Ruth A Kleinerman

National Institutes of Health, Bethesda, MD, United States

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Publications (134)872.06 Total impact

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    ABSTRACT: Background: Retinoblastoma is a rare childhood eye cancer caused by germline or somatic mutations in the RB1 gene. Previous studies observed elevated breast cancer risk among retinoblastoma survivors. However, there has been no research on breast cancer risk in relation to radiation (primarily scatter radiation from the primary treatment) and genetic susceptibility of retinoblastoma survivors. Methods: Two groups of retinoblastoma survivors from the US and UK were selected, and breast cancer risk analysed using a case–control methodology, nesting within the respective cohorts, matching on heritability (that is to say, having bilateral retinoblastoma or being unilateral cases with at least one relative with retinoblastoma), and using exact statistical methods. There were a total of 31 cases and 77 controls. Results: Overall there was no significant variation of breast cancer risk with dose (P>0.5). However, there was a pronounced and significant (P=0.047) increase in the risk of breast cancer with increasing radiation dose for non-heritable retinoblastoma patients and a slight and borderline significant (P=0.072) decrease in risk of breast cancer with increasing radiation dose for heritable retinoblastoma patients, implying significant (P=0.024) heterogeneity in radiation risk between the heritable and non-heritable retinoblastoma groups; this was unaffected by the blindness status. There was no significant effect of any type of alkylating-agent chemotherapy on breast cancer risk (P>0.5). Conclusions: There is significant radiation-related risk of breast cancer for non-heritable retinoblastoma survivors but no excess risk for heritable retinoblastoma survivors, and no significant risk overall. However, these results are based on very small numbers of cases; therefore, they must be interpreted with caution.
    British Journal of Cancer 04/2014; 110(10):2623-2632. · 5.08 Impact Factor
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    ABSTRACT: IMPORTANCE Several studies have found no temporal or demographic differences in the incidence of retinoblastoma except for age at diagnosis, whereas other studies have reported variations in incidence by sex and race/ethnicity. OBJECTIVE To examine updated US retinoblastoma incidence patterns by sex, age at diagnosis, laterality, race/ethnicity, and year of diagnosis. DESIGN, SETTING, AND PARTICIPANTS The Surveillance, Epidemiology, and End Results (SEER) databases were examined for retinoblastoma incidence patterns by demographic and tumor characteristics. We studied 721 children in SEER 18 registries, 659 in SEER 13 registries, and 675 in SEER 9 registries. MAIN OUTCOMES AND MEASURES Incidence rates, incidence rate ratios (IRRs), and annual percent changes in rates. RESULTS During 2000-2009 in SEER 18, there was a significant excess of total retinoblastoma among boys compared with girls (IRR, 1.18; 95% CI, 1.02 to 1.36), in contrast to earlier reports of a female predominance. Bilateral retinoblastoma among white Hispanic boys was significantly elevated relative to white non-Hispanic boys (IRR, 1.81; 95% CI, 1.22 to 2.79) and white Hispanic girls (IRR, 1.75; 95% CI, 1.11 to 2.91) because of less rapid decreases in bilateral rates since the 1990s among white Hispanic boys than among the other groups. Retinoblastoma rates among white non-Hispanics decreased significantly since 1992 among those younger than 1 year and since 1998 among those with bilateral disease. CONCLUSIONS AND RELEVANCE Although changes in the availability of prenatal screening practices for retinoblastoma may have contributed to these incidence patterns, further research is necessary to determine their actual effect on the changing incidence of retinoblastoma in the US population. In addition, consistent with other cancers, an excess of retinoblastoma diagnosed in boys suggests a potential effect of sex on cancer origin.
    Jama Ophthalmology 02/2014; · 3.83 Impact Factor
