Utilization of standardized preimplantation genetic testing for aneuploidy (PGT-A) via artificial intelligence (AI) technology is correlated with improved pregnancy outcomes in single thawed euploid embryo transfer (STEET) cycles.

PURPOSE: To investigate the role of standardized preimplantation genetic testing for aneuploidy (PGT-A) using artificial intelligence (AI) in patients undergoing single thawed euploid embryo transfer (STEET) cycles. METHODS: Retrospective cohort study at a single, large university-based fertility center with patients undergoing in vitro fertilization (IVF) utilizing PGT-A from February 2015 to April 2020. Controls included embryos tested using subjective NGS. The first experimental group included embryos analyzed by NGS utilizing AI and machine learning (PGTaiSM Technology Platform, AI 1.0). The second group included embryos analyzed by AI 1.0 and SNP analysis (PGTai2.0, AI 2.0). Primary outcomes included rates of euploidy, aneuploidy and simple mosaicism. Secondary outcomes included rates of implantation (IR), clinical pregnancy (CPR), biochemical pregnancy (BPR), spontaneous abortion (SABR) and ongoing pregnancy and/or live birth (OP/LBR). RESULTS: A total of 24,908 embryos were analyzed, and classification rates using AI platforms were compared to subjective NGS. Overall, those tested via AI 1.0 showed a significantly increased euploidy rate (36.6% vs. 28.9%), decreased simple mosaicism rate (11.3% vs. 14.0%) and decreased aneuploidy rate (52.1% vs. 57.0%). Overall, those tested via AI 2.0 showed a significantly increased euploidy rate (35.0% vs. 28.9%) and decreased simple mosaicism rate (10.1% vs. 14.0%). Aneuploidy rate was insignificantly decreased when comparing AI 2.0 to NGS (54.8% vs. 57.0%). A total of 1,174 euploid embryos were transferred. The OP/LBR was significantly higher in the AI 2.0 group (70.3% vs. 61.7%). The BPR was significantly lower in the AI 2.0 group (4.6% vs. 11.8%). CONCLUSION: Standardized PGT-A via AI significantly increases euploidy classification rates and OP/LBR, and decreases BPR when compared to standard NGS.

What proportion of embryos should be considered for transfer following a mosaic diagnosis? A study of 115 clinics from a central diagnostic laboratory.

PURPOSE: The aim of this study is to identify what proportion of mosaic embryo diagnoses should be considered for transfer, and thereby assess the impact on patient cases. METHODS: We categorised mosaic embryos into 3 groups; high, medium and low priority for transfer based on the percentage of biopsy sample being aneuploid and the chromosomes involved. The categories were applied to those patients that had no euploid embryo diagnoses but 1 or more mosaic embryos identified as mosaic available after PGT-A. RESULTS: In total, 6614 PGT-A cases from 115 clinics and a single diagnostic laboratory were reviewed. Further, 1384 [20.9%] cases only had aneuploid embryos, 4538 [68.6%] cases had one or more euploid embryos and 692 [10.5%] cases had no euploid and one or more mosaic embryo. The mosaic embryos in the no euploid, one or more mosaic group, when reviewed using priorities, resulted in: 111 [1.7%] of cases having at least one high priority mosaic available. 184 [2.8%] of cases having no high priority but at least one medium priority mosaic available. 397 [6.0%] of cases only having low priority mosaic embryos available. CONCLUSION: Based on this data, embryos identified as mosaic will only be considered for transfer in the first instance for around 4.5% (when taking high and medium priority and excluding low priority cases) of all PGT-A cases.

Biodynamic prediction of neoadjuvant chemotherapy response: Results from a prospective multicenter study of predictive accuracy among muscle-invasive bladder cancer patients.

