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Biomedical subjects

J D Boice

Publications and source records attributed to J D Boice.

At least 55 records · Page 3Linked to original sources
PubMed1998

p53 mutations in cyclophosphamide-associated bladder cancer.

Cyclophosphamide is a known bladder carcinogen, with cumulative dose directly related to increased risk. There is no consensus, however, on which major cyclophosphamide metabolite (i.e., acrolein or phosphoramide mustard) drives bladder carcinogenesis. We examined 19 cyclophosphamide-related bladder tumors to test the hypothesis that they might contain somatic mutations in the p53 tumor suppressor gene that could link a specific metabolite to the etiology of these cancers. Forty-three % (9 of 19) of the cases had a mutation in p53, with a predominance at G:C bp (7 of 9, 77%), a preference for non-CpG sites (6 of 7, 86%), and frequent G:C-->A:T transitions (5 of 7, 71%). The p53 mutation spectrum of these cyclophosphamide-associated bladder cancers differed significantly from patterns reported for sporadic (P = 0.020), smoking-related (0.043), and schistosomiasis-linked (P = 0.002) tumors but not arylamine-associated neoplasms (P = 0.860). Differences between the cyclophosphamide and arylamine-associated spectra included an unusual degree of clustering of exon 6 mutations (43% versus 17%, respectively) and an absence of multiple mutations in the former. Notably lacking in our series were G:C-->T:A transversions, the principal mutation associated with acrolein. Instead, the mutation spectrum matches the phosphoramide mustard adduction sequences determined by a repetitive primer-extension assay (P = 0.024), indicating that this metabolite might be a key mutagen in cyclophosphamide-related bladder cancer.

Adult↗
PubMed1998

Do recorded doses overestimate true doses received by Chernobyl cleanup workers? Results of cytogenetic analyses of Estonian workers by fluorescence in situ hybridization.

Studies of workers who were sent to Chernobyl after the 1986 reactor accident are being conducted to provide a better understanding of the effects of chronic low-dose radiation exposures. A crucial component to these investigations is an accurate assessment of the radiation doses received during the cleanup activities. To provide information on biological measurements of dose, fluorescence in situ hybridization (FISH) with whole-chromosome painting probes has been applied to quantify stable chromosome aberrations (translocations and insertions) among a defined cohort of 4,833 cleanup workers from Estonia. Cytogenetic analysis of 48-h lymphocyte cultures from 118 Estonian cleanup workers (10.3 cGy mean recorded dose; 25 cGy maximum), 29 Estonian population controls and 21 American controls was conducted by three laboratories. More than 258,000 painted metaphases were evaluated. Overall, we observed lower translocation frequencies than has been reported in previous studies using FISH among Chernobyl cleanup workers. In our data, a clear association with increased levels of translocations was seen with increasing age at blood drawing. There was no correlation, however, between aberration frequency and recorded measurements of physical dose or any category of potential high-dose and high-dose-rate exposure such as being sent to Chernobyl in 1986, working on the roof near the damaged nuclear reactor, working in special zones or having multiple tours. In fact, the translocation frequency was lower among the exposed workers than the controls, though not significantly so. To estimate the level of effect that would have been expected in a population of men having an average dose of approximately 10 cGy, blood from six donors was exposed to low-LET radiation, and more than 32,000 metaphases were scored to estimate dose-response coefficients for radiation-induced translocations in chromosome pairs 1, 2 and 4. Based on these results, we estimate that had this group of 118 men received an average whole-body dose of 10-11 cGy, as chronic or acute exposures, an increase in the mean frequency of chromosome translocations of more than 40-65% would have been observed in their lymphocytes compared to findings in nonirradiated controls. In spite of evaluating more than a quarter of a million metaphases, we were unable to detect any increase in the mean, median or range in chromosome aberrations in lymphocyte cultures from a group of Estonian men who took part in the cleanup of the Chernobyl nuclear power site and those who did not. We conclude that it is likely that recorded doses for these cleanup workers overestimate their average bone marrow doses, perhaps substantially. These results are consistent with several negative studies of cancer incidence in Chernobyl cleanup workers and, if borne out, suggest that future studies may not be sufficiently powerful to detect increases in leukemia or cancer, much less distinguish differences between the effects of chronic compared to brief radiation exposures.

