Longitudinal assessment of lung function in Swiss childhood cancer survivors-A multicenter cohort study.

OBJECTIVE: Childhood cancer survivors are at risk for pulmonary morbidity due to exposure to lung-toxic treatments, including specific chemotherapeutics, radiotherapy, and surgery. Longitudinal data on lung function and its change over time are scarce. We investigated lung function trajectories in survivors over time and the association with lung-toxic treatments. METHODS: This retrospective, multicenter cohort study included Swiss survivors diagnosed between 1990 and 2013 and exposed to lung-toxic chemotherapeutics or thoracic radiotherapy. Pulmonary function tests (PFTs), including forced expiration volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC, total lung capacity,  and diffusion capacity of the lung for carbon monoxide, were obtained from hospital charts. We calculated z-scores and percentage predicted, described lung function over time, and determined risk factors for change in FEV1 and FVC using multivariable linear regression. RESULTS: We included 790 PFTs from 183 survivors, with a median age of 12 years at diagnosis and 5.5 years of follow-up. Most common diagnosis was lymphoma (55%). Half (49%) of survivors had at least one abnormal pulmonary function parameter, mainly restrictive (22%). Trajectories of FEV1 and FVC started at z-scores of -1.5 at diagnosis and remained low throughout follow-up. Survivors treated with thoracic surgery started particularly low, with an FEV1 of -1.08 z-scores (-2.02 to -0.15) and an FVC of -1.42 z-scores (-2.27 to -0.57) compared to those without surgery. CONCLUSION: Reduced pulmonary function was frequent but mainly of mild to moderate severity. Nevertheless, more research and long-term surveillance of this vulnerable population is needed.

Functional assessment of two variants of unknown significance in TEK by endothelium-specific expression in zebrafish embryos.

Vascular malformations are most often caused by somatic mutations of the PI3K/mTOR and the RAS signaling pathways, which can be identified in the affected tissue. Venous malformations (VMs) commonly harbor PIK3CA and TEK mutations, whereas arteriovenous malformations (AVMs) are usually caused by BRAF, RAS or MAP2K1 mutations. Correct identification of the underlying mutation is of increasing importance, since targeted treatments are becoming more and more relevant, especially in patients with extensive vascular malformations. However, variants of unknown significance (VUSs) are often identified and their pathogenicity and response to targeted therapy cannot be precisely predicted. Here, we show that zebrafish embryos can be used to rapidly assess the pathogenicity of novel VUSs in TEK, encoding for the receptor TIE2, present on endothelial cells of VMs. Endothelium-specific overexpression of TEK mutations leads to robust induction of VMs, whereas MAP2K1 mutations cause AVMs in our zebrafish model. TEK mutations are often found as double mutations in cis; using our model, we show that double mutations have an additive effect in inducing VMs compared with the respective single variants. The clinically established mTOR-inhibitor sirolimus (rapamycin) efficiently abrogates the development of VMs in this zebrafish model. In summary, endothelium-specific overexpression of patient-derived TEK variants in the zebrafish model allows assessment of their pathogenic significance as well as testing of candidate drugs in a personalized and mutation-specific approach.