Michael Risk

PMN and anti-tumor immunity--the case of bladder cancer immunotherapy.

Urothelial carcinoma of the bladder accounts for ∼5% of all cancer deaths in humans. The majority of bladder tumors are non-muscle invasive at diagnosis, and there is a high rate of tumor recurrence and progression even after local surgical therapy. Thus, many patients require lifelong follow-up examinations that include additional prophylactic treatments in the event of recurrence. Since its first use in 1976, Mycobacterium bovis bacillus Calmette-Guerin (BCG) has been the treatment of choice for non-muscle invasive bladder cancer. Despite nearly 40 years of clinical use, the mechanism(s) by which intravesical administration of BCG results in elimination of bladder tumors remains undefined. Granulocytes (polymorphonuclear neutrophils (PMN)) are the predominant immune cell (in number) that enters the bladder after BCG installation, and a number of studies have highlighted the importance of PMN in the antitumor activity of BCG. Studies from our laboratory demonstrated presence of intracellular stores of the apoptosis-inducing protein TNF-related apoptosis-inducing ligand (TRAIL) in PMN that are rapidly released after interaction with BCG cell wall components, along with a correlation between increased urinary levels of TRAIL and BCG responsiveness. Mature PMN in circulation are terminally differentiated cells with limited biosynthetic capacity, so the proteins located in the distinct PMN granule populations are compartmentalized concomitant with their synthesis during myelopoiesis. Thus, understanding PMN production, localization, and release of TRAIL is important in the design of future BCG-based bladder tumor immunotherapy protocols.

Diagnostics techniques in nonmuscle invasive bladder cancer.

Introduction: Nonmuscle invasive bladder cancer (NMIBC) is the most common presentation of bladder cancer and is often treatable with endoscopic resection and intravesical therapies. Cystoscopy and urine cytology are the gold standard in diagnosis and surveillance but are limited by their sensitivity in some situations. We seek to provide an overview of recent additions to the diagnostic armamentarium for urologists treating this disease. Methods: Articles were identified through a literature review of articles obtained through PubMed searches including the terms “bladder cancer”and various diagnostic techniques described in the article. Results: A variety of urinary biomarkers are available to assist the diagnosis and management of patients with NMIBC. Many have improved sensitivity over urine cytology, but less specificity. There are certain situations in which this has proved valuable, but as yet these are not part of the standard guidelines for NMIBC. Fluorescence cystoscopy has level 1 evidence demonstrating increased rates of tumor detection and prolonged recurrence-free survival when utilized for transurethral resection. Other technologies seeking to enhance cystoscopy, such as narrow band imaging, confocal laser endomicroscopy, and optical coherence tomography are still under evaluation. Conclusions: A variety of urine biomarker and adjunctive endoscopic technologies have been developed to assist the management of NMIBC. While some, such as fluorescence cystoscopy, have demonstrated a definite benefit in this disease, others are still finding their place in the diagnosis and treatment of this disease. Future studies should shed light on how these can be incorporated to improve outcomes in NMIBC.

Management of clinical stage I nonseminomatous germ cell tumors

Therapeutic options for clinical stage I nonseminomatous germ cell tumor include active surveillance, adjuvant chemotherapy and retroperitoneal lymph node dissection (RPLND). Lymphovascular invasion (LVI) determines risk of recurrence, as those without LVI have 15% risk of relapse on surveillance while those with LVI have a 50% risk. This stratifies patients into high risk(LVI+) and low risk(LVI-) groups which direct treatment recommendations. Surveillance is preferred for those with low risk disease, and is an option for those with high risk disease, as at least half are over-treated with other options. Adjuvant chemotherapy is an option for all patients as it can eradicate micrometastatic disease and reduce recurrence by at least 90%. RPLND benefits patients with low volume retroperitoneal disease with a cure rate of RPLND alone at approximately 70%. All three treatment modalities have similar survival rates approaching 100% but differing potential morbidities, which, along with patient preferences and compliance, should guide treatment decisions.

