Hans Van Zon

Validation of Cyclic Adenosine Monophosphate Phosphodiesterase-4D7 for its Independent Contribution to Risk Stratification in a Prostate Cancer Patient Cohort with Longitudinal Biological Outcomes

BACKGROUND The clinical metrics used to date to assess the progression risk of newly diagnosed prostate cancer patients only partly represent the true biological aggressiveness of the underlying disease. OBJECTIVE Validation of the prognostic biomarker phosphodiesterase-4D7 (PDE4D7) in predicting longitudinal biological outcomes in a historical surgery cohort to improve postsurgical risk stratification. DESIGN, PATIENTS, AND METHODS RNA was extracted from biopsy punches of resected tumors from 550 patients. PDE4D7 was quantified using one-step quantitative reverse transcription-polymerase chain reaction. PDE4D7 scores were calculated by normalization of PDE4D7 to reference genes. Multivariate analyses were adjusted for clinical prognostic variables. Outcomes tested were: prostate-specific antigen relapse, start of salvage treatment, progression to metastases, overall mortality, and prostate cancer-specific mortality. The PDE4D7 score was combined with the clinical risk model Cancer of the Prostate Risk Assessment Postsurgical Score (CAPRA-S) using multivariate regression modeling; the combined score was tested in post-treatment progression free survival prediction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Correlations with outcomes were analyzed using multivariate Cox regression and logistic regression statistics. RESULTS AND LIMITATIONS The PDE4D7 score was significantly associated with time-to-prostate specific antigen failure after prostatectomy (hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.41-0.67 for each unit increase, p<0.0001). After adjustment for postsurgical prognostic variables the HR was 0.56 (95% CI: 0.43-0.73, p<0.0001). The PDE4D7 score remained significant after adjusting the multi-variate analysis for the CAPRA-S model categories (HR=0.54, 95% CI=0.42-0.69, p<0.0001). Combination of the PDE4D7 score with the CAPRA-S demonstrated a significant incremental value of 4-6% in 2-yr (p=0.004) or 5-yr (p=0.003) prediction of progression free survival after surgery. The combined model of PDE4D7 and CAPRA-S improves patient selection with very high risk of fast disease relapse after primary intervention. CONCLUSIONS The PDE4D7 score has the potential to provide independent risk information and to restratify patients with clinical intermediate- to high-risk characteristics to a very low-risk profile. PATIENT SUMMARY In this report, we studied the potential of a novel biomarker to predict outcomes of a cohort of prostate cancer patients who underwent surgery more than 10 yr ago. We found that a gene called phosphodiesterase-4D7 added extra information to the available clinical data. We conclude that the measurement of this gene in tumor tissue may contribute to more effective treatment decisions.

Electrostatic height modulation of bound particle labels by buffer exchange in an evanescent wave biosensor

We introduce a technique to electrostatically modulate the height of bound particle labels on a biosensor surface by exchanging the buffer. In an evanescent wave biosensor, height modulation leads to a modulation of the scattered and reflected light intensity. We measured a lower scattering and, therefore, a higher reflection for a decreasing ionic strength, which can be explained by an increasing electrostatic force repelling bound particles from the surface. By comparing bonds with troponin, 105 base pair (bp) DNA and 290 bp DNA, we found that the signal change for an ensemble of bound particles was related to the length of the analyte. Additionally, we observed for individual particles that the thermal fluctuations of scattered light intensity became smaller for decreasing ionic strength and that the average intensity shifted toward lower values, corresponding to larger particle heights. A quantitative model comprising electrostatic repulsion and van der Waals interaction could fit the measured height ...