BACKGROUND: Biodynamic signatures (temporal patterns of microscopic motion within a 3-dimensional tumor explant) offer phenomic biomarkers that are highly predictive for therapeutic response. OBJECTIVE: By utilizing motility contrast tomography, which provides a simple, fast assessment of motion patterns in living tissue, we evaluated the predictive accuracy of a biodynamic drug response classifier in muscle-invasive bladder cancer (MIBC) patients undergoing neoadjuvant chemotherapy (NAC). DESIGN, SETTING, AND PARTICIPANTS: One hundred five consecutive bladder cancer patients suspected of having MIBC were screened in a multi-institutional prospective observational study (NCT03739177) from July 2018 to June 2020, of whom, 30 completed NAC and radical cystectomy. INTERVENTION(S): Biodynamic signatures from treatment-naïve fresh bladder tumor specimens obtained after transurethral resection were measured in living tumor fragments challenged by standard-of-care cytotoxins. Patients received gemcitabine and cisplatin or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin per institutional guidelines and were followed through radical cystectomy. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: A 4-level classifier was developed to predict pathologic complete response (pCR) vs. incomplete response utilizing a one-left-out cross-validation protocol to minimize over-fitting. Area under the curve evaluated predictive utility. RESULTS: Thirty percent (9 of 30) achieved pCR. Utilizing the 4-level classifier, biodynamically "favored" (scoring ≥ 3) and "strongly favored" (scoring 4) regimens accurately predicted pCR at rates of 66.7% (4 of 6 patients) and 100% (4 of 4 patients), respectively. Biodynamically "favored" scores predicted pCR with 88% sensitivity and 95% negative predictive value, P < 0.0001. Only 5.0% (1 of 20 patients) achieved pCR from regimens scoring 1 or 2, indicating poor to no response from NAC. Area under the receiver operating curve was 96% (95% Confidence Interval: 79%-99%, P < 0.0001). Future direction involves validating this model prospectively. PRINCIPAL CONCLUSIONS: Biodynamic scoring accurately predicts response in MIBC patients receiving NAC and holds promise to substantially improve the scope of appropriate management intervention.

Implications of micropapillary urothelial carcinoma variant on prognosis following radical cystectomy: A multi-institutional investigation.

PURPOSE: To determine the association of micropapillary urothelial carcinoma (MUC) variant histology with bladder cancer outcomes after radical cystectomy. MATERIALS AND METHODS: Information on MUC patients treated with radical cystectomy was obtained from five academic centers. Data on 1,497 patients were assembled in a relational database. Tumor histology was categorized as urothelial carcinoma without any histological variants (UC; n = 1,346) or MUC (n = 151). Univariable and multivariable models were used to analyze associations with recurrence-free (RFS) and overall (OS) survival. RESULTS: Median follow-up was 10.0 and 7.8 years for the UC and MUC groups, respectively. No significant differences were noted between UC and MUC groups with regard to age, gender, clinical disease stage, and administration of neoadjuvant and adjuvant chemotherapy (all, P ≥ 0.10). When compared with UC, presence of MUC was associated with higher pathologic stage (organ-confined, 60% vs. 27%; extravesical, 18% vs. 23%; node-positive, 22% vs. 50%; P < 0.01) and lymphovascular invasion (29% vs. 58%; P < 0.01) at cystectomy. In comparison with UC, MUC patients had poorer 5-year RFS (70% vs. 44%; P < 0.01) and OS (61% vs. 38%; P < 0.01). However, on multivariable analysis, tumor histology was not independently associated with the risks of recurrence (P = 0.27) or mortality (P = 0.12). CONCLUSIONS: This multi-institutional analysis demonstrated that the presence of MUC was associated with locally advanced disease at radical cystectomy. However, clinical outcomes were comparable to those with pure UC after controlling for standard clinicopathologic predictors.

Detailed investigation into the cytogenetic constitution and pregnancy outcome of replacing mosaic blastocysts detected with the use of high-resolution next-generation sequencing.

