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LE Magazine April 2004

Ionizing radiation and cancer risk: evidence from epidemiology.
Epidemiological studies provide the primary data on the carcinogenic effects of radiation in humans. Much of what is known has come from studies of the atomic bomb survivors, and to a lesser extent from patients receiving radiotherapy. These studies demonstrate that exposure to moderate to high doses of radiation increases the risk of cancer in most organs. For all solid cancers combined, cancers of the thyroid, breast and lung, and leukemia, risk estimates are fairly precise, and associations have been found at relatively low doses (<0.2 Gy). Associations between radiation and cancers of the salivary glands, stomach, colon, bladder, ovary, central nervous system and skin have also been reported, but the relationships are not as well quantified. Associations between radiation and cancers of the liver and esophagus, and to a lesser extent multiple myeloma and non-Hodgkin's lymphoma, have been reported in a few studies, but results are inconsistent. Chronic lymphocytic leukemia, Hodgkin's disease, and cancers of the pancreas, prostate, testis and cervix have rarely been linked to radiation exposure. A linear no-threshold model adequately describes the dose-response relationship for solid cancers, although at extremely high doses the risk appears to flatten out. Because few populations have been followed until the end of life, the temporal patterns of risk are not completely known. An increased risk, however, does continue for several decades. In contrast, radiation-related leukemias begin to occur shortly (2-3 years) after exposure and, at least in the A-bomb survivors, a linear-quadratic dose response seems to fit the data better than a pure linear model. Radiation does not act entirely in isolation. It can interact with other carcinogens, e.g. tobacco or chemotherapeutic agents, and with host factors such as age at exposure, gender or reproductive history. Interactions with medical interventions or with certain heritable mutations have also been suggested. While the studies of high-dose exposures are essential for understanding the overall biological consequences of radiation exposure, the public is more concerned about the long-term health effects from protracted exposures at low doses. Unfortunately, the inherent limitations of epidemiology make it extremely difficult to directly quantify health risks from these exposures. While most epidemiological data are compatible with linear extrapolations from exposures at high doses or high dose rates, they cannot entirely exclude other possibilities. As the field of epidemiology advances, understanding more about the health effects of prolonged and low-dose exposures will be the next challenge.

Radiat Res . 1998 Nov;150(5 Suppl):S30-41

The risk of breast cancer after irradiation of the thymus in infancy.
It is well established that exposure to ionizing radiation during or after puberty increases a woman's risk for breast cancer, but it is less clear whether exposure to ionizing radiation very early in life is also carcinogenic. We studied the incidence of breast cancer prospectively in a cohort of 1201 women who received x-ray treatment in infancy for an enlarged thymus gland and in their 2469 nonirradiated sisters. After an average of 36 years of follow-up, there were 22 breast cancers in the irradiated group and 12 among their sisters, yielding an adjusted rate ratio of 3.6 (95% confidence interval, 1.8 to 7.3). The estimated mean absorbed dose of radiation to the breast was 0.69 Gy. The first breast cancer was diagnosed 28 years after irradiation. The dose-response relation was linear (P less than 0.0001), with a relative risk of 3.48 for 1 Gy of radiation (95% confidence interval, 2.1 to 6.2) and an additive excess risk of 5.7 per 10(4) person-years per gray (95% confidence interval, 2.9 to 9.5). We conclude that exposure of the female breast to ionizing radiation in infancy increases the risk of breast cancer later in life.

