Subtle excess in lifetime cancer risk related to CT scanning in Spanish young people

Background: CT scan is a life-saving medical diagnostic tool, entailing higher levels of ionising radiation exposure than conventional radiography, which may result in an increase in cancer risk, particularly in children. Information about the use and potential health effects of CT scan imaging among young people in Spain is scarce. Objective: This paper aims to estimate the number of radiation-related cancer cases which can be expected due to the use of CT scanning in Spanish children and young adults in a single year (2013). Methods: The 2013 distribution of number and types of CT scans performed in young people was obtained for Catalonia and extrapolated to the whole Spain. Organ doses were estimated based on the technical characteristics of 17,406 CT examinations extracted from radiology records. Age and sex-specific data on cancer incidence and life tables were obtained for the Spanish population. Age and sex-specific risk models developed by the Committee on Health Risks of Exposure to Low Levels of Ionizing Radiations (BEIR VII) and Berrington de Gonzalez were used, together, with the dose estimates to derive the lifetime attributable risks of cancer in Spain due to one year of CT scanning and project the number of future cancer cases to be expected. Results: In 2013, 105,802 CT scans were estimated to have been performed in people younger than age 21. It was estimated that a total of 168.6 cancer cases (95% CrI: 30.1-421.1) will arise over life due to the ionising radiation exposure received during these CTs. Lifetime attributable risks per 100,000 exposed patients were highest for breast and lung cancer. The largest proportion of CTs was to the head and neck and hence the highest numbers of projected cancer cases were of thyroid and oral cavity/pharynx. Conclusions: Despite the undeniable medical effectiveness of CT scans, this risk assessment suggests a small excess in cancer cases which underlines the need for justification and optimisation in paediatric scanning. Given the intrinsic uncertainties of these risk projection exercises, care should be taken when interpreting the predicted risks

Automatic segmentation of cardiac structures for breast cancer radiotherapy

Background and purpose We developed an automatic method to segment cardiac substructures given a radiotherapy planning CT images to support epidemiological studies or clinical trials looking at cardiac disease endpoints after radiotherapy. Material and methods We used a most-similar atlas selection algorithm and 3D deformation combined with 30 detailed cardiac atlases. We cross-validated our method within the atlas library by evaluating geometric comparison metrics and by comparing cardiac doses for simulated breast radiotherapy between manual and automatic contours. We analyzed the impact of the number of cardiac atlas in the library and the use of manual guide points on the performance of our method. Results The Dice Similarity Coefficients from the cross-validation reached up to 97% (whole heart) and 80% (chambers). The Average Surface Distance for the coronary arteries was less than 10.3 mm on average, with the best agreement (7.3 mm) in the left anterior descending artery (LAD). The dose comparison for simulated breast radiotherapy showed differences less than 0.06 Gy for the whole heart and atria, and 0.3 Gy for the ventricles. For the coronary arteries, the dose differences were 2.3 Gy (LAD) and 0.3 Gy (other arteries). The sensitivity analysis showed no notable improvement beyond ten atlases and the manual guide points does not significantly improve performance. Conclusion We developed an automated method to contour cardiac substructures for radiotherapy CTs. When combined with accurate dose calculation techniques, our method should be useful for cardiac dose reconstruction of a large number of patients in epidemiological studies or clinical trials

Cancer incidence among children and young adults who have undergone x-ray guided cardiac catheterization procedures

Children and young adults with heart disease appear to be at increased risk of developing cancer, although the reasons for this are unclear. A cohort of 11,270 individuals, who underwent cardiac catheterizations while aged B 22 years in the UK, was established from hospital records. Radiation doses from cardiac catheterizations and CT scans were estimated. The cohort was matched with the NHS Central Register and NHS Transplant Registry to determine cancer incidence and transplantation status. Standardized incidence ratios (SIR) with associated confidence intervals (CI) were calculated. The excess relative risk (ERR) of lymphohaematopoietic neoplasia was also calculated using Poisson regression. The SIR was raised for all malignancies (2.32, 95% CI 1.65, 3.17), lymphoma (8.34, 95% CI 5.22, 12.61) and leukaemia (2.11, 95% CI 0.82, 4.42). After censoring transplant recipients, post-transplant, the SIR was reduced to 0.90 (95% CI 0.49, 1.49) for all malignancies. All lymphomas developed post-transplant. The SIR for all malignancies developing 5 years from the first cardiac catheterization (2 years for leukaemia/lymphoma) remained raised (3.01, 95% CI 2.09, 4.19) but was again reduced after censoring transplant recipients (0.98, 95% CI 0.48, 1.77). The ERR per mGy bone marrow dose for lympho-haematopoietic neoplasia was reduced from 0.541 (95% CI 0.104, 1.807) to 0.018 (95% CI - 0.002, 0.096) where transplantation status was accounted for as a time-dependent background risk factor. In conclusion, transplantation appears to be a large contributor to elevated cancer rates in this patient group. This is likely to be mainly due to associated immunosuppression, however, radiation exposure may also be a contributing factor