Adult↗
PubMed1997

Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk.

CONTEXT: There is a substantial risk of a second cancer for persons with hereditary retinoblastoma, which is enhanced by radiotherapy. OBJECTIVE: To examine long-term risk of new primary cancers in survivors of childhood retinoblastoma and quantify the role of radiotherapy in sarcoma development. DESIGN: Cohort incidence study of patients with retinoblastoma followed for a median of 20 years, and nested case-control study of a radiation dose-response relationship for bone and soft tissue sarcomas. SETTING/PARTICIPANTS: A total of 1604 patients with retinoblastoma who survived at least 1 year after diagnosis, identified from hospital records in Massachusetts and New York during 1914 to 1984. RESULTS: Incidence of subsequent cancers was statistically significantly elevated only in the 961 patients with hereditary retinoblastoma, in whom 190 cancers were diagnosed, vs 6.3 expected in the general population (relative risk [RR], 30 [95% confidence interval, 26-47]). Cumulative incidence (+/-SE) of a second cancer at 50 years after diagnosis was 51.0% (+/-6.2%) for hereditary retinoblastoma, and 5.0% (+/-3.0%) for nonhereditary retinoblastoma. All 114 sarcomas of diverse histologic types occurred in patients with hereditary retinoblastoma. For soft tissue sarcomas, the RRs showed a stepwise increase at all dose categories, and were statistically significant at 10 to 29.9 Gy and 30 to 59.9 Gy. A radiation risk for all sarcomas combined was evident at doses above 5 Gy, rising to 10.7-fold at doses of 60 Gy or greater (P<.05). CONCLUSIONS: Genetic predisposition has a substantial impact on risk of subsequent cancers in retinoblastoma patients, which is further increased by radiation treatment. A radiation dose-response relationship is demonstrated for all sarcomas and, for the first time in humans, for soft tissue sarcomas. Retinoblastoma patients should be examined for new cancers and followed into later life to determine whether their extraordinary cancer risk extends to common cancers of adulthood.

Adolescent↗
PubMed1997

Risk of second malignant neoplasms among long-term survivors of testicular cancer.

BACKGROUND: We have quantified the site-specific risk of second malignant neoplasms among nearly 29,000 survivors (> or = 1 year) of testicular cancer, taking into account the histologic type of initial cancer and the primary therapy used to treat it. METHODS: The study cohort consisted of 28,843 men identified within 16 population-based tumor registries in North America and Europe; over 3300 men had survived more than 20 years. New invasive cancers were identified through a search of registry files. RESULTS: Second cancers were reported in 1406 men (observed-to-expected ratio [O/E] = 1.43; 95% confidence interval = 1.36-1.51), with statistically significant excesses noted for acute lymphoblastic leukemia (O/E = 5.20), acute nonlymphocytic leukemia (O/E = 3.07), melanoma (O/E = 1.69), non-Hodgkin's lymphoma (O/E = 1.88), and cancers of the stomach (O/E = 1.95), colon (O/E = 1.27), rectum (O/E = 1.41), pancreas (O/E = 2.21), prostate (O/E = 1.26), kidney (O/E = 1.50), bladder (O/E = 2.02), thyroid (O/E = 2.92), and connective tissue (O/E = 3.16). Overall risk was similar after seminomas (O/E = 1.42) or nonseminomatous tumors (O/E = 1.50). Risk of solid tumors increased with time since the diagnosis of testicular cancer, yielding an O/E = 1.54 (O = 369) among 20-year survivors (two-sided P for trend = .00002). Secondary leukemia was associated with both radiotherapy and chemotherapy, whereas excess cancers of the stomach, bladder, and, possibly, pancreas were associated mainly with radiotherapy. CONCLUSIONS: Men with testicular cancer continue to be at significantly elevated risk of second malignant neoplasms for more than two decades following initial diagnosis. Patterns of excess second cancers suggest that many factors may be involved, although the precise roles of treatment, natural history, diagnostic surveillance, and other influences are yet to be clarified.

