Levels of Evidence Supporting the North American and European Perioperative Care Guidelines for Anesthesiologists between 2010 and 2020: A Systematic Review.

BACKGROUND: Although there are thousands of published recommendations in anesthesiology clinical practice guidelines, the extent to which these are supported by high levels of evidence is not known. This study hypothesized that most recommendations in clinical practice guidelines are supported by a low level of evidence. METHODS: A registered (Prospero CRD42020202932) systematic review was conducted of anesthesia evidence-based recommendations from the major North American and European anesthesiology societies between January 2010 and September 2020 in PubMed and EMBASE. The level of evidence A, B, or C and the strength of recommendation (strong or weak) for each recommendation was mapped using the American College of Cardiology/American Heart Association classification system or the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The outcome of interest was the proportion of recommendations supported by levels of evidence A, B, and C. Changes in the level of evidence over time were examined. Risk of bias was assessed using Appraisal of Guidelines for Research and Evaluation (AGREE) II. RESULTS: In total, 60 guidelines comprising 2,280 recommendations were reviewed. Level of evidence A supported 16% (363 of 2,280) of total recommendations and 19% (288 of 1,506) of strong recommendations. Level of evidence C supported 51% (1,160 of 2,280) of all recommendations and 50% (756 of 1,506) of strong recommendations. Of all the guidelines, 73% (44 of 60) had a low risk of bias. The proportion of recommendations supported by level of evidence A versus level of evidence C (relative risk ratio, 0.93; 95% CI, 0.18 to 4.74; P = 0.933) or level of evidence B versus level of evidence C (relative risk ratio, 1.63; 95% CI, 0.72 to 3.72; P = 0.243) did not increase in guidelines that were revised. Year of publication was also not associated with increases in the proportion of recommendations supported by level of evidence A (relative risk ratio, 1.07; 95% CI, 0.93 to 1.23; P = 0.340) or level of evidence B (relative risk ratio, 1.05; 95% CI, 0.96 to 1.15; P = 0.283) compared to level of evidence C. CONCLUSIONS: Half of the recommendations in anesthesiology clinical practice guidelines are based on a low level of evidence, and this did not change over time. These findings highlight the need for additional efforts to increase the quality of evidence used to guide decision-making in anesthesiology.

ROS-mediated p53 induction of Lpin1 regulates fatty acid oxidation in response to nutritional stress.

The p53 protein is activated by stress signals and exhibits both protective and death-promoting functions that are considered important for its tumor suppressor function. Emerging evidence points toward an additional role for p53 in metabolism. Here, we identify Lpin1 as a p53-responsive gene that is induced in response to DNA damage and glucose deprivation. Lpin1 is essential for adipocyte development and fat metabolism, and mutation in this gene is responsible for the lypodystrophy phenotype in fld mice. We show that p53 and Lpin1 regulate fatty acid oxidation in mouse C2C12 myoblasts. p53 phosphorylation on Ser18 in response to low glucose is ROS and ATM dependent. Lpin1 expression in response to nutritional stress is controlled through the ROS-ATM-p53 pathway and is conserved in human cells. Lpin1 provides a critical link between p53 and metabolism that may be an important component in mediating the tumor suppressor function of p53.

Does biomarker use in oncology improve clinical trial failure risk? A large-scale analysis.

PURPOSE: To date there has not been an extensive analysis of the outcomes of biomarker use in oncology. METHODS: Data were pooled across four indications in oncology drawing upon trial outcomes from www.clinicaltrials.gov: breast cancer, non-small cell lung cancer (NSCLC), melanoma and colorectal cancer from 1998 to 2017. We compared the likelihood drugs would progress through the stages of clinical trial testing to approval based on biomarker status. This was done with multi-state Markov models, tools that describe the stochastic process in which subjects move among a finite number of states. RESULTS: Over 10000 trials were screened, which yielded 745 drugs. The inclusion of biomarker status as a covariate significantly improved the fit of the Markov model in describing the drug trajectories through clinical trial testing stages. Hazard ratios based on the Markov models revealed the likelihood of drug approval with biomarkers having nearly a fivefold increase for all indications combined. A 12, 8 and 7-fold hazard ratio was observed for breast cancer, melanoma and NSCLC, respectively. Markov models with exploratory biomarkers outperformed Markov models with no biomarkers. CONCLUSION: This is the first systematic statistical evidence that biomarkers clearly increase clinical trial success rates in three different indications in oncology. Also, exploratory biomarkers, long before they are properly validated, appear to improve success rates in oncology. This supports early and aggressive adoption of biomarkers in oncology clinical trials.

