Does prophylactic ureteric stenting at the time of colorectal surgery reduce the risk of ureteric injury? A systematic review and meta-analysis.

AIM: Cystoscopic placement of ureteric stents during colorectal surgery (CRS) may aid in the intraoperative identification of the ureters and thus prevent ureteric injury, but may also be associated with prolonged operating time, increased cost and adverse events. No formal recommendations exist regarding the use of ureteric stents prior to CRS. Our aim was to determine the effect of prophylactic ureteric stent insertion on the risk of ureteric injury among adult patients undergoing CRS. METHOD: A systematic search using the Ovid platform was completed. The primary outcome was risk of ureteric injury. Secondary outcomes included the risk of acute kidney injury (AKI), urinary tract infection (UTI), sepsis, length of stay (LOS) and mortality. The Paule-Mandel pooling and a random effects model was used to produce odds ratios (ORs) with 95% confidence intervals (CIs) for binary outcomes. Standardized mean differences (MD) were reported for continuous variables. Analyses were completed using R3.5. RESULTS: Nine retrospective cohort studies evaluating 98 507 patients were included. The incidence of ureteric injury was 0.6%. Overall, 5.1% of patients underwent ureteric stenting. There was no change in the odds of ureteric injury among stented patients compared with controls (OR 1.30, 95% CI 0.39-4.29, I2  = 25%). Operating time was significantly longer (MD 49.3 min, 95% CI 35.3-63.4, I2  = 96%) in the intervention group. There was no difference in rates of AKI, UTI, sepsis, LOS or mortality between groups. CONCLUSION: Given the retrospective nature of the identified studies, the benefit of prophylactic ureteric stenting remains uncertain. Prophylactic ureteric stenting was not associated with increased patient morbidity but did significantly increase operating time.

Is There an Association between Urinary Incontinence and Mortality? A Retrospective Cohort Study.

PURPOSE: Previous studies have shown an association between urinary incontinence and increased mortality independently of demographics and health status. However, they do not account for the effect of frailty as a state of vulnerability. We evaluated whether there is an association between urinary incontinence and mortality and, if so, whether adjustment for a frailty index would affect the association. MATERIALS AND METHODS: We performed a cross-sectional study in a nationally representative sample of 2,282 community dwelling individuals 50 years old or older who were surveyed between 2003 and 2006. The study primary outcome was overall survival as reported on December 31, 2011. We used design adjusted Cox proportional hazards regression models to estimate the hazard of mortality associated with urinary incontinence. We adjusted the models for demographics and a validated 45-item frailty index incorporating an accumulation of deficits in the domains of health and independence. RESULTS: Of the individuals 23% reported having urinary incontinence at least a few times per week. Stress urinary incontinence and urge urinary incontinence were associated with a 13.3% (95% CI 7.2-19.7) and 18.4% (95% CI 8.3-29.4) increase in the frailty index, respectively. Without controlling for frailty individuals with urinary incontinence were at higher risk for death (HR 1.39, 95% CI 1.13-1.72). When adjusted for the frailty index, the association between urinary incontinence and mortality was no longer significant (HR 1.10, 95% CI 0.89-1.36). CONCLUSIONS: The association between urinary incontinence and mortality can be understood based on increased frailty in incontinent individuals. Urinary incontinence itself is not independently associated with mortality. In clinical practice these findings underscore the importance of screening for frailty in addition to urinary incontinence.

MicroRNA-139 is a predictor of prostate cancer recurrence and inhibits growth and migration of prostate cancer cells through cell cycle arrest and targeting IGF1R and AXL.

