性、年龄小、BMI低的患者,完善相关评估,颈椎于术前发现甲状腺异常可降低其潜在的手术风险。     

Male suicide and occupation in Scotland

Some occupational groups in England and Wales have higher than expected proportion of deaths from suicide or undetermined intent. This study examined the association of occupation with suicide in men in, Scotland. Information from the General Register Office for Scotland was used to identify deaths from suicide and undetermined intent in 1981-1999 for men aged 16-64 years. Proportional Mortality Ratios (PMRs) and 95 per cent confidence intervals were calculated for all occupational categories. The largest number of male deaths in groups with elevated PMRs occurred in low paying occupations, such as labourers. Counterhands (sales and stores assistants) and assistants and chefs and cooks had increased PMRs in the 16-45 year age group. Some occupations with access to lethal means of suicide had high PMRs, including medical practitioners in the 16-45 and 46-64 year age groups and hospital ward orderlies, in the younger age group. There were increased PMRs in some rural occupations including farmers, forestry workers, fishermen, and some ships' crewmembers. Groups with low     

Monitoring of pulmonary ventilation function and respiratory symptoms in cotton-processing workers

A follow-up study in cotton workers (35 female and 31 male) was performed ten years after the original cross-sectional study. The prevalence of byssinosis considerably increased during the follow-up study in female (22.9%; 42.9%) and in male (25.8%; 51.6%) workers. Similarly, the prevalence of almost all respiratory symptoms was significantly higher during the follow-up study than at the time of the initial study. Significant acute reductions of FVC and FEV1 during the work shift were recorded in both surveys. The mean annual decline in ventilatory capacity was greater than expected for both female (FVC: -0.036 L/year; FEV1: -0.059 L/year) and male workers (FVC: -0.059 L/year; FEV1: -0.068 L/year). The mean total airborne dust concentration was 3.95 mg/m3 with an average respirable dust concentration of 0.97 mg/m3. Our study demonstrated an association between exposure to cotton dust and increasing prevalence of respiratory symptoms and progressive impairment of ventilatory capacity.     

Correlation between BRAF mutation and the clinicopathological parameters in papillary thyroid carcinoma with particular reference to follicular variant

Mutation of the BRAF gene is common in thyroid cancer. Follicular variant of papillary thyroid carcinoma is a variant of papillary thyroid carcinoma that has created continuous diagnostic controversies among pathologists. The aims of this study are to (1) investigate whether follicular variant of papillary thyroid carcinoma has a different pattern of BRAF mutation than conventional papillary thyroid carcinoma in a large cohort of patients with typical features of follicular variant of papillary thyroid carcinoma and (2) to study the relationship of clinicopathological features of papillary thyroid carcinomas with BRAF mutation. Tissue blocks from 76 patients with diagnostic features of papillary thyroid carcinomas (40 with conventional type and 36 with follicular variant) were included in the study. From these, DNA was extracted and BRAF V600E mutations were detected by polymerase chain reaction followed by restriction enzyme digestion and sequencing of exon 15. Analysis of the data indicated that BRAF V600E mutation is significantly more common in conventional papillary thyroid carcinoma (58% versus 31%, P = .022). Furthermore, the mutation was often noted in female patients (P = .017), in high-stage cancers (P = .034), and in tumors with mild lymphocytic thyroiditis (P = .006). We concluded that follicular variant of papillary thyroid carcinoma differs from conventional papillary thyroid carcinoma in the rate of BRAF mutation. The results of this study add further information indicating that mutations in BRAF play a role in thyroid cancer development and progression.     

Mortality among workers exposed to ethylene oxide

BACKGROUND. Ethylene oxide is a sterilant gas that causes leukemia and other cancers in animals. Studies in Sweden have shown an excess of leukemia and stomach cancer in humans exposed to ethylene oxide, but other studies have generally failed to confirm these findings. METHODS. We conducted a study of mortality in 18,254 U.S. workers exposed to ethylene oxide at 14 plants producing sterilized medical supplies and spices. The subjects averaged 4.9 years of exposure to the gas and 16 years of follow-up. The exposure levels in recent years averaged 4.3 ppm (eight-hour time-weighted adjusted exposure) for sterilizer operators and 2.0 ppm for other workers. The levels in earlier years are likely to have been several times higher. Mortality in this cohort was compared with that in the general U.S. population. RESULTS. Overall there was no significant increase in mortality from any cause in the study cohort. The standardized mortality ratios (SMRs) were 0.97 for leukemia (95 percent confidence interval, 0.52 to 1.67; 13 deaths observed), 1.06 for all hematopoietic cancers (95 percent confidence interval, 0.75 to 1.47; 36 deaths), and 0.94 for stomach cancer (95 percent confidence interval, 0.45 to 1.70; 11 deaths). Analyses according to job category and according to the duration of exposure showed no excess in cancers, as compared with the rate in the general population, but there was a significant trend toward increased mortality with increasing lengths of time since the first exposure for all hematopoietic cancers. The rate of death from hematopoietic cancer (especially non-Hodgkin's lymphoma) was significantly increased among men (SMR, 1.55; 27 deaths). Mortality from leukemia in recent years (1985 through 1987) was significantly increased among men (SMR, 3.45; 5 deaths). CONCLUSIONS. For the entire cohort, there was no increase in mortality from hematopoietic cancer. There was a slight but significant increase among men, however. Among men and women combined, there was a trend toward an increased risk of death from hematopoietic cancer with increasing lengths of time since the first exposure to ethylene oxide.     

