A Matched Analysis of Active Surveillance Versus Nephrectomy for T1a Small Renal Masses.

While patients with a small renal mass (SRM) on active surveillance (AS) experience excellent metastasis-free survival (MFS) and cancer-specific survival (CSS), differences in overall survival (OS) observed may be explained by selection of older/comorbid patients for AS. Few studies have evaluated AS versus primary intervention in clinically balanced groups. We identified patients aged 55-75 yr with an SRM (≤4 cm, T1a) in our institutional database (2000-2020). Patients from AS and nephrectomy subgroups were matched exactly for age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, biopsy status, and histology. The primary outcomes were OS and an event-free survival (EFS) composite that included OS, CSS, MFS, progression, or systemic therapy, which we tested in Cox proportional-hazards models. We identified 377 patients (205 AS, 172 nephrectomy). The cohort was balanced after matching (n = 110; mean age 64 yr, 77% male, and 75% ECOG score 0). In each arm, 47% were biopsied (predominantly clear-cell histology). The predicted 5-yr OS was 96% for the nephrectomy group and 95% for the AS group (hazard ratio for nephrectomy vs AS [HR] 0.83, 95% confidence interval [CI] 0.13-5.32; p = 0.8), with corresponding 5-yr EFS rates of 93% and 96% (HR 1.88, 95% CI 0.35-10.15; p = 0.5). Among SRM cases well matched for age and overall health status, we observed higher 5-yr OS and EFS rates for AS than previously reported; the rates were not significantly different from those after nephrectomy. The matched characteristics of our population are similar to those for treatment arms in contemporary cohorts and the results support the safety of AS in younger, healthier patients. PATIENT SUMMARY: While it has been shown that active surveillance for small kidney tumors is safe in older and more frail patients, its safety in younger, healthier patients has not been confirmed. We compared outcomes for patients aged 55-75 yr who were managed with surgery or active surveillance, and were similar in age and overall health. The probability of death after 5 years was low overall and not significantly different between the groups, suggesting that active surveillance is safe in routine clinical practice.

Low-volume grade group 2 prostate cancer candidates for active surveillance: a radical prostatectomy retrospective analysis.

OBJECTIVE: Guidelines support considering selected men with ISUP grade group (GG) 2 prostate cancer for active surveillance (AS). We assessed the association of clinical variables with unfavorable pathology at radical prostatectomy in low-volume GG 2 prostate cancer on biopsy in a retrospective cohort. MATERIALS AND METHODS: This was a retrospective analysis of 378 men with low-volume (≤ 2 cores) GG 2 localized prostate cancer who underwent prostatectomy at a single tertiary cancer center. Multivariable logistic regression of unfavorable pathology, upgrading to ≥ T3, or GG ≥ 3 was performed in relation to clinical factors, common variables used in AS in GG 1 and percentage Gleason 4 at biopsy. We compared the performance of potential variables with commonly used combined AS restrictions in GG 1 prostate cancer. RESULTS: In total, 128/378 (34%) men had unfavorable pathology at radical prostatectomy. On multivariable analysis, > 5% Gleason pattern 4 was independently associated with an increased risk of GG ≥ 3. A maximum percentage core involvement > 50% was independently associated with an increased risk of pT-stage ≥ 3 and unfavorable pathology. Restriction to patients with ≤ 5% Gleason 4 decreased the upgrading of both unfavorable pathology (OR = 0.62, p = 0.041) and GG ≥ 3 (OR = 0.17, p = 0.0007) compared to the full cohort, while restriction to those with ≤ 50% of max core involvement did not. CONCLUSION: In low-volume GG 2, the percentage of Gleason 4 of ≤ 5% was the strongest predictor in reducing upgrading at final pathology. This easily available pathological descriptor could be used to guide urologists and patients when considering AS in this setting.

Androgen deprivation therapy for prostate cancer: Prescribing behaviors and preferences among urologists.

