In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways in colorectal cancer is uncertain, which led us to systematically review the impact of alterations in KRAS (outside of exon 2), NRAS, BRAF, PIK3CA and PTEN in relation to the clinical benefit from anti-EGFR treatment. In total, 22 studies that include 2395 patients formed the basis for a meta-analysis on alterations in KRAS exons 3 and 4, NRAS, BRAF, and PIK3CA and PTEN and outcome of anti-EGFR treatment. Odds ratios for objective response rate (ORR) and hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) were calculated. Mutations in KRAS exons 3 and 4, BRAF, PIK3CA and non-functional PTEN (mutations or loss of protein expression) significantly predicted poor ORR (OR = 0.26, OR = 0.29, OR = 0.39, and OR = 0.41, respectively). Significantly shorter PFS applied to mutations in KRAS exons 3 and 4 (HR = 2.19), NRAS (HR = 2.30) and BRAF (HR = 2.95) and non-functional PTEN (HR = 1.88). Significantly shorter OS applied to mutations in KRAS exons 3 and 4 (HR = 1.78), NRAS (HR = 1.85), BRAF (HR = 2.52), PIK3CA (HR = 1.43) and alterations in PTEN (HR = 2.09). Meta-analysis suggests that mutations in KRAS exons 3 and 4, NRAS, BRAF and PIK3CA and non-functional PTEN predict resistance to anti-EGFR therapies and demonstrates that biomarker analysis beyond KRAS exon 2 should be implemented for prediction of clinical benefit from anti-EGFR antibodies in metastatic colorectal cancer.

Abstract.  Eugen‐Olsen J, Andersen O, Linneberg A, Ladelund S, Hansen TW, Langkilde A, Petersen J, Pielak T, Møller LN, Jeppesen J, Lyngbæk S, Fenger M, Olsen MH, Hildebrandt PR, Borch‐Johnsen K, Jørgensen T, Haugaard SB (Copenhagen University, Hvidovre Hospital, Hvidovre; Copenhagen University Hospital, Glostrup; Copenhagen University Hospital, Copenhagen; Copenhagen University Hospital, Glostrup; Copenhagen University, Hvidovre Hospital, Hvidovre; Steno Diabetes Center, Gentofte; University of Aarhus, Aarhus; University of Copenhagen, Copenhagen; Copenhagen University, Hvidovre Hospital, Hvidovre, Denmark). Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med 2010; 268: 296–308.Background.  Low‐grade inflammation is thought to contribute to the development of cardiovascular disease (CVD), type‐2 diabetes mellitus (T2D), cancer and mortality. Biomarkers of inflammation may aid in risk prediction and enable early intervention and prevention of disease.Objective.  The aim of this study was to investigate whether plasma levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) are predictive of disease and mortality in the general population.Design.  This was an observational prospective cohort study. Cohort participants were included from June 1993 to December 1994 and followed until the end of 2006.Setting.  General adult Caucasian population.Participants.  The MONICA10 study, a population‐based cohort recruited from Copenhagen, Denmark, included 2602 individuals aged 41, 51, 61 or 71 years.Measurements.  Blood samples were analysed for suPAR levels using a commercially available enzyme‐linked immunosorbent assay. Risk of cancer (n = 308), CVD (n = 301), T2D (n = 59) and mortality (n = 411) was assessed with a multivariate proportional hazards model using Cox regression.Results.  Elevated baseline suPAR level was associated with an increased risk of cancer, CVD, T2D and mortality during follow‐up. suPAR was more strongly associated with cancer, CVD and mortality in men than in women, and in younger compared with older individuals. suPAR remained significantly associated with the risk of negative outcome after adjustment for a number of relevant risk factors including C‐reactive protein levels.Limitation.  Further validation in ethnic populations other than Caucasians is needed.Conclusion.  The stable plasma protein suPAR may be a promising biomarker because of its independent association with incident cancer, CVD, T2D and mortality in the general population.

High-dose glucocorticoid may reduce postsurgical pain and improve recovery. We hypothesized that 125 mg methylprednisolone (MP) would reduce time to meet functional discharge criteria after total hip arthroplasty (THA). Forty-eight patients undergoing unilateral THA under spinal anaesthesia were consecutively included in this randomized, double-blind, placebo-controlled trial receiving preoperative i.v. MP or saline. All patients received a standardized, multimodal analgesic regime with paracetamol, celecoxib, and gabapentin. The primary outcome was time to meet well-defined functional discharge criteria. Secondary outcomes were handgrip strength and endurance, pain, nausea, vomiting, fatigue, sleep quality, and rescue analgesic-, antiemetic-, and hypnotic medicine requirements. The inflammatory response measured by C-reactive protein (CRP) and actual length of stay were also registered. Discharge criteria were assessed twice daily (at 09:00 and 14:00 h) until discharge. Other outcomes were assessed at 2, 4, 6, 8, and 24 h after operation, and also in a questionnaire from postoperative day (POD) 1–4. Time to meet discharge criteria was [median (IQR) (95% CI), MP vs placebo]: 23.5 (23.3–23.7) (17.8–43.8) vs 23.5 (23.0–23.8) (20.0–46.8) h, the mean difference (95% CI) being −1.3 (−4.7 to 2.2) h, P=0.65. Overall pain for the first 24 h after surgery was significantly reduced in the MP vs the placebo group (P<0.01), as was CRP at 24 h (P<0.0001). No other between-group differences were observed. No drug-related complications were observed at follow-up on POD30. MP 125 mg i.v. before surgery added to a multimodal oral analgesic regime did not reduce time to meet functional discharge criteria after THA, but improved analgesia for the first 24 h.

The plasma level of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is a strong predictor of disease development and premature mortality in the general population. Unhealthy lifestyle habits such as smoking or unhealthy eating is known to elevate the suPAR level. We aimed to investigate whether change in lifestyle habits impact on the suPAR level, and whether the resultant levels are associated with mortality. Paired suPAR measurements from baseline- and the 5-year visit of the population-based Inter99 study were compared with the habits of diet, smoking, alcohol consumption, and physical activity. Paired suPAR measurements for 3225 individuals were analyzed by linear regression, adjusted for demographics and lifestyle habits. Compared to individuals with a healthy lifestyle, an unhealthy diet, low physical activity, and daily smoking were associated with a 5.9, 12.8, and 17.6% higher 5-year suPAR, respectively. During 6.1 years of follow-up after the 5-year visit, 1.6% of those with a low suPAR (mean 2.93 ng/ml) died compared with 3.8% of individuals with a high suPAR (mean 4.73 ng/ml), P < 0.001. In Cox regression analysis, adjusted for demographics and lifestyle, the hazard ratio for mortality per 5-year suPAR doubling was 2.03 (95% CI: 1.22–3.37). Lifestyle has a considerable impact on suPAR levels; the combination of unhealthy habits was associated with 44% higher 5-year suPAR values and the 5-year suPAR was a strong predictor of mortality. We propose suPAR as a candidate biomarker for lifestyle changes as well as the subsequent risk of mortality.