Peter A. McArdle

The relationship between tumour T-lymphocyte infiltration, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer

There is increasing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of common solid tumours. The aim of the present study was to examine the relationship between tumour T-lymphocyte subset infiltration, the systemic inflammatory response and cancer-specific survival in patients with colorectal cancer. In all, 147 patients undergoing potentially curative resection for colorectal cancer were studied. Circulating concentrations of C-reactive protein were measured prior to surgery. CD4+ and CD8+ T-lymphocyte infiltration of the tumour was assessed using immunohistochemistry and a point counting technique. When patients were grouped according to the percentage tumour volume of CD4+ T-lymphocytes, there was no difference in terms of age, sex, tumour site, stage and tumour characteristics. However, there was an inverse relationship between percentage tumour CD4+ T-lymphocytes and C-reactive protein (P<0.01). On univariate analysis, both C-reactive protein concentrations (P<0.001) and percentage tumour volume of CD4+ (P<0.05) T-lymphocytes were associated with cancer-specific survival. The results of the present study show that low tumour CD4+ T-lymphocyte infiltration is associated with elevated C-reactive protein concentrations and both predict poor cancer-specific survival.

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.

The relationship between T-lymphocyte subset infiltration and survival in patients with prostate cancer

The relationship between tumour stage, T-lymphocyte subset infiltration and survival was examined in patients with prostate cancer (n=80). On multivariate analysis PSA (HR 2.47, 95% CI 1.27–4.83, P=0.008) and CD4+ T-lymphocyte count (HR 2.29, 95% CI 1.25–4.22, P=0.008) had independent significance. Increased CD4+ T-lymphocyte infiltration within the tumour was stage independent and associated with poor outcome in patients with prostate cancer.

Systemic Inflammatory Response, Prostate-Specific Antigen and Survival in Patients with Metastatic Prostate Cancer

Background: It is increasingly recognised that, in cancer patients, disease progression is dependent on a complex interaction of the tumour and the host inflammatory response and that the systemic inflammatory response, as evidenced by an elevated C-reactive protein (CRP) concentration, may be a useful prognostic factor. Materials and Methods: The prognostic value of CRP compared with prostate-specific antigen (PSA) was examined in 62 patients with metastatic prostate cancer receiving androgen-deprivation therapy. Results: In all, 41 (66%) of patients died, 38 (61%) of their disease. On univariate survival analysis, PSA (p < 0.05) and CRP (p < 0.05) were significant predictors of cancer-specific survival. On multivariate analysis, both PSA (HR 1.96, 95% CI 1.00–3.83, p = 0.049) and CR (HR 1.97, 95% CI 0.99–3.92, p = 0.052) were independent predictors of cancer-specific survival. PSA concentrations were significantly correlated with those of CRP (rs = 0.46, p < 0.001). Conclusion: The results of the present study suggest that, in patients with metastatic prostate cancer, the presence of an elevated CRP concentration predicts poor outcome, independent of PSA.

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.

Vitamin antioxidants, lipid peroxidation and the systemic inflammatory response in patients with prostate cancer.

The relationship between lipid soluble antioxidant vitamins, lipid peroxidation, disease stage and the systemic inflammatory response were examined in healthy subjects (n = 14), patients with benign prostate hyperplasia BPH (n = 20), localized (n = 40) and metastatic (n = 38) prostate cancer. Prostate cancer patients had higher concentrations of malondialdehyde (p < 0.05) and lower circulating concentrations of lutein (p < 0.05), lycopene (p < 0.001) and β‐carotene (p < 0.05). Patients with metastatic prostate cancer, when compared with patients having localized disease, had a higher Gleason score (p < 0.01) and had more hormonal treatment, but lower concentrations of PSA (p < 0.05), α‐tocopherol (p ≤ 0.05), retinol (p < 0.01), lutein (p < 0.05) and lycopene (p < 0.01). In the prostate cancer patients, PSA was correlated with the concentrations of the lipid peroxidation product, malondialdehyde (rs = 0.353, p = 0.002). C‐reactive protein was not correlated with the vitamin antioxidants nor malondialdehyde. In contrast, there was a negative correlation between malondialdehyde concentrations and both lutein (rs = −0.263, p = 0.020) and lycopene (rs = −0.269, p = 0.017). These results indicate that lower concentrations of carotenoids, in particular, lycopene reflect disease progression rather than the systemic inflammatory response in patients with prostate cancer.

The relationship between interleukin-6 and C-reactive protein in patients with benign and malignant prostate disease

The relationship between interleukin-6 and C-reactive protein was evaluated in patients with benign (n=59) and malignant (n=86) prostate disease. The correlation coefficients for patients with benign prostatic disease and prostate cancer were rs=0.632, P<0.001 and rs=0.663, P<0.001, respectively. These results indicate that the relationship between interleukin-6 and C-reactive protein is similar in patients with benign and malignant prostate disease.

