Long-Term Outcomes in Patients Using Protocol-Directed Active Surveillance for Prostate Cancer.

Importance: Outcomes from protocol-directed active surveillance for favorable-risk prostate cancers are needed to support decision-making. Objective: To characterize the long-term oncological outcomes of patients receiving active surveillance in a multicenter, protocol-directed cohort. Design, Setting, and Participants: The Canary Prostate Active Surveillance Study (PASS) is a prospective cohort study initiated in 2008. A cohort of 2155 men with favorable-risk prostate cancer and no prior treatment were enrolled at 10 North American centers through August 2022. Exposure: Active surveillance for prostate cancer. Main Outcomes and Measures: Cumulative incidence of biopsy grade reclassification, treatment, metastasis, prostate cancer mortality, overall mortality, and recurrence after treatment in patients treated after the first or subsequent surveillance biopsies. Results: Among 2155 patients with localized prostate cancer, the median follow-up was 7.2 years, median age was 63 years, 83% were White, 7% were Black, 90% were diagnosed with grade group 1 cancer, and median prostate-specific antigen (PSA) was 5.2 ng/mL. Ten years after diagnosis, the incidence of biopsy grade reclassification and treatment were 43% (95% CI, 40%-45%) and 49% (95% CI, 47%-52%), respectively. There were 425 and 396 patients treated after confirmatory or subsequent surveillance biopsies (median of 1.5 and 4.6 years after diagnosis, respectively) and the 5-year rates of recurrence were 11% (95% CI, 7%-15%) and 8% (95% CI, 5%-11%), respectively. Progression to metastatic cancer occurred in 21 participants and there were 3 prostate cancer-related deaths. The estimated rates of metastasis or prostate cancer-specific mortality at 10 years after diagnosis were 1.4% (95% CI, 0.7%-2%) and 0.1% (95% CI, 0%-0.4%), respectively; overall mortality in the same time period was 5.1% (95% CI, 3.8%-6.4%). Conclusions and Relevance: In this study, 10 years after diagnosis, 49% of men remained free of progression or treatment, less than 2% developed metastatic disease, and less than 1% died of their disease. Later progression and treatment during surveillance were not associated with worse outcomes. These results demonstrate active surveillance as an effective management strategy for patients diagnosed with favorable-risk prostate cancer.

Pathological Effects of Apalutamide in Lower-risk Prostate Cancer: Results From a Phase II Clinical Trial.

PURPOSE: Active surveillance is a safe and effective strategy for men with lower-risk prostate cancer who want to avoid local therapy; however, many patients on active surveillance progress to active treatment (eg, prostatectomy or radiation). We hypothesized that apalutamide would decrease active surveillance attrition rates through downstaging low-grade tumors. MATERIALS AND METHODS: This was an open-label, single-arm, phase II study testing 90 days of oral apalutamide 240 mg daily in men with low- to intermediate-risk prostate cancer on active surveillance. The primary objective was to determine the percentage of patients with a negative biopsy immediately following treatment. Secondary objectives were to assess long-term clinical outcomes, quality of life, safety, and biomarkers of response/resistance. RESULTS: Twenty-three patients enrolled and 22 completed 90 days of apalutamide with post-treatment biopsy. Fifteen (65%) had Grade Group 1 disease, and all others had Grade Group 2 disease. Seven (30%) had favorable- to intermediate-risk disease. Of 22 evaluable patients, 13 (59%) had no residual cancer on post-treatment biopsy. The median time to first positive biopsy was 364 days (95% CI: 91-742 days). The impact of apalutamide on quality of life was minimal and transient. Decipher risk classifier revealed a greater number of negative post-treatment biopsies in those with higher baseline genomic risk score (P = .01). CONCLUSIONS: The negative repeat biopsy rate following 90 days of apalutamide was high in men with prostate cancer followed on active surveillance. Apalutamide was safe, well tolerated, and had minimal impact on quality of life. Randomized studies evaluating the effects of apalutamide in men enrolled on active surveillance are warranted.

Dietary Patterns and Risk of Gleason Grade Progression among Men on Active Surveillance for Prostate Cancer: Results from the Canary Prostate Active Surveillance Study.