BACKGROUND: We previously identified a panel of five microRNAs (miRNAs) associated with biochemical recurrence and metastasis following prostatectomy from prostate cancer patients using next-generation sequencing-based whole miRNome sequencing and quantitative polymerase chain reaction-based validation analysis. In this study, we examined the mechanism of action of miR-139-5p, one of the downregulated miRNAs identified in the panel. METHODS: Using a cohort of 585 patients treated with radical prostatectomy, we examined the prognostic significance of miR-139 (dichotomized around the median) using the Kaplan-Meier method and Cox proportional hazard models. We validated these results using The Cancer Genome Atlas (TCGA) data. We created cell lines that overexpressed miR-139 to confirm its targets as well as examine pathways through which miR-139 may function using cell-based assays. RESULTS: Low miR-139 expression was significantly associated with a variety of prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity, and lymph node status. MiR-139 expression was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis were significantly lower among patients with high miR-139 expression (P = .0004 and .038, respectively). Validation in the TCGA data set showed a significant association between dichotomized miR-139 expression and biochemical recurrence (odds ratio, 0.52; 95% confidence interval, 0.33-0.82). Overexpression of miR-139 in prostate cancer cells led to a significant reduction in cell proliferation and migration compared with control cells, with cells arrested in G2 of cell cycle. IGF1R and AXL were identified as potential targets of miR-139 based on multiple miRNA-binding sites in 3'-untranslated regions of both the genes and their association with prostate cancer growth pathways. Luciferase assays verified AXL and IGF1R as direct targets of miR-139. Furthermore, immunoblotting of prostate cancer cells demonstrated IGF1R and AXL protein expression were inhibited by miR-139 treatment, which was reversed by the addition of miR-139 antagomir. Examination of the molecular mechanism of growth inhibition by miR-139 revealed the downregulation of activated AKT and cyclin D1, with upregulation of the CDK inhibitor p21. CONCLUSIONS: miR-139 is associated with improved prognosis in patients with localized prostate cancer, which may be mediated through downregulation of IGF1R and/or AXL and associated signaling pathway components.

Cancer diagnosis and risk of suicide after accounting for prediagnosis psychiatric care: A matched-cohort study of patients with incident solid-organ malignancies.

BACKGROUND: Previous studies have demonstrated an association between a diagnosis of cancer and the risk of suicide; however, they failed to account for psychiatric care before a cancer diagnosis, which may confound this relationship. The objective of this study was to assess the effect of a cancer diagnosis on the risk of suicide, accounting for prediagnosis psychiatric care utilization. METHODS: All adult residents of Ontario, Canada who were diagnosed with cancer (1 of prostate, breast, colorectal, melanoma, lung, bladder, endometrial, thyroid, kidney, or oral cancer) between 1997 and 2014 were identified. Noncancer controls were matched 4:1 based on sociodemographics, including a psychiatric utilization gradient (PUG) score (with 0 indicating none; 1, outpatient; 2, emergency department; and 3, hospital admission). A marginal, cause-specific hazard model was used to assess the effect of cancer on the risk of suicidal death. RESULTS: Among 676,470 patients with cancer and 2,152,682 matched noncancer controls, there were 8.2 and 11.4 suicides per 1000 person-years of follow-up, respectively. Patients with cancer had an overall higher risk of suicidal death compared with matched patients without cancer (hazard ratio, 1.34; 95% CI, 1.22-1.48). This effect was pronounced in the first 50 months after cancer diagnosis (hazard ratio, 1.60; 95% CI, 1.42-1.81); patients with cancer did not demonstrate an increased risk thereafter. Among individuals with a PUG score 0 or 1, those with cancer were significantly more likely to die of suicide compared with controls. There was no difference in suicide risk between patients with cancer and controls for those who had a PUG score of 2 or 3. CONCLUSIONS: A cancer diagnosis is associated with increased risk of death from suicide compared with the general population even after accounting for precancer diagnosis psychiatric care utilization. The specific factors underlying the observed associations remain to be elucidated.

The impact of psychiatric utilisation prior to cancer diagnosis on survival of solid organ malignancies.

