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.     

Usefulness of three-dimensional navigable intraoperative ultrasound in resection of brain tumors with a special emphasis on malignant gliomas

Background

Intraoperative imaging is increasingly being used in resection of brain tumors. Navigable three-dimensional (3D)-ultrasound is a novel tool for planning and guiding such resections. We review our experience with this system and analyze our initial results, especially with respect to malignant gliomas.

Methods

A prospective database for all patients undergoing sononavigation-guided surgery at our center since this surgery’s introduction in June 2011 was queried to retrieve clinical data and technical parameters. Imaging was reviewed to categorize tumors based on enhancement and resectability. Extent of resection was also assessed.

Results

Ninety cases were operated and included in this analysis, 75 % being gliomas. The 3D ultrasound mode was used in 87 % cases (alone in 40, and combined in 38 cases). Use of combined mode function [ultrasound (US) with magnetic resonance (MR) images] facilitated orientation of anatomical data. Intraoperative power Doppler angiography was used in one-third of the cases, and was extremely beneficial in delineating the vascular anatomy in real-time. Mean duration of surgery was 4.4 hours. Image resolution was good or moderate in about 88 % cases. The use of the intraoperative imaging prompted further resection in 59 % cases. In the malignant gliomas (51 cases), gross-total resection was achieved in 47 % cases, increasing to 88 % in the “resectable” subgroup.

Conclusions

Navigable 3D US is a versatile, useful and reliable intraoperative imaging tool in resection of brain tumors, especially in resource-constrained settings where Intraoperative MR (IOMR) is not available. It has multiple functionalities that can be tailored to suit the procedure and the experience of the surgeon.     

Corticosteroid treatment exacerbates nephrotic syndrome in a zebrafish model of magi2a knockout

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Wear Rates With Large Metal and Ceramic Heads on a Second Generation Highly Cross-Linked Polyethylene at Mean 6-Year Follow-Up

Background

Bearing surface wear and osteolysis are major factors limiting the durability of total hip arthroplasty (THA). Second generation annealed highly cross-linked polyethylene (HXLPE) and ceramics were introduced to THA for their excellent wear rates. However, there is little data comparing the wear rates of metal and ceramic heads on second generation HXLPE.

Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas

No reliable classification is in clinical use for the therapeutic stratification of children with ependymoma, such that disease risk might be identified and patients treated to ensure a combination of maximal cure rates and minimal adverse therapeutic effects. This study has examined associations between clinicopathologic and cytogenetic variables and outcome in a trial cohort of children with ependymoma, with the aim of defining a practical scheme for stratifying this heterogeneous tumor. Intracranial ependymomas (n = 146) from children treated on the RT1 trial at St. Jude Children’s Research Hospital were evaluated for the status of multiple pathological features. Interphase FISH (iFISH) defined the status of loci on chromosomes 1q (EXO1), 6q (LATS1) and 9, including 9p21 (CDKN2A). Data relating to these clinicopathological and cytogenetic variables were compared with survival data in order to model disease risk groups. Extent of surgical resection was a significant determinant of outcome in both supratentorial and infratentorial compartments. Tumor cell density and mitotic count were associated with outcome among children with posterior fossa ependymomas (n = 119). Among pathologic features, only brain invasion was associated with outcome in children with supratentorial ependymomas (n = 27). For posterior fossa tumors, gain of 1q was independently associated with outcome and in combination with clinicopathological variables defined both a two-tier and three-tier system of disease risk. Among children developing posterior fossa ependymomas treated with maximal surgical resection and conformal radiotherapy, key clinicopathological variables and chromosome 1q status can be used to define tiers of disease risk. In contrast, risk factors for pediatric supratentorial tumors are limited to sub-total resection and brain invasion.     

Involvement of NR2A- or NR2B-containing N-methyl-D-aspartate receptors in the potentiation of cortical layer 5 pyramidal neurone inputs depends on the developmental stage

In the cortex, N-methyl-D-aspartate receptors (NMDARs) play a critical role in the control of synaptic plasticity processes. We have previously shown in rat visual cortex that the application of a high-frequency stimulation (HFS) protocol used to induce long-term potentiation in layer 2/3 leads to a parallel potentiation of excitatory and inhibitory inputs received by cortical layer 5 pyramidal neurones without changing the excitation/inhibition balance of the pyramidal neurone, indicating a homeostatic control of this parameter. We show here that the blockade of NMDARs of the neuronal network prevents the potentiation of excitatory and inhibitory inputs, and this result leaves open to question the role of the NMDAR isoform involved in the induction of long-term potentiation, which is actually being strongly debated. In postnatal day (P)18-23 rat cortical slices, the blockade of synaptic NR2B-containing NMDARs prevents the induction of the potentiation induced by the HFS protocol, whereas the blockade of NR2A-containing NMDARs reduced the potentiation itself. In P29-P32 cortical slices, the specific activation of NR2A-containing receptors fully ensures the potentiation of excitatory and inhibitory inputs. These results constitute the first report of a functional shift in subunit composition of NMDARs during the critical period (P12-P36), which explains the relative contribution of both NR2B- and NR2A-containing NMDARs in synaptic plasticity processes. These effects of the HFS protocol are mediated by the activation of synaptic NMDARs but our results also indicate that the homeostatic control of the excitation/inhibition balance is independent of NMDAR activation and is due to specialized recurrent interactions between excitatory and inhibitory networks.     

Six Weeks of Voluntary Exercise don’t Protect C57BL/6 Mice Against Neurotoxicity of MPTP and MPP+

Exercise improves the central nervous system (CNS) functions and is widely recommended for neurological patients with, e.g., Alzheimer’s and Parkinson’s disease (PD). However, exercise-induced neuroprotection is an open discussion. Here, the intranasal administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 65 mg/kg) caused death of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the striatum of C57BL/6 mice. 1-Methyl-4-phenylpyridinium, the active metabolite of MPTP, also inhibited complex-I activity of mitochondria isolated from the CNS of mice. However, 6 weeks of exercise on voluntary running wheels did not protect against nigrostriatal neurodegeneration or mitochondrial inhibition, suggesting that benefits of exercise for PD may not be associated with neuroprotection. The literature presents other candidates, such as neurotrophins or increased antioxidant defenses.     

Ureteropelvic junction obstruction with associated renal anomalies

Ureteropelvic junction obstruction when associated with other congenital anomalies of the kidney often presents a diagnostic and therapeutic dilemma. These anomalies include fusion abnormalities, malrotation, renal ectopia and duplicated systems. We report our experience in the management of 27 patients with ureteropelvic junction obstruction and associated renal anomalies, including horseshoe kidney in 9, duplicated systems in 12, ectopic kidney in 5 and malrotation in 1.