Diagnostic and Prognostic Molecular Markers for Renal Cell Carcinoma: A Critical Appraisal of the Current State of Research and Clinical Applicability

Context

Earlier detection of renal cell carcinoma (RCC) and the recent expansion of treatment possibilities have positively influenced the outlook for patients with this disease. However, progression and treatment response are still not sufficiently predictable. Molecular markers could help to refine individual risk stratification and treatment planning, although they have not yet become clinically routine.

Objective

This review presents an overview of diagnostic and prognostic molecular markers for RCC and a subgrouping of these markers for different clinical issues.

Evidence acquisition

Literature and recent meeting abstracts were searched using these terms: renal (cell) carcinoma, molecular/tumor markers, biopsy, blood, urine, disease progression/prognosis, immunohistochemistry, risk factors, and survival.Due to the resulting large number of articles, studies were subjectively selected according to the importance of a study on the field, number of investigated patients, originality, multivariate analyses performed, contrast with previously published data, actuality, and assumed clinical applicability of the described results. More then 90% of the selected studies originated from the past 10 yr; >50% of the articles were written in 2006 or later.

Evidence synthesis

These data were predominantly obtained via nonrandomized, retrospective, but often controlled studies. Thereby, the resulting level of evidence is 2A/2B. The broad spectrum of described molecular markers (MMs) for RCC consists of markers already extensively studied in other malignancies (eg, p53), as well as MMs typically associated with specific RCC-altered gene functions and pathways (eg, von Hippel–Lindau [VHL]). The main goal of using MMs is to refine the prediction of clinical end points like tumor progression, treatment response, and cancer-specific and/or overall survival. Further, MMs might facilitate the clinical work-up of undefined renal masses and prove to be more convenient tools for screening and follow-up in blood and urine.

Conclusions

Presently, there are a number of promising MMs for diverse clinical questions, but the available data are not yet valid enough for routine, clinical application. We should comply with the demand for large multicenter prospective investigations, stratified for RCC type and treatment modalities, to lift the use of molecular markers in RCC to a practical level, thereby providing a better consultation for our patients regarding diagnosis, treatment, and follow-up.     

Burn-induced organ dysfunction: Vagus nerve stimulation attenuates organ and serum cytokine levels

Introduction

The interaction of the CNS and the immune system is well known. A parasympathetic anti-inflammatory pathway has recently been described. Both electrical and pharmacological parasympathetic stimulation attenuate proinflammatory mediator generation. Burn induces abacterial cytokine generation and we sought to evaluate whether parasympathetic stimulation after experimental burn decreases cardiodepressive mediator generation.

Material and methods

A 30% TBSA full-thickness rat burn model was used. After microsurgical preparation of the cervical portion of the vagus nerve, we performed electric vagus nerve stimulation. Serum was harvested and organ samples of heart and liver were homogenized. Samples were subjected to sandwich-ELISA specific for TNF-α, IL-1β and IL-6. Heart rate measurements were done using left ventricular microcatheterization. Statistical analysis was done using Student's t-tests and analysis of variance (ANOVA).

Results

Burn induced a significant rise of TNF-α, IL-1β and IL-6 in organ homogenates and serum. After cervical vagal electrostimulation, serum and organ homogenate levels of proinflammatory cytokines were markedly reduced compared to burn controls. Left ventricular microcatheter assessment demonstrated no cardiodepressive effect of the vagal stimulation itself.

Conclusion

Our results encourage further research regarding the neuroimmunologic background of burn, possibly leading to the development of a novel therapeutic approach to burn-induced organ dysfunction and immunodysregulation.     

Long-term results after two-stage operative treatment of late developmental displacement of the hip

The purpose of this study was to evaluate the long-term results of 43 patients who underwent two-stage operative treatment of late developmental displacement of the hip (LDH). The average age at the time of open reduction was 20.7 months. An intertrochanteric osteotomy was performed after an average of 6.7 weeks. The mean clinical and radiological follow-up was 32.75 years. Degenerative changes were documented according to Kellgren. For assessment of outcome we used Severin's classification and score according to Merle d'Aubigné. One patient required a total hip replacement. Complications included one superficial infection and three recurrent dislocations. One patient developed coxa magna and two additional avascular necrosis of the hip. The score according to Merle d'Aubigné was 16.1. At the latest follow-up 35 hips had degenerative changes grade 0 or 1 and 7 grade 2. Using the Severin classification 13 hips had a satisfactory result (class I), 14 were rated as class II, 7 as class III, 5 as class IV and 2 as class V. The two-stage procedure seems to be a successful principle in the operative treatment of LDH.     