INTRODUCTION: Several androgen deprivation therapy (ADT) medications are available for treating advanced prostate cancer with roughly equivalent oncological efficacy and tolerability. We investigated the proportion of physicians who predominantly prescribe one type of ADT drug ("mono-prescriber") and assessed characteristics associated with prescription behavior. METHODS: Ontario men aged ≥65 years who were diagnosed with advanced prostate cancer (1997-2017) and initiated ADT thereafter for ≥3 consecutive months were identified using population-level administrative data. Their first prescription for injectable ADT was linked to a physician, and urologists with ≥10 prescriptions over the study period were included in the analysis (n=282). Urologists were classified as high mono-prescribers if ≥80% of their prescriptions were for one drug type. Multivariable logistic regression was used to examine the association of physician characteristics with the odds of being a high mono-prescriber. RESULTS: Overall, 67 (23.8%) of urologists were classified as high mono-prescribers but the frequency varied across health planning regions. The most commonly prescribed drugs and those used by mono-prescribers were goserelin (41.8% and 56.7%) and leuprolide (44.3% and 43.3%), respectively. In multivariable analysis, the odds of a physician being a high mono-prescriber were higher with more years in practice (odds ratio [OR] 1.06/year, 95% confidence interval [CI] 1.03-1.09, p<0.0001) and lower for higher patient volume (OR 0.33 for above vs. below median, 95% CI 0.17-0.63, p=0.0008). CONCLUSIONS: Overall, one in four urologists were classified as high mono-prescribers. Mono-prescribers had more years in practice and smaller volume practices, potentially suggesting habitual prescription behavior and/or the effect of external pressures.

Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

Treatment on active surveillance of small renal masses: Progression vs. preference.

INTRODUCTION: Active surveillance (AS) of small renal masses (SRM) is increasingly recognized as a safe option. A recent U.S. study found that half of patients receiving treatment on AS were for preference, but these findings may not be generalizable to other jurisdictions and healthcare models. We aimed to investigate AS failure rates and causes among a contemporary biopsy-evaluated cohort in Canada. METHODS: A retrospective review was performed of SRM patients on AS undergoing treatment at our tertiary care center (1999-2018). All patients had undergone renal biopsy and been diagnosed with renal cell carcinoma (RCC). Demographic and clinical parameters surrounding the decision to treat were extracted from chart review. Indications for treatment were dichotomized into clinical (radiographical) progression or preference. Qualitative assessment of clinic notes confirmed treatment indication. Ethics approval was obtained. RESULTS: A total of 38 SRM-RCC patients who underwent treatment on AS were identified, of which 29 had been on AS ≥1 year. Most (75.9%) were male and the mean age beginning AS was 65.9±9.0 years. Most patients had clear-cell RCC with low-grade disease. Seventeen of 29 (58.6%) patients experienced clinical progression after 3.82 (2.57-7.16) years, whereas preference accounted for 12/29 (41.4%) after 2.22 (1.69-3.53) years (time-to-treatment p=0.032). The longest duration on AS was 14.2 years prior to clinical progression. No patients had metastatic progression before treatment. CONCLUSIONS: Two-fifths of patients received treatment for preference and at a much higher rate vs. clinical progression. These findings suggest a clinical gap where effective patient counselling prior to and during AS may improve adherence.

Long-term outcomes after radical or partial nephrectomy for T1a renal cell carcinoma: A population-based study.

INTRODUCTION: The benefit of partial nephrectomy (PN) compared to radical nephrectomy (RN) for T1a renal cell carcinoma (RCC) remains uncertain, with observational studies conflicting with level 1 evidence. Therefore, the purpose of this population-based study was to compare long-term outcomes in patients undergoing PN or RN for T1a RCC. METHODS: We studied 5670 patients in Ontario, Canada undergoing PN or RN for T1a RCC. The primary outcome was overall survival (OS). Secondary outcomes were cancer-specific survival (CSS), chronic kidney disease (CKD), renal replacement therapy, and myocardial infarction (MI). We used multivariable Cox proportional hazard models to evaluate the association between PN or RN and these outcomes. A sensitivity analysis was performed in patients with a preoperative serum creatinine available. RESULTS: Median followup was 77 months. Compared to RN, PN was associated with significantly improved OS (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.63-0.84), reduced risk of CKD (HR 0.18, 95% CI 0.12-0.27), and improved CSS (HR 0.45, 95% CI 0.30-0.65). The risk of MI was not significantly different between groups (HR 0.91, 95% CI 0.62-1.34). Few patients (n=15) required renal replacement therapy. In the sensitivity analysis, the association between type of surgery and OS and CKD persisted, while the association with CSS did not. CONCLUSIONS: Our study found that in patients undergoing surgery for T1a RCC, PN was associated with improved OS and reduced risk of CKD compared to RN. However, few patients in either group required renal replacement therapy.

Does Time Spent on Active Surveillance Adversely Affect the Pathological and Oncologic Outcomes in Patients Undergoing Delayed Radical Prostatectomy?

