Different Evidence-Summaries have Implications for Contextualizing Findings of Meta-Analysis of Diagnostic Tests.
J Clin Epidemiol. 2019 Jan 14;:
Authors: Zgodic A, Schmid CH, Olkin I, Trikalinos TA
OBJECTIVE: To evaluate diagnostic tests, analysts use meta-analyses to provide inputs to parameters in decision models. Choosing parameter estimands from meta-analyses requires understanding the meta-analytic and decision-making contexts.
STUDY DESIGN AND SETTING: We expand on an analysis comparing positron emission tomography (PET), PET with computed tomography (PET/CT), and conventional workup (CW) in women with suspected recurrent breast cancer. We discuss Bayesian meta-analytic summaries (posterior mean over a set of existing studies, posterior estimate in an existing study, posterior predictive mean in a new study) used to estimate diagnostic test parameters (prevalence, sensitivity, specificity) needed to calculate quality-adjusted life years in a decision model contextualizing PET, PET/CT, and CW.
RESULTS: The mean and predictive mean give similar estimates, but the latter displays greater uncertainty. Namely, PET/CT outperforms CW on average but may not do better than CW when implemented in future settings.
CONCLUSION: Selecting estimands for decision model parameters from meta-analyses requires understanding the relationship between decision settings and meta-analysis studies' settings, specifically whether the former resemble one or all study settings or represent new settings. We provide an algorithm recommending appropriate estimands as input parameters in decision models for diagnostic tests to obtain output parameters consistent with the decision context.
PMID: 30654146 [PubMed - as supplied by publisher]
Crk Tyrosine Phosphorylation Regulates PDGF-BB-inducible Src Activation and Breast Tumorigenicity and Metastasis.
Mol Cancer Res. 2018 01;16(1):173-183
Authors: Kumar S, Lu B, Davra V, Hornbeck P, Machida K, Birge RB
The activity of Src family kinases (Src being the prototypical member) is tightly regulated by differential phosphorylation on Tyr416 (positive) and Tyr527 (negative), a duet that reciprocally regulates kinase activity. The latter negative regulation of Src on Tyr527 is mediated by C-terminal Src kinase (CSK) that phosphorylates Tyr527 and maintains Src in a clamped negative regulated state by promoting an intramolecular association. Here it is demonstrated that the SH2- and SH3-domain containing adaptor protein CrkII, by virtue of its phosphorylation on Tyr239, regulates the Csk/Src signaling axis to control Src activation. Once phosphorylated, the motif (PIpYARVIQ) forms a consensus sequence for the SH2 domain of CSK to form a pTyr239-CSK complex. Functionally, when expressed in Crk-/- MEFs or in Crk+/+ HS683 cells, Crk Y239F delayed PDGF-BB-inducible Src Tyr416 phosphorylation. Moreover, expression of Crk Y239F in HS683 cells delayed Src kinase activation and suppressed the cell-invasive and -transforming phenotypes. Finally, through loss-of-function and epistasis experiments using CRISPR-Cas9-engineered 4T1 murine breast cancer cells, Crk Tyr239 is implicated in breast cancer tumor growth and metastasis in orthotopic immunocompetent 4T1 mice model of breast adenocarcinoma. These findings delineate a novel role for Crk Tyr239 phosphorylation in the regulation of Src kinases, as well as a potential molecular explanation for a long-standing question as to how Crk regulates the activation of Src kinases.Implications: These findings provide new perspectives on the versatility of Crk in cancer by demonstrating how Crk mechanistically drives, through a tyrosine phosphorylation-dependent manner, tumor growth, and metastasis. Mol Cancer Res; 16(1); 173-83. ©2017 AACR.
PMID: 28974561 [PubMed - indexed for MEDLINE]
Safety and Tolerability of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors in Oncology.
Drug Saf. 2019 Jan 16;:
Authors: Shah RR, Shah DR
Tyrosine kinase inhibitors (TKIs) that target epidermal growth factor receptor (EGFR) have dramatically improved progression-free survival in non-small-cell lung cancer (NSCLC) patients who carry sensitizing EGFR-activating mutations and in patients with breast and pancreatic cancers. However, EGFR-TKIs are associated with significant and disabling undesirable effects that adversely impact on quality of life and compliance. These effects include dermatological reactions, diarrhoea, hepatotoxicity, stomatitis, interstitial lung disease and ocular toxicity. Each individual EGFR-TKI is also associated with additional adverse effect(s) that are not shared widely by the other members of its class. Often, these effects call for dose reduction, treatment discontinuation or pharmacotherapeutic intervention. Since dermatological effects result from on-target effects on wild-type EGFR, rash is often considered to be a biomarker of efficacy. A number of studies have reported better outcomes in patients with skin reactions compared with those without. This has led to a 'dosing-to-rash' strategy to optimize therapeutic outcomes. Although conceptually attractive, there is currently insufficient evidence-based support for this strategy. While skin reactions following EGFR-TKIs are believed to result from an effect on wild-type EGFR, their efficacy is related to effects on mutant variants of EGFR. It is noteworthy that newer EGFR-TKIs that spare wild-type EGFR are associated with fewer dermatological reactions. Furthermore, secondary mutations such as T790M in exon 20 often lead to development of resistance to the clinical activity and efficacy of first- and second-generation EGFR-TKIs. This has stimulated the search for later-generations of EGFR-TKIs with the ability to overcome this resistance and with greater target selectivity to spare wild-type EGFR in expectations of an improved safety profile. However, available data reviewed herein indicate that not only are these newer agents associated with the aforementioned adverse effects typical of earlier agents, but they are also susceptible to resistance due to tertiary mutations, most frequently C797S. At least three later-generation EGFR-TKIs, canertinib, naquotinib and rociletinib, have been discontinued from further development in NSCLC following concerns about their safety and risk/benefit.
PMID: 30649743 [PubMed - as supplied by publisher]