Modifiable lifestyle factors, such as following a healthy dietary pattern may delay or prevent prostate cancer (PCa) progression. However, few studies have evaluated whether following specific dietary patterns after PCa diagnosis impacts risk of disease progression among men with localized PCa managed by active surveillance (AS). 564 men enrolled in the Canary Prostate Active Surveillance Study, a protocol-driven AS study utilizing a pre-specified prostate-specific antigen monitoring and surveillance biopsy regimen, completed a food frequency questionnaire (FFQ) at enrollment and had ≥ 1 surveillance biopsy during follow-up. FFQs were used to evaluate adherence to the Dietary Guidelines for Americans (Healthy Eating index (HEI))-2015, alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH) dietary patterns. Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals were estimated using Cox proportional hazards models. During a median follow-up of 7.8 years, 237 men experienced an increase in Gleason score on subsequent biopsy (grade reclassification). Higher HEI-2015, aMED or DASH diet scores after diagnosis were not associated with significant reductions in the risk of grade reclassification during AS. However, these dietary patterns have well-established protective effects on chronic diseases and mortality and remain a prudent choice for men with prostate cancer managed by AS.

Revisiting the relationship between examination pass rate and eligibility pathway among candidates for pharmacist board certification.

BACKGROUND: Pharmacists with specialized knowledge and skills are able to seek board certification from the Board of Pharmacy Specialties (BPS). In 2018, BPS conducted research to evaluate the relationship between eligibility pathways (i.e., completion of a postgraduate year 2 [PGY-2] specialty residency, completion of a postgraduate year 1 [PGY-1] residency plus 2 years of practice experience, or 4 years of practice experience) and certification examination pass rate. The study found statistically significant differences in pass rate based on eligibility criteria across all 6 specialties studied. There was a trend for higher pass rates in cohorts of examinees eligible for board certification based on completion of postgraduate residency training. OBJECTIVES: This study aimed to compare examination pass rates among different eligibility cohorts for board certification in recognized pharmacy practice specialties and compare contemporary findings with previously published findings. DESIGN: This cross-sectional study was conducted on data retrieved from BPS certification applications and examination administration records. SETTING AND PARTICIPANTS: Examinees in the United States and Canada for 9 BPS certification programs. OUTCOME MEASURES: A chi-square analysis was used to identify whether there were differences in pass rate among eligibility pathway cohorts. RESULTS: A total of 14,894 examinees met inclusion criteria; 6312 (42.4%) of the 14,894 examinees analyzed were eligible via practice experience, 5768 (38.7%) were eligible via PGY-1 completion, and 2814 (18.9%) were eligible via PGY-2 completion. A statistically significant difference was found for the relationship between pass rate and eligibility pathway for 8 of 9 BPS certification examinations analyzed (significant: ambulatory care pharmacy, critical care pharmacy, cardiology pharmacy, infectious diseases pharmacy, oncology pharmacy, psychiatric pharmacy, pediatric pharmacy, pharmacotherapy; not significant: solid organ transplantation pharmacy). Post hoc analyses showed that, in most cases, the PGY-2 eligibility cohort outperformed the PGY-1 eligibility cohort, which in turn outperformed the practice experience pathway cohort. CONCLUSION: Analysis of contemporary BPS certification examination administration data yields statistically significant differences among the pass rates by eligibility pathway, replicating previous findings and expanding the scope of the analysis.

Treatment in the absence of disease reclassification among men on active surveillance for prostate cancer.

BACKGROUND: Maintaining men on active surveillance for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progression, a smaller subset elects treatment in the absence of disease reclassification. This study sought to understand factors associated with treatment in a large, contemporary, prospective cohort. METHODS: This study identified 1789 men in the Canary Prostate Cancer Active Surveillance Study cohort enrolled as of 2020 with a median follow-up of 5.6 years. Clinical and demographic data as well as information on patient-reported quality of life and urinary symptoms were used in multivariable Cox proportional hazards regression models to identify factors associated with the time to treatment RESULTS: Within 4 years of their diagnosis, 33% of men (95% confidence interval [CI], 30%-35%) underwent treatment, and 10% (95% CI, 9%-12%) were treated in the absence of reclassification. The most significant factor associated with any treatment was an increasing Gleason grade group (adjusted hazard ratio [aHR], 14.5; 95% CI, 11.7-17.9). Urinary quality-of-life scores were associated with treatment without reclassification (aHR comparing "mostly dissatisfied/terrible" with "pleased/mixed," 2.65; 95% CI, 1.54-4.59). In a subset analysis (n = 692), married men, compared with single men, were more likely to undergo treatment in the absence of reclassification (aHR, 2.63; 95% CI, 1.04-6.66). CONCLUSIONS: A substantial number of men with prostate cancer undergo treatment in the absence of clinical changes in their cancers, and quality-of-life changes and marital status may be important factors in these decisions. LAY SUMMARY: This analysis of men on active surveillance for prostate cancer shows that approximately 1 in 10 men will decide to be treated within 4 years of their diagnosis even if their cancer is stable. These choices may be related in part to quality-or-life or spousal concerns.