OBJECTIVE: To determine the pregnancy outcome potential of mosaic embryos, detected by means of preimplantation genetic screening (PGS) with the use of next-generation sequencing (NGS). DESIGN: Retrospective study. SETTING: Genetics laboratories. PATIENT(S): PGS cycles during which either mosaic or euploid embryos were replaced. INTERVENTION(S): Blastocysts were biopsied and processed with the use of NGS, followed by frozen embryo transfer. Trophectoderm (TE) biopsies were classified as mosaic if they had 20%-80% abnormal cells. MAIN OUTCOME MEASURE(S): Implantation, miscarriage rates, and ongoing implantation rates (OIRs) were compared between euploid and types of mosaic blastocysts. RESULT(S): Complex mosaic embryos had a significantly lower OIR (10%) than aneuploidy mosaic (50%), double aneuploidy mosaic (45%), and segmental mosaic (41%). There was a tendency for mosaics with 40%-80% abnormal cells to have a lower OIR than those with <40% (22% vs. 56%). However, few embryos (n = 34) with a mosaic error in 40%-80% of the TE sample were replaced. There was no difference between monosomic and trisomic mosaics or between entire chromosome mosaicism or segmental mosaicism. Implantation rates were significantly higher (70% vs. 53%), miscarriage rates lower (10% vs. 25%), and OIRs higher (63% vs. 40%) after euploid embryo transfer than after mosaic embryo transfer. CONCLUSION(S): Forty-one percent of mosaic embryos produced an ongoing implantation. Complex mosaic blastocysts had a lower OIR than other mosaics. Mosaic monosomies performed as well as mosaic trisomies and mosaic segmental aneuploidies. The results suggest that embryos with >40% abnormal cells and those with multiple mosaic abnormalities (chaotic mosaics) are likely to have lower OIRs and should be given low transfer priority.

Single-Incision Thoracoabdominal Approach With Normothermic Cardiopulmonary Bypass for the Management of Urologic Tumors Invading the Inferior Vena Cava.

Urologic tumors invading the inferior vena cava can be a difficult management problem. They are traditionally dealt with utilizing hypothermic circulatory arrest through central cannulation for cardiopulmonary bypass performed through a median sternotomy in addition to the large abdominal incision for the kidney tumor. We describe a single incision approach utilizing normothermic cardiopulmonary bypass to address this technical challenge.

The effect of length of ureteral resection on benign ureterointestinal stricture rate in ileal conduit or ileal neobladder urinary diversion following radical cystectomy.

OBJECTIVES: To assess the effect of the length of the ureter resected and other clinical variables on ureterointestinal anastomotic (UIA) stricture rate following radical cystectomy and ileal segment urinary diversion. METHODS AND MATERIALS: We identified 519 consecutive patients who underwent cystectomy and ileal conduit or ileal orthotopic neobladder diversion from January 2007 to August 2012. The length of the ureter resected was defined as the length of the ureter in the cystectomy specimen plus the length of the distal ureter submitted for pathologic analysis. The primary end point was the risk of UIA stricture formation, assessed by Cox proportional hazards analysis. RESULTS: A total of 463 patients met the inclusion criteria with complete data. Median follow-up was 459 days (interquartile range [IQR]: 211-927). Median time to stricture formation was 235 (IQR: 134-352) and 232 days (IQR: 132-351) on the right and the left ureter, respectively. Overall stricture rate per ureter was 5.9% on the right vs. 10.0% on the left (P = 0.03). There was no difference in demographic, operative, or perioperative variables between patients with and without UIA strictures. On multivariate analysis adjusted for age, sex, anastomosis technique (running vs. interrupted), and length of ureter resected, only a Clavien complication≥III (hazard ratio = 2.11, 1.01-4.40) and urine leak (hazard ratio = 3.37, 1.08-10.46) significantly predicted for left- and right-sided stricture formation, respectively. The length of the ureter resected did not predict UIA stricture formation on either side. CONCLUSIONS: The etiology of benign UIA strictures following ileal urinary diversion is likely multifactorial. Our data suggest that a complicated postoperative course and urine leak are risk factors for UIA stricture formation. The length of the distal ureter resected did not significantly affect stricture rate.

Prospective health-related quality of life analysis for patients undergoing radical cystectomy and urinary diversion.

