Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas.

PURPOSE: Chemokines are involved in cancer-related inflammation and malignant progression. In this study, we evaluated expression of CCR8 and its natural cognate ligand CCL1 in patients with urothelial carcinomas of bladder and renal cell carcinomas. EXPERIMENTAL DESIGN: We examined CCR8 expression in peripheral blood and tumor tissues from patients with bladder and renal carcinomas. CCR8-positive myeloid cells were isolated from cancer tissues with magnetic beads and tested in vitro for cytokine production and ability to modulate T-cell function. RESULTS: We show that monocytic and granulocytic myeloid cell subsets in peripheral blood of patients with cancer with urothelial and renal carcinomas display increased expression of chemokine receptor CCR8. Upregulated expression of CCR8 is also detected within human cancer tissues and primarily limited to tumor-associated macrophages. When isolated, CD11b(+)CCR8(+) cell subset produces the highest levels of proinflammatory and proangiogenic factors among intratumoral CD11b myeloid cells. Tumor-infiltrating CD11b(+)CCR8(+) cells selectively display activated Stat3 and are capable of inducing FoxP3 expression in autologous T lymphocytes. Primary human tumors produce substantial amounts of the natural CCR8 ligand CCL1. CONCLUSIONS: This study provides the first evidence that CCR8(+) myeloid cell subset is expanded in patients with cancer. Elevated secretion of CCL1 by tumors and increased presence of CCR8(+) myeloid cells in peripheral blood and cancer tissues indicate that CCL1/CCR8 axis is a component of cancer-related inflammation and may contribute to immune evasion. Obtained results also implicate that blockade of CCR8 signals may provide an attractive strategy for therapeutic intervention in human urothelial and renal cancers.

A systematic review of the quality of evidence of ablative therapy for small renal masses.

PURPOSE: We critically assessed the methodological and reporting quality of published studies of ablative techniques for small renal masses. MATERIALS AND METHODS: We performed a systematic PubMed® and EMBASE® literature search from January 1966 to March 2010 to identify all full text, original research publications on ablative therapy for renal masses. Six reviewers working independently in 3 teams performed duplicate data abstraction using Strengthening the Reporting of Observational Studies in Epidemiology criteria, which were pilot tested in a separate sample. RESULTS: A total of 117 original research publications published in a 15-year period (1995 to 2009) met eligibility criteria. No randomized, controlled trials were identified. All studies were observational and 88.9% had 1 arm with no comparison group. Median sample size was 18 patients (IQR 5.5, 40.0) and 53.8% of studies included 20 or fewer patients. Median followup was 14.0 months (IQR 8.0, 23.8) and only 19.7% of studies had an average followup of greater than 24 months. Of the studies 20.5% mentioned the number of operators involved and only 6.0% provided information on their experience level. Of the studies 66.7% addressed the recurrence rate. Disease specific and overall survival was reported in only 15.4% and 16.2% of studies, respectively. CONCLUSIONS: The published literature on the therapeutic efficacy of ablative therapy for renal masses is largely limited to uncontrolled, 1-arm observational studies. In the absence of higher quality evidence ablative therapy outside research studies should be limited to select patients who are not candidates for surgical intervention.

Tumor-associated macrophages mediate immunosuppression in the renal cancer microenvironment by activating the 15-lipoxygenase-2 pathway.

Renal cell carcinoma (RCC), the most common human kidney cancer, is frequently infiltrated with tumor-associated macrophages (TAM) that can promote malignant progression. Here, we show that TAMs isolated from human RCC produce substantial amounts of the proinflammatory chemokine CCL2 and immunosuppressive cytokine IL-10, in addition to enhanced eicosanoid production via an activated 15-lipoxygenase-2 (15-LOX2) pathway. TAMs isolated from RCC tumors had a high 15-LOX2 expression and secreted substantial amounts of 15(S)-hydroxyeicosatetraenoic acid, its major bioactive lipid product. Inhibition of lipoxygenase activity significantly reduced production of CCL2 and IL-10 by RCC TAMs. In addition, TAMs isolated from RCC were capable of inducing in T lymphocytes, the pivotal T regulatory cell transcription factor forkhead box P3 (FOXP3), and the inhibitory cytotoxic T-lymphocyte antigen 4 (CTLA-4) coreceptor. However, this TAM-mediated induction of FOXP3 and CTLA-4 in T cells was independent of lipoxygenase and could not be reversed by inhibiting lipoxygenase activity. Collectively, our results show that TAMs, often present in RCCs, display enhanced 15-LOX2 activity that contributes to RCC-related inflammation, immunosuppression, and malignant progression. Furthermore, we show that TAMs mediate the development of immune tolerance through both 15-LOX2-dependent and 15-LOX2-independent pathways. We propose that manipulating LOX-dependent arachidonic acid metabolism in the tumor microenvironment could offer new strategies to block cancer-related inflammation and immune escape in patients with RCC.

