Tumor protein expression of the DNA repair gene BRCA1 and lethal prostate cancer.

DNA repair genes are commonly altered in metastatic prostate cancer, but BRCA1 mutations are rare. Preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. We undertook a prospective study among men with prostate cancer in the Health Professionals Follow-up Study and evaluated BRCA1 via immunohistochemical staining on tissue microarrays. BRCA1 was expressed in 60 of 589 tumors. Prevalence of BRCA1 positivity was 43% in the 14 men with metastases at diagnosis compared with 9% in non-metastatic tumors [difference, 33 percentage points; 95% confidence interval (CI), 7-59]. BRCA1-positive tumors had 2.16-fold higher Ki-67 proliferative indices (95% CI, 1.18-3.95), higher tumor aneuploidy as predicted from whole-transcriptome profiling, and higher Gleason scores. Among the 575 patients with non-metastatic disease at diagnosis, we evaluated the association between BRCA1 expression and development of lethal disease (metastasis or cancer-specific death, 69 events) during long-term follow-up (median, 18.3 years). A potential weak association of BRCA1 positivity with lethal disease (hazard ratio, 1.61; 95% CI, 0.82-3.15) was attenuated when adjusting for age, Gleason score and clinical stage (hazard ratio, 1.11; 95% CI, 0.54-2.29). In summary, BRCA1 protein expression is a feature of more proliferative and more aneuploid prostate tumors and is more common in metastatic disease. While not well suited as a prognostic biomarker in primary prostate cancer, BRCA1 protein expression may be most relevant in advanced disease.

Patient-reported pain, discomfort, and anxiety during magnetic resonance imaging-targeted prostate biopsy.

INTRODUCTION: The addition of targeted prostate biopsy to systemic biopsy impacts patient experience. We examined patient-reported pain, discomfort, anxiety, and tolerability among men undergoing magnetic resonance imaging (MRI)-targeted prostate biopsy in addition to transrectal ultrasound-guided systematic biopsy compared to those undergoing systematic biopsy alone. METHODS: All patients underwent transrectal systematic 14-core biopsies. Patients with regions of interest on MRI underwent additional targeted biopsies. All patients received equivalent periprostatic nerve block. Four single-item, standard, 11-point numerical rating scales evaluating pain, discomfort, anxiety, and tolerability were completed immediately after biopsy. Differences in means were compared using t-tests. Correlation between rated domains was tested using Spearman's correlation coefficient. RESULTS: Of 273 consecutive patients, 195 (71%) underwent targeted biopsy and 188 (69%) had undergone prior biopsy. In all men, the median score for pain and tolerability was 3, while the median score for discomfort and anxiety was 4. Pain was rated at 7 or above by 15% of patients. Moderate correlation between pain, discomfort, anxiety, and tolerability of repeat biopsy was observed (Spearman's ρ between 0.48 and 0.76). Compared to patients undergoing systematic biopsy alone, men who received both targeted and systematic biopsies reported higher anxiety scores (difference 1.2; 95% confidence interval [CI] 0.4-2.0; p=0.004) and discomfort (difference 1.0; 95% CI 0.3-1.7; p<0.001). CONCLUSIONS: Patients undergoing targeted and systematic biopsies report more discomfort and anxiety than patients undergoing systematic biopsies alone. Absolute differences are small, and patients are willing to undergo repeat biopsy if advised. Interventions to reduce biopsy-related anxiety are needed.

The prognostic significance of nodal disease burden in patients with lymph node metastases from renal cell carcinoma.

OBJECTIVES: To assess the relationship between nodal disease burden and overall survival (OS) among patients with lymph node (LN) metastases from renal cell carcinoma (RCC) METHODS: The National Cancer Data Base was used to identify 2,975 patients with RCC who were treated with radical nephrectomy and were found to have regional LN metastases. Associations between the number of positive and negative LN removed and OS were assessed using Cox proportional hazards regression. The median follow-up time among survivors was 3.6years. RESULTS: The median number of positive LN was 1 (interquartile range 1-3). A higher number of positive LN was associated with higher all-cause mortality on multivariable analysis (HR 1.06 per 1 positive LN, 95% CI 1.04, 1.07, P < 0.001). Conversely, higher negative LN counts were associated with better OS (HR 0.97 per 1 negative LN, 95% CI 0.96, 0.99, P < 0.001). The adjusted probability of a patient with 1 LN removed that was positive surviving at least 2 years was 56%, a figure that increased to 64% when 1 out of 10 LN removed was positive and decreased to 38% when 10 out of 10 LN removed were positive. CONCLUSIONS: Ours is the first study to show that differences in nodal disease burden translate into clinically significant differences in survival among patients with LN metastases from RCC.

