Aleksandra Stanimirovic

Increasing Hospital Admission Rates for Urological Complications After Transrectal Ultrasound Guided Prostate Biopsy

PURPOSE Transrectal ultrasound guided prostate biopsy is widely used to confirm the diagnosis of prostate cancer. The technique has been associated with significant morbidity in a small proportion of patients. MATERIALS AND METHODS We conducted a population based study of 75,190 men who underwent a transrectal ultrasound guided biopsy in Ontario, Canada, between 1996 and 2005. We used hospital and cancer registry administrative databases to estimate the rates of hospital admission and mortality due to urological complications associated with the procedure. RESULTS Of the 75,190 men who underwent transrectal ultrasound biopsy 33,508 (44.6%) were diagnosed with prostate cancer and 41,682 (55.4%) did not have prostate cancer. The hospital admission rate for urological complications within 30 days of the procedure for men without cancer was 1.9% (781/41,482). The 30-day hospital admission rate increased from 1.0% in 1996 to 4.1% in 2005 (p for trend <0.0001). The majority of hospital admissions (72%) were for infection related reasons. The probability of being admitted to hospital within 30 days of having the procedure increased 4-fold between 1996 and 2005 (OR 3.7, 95% CI 2.0-7.0, p <0.0001). The overall 30-day mortality rate was 0.09% but did not change during the study period. CONCLUSIONS The hospital admission rates for complications following transrectal ultrasound guided prostate biopsy have increased dramatically during the last 10 years primarily due to an increasing rate of infection related complications.

Prospective Multi-Institutional Study Evaluating the Performance of Prostate Cancer Risk Calculators

PURPOSE Prostate cancer risk calculators incorporate many factors to evaluate an individuals risk for prostate cancer. We validated two common North American-based, prostate cancer risk calculators. PATIENTS AND METHODS We conducted a prospective, multi-institutional study of 2,130 patients who underwent a prostate biopsy for prostate cancer detection from five centers. We evaluated the performance of the Sunnybrook nomogram-based prostate cancer risk calculator (SRC) and the Prostate Cancer Prevention Trial (PCPT) -based risk calculator (PRC) to predict the presence of any cancer and high-grade cancer. We examined discrimination, calibration, and decision curve analysis techniques to evaluate the prediction models. RESULTS Of the 2,130 patients, 867 men (40.7%) were found to have cancer, and 1,263 (59.3%) did not have cancer. Of the patients with cancer, 403 (46.5%) had a Gleason score of 7 or more. The area under the [concentration-time] curve (AUC) for the SRC was 0.67 (95% CI, 0.65 to 0.69); the AUC for the PRC was 0.61 (95% CI, 0.59 to 0.64). The AUC was higher for predicting aggressive disease from the SRC (0.72; 95% CI, 0.70 to 0.75) compared with that from the PRC (0.67; 95% CI, 0.64 to 0.70). Decision curve analyses showed that the SRC performed better than the PRC for risk thresholds of more than 30% for any cancer and more than 15% for aggressive cancer. CONCLUSION The SRC performed better than the PRC, but neither one added clinical benefit for risk thresholds of less than 30%. Further research is needed to improve the AUCs of the risk calculators, particularly for higher-grade cancer.

Protein-Coding and MicroRNA Biomarkers of Recurrence of Prostate Cancer Following Radical Prostatectomy

An important challenge in prostate cancer research is to develop effective predictors of tumor recurrence following surgery to determine whether immediate adjuvant therapy is warranted. To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed, paraffin-embedded radical prostatectomy specimens with known long-term outcomes to perform DASL expression profiling with a custom panel that we designed of 522 prostate cancer-relevant genes. We identified a panel of 10 protein-coding genes and two miRNA genes (RAD23B, FBP1, TNFRSF1A, CCNG2, NOTCH3, ETV1, BID, SIM2, LETMD1, ANXA1, miR-519d, and miR-647) that could be used to separate patients with and without biochemical recurrence (P < 0.001), as well as for the subset of 42 Gleason score 7 patients (P < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of biochemical recurrence for all cases (P = 0.013) and for a subset of 19 Gleason score 7 cases (P = 0.010), both of which were adjusted for relevant clinical information including T-stage, prostate-specific antigen, and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason score 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens.