BACKGROUND: Among patients with cancer, prior research suggests that patients with mental illness may have reduced survival. The objective was to assess the impact of psychiatric utilisation (PU) prior to cancer diagnosis on survival outcomes. METHODS: All residents of Ontario diagnosed with one of the top 10 malignancies (1997-2014) were included. The primary exposure was psychiatric utilisation gradient (PUG) score in 5 years prior to cancer: 0: none, 1: outpatient, 2: emergency department, 3: hospital admission. A multivariable, cause-specific hazard model was used to assess the effect of PUG score on cancer-specific mortality (CSM), and a Cox proportional hazard model for effect on all-cause mortality (ACM). RESULTS: A toal of 676,125 patients were included: 359,465 (53.2%) with PUG 0, 304,559 (45.0%) PUG 1, 7901 (1.2%) PUG 2, and 4200 (0.6%) PUG 3. Increasing PUG score was independently associated with worse CSM, with an effect gradient across the intensity of pre-diagnosis PU (vs PUG 0): PUG 1 h 1.05 (95% CI 1.04-1.06), PUG 2 h 1.36 (95% CI 1.30-1.42), and PUG 3 h 1.73 (95% CI 1.63-1.84). Increasing PUG score was also associated with worse ACM. CONCLUSIONS: Pre-cancer diagnosis PU is independently associated with worse CSM and ACM following diagnosis among patients with solid organ malignancies.

Evaluating the accuracy of multicomponent T2 parameters for luminal water imaging of the prostate with acceleration using inner-volume 3D GRASE.

PURPOSE: Prostate cancer can be detected using a multicomponent T2 mapping technique termed luminal water imaging. The purpose of this study is twofold: 1) To accelerate the luminal water imaging acquisition by using inner volume selection as part of a gradient and spin echo sequence, and 2) to evaluate the accuracy of luminal water fractions and multicomponent T2 relaxation times. METHODS: The accuracy of parameter estimates was assessed using Monte Carlo simulations, in phantom experiments and in the prostate (in 5 healthy subjects). Two fitting methods, nonnegative least squares and biexponential fitting with stimulated echo correction, were compared. RESULTS: Results demonstrate that inner volume selection in a gradient and spin echo sequence is effective for accelerating prostate luminal water imaging by at least threefold. Evaluation of the accuracy shows that the estimated luminal water fractions are relatively accurate, but the short- and long-T2 relaxation times should be interpreted with caution in noisy scenarios (SNR < 100) and when the corresponding fractions are small ( < 0.5). The mean luminal water fractions obtained at SNR above 100 are 0.27 ± 0.07 for the peripheral zone for both fitting methods, 0.16 ± 0.04 for the transition zone with nonnegative least squares, and 0.16 ± 0.03 for the transition zone with biexponential fitting including stimulated echo correction. CONCLUSION: The shortened scan duration allows the luminal water imaging sequence to be easily integrated into a standard multiparametric prostate MRI protocol.

Survival and peri-operative outcomes among patients with rectal cancer: the role of prior radiotherapy due to prostate cancer.

PURPOSE: Patients with rectal cancer (RCa) and prior radiation for prostate cancer (PCa) are clinically complicated and may have worse outcomes than other RCa patients. This study investigates the impact of previous radiation for PCa on survival for patients with RCa. METHOD: We conducted a population-based study identifying men who underwent surgical treatment of RCa from 2002 to 2010. Patients were classified into three cohorts: no prior PCa, prior PCa treated without radiotherapy, and prior PCa treated with radiotherapy. The primary outcome was overall survival. Secondary outcomes included RCa surgical approach, ICU admission, length of stay, ER visits, and delayed formation of a new stoma. RESULTS: Seven thousand ninety-six men underwent surgery for RCa; 6867 patients had no prior PCa, 58 had prior PCa treated without radiotherapy, and 171 had prior PCa treated with radiotherapy. The 5-year overall survival was 62% (95% CI 61-64%) for patients without prior PCa, 46% (95% CI 25-65%) for patients with prior PCa treated without radiotherapy, and 42% (95% CI 29-54%) for patients with prior PCa treated with radiotherapy (p < 0.0001). In multivariable analysis, patients with prior PCa treated with radiotherapy were at increased risk of death (aHR 1.38, 95% CI 1.12-1.69) compared to those without prior PCa. Furthermore, patients with prior PCa treated with radiotherapy had a significantly increased risk of resection with permanent stoma. CONCLUSIONS: Prior radiotherapy for PCa is a poor prognostic factor in RCa patients with significantly increased risk of death. Additionally, patients with prior radiotherapy for PCa are more likely to require a permanent stoma.

