Biomedical subjects

Charles E Land

Publications and source records attributed to Charles E Land.

16 recordsLinked to original sources

PubMed2006

Heterozygous individuals bearing a founder mutation in the XPA DNA repair gene comprise nearly 1% of the Japanese population.

Individuals who are homozygotes for mutations in DNA repair genes are at high risk for cancer. It is not well documented, however, if the heterozygous carriers of the mutation are also predisposed to cancer. To address the issue, xeroderma pigmentosum (XP) in Japan is an interesting candidate because of three major reasons: XP is an autosomal recessive disorder with an enormously elevated risk of skin cancer, the frequency of XP patients is higher in Japan than in other parts of the world, and more than half of Japanese XP patients are homozygous for the same founder mutation in the XPA gene. We screened archival blood samples from Japanese individuals who resided in Hiroshima or Nagasaki. A simple PCR-RFLP method was developed that is highly specific for detection of XPA heterozygotes carrying the founder mutation. We identified nine XPA heterozygotes among 1,020 individuals screened for a prevalence of 0.88%. This rate, if representative, implies that there are about 1 million carriers of the XPA founder mutation in the Japanese population. Thus, investigation of their cancer risk may be warranted.

Adolescent↗

PubMed2006

A pathology study of malignant and benign ovarian tumors among atomic-bomb survivors--case series report.

The present article describes the series of incident primary ovarian tumors in the Life Span Study (LSS) cohort of the Radiation Effects Research Foundation, with particular emphasis on case ascertainment and characterization of histological features of the tumors. We identified 723 ovarian tumors (260 malignant, 463 benign) in 648 individuals of about 70,000 female LSS subjects; 71 cases had more than one ovarian tumor. We histologically confirmed 601 tumors (182 malignant, 419 benign tumors). The most frequent histological type was common epithelial tumor (90.7% for malignant and 59.7% for benign tumors). The distributions of ovarian tumors by histological type were similar to those from other studies. Among malignancies, the frequency of common epithelial types relative to other tumor types increased with radiation dose (p = 0.02). Among benign tumors, the relative frequency of sex-cord stromal tumors increased with radiation dose (p = 0.04). The women with mucinous cancer had better survival than those with serous cancers (p = 0.03). Within tumor types, there was no consistent pattern of survival by radiation dose. Variations in histological types of ovarian tumors in response to radiation dose, suggested by the case series data need to be followed up by population-based incidence analysis.

Age Distribution↗

PubMed2006

External dose estimates for Dolon village: application of the U.S./Russian joint methodology.

Methods to estimate external dose from radioactive fallout from nuclear tests have for many years depended on two types of data: measurements of exposure rate in air and an empirically derived power function to describe the change in exposure rate with time, Over the last four years, a working group with American and Russian participation has developed a bi-national joint methodology that offers an improved capability for estimating external dose. In this method, external dose is estimated using exposure rate functions derived from data from American nuclear tests similar in construction to SNTS (Semipalatinsk Nuclear Test Site) devices. For example, in this paper, we derive doses for test #1 (August 29, 1949) at the SNTS using an exposure rate function for the U.S. TRINITY test. For the case of test #1, the average external dose for a person in Dolon is estimated to have been about 0.5 Gy compared to 1 to 2 Gy estimated in other work. This prediction agrees better with reported EPR measurements in teeth from village residents and with measurements of TL signals in bricks from Dolon buildings. This report presents the basic elements of the joint methodology model for estimation of external dose received from SNTS fallout.

Body Burden↗

PubMed2006

Thyroid cancer in childhood cancer survivors: a detailed evaluation of radiation dose response and its modifiers.