Population Based Study of Long-Term Rates of Surgery for Urinary Incontinence After Radical Prostatectomy for Prostate Cancer

PURPOSE Urinary incontinence can be a significant complication of radical prostatectomy. It can be treated with post-prostatectomy surgical procedures. The long-term rate of patients who undergo these surgeries, including artificial urinary sphincter or urethral sling insertion, is not well described. We examined the long-term rate of post-prostatectomy incontinence surgery and factors influencing it. MATERIALS AND METHODS We performed a population based study of 25,346 men who underwent radical prostatectomy for prostate cancer in Ontario, Canada between 1993 and 2006. We used hospital and cancer registry administrative data to identify patients from this cohort who were later treated with surgery for urinary incontinence. RESULTS Of the 25,346 patients 703 (2.8%) underwent artificial urinary sphincter insertion and 282 (1.1%) underwent urethral sling placement a median of 2.9 years after prostatectomy. The probability of an artificial urinary sphincter/sling procedure increased with time from prostatectomy. Cumulative 5, 10 and 15-year Kaplan-Meier rates of an artificial urinary sphincter/sling procedure were 2.6% (95% CI 2.4-2.8), 3.8% (95% CI 3.6-4.1) and 4.8% (95% CI 4.4-5.3), respectively. Factors predicting surgery for incontinence were patient age at radical prostatectomy (HR 1.24 per decade, 95% CI 1.11-1.38, p = 0.0002), radiotherapy after surgery (HR 1.61, 95% CI 1.36-1.90, p <0.0001) and surgeon volume (49 or greater prostatectomies per year) (HR 0.59, 95% CI 0.46-0.77, p <0.0001). CONCLUSIONS Of patients who undergo radical prostatectomy 5% are expected to be treated with surgery for urinary incontinence during a 15-year period. Increasing patient age, radiation treatment and low surgeon volume are associated with significantly higher risk.

Utility of Incorporating Genetic Variants for the Early Detection of Prostate Cancer

Purpose: Several single nucleotide polymorphisms (SNP) have been associated with the risk of prostate cancer. The clinical utility of using SNPs in the early detection of prostate cancer has not been evaluated. Experimental Design: We examined a panel of 25 SNPs from candidate genes and chromosomal regions in 3,004 unselected men who were screened for prostate cancer using serum prostate-specific antigen (PSA) and digital rectal examination. All underwent a prostate biopsy. We evaluated the ability of these SNPs to help predict the presence of prostate cancer at biopsy. Results: Of the 3,004 patients, 1,389 (46.2%) were found to have prostate cancer. Fifteen of the 25 SNPs studied were significantly associated with prostate cancer (P = 0.02-7 × 10−8). We selected a combination of 4 SNPs with the best predictive value for further study. After adjusting for other predictive factors, the odds ratio for patients with all four of the variant genotypes compared with men with no variant genotype was 5.1 (95% confidence interval, 1.6-16.5; P = 0.006). When incorporated into a nomogram, genotype status contributed more significantly than PSA, family history, ethnicity, urinary symptoms, and digital rectal examination (area under the curve = 0.74). The positive predictive value of the PSA test ranged from 42% to 94% depending on the number of variant genotypes carried (P = 1 × 10−15). Conclusions: SNP genotyping can be used in a clinical setting for the early detection of prostate cancer in a nomogram approach and by improving the positive predictive value of the PSA test.

Chip-based nanostructured sensors enable accurate identification and classification of circulating tumor cells in prostate cancer patient blood samples.

The identification and analysis of circulating tumor cells (CTCs) is an important goal for the development of noninvasive cancer diagnosis. Here we describe a chip-based method using nanostructured microelectrodes and electrochemical readout that confirms the identity of isolated CTCs and successfully interrogates them for specific biomarkers. We successfully analyze and classify prostate tumor cells, first in cultured cells, and ultimately in a pilot study involving blood samples from 16 prostate cancer patients as well as additional healthy controls. In all cases, and for all biomarkers investigated, the novel chip-based assay produced results that agreed with polymerase chain reaction (PCR). The approach developed has a simple workflow and scalable multiplexing, which makes it ideal for further studies of CTC biomarkers.

Global transcriptome analysis of formalin-fixed prostate cancer specimens identifies biomarkers of disease recurrence

Prostate cancer remains the second leading cause of cancer death in American men and there is an unmet need for biomarkers to identify patients with aggressive disease. In an effort to identify biomarkers of recurrence, we performed global RNA sequencing on 106 formalin-fixed, paraffin-embedded prostatectomy samples from 100 patients at three independent sites, defining a 24-gene signature panel. The 24 genes in this panel function in cell-cycle progression, angiogenesis, hypoxia, apoptosis, PI3K signaling, steroid metabolism, translation, chromatin modification, and transcription. Sixteen genes have been associated with cancer, with five specifically associated with prostate cancer (BTG2, IGFBP3, SIRT1, MXI1, and FDPS). Validation was performed on an independent publicly available dataset of 140 patients, where the new signature panel outperformed markers published previously in terms of predicting biochemical recurrence. Our work also identified differences in gene expression between Gleason pattern 4 + 3 and 3 + 4 tumors, including several genes involved in the epithelial-to-mesenchymal transition and developmental pathways. Overall, this study defines a novel biomarker panel that has the potential to improve the clinical management of prostate cancer.

