IntroductionThe aim of this research was to study molecular changes in the articular cartilage and subchondral bone of the tibial plateau from mice deficient in frizzled-related protein (Frzb) compared to wild-type mice by transcriptome analysis.MethodsGene-expression analysis of the articular cartilage and subchondral bone of three wild-type and three Frzb-/- mice was performed by microarray. Data from three wild-type and two Frzb-/- samples could be used for pathway analysis of differentially expressed genes and were explored with PANTHER, DAVID and GSEA bioinformatics tools. Activation of the wingless-type (WNT) pathway was analysed using Western blot. The effects of Frzb gain and loss of function on chondrogenesis and cell proliferation was examined using ATDC5 micro-masses and mouse ribcage chondrocytes.ResultsExtracellular matrix-associated integrin and cadherin pathways, as well as WNT pathway genes were up-regulated in Frzb-/- samples. Several WNT receptors, target genes and other antagonists were up-regulated, but no difference in active β-catenin was found. Analysis of ATDC5 cell micro-masses overexpressing FRZB indicated an up-regulation of aggrecan and Col2a1, and down-regulation of molecules related to damage and repair in cartilage, Col3a1 and Col5a1. Silencing of Frzb resulted in down-regulation of aggrecan and Col2a1. Pathways associated with cell cycle were down-regulated in this transcriptome analysis. Ribcage chondrocytes derived from Frzb-/- mice showed decreased proliferation compared to wild-type cells.ConclusionsOur analysis provides evidence for tight regulation of WNT signalling, shifts in extracellular matrix components and effects on cell proliferation and differentiation in the articular cartilage - subchondral bone unit in Frzb-/- mice. These data further support an important role for FRZB in joint homeostasis and highlight the complex biology of WNT signaling in the joint.

Osteoporosis and osteoarthritis are common musculoskeletal disorders in which cause and outcome are determined by genetic and environmental factors. The WNT signaling pathway plays an important role in skeletal development and growth. Polymorphisms in a number of genes that belong to this pathway are associated with osteoarthritis and/or osteoporosis. This suggests a role for this molecular signaling pathway in postnatal joint and bone homeostasis and pathology. Increased activity of WNT signaling strengthens the bone but may have adverse effects on the articular cartilage. Frizzled related protein (FRZB) plays a role in both bone and cartilage. Better understanding of the WNT pathway and its modulators may lead to specific therapeutics for both osteoarthritis and osteoporosis. This review focuses on recent studies in human genetics and animal models and highlights the potential clinical relevance of this rapidly evolving field of research.

These data show that loss of function of Lrp5 increases cartilage degradation in mild instability-induced OA models in mice. Low bone mass density could have contributed to this effect.

Background Treatment of patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) continues to evolve expeditiously. Objectives This retrospective study investigated real-world treatment patterns and EGFR mutation testing in patients with EGFRm advanced NSCLC in Belgium. Methods Data were extracted from medical records of adults diagnosed with EGFRm locally advanced/metastatic NSCLC between 1 September 2015 and 31 December 2017. Patients were followed retrospectively from diagnosis until 1 September 2018, end of clinical activity or death. Data on demographics, patient outcomes and disease characteristics, treatment patterns and EGFR mutation testing at diagnosis and progression were analyzed descriptively. Results A total of 141 patients were enrolled. At diagnosis, median age was 69 years, 63.1% were female, 88.7% had metastatic disease, 94.3% had adenocarcinoma histology, 76.6% had ECOG 0/1, 70.9% had common EGFR mutations and 29.1% had only rare mutations. In first line, 73.8% of patients received first/second-generation EGFR-tyrosine kinase inhibitors (1G/2G EGFR-TKIs), while 21.9% received other systemic treatments. Among 61 patients progressing on and discontinuing a first 1G/2G EGFR-TKI, 45 (73.8%) received subsequent systemic treatment while 16 (26.2%) did not; 20 (32.8%) received osimertinib. Among 65 patients progressing on a first 1G/2G EGFR-TKI, 47 (72.3%) were tested for T790M, of whom 25 (53.2%) were positive. Conclusion These real-world data from Belgium show that a substantial fraction of patients with EGFRm NSCLC do not receive 1G/2G EGFR-TKIs in first line and do not receive subsequent systemic treatment after progression on 1G/2G EGFR-TKIs. Only a third receive osimertinib upon progression on 1G/2G EGFR-TKIs. These observations should be considered in first-line treatment decisions. Trial Registration ClinicalTrials.gov: NCT03761901

Methods: A hybrid decision-analytic model was developed to estimate the cost and health outcomes of NSCLC patients comparing the current testing scenario vs a notesting scenario. Current distribution of ALK testing techniques and the sensitivity and specificity data were retrieved from the literature. Target treatments were based on expert opinion and test results. For each treatment, a 3-states Markov model was developed, where progression-free survival (PFS) and overall survival (OS) curves were parameterized using exponential extrapolations to model transition of patients among health states (lifetime horizon). A Spanish Health System perspective was used and 3% discount rate applied. Deterministic and probabilistic sensitivity analyses were performed to address uncertainty.Results: A target population of 7,628 NSCLC (non-squamous and never-smoker squamous) patients per year was estimated. Over a lifetime horizon, the current ALK testing scenario produced an additional 5,060 life years (LYs) and 3,906 qualityadjusted life-years (QALYs) compared with the no-testing scenario. The incremental cost-effectiveness ratio (ICER) was 13.136 V/QALY. Further parameters were measured such as median cost and median QALYs of the four possible test results plus no tested patients. The sensitivity analyses carried out confirmed the robustness of the base-case results, with the sensitivity and specificity variables being the key drivers of the model.Conclusions: ALK testing in non-squamous and never-smoker squamous NSCLC patients is a cost-effective strategy, which generates more than 3,000 QALYs in Spain over a lifetime horizon. Comparing this gain in health outcomes with the incremental costs (associated mainly with targeted treatments), the resulting ICER shows that testing non-squamous and never-smoker squamous NSCLC is a cost-effective strategy in Spain.

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