The effect of selection and referral biases for the treatment of localised prostate cancer with surgery or radiation.

BACKGROUND: Consultation with radiation oncologists, in addition to urologists, is advocated for patients diagnosed with prostate cancer. Treatment patterns for patients receiving consultation from radiation oncologists in addition to urologists have not previously been described. METHODS: We conducted a matched cohort study of men with newly diagnosed non-metastatic prostate cancer in Ontario, Canada. Patients who underwent consultation with a radiation oncologist prior to treatment were matched 1:1 with patients managed by a urologist alone based on tumour and patient characteristics. We examined rates of active treatment (surgery or radiotherapy) within one year following diagnosis. RESULTS: Among 5708 matched pairs (11,416 patients), those who received radiation oncology consultation were more likely to undergo active treatments whether they had intermediate or high-risk disease (88.6% vs. 65.9%, p < 0.0001; adjusted odds ratio 4.0, 95% CI: 3.6-4.4) or low-risk disease (56.1% vs. 13.3%, p < 0.0001; adjusted odds ratio 8.4, 95% CI: 6.7-10.6). This effect persisted after considering age, comorbidity, tumour volume and year of diagnosis. CONCLUSIONS: Patients newly diagnosed with prostate cancer who receive radiation oncology consultation are associated with a higher rate of active treatment, compared to patients managed by urologists only. Selection and referral biases, and unmeasured confounding such as patient preference must be considered as important factors attributing this association.

A Population-Based Assessment of Urologic Procedures and Operations After Surgery or Pelvic Radiation for Cervical Cancer.

OBJECTIVE: The treatment of cervical cancer can result in genitourinary morbidity. We measured selected urologic procedures after the treatment of cervical cancer with either surgery or radiation. METHODS: We used administrative data from the province of Ontario Canada to identify adult women who had nonmetastatic cervical cancer and were treated with surgery or radiation between 1994 and 2014. Study outcomes were surgical or procedure codes representing ureteric repair or fistula repair. Stress incontinence surgery, minimally invasive urologic procedures, open bowel/bladder surgeries, and secondary malignancy were measured to compare between treatment modalities. Multivariable Cox proportional hazards models were used. RESULTS: Our final cohort consisted of 7311 women (median follow-up, 7.0 years [interquartile range, 2.9-13.3 years]), of which 3354 (44.9%) underwent radiation, and 3957 (54.1%) underwent surgery. After treatment of cervical cancer, ureteral repair was less common after surgery (3.4%) compared with radiation (10.3%) (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.19-0.32). Fistula repair was uncommon (0.9%) and occurred significantly more often in the surgery and radiation group compared with the radiation-alone group (HR, 4.02; 95% CI, 1.80-9.00). Overall, stress incontinence surgery was uncommon (2.2%) but was significantly more likely after surgery versus radiation (HR, 3.73; 95% CI, 2.13-6.53). Minimally invasive urologic procedures were less common after surgery compared with radiation (HR, 0.49; 95% CI, 0.44-0.54). Open bowel/bladder surgeries were similar among treatment modalities, and secondary malignancy was less common after treatment with surgery versus radiation (HR, 0.60; 95% CI, 0.39-0.92; P = 0.02). CONCLUSIONS: Women treated for cervical cancer undergo ureteral stricture interventions at 0.8% per year over the 20 years after their treatment; this risk is higher among women who receive radiation treatment. Fistula repair is rare after cervical cancer.

Estimating the effect of immortal-time bias in urological research: a case example of testosterone-replacement therapy.