A porcine model of massive, totally occlusive, pulmonary embolism

Background

A reliable, animal model of massive, totally occlusive, pulmonary embolism (PE) is lacking.

Objectives

To design an animal model of totally occlusive PE and to challenge the model by a plasminogen activator.

Methods

In eight anaesthetized pigs (~ 90 kg) a massive preformed autologous thrombus was injected into the caval vein. One animal was autopsied to assess the extent of injected clot, whereas in the other animals extracorporeal life support (ECLS) was initiated and continued for three hours. These animals received 100 mg rt-PA. Blood gases, coagulation tests, creatine kinase (CK), lactate dehydrogenase (LDH), end-tidal CO2, systemic and pulmonary artery blood pressures and flow were registered.

Results

All animals went into circulatory arrest within 2 minutes after injection of the thrombus. In the animal where ECLS was not started, autopsy relieved a totally occlusive embolus of the pulmonary artery. The ECLS maintained a systemic blood flow of 6-8 L/min with adequate oxygenation and CO2-removal. However, lactate increased and base-excess became negative. Ddimer increased, fibrinogen decreased, and CK and LDH increased. All seven animals were weaned from ECLS. Despite the rt-PA treatment, the animals had at that time low end tidal CO2/PaCO2 ratio and increased mean pulmonary arterial pressure, suggesting a significant amount of embolic material remaining in the pulmonary artery.

Conclusion

This model of massive, totally occlusive, pulmonary embolism mimics well fatal PE seen in the clinic, and has the potential for use in testing of new therapeutic interventions.     

Increased serum brain-derived neurotrophic factor protein upon hypoxia in healthy young men

Exposing animals to brief hypoxic periods leads to neuroprotective ischemic tolerance termed preconditioning. This phenomenon is well documented in the brain, but the underlying mechanisms require further elucidation. As nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important mediators of maintaining homeostatic conditions in the adult nervous system in terms of physiological and pathophysiological processes, we hypothesized that hypoxic preconditioning might modulate serum neurotrophin concentrations. Hypoxia was induced for 30 min in 14 healthy young men resulting in a constant blood oxygen saturation of 75%. Hyperinsulinemic euglycemic clamps were performed and serum concentrations of BDNF and NGF were measured at baseline, directly after the intervention, and at the end of the session. Overall, serum BDNF concentrations decreased over time by maximally 35% (P = 0.001) while in contrast NGF concentrations remained unchanged. Acute hypoxia alleviated the decrease of BDNF resulting in higher BDNF concentrations as compared to normoxic control (P < 0.01). Our findings show that acute hypoxia results in significantly higher serum BDNF concentrations pointing to a potential role of BDNF in the underlying mechanism of hypoxic preconditioning. Based on its neuroprotective properties, BDNF may be of high clinical relevance for therapeutic options in ischemic neurovascular diseases.     

Copy number gain at 8q12.1‐q22.1 is associated with a malignant tumor phenotype in salivary gland myoepitheliomas

Salivary gland myoepithelial tumors are relatively uncommon tumors with an unpredictable clinical course. More knowledge about their genetic profiles is necessary to identify novel predictors of disease. In this study, we subjected 27 primary tumors (15 myoepitheliomas and 12 myoepithelial carcinomas) to genome‐wide microarray‐based comparative genomic hybridization (array CGH). We set out to delineate known chromosomal aberrations in more detail and to unravel chromosomal differences between benign myoepitheliomas and myoepithelial carcinomas. Patterns of DNA copy number aberrations were analyzed by unsupervised hierarchical cluster analysis. Both benign and malignant tumors revealed a limited amount of chromosomal alterations (median of 5 and 7.5, respectively). In both tumor groups, high frequency gains (≥20%) were found mainly at loci of growth factors and growth factor receptors (e.g., PDGF, FGF(R)s, and EGFR). In myoepitheliomas, high frequency losses (≥20%) were detected at regions of proto‐cadherins. Cluster analysis of the array CGH data identified three clusters. Differential copy numbers on chromosome arm 8q and chromosome 17 set the clusters apart. Cluster 1 contained a mixture of the two phenotypes (n = 10), cluster 2 included mostly benign tumors (n = 10), and cluster 3 only contained carcinomas (n = 7). Supervised analysis between malignant and benign tumors revealed a 36 Mbp‐region at 8q being more frequently gained in malignant tumors (P = 0.007, FDR = 0.05). This is the first study investigating genomic differences between benign and malignant myoepithelial tumors of the salivary glands at a genomic level. Both unsupervised and supervised analysis of the genomic profiles revealed chromosome arm 8q to be involved in the malignant phenotype of salivary gland myoepitheliomas. © 2008 Wiley‐Liss, Inc.