The contemporary role of lymph node dissection in the management of renal cell carcinoma.

The appropriate role of lymph node dissection (LND) in the management of patients with renal cell carcinoma (RCC) is still a matter of debate. There is ample evidence that LND is the most accurate modality for staging the regional lymph nodes (LNs), which may harbor metastatic disease in greater than one-third of patients with high-risk RCC. The presence of LN metastases is an independent negative prognostic factor in this disease and accurate determination of LN status not only helps with patient counselling regarding prognosis and tailoring of postoperative surveillance schedules, but it also identifies patients at high risk of systemic disease recurrence who may qualify for clinical trials of adjuvant systemic therapies. Meanwhile, the therapeutic value of LND has been brought into question by a randomized trial (European Organisation for Research and Treatment of Cancer; EORTC 30881) that showed no difference in progression-free or overall survival between patients who were treated with radical nephrectomy (RN) and LND and those treated with RN alone. Given that most patients enrolled in this trial had small renal masses and therefore were at low risk for LN metastases, the question of whether patients with high-risk tumors derive a therapeutic benefit from a standardized, extended LND remains unanswered.

Thromboembolism in Patients with Bladder Cancer: Incidence, Risk Factors and Prevention.

Patients with bladder cancer are at high risk of developing both venous and arterial thromboembolic events. Factors that contribute to this phenomenon include the hypercoagulable state induced by the malignancy itself, medical comorbidities that are common in this predominantly elderly patient population as well as treatments such as prolonged pelvic surgery and cisplatin-based chemotherapy. While formal guidelines address prevention of venous thromboembolism in patients undergoing radical cystectomy, consensus regarding the role of pharmacologic prophylaxis in patients with bladder cancer being treated with chemotherapy, either with neoadjuvant or adjuvant intent in conjunction with radical cystectomy, as part of bladder preservation protocols or for metastatic disease, has proved elusive. The present narrative review was undertaken to define the incidence of and identify risk factors for thromboembolism among patients with bladder cancer, as well as to assess the efficacy of pharmacologic prophylaxis in reducing the risk of thromboembolism in this patient population.

Contemporary Patterns of Care and Outcomes of Men Found to Have Lymph Node Metastases at the Time of Radical Prostatectomy.

PURPOSE: A thorough understanding of the natural history and consensus regarding the optimal management of pathological lymph node positive (pN1) prostate cancer are lacking. Our objective was to describe patterns of care and outcomes of a contemporary cohort of men with pN1 prostate cancer. MATERIALS AND METHODS: We used the National Cancer Database to identify 7,791 men who were found to have lymph node metastases at radical prostatectomy. Multinomial logistic regression and Cox proportional hazards regression were used to identify patient, tumor and facility characteristics associated with the choice of management strategy after radical prostatectomy and overall survival, respectively. RESULTS: Initial post-prostatectomy management was observation in 63% of the men, androgen deprivation therapy alone in 20%, radiation therapy alone in 5%, and androgen deprivation therapy and radiation therapy in 13%. Younger age, lower comorbidity burden, higher grade and stage, and positive surgical margins were associated with a higher likelihood of receiving combination therapy. Grade group 4-5 disease, pT3b-T4 disease, positive surgical margins and a higher number of positive lymph nodes were independent predictors of worse overall survival. The adjusted 10-year overall survival probability decreased from 84% to 32% with the presence of an increasing number of adverse prognostic factors. Treatment with combined androgen deprivation therapy and radiation therapy was associated with better overall survival (multivariable HR 0.69, 95% CI 0.52-0.92, p = 0.010 for combination therapy vs observation). CONCLUSIONS: Patient and tumor characteristics are associated with the choice of management strategy after radical prostatectomy and survival in men with pN1 prostate cancer. Multimodal therapy may be of benefit in this patient population.