Cancer morbidity of foundry workers in Korea

Foundry workers are potentially exposed to a number of carcinogens. This study was conducted to describe the cancer incidence associated with employment in small-sized Korean iron foundries and to compare those findings to the Korean population. Cancer morbidity in 208 Korean foundries was analyzed using the Standardized Incidence Ratio (SIR) and Standardized Rate Ratio (SRR). Overall cancer morbidity in foundry workers (SIR=1.11, 95% confidence interval [CI]=1.01-1.21) was significantly higher than that of Korean general population. Lung cancer (SIR=1.45, 95%CI=1.11-1.87) and lymphohematopoietic cancer (SIR=1.58, 95%CI=1.00-2.37) in production workers were significantly high compared to Korean general population. Stomach cancer in fettling (SRR=2.10, 95%CI=1.10-4.01) and lung cancer in molding (SRR=3.06, 95%CI=1.22-7.64) and in fettling (SRR=2.63, 95%CI=1.01-6.84) were there significant elevations compared to office workers. In this study, statistically significant excess lung cancer was observed in production workers comparing to Korean general population and office workers. Also, cancer morbidity of overall cancer, lung cancer and stomach cancer was significantly increased with duration of employment at ten and more years comparing to Korean general population. These findings suggest in causal association between exposure to carcinogens during foundry work and cancer morbidity.     

Effective surgical adjuvant therapy for high-risk rectal carcinoma

BACKGROUND. Radiation therapy as an adjunct to surgery for rectal cancer has been shown to reduce local recurrence but has not improved survival. In a previous study, combined radiation and chemotherapy improved survival significantly as compared with surgery alone, but not as compared with adjuvant radiation, which many regard as standard therapy. We designed a combination regimen to optimize the contribution of chemotherapy, decrease recurrence, and improve survival as compared with adjuvant radiation alone. METHODS. Two hundred four patients with rectal carcinoma that was either deeply invasive or metastatic to regional lymph nodes were randomly assigned to postoperative radiation alone (4500 to 5040 cGy) or to radiation plus fluorouracil, which was both preceded and followed by a cycle of systemic therapy with fluorouracil plus semustine (methyl-CCNU). RESULTS. After a median follow-up of more than seven years, the combined therapy had reduced the recurrence of rectal cancer by 34 percent (P = 0.0016; 95 percent confidence interval, 12 to 50 percent). Initial local recurrence was reduced by 46 percent (P = 0.036; 95 percent confidence interval, 2 to 70 percent), and distant metastasis by 37 percent (P = 0.011; 95 percent confidence interval, 9 to 57 percent). In addition, combined therapy reduced the rate of cancer-related deaths by 36 percent (P = 0.0071; 95 percent confidence interval, 14 to 53 percent) and the overall death rate by 29 percent (P = 0.025; 95 percent confidence interval, 7 to 45 percent). Its acute toxic effects included nausea, vomiting, diarrhea, leukopenia, and thrombocytopenia. These effects were seldom severe. Severe, delayed treatment-related reactions, usually small-bowel obstruction requiring surgery, occurred in 6.7 percent of all patients receiving radiation, and the frequencies of these complications were comparable in both treatment groups. CONCLUSIONS. The combination of postoperative local therapy with radiation plus fluorouracil and systemic therapy with a fluorouracil-based regimen significantly and substantively improves the results of therapy for rectal carcinoma with a poor prognosis, as compared with postoperative radiation alone.     

Estimating cancer risk in HNPCC by the GRL method

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome caused by germline mutations of the mismatch repair (MMR) genes. Only a few studies have taken into account the selection of families tested for these mutations in estimating colorectal cancer (CRC) risk in carriers. They found much lower estimates of CRC risks than previous ones, but these estimates lacked precision despite the large number of families. The aim of this study was to evaluate the efficiency of the 'genotype restricted likelihood' (GRL) method that provides unbiased estimates of risks whatever the ascertainment process of families, and to estimate CRC and endometrial cancer risk for carriers of the MMR genes. Efficiency of the GRL method was evaluated using simulations. Risks were estimated from a sample of 36 families diagnosed with HNPCC and carrying a mutation of MSH2 or MLH1, ascertained through a cancer family clinic in Lyon (France). The efficiency of the GRL method was found to be strongly dependent on the proportion of family members tested. By age 70 years, CRC risk was estimated at 47% (95% confidence interval: 12-98%) for men and 33% (95% confidence interval: 24-54%) for women. The endometrial cancer risk was only 14% (confidence interval: 6-20%). As methods allowing for the selection of families lack efficiency, large-scale family studies should be undertaken and data should be pooled to provide reliable and precise estimates of risks for an optimal familial management.