OBJECTIVE: To better define health-related quality of life (HRQOL) for patients undergoing radical cystectomy (RC) and urinary diversion. MATERIALS AND METHODS: Patients undergoing RC and urinary diversion for urothelial carcinoma by 1 of 2 surgeons (G.D.S. or N.D.S.) had a HRQOL assessment at baseline and at follow-up using the validated, bladder cancer-specific Functional Assessment of Cancer Therapy-Vanderbilt Cystectomy Index questionnaire. The primary outcome was change in HRQOL between baseline and follow-up. RESULTS: From September 15, 2011, to July 23, 2012, 74 of 103 eligible patients were enrolled, and all but 1 completed the baseline Functional Assessment of Cancer Therapy-Vanderbilt Cystectomy Index leaving 73 patients in the study. Median age was 68 years (interquartile range, 60-74 years), 58 (78%) were Caucasian, 53 (73%) were ≥ cT2, 45 (62%) underwent incontinent diversion, and the mean age-adjusted Charlson Comorbidity Index score was 2.4 ± 1.8, with no significant differences among the 73 participants and 30 nonparticipants. The median time from surgery to response was 175 days (interquartile range, 102-232 days), and the response rate was 67%, with 9 deaths during follow-up. Baseline HRQOL scores did not significantly differ between respondents and nonrespondents or between those living vs deceased. Overall, RC-specific, physical, social, and functional HRQOL scores did not differ from baseline to follow-up, whereas emotional HRQOL scores were significantly improved (15.7 ± 5.8 vs 18.1 ± 3.9, P = .03). Overall or domain-specific HRQOL measures did not differ significantly between patients undergoing incontinent (n = 27) vs continent (n = 16) diversions. CONCLUSION: Overall, HRQOL scores did not statistically differ from baseline to the median 6-month follow-up for patients undergoing RC and urinary diversion for urothelial carcinoma. Patients undergoing continent vs incontinent urinary diversions had similar overall HRQOL scores at follow-up.

The epidermal growth factor receptor critically regulates endometrial function during early pregnancy.

Infertility and adverse gynecological outcomes such as preeclampsia and miscarriage represent significant female reproductive health concerns. The spatiotemporal expression of growth factors indicates that they play an important role in pregnancy. The goal of this study is to define the role of the ERBB family of growth factor receptors in endometrial function. Using conditional ablation in mice and siRNA in primary human endometrial stromal cells, we identified the epidermal growth factor receptor (Egfr) to be critical for endometrial function during early pregnancy. While ablation of Her2 or Erbb3 led to only a modest reduction in litter size, mice lacking Egfr expression are severely subfertile. Pregnancy demise occurred shortly after blastocyst implantation due to defects in decidualization including decreased proliferation, cell survival, differentiation and target gene expression. To place Egfr in a genetic regulatory hierarchy, transcriptome analyses was used to compare the gene signatures from mice with conditional ablation of Egfr, wingless-related MMTV integration site 4 (Wnt4) or boneless morphogenic protein 2 (Bmp2); revealing that not only are Bmp2 and Wnt4 key downstream effectors of Egfr, but they also regulate distinct physiological functions. In primary human endometrial stromal cells, marker gene expression, a novel high content image-based approach and phosphokinase array analysis were used to demonstrate that EGFR is a critical regulator of human decidualization. Furthermore, inhibition of EGFR signaling intermediaries WNK1 and AKT1S1, members identified in the kinase array and previously unreported to play a role in the endometrium, also attenuate decidualization. These results demonstrate that EGFR plays an integral role in establishing the cellular context necessary for successful pregnancy via the activation of intricate signaling and transcriptional networks, thereby providing valuable insight into potential therapeutic targets.

Sex disparities in diagnosis of bladder cancer after initial presentation with hematuria: a nationwide claims-based investigation.

