A Systematic Review of the Evidence for the Decipher Genomic Classifier in Prostate Cancer

ContextMolecular biomarkers aim to address the established limitations of clinicopathologic factors to accurately risk stratify patients with prostate cancer (PCa). Questions remain as to whether sufficient evidence supports adoption of these biomarkers for clinical use.ObjectiveTo perform a systematic review of the available evidence supporting the clinical utility of the Decipher genomic classifier (GC).Evidence acquisitionThe review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching PubMed and conference abstracts from January 2010 to June 2020. Evidence was then graded using the criteria of Simon et al (Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009;101:1446–52) and American Urology Association (AUA) criteria.Evidence synthesisIn total, 42 studies and 30 407 patients were included. GC performance data were available for localized, postprostatectomy, nonmetastatic castration-resistant, and metastatic hormone-sensitive PCa as part of retrospective studies (n = 12 141), prospective registries (n = 17 053), and prospective and post hoc randomized trial analyses (n = 1213). In 32 studies (n = 12 600), the GC was independently prognostic for all study endpoints (adverse pathology, biochemical failure, metastasis, and cancer-specific and overall survival) on multivariable analysis and improved the discrimination over standard of care in 24 studies (n = 8543). GC use changed the management in active surveillance (number needed to test [NNT] = 9) and postprostatectomy (NNT = 1.5–4) settings in five studies (n = 4331). Evidence strength was levels 1 and 2 by the Simon criteria for all disease states other than high-risk PCa, and grades A and B by AUA criteria depending on disease state.ConclusionsConsistent data are now present from diverse levels of evidence, which when viewed together, have demonstrated clinical utility of the GC in PCa. The utility of the GC is strongest for intermediate-risk PCa and postprostatectomy decision-making.Patient summaryIn this paper, we review the evidence of the Decipher genomic classification tool for men with prostate cancer. We found consistent evidence that the test helps identify which cancers are more or less aggressive, which in turn aids in personalized treatment decision-making.     

Endothelial-Derived miR-17∼92 Promotes Angiogenesis to Protect against Renal Ischemia-Reperfusion Injury

BackgroundDamage to the renal microvasculature is a hallmark of renal ischemia-reperfusion injury (IRI)–mediated AKI. The miR-17∼92 miRNA cluster (encoding miR-17, -18a, -19a, -20a, -19b-1, and -92a-1) regulates angiogenesis in multiple settings, but no definitive role in renal endothelium during AKI pathogenesis has been established.MethodsAntibodies bound to magnetic beads were utilized to selectively enrich for renal endothelial cells from mice. Endothelial-specific miR-17∼92 knockout (miR-17∼92^endo−/−) mice were generated and given renal IRI. Mice were monitored for the development of AKI using serum chemistries and histology and for renal blood flow using magnetic resonance imaging (MRI) and laser Doppler imaging. Mice were treated with miRNA mimics during renal IRI, and therapeutic efficacies were evaluated.ResultsmiR-17, -18a, -20a, -19b, and pri–miR-17∼92 are dynamically regulated in renal endothelial cells after renal IRI. miR-17∼92^endo−/− exacerbates renal IRI in male and female mice. Specifically, miR-17∼92^endo−/− promotes renal tubular injury, reduces renal blood flow, promotes microvascular rarefaction, increases renal oxidative stress, and promotes macrophage infiltration to injured kidneys. The potent antiangiogenic factor thrombospondin 1 (TSP1) is highly expressed in renal endothelium in miR-17∼92^endo−/− after renal IRI and is a target of miR-18a and miR-19a/b. miR-17∼92 is critical in the angiogenic response after renal IRI, which treatment with miR-18a and miR-19b mimics can mitigate.ConclusionsThese data suggest that endothelial-derived miR-17∼92 stimulates a reparative response in damaged renal vasculature during renal IRI by regulating angiogenic pathways.     