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    ABSTRACT: Treatment-related stomach cancer is an important cause of morbidity and mortality among the growing number of Hodgkin lymphoma (HL) survivors, but risks associated with specific HL treatments are unclear. We conducted an international case-control study of stomach cancer nested in a cohort of 19,882 HL survivors diagnosed from 1953 to 2003, including 89 cases and 190 matched controls. For each patient, we quantified cumulative doses of specific alkylating agents (AAs) and reconstructed radiation dose to the stomach tumor location. Stomach cancer risk increased with increasing radiation dose to the stomach (Ptrend < .001) and with increasing number of AA-containing chemotherapy cycles (Ptrend = .02). Patients who received both radiation to the stomach ≥ 25 Gy and high-dose procarbazine (≥ 5,600 mg/m(2)) had strikingly elevated stomach cancer risk (25 cases, two controls; odds ratio [OR], 77.5; 95% CI, 14.7 to 1452) compared with those who received radiation < 25 Gy and procarbazine < 5,600 mg/m(2) (Pinteraction < .001). Risk was also elevated (OR, 2.8; 95% CI, 1.3 to 6.4) among patients who received radiation to the stomach ≥ 25 Gy but procarbazine < 5,600 mg/m(2); however, no procarbazine-related risk was evident with radiation < 25 Gy. Treatment with dacarbazine also increased stomach cancer risk (12 cases, nine controls; OR, 8.8; 95% CI, 2.1 to 46.6), after adjustment for radiation and procarbazine doses. Patients with HL who received subdiaphragmatic radiotherapy had dose-dependent increased risk of stomach cancer, with marked risks for patients who also received chemotherapy containing high-dose procarbazine. For current patients, risks and benefits of exposure to both procarbazine and subdiaphragmatic radiotherapy should be weighed carefully. For patients treated previously, GI symptoms should be evaluated promptly.
    Journal of Clinical Oncology 08/2013; · 18.04 Impact Factor
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    ABSTRACT: Rapid innovations in radiation therapy techniques have resulted in an urgent need for risk projection models for second cancer risks from high-dose radiation exposure, because direct observation of the late effects of newer treatments will require patient follow-up for a decade or more. However, the patterns of cancer risk after fractionated high-dose radiation are much less well understood than those after lower-dose exposures (0.1-5 Gy). In particular, there is uncertainty about the shape of the dose-response curve at high doses and about the magnitude of the second cancer risk per unit dose. We reviewed the available evidence from epidemiologic studies of second solid cancers in organs that received high-dose exposure (>5 Gy) from radiation therapy where dose-response curves were estimated from individual organ-specific doses. We included 28 eligible studies with 3434 second cancer patients across 11 second solid cancers. Overall, there was little evidence that the dose-response curve was nonlinear in the direction of a downturn in risk, even at organ doses of ≥60 Gy. Thyroid cancer was the only exception, with evidence of a downturn after 20 Gy. Generally the excess relative risk per Gray, taking account of age and sex, was 5 to 10 times lower than the risk from acute exposures of <2 Gy among the Japanese atomic bomb survivors. However, the magnitude of the reduction in risk varied according to the second cancer. The results of our review provide insights into radiation carcinogenesis from fractionated high-dose exposures and are generally consistent with current theoretical models. The results can be used to refine the development of second solid cancer risk projection models for novel radiation therapy techniques.
    International journal of radiation oncology, biology, physics 06/2013; 86(2):224-233. · 4.59 Impact Factor
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    ABSTRACT: PURPOSE: To assess the dose-response relationship for stomach cancer after radiation therapy for cervical cancer. METHODS AND MATERIALS: We conducted a nested, matched case-control study of 201 cases and 378 controls among 53,547 5-year survivors of cervical cancer diagnosed from 1943 to 1995, from 5 international, population-based cancer registries. We estimated individual radiation doses to the site of the stomach cancer for all cases and to corresponding sites for the matched controls (overall mean stomach tumor dose, 2.56 Gy, range 0.03-46.1 and after parallel opposed pelvic fields, 1.63 Gy, range 0.12-6.3). RESULTS: More than 90% of women received radiation therapy, mostly with external beam therapy in combination with brachytherapy. Stomach cancer risk was nonsignificantly increased (odds ratio 1.27-2.28) for women receiving between 0.5 and 4.9 Gy to the stomach cancer site and significantly increased at doses ≥5 Gy (odds ratio 4.20, 95% confidence interval 1.41-13.4, Ptrend=.047) compared with nonirradiated women. A highly significant radiation dose-response relationship was evident when analyses were restricted to the 131 cases (251 controls) whose stomach cancer was located in the middle and lower portions of the stomach (Ptrend=.003), whereas there was no indication of increasing risk with increasing dose for 30 cases (57 controls) whose cancer was located in the upper stomach (Ptrend=.23). CONCLUSIONS: Our findings show for the first time a significant linear dose-response relationship for risk of stomach cancer in long-term survivors of cervical cancer.