BACKGROUND: Women have disproportionately higher mortality rates relative to incidence for bladder cancer. Multiple etiologies have been proposed, including delayed diagnosis and treatment. Guidelines recommend ruling out malignancy in men and women presenting with hematuria. This study sought to determine the difference in timing from presentation with hematuria to diagnosis of bladder cancer in women versus men. METHODS: This is a retrospective population-based study examining the timing from presentation with hematuria to diagnosis of bladder cancer, based on data from the MarketScan databases, which include enrollees of more than 100 health insurance plans of approximately 40 large US employers from 2004 through 2010. All study patients presented with hematuria and were subsequently diagnosed with bladder cancer. The primary outcome measure was number of days between initial presentation with hematuria and diagnosis of bladder cancer by sex. RESULTS: A total of 5416 men and 2233 women met inclusion criteria. Mean days from initial hematuria claim to bladder cancer claim was significantly longer in women (85.4 versus 73.6 days, P < .001), and the proportion of women with >6 month delay in bladder cancer diagnosis was significantly higher (17.3% versus 14.1%, P < .001). Women were more likely to be diagnosed with urinary tract infection (odds ratio = 2.32, 95% confidence interval = 2.07-2.59) and less likely to undergo abdominal or pelvic imaging (odds ratio = 0.80, 95% confidence interval = 0.71-0.89). CONCLUSIONS: Both men and women experience significant delays between presentation with hematuria and diagnosis of bladder cancer, with longer delays for women. This may be partly responsible for the sex-based discrepancy in outcomes associated with bladder cancer.

Early removal of urethral catheter with suprapubic tube drainage versus urethral catheter drainage alone after robot-assisted laparoscopic radical prostatectomy.

PURPOSE: Retrospective single institution data suggest that postoperative pain after robot-assisted laparoscopic radical prostatectomy is decreased by early removal of the urethral catheter with suprapubic tube drainage. In a randomized patient population we determined whether suprapubic tube drainage with early urethral catheter removal would improve postoperative pain compared with urethral catheter drainage alone. MATERIALS AND METHODS: Men with a body mass index of less than 40 kg/m(2) who had newly diagnosed prostate cancer and elected robot-assisted laparoscopic radical prostatectomy were included in analysis. Block randomization by surgeon was used and randomization assignment was done after completing the urethrovesical anastomosis. In patients assigned to suprapubic tube drainage the urethral catheter was removed on postoperative day 1 and all catheters were removed on postoperative day 7. Visual analog pain scale and satisfaction questionnaires were administered on postoperative days 0, 1 and 7. RESULTS: A total of 29 patients were randomized to the urethral catheter vs 29 to the suprapubic tube plus early urethral catheter removal at the time of interim futility analysis. Mean visual analog pain scale scores did not differ between the groups at any time point and a similar percent of patients cited the catheter as the greatest bother with nonsignificant differences in treatment related satisfaction. Complications during postoperative week 1 did not vary between the groups. Based on interim results the trial was terminated due to lack of effect. CONCLUSIONS: Patients randomized to suprapubic tube vs urethral catheter drainage for the week after prostatectomy had similar pain, catheter related bother and treatment related satisfaction in the perioperative period. We no longer routinely offer suprapubic tube drainage with early urethral catheter removal at our institution.

Cystectomy and urinary diversion as management of treatment-refractory benign disease: the impact of preoperative urological conditions on perioperative outcomes.

OBJECTIVES: To investigate perioperative outcomes associated with cystectomy and urinary diversion for treatment-refractory benign urological disease. METHODS: A cohort of patients who underwent cystectomy for infection, fistula, bleeding, incontinence, neurogenic bladder or pain between January 2004 and June 2012 was established. Data included baseline demographics, indications for cystectomy and prior treatments, and complications at 30 and 90 days. Primary outcome measures were 30-day and 30 to 90-day complications. RESULTS: The study group comprised eight males and 18 females. The mean age was 57.8 years (95% CI 50.8-64.7). A total of 19 patients (73%) had resolution of their underlying urological pathology at 90 days. A total of 19 patients (73%) experienced a complication in the first 30 days, of which nine (47%) were Clavien grade III or higher. The most common 30-day complications were urinary tract infection (n = 6, 23%) and wound infection (n = 6, 23%). A total of 44% (4/9) of patients with neurogenic bladder experienced a complication within the first 30 days of cystectomy compared with 100% (8/8) of patients with radiation-induced fistula (P = 0.03) and 78% (7/9) of non-neurogenic, non-radiation-induced fistula patients (P = 0.34). CONCLUSIONS: Cystectomy with urinary diversion for benign disease might be successful, but is associated with a high rate of perioperative complications. Those with radiation-induced fistula are more likely to experience complications, whereas those with neurogenic bladder carry a lower risk. Patients should be counseled appropriately regarding expected postoperative outcomes.

