Cut-off Value For Risk Stratification Research Articles

Ki67 as a Biomarker of Prognosis and Prediction: Is it Ready for Use in Routine Pathology Practice?

Breast cancer is the most common cancer in women, and the search for effective markers to design therapeutic strategies and patient management algorithms is still a work in progress. Ki67, a proliferative marker, has gained attention as a prognostic and predictive factor in early breast cancer and/or to decide response to chemotherapy. Individual studies and meta-analyses have provided evidence of its usefulness in this regard. Immunohistochemical staining Ki67 has emerged as an easy and cheap tool to assess proliferation in laboratory setting. However, debate continues over its meaningful clinical use, given the lack of standardization of staining techniques and firm recommendations about pre-analytical tissue handling, interpretation of the stain, and methods to estimate Ki67, resulting in high interlaboratory and interobserver variability. Importantly, no consensus has been reached on the cut-off values for risk stratification. The Breast Cancer Working Group proposed guidelines for immunohistochemical evaluation of Ki67 in 2011. However, the follow-up study showed poor reproducibility even among experts, and the use of Ki67 in daily practice is still in question.

Validation of N-terminal pro-brain natriuretic peptide cut-off values for risk stratification of pulmonary embolism

The optimal N-terminal pro-brain natriuretic peptide (NT-proBNP) cut-off value for risk stratification of pulmonary embolism remains controversial. In this study we validated and compared different proposed NT-proBNP cut-off values in 688 normotensive patients with pulmonary embolism. During the first 30 days, 28 (4.1%) patients reached the primary outcome (pulmonary embolism-related death or complications) and 29 (4.2%) patients died. Receiver operating characteristic analysis yielded an area under the curve of 0.70 (0.60-0.80) for NT-proBNP. A cut-off value of 600 pg·mL(-1) was associated with the best prognostic performance (sensitivity 86% and specificity 50%) and the highest odds ratio (6.04 (95% CI 2.07-17.59), p=0.001) compared to the cut-off values of 1000, 500 or 300 pg·mL(-1). Using multivariable logistic regression analysis, NT-proBNP ≥ 600 pg·mL(-1) had a prognostic impact on top of that of the simplified Pulmonary Embolism Severity Index and right ventricular dysfunction on echocardiography (OR 4.27 (95% CI 1.22-15.01); p=0.024, c-index 0.741). The use of a stepwise approach based on the simplified Pulmonary Embolism Severity Index, NT-proBNP ≥ 600 pg·mL(-1) and echocardiography helped optimise risk assessment. Our findings confirm the prognostic value of NT-proBNP and suggest that a cut-off value of 600 pg·mL(-1) is most appropriate for risk stratification of normotensive patients with pulmonary embolism. NT-proBNP should be used in combination with a clinical score and an imaging procedure for detecting right ventricular dysfunction.

Validity, prognostic value and optimal cutoff of respiratory muscle strength in patients with chronic heart failure changes with beta-blocker treatment

Training studies frequently use maximum inspiratory mouth occlusion pressure (PImax) as a therapeutic target and surrogate marker. For patients on beta-blocker (BBL), prognostic data allowing this extrapolation do not exist. Furthermore, the effects of BBL, mainstay of modern chronic heart failure therapy, on respiratory muscle function remain controversial. Finally, no proper separate cutoff according to treatment exists. Prospective, observational inclusion of patients with stable systolic chronic heart failure and recording of 1 year and all-time mortality for endpoint analysis. In 686 patients, 81% men, 494 patients on BBL, PImax was measured along with clinical evaluation. The median follow-up was 50 months (interquartile range: 26-75 months). Patients with or without BBL did not differ significantly for PImax, percentage of predicted PImax or other marker of disease severity. PImax was a significant (hazard ratio: 0.925; 95% confidence interval: 0.879-0.975; chi(2): 8.62) marker of adverse outcome, independent of BBL-status or aetiology. Percentage of predicted PImax was not independent of PImax. The cutoff identified through receiver-operated characteristics for 1-year mortality was 4.14 kPa for patients on BBL and 7.29 kPa for patients not on BBL. When separated accordingly, 1-year mortality was 8.5 versus 21.4%, P=0.02, for patients not on BBL and 4.3 versus 16.2%, P<0.001, for patients on BBL. This study fills the gap between trials targeting respiratory muscle on a functional basis and the resultant prognostic information with regard to BBL. BBL lowered the optimal PImax cutoff values for risk stratification without changing the measured values of PImax. This should be considered at inclusion and evaluation of trials and interpretation of exercise parameters.

Prognostic impact of peakVO2-changes in stable CHF on chronic beta-blocker treatment

Background Peak oxygen uptake (pVO2) is used for risk stratification in chronic heart failure (CHF), but little is known about the prognostic impact of pVO2-changes in patients on chronic beta-blocker (BBL) therapy. We therefore prospectively evaluated individual pVO2-changes at a 6-month interval in patients all receiving BBL. Methods 194 patients with stable CHF on stable medication were included (V1) and underwent clinical evaluation and exercise testing. Testing was repeated (V2) at 5.7 ± 1.5 months after V1 and patients were followed > 12 months after V2. Death or hospitalisation due to cardiac reasons was the predefined EP (EPP, end-point positive; n = 62; EPN, end-point negative; n = 113). Results Initial characteristics did not differ between EPP and EPN. Multivariate cox regression analysis revealed that change of pVO2 (EPP: − 0.6 ± 2.6 ml/kg min; EPN: + 2.5 ± 3.3 ml/kg min; p < 0.001) was independent to pVO2, LVEF, NTproBNP and NYHA at V2 for prediction of the combined end-point during follow-up. An increase of pVO2 by 10% was identified as an adequate cut-off value for risk stratification and ROC-analysis showed the significant incremental prognostic value of the determination of pVO2 changes in combination with pVO2. Conclusions Serial measurements of pVO2 yield additional information for risk stratification in clinically homogenous CHF patients receiving BBL. This is the first study demonstrating this fact within a narrow predefined interval with all patients on BBL.