Does antithrombotic use enable earlier diagnosis of bladder cancer? A brief institutional assessment.

INTRODUCTION: Wallis et al (JAMA 2017) demonstrated use of antithrombotic medications (ATMs) is associated with increased prevalence of hematuria-related complications and subsequent bladder cancer diagnosis within 6 months. Stage of diagnosis was lacking in this highly publicized study. This study examined the association of ATM use on bladder cancer stage at the time of diagnosis. MATERIALS AND METHODS: We completed a retrospective chart review of patients with a bladder cancer diagnosis at our institution. Patient demographics and bladder cancer work up information were assessed. Patients were stratified based on use of ATMs at time diagnosis. Descriptive statistics were completed to identify association between ATM use and stage of bladder cancer diagnosis, as stratified by non-muscle invasive bladder cancer (NMIBC) versus muscle invasive bladder cancer (MIBC). RESULTS: A total of 1052 patient charts were reviewed. Eight hundred and forty-four were included and 208 excluded due to unavailability of diagnosis history. At diagnosis, 357 (42.3%) patients were taking ATMs. Patients on ATMs presented with NMIBC at similar rates as patients not taking ATMs (81.2% vs. 77.8%, p = 0.23). Subgroup analysis by ATM class similarly demonstrated no statistically significant differences in staging. CONCLUSION: While Wallis et al established that patients on blood thinners who present with hematuria are more likely to be diagnosed with genitourinary pathology, this factor does not appear to enable an earlier diagnosis of bladder cancer. Future study may assess hematuria at presentation (gross, microscopic), type of blood thinners, and low versus high risk NMIBC presentation.

Simple frameshifts in minimally invasive surgery postoperative pain management significantly reduce opiate prescriptions.

INTRODUCTION: To evaluate the impact of an 'opt-in' non-narcotic postoperative pain regimen on narcotic utilization and patient-reported pain scores. MATERIALS AND METHODS: A prospective, non-blinded pre- and post-interventional trial was conducted, including a lead-in period for baseline evaluation. The intervention group received a new pain protocol prioritizing non-narcotic medications, an 'opt-in' requirement for opiates, and standardized patient education. Study outcomes included opiate prescription and utilization (measured in Morphine Equivalent Doses) and reported pain scores on postoperative day (POD) 1, discharge and follow up. RESULTS: At discharge, 70% fewer patients were prescribed any opioids (ARR: -0.7; p < 0.001); the amount prescribed was reduced by 95% (pre-intervention 69.3 mg versus post-intervention 3.5 mg, p < 0.001). Mean opioids used following discharge decreased by 76% (14.7 mg versus 3.5 mg, p = 0.011). In a subgroup analysis of robotic prostatectomies, there was a 95% reduction in mean opioids prescribed at discharge (64.6 mg versus 3.2 mg, p < 0.001) and 82% reduction in utilization over entire postoperative course (87.6 mg versus 15.7 mg, p = 0.001). There was no significant difference in pain scores between intervention groups at POD 1, discharge and follow up for patients (entire cohort and post-prostatectomy). CONCLUSION: A standardized pain protocol with 'opt-in' requirements for opiate prescription, emphasis on non-narcotic medications, and patient education, resulted in significant reductions in opioid use. Simple frameshifts in pain management can yield significant gains in the opioid epidemic.

Fluorescence in situ hybridization (FISH) in the diagnosis of bladder and upper tract urothelial carcinoma: the largest single-institution experience to date.

INTRODUCTION: We evaluated the UroVysion (Abbott Molecular, IL, USA) fluorescence in situ hybridization (FISH) assay for the diagnosis of urothelial cancer in patients diagnosed with or suspected to have bladder, upper tract urothelial carcinoma (UTUC), and combined upper and lower tract urothelial carcinoma (BC). MATERIALS AND METHODS: A single institution retrospective analysis comparing sensitivity, specificity, positive predictive value, and negative predictive values for FISH and urinary cytology. FISH within 6 months of endoscopic evaluation were obtained from outpatient voided urine samples. Our institutional pathology department confirmed pathologic disease from specimens obtained during endoscopic evaluations for lower tract disease. For upper tract disease, disease was confirmed by retrograde ureteroscopy, biopsies of visual lesions, and site-specific upper tract cytology. RESULTS: A total of 415 patients submitted FISH specimens. Overall, FISH was more sensitive than cytology 54.9% in comparison with cytology 42.2% (p = 0.01), specificity favored cytology 92.9% compared to 73.5% with FISH (p < 0.01). For BC only patients, the same significant finding of increased sensitivity and decreased specificity was identified, but for UTUC alone and combined UTUC and BC, there was no significant difference. Cytology had improved positive predictive value (PPV) over FISH, 76.9% in comparison to 64.6% (p = 0.02). Negative predictive value (NPV) also favored cytology 74.2% versus 64.9% (p = 0.02). When analyzing individual cohorts, cytology had improved PPV for BC alone patients. UTUC showed no difference for PPV and NPV. For both UTUC and BC, NPV was slightly favored for FISH over cytology 93.2% versus 91.2% (p = 0.03). CONCLUSIONS: Voided urine FISH testing does offer a higher detection of urothelial carcinoma for BC compared to voided cytology; however, specificity was worse. FISH does not appear to improve detection of urothelial carcinoma in patients with either UTUC only or both BC and UTUC.