Activin-like kinase 2 functions in peri-implantation uterine signaling in mice and humans.

Implantation of a blastocyst in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the uterus of pregnant mice, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing mice carrying a conditional ablation of Alk2 in the uterus (Alk2 cKO mice). In the absence of ALK2, embryos demonstrate delayed invasion into the uterine epithelium and stroma, and upon implantation, stromal cells fail to undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein ß (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of CEBPB in the stroma to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (hESC) and discovered that ablation of ALK2 alters hESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing hESC confirmed that BMP signaling proteins, SMAD1/5, directly regulate expression of CEBPB by binding a distinct regulatory sequence in the 3' UTR of this gene; CEBPB, in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate peri-implantation in rodents and primates and, for the first time, uncovers a linear pathway of BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization.

COUP-TFII regulates human endometrial stromal genes involved in inflammation.

Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII; NR2F2) is an orphan nuclear receptor involved in cell-fate specification, organogenesis, angiogenesis, and metabolism. Ablation of COUP-TFII in the mouse uterus causes infertility due to defects in embryo attachment and impaired uterine stromal cell decidualization. Although the function of COUP-TFII in uterine decidualization has been described in mice, its role in the human uterus remains unknown. We observed that, as in mice, COUP-TFII is robustly expressed in the endometrial stroma of healthy women, and its expression is reduced in the ectopic lesions of women with endometriosis. To interrogate the role of COUP-TFII in human endometrial function, we used a small interfering RNA-mediated loss of function approach in primary human endometrial stromal cells. Attenuation of COUP-TFII expression did not completely block decidualization; rather it had a selective effect on gene expression. To better elucidate the role of COUP-TFII in endometrial stroma cell biology, the COUP-TFII transcriptome was defined by pairing microarray comparison with chromatin immunoprecipitation followed by deep sequencing. Gene ontology analysis demonstrates that COUP-TFII regulates a subset of genes in endometrial stroma cell decidualization such as those involved in cell adhesion, angiogenesis, and inflammation. Importantly this analysis shows that COUP-TFII plays a role in controlling the expression of inflammatory cytokines. The determination that COUP-TFII plays a role in inflammation may add insight into the role of COUP-TFII in embryo implantation and in endometrial diseases such as endometriosis.

Liver receptor homolog-1 is essential for pregnancy.

Successful pregnancy requires coordination of an array of signals and factors from multiple tissues. One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis. It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents and humans. Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation. Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation. To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency. Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death. Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization. These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta. It therefore has multiple, indispensible roles in establishing and sustaining pregnancy.

Empiric antibiotics for an elevated prostate-specific antigen (PSA) level: a randomised, prospective, controlled multi-institutional trial.