A Multi-Institutional Prospective Trial Confirms Noninvasive Blood Test Maintains Predictive Value in African American Men

Purpose: The 4Kscore® test accurately detects aggressive prostate cancer and reduces unnecessary biopsies. However, its performance in African American men has been unknown. We assessed test performance in a cohort of men with a large African American representation. Materials and Methods: Men referred for prostate biopsy at 8 Veterans Affairs medical centers were prospectively enrolled in the study. All men underwent phlebotomy for 4Kscore test assessment prior to prostate biopsy. The primary outcome was the detection of Grade Group 2 or higher cancer on biopsy. We assessed the discrimination, calibration and clinical usefulness of 4Kscore to predict Grade Group 2 or higher prostate cancer and compared it to a base model consisting of age, digital rectal examination and prostate specific antigen. Additionally, we compared test performance in African American and nonAfrican American men. Results: Of the 366 enrolled men 205 (56%) were African American and 131 (36%) had Grade Group 2 or higher prostate cancer. The 4Kscore test showed better discrimination (AUC 0.81 vs 0.74, p <0.01) and higher clinical usefulness on decision curve analysis than the base model. Test prediction closely approximated the observed risk of Grade Group 2 or higher prostate cancer. There was no difference in test performance in African American and nonAfrican American men (0.80 vs 0.84, p = 0.32), The test outperformed the base model in each group. Conclusions: The 4Kscore test accurately predicts aggressive prostate cancer for biopsy decision making in African American and nonAfrican American men.

A Multi-institutional Prospective Trial in the Veterans Affairs Health System confirms the 4Kscore maintains its Predictive value among African American Men

Purpose: The 4Kscore® test accurately detects aggressive prostate cancer and reduces unnecessary biopsies. However, its performance in African American men has been unknown. We assessed test performance in a cohort of men with a large African American representation. Materials and Methods: Men referred for prostate biopsy at 8 Veterans Affairs medical centers were prospectively enrolled in the study. All men underwent phlebotomy for 4Kscore test assessment prior to prostate biopsy. The primary outcome was the detection of Grade Group 2 or higher cancer on biopsy. We assessed the discrimination, calibration and clinical usefulness of 4Kscore to predict Grade Group 2 or higher prostate cancer and compared it to a base model consisting of age, digital rectal examination and prostate specific antigen. Additionally, we compared test performance in African American and nonAfrican American men. Results: Of the 366 enrolled men 205 (56%) were African American and 131 (36%) had Grade Group 2 or higher prostate cancer. The 4Kscore test showed better discrimination (AUC 0.81 vs 0.74, p <0.01) and higher clinical usefulness on decision curve analysis than the base model. Test prediction closely approximated the observed risk of Grade Group 2 or higher prostate cancer. There was no difference in test performance in African American and nonAfrican American men (0.80 vs 0.84, p = 0.32), The test outperformed the base model in each group. Conclusions: The 4Kscore test accurately predicts aggressive prostate cancer for biopsy decision making in African American and nonAfrican American men.

Efficacy of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: a systematic review

Abstract We conducted a systematic review to evaluate the efficacy and adverse effects of newer drugs used to treat lower urinary tract symptoms (LUTS). The drugs were either Food and Drug Administration (FDA) approved for benign prostatic hyperplasia (BPH) or not FDA approved for BPH but have been evaluated for treatment of BPH since 2008. We searched bibliographic databases through September 2017. We included randomized controlled trials (RCTs) lasting one month or longer published in English. Outcomes of interest were LUTS assessed by validated measures. Efficacy was interpreted using established thresholds indicating clinical significance that identified the minimal detectable difference. Twenty-three unique, generally short-term, RCTs evaluating over 9000 participants were identified. Alpha-blocker silodosin and phosphodiesterase type 5 inhibitor tadalafil were more effective than placebo in improving LUTS (moderate strength evidence) but these drugs had more adverse effects, including abnormal ejaculation (silodosin). Anticholinergics were only effective versus placebo when combined with an alpha-blocker. Evidence was generally low strength or insufficient for other drugs. Evidence was insufficient to assess long-term efficacy, prevention of symptom progression, need for surgical intervention, or long-term adverse effects. Longer trials are needed to assess the effect of these therapies on response rates using established minimal detectable difference thresholds, disease progression, and harms.