N Engl J Med. 1989 Nov 9;321(19):1281-4

Breast cancer in women with scoliosis exposed to multiple diagnostic x rays.
Although exposure to ionizing radiation is a recognized risk factor for breast cancer, the potential hazard from low-dose, fractionated exposures during early breast development has not been thoroughly evaluated. Women with scoliosis represent a valuable population for studying this issue because they are exposed to multiple diagnostic x rays during childhood and adolescence, times when the breast may be highly sensitive to the carcinogenic effects of radiation. A study was conducted of 1,030 women with scoliosis who were seen at four Minneapolis area medical facilities between 1935 and 1965. The average age at diagnosis was 12.3 years; 60% of the women had idiopathic scoliosis. Individual x-ray films were counted and the number per patient ranged from 0 to 618 films (mean, 41.5). On average, the x-ray exposures were given over an 8.7-year period. Ninety percent of the women were located, of whom over 92% responded to a mail questionnaire or telephone interview. The average period of observation was 26 years. Overall, 11 cases of breast cancer were reported, compared with six expected (standardized incidence ratio = 1.82, 90% confidence interval = 1.0-3.0). Excess risk increased with time since exposure and was highest among those followed for more than 30 years (standardized incidence ratio = 2.4). Risk also increased with the number of x rays and with the estimated radiation dose to the breast (mean, 13 rad). These data suggest that frequent exposure to low-level diagnostic radiation during childhood or adolescence may increase the risk of breast cancer.

J Natl Cancer Inst. 1989 Sep 6;81(17):1307-12

Incidence and occurrence of total (first-ever and recurrent) stroke.
BACKGROUND AND PURPOSE: It has recently been hypothesized that the figure of approximately half a million strokes substantially underestimates the actual annual stroke burden for the United States . The majority of previously reported studies on the epidemiology of stroke used relatively small and homogeneous population-based stroke registries. This study was designed to estimate the occurrence, incidence, and characteristics of total (first-ever and recurrent) stroke by using a large administrative claims database representative of all 1995 US inpatient discharges. METHODS: We used the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, release 4, which contains approximately 20% of all 1995 US inpatient discharges. Because the accuracy of International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) coding is suboptimal, we performed a literature review of ICD-9-CM 430 to 438 validation studies. The pooled results from the literature review were used to make appropriate adjustments in the analysis to correct for some of the inaccuracies of the diagnostic codes. RESULTS: There were 682 000 occurrences of stroke with hospitalization (95% CI 660 000 to 704 000) and an estimated 68 000 occurrences of stroke without hospitalization. The overall incidence rate for occurrence of total stroke (first-ever and recurrent) was 259 per 100,000 population (age- and sex-adjusted to 1995 US population). Incidence rates increased exponentially with age and were consistently higher for males than for females. CONCLUSIONS: We conservatively estimate that there were 750,000 first-ever or recurrent strokes in the United States during 1995. This new figure emphasizes the importance of preventive measures for a disease that has identifiable and modifiable risk factors and for the development of new and improved treatment strategies and infrastructures that can reduce the consequences of stroke.

Stroke. 1999 Dec;30(12):2523-8

Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group.
BACKGROUND: The combined thickness of the intima and media of the carotid artery is associated with the prevalence of cardiovascular disease. We studied the associations between the thickness of the carotid-artery intima and media and the incidence of new myocardial infarction or stroke in persons without clinical cardiovascular disease. METHODS: Noninvasive measurements of the intima and media of the common and internal carotid artery were made with high-resolution ultrasonography in 5,858 subjects 65 years of age or older. Cardiovascular events (new myocardial infarction or stroke) served as outcome variables in subjects without clinical cardiovascular disease (4,476 subjects) over a median follow-up period of 6.2 years. RESULTS: The incidence of cardiovascular events correlated with measurements of carotid-artery intima-media thickness. The relative risk of myocardial infarction or stroke increased with intima-media thickness (P<0.001). The relative risk of myocardial infarction or stroke (adjusted for age and sex) for the quintile with the highest thickness as compared with the lowest quintile was 3.87 (95% confidence interval, 2.72 to 5.51). The association between cardiovascular events and intima-media thickness remained significant after adjustment for traditional risk factors, showing increasing risks for each quintile of combined intima-media thickness, from the second quintile (relative risk, 1.54; 95% confidence interval, 1.04 to 2.28), to the third (relative risk, 1.84; 95% confidence interval, 1.26 to 2.67), fourth (relative risk, 2.01; 95% confidence interval, 1.38 to 2.91), and fifth (relative risk, 3.15; 95% confidence interval, 2.19 to 4.52). The results of separate analyses of myocardial infarction and stroke paralleled those for the combined end point. CONCLUSIONS: Increases in the thickness of the intima and media of the carotid artery, as measured noninvasively by ultrasonography, are directly associated with an increased risk of myocardial infarction and stroke in older adults without a history of cardiovascular disease.