Noninferiority of Hypofractionated vs Conventional Postprostatectomy Radiotherapy for Genitourinary and Gastrointestinal Symptoms: The NRG-GU003 Phase 3 Randomized Clinical Trial.

Importance: No prior trial has compared hypofractionated postprostatectomy radiotherapy (HYPORT) to conventionally fractionated postprostatectomy (COPORT) in patients primarily treated with prostatectomy. Objective: To determine if HYPORT is noninferior to COPORT for patient-reported genitourinary (GU) and gastrointestinal (GI) symptoms at 2 years. Design, Setting, and Participants: In this phase 3 randomized clinical trial, patients with a detectable prostate-specific antigen (PSA; ≥0.1 ng/mL) postprostatectomy with pT2/3pNX/0 disease or an undetectable PSA (<0.1 ng/mL) with either pT3 disease or pT2 disease with a positive surgical margin were recruited from 93 academic, community-based, and tertiary medical sites in the US and Canada. Between June 2017 and July 2018, a total of 296 patients were randomized. Data were analyzed in December 2020, with additional analyses occurring after as needed. Intervention: Patients were randomized to receive 62.5 Gy in 25 fractions (HYPORT) or 66.6 Gy in 37 fractions (COPORT). Main Outcomes and Measures: The coprimary end points were the 2-year change in score from baseline for the bowel and urinary domains of the Expanded Prostate Cancer Composite Index questionnaire. Secondary objectives were to compare between arms freedom from biochemical failure, time to progression, local failure, regional failure, salvage therapy, distant metastasis, prostate cancer-specific survival, overall survival, and adverse events. Results: Of the 296 patients randomized (median [range] age, 65 [44-81] years; 100% male), 144 received HYPORT and 152 received COPORT. At the end of RT, the mean GU change scores among those in the HYPORT and COPORT arms were neither clinically significant nor different in statistical significance and remained so at 6 and 12 months. The mean (SD) GI change scores for HYPORT and COPORT were both clinically significant and different in statistical significance at the end of RT (-15.52 [18.43] and -7.06 [12.78], respectively; P < .001). However, the clinically and statistically significant differences in HYPORT and COPORT mean GI change scores were resolved at 6 and 12 months. The 24-month differences in mean GU and GI change scores for HYPORT were noninferior to COPORT using noninferiority margins of -5 and -6, respectively, rejecting the null hypothesis of inferiority (mean [SD] GU score: HYPORT, -5.01 [15.10] and COPORT, -4.07 [14.67]; P = .005; mean [SD] GI score: HYPORT, -4.17 [10.97] and COPORT, -1.41 [8.32]; P = .02). With a median follow-up for censored patients of 2.1 years, there was no difference between HYPORT vs COPORT for biochemical failure, defined as a PSA of 0.4 ng/mL or higher and rising (2-year rate, 12% vs 8%; P = .28). Conclusions and Relevance: In this randomized clinical trial, HYPORT was associated with greater patient-reported GI toxic effects compared with COPORT at the completion of RT, but both groups recovered to baseline levels within 6 months. At 2 years, HYPORT was noninferior to COPORT in terms of patient-reported GU or GI toxic effects. HYPORT is a new acceptable practice standard for patients receiving postprostatectomy radiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT03274687.

A phase I trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer.

PURPOSE: Up to 50% of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence. Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary. Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use. Nanoparticle albumin-bound paclitaxel (Abraxane®, ABI-007) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy. Thus, we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel. MATERIALS AND METHODS: Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta, T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior standard intravesical regimen failed. Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved. The primary end point was dose limiting toxicity and the secondary end point was response rate. RESULTS: A total of 18 patients were enrolled in the study. One patient demonstrated measurable systemic absorption after 1 infusion. Grade 1 local toxicities were experienced by 10 (56%) patients with dysuria being the most common, and no grade 2, 3 or 4 drug related local toxicities were encountered. Of the 18 patients 5 (28%) had no evidence of disease at posttreatment evaluation. CONCLUSIONS: Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge. A larger phase II study has begun to formally evaluate the activity of this regimen.

