Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD

Right heart thrombus in transit and peripherally inserted central catheters

Abstract Right heart thrombus in transit or “free-floating right heart thrombus” is defined as thrombus(i) arising from the deep veins that embolises to the right atrium or right ventricle before reaching the pulmonary vasculature. It is almost always associated with pulmonary thromboembolism and is a medical emergency with reported mortality rates of over 40%. We present two cases of right heart thrombus in transit with pulmonary thromboembolism resulting from venous thrombosis associated with peripherally inserted central catheters that were managed with different approaches. The cases highlight that clinicians should have a low threshold to utilise imaging modalities such as computerised tomography and transthoracic echocardiography when there is an untoward change in physiological parameters among patients with peripherally inserted central catheters, particularly those with risk factors for peripherally inserted central catheter associated venous thrombosis. Furthermore, procedural optimisation surrounding peripherally inserted central catheters, such as insertion technique and choice of lumen size, is underscored