Jason Izard

A pilot study of urinary microRNA as a biomarker for urothelial cancer

Objective : MicroRNAs (miRNAs) are part of a class of small ribonucleic acid (RNAs). They are important regulatory molecules, involved in several cell processes, such as developmental timing, stem cell division and apoptosis. Dysregulated miRNAs have been identified in several human malignancies, including bladder cancer tissue samples, and may confer a “tumour signature” that can be exploited for diagnostic purposes. We report on a prospective pilot study investigating the diagnostic capability of miRNAs in the urine of patients with urothelial cancer. Methods : Voided urine samples were collected from patients with urothelial carcinoma just prior to bladder tumour resection, as well as age-matched healthy control patients. Pathology demonstrated both low- and high-grade cancer. Total RNA was isolated and quantitative reverse transcriptase-polymerase chain reaction was performed on the RNA extracts using primers for 4 miRNAs shown previously to be dysregulated in solid urothelial carcinomas with RNU6B as the endogenous control. Standard urine cytology was performed on all samples in a blinded fashion. Results : Two miRNAs of interest were dysregulated in the urine from cancer patients with miR-125b showing an average 10.42-fold decrease (p < 0.01) and miR-126 showing an average 2.70-fold increase (p = 0.30) in the cancer samples compared to the normal controls. The sensitivity and specificity of the cytology on the same urine samples were 50% and 80%, respectively. Using these 2miRNAs only, a decision-tree prediction model was generated for a validation cohort of patients yielding a specificity of 100% and a sensitivity of 80%. Discussion : This preliminary study of candidate urinary miRNA inpatients with low- and high-grade urothelial cancer demonstrated a significantly improved diagnostic accuracy over cytology. These results provide rationale for further studies on discovery and validation of candidate miRNAs in voided urine and may potentially lead to the development of a non-invasive and sensitive test for bladder cancer diagnosis and prognosis.

Impact of medical therapy on transurethral resection of the prostate: two decades of change

Study Type – Therapy (case series) 
Level of Evidence 4

User-centered design of quality of life reports for clinical care of patients with prostate cancer.

BACKGROUND Primary treatment of localized prostate cancer can result in bothersome urinary, sexual, and bowel symptoms. Yet clinical application of health-related quality-of-life (HRQOL) questionnaires is rare. We employed user-centered design to develop graphic dashboards of questionnaire responses from patients with prostate cancer to facilitate clinical integration of HRQOL measurement. METHODS We interviewed 50 prostate cancer patients and 50 providers, assessed literacy with validated instruments (Rapid Estimate of Adult Literacy in Medicine short form, Subjective Numeracy Scale, Graphical Literacy Scale), and presented participants with prototype dashboards that display prostate cancer-specific HRQOL with graphic elements derived from patient focus groups. We assessed dashboard comprehension and preferences in table, bar, line, and pictograph formats with patient scores contextualized with HRQOL scores of similar patients serving as a comparison group. RESULTS Health literacy (mean score, 6.8/7) and numeracy (mean score, 4.5/6) of patient participants was high. Patients favored the bar chart (mean rank, 1.8 [P = .12] vs line graph [P < .01] vs table and pictograph); providers demonstrated similar preference for table, bar, and line formats (ranked first by 30%, 34%, and 34% of providers, respectively). Providers expressed unsolicited concerns over presentation of comparison group scores (n = 19; 38%) and impact on clinic efficiency (n = 16; 32%). CONCLUSION Based on preferences of prostate cancer patients and providers, we developed the design concept of a dynamic HRQOL dashboard that permits a base patient-centered report in bar chart format that can be toggled to other formats and include error bars that frame comparison group scores. Inclusion of lower literacy patients may yield different preferences.

Identification of underserved areas for urologic cancer care.

The delivery of urologic oncology care is susceptible to regional variation. In the current study, the authors sought to define patterns of care for patients undergoing genitourinary cancer surgery to identify underserved areas for urologic cancer care in Washington State.