Application of an Automatic Segmentation Method for Evaluating Cardiac Structure Doses Received by Breast Radiotherapy Patients

BACKGROUND AND PURPOSE: Quantifying radiation dose to cardiac substructures is important for research on the etiology and prevention of complications following radiotherapy; however, segmentation of substructures is challenging. In this study we demonstrate the application of our atlas-based automatic segmentation method to breast cancer radiotherapy plans for generating radiation doses in support of late effects research. MATERIAL AND METHODS: We applied our segmentation method to contour heart substructures on the computed tomography (CT) images of 70 breast cancer patients who received external photon radiotherapy. Two cardiologists provided manual segmentation of the whole heart (WH), left/right atria, left/right ventricles, and left anterior descending artery (LAD). The automatically contours were compared with manual delineations to evaluate similarity in terms of geometry and dose. RESULTS: The mean Dice similarity coefficient between manual and automatic segmentations was 0.96 for the WH, 0.65 to 0.82 for the atria and ventricles, and 0.06 for the LAD. The mean average surface distance was 1.2 mm for the WH, 3.4 to 4.1 mm for the atria and ventricles, and 6.4 mm for the LAD. We found the dose to the cardiac substructures based on our automatic segmentation agrees with manual segmentation within expected observer variability. For left breast patients, the mean absolute difference in mean dose was 0.1 Gy for the WH, 0.2 to 0.7 Gy for the atria and ventricles, and 1.8 Gy for the LAD. For right breast patients, these values were 0.0 Gy, 0.1 to 0.4 Gy, and 0.4 Gy, respectively. CONCLUSION: Our automatic segmentation method will facilitate the development of radiotherapy prescriptive criteria for mitigating cardiovascular complications

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

Mitigating information imperfections in proxy contests: The effect of dissidents\u27 proxy solicitation

This study examines dissidents\u27 expenses related to proxy solicitation activities in a contested director election. I find that dissidents\u27 solicitation expenses are associated with higher chances of winning board seats. This association is consistent with my conjecture that dissidents extend their efforts in proxy solicitation and thus persuade more shareholders in dissidents\u27 favor, but this is not likely driven by retained solicitor\u27s reputation, dissidents\u27 opportunistic behavior for reimbursement, or other popular strategic activities in proxy contests. Furthermore, I show that proxy solicitation activities are considered to be an information channel that substitutes for investors\u27 own search for proxy statements from the SEC\u27s EDGAR. Overall, this study suggests that proxy solicitation plays an important role in proxy contests

Managerial reliance on the retail shareholder vote: Evidence from proxy delivery methods

Recent studies document the increasing effectiveness of shareholder voting as a monitoring mechanism. Because both directors and the market respond to shareholder votes, management has stronger incentives to influence voting outcomes. We identify one channel through which management can affect voting outcomes: increasing the turnout of (typically management-friendly) retail shareholders. Our study focuses on an observable managerial choice of how to deliver proxy materials to maximize retail turnout. Management can opt to send a full set of proxy materials to all shareholders, which increases retail turnout but also increases printing and mailing costs, or they can send a notice directing shareholders to proxy materials available online, which reduces costs but also decreases retail turnout. We find that managers are more likely to choose to deliver a full set of proxy materials when there are contentious items on the ballot for which they need additional voting support; and, indeed, the resulting support increases the likelihood that voting outcomes will align with management recommendations

Voting methods for director election, monitoring costs, and institutional ownership

We show that firms that employ the majority voting method for director election exhibit higher institutional ownership than firms that employ the plurality voting method, especially after the 2010 amendment to NYSE Rule 452. Firms that adopt majority voting in a bylaw or charter exhibit increases in institutional ownership and share price. These results are consistent with our conjecture that institutional investors favor companies with majority voting and investors react favorably to the adoption of majority voting because it reduces management monitoring costs by improving the accountability of elected board members