Proceeding of the European Group for Blood and Marrow Transplantation (EBMT) congress on sickle cell disease, 16-17 may 2019, Regensburg, Germany: What is the impact of antithymocyte globulin pharmacokinetics on haploidentical hematopoietic stem cell transplantation?

Antithymocyte globulin (ATG) is a widely accepted part of the conditioning regimen applied in the setting of hematopoietic stem cell transplantation (HSCT) to prevent graft rejection and graft-versus-host disease. Although weight-based dosing of ATG has been introduced to optimize ATG dosing, substantial variance in clearance of active ATG, the actual lymphocyte binding component, remains a challenge. Therefore, further research regarding ATG pharmacokinetics and pharmacodynamics in different HSCT settings and in patients with different types of underlying diseases is required.

Cellular/intramuscular myxoma and grade I myxofibrosarcoma are characterized by distinct genetic alterations and specific composition of their extracellular matrix.

Cellular myxoma and grade I myxofibrosarcoma are mesenchymal tumours that are characterized by their abundant myxoid extracellular matrix (ECM). Despite their histological overlap, they differ clinically. Diagnosis is therefore difficult though important. We investigated their (cyto) genetics and ECM. GNAS1-activating mutations have been described in intramuscular myxoma, and lead to downstream activation of cFos. KRAS and TP53 mutations are commonly involved in sarcomagenesis whereby KRAS subsequently activates c-Fos. A well-documented series of intramuscular myxoma (three typical cases and seven cases of the more challenging cellular variant) and grade I myxofibrosarcoma (n = 10) cases were karyotyped, analyzed for GNAS1, KRAS and TP53 mutations and downstream activation of c-Fos mRNA and protein expression. ECM was studied by liquid chromatography mass spectrometry and expression of proteins identified was validated by immunohistochemistry and qPCR. Grade I myxofibrosarcoma showed variable, non-specific cyto-genetic aberrations in 83,5% of cases (n = 6) whereas karyotypes of intramuscular myxoma were all normal (n = 7). GNAS1-activating mutations were exclusively found in 50% of intramuscular myxoma. Both tumour types showed over-expression of c-Fos mRNA and protein. No mutations in KRAS codon 12/13 or in TP53 were detected. Liquid chromatography mass spectrometry revealed structural proteins (collagen types I, VI, XII, XIV and decorin) in grade I myxofibrosarcoma lacking in intramuscular myxoma. This was confirmed by immunohistochemistry and qPCR. Intramuscular/cellular myxoma and grade I myxofibrosarcoma show different molecular genetic aberrations and different composition of their ECM that probably contribute to their diverse clinical behaviour. GNAS1 mutation analysis can be helpful to distinguish intramuscular myxoma from grade I myxofibrosarcoma in selected cases.