Mesenchymal neoplasms with NTRK and other kinase gene alterations

Kinase alterations are increasingly recognised as oncogenic drivers in mesenchymal tumours. Infantile fibrosarcoma and the related renal tumour, congenital mesoblastic nephroma, were among the first solid tumours shown to harbour recurrent tyrosine kinase fusions, with the canonical ETV6::NTRK3 fusion identified more than 20 years ago. Although targeted testing has long been used in diagnosis, the advent of more robust sequencing techniques has driven the discovery of kinase alterations in an array of mesenchymal tumours. As our ability to identify these genetic alterations has improved, as has our recognition and understanding of the tumours that harbour these alterations. Specifically, this study will focus upon mesenchymal tumours harbouring NTRK or other kinase alterations, including tumours with an infantile fibrosarcoma-like appearance, spindle cell tumours resembling lipofibromatosis or peripheral nerve sheath tumours and those occurring in adults with a fibrosarcoma-like appearance. As publications describing the histology of these tumours increase so, too, do the variety kinase alterations reported, now including NTRK1/2/3, RET, MET, RAF1, BRAF, ALK, EGFR and ABL1 fusions or alterations. To date, these tumours appear locally aggressive and rarely metastatic, without a clear link between traditional features used in histological grading (e.g. mitotic activity, necrosis) and outcome. However, most of these tumours are amenable to new targeted therapies, making their recognition of both diagnostic and therapeutic import. The goal of this study is to review the clinicopathological features of tumours with NTRK and other tyrosine kinase alterations, discuss the most common differential diagnoses and provide recommendations for molecular confirmation with associated treatment implications.     

Priorities for content for a short-course on postoperative care relevant for low- and middle-income countries: an e-Delphi process with training facilitators

Most surgical and anaesthetic mortality and morbidity occurs postoperatively, disproportionately affecting low- and middle-income countries. Various short courses have been developed to improve patient outcomes in low- and middle-income countries, but none specifically to address postoperative care and complications. We aimed to identify key features of a proposed short-course addressing this topic using a Delphi process with low- and middle-income country anaesthesia providers trained as short-course facilitators. An initial questionnaire was co-developed from literature review and exploratory workshops to include 108 potential course features. Features included content; teaching method; appropriate participants; and appropriate faculty. Over three Delphi rounds (panellists numbered 86, 64 and 35 in successive cycles), panellists indicated which features they considered most important. Responses were analysed by geographical regions: Africa, the Americas, south-east Asia and Western Pacific. Ultimately, panellists identified 60, 40 and 54 core features for the proposed course in each region, respectively. There were high levels of consensus within regions on what constituted core course content, but not between regions. All panellists preferred the small group workshop teaching method irrespective of region. All regions considered anaesthetists to be key facilitators, while all agreed that both anaesthetists and operating theatre nurses were key participants. The African and Americas regional panels recommended more multidisciplinary healthcare professionals for participant roles. Faculty from high-income countries were not considered high priority. Our study highlights variability between geographical regions as to which course features were perceived as most locally relevant, supporting regional adaptation of short-course design rather than a one-size-fits-all model.     

Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.