    International journal of radiation oncology, biology, physics 05/2013; · 4.59 Impact Factor
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    ABSTRACT: PURPOSE: To assess the shape of the dose response for various cancer endpoints and modifiers by age and time. METHODS AND MATERIALS: Reanalysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by cancer endpoint (stomach, pancreas, lung, leukemia, all other). RESULTS: There are statistically significant (P<.05) excess risks for all cancer and for lung cancer and borderline statistically significant risks for stomach cancer (P=.07), and leukemia (P=.06), with excess relative risks Gy(-1) of 0.024 (95% confidence interval [CI] 0.011, 0.039), 0.559 (95% CI 0.221, 1.021), 0.042 (95% CI -0.002, 0.119), and 1.087 (95% CI -0.018, 4.925), respectively. There is statistically significant (P=.007) excess risk of pancreatic cancer when adjusted for dose-response curvature. General downward curvature is apparent in the dose response, statistically significant (P<.05) for all cancers, pancreatic cancer, and all other cancers (ie, other than stomach, pancreas, lung, leukemia). There are indications of reduction in relative risk with increasing age at exposure (for all cancers, pancreatic cancer), but no evidence for quadratic variations in relative risk with age at exposure. If a linear-exponential dose response is used, there is no significant heterogeneity in the dose response among the 5 endpoints considered or in the speed of variation of relative risk with age at exposure. The risks are generally consistent with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers. CONCLUSIONS: There are excess risks for various malignancies in this data set. Generally there is a marked downward curvature in the dose response and significant reduction in relative risk with increasing age at exposure. The consistency of risks with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.
    International journal of radiation oncology, biology, physics 02/2013; 85(2):451-459. · 4.59 Impact Factor
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    ABSTRACT: PURPOSE: To assess the shape of the dose-response for various circulatory disease endpoints, and modifiers by age and time since exposure. METHODS AND MATERIALS: This was an analysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by circulatory disease endpoint (ischemic heart, cerebrovascular, other circulatory disease). RESULTS: There were significant excess risks for all circulatory disease, with an excess relative risk Gy(-1) of 0.082 (95% CI 0.031-0.140), and ischemic heart disease, with an excess relative risk Gy(-1) of 0.102 (95% CI 0.039-0.174) (both p = 0.01), and indications of excess risk for stroke. There were no statistically significant (p > 0.2) differences between risks by endpoint, and few indications of curvature in the dose-response. There were significant (p < 0.001) modifications of relative risk by time since exposure, the magnitude of which did not vary between endpoints (p > 0.2). Risk modifications were similar if analysis was restricted to patients receiving radiation, although the relative risks were slightly larger and the risk of stroke failed to be significant. The slopes of the dose-response were generally consistent with those observed in the Japanese atomic bomb survivors and in occupationally and medically exposed groups. CONCLUSIONS: There were excess risks for a variety of circulatory diseases in this dataset, with significant modification of risk by time since exposure. The consistency of the dose-response slopes with those observed in radiotherapeutically treated groups at much higher dose, as well as in lower dose-exposed cohorts such as the Japanese atomic bomb survivors and nuclear workers, implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.
    International journal of radiation oncology, biology, physics 12/2012; 84(5):1101-1109. · 4.59 Impact Factor
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    Ruth A Kleinerman, Sara J Schonfeld, Margaret A Tucker
