Uptake of genetic testing and long-term tumor surveillance in von Hippel-Lindau disease

<p>Abstract</p> <p>Background</p> <p>von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the <it>VHL </it>gene. Patients have significant morbidity and mortality secondary to vascular tumors. Disease management is centered on tumor surveillance that allows early detection and treatment. Presymptomatic genetic testing is therefore recommended, including in at-risk children.</p> <p>Methods</p> <p>We tested 17 families (n = 109 individuals) for <it>VHL </it>mutations including 43 children under the age of 18. Personalized genetic counseling was provided pre and post-test and the individuals undergoing presymptomatic testing filled out questionnaires gathering socio-demographic, psychological and psychiatric data. Mutation analysis was performed by direct sequencing of the <it>VHL </it>gene. Mutation-carriers were screened for VHL disease-related tumors and were offered follow-up annual examinations.</p> <p>Results</p> <p>Mutations were identified in 36 patients, 17 of whom were asymptomatic. In the initial screening, we identified at least one tumor in five of 17 previously asymptomatic individuals. At the end of five years, only 38.9% of the mutation-carriers continued participating in our tumor surveillance program. During this time, 14 mutation carriers developed a total of 32 new tumors, three of whom died of complications. Gender, education, income, marital status and religiosity were not found to be associated with adherence to the surveillance protocol. Follow-up adherence was also independent of pre-test depression, severity of disease, or number of affected family members. The only statistically significant predictor of adherence was being symptomatic at the time of testing (OR = 5; 95% CI 1.2 - 20.3; p = 0.02). Pre-test anxiety was more commonly observed in patients that discontinued follow-up (64.7% vs. 35.3%; p = 0.01).</p> <p>Conclusions</p> <p>The high initial uptake rate of genetic testing for VHL disease, including in minors, allowed the discontinuation of unnecessary screening procedures in non mutation-carriers. However, mutation-carriers showed poor adherence to long-term tumor surveillance. Therefore, many of them did not obtain the full benefit of early detection and treatment, which is central to the reduction of morbidity and mortality in VHL disease. Studies designed to improve adherence to vigilance protocols will be necessary to improve treatment and quality of life in patients with hereditary cancer syndromes.</p

Role of dislocation elastic field on impurity segregation in Fe-based alloys

International audienceAbstract Dislocation engineering in crystalline materials is essential when designing materials for a large range of applications. Segregation of additional elements at dislocations is frequently used to modify the influence of dislocations on material properties. Thus, the influence of the dislocation elastic field on impurity segregation is of major interest, as its understanding should lead to engineering solutions that improve the material properties. We report the experimental study of the elastic field influence on atomic segregation in the core and in the area surrounding edge dislocations in Fe-based alloys. Each element is found either to segregate in the edge dislocation core or to form atmospheres. The elastic field has a strong effect on the segregation atmosphere, but no effect on the dislocation core segregation. The theory is in good agreement with experiments, and should support dislocation engineering

Thermal ageing effect on solute segregation and precipitation in the heat-affected-zone of dissimilar metal welds for nuclear power plants

Solute segregation in the carbon-depleted (CDZ) heat-affected zone of dissimilar metal welds (DMW) designed for nuclear power plant EPRTM reactors has been investigated by atom probe tomography (APT) and related to the mechanical properties (toughness test). The analysis of grain boundaries (GBs) by APT allowed the quantification of the P segregation and other solute elements, in all the analyzed samples, before and after long-term ageing heat treatments. The post-weld stress-relief heat treatment applied to the samples before the ageing heat treatments leads to important GBs segregation levels. Following thermal ageing treatments allow a relative increase of GB segregation. P segregation increases with the various thermal ageing conditions. The experimental data were used to model P segregation in high-angle GBs. The simulations show that P segregation is kinetically limited by bulk diffusion, explaining the observed P segregation increase with temperature. P segregation in GBs in the CDZ of the DMW should remain low compared to the expected equilibrium segregation level during the entire reactor service. In addition to solute segregation in extended defects, APT measurements revealed the presence of Cu-rich clusters in GBs, dislocations, and grains in all the aged samples. These clusters were not observed in the sample before ageing

Effect of thermal ageing on atomic redistribution at the ferrite/ferrite and ferrite/cementite interfaces

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Microstructural and mechanical investigation of the near fusion boundary region in thermally aged 18MND5 / Alloy 52 narrow-gap dissimilar metal weld

International audienceDetailed characterization of the near fusion-boundary region of 18MND5 / Alloy 52 dissimilar metal weld joints was performed to investigate the effect of thermal aging on the microstructure and mechanical properties and to quantify the diffusion of carbon into the weld metal. It was shown that the microstructural features of dissimilar metal welds, such as the size of the partially mixed zone in the weld and the adjacency to micro-segregations in the low-alloy steel have an effect on the peak carbon concentration in the enriched region of the weld. Aging conditions (time and temperature) influence the position of this concentration peak in the weld. Those trends were supported by thermodynamic calculations

Multi-technique study of precipitation in the nearfusion boundary region of an aged narrow-gap dissimilar metal weld

International audienceIn ferrite/austenite dissimilar metal welds, carbon can diffuse from the ferritic low-alloy steel to the austenitic weld metal during heat treatment and thermal aging due to the large carbon and chromium content differences between the two alloys. This carbon influx leads to the precipitation of carbides in the high-alloy weld metal, near the fusion boundary, which can affect the properties of the joint. This precipitation was investigated using multiple characterization techniques: electron probe microanalysis, small angle X-ray scattering and atom probe tomography. The studied joint consisted of low-alloy steel and stainless steel base metals that were arc welded using a nickel-based filler metal. Given the heterogeneous microstructure of such joints, a microstructure navigation strategy was implemented to ensure all characterizations were carried out in the same regions of interest and the associated data could later be correlated. The precipitates were found to be mostly M23C6. The precipitation was quantified using two different methods that gave comparable results, whose differences highlight the capabilities and limitations of each technique. Precipitate fractions are higher following thermal aging but remain far from equilibrium in all cases, indicating that precipitation kinetics should be accounted for to model the microstructural evolution of such dissimilar metal welds more accurately

Multi-technique study of precipitation in the nearfusion boundary region of an aged narrow-gap dissimilar metal weld

International audienceIn ferrite/austenite dissimilar metal welds, carbon can diffuse from the ferritic low-alloy steel to the austenitic weld metal during heat treatment and thermal aging due to the large carbon and chromium content differences between the two alloys. This carbon influx leads to the precipitation of carbides in the high-alloy weld metal, near the fusion boundary, which can affect the properties of the joint. This precipitation was investigated using multiple characterization techniques: electron probe microanalysis, small angle X-ray scattering and atom probe tomography. The studied joint consisted of low-alloy steel and stainless steel base metals that were arc welded using a nickel-based filler metal. Given the heterogeneous microstructure of such joints, a microstructure navigation strategy was implemented to ensure all characterizations were carried out in the same regions of interest and the associated data could later be correlated. The precipitates were found to be mostly M23C6. The precipitation was quantified using two different methods that gave comparable results, whose differences highlight the capabilities and limitations of each technique. Precipitate fractions are higher following thermal aging but remain far from equilibrium in all cases, indicating that precipitation kinetics should be accounted for to model the microstructural evolution of such dissimilar metal welds more accurately