Guy's and St Thomas' NHS Foundation Trust

About: Guy's and St Thomas' NHS Foundation Trust is a healthcare organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Medicine. The organization has 7686 authors who have published 9631 publications receiving 399353 citations. The organization is also known as: Guy's and St Thomas' National Health Service Foundation Trust & Guy's and St Thomas' National Health Service Trust.

Ultraviolet-induced p53 mutations in atypical fibroxanthoma.

Abstract: Atypical fibroxanthoma (AFX) is an uncommon neoplasm of the superficial soft tissue occurring in actinically damaged skin of elderly patients. Sun-exposed skin also represents the main site of squamous and basal cell carcinomas and malignant melanoma, and a key role for ultraviolet (UV) radiation in their pathogenesis has long been suspected. UV-related mutations of the p53 gene have been identified in human skin cancers. To verify whether the pathogenesis of AFX is related to the effect of sunlight, p53 protein and gene status have been investigated in a series of 10 cases of AFX. Seven of 10 showed p53 immunoreactivity in most of the neoplastic cells. Molecular analysis of the p53 gene revealed an abnormal single strand conformation polymorphism pattern in all the p53 positive cases. Polymerase chain reaction direct sequencing revealed that all the mutations involved cytosine bases. Four cases showed C to T transitions (including two CC-TT double base substitutions) and two cases showed C to G transversion. All but one mutation took place at dipyrimidine sites. These findings provide the first objective evidence for the central role of UV radiation in the development of AFX and also represent the first in vivo demonstration of solar UV-induced mutations in a human mesenchymal neoplasm.

Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis

Abstract: Mastocytosis is an emerging differential diagnosis in patients with more or less specific mediator-related symptoms In some of these patients, typical skin lesions are found and the diagnosis of mastocytosis can be established In other cases, however, skin lesions are absent, which represents a diagnostic challenge In the light of this unmet need, we developed a diagnostic algorithm for patients with suspected mastocytosis In adult patients with typical lesions of mastocytosis in the skin, a bone marrow (BM) biopsy should be considered, regardless of the basal serum tryptase concentration In adults without skin lesions who suffer from mediator-related or other typical symptoms, the basal tryptase level is an important parameter In those with a slightly increased tryptase level, additional investigations, including a sensitive KIT mutation analysis of blood leucocytes or measurement of urinary histamine metabolites, may be helpful In adult patients in whom (i) KIT D816V is detected and/or (ii) the basal serum tryptase level is clearly increased (>25-30 ng/ml) and/or (iii) other clinical or laboratory features suggest the presence of 'occult' mastocytosis or another haematologic neoplasm, a BM investigation is recommended In the absence of KIT D816V and other signs or symptoms of mastocytosis or another haematopoietic disease, no BM investigation is required, but the clinical course and tryptase levels are monitored in the follow-up In paediatric patients, a BM investigation is usually not required, even if the tryptase level is increased Although validation is required, it can be expected that the algorithm proposed herein will facilitate the management of patients with suspected mastocytosis and help avoid unnecessary referrals and investigations

Mutation in Vascular Endothelial Growth Factor-C, a Ligand for Vascular Endothelial Growth Factor Receptor-3, Is Associated With Autosomal Dominant Milroy-Like Primary Lymphedema

Abstract: Rationale: Mutations in vascular endothelial growth factor (VEGF) receptor-3 ( VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity. Objective: To investigate the underlying cause in patients with clinical signs resembling Milroy disease in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation. Methods and Results: Exome sequencing of 5 such patients was performed, and a novel frameshift variant, c.571_572insTT in VEGFC , a ligand for VEGFR3, was identified in 1 proband. The variant cosegregated with the affected status in the family. An assay to assess the biological function of VEGFC activity in vivo, by expressing human VEGFC in the zebrafish floorplate was established. Forced expression of wild-type human VEGFC in the floorplate of zebrafish embryos leads to excessive sprouting in neighboring vessels. However, when overexpressing the human c.571_572insTT variant in the floorplate, no sprouting of vessels was observed, indicating that the base changes have a marked effect on the activity of VEGFC. Conclusions: We propose that the mutation in VEGFC is causative for the Milroy disease-like phenotype seen in this family. This is the first time a mutation in one of the ligands of VEGFR3 has been reported to cause primary lymphedema.

Standardization of thromboelastography: a report from the TEG‐ROTEM working group

Abstract: Laboratory evaluation of bleeding disorders has been performed with the standard clotting assays such as the PT and PTT for several decades. Our improved understanding of the process of blood coagulation has now revealed the important role played by the cellular elements such as platelets, monocytes and red blood cells. The need for a test that can assess clotting in a more 'global' manner, beyond the initiation of clot formation, has led to greater interest in assays such as thrombin generation and thromboelastography. Even though there are several publications using thromboelastography it remains a research tool as the methodology is not standardized. In an attempt to show reproducibility and consistency using thromboelastography, a group of investigators from different countries joined hands to form the TEG-ROTEM Working Group. Two studies were performed using PRP and FVIII deficient plasma and an intrinsic pathway activator. This article summarizes the results of the first international effort at standardization of thromboelastography. Both of the instruments using this technology (TEG(®) and ROTEM(®)) were used. Nine laboratories from countries around the globe participated in this effort. The results showed a significant inter-laboratory variance with CV's greater than 10%. Although these results were not satisfactory, this has been the first effort to standardize this methodology and significant work remains to be done to improve reliability and reproducibility. These studies were performed on PRP and the results may be more reliable when preformed on whole blood samples. We believe that it is important to continue this work so that we may investigate the usefulness and potential applications of thromboelastography in the evaluation of bleeding and thrombosis.