Retrospective methods to estimate radiation dose at the site of breast cancer development after Hodgkin lymphoma radiotherapy.

Background:An increased risk of breast cancer following radiotherapy for Hodgkin lymphoma (HL) has now been robustly established. In order to estimate the dose-response relationship more accurately, and to aid clinical decision making, a retrospective estimation of the radiation dose delivered to the site of the subsequent breast cancer is required. Methods:For 174 Dutch and 170 UK female patients with breast cancer following HL treatment, the 3-dimensional position of the breast cancer in the affected breast was determined and transferred onto a CT-based anthropomorphic phantom. Using a radiotherapy treatment planning system the dose distribution on the CT-based phantom was calculated for the 46 different radiation treatment field set-ups used in the study population. The estimated dose at the centre of the breast cancer, and a margin to reflect dose uncertainty were determined on the basis of the location of the tumour and the isodose lines from the treatment planning. We assessed inter-observer variation and for 47 patients we compared the results with a previously applied dosimetry method. Results:The estimated median point dose at the centre of the breast cancer location was 29.75 Gy (IQR 5.8-37.2), or about 75% of the prescribed radiotherapy dose. The median dose uncertainty range was 5.97 Gy. We observed an excellent inter-observer variation (ICC 0.89 (95% CI: 0.74-0.95)). The absolute agreement intra-class correlation coefficient (ICC) for inter-method variation was 0.59 (95% CI: 0.37-0.75), indicating (nearly) good agreement. There were no systematic differences in the dose estimates between observers or methods. Conclusion:Estimates of the dose at the point of a subsequent breast cancer show good correlation between methods, but the retrospective nature of the estimates means that there is always some uncertainty to be accounted for

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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Comorbidities and co-existing conditions in heart failure around pregnancy

It is estimated that 0.2 to 4% of all pregnancies in industrialized countries are complicated by cardiovascular diseases (CVD) with increasing number of women who develop cardiac problems during pregnancy [1]. Indeed, pregnancy challenges the cardiovascular system and may lead to disease states such as hypertensive complications with its severe forms preeclampsia and the HELLP syndrome (H: hemolysis, EL: elevated liver enzymes, LP: low platelets counts) [2]. Especially the phase towards the end of pregnancy, during delivery and postpartum is a special challenge for the cardiovascular system since it has to cope with massive hormonal fluctuations, fluid changes and mechanical stress. Alterations in metabolism (subclinical insulin resistance in pregnancy) and immune response (repressed in pregnancy and activated after delivery) take place as well. Moreover, endothelial stress promotes hypertensive disorders and additional enhanced coagulation activity lead to higher risk for myocardial infarction and stroke and cardiomyopathies as outlined below. It is therefore not surprising that acceleration of heart failure towards the end of the second trimester, under delivery or in the early postpartum phase is frequently observed in women with pre-existing cardiomyopathies or pulmonary hypertension and is associated with adverse maternal and perinatal outcome [3]. Moreover, the cardiac stress model “pregnancy” may even unmask unrecognized genetic and non-genetic heart diseases [2, 4, 5]

Apolipoprotein E genotype affects tissue metallothionein levels: studies in targeted gene replacement mice

The apolipoprotein E (APOE) genotype is an important risk factor for ageing and age-related diseases. The APOE4 genotype (in contrast to APOE3) has been shown to be associated with oxidative stress and chronic inflammation. Metallothioneins (MT) exhibit antioxidant and anti-inflammatory activity, and MT overexpression has been shown to increase lifespan in mice. Interactions between APOE and MT, however, are largely unknown. Hence, we determined the effect of the APOE4 versus APOE3 genotype on MT levels in targeted gene replacement mice. APOE4 versus APOE3 mice exhibited significantly lower hepatic MT1 and MT2 mRNA as well as lower MT protein levels. The decrease in hepatic MT protein levels in APOE4 as compared to APOE3 mice was accompanied by lower nuclear Nrf1, a protein partly controlling MT gene expression. Cell culture experiments using hepatocytes identified allyl-isothiocyanate (AITC) as a potent MT inductor in vitro. Therefore, we supplemented APOE3 and APOE4 mice with AITC. However, AITC (15 mg/kg b.w.) could only partly correct for decreased MT1 and MT2 gene expression in APOE4 mice in vivo. Furthermore, cholesterol significantly decreased both Nrf1 and MT mRNA levels in Huh7 cells indicating that differences in MT gene expression between the two genotypes could be related to differences in hepatic cholesterol concentrations. Overall, present data suggest that the APOE genotype is an important determinant of tissue MT levels in mice and that MT gene expression may be impaired by the APOE4 genotype