New variants at 10q26 and 15q21 are associated with aggressive prostate cancer in a genome-wide association study from a prostate biopsy screening cohort

Purpose: To identify and examine polymorphisms of genes associated with aggressive and clinical significant forms of prostate cancer among a screening cohort. Experimental Design: We conducted a genome-wide association study among patients with aggressive forms of prostate cancer and biopsy-proven normal controls ascertained from a prostate cancer screening program. We then examined significant associations of specific polymorphisms among a prostate cancer screened cohort to examine their predictive ability in detecting prostate cancer. Results: We found significant associations between aggressive prostate cancer and five single nucleotide polymorphisms (SNPs) in the 10q26 (rs10788165, rs10749408, and rs10788165, p value for association 1.3 × 10−10 to 3.2 × 10−11) and 15q21 (rs4775302 and rs1994198, p values for association 3.1 × 10−8 to 8.2 × 10−9) regions. Results of a replication study done in 3439 patients undergoing a prostate biopsy, revealed certain combinations of these SNPs to be significantly associated not only with prostate cancer but with aggressive forms of prostate cancer using an established classification criterion for prostate cancer progression (odds ratios for intermediate to high-risk disease 1.8–3.0, p value 0.003–0.001). These SNP combinations were also important clinical predictors for prostate cancer detection based on nomogram analysis that assesses prostate cancer risk. Conclusions: Five SNPs were found to be associated with aggressive forms of prostate cancer. We demonstrated potential clinical applications of these associations.

A multi-level qualitative analysis of Telehomecare in Ontario: challenges and opportunities

BackgroundDespite research demonstrating the potential effectiveness of Telehomecare for people with Chronic Obstructive Pulmonary Disease and Heart Failure, broad-scale comprehensive evaluations are lacking. This article discusses the qualitative component of a mixed-method program evaluation of Telehomecare in Ontario, Canada. The objective of the qualitative component was to explore the multi-level factors and processes which facilitate or impede the implementation and adoption of the program across three regions where it was first implemented.MethodsThe study employs a multi-level framework as a conceptual guide to explore the facilitators and barriers to Telehomecare implementation and adoption across five levels: technology, patients, providers, organizations, and structures. In-depth semi-structured interviews and ethnographic observations with program stakeholders, as well as a Telehomecare document review were used to elicit key themes. Study participants (n = 89) included patients and/or informal caregivers (n = 39), health care providers (n = 23), technicians (n = 2), administrators (n = 12), and decision makers (n = 13) across three different Local Health Integration Networks in Ontario.ResultsKey facilitators to Telehomecare implementation and adoption at each level of the multi-level framework included: user-friendliness of Telehomecare technology, patient motivation to participate in the program, support for Telehomecare providers, the integration of Telehomecare into broader health service provision, and comprehensive program evaluation. Key barriers included: access-related issues to using the technology, patient language (if not English or French), Telehomecare provider time limitations, gaps in health care provision for patients, and structural barriers to patient participation related to geography and social location.ConclusionsThough Telehomecare has the potential to positively impact patient lives and strengthen models of health care provision, a number of key challenges remain. As such, further implementation and expansion of Telehomecare must involve continuous assessments of what is working and not working with all stakeholders. Increased dialogue, evaluation, and knowledge translation within and across regions to understand the contextual factors influencing Telehomecare implementation and adoption is required. This can inform decision-making that better reflects and addresses the needs of all program stakeholders.

Abstract C68: Global transcriptome sequencing of ethnically diverse formalin-fixed patient samples identifies biomarkers of recurrence in prostate cancer

Prostate cancer remains the second leading cause of cancer death in American men, but biomarkers that can predict outcome following treatment are urgently needed to identify patients with aggressive disease. In an effort to identify biomarkers of recurrence, we have performed global RNA-sequencing on 106 formalin-fixed, paraffin-embedded (FFPE) prostatectomy samples from 100 patients at three independent sites, and identified a new set of biomarkers of biochemical recurrence composed of a 24-gene panel including 22 protein-coding genes and two non-coding genes. We observed excellent correlation between TaqMan and RNAseq values, as well as for RNAseq between replicate libraries. We validated this 24-gene panel on an independent publicly available dataset of 140 patients and this new panel outperformed previously published markers based on cell proliferation gene sets. In addition, we have identified genes that are differentially expressed between African-American and Caucasian prostate cancer patients, and mitochondrial SNPs that are associated with both race and outcome. We observed a number of genes relevant to prostate cancer biology including ETV5, ZEB1, ZEB2, B2M, FYN, and miR-183 that were differentially expressed between African-American and Caucasian patients. These genes may play a role in the disparities observed in African-American patients who have significantly worse outcomes relative to Caucasian patients with prostate cancer. Citation Format: Jianpeng Xu, Qi Long, Adeboye O. Osunkoya, Soma Sannigrahi, Brent A. Johnson, Wei Zhou, Theresa Gillespie, Jong Y. Park, Robert K. Nam, Linda Sugar, Aleksandra Stanimirovic, Arun K. Seth, John A. Petros, Carlos S. Moreno. Global transcriptome sequencing of ethnically diverse formalin-fixed patient samples identifies biomarkers of recurrence in prostate cancer. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C68. doi:10.1158/1538-7755.DISP13-C68