OBJECTIVE: To quantify the effect of immortal-time bias in an observational study examining the effect of cumulative testosterone exposure on mortality. PATIENTS AND METHODS: We used a population-based matched cohort study of men aged ≥66 years, newly treated with testosterone-replacement therapy (TRT), and matched-controls from 2007 to 2012 in Ontario, Canada to quantify the effects of immortal-time bias. We used generalised estimating equations to determine the association between cumulative TRT exposure and mortality. Results produced by models using time-fixed and time-varying exposures were compared. Further, we undertook a systematic review of PubMed to identify studies addressing immortal-time bias or time-varying exposures in the urological literature and qualitatively summated these. RESULTS: Among 10 311 TRT-exposed men and 28 029 controls, the use of a time-varying exposure resulted in the attenuation of treatment effects compared with an analysis that did not account for immortal-time bias. While both analyses showed a decreased risk of death for patients in the highest tertile of TRT exposure, the effect was overestimated when using a time-fixed analysis (adjusted hazard ratio [aHR] 0.56, 95% confidence interval [CI]: 0.52-0.61) when compared to a time-varying analysis (aHR 0.67, 95% CI: 0.62-0.73). Of the 1 241 studies employing survival analysis identified in the literature, nine manuscripts met criteria for inclusion. Of these, five used a time-varying analytical method. Each of these was a large, population-based retrospective cohort study assessing potential harms of pharmacological agents. CONCLUSIONS: Where exposures vary over time, a time-varying exposure is necessary to draw meaningful conclusions. Failure to use a time-varying analysis will result in overestimation of a beneficial effect. However, time-varying exposures are uncommonly utilised among manuscripts published in prominent urological journals.

Association Between Use of Antithrombotic Medication and Hematuria-Related Complications.

Importance: Antithrombotic medications are among the most commonly prescribed medications. Objective: To characterize rates of hematuria-related complications among patients taking antithrombotic medications. Design, Setting, and Participants: Population-based, retrospective cohort study including all citizens in Ontario, Canada, aged 66 years and older between 2002 and 2014. The final follow-up date was December 31, 2014. Exposures: Receipt of an oral anticoagulant or antiplatelet medication. Main Outcomes and Measures: Hematuria-related complications, defined as emergency department visit, hospitalization, or a urologic procedure to investigate or manage gross hematuria. Results: Among 2 518 064 patients, 808 897 (mean [SD] age, 72.1 [6.8] years; 428 531 [53%] women) received at least 1 prescription for an antithrombotic agent over the study period. Over a median follow-up of 7.3 years, the rates of hematuria-related complications were 123.95 events per 1000 person-years among patients actively exposed to antithrombotic agents vs 80.17 events per 1000 person-years among patients not exposed to these drugs (difference, 43.8; 95% CI, 43.0-44.6; P < .001, and incidence rate ratio [IRR], 1.44; 95% CI, 1.42-1.46). The rates of complications among exposed vs unexposed patients (80.17 events/1000 person-years) were 105.78 for urologic procedures (difference, 33.5; 95% CI, 32.8-34.3; P < .001, and IRR, 1.37; 95% CI, 1.36-1.39), 11.12 for hospitalizations (difference, 5.7; 95% CI, 5.5-5.9; P < .001, and IRR, 2.03; 95% CI, 2.00-2.06), and 7.05 for emergency department visits (difference, 4.5; 95% CI, 4.3-4.7; P < .001, and IRR, 2.80; 95% CI, 2.74-2.86). Compared with patients who were unexposed to thrombotic agents, the rates of hematuria-related complications were 191.61 events per 1000 person-years (difference, 117.3; 95% CI, 112.8-121.8) for those exposed to both an anticoagulant and antiplatelet agent (IRR, 10.48; 95% CI, 8.16-13.45), 140.92 (difference, 57.7; 95% CI, 56.9-58.4) for those exposed to anticoagulants (IRR, 1.55; 95% CI, 1.52-1.59), and 110.72 (difference, 26.5; 95% CI, 25.9-27.0) for those exposed to antiplatelet agents (IRR, 1.31; 95% CI, 1.29-1.33). Patients exposed to antithrombotic agents, compared with patients not exposed to these drugs, were more likely to be diagnosed as having bladder cancer within 6 months (0.70% vs 0.38%; odds ratio, 1.85; 95% CI, 1.79-1.92). Conclusions and Relevance: Among older adults in Ontario, Canada, use of antithrombotic medications, compared with nonuse of these medications, was significantly associated with higher rates of hematuria-related complications (including emergency department visits, hospitalizations, and urologic procedures to manage gross hematuria).

