Michael Aitchison

The relationship between T-lymphocyte infiltration, stage, tumour grade and survival in patients undergoing curative surgery for renal cell cancer.

The present study examined the relationship between tumour stage, grade, T-lymphocyte subset infiltration and survival in patients who had undergone potentially curative surgery for renal clear-cell cancer (n=73). Intratumoural CD4+ T-lymphocyte infiltrate was associated with poor cancer-specific survival, independent of grade, in this cohort.

Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial

Summary Background In metastatic renal cell carcinoma combinations of interferon alfa-2a, interleukin-2, and fluorouracil produce higher response rates and longer progression-free survival than do single agents. We aimed to compare overall survival in patients receiving combination treatment or interferon alfa-2a. Methods RE04/30012 was an open-label randomised trial undertaken in 50 centres across eight countries. 1006 treatment-naive patients diagnosed with advanced metastatic renal cell carcinoma were randomly allocated (1 to 1) by minimisation to receive interferon alfa-2a alone or combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil. Treatment was not masked. The primary endpoint was overall survival. Treatment groups were compared with a non-stratified log-rank test. Analysis was by intention to treat. This study is registered, number ISRCTN 46518965. Findings 502 patients were randomly assigned to receive interferon alfa-2a and 504 to receive combined treatment. Median follow-up was 37·2 months (24·8–52·3). Median overall survival was 18·8 months (17·0–23·2) for patients receiving interferon alfa-2a versus 18·6 months (16·5–20·6) for those receiving combination therapy. Overall survival did not differ between the two groups (hazard ratio 1·05 [95% CI 0·90–1·21], p=0·55; absolute difference 0·3% (−5·1 to 5·6) at 1 year and 2·7% (−8·2 to 2·9) at 3 years). Serious adverse events were reported in 113 (23%) patients receiving interferon alfa-2a and 131 (26%) of those receiving combined treatment. Interpretation Although combination therapy does not improve overall or progression-free survival compared with interferon alfa-2a alone, immunotherapy might still have a role because it can produce remissions that are of clinically relevant length in some patients. Identification of patients who will benefit from immunotherapy is crucial. Funding UK Medical Research Council.

The relationship between the preoperative systemic inflammatory response and cancer-specific survival in patients undergoing potentially curative resection for renal clear cell cancer.

The relationship between tumour stage, grade (Fuhrman), performance status (ECOG), a combined score (UCLA Integrated Staging System, UISS), systemic inflammatory response (elevated C-reactive protein concentration), and cancer-specific survival was examined in patients undergoing potentially curative resection for renal clear cell cancer (n=100). On univariate survival analysis, sex (P=0.050), tumour stage (P=0.001), Fuhrman grade (P<0.001), UISS (P<0.001), C-reactive protein (P=0.002) were significant predictors of survival. On multivariate analysis with sex, UISS and C-reactive protein entered as covariates, only UISS (HR 2.70, 95% CI 1.00–7.30, P=0.050) and C-reactive protein (HR 4.00, 95% CI 1.21–13.31, P=0.024) were significant independent predictors of survival. The presence of a preoperative systemic inflammatory response predicts poor cancer-specific survival in patients who have undergone potentially curative resection for renal clear cell cancer.

Prospective study of the relationship between the systemic inflammatory response, prognostic scoring systems and relapse-free and cancer-specific survival in patients undergoing potentially curative resection for renal cancer.

To examine the prognostic value of markers of systemic inflammatory response, together with established scoring systems, in predicting relapse‐free and cancer‐specific survival in patients with primary operable renal cancer, as there is increasing evidence that such markers provide prognostic information, in addition to scoring systems, in patients with metastatic renal cancer.

Modulation of lamellipodial structure and dynamics by NO-dependent phosphorylation of VASP Ser239

The initial step in directed cell movement is lamellipodial protrusion, an action driven by actin polymerization. Enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) family proteins are key regulators of this actin polymerization and can control lamellipodial protrusion rate. Ena/VASP proteins are substrates for modification by cyclic-nucleotide-dependent protein kinases at a number of sites. Phosphorylation of Ser239 of VASP in vitro inhibits its anti-capping and filament-bundling activity but the effects of this modification on lamellipodial structure and function are unknown. To examine the functional effects of this modification in living cells, we studied VASP phosphorylation at Ser239 by nitric oxide (NO) stimulation of cGMP-dependent protein kinase. Using live cell imaging of primary cells transfected with GFP-VASP constructs, we found that NO produced rapid retraction of lamellipodia together with cell rounding that was dependent on guanylate cyclase and type II cGMP-dependent protein kinase. In cells expressing a mutant VASP (Ser239Ala) lacking the site preferentially phosphorylated by this kinase, NO had no effect. Phosphorylation of Ser239 of VASP results in loss of lamellipodial protrusions and cell rounding, and is a powerful means of controlling directed actin polymerization within lamellipodia.

The systemic inflammatory response, performance status and survival in patients undergoing alpha-interferon treatment for advanced renal cancer.

The prognostic value of C-reactive protein, compared with ECOG performance status (ECOG-ps), in patients receiving alpha-interferon treatment for advanced renal cancer was assessed in 58 patients. In all, 55 patients died on follow-up. On multivariate analysis with ECOG-ps and C-reactive protein entered as covariates, only C-reactive protein was a significant independent predictor of survival (HR 2.03, 95% CI 1.09–3.80, P=0.026).