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    ABSTRACT: Children diagnosed with the hereditary form of retinoblastoma (Rb), a rare eye cancer caused by a germline mutation in the RB1 tumor suppressor gene, have excellent survival, but face an increased risk of bone and soft tissue sarcomas. This predisposition to sarcomas has been attributed to genetic susceptibility due to inactivation of the RB1 gene as well as past radiotherapy for Rb. The majority of bone and soft tissue sarcomas among hereditary Rb survivors occur in the head, within the radiation field, but they also occur outside the radiation field. Sarcomas account for almost half of the second primary cancers in hereditary Rb survivors, but they are very rare following non-hereditary Rb. Sarcomas among hereditary Rb survivors arise at ages similar to the pattern of occurrence in the general population. There has been a trend over the past two decades to replace radiotherapy with chemotherapy and other focal therapies (laser or cryosurgery), and most recently, chemosurgery in order to reduce the incidence of sarcomas and other second cancers in Rb survivors. Given the excellent survival of most Rb patients treated in the past, it is important for survivors, their families and health care providers to be aware of the heightened risk for sarcomas in hereditary patients.
    Clinical sarcoma research. 10/2012; 2(1):15.
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    ABSTRACT: BACKGROUND: Radiotherapy decreases cancer mortality, but is associated with an increased incidence of second primary cancers, including osteosarcomas, especially after exposure in childhood. It remains uncertain whether radiation is related to other histologic types of bone sarcomas such as chondrosarcomas that are more common in adulthood. METHODS: Using data from 1973-2008 SEER registries, we evaluated long-term risk of bone cancer in 1,284,537 adult 5-year cancer survivors. We used standardized incidence ratios (SIRs) to compare second bone sarcoma rates to the general population for each histologic type. We also used multivariate Poisson regression to estimate the relative risk (RR) associated with radiotherapy for the most common subtypes, osteosarcoma and chondrosarcoma. RESULTS: By the end of 2008, 159 second bone sarcomas were reported. Compared with the general population, the risk of developing any bone sarcoma was increased by 25% in patients with no history of radiotherapy (Observed(O)=89,SIR=1.25(1.00-1.54)) and by 257% in patients with a history of radiotherapy (O=70,SIR=3.57(2.78-4.50)). For each histologic subtype SIRs were higher among patients who had previously received radiotherapy than among those who had not. The RR for radiotherapy for osteosarcoma(n=63) was 5.08(3.05-8.59) and for chondrosarcoma(n=69) was 1.54(0.88-2.59), and these risks were even greater for second sarcomas that arose in the radiotherapy field used to treat the first cancer (osteosarcoma RR=10.35(4.96-23.66), chondrosarcoma RR=8.21(2.09-39.89)). CONCLUSIONS: Our findings provide the first evidence of a likely association between radiation exposure and chondrosarcoma. Impact: These results further our understanding of radiotherapy-related cancer risks and will potentially direct practices in long-term surveillance of cancer survivors.
    Cancer Epidemiology Biomarkers &amp Prevention 09/2012; · 4.56 Impact Factor
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    Journal of Clinical Oncology 08/2012; 30(24):3028-3029. · 18.04 Impact Factor

Publication Stats

3k Citations
872.06 Total Impact Points

Institutions

  • 1990–2013
    • National Institutes of Health
      • • Division of Cancer Epidemiology and Genetics
      • • Branch of Radiation Epidemiology
      Bethesda, MD, United States
    • Harvard University
      • Department of Epidemiology
      Boston, MA, United States
  • 1981–2013
    • National Cancer Institute (USA)
      • • Radiation Epidemiology
      • • Division of Cancer Epidemiology and Genetics
      • • Occupational and Environmental Epidemiology
      Maryland, United States
  • 2011
    • Lucile Packard Children’s Hospital at Stanford
      Palo Alto, California, United States
  • 2006
    • University of Texas MD Anderson Cancer Center
      • Department of Radiation Physics
      Houston, TX, United States
  • 2002
    • Mario Negri Institute for Pharmacological Research
      Milano, Lombardy, Italy
    • Institute of Electrical and Electronics Engineers
      Washington, Washington, D.C., United States
  • 1997
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 1991
    • Oak Ridge Associated Universities
      Oak Ridge, Tennessee, United States