Koala Retrovirus in Northern Australia Shows a Mixture of Stable Endogenization and Exogenous Lineage Diversification within Fragmented Koala Populations.

The koala population in northern Australia has become increasingly fragmented due to natural and man-made barriers and interventions. This situation has created a unique opportunity to study both endogenous and exogenous koala retrovirus (KoRV). To determine the impact that population isolation has had on KoRV diversity in Queensland, 272 koalas from six fragmented koala populations were profiled for their KoRV provirus across two natural biogeographical barriers (the St Lawrence Gap and the Brisbane Valley Barrier), one man-made geographical barrier (the city of Brisbane) and two translocation events (the single movement of koalas to an island and the repeated movement of koalas into a koala sanctuary). Analysis revealed that all koalas tested were KoRV-A positive, with 90 - 96% of the detected KoRV provirus from each koala representing a single, likely endogenous, KoRV-A strain. The next most abundant proviral sequence was a defective variant of the dominant KoRV-A strain, accounting for 3 - 10% of detected provirus. The remaining KoRV provirus represented expected exogenous strains of KoRV and included geographically localized patterns of KoRV-B, -C, -D, -F, -G, and -I. These results indicate that lineage diversification of exogenous KoRV is actively ongoing. In addition, comparison of KoRV provirus within known dam-sire-joey family groups from the koala sanctuary revealed that joeys consistently had KoRV proviral patterns more similar to their dams than their sires in KoRV-B, -C and -D provirus composition. Collectively, this study highlights both the consistency of endogenous KoRV and the diversity of exogenous KoRV across the fragmented koala populations in northern Australia.IMPORTANCE KoRV infection has become a permanent part of koalas in northern Australia. With KoRV presence and abundance linked to more severe chlamydial disease and neoplasia in these koalas, understanding how KoRV exists throughout an increasingly fragmented koala population is a key first step in designing conservation and management strategies. This survey of KoRV provirus in Queensland koalas indicates that endogenous KoRV provirus is ubiquitous and consistent throughout the state while exogenous KoRV provirus is diverse and distinct in fragmented koala populations. Understanding the prevalence and impact of both endogenous and exogenous KoRV will be needed to ensure a future for all koala populations.

Impact of Prostate Health Index Results for Prediction of Biopsy Grade Reclassification During Active Surveillance.

PURPOSE: We assessed whether Prostate Health Index results improve prediction of grade reclassification for men on active surveillance. METHODS AND MATERIALS: We identified men in Canary Prostate Active Surveillance Study with Grade Group 1 cancer. Outcome was grade reclassification to Grade Group 2+ cancer. We considered decision rules to maximize specificity with sensitivity set at 95%. We derived rules based on clinical data (R1) vs clinical data+Prostate Health Index (R3). We considered an "or"-logic rule combining clinical score and Prostate Health Index (R4), and a "2-step" rule using clinical data followed by risk stratification based on Prostate Health Index (R2). Rules were applied to a validation set, where values of R2-R4 vs R1 for specificity and sensitivity were evaluated. RESULTS: We included 1,532 biopsies (n = 610 discovery; n = 922 validation) among 1,142 men. Grade reclassification was seen in 27% of biopsies (23% discovery, 29% validation). Among the discovery set, at 95% sensitivity, R2 yielded highest specificity at 27% vs 17% for R1. In the validation set, R3 had best performance vs R1 with Δsensitivity = -4% and Δspecificity = +6%. There was slight improvement for R3 vs R1 for confirmatory biopsy (AUC 0.745 vs R1 0.724, ΔAUC 0.021, 95% CI 0.002-0.041) but not for subsequent biopsies (ΔAUC -0.012, 95% CI -0.031-0.006). R3 did not have better discrimination vs R1 among the biopsy cohort overall (ΔAUC 0.007, 95% CI -0.007-0.020). CONCLUSIONS: Among active surveillance patients, using Prostate Health Index with clinical data modestly improved prediction of grade reclassification on confirmatory biopsy and did not improve prediction on subsequent biopsies.