Preventing Prostate Biopsy Complications: to Augment or to Swab?

OBJECTIVE: To use data from a large, prospectively- acquired regional collaborative database to compare the risk of infectious complications associated with three American Urologic Association- recommended antibiotic prophylaxis pathways, including culture-directed or augmented antibiotics, following prostate biopsy. METHODS: Data on prostate biopsies and outcomes were collected from the Pennsylvania Urologic Regional Collaborative, a regional quality collaborative working to improve the diagnosis and treatment of prostate cancer. Patients were categorized as receiving one of three prophylaxis pathways: culture-directed, augmented, or provider-discretion. Infectious complications included fever, urinary tract infections or sepsis within one month of biopsy. Odds ratios of infectious complication by pathway were determined, and univariate and multivariate analyses of patient and biopsy characteristics were performed. RESULTS: 11,940 biopsies were included, 120 of which resulted in infectious outcomes. Of the total biopsies, 3246 used "culture-directed", 1446 used "augmented" and 7207 used "provider-discretion" prophylaxis. Compared to provider-discretion, the culture-directed pathway had 84% less chance of any infectious outcome (OR= 0.159, 95% CI = [0.074, 0.344], P < 0.001). There was no difference in infectious complications between augmented and provider-discretion pathways. CONCLUSIONS: The culture-directed pathway for transrectal prostate biopsy resulted in significantly fewer infectious complications compared to other prophylaxis strategies. Tailoring antibiotics addresses antibiotic-resistant bacteria and reduces future risk of resistance. These findings make a strong case for incorporating culture-directed antibiotic prophylaxis into clinical practice guidelines to reduce infection following prostate biopsies.

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

Sex differences in the familial transmission of mood disorders.

BACKGROUND: Mood disorders exhibit familial transmission due to both environmental and genetic risk factors. Mood disorders are more common in women, yet the role of gender in the familial transmission of mood disorders is unclear. This study examines rates of mood disorder transmission to offspring based on the sex of affected parent, sex of offspring and role of clinical factors, such as childhood abuse history, comorbid psychiatric disorders, and traits of aggression and impulsivity. METHODS: Risk of transmission of mood disorder to offspring from females and males was compared in a sample of 272 probands with a major mood disorder using generalized estimating equations (GEE). Demographic and clinical characteristics of all male and female probands were compared. Characteristics that differed in probands were entered into the model to obtain an unbiased test of gender differences in transmission rate. Multivariate GEE models, one for male probands and one for female probands, were used to test for risk factors in transmission of mood disorder. RESULTS: Familial transmission rate of mood disorders from female probands was almost double that of males. There was no difference in transmission to male or female offspring. For male probands, offspring mood disorder was independently associated with earlier age of proband mood disorder onset, greater number of proband years ill, and proband history of childhood abuse. For female probands, offspring mood disorder was associated with higher aggression scores in probands. LIMITATIONS: We did not directly interview offspring and also had limited data on psychopathology in co-parents. This is a cross-sectional study and cannot account for emergence of illness in offspring in the future. CONCLUSIONS: The two-fold higher rate of maternal transmission of mood disorder may reflect differences in regulation of maternal and paternal transmission of mood disorder. Future studies need to determine the relative contribution of genetic and non-genetic factors and identify the factors responsible for higher rates of transmission of mood disorders by females with a mood disorder.

Utilization and timing of blood transfusions following open and robot-assisted radical prostatectomy.

INTRODUCTION AND OBJECTIVES: Radical prostatectomy (RP) is associated with a high risk of intraoperative blood loss and subsequent blood transfusions. The shift in surgical technique from open radical prostatectomy (ORP) to robot-assisted radical prostatectomy (RARP) has resulted in lower operative blood loss, and reduced the need for transfusions. We analyzed the American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) database to compare real-world, contemporary trends in utilization and timing of blood transfusion following ORP and RARP. METHODS: We identified men undergoing both RARP and ORP and then queried for patients who received a blood transfusion in the perioperative period. The outcomes of interest were need and timing of perioperative blood transfusion (PBT), which was categorized into early (postoperative day [POD] ≤1) or late (POD ≥2). Logistic regression analysis was used to identify variables associated with the need and timing for PBT. RESULTS: A total of 16,144 men who underwent RP were identified from 2007 to 2012. The overall PBT rate was 3.1%. Highest rate of transfusions occurred on day of surgery for patients undergoing ORP, and first POD for patients undergoing RARP. On multivariate analysis significant predictors of blood transfusion included history of bleeding disorder (OR: 2.8, p=0.002), preoperative dyspnea (odds ratio [OR]: 1.7, p=0.03), starting hematocrit <42% (OR: 1.9, p<0.001), open approach (OR: 0.09, p<0.001), year of surgery (OR: 0.5, p<0.001), resident involvement (OR: 1.6, p=0.003), and operative time (OR: 4.4, p<0.001). The only predictor of receiving a blood transfusion on POD 2 or later was having the procedure performed through a robot-assisted approach (OR: 3.7, p<0.001). CONCLUSIONS: In this study we found that the rate of perioperative transfusions is lower than previously published. A clear separation in timing of transfusion exists based on the utilized surgical approach. It is prudent that surgeons performing RARP be aware of the low, but present risk of a delayed blood transfusion.