PURPOSE: Pathological and oncologic outcomes of delayed radical prostatectomy following prostate cancer active surveillance are not well established. We determined the pathological and oncologic outcomes of favorable risk, Grade Group 1, prostate cancer managed with active surveillance and progressing to radical prostatectomy for clinically significant prostate cancer (Grade Group 2 or greater). MATERIALS AND METHODS: Between 1992 and 2015, 170 men with favorable risk prostate cancer underwent delayed radical prostatectomy for clinically significant prostate cancer (ASRP) at the Princess Margaret Cancer Centre. Pathological and oncologic outcomes of the ASRP cohort were compared with a matched cohort treated with up-front radical prostatectomy (405) immediately before surgery. Biochemical recurrence-free survival, overall survival and cancer specific survival were compared. We examined the association between delayed radical prostatectomy and adverse pathology at radical prostatectomy and biochemical recurrence using logistic and Cox regression analyses, respectively. RESULTS: Median time spent on active surveillance before radical prostatectomy was 31.0 months. At radical prostatectomy pT3 (extraprostatic extension, seminal vesicle invasion), positive surgical margin and pN1 rates were comparable between the 2 cohorts. Median followup after radical prostatectomy was 5.6 years. The 5-year biochemical recurrence-free survival rate in the ASRP cohort and up-front radical prostatectomy cohort were 85.8% and 82.4%, respectively (p=0.38). Overall survival and cancer specific survival were comparable between the 2 groups. Delayed radical prostatectomy was not associated with adverse pathological outcomes and biochemical recurrence on regression analyses. CONCLUSIONS: Curative intent radical prostatectomy after a period of active surveillance results in excellent pathological and oncologic outcomes at 5 years. A period of active surveillance does not result in inferior outcomes compared to patients with similar risk characteristics undergoing up-front radical prostatectomy.

The long-term outcomes of Gleason grade groups 2 and 3 prostate cancer managed by active surveillance: Results from a large, population-based cohort.

INTRODUCTION: Active surveillance (AS) is an accepted management strategy for low-risk prostate cancer (PCa), but its role in the management of favorable intermediate-risk PCa remains controversial. Most reports studying the role of AS for these men generally lack long-term followup and include small numbers of patients. Our objective was to report the outcomes of men diagnosed with Gleason grade groups (GGG) 2 and 3 PCa who were managed expectantly. METHODS: Using administrative datasets and pathology reports, we identified all men who were diagnosed with GGG 2 and 3 PCa and managed expectantly between 2002 and 2011 in Ontario, Canada. Outcomes and associated factors were estimated using cumulative incidence function methods and multivariable Cox regression models, respectively. RESULTS: We identified 926 men who were managed expectantly (AS [n=374] or watchful waiting [n=552]). The eight-year cancer-specific survival was 94% and 89% for the AS and watchful waiting cohorts, respectively. Among AS men, 266 (71%) received treatment after a followup of approximately eight years. Cumulative AS discontinuation rates at one and five years were 30.5% and 65.1%, respectively. CONCLUSIONS: Expectant management of GGG 2 and 3 PCa may be an option for certain men. Notably for AS patients, the cancer-specific mortality at eight years was 6%, and over 65% of men underwent treatment within five years. Further studies are required to evaluate which patients, based on disease-specific features and competing health risks, would benefit most from a conservative strategy.

Identification of subgroups of metastatic castrate-resistant prostate cancer (mCRPC) patients treated with abiraterone plus prednisone at low- vs. high-risk of radiographic progression: An analysis of COU-AA-302.

INTRODUCTION: Radiographic imaging is used to monitor disease progression for men with metastatic castrate-resistant prostate cancer (mCRPC). The optimal frequency of imaging, a costly and limited resource, is not known. Our objective was to identify predictors of radiographic progression to inform the frequency of imaging for men with mCRPC. METHODS: We accessed data for men with chemotherapy-naive mCRPC in the abiraterone acetate plus prednisone (AA-P) group of a randomized trial (COU-AA-302) (n=546). We used Cox proportional hazards modelling to identify predictors of time to progression. We divided patients into groups based on the most important predictors and estimated the probability of radiographic progression-free survival (RPFS) at six and 12 months. RESULTS: Baseline disease and change in prostate-specific antigen (PSA) at eight weeks were the strongest determinants of RPFS. The probability of RPFS for men with bone-only disease and a ≥50% fall in PSA was 93% (95% confidence interval [CI] 87-96) at six months and 80% (95% CI 72-86) at 12 months. In contrast, the probability of RPFS for men with bone and soft tissue metastasis and <50% fall in PSA was 55% (95% CI 41-67) at six months and 34% (95% CI 22-47) at 12 months. These findings should be externally validated. CONCLUSIONS: Patients with chemotherapy-naive mCRPC treated with first-line AA-P can be divided into groups with significantly different risks of radiographic progression based on a few clinically available variables, suggesting that imaging schedules could be individualized.

