Derivation and validation of actionable quality indicators targeting reductions in complications for injury admissions.

PURPOSE: Approximately, one out of five patients hospitalized following injury will develop at least one hospital complication, more than three times that observed for general admissions. We currently lack actionable Quality Indicators (QI) targeting specific complications in this population. We aimed to derive and validate QI targeting hospital complications for injury admissions and develop algorithms to identify patient charts to review. METHODS: We conducted a retrospective cohort study including patients with major trauma admitted to any level I or II adult trauma center an integrated Canadian trauma system (2014-2019). We used the trauma registry to develop five QI targeting deep vein thrombosis/pulmonary embolism (DVT/PE), decubitus ulcers, delirium, pneumonia and urinary tract infection (UTI). We developed algorithms to identify patient charts to revise on consultation with a group of clinical experts. RESULTS: The study population included 14,592 patients of whom 5.3% developed DVT or PE, 2.7% developed a decubitus ulcer, 8.6% developed delirium, 14.7% developed pneumonia and 7.3% developed UTI. The indicators demonstrated excellent predictive performance (Area Under the Curve 0.81-0.87). We identified 4 hospitals with a higher than average incidence of at least one of the targeted complications. The algorithms identified on average 50 and 20 charts to be reviewed per year for level I and II centers, respectively. CONCLUSION: In line with initiatives to improve the quality of trauma care, we propose QI targeting reductions in hospital complications for injury admissions and algorithms to generate case lists to facilitate the review of patient charts.

Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation.

Although targeting the Ras/Raf/MEK pathway remains a promising anticancer strategy, mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitors in clinical development are likely to be limited in their ability to produce durable clinical responses due to the emergence of acquired drug resistance. To identify potential mechanisms of such resistance, we established MEK inhibitor-resistant clones of human HT-29 colon cancer cells (HT-29R cells) that harbor the B-RafV600E mutation. HT-29R cells were specifically resistant to MEK inhibition in vitro and in vivo, with drug-induced elevation of MEK/ERK and their downstream targets primarily accountable for drug resistance. We identified MEK1(F129L) mutation as a molecular mechanism responsible for MEK/ERK pathway activation. In an isogenic cell system that extended these findings into other cancer cell lines, the MEK1(F129L) mutant exhibited higher intrinsic kinase activity than wild-type MEK1 [MEK1(WT)], leading to potent activation of ERK and downstream targets. The MEK1(F129L) mutation also strengthened binding to c-Raf, suggesting an underlying mechanism of higher intrinsic kinase activity. Notably, the combined use of Raf and MEK inhibitors overcame the observed drug resistance and exhibited greater synergy in HT-29R cells than the drug-sensitive HT-29 parental cells. Overall, our findings suggested that mutations in MEK1 can lead to acquired resistance in patients treated with MEK inhibitors and that a combined inhibition of Raf and MEK may be potentially useful as a strategy to bypass or prevent drug resistance in the clinic.

High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the γ-secretase inhibitor, RO4929097.

Interest continues to build around the early application of patient selection markers to prospectively identify patients likely to show clinical benefit from cancer therapies. Hypothesis generation and clinical strategies often begin at the preclinical stage where responder and nonresponder tumor cell lines are first identified and characterized. In the present study, we investigate the drivers of in vivo resistance to the γ-secretase inhibitor RO4929097. Beginning at the tissue culture level, we identified apparent IL6 and IL8 expression differences that characterized tumor cell line response to RO4929097. We validated this molecular signature at the preclinical efficacy level identifying additional xenograft models resistant to the in vivo effects of RO4929097. Our data suggest that for IL6 and IL8 overexpressing tumors, RO4929097 no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts. These preclinical data provide a rationale for preselecting patients possessing low levels of IL6 and IL8 prior to RO4929097 dosing. Extending this hypothesis into the clinic, we monitored patient IL6 and IL8 serum levels prior to dosing with RO4929097 during Phase I. Interestingly, the small group of patients deriving some type of clinical benefit from RO4929097 presented with low baseline levels of IL6 and IL8. Our data support the continued investigation of this patient selection marker for RO4929097 and other types of Notch inhibitors undergoing early clinical evaluation.

Preclinical in vivo evaluation of efficacy, pharmacokinetics, and pharmacodynamics of a novel MEK1/2 kinase inhibitor RO5068760 in multiple tumor models.

Targeting the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway represents a promising anticancer strategy. Recently, we have reported a novel class of potent and selective non-ATP-competitive MEK1/2 inhibitors with a unique structure and mechanism of action. RO5068760 is a representative of this class showing significant efficacy in a broad spectrum of tumors with aberrant mitogen-activated protein kinase pathway activation. To understand the relationship between systemic exposures and target (MEK1/2) inhibition as well as tumor growth inhibition, the current study presents a detailed in vivo characterization of efficacy, pharmacokinetics, and pharmacodynamics of RO5068760 in multiple xenograft tumor models. For inhibition of MEK1/2 as measured by the phosphorylated ERK levels, the estimated EC(50)s in plasma were 1.36 micromol/L (880 ng/mL) and 3.35 micromol/L (2168 ng/mL) in LOX melanoma and HT-29 colorectal cancer models, respectively. A similar EC(50) (1.41 micromol/L or 915 ng/mL) was observed in monkey peripheral blood lymphocytes. To achieve tumor growth inhibition (>or=90%), an average plasma drug concentration of 0.65 or 5.23 micromol/L was required in B-RafV600E or K-Ras mutant tumor models, respectively, which were remarkably similar to the IC(90) values (0.64 or 4.1 micromol/L) determined in vitro for cellular growth inhibition. With equivalent in vivo systemic exposures, RO5068760 showed superior efficacy in tumors harboring B-RafV600E mutation. The plasma concentration time profiles indicate that constant p-ERK suppression (>50%) may not be required for optimal efficacy, especially in highly responsive tumors. This study may facilitate future clinical trial design in using biochemical markers for early proof of mechanism and in selecting the right patients and optimal dose regimen.