Recovery of erectile function after robotic prostatectomy: evidence-based outcomes.

Several reported advantages of the robotic-assisted laparoscopic approach to the treatment of clinically localized prostate cancer include superior results for erectile function as one of the critical outcomes of radical prostate surgery. This article provides a critical assessment of the evidence that exists for erectile function outcomes based on a systematic literature review. We found that the low methodological and reporting quality of existing studies did not appear well suited to guide clinical practice. A new framework of prospective investigation using validated patient self-assessment instruments would seem critical to the future advancement of this field.

Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To examine the evidence on the benefits and harms of screening for prostate cancer. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Electronic databases including Medline, Embase, CENTRAL, abstract proceedings, and reference lists up to July 2010. Review methods Included studies were randomised controlled trials comparing screening by prostate specific antigen with or without digital rectal examination versus no screening. Data abstraction and assessment of methodological quality with the GRADE approach was assessed by two independent reviewers and verified by the primary investigator. Mantel-Haenszel and inverse variance estimates were calculated and pooled under a random effects model expressing data as relative risks and 95% confidence intervals. RESULTS: Six randomised controlled trials with a total of 387 286 participants that met inclusion criteria were analysed. Screening was associated with an increased probability of receiving a diagnosis of prostate cancer (relative risk 1.46, 95% confidence interval 1.21 to 1.77; P<0.001) and stage I prostate cancer (1.95, 1.22 to 3.13; P=0.005). There was no significant effect of screening on death from prostate cancer (0.88, 0.71 to 1.09; P=0.25) or overall mortality (0.99, 0.97 to 1.01; P=0.44). All trials had one or more substantial methodological limitations. None provided data on the effects of screening on participants' quality of life. Little information was provided about potential harms associated with screening. CONCLUSIONS: The existing evidence from randomised controlled trials does not support the routine use of screening for prostate cancer with prostate specific antigen with or without digital rectal examination.

Low quality of evidence for robot-assisted laparoscopic prostatectomy: results of a systematic review of the published literature.

BACKGROUND: Robot-assisted laparoscopic prostatectomy (RALP) is displacing radical retropubic prostatectomy as the gold standard surgical approach for clinically localised prostate cancer in the United States and is also being increasingly used in Europe and other parts of the world. This trend has occurred despite the paucity of high-quality evidence to support its relative superiority to more established treatment modalities. OBJECTIVE: We performed this study to critically assess the quality of published evidence on RALP to support this major shift in practice patterns. DESIGN, SETTING, AND PARTICIPANTS: We conducted a systematic review of the published literature through Medline and Embase (1966 to December 2008). All original research publications on RALP were included. Editorials, letters to the editor, and review articles were excluded. MEASUREMENTS: Two reviewers independently performed the data abstraction using a standardised form derived from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria. RESULTS AND LIMITATIONS: Seventy-five original research publications met eligibility criteria. Fifty-five (73.3%) studies were published between 2005 and 2008, and 20 studies (26.7%) were published between 2001 and 2004. Approximately three-quarters of the studies were case series (74.7%), and only two (2.7%) randomised, controlled trials (RCT) were identified. Twelve authors cowrote 72% (54 of 75) of the published studies. Reporting of STROBE criteria ranged from 100.0% (scientific rationale/background explained) to 1.3% (consideration of sample size), with no improvement over time. The study was limited to published literature in the English language. CONCLUSIONS: The published RALP literature is limited to observational studies of mostly low methodologic quality. Our findings draw into question to what extent valid conclusions about the relative superiority or equivalence of RALP to other surgical approaches can be drawn and whether published outcomes can be generalised to the broader community. There is an urgent need to raise the methodologic standards for clinical research on new urologic procedures and devices.