R. Christopher Doiron

Clinical Phenotyping Does Not Differentiate Hunner Lesion Subtype of Interstitial Cystitis/Bladder Pain Syndrome: A Relook at the Role of Cystoscopy

PURPOSE Identifying Hunner lesions in patients with interstitial cystitis/bladder pain syndrome presents an opportunity for objective classification into Hunner lesion interstitial cystitis/bladder pain syndrome (classic interstitial cystitis) and nonHunner lesion bladder pain syndrome. While currently the former diagnosis requires cystoscopy, limited data suggest that these subtypes can be distinguished without endoscopy based on the degree of bladder focused centricity and the infrequent association with generalized pain conditions. MATERIALS AND METHODS Patients in a prospective, single center database of interstitial cystitis/bladder pain syndrome who had documented cystoscopic findings were categorized with Hunner lesion interstitial cystitis/bladder pain syndrome or nonHunner lesion bladder pain syndrome. Demographics, pain and symptom scores, voiding symptoms, irritable bowel syndrome and clinical UPOINT (urinary, psychosocial, organ specific, infection, neurological and tenderness) scoring were comparatively analyzed. RESULTS We reviewed the records of 469 patients, including 359 with documented local anesthetic cystoscopic findings, 44 (12.3%) with Hunner lesion interstitial cystitis/bladder pain syndrome and 315 (87.7%) with nonHunner bladder pain syndrome. Patients with Hunner lesions were older (p = 0.004) and had greater urinary frequency (p = 0.013), more nocturia (p = 0.0004) and higher ICSI (Interstitial Cystitis Symptom Index) scores (p = 0.017). Hunner lesion prevalence was significantly lower in those younger than 50 years vs those 50 years old or older (7.8% vs 14.9%, p = 0.0095). There was no difference in the number of UPOINT phenotype domains reported, overall UPOINT scores or the prevalence of irritable bowel syndrome between the groups. CONCLUSIONS A subtype of interstitial cystitis with Hunner lesions has worse bladder centric symptoms but did not show a distinct bladder centric phenotype. Given the management implications of distinguishing classic interstitial cystitis from nonHunner lesion bladder pain syndrome, we recommend cystoscopy with local anesthesia in patients diagnosed with interstitial cystitis/bladder pain syndrome.

MOLECULAR CHARACTERIZATION OF GLEASON PATTERNS 3 AND 4 PROSTATE CANCER USING REVERSE WARBURG EFFECT-ASSOCIATED GENES

BackgroundGleason scores (GS) 3+3 and 3+4 prostate cancers (PCa) differ greatly in their clinical courses, with Gleason pattern (GP) 4 representing a major independent risk factor for cancer progression. However, Gleason grade is not reliably ascertained by diagnostic biopsy, largely due to sampling inadequacies, subjectivity in the Gleason grading procedure, and a lack of more objective biomarker assays to stratify prostate cancer aggressiveness. In most aggressive cancer types, the tumor microenvironment exhibits a reciprocal pro-tumorigenic metabolic phenotype consistent with the reverse Warburg effect (RWE). The RWE can be viewed as a physiologic response to the epithelial phenotype that is independent of both the epithelial genotype and of direct tumor sampling. We hypothesize that differential expression of RWE-associated genes can be used to classify Gleason pattern, distinguishing GP3 from GP4 PCa foci.MethodsGene expression profiling was conducted on RNA extracted from laser-capture microdissected stromal tissue surrounding 20 GP3 and 21 GP4 cancer foci from PCa patients with GS 3+3 and GS ≥4+3, respectively. Genes were probed using a 102-gene NanoString probe set targeted towards biological processes associated with the RWE. Differentially expressed genes were identified from normalized data by univariate analysis. A top-scoring pair (TSP) analysis was completed on raw gene expression values. Genes were analyzed for enriched Gene Ontology (GO) biological processes and protein-protein interactions using STRING and GeneMANIA.ResultsUnivariate analysis identified nine genes (FOXO1 (AUC: 0.884), GPD2, SPARC, HK2, COL1A2, ALDOA, MCT4, NRF2, and ATG5) that were differentially expressed between GP3 and GP4 stroma (p<0.05). However, following correction for false discovery, only FOXO1 retained statistical significance at q<0.05. The TSP analysis identified a significant gene pair, namely ATG5/GLUT1. Greater expression of ATG5 relative to GLUT1 correctly classified 77.4 % of GP3/GP4 samples. Enrichment for GO-biological processes revealed that catabolic glucose processes and oxidative stress response pathways were strongly associated with GP3 foci but not GP4. FOXO1 was identified as being a primary nodal protein.ConclusionsWe report that RWE-associated genes can be used to distinguish between GP3 and GP4 prostate cancers. Moreover, we find that the RWE response is downregulated in the stroma surrounding GP4, possibly via modulation of FOXO1.