OBJECTIVE: To determine the impact of empiric antibiotics on men with an elevated prostate-specific antigen (PSA) level. SUBJECTS/PATIENTS AND METHODS: Men of any age with a PSA level of >2.5 ng/mL and normal digital rectal examination undergoing their first prostate biopsy were recruited from five medical centres. Patients with previous biopsy, prostate cancer, urinary tract infection (UTI) or prostatitis within the prior year, antibiotic use within 1 month, 5α-reductase inhibitor use, allergy to fluoroquinolones or clinical suspicion of UTI were excluded. Men were randomised to 2 weeks of ciprofloxacin or no antibiotic. A PSA measurement was obtained 21-45 days after randomisation immediately before prostate biopsy. The primary endpoint was the change in PSA level between baseline and immediately before biopsy. RESULTS: Complete data were available for 77 men with a mean (interquartile range) age of 60.6 (53-66) years. In the control group of men not receiving antibiotic (39 men), the mean baseline and pre-biopsy PSA levels were 6.5 and 6.9 ng/mL, respectively (P = 0.8). In men receiving ciprofloxacin (38 men), the mean baseline PSA level was 7.6 ng/mL and after 2 weeks of ciprofloxacin was 8.5 ng/mL (P = 0.7). Compared with controls not receiving antibiotic, use of ciprofloxacin was not associated with a statistically significant change in PSA level (P = 0.33). Prostate cancer was detected in 36 (47%) men, 23 (59%) in the control group and 13 (34%) in the antibiotic group (P = 0.04). Detection rates were not significantly associated with the change in PSA level between baseline and biopsy. The primary limitation of the study is early stoppage due to an interim futility analysis and poor accrual. CONCLUSION: Despite not meeting the target accrual goal, empiric use of antibiotics for asymptomatic men with an elevated PSA level does not appear to be of clinical benefit.

Optimal risk-adapted surveillance strategies for NMIBC, including upper tract imaging.

Non-muscle invasive bladder cancer (NMIBC) represents approximately 70% of all incident cases of bladder cancer. The financial burden of NMIBC continues to increase, underscoring the importance of efficient, evidence-based management of this disease. Consensus guidelines differ on risk definition and in management recommendations. This article reviews the incidence and financial impact of NMIBC and details the recommendations for diagnosis, treatment, and surveillance made by the American Urological Association, International Consultation on Bladder Cancer-European Association of Urology, and National Comprehensive Cancer Network. Established and developing adjunctive laboratory and imaging tests directed at diagnosis and management of NMIBC are also discussed.

The impact of running versus interrupted anastomosis on ureterointestinal stricture rate after radical cystectomy.

PURPOSE: Benign ureterointestinal anastomotic stricture is not uncommon after radical cystectomy and urinary diversion. We studied the impact of the running vs the interrupted technique on the ureterointestinal anastomotic stricture rate. MATERIALS AND METHODS: From July 2007 to December 2008 interrupted end-to-side anastomoses were created and from January 2009 to July 2010 running anastomoses were created. The primary study end point was time to ureterointestinal anastomotic stricture. RESULTS: Of 266 consecutive patients 258 were alive 30 days after radical cystectomy, including 149 and 109 with an interrupted and a running anastomosis, respectively. The groups did not differ in age, gender, body mass index, age adjusted Charlson comorbidity index, receipt of chemotherapy or radiation, blood loss, operative time, diversion type or postoperative pathological findings. The stricture rate per ureter was 8.5% (25 of 293) and 12.7% (27 of 213) in the interrupted and running groups, respectively (p = 0.14). Univariate analysis suggested that postoperative urinary tract infection (HR 2.1, 95% CI 1.1-4.1, p = 0.04) and Clavien grade 3 or greater complications (HR 2.6, 95% CI 1.4-4.9, p <0.01) were associated with ureterointestinal anastomotic stricture. On multivariate analysis postoperative urinary tract infection (HR 2.4, 95% CI 1.2-5.1, p = 0.02) and running technique (HR 1.9, 95% CI 1.0-3.7, p = 0.05) were associated with ureterointestinal anastomotic stricture. Median time to stricture and followup was 289 (IQR 120-352) and 351 days (IQR 132-719) in the running cohort vs 213 (IQR 123-417) and 497 days (IQR 174-1,289) in the interrupted cohort, respectively. Of the 52 strictures 33 (63%) developed within 1 year. Kaplan-Meier analysis controlling for differential followup showed a trend toward higher freedom from stricture for the interrupted ureterointestinal anastomosis (p = 0.06). CONCLUSIONS: A running anastomosis and postoperative urinary tract infection may be associated with ureterointestinal anastomotic stricture. Larger series with multiple surgeons are needed to confirm these findings.