MiR-301a regulates E-cadherin expression and is predictive of prostate cancer recurrence.

BACKGROUND: MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression post-transcriptionally. Dysregulation of miRNA has been implicated in the development and progression of prostate cancer. Through next generation miRNA sequencing, we recently identified a panel of five miRNAs associated with prostate cancer recurrence and metastasis. Of the five miRNAs, miR-301a had the strongest association with prostate cancer recurrence. Overexpression of miR-301a in prostate cancer cells, PC3, and LNCaP resulted in increased growth both in vitro and in xenografted tumors. We therefore sought to examine its role in prostate carcinogenesis in greater detail. METHODS: We examined the effect of miR-301a expression on biochemical recurrence and metastasis among 585 men treated with radical prostatectomy for prostate cancer. We examined the mechanism of growth deregulation by miR-301a in prostate cancer cells using analysis of the miRome of prostate cancer cell lines, quantitative PCR, and Western blotting. RESULTS: High levels of miR-301a (above the median) were associated with an increased risk of biochemical recurrence (adjusted hazard ratio [aHR] 1.42, 95% confidence interval (CI) 1.06-1.90, P = 0.002) but not of metastasis (aHR 0.84, 95%CI 0.41-1.70, P = 0.6) after adjustment for known prognostic factors. RNA transcriptome sequencing analysis of miR-301a overexpressing prostate cancer cell lines identified the tumor suppressor p63 as a potential direct miR-301a target. Transcriptome sequencing, qPCR and Western blotting showed that miR-301a induced epithelial-mesenchymal transition (EMT) in prostate cancer cells through a pathway initiated by p63 inhibition. Luciferase assay verified p63 as a direct target of miR-301a. Loss of p63 resulted in miR-205 downregulation, releasing Zeb1 and Zeb2 from inhibition, culminating in Zeb1/Zeb2 suppression of E-cadherin. This pathway of growth alteration mediated by miR-301a upregulation was shown to be valid in prostate cancer cell lines and patient-derived tumors. CONCLUSIONS: These data indicate that miR-301a functions as an oncogene in prostate cancer by directly targeting the p63 tumor suppressor leading to loss of E-cadherin and EMT. Hence, miR-301a may serve as a novel biomarker in prostate cancer as well as a therapeutic target for prostate cancer management. Prostate 76:869-884, 2016. © 2016 Wiley Periodicals, Inc.

Interrogating Circulating Microsomes and Exosomes Using Metal Nanoparticles.

A chip-based approach for electrochemical characterization and detection of microsomes and exosomes based on direct electro-oxidation of metal nanoparticles (MNPs) that specifically recognize surface markers of these vesicles is reported. It is found that exosomes and microsomes derived from prostate cancer cells can be identified by their surface proteins EpCAM and PSMA, suggesting the potential of exosomes and microsomes for use as diagnostic biomarkers.

A Pilot Study to Evaluate the Role of Magnetic Resonance Imaging for Prostate Cancer Screening in the General Population.