Antineoplastic Agents↗
PubMed1997

Breast implants and cancer risk in Denmark.

Although millions of women worldwide have received breast implants for cosmetic or medical reasons, possible late effects (in particular cancer) have not been well studied. To provide quantitative information on cancer occurrence among women undergoing breast implant surgery, 1,135 women treated for cosmetic reasons in Denmark were evaluated. Patients were identified using the nationwide Hospital Discharge Registry with linkage to the nationwide Danish Cancer Registry to determine subsequent cancer incidence. The average age of the women at implant surgery was 31 years, and the average follow-up was 8.4 years, up to a maximum of 17 years. Overall, 27 cancers developed after implant surgery compared with 24.7 expected based on incidence rates from the general population (standardized incidence ratio [SIR] = 1.1; 95% CI: 0.7-1.6). Eight breast cancers were observed vs. 7.8 expected (SIR = 1.0; 95% CI: 0.4-2.0). No evidence was found to link breast implants with increased cancer risk in the decade after surgery. While the results are encouraging, longer follow-up into later life will be necessary to assess fully any possible adverse effects.

Adolescent↗
PubMed1997

Solid cancers after bone marrow transplantation.

BACKGROUND: The late effects of bone marrow transplantation, including cancer, need to be determined in a large population at risk. METHODS: We studied 19,229 patients who received allogeneic transplants (97.2 percent) or syngeneic transplants (2.8 percent) between 1964 and 1992 at 235 centers to evaluate the risk of the development of a new solid cancer. Risk factors relating to the patient, the transplant, and the course after transplantation were evaluated. RESULTS: The transplant recipients were at significantly higher risk of new solid cancers than the general population (observed cases, 80; ratio of observed to expected cases, 2.7; P<0.001). The risk was 8.3 times higher than expected among those who survived 10 or more years after transplantation. The cumulative incidence rate was 2.2 percent (95 percent confidence interval, 1.5 to 3.0 percent) at 10 years and 6.7 percent (95 percent confidence interval, 3.7 to 9.6 percent) at 15 years. The risk was significantly elevated (P<0.05) for malignant melanoma (ratio of observed to expected cases, 5.0) and cancers of the buccal cavity (11.1), liver (7.5), brain or other parts of the central nervous system (7.6), thyroid (6.6), bone (13.4), and connective tissue (8.0). The risk was higher for recipients who were younger at the time of transplantation than for those who were older (P for trend <0.001). In multivariate analyses, higher doses of total-body irradiation were associated with a higher risk of solid cancers. Chronic graft-versus-host disease and male sex were strongly linked with an excess risk of squamous-cell cancers of the buccal cavity and skin. CONCLUSIONS: Patients undergoing bone marrow transplantation have an increased risk of new solid cancers later in life. The trend toward an increased risk over time after transplantation and the greater risk among younger patients indicate the need for life-long surveillance.

Adolescent↗
PubMed1997

[Cancer in the parents of children with cancer].

Certain types of cancer in children and young adults have been linked with an increased risk of cancer in close relatives. However, the relation between childhood cancer and familial risk remains to be fully assessed in population-based studies. We conducted a nationwide study in Denmark of 11,380 parents of children with cancer. The children were identified from records in the Danish Cancer Registry; their parents were identified from population registers. The occurrence and rate of cancer in the parents were determined with use of the Cancer Registry's files and compared with national incidence rates for various categories of tumour. Overall, 1445 cancers were diagnosed in the parents, as compared with 1496 expected from national incidence rates, to yield standardized incidence ratios of 0.97 (95 percent confidence interval, 0.92 to 1.02) for all parents, 0.99 for mothers, and 0.94 for fathers. The lower rate of cancer among fathers reflected their lower standardized incidence ratio for lung cancer (0.76; 95 percent confidence interval, 0.63 to 0.91), as calculated from 114 observations. Genetic determinants are important in several types of childhood cancer, but the genetic susceptibility to tumours does not generally extend to the parents of children with cancer, not do the patterns of incidence point to the influence of shared environmental factors. Thus, cancer in children should not be viewed as a general marker for an increased risk of cancer in the patient's parents.