Systemic Inflammatory Response and Survival in Patients with Localised Prostate Cancer: 10-Year Follow-Up

Aim: To examine the prognostic value of circulating C-reactive protein concentrations at diagnosis in patients with organ-confined prostate cancer. Patients and Methods: Ninety-eight patients with histologically proven clinically localised prostate cancer were studied. Clinical stage, tumour grade, circulating PSA and C-reactive protein concentrations at diagnosis were recorded. Results: The majority of patients was under the age of 70 years and had low-grade tumours. Approximately half the patients received radical local treatment. During the follow-up period (median 10 years) 38 patients died, of whom 18 died of prostate cancer, 6 of other cancers and 14 of non-cancer causes. On univariate survival analysis, age (p < 0.001), Gleason score (p < 0.05), C-reactive protein (p < 0.05) and treatment (p < 0.05) were significant predictors of overall survival. On univariate survival analysis, age (p < 0.001), Gleason score (p < 0.05) and C-reactive protein (p < 0.05) were significant predictors of prostate cancer-specific survival. On multivariate analysis of these significant variables age (HR 4.88, 95% CI 1.79–13.29, p < 0.01), Gleason score (HR 2.16, 95% CI 1.23–3.78, p < 0.01) and C-reactive protein (HR 1.88, 95% CI 1.01–3.52, p < 0.05) remained significant independent predictors of prostate cancer-specific survival. Conclusion: The results of the present study show that the presence of a systemic inflammatory response, at diagnosis, independently predicts poor long-term cancer outcome in patients with localised prostate cancer.

Prospective study of the role of inflammation in renal cancer

Background: The local and systemic inflammatory responses provide prognostic information in cancer. The modified Glasgow Prognostic Score (mGPS) provides additional prognostic information than C-reactive protein (CRP) alone when assessing the systemic inflammation in cancer. The aim of this study was to determine the role of local and systemic inflammation in renal cancer. Methods: The cohort consisted of 79 patients who had undergone potential curative resection. Systemic inflammation, mGPS, was constructed by measuring preoperative CRP and albumin concentrations and the Klintrup-Makinen score was evaluated histologically for the local inflammatory response. Pathological parameters such as T stage, grade and tumour necrosis were also assessed. The local inflammatory response was assessed by examining all inflammatory cells at the tumour edge on diagnostic haematoxylin and eosin slides. Results: On univariate analysis, T stage (p < 0.001), grade (p = 0.044) and mGPS (p < 0.001) were significant predictors of cancer-specific survival. On multivariate analysis, mGPS (hazard ratio 8.64, 95% confidence interval 3.5–21.29, p < 0.001) was the only significant independent predictor of cancer-specific survival. Conclusion: A preoperative systemic inflammatory response as measured by the mGPS is an independent predictor of poor cancer-specific survival in renal cancer in patients undergoing potential curative resection.

Expression and prognostic significance of Src family members in renal clear cell carcinoma

Background:The aim of this study was to determine whether Src family kinases (SFK) are expressed in renal cell cancer and to assess their prognostic significance.Methods:mRNA expression levels were investigated for the 8 SFK members by quantitative real-time PCR in 19 clear cell cancer tissue samples. Immunohistochemical staining was utilised to assess expression of Src kinase, dephosphorylated Src kinase at Y530 (SrcY530), phosphorylated Src at Y419 (SrcY419) and the downstream focal adhesion kinase (FAK) marker at the Y861 site (FAK Y861) in a cohort of 57 clear cell renal cancer specimens. Expression was assessed using the weighted histoscore method.Results:Src, Lyn, Hck, Fgr and Fyn were the most highly expressed in renal cancer. All members were more highly expressed in T2 disease, and furthermore expression levels between T2 and T3 disease showed a significant decrease for Lck, Lyn, Fyn, Blk and Yes (P=0.032). Assessment of membrane, cytoplasm and nuclear expression of Src kinase, SrcY530 and SrcY419 were not significantly associated with cancer-specific survival. High expression of cytoplasmic FAK Y861 was associated with decreased cancer-specific survival (P=0.001). On multivariate analysis, cytoplasmic FAK Y861 was independently associated with cancer-specific survival (hazard ratio 3.35, 95% CI 1.40–7.98, P=0.006).Conclusion:We have reported that all SFK members are expressed in renal cell carcinoma. The SFK members had their highest levels of expression before the disease no longer being organ confined. We hypothesise that these SFK members are upregulated before the cancer spreading out-with the organ and given that Src itself is not associated with cancer-specific survival but the presence of FAK Y861, a downstream marker for SFK member activity is associated with decreased cancer-specific survival, we hypothesise that another SFK member is associated with decreased cancer-specific survival in renal cell cancer.