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Targeted therapy aims to block tumor-driving signaling pathways and is generally based on analysis of one primary tumor (PT) biopsy. Tumor heterogeneity within PT and between PT and metastatic breast lesions may, however, impact the effect of a chosen therapy. Whereas studies are available that investigate genetic heterogeneity, we present results on phenotypic heterogeneity by analyzing the variation in the functional activity of signal transduction pathways, using an earlier developed platform to measure such activity from mRNA measurements of pathways' direct target genes. Statistical analysis comparing macro-scale variation in pathway activity on up to five spatially distributed PT tissue blocks ( n = 35), to micro-scale variation in activity on four adjacent samples of a single PT tissue block ( n = 17), showed that macro-scale variation was not larger than micro-scale variation, except possibly for the PI3K pathway. Simulations using a "checkerboard clone-size" model showed that multiple small clones could explain the higher micro-scale variation in activity found for the TGFβ and Hedgehog pathways, and that intermediate/large clones could explain the possibly higher macro-scale variation of the PI3K pathway. While within PT, pathway activities presented a highly positive correlation, correlations weakened between PT and lymph node metastases ( n = 9), becoming even worse for PT and distant metastases ( n = 9), including a negative correlation for the ER pathway. While analysis of multiple sub-samples of a single biopsy may be sufficient to predict PT response to targeted therapies, metastatic breast cancer treatment prediction requires analysis of metastatic biopsies. Our findings on phenotypic intra-tumor heterogeneity are compatible with emerging ideas on a Big Bang type of cancer evolution in which macro-scale heterogeneity appears not dominant.

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., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The consent process for organ and tissue donation is complex, both for families and professionals. To help professionals in broaching this subject we performed a multicenter study. We compared family consent to donation in three hospitals between December 2007 and December 2009. In the intervention hospital, trained donation practitioners (TDP) guided 66 families throughout the time in the ICU until a decision regarding donation had been reached. In the first control hospital, without any family guidance or training, 107 families were approached. In the second control hospital 'hostesses', who were not trained in donation questions, supported 99 families during admittance. A total of 272 families were requested to donate. We primarily compared consent rates, but also asked families about their experiences through a questionnaire. Family consent rate was significantly higher in the intervention hospital: 57.6% (38/66), than in the control hospitals: 34.6% (37/107) and 39.4% (39/99). The 69% response rate to the questionnaire -~5 months after death - showed no confounding variables that could have influenced the consent rate. Appointing TDPs in the intervention hospital to guide families during admittance and the donation decision-making process, results in higher family consent rates., (© 2011 The Authors. Transplant International © 2011 European Society for Organ Transplantation.)