Radiation exposure at a young age is a strong risk factor for thyroid cancer. We conducted a nested case-control study of 69 thyroid cancer cases and 265 controls from a cohort of 14,054 childhood cancer survivors to evaluate the shape of the radiation dose-response relationship, in particular at high doses, and to assess modification of the radiation effects by patient and treatment characteristics. We considered several types of statistical models to estimate the excess relative risk (ERR), mainly guided by radiobiological models. A two-parameter model with a term linear in dose and a negative exponential in dose squared provided the best parsimonious description with an ERR of 1.3 per gray (95% confidence interval 0.4-4.1) at doses below 6 Gy and a relative decrease in ERR of 0.2% per unit dose squared with increasing dose, that is, decreases in the ERR/Gy of 53% at 20 Gy and 95% at 40 Gy. Further analyses using spline models suggested that the significant nonlinearity at high doses was characterized most appropriately as a true downturn rather than a flattening of the dose-response curve. We found no statistically significant modification of the dose-response relationship by patient characteristics; however, the linear parameter (i.e., the ERR/ Gy at doses less than 6 Gy) did decrease consistently and linearly with increasing age at childhood cancer diagnosis, from 4.45 for 0-1-year-olds to 0.48 for 15-20-year-olds. In summary, we applied models derived from radiobiology to describe the radiation dose-response curve for thyroid cancer in an epidemiological study and found convincing evidence for a downturn in risk at high doses.

Child↗

PubMed2005

Breast cancer.

Explore the source record for details and available documents.

Adolescent↗

PubMed2005

Coronary heart disease after radiotherapy for peptic ulcer disease.

PURPOSE: To evaluate the risk of coronary heart disease (CHD) and cerebrovascular disease after radiotherapy (RT) for peptic ulcer disease. METHODS AND MATERIALS: Peptic ulcer disease patients treated with RT (n = 1859) or by other means (n = 1860) at the University of Chicago Medical Center between 1936 and 1965, were followed through 1997. The observed numbers of cause-specific deaths were compared with the expected numbers from the general population rates. During RT, 5% of the heart was in the treatment field and the remainder of the heart mostly received scattered radiation. A volume-weighted cardiac dose was computed to describe the average tissue dose to the entire organ. We used Cox proportional hazards regression analysis to analyze the CHD and cerebrovascular disease risk associated with RT, adjusting for confounding factors. RESULTS: Greater than expected CHD mortality was observed among the irradiated patients. The irradiated patients received volume-weighted cardiac doses ranging from 1.6 to 3.9 Gy and the portion of the heart directly in the field received doses of 7.6-18.4 Gy. The CHD risk increased with the cardiac dose (p trend = 0.01). The cerebrovascular disease risk was not associated with the surrogate carotid dose. CONCLUSION: The excess CHD risk in patients undergoing RT for peptic ulcer disease decades previously indicates the need for long-term follow-up for cardiovascular disease after chest RT.

Adult↗

PubMed2004

Radiation and breast cancer: a review of current evidence.

This paper summarizes current knowledge on ionizing radiation-associated breast cancer in the context of established breast cancer risk factors, the radiation dose-response relationship, and modifiers of dose response, taking into account epidemiological studies and animal experiments. Available epidemiological data support a linear dose-response relationship down to doses as low as about 100 mSv. However, the magnitude of risk per unit dose depends strongly on when radiation exposure occurs: exposure before the age of 20 years carries the greatest risk. Other characteristics that may influence the magnitude of dose-specific risk include attained age (that is, age at observation for risk), age at first full-term birth, parity, and possibly a history of benign breast disease, exposure to radiation while pregnant, and genetic factors.

Adolescent↗

PubMed2004

Improving the efficiency of nested case-control studies of interaction by selecting controls using counter matching on exposure.

BACKGROUND: Studies of the effect of exposure to a risk factor measured in an entire cohort may be augmented by nested case-control subsets to investigate confounding or effect modification by additional factors not practically assessed on all cohort members. We compared three control-selection strategies-matching on exposure, counter matching on exposure, and random sampling-to determine which was most efficient in a situation where exposure is a known, continuous variable and high doses are rare. METHODS: We estimated the power to detect interaction using four control-to-case ratios (1:1, 2:1, 4:1, and 8:1) in a planned case-control study of the joint effect of atomic bomb radiation exposure and serum oestradiol levels on breast cancer. Radiation dose is measured in the entire cohort, but because neither serum oestradiol level nor the true degree of interaction was known, we simulated values of oestradiol and hypothetical levels of oestradiol-radiation interaction. RESULTS: Compared with random sampling, power to detect interaction was similarly higher with either matching or counter matching with two or more controls. CONCLUSIONS: Because counter matching is generally at least as efficient as random sampling, whereas matching on exposure can result in loss of efficiency and precludes estimation of exposure risk, we recommend counter matching for selecting controls in nested case-control studies of the joint effects of multiple risk factors when one is previously measured in the full cohort.