Has the advent of minimally invasive surgery altered the risk profile of patients undergoing prostatectomy?

OBJECTIVES: To determine whether the decreased short-term morbidity associated with minimally invasive surgery (MIS) has resulted in an alteration in the disease-specific risk profile of prostatectomy patients. MIS in many fields has resulted in an expansion in the pool of patients willing to undergo surgery. METHODS: The Columbia Urologic Oncology Database was queried, and 1751 patients undergoing radical prostatectomy between 2000 and 2007 were identified. The cohort was divided into 2 groups: patients who received surgery before or after the initiation of robotic-assisted laparoscopic radical prostatectomy (RALRP) at our institution (from 2003 onward). Age at surgery, Kattan Nomogram (KN) score, prostate-specific antigen (PSA), Gleason score sum, and tumor stage were compared using unpaired t tests with Welch correction and Mann-Whitney tests. RESULTS: A total of 663 patients underwent prostatectomy from 2000 to 2002 ("pre-MIS era"), and 1088 patients had surgery in 2003 or later ("MIS era"), of which 519 and 569 underwent RALRP and open prostatectomy, respectively. There was no significant difference between the 2 eras regarding age, Kattan Nomogram score, or tumor stage. However, there was a significant difference in preoperative PSA (P = .01) and Gleason sum (P = .0002). In a comparison of the pre-MIS era with RALRP patients, only PSA differed significantly (P = .0002). CONCLUSIONS: The advent of MIS for prostate cancer did not significantly alter the characteristics of patients undergoing prostatectomy at our institution. Although advancements in surgical techniques may improve clinical outcomes, this study does not suggest a consequential effect on the risk stratification of patients choosing surgery for prostate cancer.

Wolframin gene H611R polymorphism: no direct association with suicidal behavior but possible link to mood disorders.

Wolframin gene polymorphisms, including the H611R polymorphism, are reportedly associated with mood disorders and psychiatric hospitalization, but there is disagreement about the association of this specific variant with suicidality and impulsive traits. This study tested the association of the H611R polymorphism with mood disorders, suicidal behavior, and aggressive-impulsive traits. Two hundred and one subjects with mood disorders and 113 healthy volunteers were genotyped for the H611R polymorphism and underwent structured interviews for diagnosis and clinical ratings. All were Caucasians. The H611R polymorphism was associated with mood disorders but not suicidal behavior, aggressive/impulsive traits or suicidality in first-degree relatives. The HR heterozygote genotype was more frequent in mood disorder (chi(2)=7.505; df=2; p=.023). If this finding will be replicated, the H611R polymorphism may be a possible marker for mood disorders in a psychiatric population, and not just in relatives of Wolfram syndrome probands.

Significant change in predicted risk of biochemical recurrence after radical prostatectomy more common in black than in white men.

OBJECTIVES: To examine by race how frequently the data after radical prostatectomy translates into a substantial change in prognosis. Many nomograms exist to predict the survival outcomes using the pretreatment clinical parameters and post-treatment pathologic parameters. Race might be an important factor affecting their predictive ability. METHODS: Kattan nomograms were used to calculate the pretreatment and post-radical prostatectomy 5-year progression-free probability for each patient. The difference between the nomogram scores was used to divide the patients into 3 groups. A decrease in probability of >or=15 percentage points was classified as a significant increase in the probability of recurrence, an increase of >or=15 points was classified as a significant decrease in the probability of recurrence, and an absolute change of <15 points was considered no significant change. RESULTS: The data from 1709 (132 black and 1577 white) men were analyzed. Among the black men, 26.5% had an increase in the probability of recurrence, 57.6% had no change, and 15.9% had a decrease in the probability of recurrence. Among the white men, 13.8% had an increase in the probability of recurrence, 64.5% had no change, and 21.7% had a decrease in the probability of recurrence. Black men were twice as likely to have a significant increase in the probability of recurrence postoperatively compared with white men after adjusting for preoperative prostate-specific antigen level, clinical stage, and biopsy Gleason sum (odds ratio 2.0, 95% confidence interval 1.3-3.1, P = .002). CONCLUSIONS: These data could assist clinicians when counseling black men regarding their treatment options according to their preoperative risk profile.