The relationship between the local and systemic inflammatory responses and survival in patients undergoing resection for localized renal cancer

To examine the relationship between the systemic inflammatory response (C‐reactive protein, CRP), tumour interleukin‐6 receptor and cyclooxygenase (COX)‐2 expression, tumour T‐lymphocytic (CD4+, CD8+) infiltration and cancer survival in patients undergoing resection for renal cell carcinoma (RCC), as both the local and systemic inflammatory responses appear to predict the outcome in these patients.

Clinical utility of the Glasgow Prognostic Score in patients undergoing curative nephrectomy for renal clear cell cancer: basis of new prognostic scoring systems

Background:Measurement of the systemic inflammatory response in malignancy has been recently refined using a selective combination of C-reactive protein and albumin (modified Glasgow Prognostic Score, mGPS). This has prognostic value in patients with metastatic kidney cancer. This study examines the prognostic value of the mGPS in patients undergoing curative nephrectomy for clear cell cancer.Methods:Patients with localised renal cell carcinoma undergoing potentially curative resection between March 1997 and July 2007 in a single institution were prospectively studied. The mGPS, University of California Los Angeles Integrated Staging System (UISS), ‘Stage Size Grade Necrosis’ (SSIGN), Kattan and Leibovich scores were constructed.Results:A total of 169 patients were studied. The minimum follow-up was 49 months; the median follow-up of the survivors was 98 months. During this period, 35 patients died of their cancer; a further 24 patients died of intercurrent disease. On univariate survival analysis of the scoring systems, Kattan (P<0.05), UISS (P<0.001), SSIGN (P<0.001) and Leibovich (P<0.001) were significantly associated with cancer-specific survival. Using cancer-specific mortality at 4 years as an endpoint, the area under the receiver operator curve was 0.726 (95% CI 0.629–0.822; P=0.001) for Kattan, 0.776 (95% CI 0.671–0.880; P<0.001) for UISS, 0.812 (95% CI 0.733–0.892; P<0.001) for SSIGN, 0.778 (95% CI 0.666–0.889; P<0.001) for Leibovich and 0.800 (95% CI 0.687–0.912; P<0.001) for the mGPS scoring system. On multivariate analysis of significant independent scoring systems and mGPS, UISS (HR 3.08, 95% CI 1.54–6.19, P=0.002) and mGPS (HR 5.13, 95% CI 2.89–9.11, P<0.001) were significant independent predictors of cancer-specific survival.Conclusions:The present prospective study shows that the mGPS, an inflammation-based prognostic score, is at least equivalent to and independent of other current validated prognostic scoring systems for patients undergoing curative nephrectomy for renal clear cell cancer. The mGPS is simple, measured preoperatively, based on well-standardised, widely available protein assays, and therefore provides an objective and rational basis before treatment for future staging systems in patients with operable renal cancer.

Cytoreductive nephrectomy: is it a realistic option in patients with renal cancer?

Objective To evaluate the role of cytoreductive nephrectomy (CRN) in improving survival in patients with renal cell cancer.

The longitudinal relationship between circulating concentrations of C-reactive protein, interleukin-6 and interleukin-10 in patients undergoing resection for renal cancer

The systemic inflammatory response, as evidenced by elevated circulating concentrations of C-reactive protein, is a stage-independent prognostic factor in patients undergoing curative nephrectomy for localised renal cancer. However, it is not clear whether the systemic inflammatory response arises from the tumour per se or as a result of an impaired immune cytokine response. The aim of the present study was to examine C-reactive protein, interleukin-6 and interleukin-10 concentrations before and following curative resection of renal cancer. Sixty-four patients with malignant renal disease and 12 with benign disease, undergoing resection were studied. Preoperatively, a blood sample was collected for routine laboratory analysis with a further sample stored before analysis of interleukin-6 and interleukin-10 using an enzyme-linked immunosorbent assay (ELISA) technique. The blood sampling procedure and analyses were repeated at approximately 3 months following resection. Circulating concentrations of both interleukin-6 and interleukin (P⩽0.01) were higher and a greater proportion were elevated (P<0.05) in malignant compared with benign disease. The renal cancer patients were grouped according to whether they had evidence of a systemic inflammatory response. In the inflammatory group T stage was higher (P<0.01), both interleukin-6 and interleukin-10 concentrations were higher (P<0.001) and elevated (P<0.10) compared with the non-inflammatory group. Tumour volume was weakly correlated with C-reactive protein (r2=0.20, P=0.002), interleukin-6 (r2=0.20, P=0.002) and interleukin-10 (r2=0.24, P=0.001). Following nephrectomy the proportion of patients with elevated C-reactive protein, interleukin-6 and interleukin-10 concentrations did not alter significantly. An elevated preoperative C-reactive protein was associated with increased tumour stage, interleukin-6 and interleukin-10 concentrations. However, resection of the primary tumour did not appear to be associated with significant normalisation of circulating concentrations of C-reactive protein, interleukin-6 or interleukin-10. Therefore, the presence of systemic inflammatory response is unlikely to be solely be determined by the tumour itself, but may be as a result of an impaired immune cytokine response in patients with renal cancer.