Adolescent↗
PubMed1997

Lung cancer risk from residential radon: meta-analysis of eight epidemiologic studies.

BACKGROUND: Studies of underground miners exposed to radioactive radon and its decay products have found that exposure increases risk of lung cancer. Consequently, when radon was found to accumulate in houses, there was concern about the public health impact from exposure to a known carcinogen. Estimates on the basis of studies of underground miners suggest that indoor radon may account for 6000-36,000 lung cancer deaths each year in the United States. Because of differences between working in underground mines and living in houses, estimates are subject to major uncertainties. Numerous case-control studies were launched to assess directly the lung cancer risk from indoor radon. Some studies report positive or weakly positive findings, while others report no increased risk. Thus, the potential hazard from indoor radon remains answered only indirectly through miner studies, experimental animal studies, and cellular studies. PURPOSE: To provide more information on the risk of lung cancer from indoor radon, we conducted a meta-analysis of all case-control studies that included at least 200 case subjects each and that used long-term indoor radon measurements. METHODS: Eight studies were available and included a total of 4263 lung cancer case subjects and 6612 control subjects. From the published results of each study, confounder-adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) for categories of radon concentration were obtained, and weighted linear regression analyses were performed. RESULTS: The combined trend in the RR was significantly different from zero (two-sided P = .03), and an estimated RR of 1.14 (95% CI = 1.0-1.3) at 150 Bq/m3 was found. An influence analysis indicated that no single study dominated the combined results. The exposure-response trend was similar to model-based extrapolations from miners and to RRs computed directly from miners with low cumulative exposures. However, there were significant differences in the study-specific estimates of the exposure response (two-sided P < .001), which were not explained by study differences in percent of the defined exposure interval covered by radon measurements, mean number of residences per subject, and other factors. CONCLUSIONS: Meta-analyses are valuable for identifying differences among studies and for summarizing results, but they should be interpreted cautiously when expected RRs are low as with indoor radon exposure, when there is study heterogeneity and where there is the potential for confounding and exposure misclassification. Nonetheless, the results of this meta-analysis suggest that the risk from indoor radon is not likely to be markedly greater than that predicted from miners and indicate that the negative exposure response reported in some ecologic studies is likely due to model misspecification or uncontrolled confounding and can be rejected. IMPLICATIONS: Until ongoing case-control studies of indoor radon are completed and the data are pooled and analyzed, the studies of underground miners remain the best source of data to use to assess risk from indoor radon. This meta-analysis provides support for their general validity.

Air Pollution, Indoor↗
PubMed1997

Cancer following breast reduction surgery in Denmark.

Intuitively, breast tissue mass should be directly related to a woman's risk of breast cancer, simply because having more cells at risk would seem to increase the potential for malignant transformation. However, studies attempting to link breast size with breast cancer risk have been inconsistent. Limitations include crude measures of breast size, the inability to distinguish glandular from adipose tissue, and the confounding influence of co-factors such as obesity. A nationwide study in Denmark was undertaken to investigate the effect of breast reduction surgery on the subsequent risk of breast cancer, including an evaluation of the patterns of risk by age and time since surgery. The Danish Hospital Discharge Registry was used to identify women who underwent reduction mammaplasty between 1977 and 1992. Linkage based on personal identification numbers with the Danish Cancer Registry provided information on cancer incidence. Expected numbers of cancers were calculated from rates in the general population. Among 7,720 women whose breasts were surgically reduced, 182 cancers were subsequently observed cf 209 expected (standardized incidence ratio [SIR] = 0.9;95 percent confidence interval [CI] = 0.7-1.0). Breast cancer was significantly reduced by nearly 50 percent (29 observed cf 53.9 expected, SIR = 0.5, CI = 0.4-0.8), and accounted for the overall deficit in cancer. The risk reductions were related inversely to age at surgery, with significant deficits apparent only among women 40 years of age and older at surgery and especially among those over age 50 (SIR = 0.3). No clear trend was apparent with increasing years post-surgery. The findings indicate that breast reduction surgery among women over age 40 is associated with a lower subsequent risk of breast cancer, but the surgery and presumably glandular mass appear less closely related to breast cancer risk among younger women.

