AZD8055 enhances in vivo efficacy of afatinib in chordomas

Chordomas are primary bone tumors that arise in the cranial base, mobile spine, and sacrococcygeal region, affecting patients of all ages. Currently, there are no approved agents for chordoma patients. Here, we evaluated the anti-tumor efficacy of small molecule inhibitors that target oncogenic pathways in chordoma, as single agents and in combination, to identify novel therapeutic approaches with the greatest translational potential. A panel of small molecule compounds was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and potentially synergistic combinations were further evaluated using chordoma cell lines and xenograft models. Among the tested agents, inhibitors of EGFR (BIBX 1382, erlotinib, and afatinib), c-MET (crizotinib), and mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, this dual inhibition completely suppressed tumor growth in vivo, showing improved tumor control. Together, these data demonstrate that individual inhibitors of EGFR, c-MET, and mTOR pathways suppress chordoma growth both in vitro and in vivo. mTOR inhibition increased the efficacy of EGFR inhibition on chordoma growth in several preclinical models. The insights gained from our study potentially provide a novel combination therapeutic strategy for patients with chordoma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland

The effects of sequential pictorial cues, self-recording, and praise on the job task sequencing of retarded adults.

The present study investigated the effects of a self-recording procedure using sequentially organized picture cues on independent task changes of four mentally retarded adults. Independent task changes were identified as the beginning of new tasks without directives or instruction. In addition to investigating treatment effects, the long-term maintenance of the task-change behavior was measured. During self-recording and picture-cue training, the subjects completed an increased proportion of independent task changes, and this behavior was maintained for more than 10 wk following removal of the training procedures. Self-recording using picture cues was shown to be an effective procedure for teaching mentally retarded adults to function more independently in a job setting

Risk Screening for Adverse Outcomes in Subacute Care

Purpose of this study was to identify variables near hospital admission that could identify patients at risk for placement, death, or readmission. The goals were to assess sensitivity and specificity of screening strategies in predicting adverse outcomes that deter or affect home health care. We evaluated whether generic screens might efficiently identify type of outcome. Criteria reported in the literature were used to predict outcomes for 1,332 admissions. Factors that discriminated type of outcome included comorbidity, mental status, living arrangement, transfer to special care, prior admission, iatrogenic trauma, and pending litigation. We conclude risk scores can accurately predict outcome of hospital treatment, which may be useful in targeting patients for intervention. Using billing data, although rather insensitive, was the most cost-effective strategy. </jats:p

Meta-Analysis with Longitudinal Studies: Controlling for Analytical Bias

A recent study published in an international medical Journal presented an opportunity to demonstrate the difficulties of interpreting meta-analysis results with longitudinal data. We conducted a new meta-analysis using identical data from the published study and showed contradictory results. </jats:p