Relevance of graph literacy in the development of patient-centered communication tools

OBJECTIVE To determine the literacy skill sets of patients in the context of graphical interpretation of interactive dashboards. METHODS We assessed literacy characteristics of prostate cancer patients and assessed comprehension of quality of life dashboards. Health literacy, numeracy and graph literacy were assessed with validated tools. We divided patients into low vs. high numeracy and graph literacy. We report descriptive statistics on literacy, dashboard comprehension, and relationships between groups. We used correlation and multiple linear regressions to examine factors associated with dashboard comprehension. RESULTS Despite high health literacy in educated patients (78% college educated), there was variation in numeracy and graph literacy. Numeracy and graph literacy scores were correlated (r=0.37). In those with low literacy, graph literacy scores most strongly correlated with dashboard comprehension (r=0.59-0.90). On multivariate analysis, graph literacy was independently associated with dashboard comprehension, adjusting for age, education, and numeracy level. CONCLUSIONS Even among higher educated patients; variation in the ability to comprehend graphs exists. PRACTICE IMPLICATIONS Clinicians must be aware of these differential proficiencies when counseling patients. Tools for patient-centered communication that employ visual displays need to account for literacy capabilities to ensure that patients can effectively engage these resources.

Outcomes of squamous histology in bladder cancer: A population-based study

OBJECTIVES Squamous cell carcinoma (SCC) of the bladder is an uncommon form of bladder cancer. Using a large population-based sample we sought to describe the outcomes of patients with squamous histology and to define the factors that influence prognosis in these patients. METHODS All incident cases of bladder cancer in Ontario undergoing cystectomy from 1994 to 2008 were identified. Electronic treatment records and detailed pathologic information were linked to the study data set. Patients were divided into 3 cohorts: pure SCC, urothelial carcinoma (UC) with squamous differentiation (UCSD), and pure UC. Cox modeling was performed to evaluate factors associated with overall survival (OS) and cancer-specific survival (CSS). RESULTS There were identified 178, 325, and 2,884 cases of SCC, UCSD, and UC, respectively. The unadjusted 5-year OS for these groups were 33%, 28%, and 34%, respectively. Patients had higher rates of T3/4 disease with SCC (72%) and UCSD (73%) than those with UC (61%, P<0.001). There was no difference in node positivity among groups (20%, 27%, and 25%, P = 0.519). After adjusting for covariates, SCC did not portend a worse survival, at 5 years. However, SCC did result in a more rapid disease trajectory, with survival curves of SCC and UC crossing at the 5-year mark. Adjusted CSS/OS of UCSD was also not significantly different from UC. Among those patients with SCC, factors associated with CSS included age>70 (hazard ratio [HR] = 1.96, 95% CI: 1.16-3.30), T category≥3 (HR = 2.09, 95% CI: 1.24-3.50), N positive disease (HR = 2.59, 95% CI: 1.55-4.32), lymphovascular invasion (HR = 1.98, 95% CI: 1.13-3.47), and positive surgical margins (HR = 2.95, 95% CI: 1.47-5.93). CONCLUSIONS After adjusting for patient and disease characteristics, we have found that SCC leads to a more rapid disease course with survival that is equivalent to UC by 5 years.

Pathologic Response Rates of Gemcitabine/Cisplatin versus Methotrexate/Vinblastine/Adriamycin/Cisplatin Neoadjuvant Chemotherapy for Muscle Invasive Urothelial Bladder Cancer

Objectives. To compare pathologic outcomes after treatment with gemcitabine and cisplatin (GC) versus methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) in the neoadjuvant setting. Methods. Data was retrospectively collected on 178 patients with T2-T4 bladder cancer who underwent radical cystectomy between 2003 and 2011. Outcomes of interest included those with complete response (pT0) and any response (≤pT1). Odds ratios were calculated using multivariate logistic regression. Results. Compared to those who did not receive neoadjuvant chemotherapy, there were more patients with complete response (28% versus 9%, OR 3.11 (95% CI: 1.45–6.64), P = 0.03) and any response (52% versus 25%, OR 3.23 (95% CI: 1.21–8.64), P = 0.01). Seventy-two patients received GC (n = 41) or MVAC (n = 31). CR was achieved in 29% and 22% of GC and MVAC patients, respectively (multivariate OR 0.39, 95% CI 0.10–1.58). Any response (≤pT1) was achieved in 56% of GC and 45% of MVAC patients (multivariate OR 0.45, 95% CI 0.12–1.71). Conclusions. We observed similar pathologic response rates for GC and MVAC neoadjuvant chemotherapy in this cohort of patients with muscle invasive urothelial cancer (MIBC). Our findings support the use of GC as an alternative regimen in the neoadjuvant setting.