Breast Neoplasms↗

PubMed2003

Cancer risks attributable to low doses of ionizing radiation: assessing what we really know.

High doses of ionizing radiation clearly produce deleterious consequences in humans, including, but not exclusively, cancer induction. At very low radiation doses the situation is much less clear, but the risks of low-dose radiation are of societal importance in relation to issues as varied as screening tests for cancer, the future of nuclear power, occupational radiation exposure, frequent-flyer risks, manned space exploration, and radiological terrorism. We review the difficulties involved in quantifying the risks of low-dose radiation and address two specific questions. First, what is the lowest dose of x- or gamma-radiation for which good evidence exists of increased cancer risks in humans? The epidemiological data suggest that it is approximately 10-50 mSv for an acute exposure and approximately 50-100 mSv for a protracted exposure. Second, what is the most appropriate way to extrapolate such cancer risk estimates to still lower doses? Given that it is supported by experimentally grounded, quantifiable, biophysical arguments, a linear extrapolation of cancer risks from intermediate to very low doses currently appears to be the most appropriate methodology. This linearity assumption is not necessarily the most conservative approach, and it is likely that it will result in an underestimate of some radiation-induced cancer risks and an overestimate of others.

Biophysical Phenomena↗

PubMed2003

Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1990.

An incidence survey of the Life Span Study (LSS) population found 1093 breast cancers among 1059 breast cancer cases diagnosed during 1950-1990. As in earlier breast cancer surveys of this population, a linear and statistically highly significant radiation dose response was found. In the analysis, particular attention was paid to modification of radiation dose response by age at exposure (e) and attained age (a). Dose-specific excess relative risk (ERR(1Sv)) decreased with increasing values of e and a. A linear dose-response model analysis, with e and a as exponential age modifiers, did not conclusively discriminate between the two variables as modifiers of dose response. A modified isotonic regression approach, requiring only that ERR(1Sv) be monotonic in age, provides a fresh perspective indicating that both e and a are important modifiers of dose response. Exposure before age 20 was associated with higher ERR(1Sv) compared to exposure at older ages, with no evidence of consistent variation by exposure age for ages under 20. ERR(1Sv) was observed to decline with increasing attained age, with by far the largest drop around age 35. Possible explanations for these observations are discussed, along with research approaches that might provide more information.

Adult↗

PubMed2003

Site-specific cancer incidence and mortality after cerebral angiography with radioactive thorotrast.

