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.     

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.     

Theory-driven development of a mobile phone supported intervention for adolescents with perinatal depression

Purpose

This paper describes the design of a theory-informed pragmatic intervention for adolescent perinatal depression in primary care in Nigeria.

Methods

We conducted Focus Group Discussions (FGDs) among 17 adolescent mothers and 25 maternal health care providers with experience in the receipt and provision of care for perinatal depression. The Consolidated Framework for Implementation Research (CFIR) was used to systematically examine the barriers and facilitators affecting adolescent mothers' use of an existing intervention package for depression. The Theoretical Domain Framework (TDF) and the Capability, Opportunity, Motivation, Behaviour (COM-B) model were used to analyze the results of the data across the five CFIR domains.

Results

FGD analysis revealed that care providers lacked knowledge on approaches to engage young mothers in treatment. Young mothers had poor treatment engagement, low social support, and little interest in parenting. A main characteristic of the newly designed intervention is the inclusion of age-appropriate psychoeducation supported with weekly mobile phone calls, to address treatment engagement and parenting behaviours of young mothers. Also in the outer setting, low social support from relatives was addressed with education, “as need arises” phone calls, and the involvement of "neighborhood mothers”. In the inner settings, care providers’ behaviour is addressed with training to increase their capacity to engage young mothers in treatment.

Conclusion

A theory-based approach helped develop an age-appropriate intervention package targeting depression and parenting skills deficit among perinatal adolescents in primary maternal care and in which a pragmatic use of mobile phone was key.