PURPOSE: To our knowledge the role of magnetic resonance imaging as a first line screening test for prostate cancer is unknown. We performed a pilot study to evaluate the feasibility of prostate magnetic resonance imaging as the primary screening test for prostate cancer. MATERIALS AND METHODS: We recruited unselected men from the general population. Prostate multiparametric magnetic resonance imaging and random or targeted biopsies were performed in all patients, in addition to prostate specific antigen testing. We compared the performance of prostate magnetic resonance imaging and prostate specific antigen test results to predict prostate cancer. RESULTS: Of the 47 recruited patients 18 (38.3%) had cancer while 29 (61.7%) had no evidence of cancer. The adjusted OR of prostate cancer was significantly higher for magnetic resonance imaging score than for prostate specific antigen level (2.7, 95% CI 1.4-5.4, p = 0.004 vs 1.1, 95% CI 0.9-1.4, p = 0.21). Among the 30 patients with a normal prostate specific antigen (less than 4.0 ng/ml) the positive predictive value in those with a magnetic resonance imaging score of 4 or more was 66.7% (6 of 9) and the negative predictive value in those with a magnetic resonance imaging score of 3 or less was 85.7% (18 of 21, p = 0.004). CONCLUSIONS: In this pilot study we determined the feasibility of using multiparametric prostate magnetic resonance imaging as the primary screening test for prostate cancer. Initial results showed that prostate magnetic resonance imaging was better to predict prostate cancer than prostate specific antigen in an unselected sample of the general population.

Sample-to-Answer Isolation and mRNA Profiling of Circulating Tumor Cells.

The isolation and rapid molecular characterization of circulating tumor cells (CTCs) from a liquid biopsy could enable the convenient and effective characterization of the state and aggressiveness of cancerous tumors. Existing technologies enumerate CTCs using immunostaining; however, these approaches are slow, labor-intensive, and often fail to enable further genetic characterization of CTCs. Here, we report on an integrated circuit that combines the capture of CTCs with the profiling of their gene expression signatures. Specifically, we use a velocity valley chip to efficiently capture magnetic nanoparticle-bound CTCs, which are then directly analyzed for their gene expression profiles using nanostructured microelectrode biosensors. CTCs are captured with 97% efficiency from 2 mL of whole blood, yielding a 500-fold concentration within 1 h. We show efficient capture of as few as 2 cancer cells/(mL of blood) and demonstrate that the gene expression module accurately profiles the expression of prostate-specific genes in CTCs captured from whole blood. This advance provides the first sample-to-answer solution for gene-based testing of CTCs. The approach was successfully validated using samples collected from prostate cancer patients: both CTCs and prostate-specific antigen (PSA) mRNA sequences were detected in all cancer patient samples and not in the healthy controls.

Chromosomal instability in cell-free DNA is a serum biomarker for prostate cancer.

BACKGROUND: Genomic instability resulting in copy number variation is a hallmark of malignant transformation and may be identified through massive parallel sequencing. Tumor-specific cell free DNA (cfDNA) present in serum and plasma provides a real-time, easily accessible surrogate. METHODS: DNA was extracted from serum of 204 patients with prostate cancer (Gleason score 2-10), 207 male controls, and patients with benign hyperplasia (n = 10) and prostatitis (n = 10). DNA was amplified by use of random primers, tagged with molecular identifiers, sequenced on a SOLID system, and aligned to the human genome. We evaluated the number of sequence reads of cfDNA in sliding 100-kbp intervals for variation from controls. We used chromosomal regions with significant variations in alignment hits for their ability to segregate patients and matched controls. RESULTS: Using ROC curves to assess diagnostic performance, we evaluated the number of regions in a first subset (n = 177), with variations in alignment hits alone, provided an area under the curve (AUC) of 0.81 (95% CI 0.7-0.9, P < 0.001). Using 5 rounds of 10-fold cross-validation with the full data set, we established a final model that discriminated prostate cancer from controls with an AUC of 0.92 (0.87-0.95), reaching a diagnostic accuracy of 83%. Both benign prostatic hypertrophy and prostatitis could be distinguished from prostate cancer by use of cfDNA, with an accuracy of 90%. CONCLUSIONS: Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls. This large cohort demonstrates the utility of cfDNA in prostate cancer recently established in other malignant neoplasms.

Nanoparticle-mediated binning and profiling of heterogeneous circulating tumor cell subpopulations.