Association between lymph node yield and survival among patients undergoing radical nephroureterectomy for urothelial carcinoma of the upper tract.

BACKGROUND: Prior studies examining the value of lymph node (LN) dissection (LND) in patients with urothelial carcinoma of the upper urinary tract (UTUC) have produced conflicting results. The objective of the current study was to assess the relationship between LN yield and survival among patients undergoing radical nephroureterectomy (RNU). METHODS: The National Cancer Data Base was used to identify patients with non-metastatic UTUC who were treated with RNU between 2004 and 2012. The association between LN yield and overall survival (OS) was assessed using Cox proportional hazards regression, with adjustment for patient, tumor, and facility characteristics. RESULTS: Of the 14,472 patients, 2926 (20%) underwent LND. The median yield was 2 LNs (interquartile range 1-6 LNs). Among the entire cohort and the LN-negative (pN0) subgroup, a higher LN yield was associated with lower all-cause mortality (multivariable hazard ratio [HR] 0.94 per 5 LNs removed, 95% confidence interval [95% CI] 0.89-1.00 [P = .034] for the entire cohort and HR 0.86, 95% CI 0.79-0.94 [P = .001] for the pN0 subgroup). Among patients with positive LNs (pN+), there was no association noted between LN yield and OS; however, positive and negative LN counts were found to be independent predictors of OS (HR 1.27 per 5 positive LNs, 95% CI 1.16-1.39 [P<.001] and HR 0.90 per 5 negative LNs, 95% CI 0.82-1.00 [P = .049]). CONCLUSIONS: In this large, contemporary cohort of patients with UTUC, LND was found to be used infrequently despite evidence that a higher LN yield is associated with lower all-cause mortality. Cancer 2017;123:1741-1750. © 2017 American Cancer Society.

Perineural Invasion and Risk of Lethal Prostate Cancer.

Background: Prostate cancer has a propensity to invade and grow along nerves, a phenomenon called perineural invasion (PNI). Recent studies suggest that the presence of PNI in prostate cancer has been associated with cancer aggressiveness.Methods: We investigated the association between PNI and lethal prostate cancer in untreated and treated prostate cancer cohorts: the Swedish Watchful Waiting Cohort of 615 men who underwent watchful waiting, and the U.S. Health Professionals Follow-Up Study of 849 men treated with radical prostatectomy. One pathologist performed a standardized histopathologic review assessing PNI and Gleason grade. Patients were followed from diagnosis until metastasis or death.Results: The prevalence of PNI was 7% and 44% in the untreated and treated cohorts, respectively. PNI was more common in high Gleason grade tumors in both cohorts. PNI was associated with enhanced tumor angiogenesis, but not tumor proliferation or apoptosis. In the Swedish study, PNI was associated with lethal prostate cancer [OR 7.4; 95% confidence interval (CI), 3.6-16.6; P < 0.001]. A positive, although not statistically significant, association persisted after adjustment for age, Gleason grade, and tumor volume (OR 1.9; 95% CI, 0.8-5.1; P = 0.17). In the U.S. study, PNI predicted lethal prostate cancer independent of clinical factors (HR 1.8; 95% CI, 1.0, 3.3; P =0.04).Conclusions: These data support the hypothesis that perineural invasion creates a microenvironment that promotes cancer aggressiveness.Impact: Our findings suggest that PNI should be a standardized component of histopathologic review, and highlights a mechanism underlying prostate cancer metastasis. Cancer Epidemiol Biomarkers Prev; 26(5); 719-26. ©2017 AACR.

Incidence, Characteristics and Implications of Thromboembolic Events in Patients with Muscle Invasive Urothelial Carcinoma of the Bladder Undergoing Neoadjuvant Chemotherapy.