Few opportunities exist to evaluate the carcinogenic effects of long-term internal exposure to alpha-particle-emitting radionuclides. Patients injected with Thorotrast (thorium-232) during radiographic procedures, beginning in the 1930s, provide one such valuable opportunity. We evaluated site-specific cancer incidence and mortality among an international cohort of 3,042 patients injected during cerebral angiography with either Thorotrast (n = 1,650) or a nonradioactive agent (n = 1,392) and who survived 2 or more years. Standardized incidence ratios (SIR) for Thorotrast and comparison patients (Denmark and Sweden) were estimated and relative risks (RR), adjusted for population, age and sex, were generated with multivariate statistical modeling. For U.S. patients, comparable procedures were used to estimate standardized mortality ratios (SMR) and RR, representing the first evaluation of long-term, site-specific cancer mortality in this group. Compared with nonexposed patients, significantly increased risks in Thorotrast patients were observed for all incident cancers combined (RR = 3.4, 95% CI 2.9-4.1, n = 480, Denmark and Sweden) and for cancer mortality (RR = 4.0, 95% CI 2.5-6.7, n = 114, U.S.). Approximately 335 incident cancers were above expectation, with large excesses seen for cancers of the liver, bile ducts and gallbladder (55% or 185 excess cancers) and leukemias other than CLL (8% or 26 excess cancers). The RR of all incident cancers increased with time since angiography (P < 0.001) and was threefold at 40 or more years; significant excesses (SIR = 4.0) persisted for 50 years. Increasing cumulative dose of radiation was associated with an increasing risk of all incident cancers taken together and with cancers of the liver, gallbladder, and peritoneum and other digestive sites; similar findings were observed for U.S. cancer mortality. A marginally significant dose response was observed for the incidence of pancreas cancer (P = 0.05) but not for lung cancer. Our study confirms the relationship between Thorotrast and increased cancer incidence at sites of Thorotrast deposition and suggests a possible association with pancreas cancer. After injection with >20 ml Thorotrast, the cumulative excess risk of cancer incidence remained elevated for up to 50 years and approached 97%. Caution is needed in interpreting the excess risks observed for site-specific cancers, however, because of the potential bias associated with the selection of cohort participants, noncomparability with respect to the internal or external comparison groups, and confounding by indication. Nonetheless, the substantial risks associated with liver cancer and leukemia indicate that unique and prolonged exposure to alpha-particle-emitting Thorotrast increased carcinogenic risks.

Adult↗

PubMed2002

Uncertainty, low-dose extrapolation and the threshold hypothesis.

Risk-based radiation protection policy is influenced by estimated risk and by the uncertainty of that estimate. Thus, if the upper limit, at (say) 95% probability, of risk associated with a given radiation dose is at an 'acceptable' level, it is unlikely (or not credible) that the true level of risk associated with the dose is at an unacceptable level. Central estimates presented alone, in the absence of probability limits, lack this safety factor. Estimating cancer risks from low doses of ionising radiation involves extrapolation of risk estimates based on high-dose data to the much lower dose levels that characterize the vast majority of exposures of regulatory concern. Proof of a universal low-dose threshold, below which there is no radiation-related risk, would revolutionise radiation protection. Available data fail to provide such proof and, in fact, leave considerable room for the possibility that DNA damage from a single photon can contribute to the carcinogenic process. Allowing for the possibility of a threshold would, however, remove very little of the regulatory burden associated with the so-called linear, no-threshold hypothesis, unless that possibility were a virtual certainty.

Humans↗

PubMed2002

Cancer incidence after nasopharyngeal radium irradiation.

BACKGROUND: From 1940 until 1970, nasopharyngeal radium irradiation was used to treat children and military personnel suffering from Eustachian tube failure attributable to local lymphoid hyperplasia. METHODS: We studied cancer incidence in a cohort of 4339 Dutch patients treated with nasopharyngeal radium irradiation, mostly in childhood, and 4104 frequency-matched nonexposed subjects. Average doses to the nasopharynx, pituitary gland, brain, and thyroid gland were 275, 10.9, 1.8, and 1.5 cGy, respectively. We assessed cancer incidence from cancer registry linkage (1989-1996), self-report including medical verification (1945-1988), and death certificates (1945-1996). RESULTS: During 18-50 years of follow-up, four thyroid malignancies (standardized incidence ratio [SIR] = 2.8; 95% confidence interval [CI] = 0.8-7.2) and five malignant brain tumors (SIR = 1.3; CI = 0.4-3.1) were observed. Increased risks were observed for malignancies of lymphoproliferative and hematopoietic origin (SIR = 1.9; CI = 1.2-2.8) and breast cancer (SIR = 1.5; CI = 1.1-2.1). Strong dose-response trends could not be demonstrated for any cancer outcome, although relative risk estimates were elevated in the highest-dose category for head and neck cancer and breast cancer. CONCLUSIONS: These data provide little evidence for a high excess risk of cancer associated with nasopharyngeal radium irradiation treatment as applied in the Netherlands. Inconsistent findings across studies and public concern warrant the continuing follow-up of available cohorts.

Adolescent↗

PubMed2002

Health effects from fallout.

