From bench to bedside: current and future applications of molecular profiling in renal cell carcinoma

Among the adult population, renal cell carcinoma (RCC) constitutes the most prevalent form of kidney neoplasm. Unfortunately, RCC is relatively asymptomatic and there are no tumor markers available for diagnostic, prognostic or predictive purposes. Molecular profiling, the global analysis of gene and protein expression profiles, is an emerging promising tool for new biomarker identification in RCC. In this review, we summarize the existing knowledge on RCC regarding clinical presentation, treatment options, and tumor marker status. We present a general overview of the more commonly used approaches for molecular profiling at the genomic, transcriptomic and proteomic levels. We also highlight the emerging role of molecular profiling as not only revolutionizing the process of new tumor marker discovery, but also for providing a better understanding of the pathogenesis of RCC that will pave the way towards new targeted therapy discovery. Furthermore, we discuss the spectrum of clinical applications of molecular profiling in RCC in the current literature. Finally, we highlight some of the potential challenging that faces the era of molecular profiling and its transition into clinical practice, and provide an insight about the future perspectives of molecular profiling in RCC

MicroRNAs: exploring a new dimension in the pathogenesis of kidney cancer

Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. The role of the von-Hippel-Lindeau (VHL) tumour suppressor gene is well established in RCC with a loss of VHL protein leading to accumulated hypoxia-induced factor (HIF) and the subsequent transcriptional activation of multiple downstream targets. Recently, microRNAs (miRNAs) have been shown to be differentially expressed in RCC and their role in RCC pathogenesis is emerging. This month, in BMC Medicine, Gleadle and colleagues show that certain miRNAs are regulated by VHL in either a hypoxia-inducible factor (HIF)-dependent or HIF-independent manner in RCC. They also show that miRNA expression correlates with the survival of RCC patients

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Postoperative Ovarian Vein Thrombosis and Treatment with Direct Oral Anticoagulant

Postoperative ovarian vein thrombosis (OVT) is a rare complication following hysterectomy. Due to its ambiguous presentation, most frequently presenting as a fever with no known source and lower quadrant abdominal pain, OVTs are commonly diagnosed incidentally on computed tomography as a low-attenuation thrombus in place of the ovarian vein. The cornerstones of OVT treatment include anticoagulation and antibiotic therapy; however, there are no current guidelines to inform provider decision-making regarding specific anticoagulant agents, dosing, or length of therapy. We present a patient with a history of deep-vein thrombosis, who presented to the emergency department with OVT following a laparoscopic hysterectomy. She was treated with apixaban, a direct oral anticoagulant (DOAC), and experienced repeated episodes of vaginal bleeding and hematoma expansion. We present this case to instill a high index of suspicion for OVT after laparoscopic hysterectomy, and to discuss the role of DOACs in patients with thromboembolic disease and concurrent bleeding

Microvascular density as an independent predictor of clinical outcome in renal cell carcinoma: An automated image analysis study

Tumor microvascular density (MVD) has been shown to correlate with the aggressiveness of several cancers. With the introduction of targeted anti-angiogenic therapy, assessment of MVD has the potential not only as a prognostic but also as a therapeutic marker. The significance of tumor vascularity in clear cell renal cell carcinoma (ccRCC) has been debated, with studies showing contradictory results. Previous studies were limited by manual quantification of MVD within a small area of tumor. Since then, the validity of this method has been questioned. To avoid the inaccuracies of manual quantification, we employed a computerized image analysis, which allowed assessment of large areas of tumor and adjacent normal tissue. The latter was used as an internal reference for normalization. MVD and vascular endothelial growth factor (VEGF) were assessed in 57 cases of ccRCC. Sections were immunostained for CD34 and VEGF. Areas of ccRCC and normal kidney medulla were analyzed within scanned images using software that counted CD34-positive vessels and measured the intensity of VEGF staining. We obtained unadjusted values from tumoral areas and calculated adjusted values as tumor/normal ratios. Unadjusted MVD had no association with clinical outcome. However, similarly to tumor stage, higher adjusted MVD was associated with shorter disease-free survival (log-rank P0.037, Cox P0.02). This was significant in univariate and multivariate analyses. MVD did not correlate with tumor stage, pointing to its independent prognostic value. As expected due to the known molecular abnormalities in ccRCC, most tumors showed higher VEGF expression than normal tissue. Higher adjusted VEGF was associated with high tumor grade (P0.049). The finding of increased MVD as an independent marker of tumor aggressiveness may prove useful in the development of new tests for prognostic and therapeutic guidance. Digital techniques can provide more accurate assessment of immunomarkers and may reveal less obvious associations. © 2012 USCAP, Inc All rights reserved