The analysis of circulating tumor cells (CTCs) is an important capability that may lead to new approaches for cancer management. CTC capture devices developed to date isolate a bulk population of CTCs and do not differentiate subpopulations that may have varying phenotypes with different levels of clinical relevance. Here, we present a new device for CTC spatial sorting and profiling that sequesters blood-borne tumor cells with different phenotypes into discrete spatial bins. Validation data are presented showing that cancer cell lines with varying surface expression generate different binning profiles within the device. Working with patient blood samples, we obtain profiles that elucidate the heterogeneity of CTC populations present in cancer patients and also report on the status of CTCs within the epithelial-to-mesenchymal transition (EMT).

Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study.

BACKGROUND: Studies of complications resulting from surgery or radiotherapy for prostate cancer have mainly focused on incontinence and erectile dysfunction. We aimed to assess other important complications associated with these treatments for prostate cancer. METHODS: We did a population-based retrospective cohort study, in which we used administrative hospital data, physician billing codes, and cancer registry data for men who underwent either surgery or radiotherapy alone for prostate cancer between 2002 and 2009 in Ontario, Canada. We measured the 5-year cumulative incidence of five treatment-related complication endpoints: hospital admissions; urological, rectal, or anal procedures; open surgical procedures; and secondary malignancies. FINDINGS: In the 32 465 patients included in the study, the 5-year cumulative incidence of admission to hospital for a treatment-related complication was 22·2% (95% CI 21·7-22·7), but was 2·4% (2·2-2·6) for patients whose length of stay was longer than 1 day. The 5-year cumulative incidence of needing a urological procedure was 32·0% (95% CI 31·4-32·5), that of a rectal or anal procedure was 13·7% (13·3-14·1), and that of an open surgical procedure was 0·9% (0·8-1·1). The 5-year cumulative incidence of a second primary malignancy was 3·0% (2·6-3·5). These risks were significantly higher than were those of 32 465 matched controls with no history of prostate cancer. Older age and comorbidity at the time of index treatment were important predictors for a complication in all outcome categories, but the type of treatment received was the strongest predictor for complications. Patients who were given radiotherapy had higher incidence of complications for hospital admissions, rectal or anal procedures, open surgical procedures, and secondary malignancies at 5 years than did those who underwent surgery (adjusted hazard ratios 2·08-10·8, p<0·0001). However, the number of urological procedures was lower in the radiotherapy than in the surgery group (adjusted hazard ratio 0·66, 95% CI 0·63-0·69; p<0·0001) INTERPRETATION: Complications after prostate cancer treatment are frequent and dependent on age, comorbidity, and the type of treatment. Patients and physicians should be aware of these risks when choosing treatment for prostate cancer, and should balance them with the clinical effectiveness of each therapy. FUNDING: Ajmera Family Chair in Urologic Oncology.

The Use of Metformin in Overactive Bladder: A Retrospective Nested Case-control, Population-based Analysis.

OBJECTIVE: To determine if metformin use is associated with a lower rate of overactive bladder (OAB) medication use. Metformin facilitates the proliferation and migration of stem cells, which have been shown to improve bladder overactivity in animal models. METHODS: We conducted a retrospective nested case-control cohort study using population-based health-care administrative databases. Our cohort included patients with diabetes mellitus type 2 (DM2) ≥69years. Cases received a prescription for an OAB medication, matched with up to 4 controls based on age, sex, and DM2 diagnosis date. Exposure was a new prescription for metformin prior to receiving an OAB medication. Adjusted odds ratios were estimated using conditional logistic regression. Sensitivity analysis was done to assess the relationship between cumulative days' supply of metformin and use of OAB medications. RESULTS: Within our cohort of 2,233,084 patients with DM2, there were 16,549 case subjects who received a prescription for an OAB medication, and 64,171 matched controls. We found a positive association between OAB medication use and metformin use (adjusted odds ratios=1.07, 95% CI=1.03-1.12). Summed days' supply of metformin was also associated with OAB medication use, except when summed metformin days was >2220. CONCLUSION: Older patients with DM2 exposed to metformin had a slightly higher rate of OAB medication use, until 2220+ days' metformin supply, whereafter no association was found. This suggests no protective role for metformin in the prevention of OAB in this patient population.

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.