Active surveillance review: contemporary selection criteria, follow-up, compliance and outcomes.

The primary goal of active surveillance (AS) is to prevent overtreatment by selecting patients with low-risk prostate cancer (PCa) and closely monitoring them so that definitive treatment can be offered when needed. With the increasing popularity of AS as a management strategy for men with localized PCa, it is important to understand all the contemporary guidelines and criteria that exist for AS and the differences among them. No single optimal management strategy for clinically localized, early-stage disease has been universally accepted. The implementation of AS varies widely between institutions, from inclusion criteria to follow-up protocols, with the most notable differences seen in maximum accepted Gleason score, T-stage and prostate-specific antigen (PSA) parameters. The objectives of this review were to systematically summarize the current literature on AS strategy, present an overview of the various published guidelines and criteria that are used for AS at several major institutions as well as discuss goals and trade-offs of the various criteria. A comprehensive search of the PubMed and Embase databases from 1990 to 2017 was performed to identify studies pertaining to AS criteria and trends. Trends in AS uptake and use in Canada, USA and Europe were reviewed to demonstrate the current trends and outcomes of AS to offer greater insight into the differences, nature and efficacy of various AS protocols. AS is a compelling antidote to the current PCa overtreatment phenomena; however, when considering patients for AS it is important to understand the differences between protocols, and review published results to appreciate the impact on follow-up.

Identifying the use and barriers to the adoption of renal tumour biopsy in the management of small renal masses.

INTRODUCTION: Renal tumour biopsies (RTBs) can provide the histology of small renal masses (SRMs) prior to treatment decision-making. However, many urologists are reluctant to use RTB as a standard of care. This study characterizes the current use of RTB in the management of SRMs and identifies barriers to a more widespread adoption. METHODS: A web-based survey was sent to members of the Canadian and Quebec Urological Associations who had registered email address (n=767) in June 2016. The survey examined physicians' practice patterns, RTB use, and potential barriers to RTB. Chi-squared tests were used to assess for differences between respondents. RESULTS: The response rate was 29% (n=223), of which 188 respondents were eligible. A minority of respondents (12%) perform RTB in >75% of cases, while 53% never perform or perform RTB in <25% of cases. Respondents with urological oncology fellowship training were more likely to request a biopsy than their colleagues without such training. The most frequent management-related reason for not using routine RTB was a belief that biopsy won't alter management, while the most frequent pathology-related reason was the risk of obtaining a false-negative or a non-diagnostic biopsy. CONCLUSIONS: Adoption of RTBs remains low in Canada. Concerns about the accuracy of RTB and its ability to change clinical practice are the largest barriers to adoption. A knowledge translation strategy is needed to address these concerns. Future studies are also required in order to define where RTB is most valuable and how to best to implement it.

Is Routine Renal Tumor Biopsy Associated with Lower Rates of Benign Histology following Nephrectomy for Small Renal Masses?

PURPOSE: Renal tumor biopsies have been proposed as a management alternative to avoid treatment of benign or low risk small renal masses. However, many urologists are reluctant to recommend renal tumor biopsy because they feel its result frequently will not impact management. Our primary objective was to evaluate if centers that routinely favor renal tumor biopsy have lower rates of benign histology after surgery than centers where a selective renal tumor biopsy approach is used. MATERIALS AND METHODS: This was a retrospective multicenter study of patients who underwent partial or radical nephrectomy for a lesion suspicious for localized renal cell carcinoma which measured 4 cm or less (cT1a and pT1a or pT3a) between 2013 and 2015. A logistic regression model was used to examine whether the odds of obtaining a benign tumor following surgery differed between centers that routinely favor renal tumor biopsy and centers where a selective renal tumor biopsy approach is used. RESULTS: A total of 542 small renal masses in 516 patients were included in study. The rate of histologically benign tumors after surgery was 11%. This rate was significantly lower at centers that routinely favor renal tumor biopsy than at centers where a selective renal tumor biopsy approach is used (5% vs 16%, p <0.001). On multivariable analysis older age, smaller tumors and centers where a selective renal tumor biopsy approach is used were significantly associated with greater odds of finding a histologically benign tumor postoperatively. Compared to centers that routinely favor renal tumor biopsy the odds of finding a benign tumor at surgery was 4 times more likely at centers where a selective renal tumor biopsy approach is used (OR 4.1, 95% CI 1.9-8.3). CONCLUSIONS: Routine renal tumor biopsy reduces surgery for benign tumors and the potential for short-term and long-term morbidity associated with these procedures. This study suggests that routine renal tumor biopsy may be a valuable tool to decrease overtreatment of small renal masses.