N Engl J Med. 1999 Jan 7;340(1):14-22

Carotid atherosclerosis and ischemic stroke in young patients.
BACKGROUND: Epidemiological studies indicate a high prevalence of carotid atherosclerosis in elderly patients with ischemic stroke. The aim of this study was to investigate the presence of early carotid atherosclerotic lesions in young subjects with ischemic stroke, in the absence of the common atherosclerotic risk factors. METHODS: We studied 98 young patients with first ischemic stroke (54 males and 44 females; mean age 41.2 years; range 32-50) and 96 healthy controls. All subjects underwent ultrasonographic scanning of the carotid arteries according to a standardized protocol. RESULTS: The carotid intima-media thickness was significantly increased in the patient group (p<0.001) compared with controls. In addition, the prevalence of carotid atherosclerotic plaques was greater in the patients than in the controls (p<0.001). In particular, we detected 18 non-occlusive carotid plaques and 16 thrombotic occlusions. In eight patients, the lesions were bilateral. The echographic pattern of the plaques was hard in eight cases, soft in five cases, and mixed in the remaining five cases. CONCLUSIONS: We detected an increased wall thickness of the carotid arteries and an increased prevalence of carotid atherosclerotic lesions and carotid thrombotic occlusions in young patients with ischemic stroke, with a relative low incidence of cardiovascular risk factors. This finding suggests that arterial intima-media thickness per se is an important determinant of vascular disease in young patients. The data also provide indirect support for the potential role of genetic factors in the genesis of atherosclerosis in young patients.

Int Angiol . 2002 Jun;21(2):117-22

Transcranial Doppler and risk of recurrence in patients with stroke and patent foramen ovale.
The importance of patent foramen ovale (PFO) in stroke of unknown cause remains disputed, as PFO may be present in up to 20% of normal people and in a high proportion of patients with non-vascular disorders. Recent evidence suggests that the amount of right-to-left shunt (RLS) may be the crucial factor for stroke occurrence and relapse. The aim of the study was to assess predictors of recurrence in PFO-related stroke patients with particular emphasis on amount of shunting. Patients less than 61 years old who had been admitted for a PFO-related stroke within the previous fiveyears, were re-evaluated on a follow-up visit. The clinical syndrome, residual disability, vascular risk factors and number of relapses as the index event were assessed. RLS sizing was semi-quantitatively performed with saline-enhanced transcranial Doppler (TCD), by assuming a cut-off of more or less 10 bubbles recorded in the cerebral vessels as a criterion to discriminate large versus small shunt, respectively. Thereafter patients were prospectively followed-up for a median time of 23 months. Total follow-up was 61 months. Fifty-nine patients (M/F = 23/36, mean age 43 +/- 13) were studied. Overall there were 23 relapses in 13 patients. The amount of shunting was the only significant independent variable associated with relapse: at the end of the follow-up period the recurrence rate was 0.66 and 8.2% per patient per year in patients with small and large shunt, respectively. This difference was statistically significant (chi2 = 10.39, P = 0.0012; OR 17.05, 95% CI 2.10-755.22). In patients with PFO-related stroke, the amount of RLS as assessed with TCD is the only independent predictor of relapse. PFO sizing is mandatory in patients with PFO.