Risk factors and timing of venous thromboembolism after radical cystectomy in routine clinical practice: a population-based study.

To describe the risk factors and timing of perioperative venous thromboembolism (VTE) and its association with survival for patients undergoing radical cystectomy (RC) in routine clinical practice.

Management of chronic prostatitis/chronic pelvic pain syndrome

�1.7 (95% confidence interval [CI], �2.8 to �0.6), �1.1 (95% CI, �1.8 to �0.3), �1.4 (95% CI, �2.3 to �0.5), and �1.0 (95% CI, �1.8 to �0.2), respectively. Patients receiving -blockers or anti-inflammatory medications had a higher chance of favorable response compared with placebo, with pooled RRs of 1.6 (95% CI, 1.1-2.3) and 1.8 (95% CI, 1.2-2.6), respectively. Contour-enhanced funnel plots suggested the presence of publication bias for smaller studies of -blocker therapies. The network meta-analysis suggested benefits of antibiotics in decreasing total symptom scores (�9.8; 95% CI, �15.1 to �4.6), pain scores (�4.4; 95% CI, �7.0 to �1.9), voiding scores (�2.8; 95% CI, �4.1 to �1.6), and quality-of-life scores (�1.9; 95% CI, �3.6 to �0.2) compared with placebo. Combining-blockers and antibiotics yielded the greatest benefits compared with placebo, with corresponding decreases of �13.8 (95% CI, �17.5 to �10.2) for total symptom scores, �5.7 (95% CI, �7.8 to �3.6) for pain scores, �3.7 (95% CI, �5.2 to �2.1) for voiding, and �2.8 (95% CI, �4.7 to �0.9) for quality-of-life scores. Conclusions -Blockers,antibiotics,andcombinationsofthesetherapiesappeartoachieve the greatest improvement in clinical symptom scores compared with placebo. Antiinflammatory therapies have a lesser but measurable benefit on selected outcomes. However, beneficial effects of -blockers may be overestimated because of publication bias.

The evolving clinical picture of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): A look at 1310 patients over 16 years

INTRODUCTION Two decades of increasing understanding of etiopathogenesis and clinical phenotyping produces an impression the clinical face of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is changing. We sought to retrospectively analyze trends in CP/CPPS patients presenting to our clinic for evaluation over a 16-year period. METHODS Patients with CP/CPPS presenting to a tertiary clinic were evaluated prospectively from 1998-2014 with Chronic Prostatitis Symptom Index (CPSI) and UPOINT (urinary, psychosocial, organ-specific, infection, neurogenic, and tenderness) categorization. Patients were stratified in four cohorts, based on year of presentation, and we retrospectively analyzed variations in symptom scores and patterns, UPOINT categorization, and treatment modalities amongst cohorts. RESULTS Mean age of the 1310 CP/CPPS patients was 44.7 years, while mean CPSI pain, urination, and total scores were 10.6, 4.8, and 23.3, respectively. The most prevalent UPOINT domain, urinary (U) (71.8%) was associated with a higher CPSI urination score (6.3), more frequent penile tip pain (37%), dysuria (48%), and more treatment with alpha-blockers (70%). Increase in UPOINT domains was associated with higher CPSI pain, quality of life (QoL), and total scores. Trends over time included increased prevalence of psychosocial (P), organ (O), and tenderness (T) domains, as well as increased use of alpha-blockers, neuromodulation, and phytotherapy as treatment modalities. There was little variation in age, CPSI scores, and pain locations over time. CONCLUSIONS The changing clinical face of CP/CPPS reflects the increased recognition of psychosocial (P domain) and pelvic floor pain (T domain), along with the concomitant use of associated therapies. There was little variation of pain/urinary symptom patterns and QoL.

PD05-01 THE EVOLVING CLINICAL PICTURE OF CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME (CP/CPPS): A LOOK AT 1310 PATIENTS OVER 16 YEARS.