Suprapubic versus urethral catheter drainage in robotic-assisted laparoscopic prostatectomy: advancing systematic review quality

We read with interest the systematic review (SR) on the current best evidence concerning the choice of a suprapubic versus urethral catheter after robot-assisted radical prostatectomy (RARP) [1], which found that patients managed with a suprapubic catheter (SPC) have both less overall pain and less penile pain on postoperative day 7, while at the same time experiencing similar continence rates, as well as catheter-related complications. Although we agree that methodologically rigorous SRs play a critical role in informing evidence-based practice, we would like to offer some cautionary notes with regard to the findings of this study. First of all, we applaud the authors for having developed an a priori protocol to serve as a blue print of what they planned to do, thereby guarding them against the temptation of post hoc, data-driven analyses that may lead to spurious findings [2]. Ideally though, protocols should be prospectively registered, placing them in the public domain to enhance transparency and avoid duplication of efforts by different review teams. Outside of Cochrane, PROSPERO is the best known and most widely used SR registry (PROSPERO). Second, we are concerned with the choice of instruments used to assess the risk of bias of individual studies, in particular the use of the Jadad scale, the use of which is actively discouraged [3]. Third, we worry about the indiscriminate pooling of randomized and non-randomized studies which should have been treated as separate bodies of evidence and which should only be combined if they showed similar results [2, 4]. Fourth, the authors may have been able to include additional study data, for example from the study by Prasad et al. [5]. Presumably, they did not, for lack of information on measures of distribution. However, standard deviations can oftentimes be calculated using other available information using one of several approaches [6]. Fifth, the study makes no effort to qualify the confidence that the reader should place in the results of the pooled analysis unlike when using an approach such as GRADE [7]. For example, the analysis for overall pain on postoperative day 7 found a mean difference of 0.53 favoring SPC. This analysis is dominated by the large non-randomized study by Yang et al. [8] and the quality of evidence as per GRADE would likely be “low”. It might be further downgraded for imprecision to “very low”, given the wide 95% confidence interval (0.13–0.93) that presumably includes the minimal clinically important difference, although this was not defined by the authors [9]. If this finding was indeed based on “very low” quality evidence, this would mean that we are in fact quite uncertain of the evidence. Similar issues of interpretation relate to the “negative” finding of similar continence rates, which have been shown to be frequently misinterpreted in the urological literature [7]. Lastly, the authors leave unanswered whether patients have traded penile pain for suprapubic pain, which several underlying studies have apparently addressed [5, 10]. We do agree with the authors that better studies are needed.

Lymphadenectomy for Muscle-Invasive Bladder Cancer and Upper Tract Urothelial Cell Carcinoma

There are currently no reported randomized trials that characterize the staging or therapeutic benefit of performing a lymph node dissection in either bladder cancer or upper tract urothelial carcinoma. Several unanswered questions remain in this domain focused on the indications and patient selection for pelvic lymph node dissection, extent of dissection, its impact on outcome, and potential risks. However, the results of observational studies suggest that the burden of metastasis is high in both diseases when muscle invasive and performing a lymphadenectomy can provide prognostic information and yield therapeutic benefit.

Persistent muscle-invasive bladder cancer after neoadjuvant chemotherapy: an analysis of Surveillance, Epidemiology and End Results-Medicare data

To evaluate whether patients with persistent muscle‐invasive bladder cancer (MIBC) after undergoing neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) have worse overall survival (OS) and cancer‐specific survival (CSS) than patients with similar pathology who undergo RC alone.

A Multi-Institutional Prospective Trial in the Veterans Affairs Health System Confirms Noninvasive Blood Test Maintains Predictive Value in African American Men

Purpose: The 4Kscore® test accurately detects aggressive prostate cancer and reduces unnecessary biopsies. However, its performance in African American men has been unknown. We assessed test performance in a cohort of men with a large African American representation. Materials and Methods: Men referred for prostate biopsy at 8 Veterans Affairs medical centers were prospectively enrolled in the study. All men underwent phlebotomy for 4Kscore test assessment prior to prostate biopsy. The primary outcome was the detection of Grade Group 2 or higher cancer on biopsy. We assessed the discrimination, calibration and clinical usefulness of 4Kscore to predict Grade Group 2 or higher prostate cancer and compared it to a base model consisting of age, digital rectal examination and prostate specific antigen. Additionally, we compared test performance in African American and nonAfrican American men. Results: Of the 366 enrolled men 205 (56%) were African American and 131 (36%) had Grade Group 2 or higher prostate cancer. The 4Kscore test showed better discrimination (AUC 0.81 vs 0.74, p <0.01) and higher clinical usefulness on decision curve analysis than the base model. Test prediction closely approximated the observed risk of Grade Group 2 or higher prostate cancer. There was no difference in test performance in African American and nonAfrican American men (0.80 vs 0.84, p = 0.32), The test outperformed the base model in each group. Conclusions: The 4Kscore test accurately predicts aggressive prostate cancer for biopsy decision making in African American and nonAfrican American men.