Eur J Neurol . 2003 Mar;10(2):129-35

The importance of Doppler studies in asymptomatic intracranial and extracranial arterial disease.
Knowledge of intracranial and carotid disease in the symptomatic and especially the asymptomatic high risk population may be useful for evaluating future treatment modalities. A group of 204 symptomatic patients and 105 asymptomatic elderly patients at high risk for stroke were tested by carotid duplex ultrasound and transcranial doppler for the presence of carotid and intracranial stenosis. Quantitative measurements of the stenosis were made directly from the hard copy of the carotid duplex and the transcranial doppler. Of the 204 symptomatic patients 168 (83%) had some degree of stenosis: 84 of the 204 (41%) in the intracranial circulation only, 59 (29%) in the internal carotid only, and 26 (13%) in both sets of vessels. Of the asymptomatic patients 85 (81%) had some degree of stenosis; 31 of 105 (30%) in the intracranial circulation only, 35 (33%) in the internal carotid only, and 19 (18%) in both sets of vessels. Statistical analysis did not reveal significant differences between the two groups. The large percentage of intracranial disease in the symptomatic as well as the asymptomatic population at high risk for stroke require further confirmation by good duplex studies of the intracranial circulation. This is important in order to create coherent treatment protocols.

Keio J Med . 2002 Dec;51(4):189-92

Using sonography to screen women with mammographically dense breasts.
OBJECTIVE: Mammographically dense breast tissue has been reported both as a cause of false-negative findings on mammography and as an indicator of increased breast cancer risk. We conducted this study to evaluate the role of breast sonography as a second-line screening test in women with mammographically dense breast tissue. MATERIALS AND METHODS: Between January 2000 and January 2002, 1,517 asymptomatic women with dense breasts and normal mammography and physical examination findings underwent physician-performed breast sonography as an adjunct screening test. Within the study group, 318 women had a first-degree family history or personal history of breast cancer. The high-risk subgroup comprised these women. The detection rate of breast cancer in this subgroup was compared with the detection rate in the remaining study population with baseline risk. RESULTS: Of 1,517 women examined, seven breast cancers were diagnosed (cancer-detection rate, 0.46%). Four carcinomas were detected in high-risk women and three in women with baseline risk. The cancer-detection rate in the subgroup of high-risk women was 1.3%, significantly higher (p < 0.04) than the cancer-detection rate of 0.25% in the baseline risk subgroup. All cancers were T1 (range, 4-12 mm; mean, 9.6 mm). Sentinel lymph nodes were negative for cancer in six of seven carcinomas. CONCLUSION: Screening breast sonography in the population of women with dense breast tissue is useful in detecting small breast cancers that are not detected on mammography or clinical breast examination. The use of sonography as an adjunct to screening mammography in women with increased risk of breast cancer and dense breasts may be especially beneficial.

AJR Am J Roentgenol . 2003 Jul;181(1):177-82

Transvaginal sonography as a screening method for the detection of early ovarian cancer.
From December 1987 to December 1993, 6,470 women underwent screening with transvaginal sonography (TVS) as part of the University of Kentucky Ovarian Cancer Screening Project . Two groups of women were eligible to participate in this investigation: (i) asymptomatic postmenopausal patients or patients >50 years of age, and (ii) asymptomatic women >30 years of age with a family history of ovarian cancer. Ovarian volume was calculated using the prolate ellipsoid formula (length x height x width x 0.523). An abnormal sonogram was defined by (1) an ovarian volume >10 cm3 in postmenopausal women or >20 cm3 in premenopausal women, and (2) a papillary or complex tissue projection into a cystic ovarian tumor. All women with an abnormal TVS had a repeat sonogram in 4-6 weeks. Patients with persistently abnormal scans had a serum CA-125 determination, tumor morphology indexing, and color Doppler sonography. Ninety patients (1.4%) with a persisting abnormality on TVS underwent exploratory laparotomy or laparoscopy for tumor removal. Thirty-seven patients had serous cystadenomas and six had primary ovarian cancers. Five patients had Stage IA ovarian cancer and one patient had Stage IIIB disease. Only one of the ovarian cancer patients had a palpable abnormality on pelvic examination, and none had an elevated (>35 u/ml) serum CA-125. All these patients are presently alive and well 1-5 years after conventional therapy. There was one false negative in this study, a 38-year-old white female who was noted to have a small ovarian cancer at the time of laparoscopic prophylactic oophorectomy 11 months after a normal scan. Over 17,000 screening years have been accrued and there have been no deaths from primary ovarian cancer in the screened population. A cost analysis of TVS screening is presented.

Gynecol Oncol. 1997 Jun;65(3):408-14