TheProstate70:1333^1339(2010) NuclearRoundnessVariancePredictsProstateCancer Progression,Metastasis,andDeath: AProspectiveEvaluationWithupto25Yearsof Follow-UpAfterRadicalProstatectomy Robert W. Veltri, 1 * Sumit Isharwal, 1 M. Craig Miller, 2 Jonathan I. Epstein, 1 and Alan W. Partin 1 1 JamesBuchananBradyUrologicalInstitute,TheJohnsHopkinsUniversitySchoolofMedicine,Baltimore,Maryland 2 Quakertown,Pennsylvania BACKGROUND. Nuclear structure is often altered in cancer due to spatial rearrangements of chromatin organization via activation of oncogenes and other chromatin remodeling genes. Therefore, we evaluated the prognostic value of nuclear roundness variance (NRV) for prostate cancer (PCa) progression, metastasis and PCa-specific death free survivals in a cohort of 116 men after radical prostatectomy (RP). METHOD. NRV was calculated for each case using the variance of the nuclear roundness from 150 nuclei captured at a magnification of 2,440 for each case in 1992 – 1993. Nuclear roundness ¼ Radius ðcircumferenceÞ radius ðareaÞ ¼ R r ¼ P=2p ffiffiffiffiffiffiffiffiffi A=p p NRV data were merged with clinical, pathologic, and follow-up data for all patients in 2009. Cox proportional hazards regression and Kaplan–Meier plots were employed to analyze the data. RESULTS. Median follow-up time after RP for all patients was 19 years (range: 1–25 years, mean: 17 years), with 92% (107/116), 71% (82/116), and 47% (55/116) patients having 10, 15, and 20 years of follow-up, respectively. NRV was the most significant parameter for prediction of all three outcomes and its concordance-index (C-Index) increased from progression (0.7080) to metastasis (0.7332) to PCa-specific death (0.8090) free survival predictions. Of note, NRV C- Index was significantly higher compared to Gleason Score C-Index for metastasis (0.7332 vs. 0.6046; P ¼ 0.027) and PCa-specific death (0.8090 vs. 0.6336; P ¼ 0.004) free survival predictions. However, the difference between NRV and Gleason Score C-Indexes was not statistically significant for progression free survival prediction (0.7080 vs. 0.6463; P ¼ 0.106). CONCLUSION. NRV is valuable nuclear structural feature that exceeds Gleason score to predict an aggressive phenotype of PCa. Prostate 70: 1333–1339, 2010. # 2010 Wiley-Liss, Inc. KEY WORDS: prostate cancer; nuclear roundness variance; prognosis INTRODUCTION Prostate cancer (PCa) is the second most common cause of cancer-specific mortality among men in the United States, with an anticipated 192,280 newly diagnosed cases and 27,360 (15%) deaths in 2009 [1]. Even with major improvement in diagnosis and treat- ment modalities for PCa, we have failed to identify and treat the aggressive phenotype of malignancy leading to death in time. The accumulation of repeated epigenetic and genetic insults to the prostate genome over time through diet, infection, inflammation, and Grant sponsor: The Johns Hopkins University Prostate Cancer SPORE; Grant number: P50CA58236; Grant sponsor: The Early Detection Research Network (EDRN) NCI/NIH; Grant number: CA086323-06; Grant sponsor: The Patana Fund; Grant sponsor: The Prostate Cancer Foundation. *Correspondence to: Dr. Robert W. Veltri, PhD, Associate Professor, James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287. E-mail: rveltri1@jhmi.edu Received 20 January 2010; Accepted 22 February 2010 DOI 10.1002/pros.21168 Published online 5 April 2010 in Wiley InterScience (www.interscience.wiley.com). ß2010Wiley-Liss,Inc.