INTRODUCTION AND OBJECTIVES: To-date there are no urine-based tests that provide clinical resolution of the severity or grade of urothelial carcinoma (UC) in patients presenting with primary hematuria. Such information permits timely diagnosis and specific management of hematuria patients identified with high grade and/or advanced UC disease. The objective of this study was, therefore, to develop and investigate the performance of Cxbladder Resolve, a new urine-based test offering identification and accurate segregation of patients with high-grade (HG) and/or late-stage disease at the time of initial urological investigation. METHODS: Participants in the study (N1⁄4863) were recruited from patients presenting with micro-(n1⁄466) or macrohematuria (n1⁄4797) across centers in the U.S., New Zealand and Australia. An index incorporating 2 clinical variables and 5 gene expression biomarkers measured in urine was developed to segregate patients into 3 groups: 1. Low risk of UC; 2. Elevated risk of low grade (LG) UC; and 3. High risk of high grade (HG) UC. RESULTS: Of the 863 recruited patients, 89 (10.3%) primary cases of UC were observed including 40 LG and 49 HG. Cxbladder Resolve segregated the 863 participants into: low risk of UC (n1⁄4479; 55%), elevated risk of LG UC (n1⁄4288; 33%) and high risk of HG UC disease (n1⁄496; 11%). (Table) Of the 40 patients with LG bladder tumors, 27 were correctly categorized as Elevated risk of low grade UC, with the remainder; 9 as High risk of HG UC, and 4 as Low risk of UC. Of the 49 patients with HG UC, 47 (96%) were correctly identified as having High risk of HG UC and the remaining 2 patients were classified as elevated risk of LG UC. No patients with HG UC were classified as low risk of UC. Overall a negative predictive value [NPV] of 1⁄499% was observed. CONCLUSIONS: Cxbladder Resolve accurately identifies over 95% of HG UC patients with a reciprocal high NPV (99%) for low risk patients. The index has a low probability of incorrectly classifying pathologic HG UC patients as low risk. Clinical utility is demonstrated for stratifying hematuria patients into risk groups allowing for prioritization of high risk patients with aggressive disease requiring early investigative procedures.

Health advocacy in a competency-based curriculum: The emerging role of global surgery

With the introduction of the CanMEDS program by the Royal College of Physicians and Surgeons of Canada (RCPSC) in the 1990s, a new comprehensive framework for medical education was introduced. The program outlined seven physician roles: medical expert, scholar, communicator, collaborator, health advocate, manager, and professional. While recognizing the importance of the broader role the physician plays in our communities and health systems, the program required that medical trainees be formally evaluated in each of these domains. The CanMEDS roles have now long formed the basis for undergraduate and postgraduate medical curricula and are well embedded within the lexicon of modern medical education. Formalizing the CanMEDS roles — defining them, integrating them into curricula, and evaluating them — was not straightforward. The role of health advocate has been a particular challenge and much literature exists describing the hurdles faced in dealing with health advocacy in residency training. We know from a 2007 survey that Canadian urology residents lack awareness of its mere existence in the framework and there was a deficiency of formal health advocacy opportunities and mentorship within our institutions. Although there have been some modest improvements, health advocacy has remained somewhat of an enigma within our residency training programs. This has undoubtedly led to its marginalization within medical curricula, particularly in residency, where the workloads of patient care dominate residents’ day-to-day and the academic burden of fulfilling the medical expert role weighs heavily. With another metamorphosis of our Canadian medical education system on the horizon — competency-based medical education (CBME) — perhaps the time is right to revisit how to address these more challenging physician roles. It certainly cannot be that the importance of competency in health advocacy among practicing urologists has diminished. One could argue instead that our patients, communities, and even our country cannot afford us to continue to treat it as an afterthought. Despite the difficulties with formalized training in health advocacy, enthusiasm for advocacy issues among trainees is unprecedented, particularly in the field of global health. Recent literature has suggested that interest in global surgery among surgical residents training in North America is at an all-time high. Herein lies a golden opportunity to align the interests of our trainees with the competencies expected of them; what better way to learn and gain competence in health advocacy than spending time providing care to the world’s most poor and marginalized? A surgical elective in a lowand middle-income country could represent the quintessential experience in health advocacy for a urology resident. Participants in global surgery work are exposed to the crippling problem of poor access to basic medical care and must grapple with troubling questions of global health equity. The role of surgery in public health and health policy are also explored. Beyond the role of health advocate, residents are exposed to a broader scope of urologic pathology, challenged to communicate often in foreign languages or with the use of a translator, and forced to rely on their history-taking and physical examination skills with minimal resources to perform investigations and imaging studies. Furthermore, it is an exciting time in the field of global surgery. While fellowship opportunities in global surgery are sprouting up at academic centres across North America, the work of the Lancet Commission in Global Surgery has helped surgery elbow its way onto the global health agenda. In fact, a case study on the commission’s work alone would be a welcomed exercise for any student of health advocacy. Although the Lancet Commission lacked both urologic and Canadian representation, as the field of global surgery continues to forge ahead, there is great opportunity for urologists and urology residents to heed the tide and get involved. Some have advocated for a global surgery elective as mandatory in surgical training programs. Perhaps a bit hyperbolic to discuss as mandatory, it at the least warrants our consideration as an excellent opportunity in health advocacy and should be supported as such by our institutions for those residents with interest. With CBME on the way, it also represents a practical and clear-cut avenue for achieving competency in health advocacy.