Targeting backdoor androgen synthesis through AKR1C3 inhibition: A presurgical hormonal ablative neoadjuvant trial in high-risk localized prostate cancer.

BACKGROUND: Localized prostate cancers (PCs) may resist neoadjuvant androgen receptor (AR)-targeted therapies as a result of persistent intraprostatic androgens arising through upregulation of steroidogenic enzymes. Therefore, we sought to evaluate clinical effects of neoadjuvant indomethacin (Indo), which inhibits the steroidogenic enzyme AKR1C3, in addition to combinatorial anti-androgen blockade, in men with high-risk PC undergoing radical prostatectomy (RP). METHODS: This was an open label, single-site, Phase II neoadjuvant trial in men with high to very-high-risk PC, as defined by NCCN criteria. Patients received 12 weeks of apalutamide (Apa), abiraterone acetate plus prednisone (AAP), degarelix, and Indo followed by RP. Primary objective was to determine the pathologic complete response (pCR) rate. Secondary objectives included minimal residual disease (MRD) rate, defined as residual cancer burden (RCB) ≤ 0.25cm3 (tumor volume multiplied by tumor cellularity) and elucidation of molecular features of resistance. RESULTS: Twenty patients were evaluable for the primary endpoint. Baseline median prostate-specific antigen (PSA) was 10.1 ng/ml, 4 (20%) patients had Gleason grade group (GG) 4 disease and 16 had GG 5 disease. At RP, 1 (5%) patient had pCR and 6 (30%) had MRD. Therapy was well tolerated. Over a median follow-up of 23.8 months, 1 of 7 (14%) men with pathologic response and 6 of 13 (46%) men without pathologic response had a PSA relapse. There was no association between prostate hormone levels or HSD3B1 genotype with pathologic response. CONCLUSIONS: In men with high-risk PC, pCR rates remained low even with combinatorial AR-directed therapy, although rates of MRD were higher. Ongoing follow-up is needed to validate clinical outcomes of men who achieve MRD.

In vitro properties of potential probiotic lactic acid bacteria originating from Ghanaian indigenous fermented milk products.

Fermented milk products are a major source of health-promoting microorganisms known as probiotics. To characterize the probiotic properties of lactic acid bacteria isolated from Ghanaian traditionally fermented milk, thirty (30) isolates comprising Enterococcus faecium (1), Lactobacillus fermentum (14), Lb. plantarum (2) and Pediococcus acidilactici (13) identified by 16S rRNA gene sequencing, were tested for survival at low pH (2.5) and bile salts (0.3% (w/v)), hydrophobicity, co-aggregation, auto-aggregation and antimicrobial activities against selected pathogens. Safety of potential probiotic bacteria was assessed by hemolytic activity on blood agar and susceptibility to nine different antibiotics. Majority (90%) of the strains showed survival rates above 80% at pH (2.5) and in bile salts (0.3% (w/v)). Hydrophobicity ranged from 5 to 61% while cell auto-aggregation ranged from 41 to 80% after 24 h. Co-aggregation with E. coli (3.7-43.9%) and S. Typhimurium (1.3-49.5%) were similar for the LAB strains at 24 h. Cell- free supernatants of all LAB strains inhibited E. coli while S. Typhimurium was not sensitive to cell-free supernatants of five Pd. acidilactici strains: OS24h20, OS18h3, OY9h19, OS9h8 and 24NL38. None of the LAB strains showed ß-hemolysis but 38% of strains showed α-hemolysis. Susceptibilities to antibiotics were strain-specific; only four strains, two Lb. fermentum and two Pd. acidilactici were susceptible to all nine antibiotics tested. Based on high survival rates in bile salts, low pH and generally good hydrophobicity, auto-aggregation, co-aggregation and inhibitory activities, 15 out of 30 strains tested were considered qualified candidates for development of probiotic cultures for fermented milk products in sub-Saharan Africa.