PURPOSE: Neoadjuvant chemotherapy and pelvic surgery are significant risk factors for thromboembolic events. Our study objectives were to investigate the timing, incidence and characteristics of thromboembolic events during and after neoadjuvant chemotherapy and subsequent radical cystectomy in patients with muscle invasive bladder cancer. MATERIALS AND METHODS: We performed a multi-institutional retrospective analysis of 761 patients who underwent neoadjuvant chemotherapy and radical cystectomy for muscle invasive bladder cancer from 2002 to 2014. Median followup from diagnosis was 21.4 months (range 3 to 272). Patient characteristics included the Khorana score, and the incidence and timing of thromboembolic events (before vs after radical cystectomy). Survival was calculated using the Kaplan-Meier method. The log rank test and multivariable Cox proportional hazards regression were used to compare survival between patients with vs without thromboembolic events. RESULTS: The Khorana score indicated an intermediate thromboembolic event risk in 88% of patients. The overall incidence of thromboembolic events in patients undergoing neoadjuvant chemotherapy was 14% with a wide variation of 5% to 32% among institutions. Patients with thromboembolic events were older (67.6 vs 64.6 years, p = 0.02) and received a longer neoadjuvant chemotherapy course (10.9 vs 9.7 weeks, p = 0.01) compared to patients without a thromboembolic event. Of the thromboembolic events 58% developed preoperatively and 72% were symptomatic. On multivariable regression analysis the development of a thromboembolic event was not significantly associated with decreased overall survival. However, pathological stage and a high Khorana score were adverse risk factors for overall survival. CONCLUSIONS: Thromboembolic events are common in patients with muscle invasive bladder cancer who undergo neoadjuvant chemotherapy before and after radical cystectomy. Our results suggest that a prospective trial of thromboembolic event prophylaxis during neoadjuvant chemotherapy is warranted.

Androgen deprivation therapy and cardiovascular disease: what is the linking mechanism?

The past decade has brought increased awareness of the potential adverse effects of androgen deprivation therapy (ADT) in men with prostate cancer. Arguably the most important and controversial of these is the increased risk of cardiovascular morbidity and mortality. Although multiple observational studies have shown that men treated with ADT are at increased risk of developing atherosclerotic cardiovascular disease, our understanding of the biological mechanisms that might underlie this phenomenon is still evolving. In this review, we discuss some of the mechanisms that have been proposed to date, including ADT-induced metabolic changes that promote the development and progression of atherosclerotic plaques as well as direct local effects of hormonal factors on plaque growth, rupture and thrombosis.

Thromboembolic events in patients with urothelial carcinoma undergoing neoadjuvant chemotherapy and radical cystectomy.

OBJECTIVES: Patients receiving cisplatin are at high risk of thromboembolic events (TEEs). The objective of this study was to assess the effect of cisplatin-based neoadjuvant chemotherapy (NCT) on the incidence of perioperative TEEs in patients undergoing radical cystectomy. METHODS AND MATERIALS: We analyzed a consecutive sample of 202 patients with urothelial carcinoma treated with radical cystectomy between 2005 and 2013. Data were collected retrospectively by reviewing medical records. Median follow-up was 16.9 months. Events of interest were defined as venous or arterial TEEs occurring from the date of diagnosis to 30 days after surgery. TEE incidence among patients treated with NCT and cystectomy was compared with that among patients treated with cystectomy alone using Fisher exact test and Cox proportional hazards regression. Proportional hazards regression was also used to assess whether TEE is a predictor of cancer progression and survival. RESULTS: Of 202 patients, 17 (8.4%) developed a TEE, including 8 of 42 (19.1%) treated with NCT and cystectomy and 9 of 160 (5.6%) treated with cystectomy alone (risk ratio = 3.39, 95% CI: 1.39-8.24). After adjustment for observation time, there remained an association between treatment with NCT and risk of TEE (hazard ratio = 2.40; 95% CI: 0.92-6.27; P = 0.07). Overall, 7 events occurred before cystectomy and 10 occurred postoperatively. Among patients treated with NCT, 6 of 8 events occurred before cystectomy. Detection of TEE was clinically significant as preoperative TEE was found to be an independent predictor of progression and cancer-specific mortality (adjusted hazard ratio = 3.91, 95% CI: 1.34-11.45). The main limitations of our study are its retrospective data collection and small absolute number of events. CONCLUSIONS: TEE occurs commonly in patients with urothelial carcinoma undergoing NCT. Preoperative TEE is an independent predictor of progression and cancer-specific mortality.

Risk factors for febrile urinary tract infection in infants with prenatal hydronephrosis: comprehensive single center analysis.

