Creation of a primary tumor tissue expression biomarker-augmented prognostic model for patients with metastatic renal cell carcinoma

BackgroundClinical and pathological factors alone have limited prognostic ability in patients with metastatic clear cell renal cell carcinoma (ccRCC). Bim, a downstream pro-apoptotic molecule in the PD-1 signaling pathway, has recently been associated with survival in other malignancies. We sought to determine if tissue biomarkers including Bim, added to a previously reported clinical metastases score, improved prediction of cancer-specific survival (CSS) for patients with metastatic ccRCC.MethodsPatients with metastatic ccRCC who underwent nephrectomy between 1990 and 2004 were identified using our institutional registry. Sections from paraffin-embedded primary tumor tissue blocks were used for immunohistochemistry staining for Bim, PD-1, B7-H1 (PD-L1), B7-H3, CA-IX, IMP3, Ki67, and survivin. Biomarkers that were significantly associated with CSS after adjusting for the metastases score were used to develop a biomarker-specific multivariable model using a bootstrap resampling approach and forward selection. Predictive ability was summarized using a bootstrap-corrected c-index.ResultsThe cohort included 602 patients: 192 (32%) with metastases at diagnosis and 410 (68%) who developed metastases after nephrectomy. Median follow-up was 9.6 years (IQR 4.2–12.8), during which 504 patients died of RCC. Bim, IMP3, Ki67, and survivin expression were significantly associated with CSS after adjusting for the metastases score, and were eligible for biomarker-specific model inclusion. After variable selection, high Bim (hazard ratio [HR] = 1.44; 95% confidence interval [CI] 1.16–1.78; P <0.001), high survivin (HR = 1.35; 95% CI 1.08–1.68; P = 0.008), and the metastases score (HR = 1.13 per 1 point; 95% CI 1.10–1.16; P <0.001) were retained in the final multivariable model (c-index = 0.69).ConclusionWe created a prognostic model combining the clinical metastases score and 2 primary tumor tissue expression biomarkers, Bim and survivin, for patients with metastatic renal cell carcinoma who underwent nephrectomy.     

Outcomes After Cryoablation Versus Partial Nephrectomy for Sporadic Renal Tumors in a Solitary Kidney: A Propensity Score Analysis

Background

While partial nephrectomy (PN) is considered the standard approach for a tumor in a solitary kidney, percutaneous cryoablation (PCA) is emerging as an alternative nephron-sparing option.

Rat models of myocardial infarction. Pathogenetic insights and clinical relevance

Animal models of cardiovascular pathology contribute towards understanding and treatment of a broad range of conditions. Specifically in the context of acute myocardial infarction (AMI), rat models have been commonly used in studies of pathogenesis, investigation and novel therapies, although there has often been difficulty in translating experimental findings to clinical benefit. However, recent years have seen two important changes to our clinical approaches to AMI. First, there is increasing recognition that the pathophysiology of human AMI is a process occurring at many levels, not just within the epicardial coronary artery, but also within the microvasculature and the myocardium. Second, contemporary treatments are shifting away from thrombolytic dissolution of epicardial coronary thrombus to direct mechanical approaches using angioplasty and stents. These changes in our understanding of AMI have implications for the relevance of these animal models. The following discussion therefore reviews and examines the current rat models of AMI, places them in a clinical context, discusses their advantages and limitations, and outlines likely future developments, providing an overview of the place of these important models of AMI.     

Coronary Hemodynamics in Patients With Severe Aortic Stenosis and Coronary Artery Disease Undergoing Transcatheter Aortic Valve Replacement: Implications for Clinical Indices of Coronary Stenosis Severity

Objectives

In this study, a systematic analysis was conducted of phasic intracoronary pressure and flow velocity in patients with severe aortic stenosis (AS) and coronary artery disease, undergoing transcatheter aortic valve replacement (TAVR), to determine how AS affects: 1) phasic coronary flow; 2) hyperemic coronary flow; and 3) the most common clinically used indices of coronary stenosis severity, instantaneous wave-free ratio and fractional flow reserve.