This paper primarily discusses health effects that have resulted from exposures received as a result of above-ground nuclear tests, with emphasis on thyroid disease from exposure to 131I and leukemia and solid cancers from low dose rate external and internal exposure. Results of epidemiological studies of fallout exposures in the Marshall Islands and from the Nevada Test Site are summarized, and studies of persons with exposures similar to those from fallout are briefly reviewed (including patients exposed to 131I for medical reasons and workers exposed externally at low doses and low dose rates). Promising new studies of populations exposed in countries of the former Soviet Union are also discussed and include persons living near the Semipalatinsk Test Site in Kazakhstan, persons exposed as a result of the Chernobyl accident, and persons exposed as a result of operations of the Mayak Nuclear Plant in the Russian Federation. Very preliminary estimates of cancer risks from fallout doses received by the United States population are presented.

Health↗

PubMed2002

Late health effects of childhood nasopharyngeal radium irradiation: nonmelanoma skin cancers, benign tumors, and hormonal disorders.

Nasopharyngeal radium irradiation (NRI) was widely used from 1940 through 1970 to treat otitis serosa in children and barotrauma in airmen and submariners. We assessed whether NRI-exposed individuals were at higher risk for benign tumors, nonmelanoma skin cancer, thyroid disorders, and conditions related to regulatory control of anterior pituitary hormones, such as growth and reproductive characteristics. We conducted a retrospective cohort study in 3,440 NRI-exposed and 3,088 nonexposed subjects, who as children were treated at nine ear, nose and throat clinics in The Netherlands between 1945 and 1981. Based on information from original medical records, we traced vital status through follow-up at municipal population registries. Disease status (including medical confirmation) and indicators of pituitary gland radiation damage were assessed from a self-administered questionnaire in 1997. The average radiation doses were 11, 7, and 1.5 cGy for pituitary, parotid, and thyroid gland, respectively, and 3.2 cGy for the facial skin. Among exposed subjects, 23 benign head and neck tumors were observed, compared with 21 among nonexposed subjects. Elevated risk of basal cell carcinoma of the head and neck area was observed in exposed subjects (odds ratio = 2.6; 95% confidence interval: 1.0-6.7). Exposed and nonexposed groups did not differ substantially with regard to thyroid disorders, height, and reproductive characteristics, although exposed males more frequently reported a history of fertility problems compared with nonexposed males (odds ratio = 1.4; 95% confidence interval: 1.0-2.1). We found no evidence of highly elevated risk of benign head and neck tumors, nonmelanoma skin cancer, thyroid disorders, or indicators of pituitary radiation damage after childhood NRI in The Netherlands.

Adolescent↗

PubMed2002

Malignant neoplasms after radiation therapy for peptic ulcer.

Most information on radiation-related cancer risk comes from the Life Span Study (LSS) of the Japanese atomic bomb survivors. Stomach cancer mortality rates are much higher in Japan than in the U.S., making the applicability of LSS findings to the U.S. population uncertain. A unique cohort of U.S. patients who were irradiated for peptic ulcer to control gastric secretion provides a different perspective on risk. Cancer mortality data were analyzed and relative risks estimated for 3719 subjects treated by radiotherapy (mean stomach dose 14.8 Gy) and/or by surgery and medication during the period 1936-1965 and followed through 1997 (average 25 years). Compared to the U.S. rates, stomach cancer mortality was significantly increased for irradiated and nonirradiated patients (observed/expected = 3.20 and 1.52, respectively). We observed strong evidence of exposure-related excess mortality from cancer of the stomach (RR 2.6, 95% CI 1.3, 5.1), pancreas (RR 2.7, 95% CI 1.5, 5.1), and lung (RR 1.5, 95% CI 1.1, 2.1), with commensurate radiation dose responses in analyses that included nonexposed patients. However, the dose responses for these cancers were not significant when restricted to exposed patients. Our excess relative risk per gray estimate of 0.20 at doses <or=10 Gy (95% CI 0, 0.73) is consistent with the estimate of 0.24 (95% CI 0.10, 0.40) obtained from the LSS study with the linear model.

Adult↗