Curative Radiation Therapy at Time of Progression Under Active Surveillance Compared With Up-front Radical Radiation Therapy for Prostate Cancer.

PURPOSE: To describe and compare outcomes in men with initially presumed indolent prostate cancer receiving definitive radiation therapy after active surveillance (AS) versus those in a risk-matched cohort undergoing up-front radiation therapy. METHODS AND MATERIALS: Men prospectively enrolled in an AS program between 1992 and 2014 and subsequently undergoing curative radiation therapy (ie, image guided radiation therapy [IGRT] or low-dose-rate brachytherapy [LDR-BT]) were identified. Biochemical relapse-free rate (bRFR), metastasis-free rate (mFR), and overall survival (OS) were compared against a cohort of men treated up front, matched by age, clinical prognostic indices (risk group, prostate-specific antigen, cT category, Gleason score, percentage of involved biopsy cores), and radiation therapy modality. RESULTS: Of 1070 patients in the AS registry, 200 underwent definitive radiation therapy (143 IGRT and 57 LDR-BT) after a median of 32.9 (interquartile range [IQR] 20.6-59.8) months on surveillance. Main reasons for treatment were grade and volume upgrading (57.5% and 26%, respectively). Median follow-up after radiation therapy was 4.9 (IQR 3.1-7.5) years. At 5 years the bRFR, mFR, and OS were, respectively, 97%, 99%, and 98.5%. No patient died of prostate cancer. Adequate risk-matching was confirmed in an independent cohort comprising 359 patients receiving up-front IGRT (71%) or LDR-BT (29%) and followed for a median of 9 (IQR 3.1-7.5) years. There was no difference in the disease-specific outcomes (bRFR, mFR) between the 2 cohorts (Gray's P value of .257 and .934, respectively). In multivariate analyses, timing of radical radiation therapy (deferred vs up-front) was not correlated to biochemical relapse or metastases occurrence. CONCLUSIONS: Curative-intent radiation therapy (ie, dose-escalated IGRT or LDR-BT) after a period of AS renders excellent oncologic outcomes at 5 years. Deferring radical therapy after a period of AS does not seem to result in inferior oncologic outcomes compared with patients with similar risk characteristics undergoing up-front treatment.

The uptake of active surveillance for the management of prostate cancer: A population-based analysis.

INTRODUCTION: Active surveillance (AS) is a strategy for the management of low-risk prostate cancer (PCa). However, few studies have assessed the uptake of AS at a population level and none of these were based on a Canadian population. Therefore, our objectives were to estimate the proportion of men being managed by AS in Ontario and to assess the factors associated with its uptake. METHODS: This was a retrospective, population-based study using administrative databases from the province of Ontario to identify men ≤75 years diagnosed with localized PCa between 2002 and 2010. Descriptive statistics were used to estimate the proportion of men managed by AS, whereas mixed models were used to assess the factors associated with the uptake of AS. RESULTS: 45 691 men met our inclusion criteria. Of these, 18% were managed by AS. Over time, the rates of AS increased significantly from 11% to 21% (p<0.001). Older age, residing in an urban centre, being diagnosed in the later years of the study period, having a neighborhood income in the highest quintile, and being managed by urologists were all associated with greater odds of receiving AS. CONCLUSIONS: There has been a steady increase in the uptake of AS between 2002 and 2010. However, only 18% of men diagnosed with localized PCa were managed by AS during the study period. The decisions to adopt AS were influenced by several individual and physician characteristics. The data suggest that there is significant opportunity for more widespread adoption of AS.

Stricter Active Surveillance Criteria for Prostate Cancer do Not Result in Significantly Better Outcomes: A Comparison of Contemporary Protocols.