Type 1 Boston keratoprosthesis: outcomes at two Canadian centres.

OBJECTIVES: To report the outcomes of patients who underwent Boston type 1 keratoprosthesis (Kpro) surgery at the University Health Network (Toronto, Ont.) and the University of Ottawa Eye Institute (Ottawa, Ont.) between June 2008 and July 2013. DESIGN: Retrospective case series. PARTICIPANTS: Forty-four eyes of 43 patients who underwent Kpro surgery. METHODS: A retrospective review was conducted of all Kpro procedures performed by 4 attending cornea surgeons. The preoperative characteristics and postoperative course of each patient were analyzed. RESULTS: In 31 eyes (70%), the primary indication for a Kpro was failed corneal transplantation. The remaining 13 eyes (30%) had Kpro as a primary procedure. In all eyes, preoperative visual acuity (VA) was 20/150 or worse, with 39 eyes (89%) having a VA of counting fingers, hand movement, or light perception. Mean follow-up time was 21 ± 12 months (range 12-57 months). The retention rate at the last follow-up was 95%. Best-achieved median VA was 20/100 (range 20/20 to no light perception [NLP]), with 37% of patients achieving a VA of >20/40 at some point during their postoperative course. At the last follow-up, median VA was 20/400 (range 20/30 to NLP). The 2 most common complications included retroprosthetic membrane formation (23 eyes, 52%) and elevated intraocular pressure (10 eyes, 23%). There were 5 cases (11%) of stromal melt and 1 case (2%) of infective keratitis. CONCLUSIONS: This study demonstrates that Kpro improves VA in a majority of cases, and is a viable option in situations in which there is a poor prognosis for traditional penetrating keratoplasty.

Biomarker use is associated with reduced clinical trial failure risk in metastatic melanoma.

Given the high morbidity and mortality associated with metastatic melanoma, considerable attention has been paid to identifying potential therapies. Until recently, few therapies have been specifically approved for treating metastatic melanoma. In an attempt to increase clinical trial successes, many therapies are implementing biomarkers for patient stratification. This strategy narrows down the population in an effort to identify appropriate subpopulations that have increased efficacy or fewer safety concerns. However, the addition of a biomarker constitutes an additional risk to clinical development and may therefore increase the overall clinical trial risk. Here, we examine the clinical trial success rate for therapies targeting metastatic melanoma. In addition, we identify the impact that biomarkers have had on the clinical development of this disease.

The effect of dutasteride on the detection of prostate cancer: A set of meta-analyses.

BACKGROUND: Dutasteride has been shown to significantly improve symptoms of benign prostatic hyperplasia (BPH) and reduce clinical progression. Recent data from studies evaluating 5-alpha reductase inhibitors (5-ARIs) for the prevention of prostate cancer, however, suggest 5ARIs, including dutasteride, may be associated with increased incidence of Gleason 8-10 prostate tumours. This meta-analysis was undertaken to quantify the effect of dutasteride on detection of prostate cancer and high-grade prostate cancer. METHODS: Our meta-analysis includes data from GlaxoSmithKline-sponsored phase III randomized clinical trials (with a study duration of ≥2 years) evaluating the effect of dutasteride, alone or in combination with tamsulosin, to treat BPH or to reduce the risk of prostate cancer. The incidence of prostate cancer, including Gleason 7-10 and Gleason 8-10, for patients taking either dutasteride, dutasteride plus tamsulosin, tamsulosin alone, or placebo, were evaluated using the Mantel-Haenszel Risk Ratio (MHRR) method of conducting meta-analyses. RESULTS: The meta-analysis demonstrated that in a population with symptomatic BPH and/or at increased risk of prostate cancer, a statistically significant lower number of detectable prostate cancers was found in men taking dutasteride compared to control groups (MHRR: 0.66, 95% CI 0.52-0.85). In our analysis, there was no increased risk for Gleason 7-10 (MHRR: 0.83, 95% CI 0.56-1.21) or Gleason 8-10 prostate cancers (MHRR: 0.99, 95% CI 0.39-2.53) in men taking dutasteride over control groups. There were several limitations that need to be considered when interpreting these results. CONCLUSION: These data provide support for the continued use of dutasteride in the treatment of symptomatic BPH patients.