Interaction between statins and clopidogrel: is there anything clinically relevant?

Since their introduction several years ago, the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors-the statins-have been widely used for hyperlipidemia and for the primary/secondary prevention of cardiovascular diseases. They have been shown to be safe as well as efficacious in a number of different clinical trials; however, studies have suggested that they can interact with other co-administered therapies. More recently, the thienopyridines have been successfully integrated with the conventional medical treatment of coronary disease as they showed effectiveness in reducing platelet activity both in stable and unstable settings. They also improve the outcome of patients treated with percutaneous coronary intervention. The potential interaction of statins and thienopyridines is a matter of concern. Despite some preclinical data suggesting an interaction between statins metabolized by the liver cytochrome P3A4-such as atorvastatin, lovastatin and simvastatin-and clopidogrel, there is no compelling clinical evidence to stop their co-administration.     

Repeat thrombolysis or conservative therapy vs. rescue percutaneous coronary intervention for failed thrombolysis: systematic review and meta-analysis

Background: Despite proven advantages of primary percutaneouscoronary intervention (PCI), thrombolysis remains the firstline treatment for ST-elevation myocardial infarction (STEMI)worldwide. Management of patients with failed thrombolysis isstill debated, and data from existing randomized controlledtrials are conflicting. Aim: To compare the risk/benefit profile of repeat thrombolysis(RT) vs. rescue PCI in patients with failed thrombolysis. Methods: Search of BioMedCentral, CENTRAL, mRCT and PubMed forrandomized controlled trials comparing rescue PCI vs. conservativetherapy and/or RT vs. conservative therapy. Outcomes of interestassessed by adjusted indirect meta-analysis: major adverse events(MAE, defined as the composite of overall mortality and re-infarction),stroke, congestive heart failure (CHF), major bleeds (MB), andminor bleeds. Overall mortality and re-infarction have beenalso analysed individually. Results: Eight trials were included (1318 patients). Follow-upranged from ‘in-hospital’ to 6 months. No significantdifference was found for the risk of MAE [OR 0.93(0.26–3.35),P = 0.4], overall mortality [OR 1.01(0.52–1.95), P = 0.15],stroke [OR 5.03(0.64–39.1), P = 0.58] and CHF [OR 0.74(0.28–1.96),P = 0.6]. Compared with conservative therapy, rescue PCI wasassociated with a 70% reduction in the risk of re-infarction[OR 0.32(0.14–0.74), P = 0.008], number needed to treat17. No difference in terms of MB was found [OR 0.5(0.1–2.5),P = 0.09], while a greater risk of minor bleeds was observedwith rescue PCI [OR 2.48(1.08–5.7), P = 0.04], numberneeded to harm 50. Conclusion: Although the observed benefit is modest, these datasupport the use of PCI after failed thrombolysis.     

Brothers in arms: DNA enzymes, short interfering RNA, and the emerging wave of small-molecule nucleic acid-based gene-silencing strategies

The past decade has seen the rapid evolution of small-molecule gene-silencing strategies, driven largely by enhanced understanding of gene function in the pathogenesis of disease. Over this time, many genes have been targeted by specifically engineered agents from different classes of nucleic acid-based drugs in experimental models of disease to probe, dissect, and characterize further the complex processes that underpin molecular signaling. Arising from this, a number of molecules have been examined in the setting of clinical trials, and several have recently made the successful transition from the bench to the clinic, heralding an exciting era of gene-specific treatments. This is particularly important because clear inadequacies in present therapies account for significant morbidity, mortality, and cost. The broad umbrella of gene-silencing therapeutics encompasses a range of agents that include DNA enzymes, short interfering RNA, antisense oligonucleotides, decoys, ribozymes, and aptamers. This review tracks current movements in these technologies, focusing mainly on DNA enzymes and short interfering RNA, because these are poised to play an integral role in antigene therapies in the future.     

Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma

Context

The role of cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) in the targeted therapy (TT) era is controversial.