PURPOSE: We assessed risk factors for urinary tract infection in children with prenatal hydronephrosis MATERIALS AND METHODS: We identified 376 infants with prenatal hydronephrosis in an institutional database. The occurrence of febrile urinary tract infection in the first 2 years of life was ascertained by chart review. Febrile urinary tract infection was defined as a positive culture from a catheterized urine specimen in a patient with a fever of 38.0C or greater. Multivariate logistic regression was used to assess gender, circumcision status, hydronephrosis grade, vesicoureteral reflux grade and antibiotic prophylaxis as predictors of the risk of urinary tract infection. RESULTS: Included in analysis were 277 males and 99 females. Hydronephrosis was high grade in 128 infants (34.0%) and vesicoureteral reflux was present in 79 (21.0%). Antibiotic prophylaxis was prescribed in 60.4% of patients, preferentially to females vs males (70.7% vs 56.7%), those with high vs low grade hydronephrosis (70.3% vs 55.2%) and those with vs without vesicoureteral reflux (96.2% vs 50.8%). On multivariate analysis there was an association between high grade hydronephrosis and an increased risk of urinary tract infection (adjusted OR 2.40, 95% CI 1.26-4.56). Females (adjusted OR 3.16, 95% CI 0.98-10.19) and uncircumcised males (adjusted OR 3.63, 95% CI 1.18-11.22) were also at higher risk than circumcised males. Antibiotic prophylaxis was not associated with a decreased risk of urinary tract infection (adjusted OR 0.93, 95% CI 0.45-1.94). CONCLUSIONS: High grade hydronephrosis, female gender and uncircumcised status in males are independent risk factors for febrile urinary tract infection in infants with prenatal hydronephrosis. Antibiotic prophylaxis did not reduce the risk of urinary tract infection in the study group.

Semen quality in relation to antioxidant intake in a healthy male population.

OBJECTIVE: To assess the relationship between dietary antioxidant intake and semen quality in young healthy males. DESIGN: Cross-sectional study. SETTING: University and college campuses in the Rochester, New York, area. PATIENT(S): One hundred eighty-nine university-aged men. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Semen volume, total sperm count, concentration, motility, total motile count, and morphology. RESULT(S): Progressive motility was 6.5 (95% confidence interval [CI], 0.6, 12.3) percentage units higher among men in the highest quartile of ß-carotene intake compared with men in the lowest quartile. Similar results were observed for lutein intake. Lycopene intake was positively related to sperm morphology. The adjusted percentages (95% CI) of morphologically normal sperm in increasing quartiles of lycopene intake were 8.0 (6.7, 9.3), 7.7 (6.4, 9.0), 9.2 (7.9, 10.5), and 9.7 (8.4, 11.0). There was a nonlinear relationship between vitamin C intake and sperm concentration, with men in the second quartile of intake having, on average, the highest sperm concentrations and men in the top quartile of intake having the lowest concentrations. CONCLUSION(S): In a population of healthy young men, carotenoid intake was associated with higher sperm motility and, in the case of lycopene, better sperm morphology. Our data suggest that dietary carotenoids may have a positive impact on semen quality.

The impact of the 2005 International Society of Urological Pathology (ISUP) consensus on Gleason grading in contemporary practice.

AIMS: To investigate the impact of the 2005 International Society of Urological Pathology (ISUP) Gleason grading consensus in contemporary practice. METHODS AND RESULTS: The Gleason scores (GS) were compared in two consecutive patient cohorts with matched biopsies and prostatectomies: (i) 908 patients evaluated before the ISUP consensus (July 2000-June 2004) and (ii) 423 patients evaluated after the ISUP consensus (October 2005-June 2007). All biopsies and prostatectomies were performed and scored in one institution and were sampled and processed identically. There was a higher percentage of biopsy and prostatectomy specimens with GS > or = 7 after the ISUP consensus (GS > or = 7 on biopsy in 32% before ISUP versus 46% after ISUP; GS > or = 7 on prostatectomy in 53% before ISUP versus 68% after ISUP; P < 0.001). No significant difference in the complete and + or -1 unit Gleason agreement was found before and after the ISUP consensus. There was a trend towards better complete agreement for GS > or = 7 after the ISUP consensus. CONCLUSIONS: There was a shift towards higher GS on biopsy and prostatectomy in our practice after the ISUP consensus, although - there was no significant impact on the biopsy-prostatectomy Gleason agreement. The significance of this shift for patient management and prognosis is uncertain.