Prostate cancer that is within 0.1 mm of the surgical margin of a radical prostatectomy predicts greater likelihood of recurrence

Abstract: Surgical margin status at prostatectomy is an important predictor of biochemical recurrence (BCR). The current convention is to categorize a margin as negative if tumor cells are not at the inked margin, even if they are within a few cells of the margin. We hypothesized that cancer within 0.1 mm of the margin conferred an increased risk for BCR. We determined the risk for BCR on the bass of surgical margin status in a cohort of 1588 patients who underwent radical prostatectomy for prostate cancer (PCa) between 1998 and 2011. Surgical margins were categorized as positive, close (<0.1 mm from tumor cells), or negative. Multivariate hazard ratios (HRs) for BCR were determined by margin status. We identified 1588 patients, of whom 193 had PCa recurrence. The margin status was negative in 1058 (67%), close in 232 (15%), and positive in 298 (19%). Cancer that was close to the margin was a significant and independent predictor of BCR (HR 1.53; 95% confidence interval, 1.00-2.32) and was not statistically different than a positive surgical margin (HR 2.10; 95% confidence interval, 1.48-2.99). Cancer that is within 0.1 mm of the surgical margin of a prostatectomy is associated with an increased risk for PCa recurrence. Patients with that margin status may be reasonable candidates for adjuvant local therapy.

Positive surgical margins at radical prostatectomy: Population-based averages within PSA and Gleason strata

BACKGROUND Positive surgical margins (PSM) are an important determinant of biochemical recurrence after radical prostatectomy (RP). We use a population-based cancer registry to evaluate PSM by stage, Gleason and prostate-specific antigen (PSA). METHODS We identified men undergoing RP from the Surveillance, Epidemiology and End Results (SEER) database between 2004 and 2007. Differences between those with and without PSM were compared with chi-squared tests. The proportion of cases with PSM were stratified by PSA and Gleason sum for both pT2 and pT3a tumours. Factors associated with PSM were analyzed using chi square and multivariate logistic regression analysis. A composite variable was used in a second multivariate analysis to display the odds ratio (OR) for a PSM for each discrete combination of PSA, Gleason score and pT stage. RESULTS In total, 28 461 RP patients were identified and a PSM was present in 19.5%. PSM were 42% in pT3a and 16% in pT2 cases. Higher PSAs (<4.0, 4-9.9, >10) were associated with higher proportions of PSM (12%, 20% and 28%, p < 0.001). Similarly, higher Gleason scores (≤6, 3+4, 4+3, ≥8) were associated with higher PSM (12%, 22%, 27% and 33%, p < 0.001). For pT2 tumours, the proportion of PSM ranged from 8% (Gleason ≤6, PSA <4.0) to 28% (Gleason 8-10, PSA ≥10). For pT3a tumours, the PSM was higher in each Gleason/PSA strata compared to those with pT2 tumours, reaching 63% for those with pT3a, Gleason 8-10, PSA >10 disease. On multivariate analysis, stage was the largest predictor for PSM (OR 3.05, 95% confidence interval 2.81-3.30), although Gleason score and PSA remained statistically significant. CONCLUSION In this population-based study of PSM after RP, the proportion of PSM vary significantly within different PSA and Gleason strata for organ-confined and extracapsular disease. These data can be used as a reference for urologist self-assessment.

Clinical practice experience with testosterone treatment in men with testosterone deficiency syndrome

To report on a clinical practice series of testosterone‐replacement therapy (TRT) in men with testosterone deficiency syndrome (TDS), examining clinical efficacy, biochemical parameters and effects on prostate health over a 2‐year period.