Adolescent↗
PubMed1997

Occupational and environmental radiation and cancer.

Epidemiologic evidence on the relation between occupational and environmental radiation and cancer is reviewed. Studies of pioneering radiation workers, underground miners, and radium dial painters revealed excess cancer deaths and contributed to the setting of radiation protection standards and to theories of carcinogenesis. Occupational exposures today are generally much lower than in the past, thus any associated increases in cancer will be difficult to detect. Pooling investigations of these more recently exposed workers, however, has the potential to validate current estimates of risk used in radiation protection. New information on the effects of chronic radiation exposure also may come from studies in the former Soviet Union of Chernobyl clean-up workers and of workers at the Mayak nuclear facilities. Studies of environmental radiation exposures, other than radon, are largely inconclusive, due mainly to the difficulties in detecting the low risks associated with low dose exposures. Thyroid cancer, however, has been linked to environmental radiation from the Chernobyl accident and from nuclear weapons tests. Low-level radiation released during normal operations at nuclear plants has not been found to increase cancer rates in surrounding populations. Radon, a human carcinogen, is the most ubiquitous exposure to human populations; remediating high residential-radon levels is recommended, recognizing that the exposure can never be removed completely because it occurs naturally.

Air Pollutants, Radioactive↗
PubMed1997

Magnetic field exposure assessment in a case-control study of childhood leukemia.

Epidemiologic evaluation of the relation between magnetic field exposures and cancer depends critically on study design, particularly the methods used for exposure assessment. We incorporated a complex magnetic field exposure assessment protocol into a large incident case-control study of childhood leukemia. We measured residential magnetic fields using a standard protocol in current and former homes of 638 cases and 620 controls and determined wire codes for 414 case-control pairs. We chose a time-weighted average of magnetic field measurements in each eligible home, weighted by the time the subject lived in each home as the main exposure metric for each subject. We found that 24-hour bedroom magnetic field measurements adequately characterize children's residential exposure and that measuring other rooms contributes only slightly to the estimate of average residential exposure to magnetic fields. Front door measured fields provide useful exposure information when interior measurements are missing. If feasible, measuring multiple homes in which the subject has resided is preferable to measuring a single home. A similar distribution of wire codes for controls agreeing or refusing to participate in our study implies that risk estimates derived from wire code data will not be influenced by response bias.

Adolescent↗
PubMed1997

Biodosimetry of Chernobyl cleanup workers from Estonia and Latvia using the glycophorin A in vivo somatic cell mutation assay.

The reactor accident at Chernobyl in 1986 necessitated a massive environmental cleanup that involved over 600,000 workers from all 15 Republics of the former Soviet Union. To determine whether the whole-body radiation received by workers in the course of these decontamination activities resulted in a detectable biological response, over 1,500 blood samples were obtained from cleanup workers sent from two Baltic countries, Estonia and Latvia. Here we report the results of studies of biodosimetry using the glycophorin A (GPA) locus in vivo somatic cell mutation assay applied to 734 blood samples from these workers, to 51 control samples from unexposed Baltic populations and to 94 samples from historical U.S. controls. The data reveal inconsistent evidence that the protracted radiation exposures received by these workers resulted in a significant dose-associated increase in GPA locus mutations compared with the controls. Taken together, these data suggest that the average radiation exposure to these workers does not greatly exceed 10 cGy, the minimum levels at which radiation effects might be detectable by the assay. Although the protracted nature of the exposure may have reduced the efficiency of induction of GPA locus mutations, it is likely that the estimated physical doses for these cleanup worker populations (median reported dose 9.5 cGy) were too low to result in radiation damage to erythroid stem cells that can be detected reliably by this method.

Alleles↗
PubMed1997

Thyroid nodularity and cancer among Chernobyl cleanup workers from Estonia.