Variability in cesarean delivery rates among individual labor and delivery nurses compared to physicians at three attribution time points

ObjectiveTo examine the variability in the cesarean delivery (CD) rates of individual labor and delivery nurses compared with physicians at three attribution time points.Data SourcesMedical record data from nine hospitals in Washington State from January 2016 through September 2018.Study DesignRetrospective, observational cohort design using an aggregated database of birth records.Data Collection/Extraction MethodsChart‐abstracted clinical data from a subset of nulliparous, term, singleton, vertex births attributed at admission, labor management, and delivery to nurses and physicians. Two classification methods were used to categorize nurse‐ and physician‐level CD rates at three attribution time points and the reliability of these methods compared.Principal FindingsThe sample included 12 556 births, 319 nurses, and 126 physicians. Overall, variation in nurse‐level CD rates did not differ significantly across the three attribution time points, and the extent of variation was similar to that observed in physicians. However, agreement between attribution time points varied between 35 percent and 65 percent when classifying individual nurses into the top and bottom deciles. The average reliability of nurse‐level CD rates was 32 percent at admission (IQR 22.0 percent to 38.7 percent), 32.6 percent at labor (IQR 23.1 percent to 40.9 percent), and 29.3 percent (IQR 20.9 percent to 35.8 percent) at delivery. The average reliability of physician‐level CD rates was higher: 54.2 percent (IQR 38.7 percent to 71.4 percent) at admission, 62.5 percent (IQR 49.0 percent to 79.6 percent) at labor management, and 66.1 percent (IQR 53.7 percent to 81.2 percent) at delivery.ConclusionFeedback on nurse‐level CD rates as part of routine clinical quality audits can provide insight into nurse performance in the context of other individual‐level and unit‐level information. To reliably distinguish individual nurse performance, larger sample sizes are needed.     

Small animal jet injection technique results in enhanced immunogenicity of hantavirus DNA vaccines

DNA vaccine evaluation in small animals is hampered by low immunogenicity when the vaccines are delivered using a needle and syringe. To overcome this technical hurdle we tested the possibility that a device developed for human intradermal medicine delivery might be adapted to successfully deliver a DNA vaccine to small animals. Disposable syringe jet injection (DSJI) does not currently exist for small animals. However, a commercialized, human intradermal device used to to administer medicines to the human dermis in a 0.1 mL volume was evaluated in Syrian hamsters. Here, we found that hantavirus DNA vaccines administered to hamsters using DSJI were substantially more immunogenic than the same vaccines delivered by needle/syringe or particle mediated epidermal delivery (gene gun) vaccination. By adjusting how the device was used we could deliver vaccine to either subcutaneous tissues, or through the skin into the muscle. RNA and/or antigen expression was detected in epidermal, subepidermal and fibroblast cells. We directly compared six optimized and non-optimized hantavirus DNA vaccines in hamsters. Optimization, including codon-usage and mRNA stability, did not necessarily result in increased immunogenicity for all vaccines tested; however, optimization of the Andes virus (ANDV) DNA vaccine protected vaccinated hamsters from lethal disease. This is the first time active vaccination with an ANDV DNA vaccine has shown protective efficacy in the hamster model. The adaptation of a human intradermal jet injection device for use as a method of subcutaneous and intramuscular jet injection of DNA vaccines will advance the development of nucleic acid based medical countermeasures for diseases modeled in hamsters.     

Flattening the organization: implementing self-directed work groups

In response to tremendous growth of managed care and threats to financial stability and job security, the Greater Baltimore Medical Center (GBMC) restructured itself into independent business units. The radiology department at GBMC resolved to reduce cost per unit-of-service, improve service, determine optimal staffing levels and reduce the number of layers of organization. It was decided to achieve those goals by implementing self-directed work groups. Staff buy-in was critical to success of the project. To begin, the staff was educated intensively about current trends in healthcare, managed care and potential changes in the job market. The radiology department was allowed to reduce the size of its staff through attrition and worked hard to focus staff concern on the impact each individual could have on the bottom line and the resultant effect on job security. Self-directed work groups were designed on a matrix that used small "service teams" in combinations to form larger "work groups." Actual work and daily activities occur at the service team level; information exchange and major decisions occue at the work group level. Seventeen months after beginning the project and 10 months after implementation, the organization has flattened, staff members have adjusted well to new roles, there have been no lay-offs, and the matrix system of small and large groups have proved particularly valuable.     

Psychological adjustment in adult adoptees: assessment of distress, depression, and anger

Psychological adjustment was assessed in a sample of 525 female and 191 male adoptees. Analyses were conducted by gender; by search status, i.e., those who had never searched, those who were searching, and those who had made contact with their biological parents; and by history of mental health service utilization. Compared to normative data, the sample reported significantly higher levels of psychological maladjustment; only women adoptees scored higher on a scale measuring anger. Overall, adoptees' scores were elevated but did not approach levels typical of outpatient populations.