PURPOSE: We reviewed various existing active surveillance criteria and determined the competing trade-offs of the stricter vs more inclusive active surveillance criteria. MATERIALS AND METHODS: Men enrolled in an active surveillance program at Princess Margaret Cancer Centre between 1998 and 2014 were identified through a prospectively maintained database. All patients were assessed for entry eligibility into the Prostate Cancer Research International: Active Surveillance, Johns Hopkins, University of Miami, University of California San Francisco, Memorial Sloan Kettering Cancer Center, University of Toronto-Sunnybrook and Royal Marsden protocols. The 2-sided t-test, ANOVA, Wilcoxon rank sum or chi-square tests were used for comparison as appropriate. RESULTS: Of the 1,365 men identified 1,085 met the Princess Margaret Cancer Centre inclusion criteria. When the Johns Hopkins, Prostate Cancer Research International: Active Surveillance and University of Miami criteria were applied 15.2%, 11.5% and 11.3% of these patients were excluded from active surveillance, respectively. No significant differences were noted between men who met the Princess Margaret Cancer Centre criteria and those who were excluded based on more stringent criteria when grade or volume reclassification was compared. No significant differences in prostate specific antigen velocity or the number of patients who proceeded to seek treatment were noted (p >0.1). Rates of biochemical recurrence among patients who chose to undergo radical prostatectomy after initial active surveillance were not different between men who met the more inclusive vs more exclusive active surveillance protocols. CONCLUSIONS: More selective criteria do not significantly improve short-term outcomes when considering the relative risk of grade reclassification or biochemical failure after treatment. In an era of increased awareness regarding the over diagnosis and overtreatment of prostate cancer, we believe that stricter entry criteria should be reconsidered.

An Increase in Gleason 6 Tumor Volume While on Active Surveillance Portends a Greater Risk of Grade Reclassification with Further Followup.

PURPOSE: We evaluated the relative risk of later grade reclassification and outcomes of patients in whom high volume Gleason 6 prostate cancer develops while on active surveillance. MATERIALS AND METHODS: A prospectively maintained database was used to identify patients on active surveillance between 1998 and 2013. Tumor volume was assessed based on the number of positive cores and proportion of core involvement. The chi-square and Fisher exact tests were used for analysis as appropriate. The primary end point was the development of grade reclassification, defined as grade only and/or grade and volume at the event biopsy. RESULTS: A total of 555 men met the study inclusion criteria. Mean followup was 46 months. Overall 70 patients demonstrated an increase in tumor volume at or after biopsy 2. Compared to those men never experiencing volume or grade reclassification, prostate specific antigen at diagnosis was not significantly different (p=0.95), but median prostate volume was smaller in patients who demonstrated volume reclassification (p <0.001). The incidence of pure volume reclassification was 6.8%, 6.1% and 7.8% at biopsy 2, 3 and 4, respectively. Men with volume reclassification were more likely to experience later grade reclassification than those without at 33.3% vs 9.3%, respectively (p <0.0001). CONCLUSIONS: While Gleason 6 prostate cancer has a favorable natural history, it appears that patients on active surveillance who experience volume reclassification are at substantially higher risk for grade reclassification. Thus, urologists should pay close attention to tumor core involvement, and monitoring should be adjusted accordingly for early volume reclassification in younger men and those in good health.

Inflammation in rat pregnancy inhibits spiral artery remodeling leading to fetal growth restriction and features of preeclampsia.

Fetal growth restriction (FGR) and preeclampsia (PE) are often associated with abnormal maternal inflammation, deficient spiral artery (SA) remodeling, and altered uteroplacental perfusion. Here, we provide evidence of a novel mechanistic link between abnormal maternal inflammation and the development of FGR with features of PE. Using a model in which pregnant rats are administered low-dose lipopolysaccharide (LPS) on gestational days 13.5-16.5, we show that abnormal inflammation resulted in FGR mediated by tumor necrosis factor-α (TNF). Inflammation was also associated with deficient trophoblast invasion and SA remodeling, as well as with altered uteroplacental hemodynamics and placental nitrosative stress. Moreover, inflammation increased maternal mean arterial pressure (MAP) and was associated with renal structural alterations and proteinuria characteristic of PE. Finally, transdermal administration of the nitric oxide (NO) mimetic glyceryl trinitrate prevented altered uteroplacental perfusion, LPS-induced inflammation, placental nitrosative stress, renal structural and functional alterations, increase in MAP, and FGR. These findings demonstrate that maternal inflammation can lead to severe pregnancy complications via a mechanism that involves increased maternal levels of TNF. Our study provides a rationale for the use of antiinflammatory agents or NO-mimetics in the treatment and/or prevention of inflammation-associated pregnancy complications.