Thyroid examinations, including palpation, ultrasound and, selectively, fine-needle aspiration biopsy, were conducted on nearly 2,000 Chernobyl cleanup workers from Estonia to evaluate the occurrence of thyroid cancer and nodular thyroid disease among men with protracted exposure to ionizing radiation. The examinations were conducted in four cities in Estonia during March-April 1995, 9 years after the reactor accident. The study population was selected from a predefined cohort of 4,833 cleanup workers from Estonia under surveillance for cancer incidence. These men had been sent to Chernobyl between 1986 and 1991 to entomb the damaged reactor, remove radioactive debris and perform related cleanup activities. A total of 2,997 men were invited for thyroid screening and 1,984 (66%) were examined. Estimates of radiation dose from external sources were obtained from military or other institutional records, and details about service dates and types of work performed while at Chernobyl were obtained from a self-administered questionnaire. Blood samples were collected for assay of chromosomal translocations in circulating lymphocytes and loss of expression of the glycophorin A (GPA) gene in erythrocytes. The primary outcome measure was the presence or absence of thyroid nodules as determined by the ultrasound examination. Of the screened workers, 1,247 (63%) were sent to Chernobyl in 1986, including 603 (30%) sent in April or May, soon after the accident. Workers served at Chernobyl for an average of 3 months. The average age was 32 years at the time of arrival at Chernobyl and 40 years at the time of thyroid examination. The mean documented radiation dose from external sources was 10.8 cGy. Biological indicators of exposure showed low correlations with documented dose, but did not indicate that the mean dose for the population was higher than the average documented dose. Ultrasound examinations revealed thyroid nodules in 201 individuals (10.2%). The prevalence of nodules increased with age at examination, but no significant associations were observed with recorded dose, date of first duty at Chernobyl, duration of service at Chernobyl, building the sarcophagus or working on the roof of neighboring buildings or close to the damaged reactor. Nodularity showed a nonsignificant (p(1) = 0.10) positive association with the proportion of lymphocytes with chromosome translocations, but associations with the frequency of variant erythrocytes in the GPA assay were weak and unstable (p(1) > or = 0.46). The majority of fine-needle biopsies taken on 77 study participants indicated benign nodular disease. However, two cases of papillary carcinoma and three benign follicular neoplasms were identified and referred for treatment. Both men with thyroid cancer had been sent to Chernobyl in May of 1986, when the potential for exposure to radioactive iodines was greatest. Chernobyl cleanup workers from Estonia did not experience a markedly increased risk of nodular thyroid disease associated with exposure to external radiation. Possible reasons for the apparent absence of effect include low radiation doses, the protracted nature of the exposure, errors in dose measurement, low sensitivity of the adult thyroid gland or the insufficient passage of time for a radiation effect to be expressed.

Adenocarcinoma, Follicular↗
PubMed1997

The Estonian study of Chernobyl cleanup workers: I. Design and questionnaire data.

Nearly 2% of the male population of Estonia aged 20-39 years were sent to Chernobyl to assist in the cleanup activities after the reactor accident. A cohort of 4,833 cleanup workers was assembled based on multiple and independent sources of information. Information obtained from 3,704 responses to a detailed questionnaire indicated that 63% of the workers were sent to Chernobyl in 1986; 54% were of Estonian and 35% of Russian ethnicity; 72% were married, and 1,164 of their 5,392 children were conceived after the Chernobyl disaster. The workers were less educated than their counterparts in the general population of Estonia, and only 8.5% had attended university. Based on doses entered in worker records, the mean dose was 11 cGy, with only 1.4% over 25 cGy. Nearly 85% of the workers were sent as part of military training activities, and more than half spent in excess of 3 months in the Chernobyl area. Thirty-six percent of the workers reported having worked within the immediate vicinity of the accident site; 11.5% worked on the roofs near the damaged reactor, clearing the highly radioactive debris. The most commonly performed task was the removal and burial of topsoil (55% of the workers). Potassium iodide was given to over 18% of the men. The study design also incorporates biological indicators of exposure based on the glycophorin A mutational assay of red blood cells and chromosome translocation analyses of lymphocytes; record linkage with national cancer registry and mortality registry files to determine cancer incidence and cause-specific mortality; thyroid screening examinations with ultrasound and fine-needle biopsy; and cryopreserved white blood cells and plasma for future molecular studies. Comprehensive studies of Chernobyl cleanup workers have potential to provide new information about cancer risks due to protracted exposures to ionizing radiation.

Alcohol Drinking↗