Magnetic Resonance Imaging for the Detection of High Grade Cancer in the Canary Prostate Active Surveillance Study.

PURPOSE: We investigated the ability of prostate magnetic resonance imaging to detect Gleason Grade Group 2 or greater cancer in a standardized, multi-institutional active surveillance cohort. MATERIALS AND METHODS: We evaluated men enrolled in Canary Prostate Active Surveillance Study with Gleason Grade Group less than 2 and who underwent biopsy within 12 months of multiparametric magnetic resonance imaging. Our primary outcome was biopsy reclassification to Gleason Grade Group 2 or greater. We evaluated the performance of magnetic resonance imaging PI-RADS® score and clinical factors. Multivariable logistic regression models were fit with magnetic resonance imaging and clinical factors and used to perform receiver operating curve analyses. RESULTS: There were 361 participants with 395 prostate magnetic resonance imaging studies with a median followup of 4.1 (IQR 2.0-7.6) years. Overall 108 (27%) biopsies showed reclassification. Defining positive magnetic resonance imaging as PI-RADS 3-5, the negative predictive value and positive predictive value for detecting Gleason Grade Group 2 or greater cancer was 83% (95% CI 76-90) and 31% (95% CI 26-37), respectively. PI-RADS was significantly associated with reclassification (PI-RADS 5 vs 1 and 2 OR 2.71, 95% CI 1.21-6.17, p=0.016) in a multivariable model but did not improve upon a model with only clinical factors (AUC 0.768 vs 0.762). In 194 fusion biopsies higher grade cancer was found in targeted cores in 21 (11%) instances, while 25 (13%) had higher grade cancer in the systematic cores. CONCLUSIONS: This study adds the largest cohort data to the body of literature for magnetic resonance imaging in active surveillance, recommending systematic biopsy in patients with negative magnetic resonance imaging and the inclusion of systematic biopsy in patients with positive magnetic resonance imaging.

Continued 5α-Reductase Inhibitor Use after Prostate Cancer Diagnosis and the Risk of Reclassification and Adverse Pathological Outcomes in the PASS.

PURPOSE: Outcomes in patients who enroll in active surveillance programs for prostate cancer while receiving 5α-reductase inhibitors have not been well defined. We sought to determine the association of 5α-reductase inhibitor use with the risk of reclassification in the PASS (Canary Prostate Active Surveillance Study). MATERIALS AND METHODS: Participants in the multicenter PASS were enrolled between 2008 and 2016. Study inclusion criteria were current or never 5α-reductase inhibitors use, Gleason score 3 + 4 or less prostate cancer at diagnosis, less than a 34% core involvement ratio at diagnosis and 1 or more surveillance biopsies. Included in study were 1,009 men, including 107 on 5α-reductase inhibitors and 902 who had never received 5α-reductase inhibitors. Reclassification was defined as increase in the Gleason score and/or an increase to 34% or greater in the ratio of biopsy cores positive for cancer. Adverse pathology at prostatectomy was defined as Gleason 4 + 3 or greater and/or nonorgan confined disease (pT3 or N1). RESULTS: On multivariable analysis there was no difference in reclassification between men who had received and those who had never received 5α-reductase inhibitors (HR 0.81, p = 0.31). Patients who had received 5α-reductase inhibitors were less likely to undergo radical prostatectomy (8% vs 18%, p = 0.01) or any definitive treatment (19% vs 24%, p = 0.04). In the 167 participants who underwent radical prostatectomy there was no suggestion of a difference in the rate of adverse pathology findings at prostatectomy between 5α-reductase inhibitor users and nonusers. CONCLUSIONS: Continued 5α-reductase inhibitor use after an initial diagnosis of prostate cancer was not associated with the risk of reclassification on active surveillance in men in the PASS cohort.

Genomic comparisons reveal biogeographic and anthropogenic impacts in the koala (Phascolarctos cinereus): a dietary-specialist species distributed across heterogeneous environments.

The Australian koala is an iconic marsupial with highly specific dietary requirements distributed across heterogeneous environments, over a large geographic range. The distribution and genetic structure of koala populations has been heavily influenced by human actions, specifically habitat modification, hunting and translocation of koalas. There is currently limited information on population diversity and gene flow at a species-wide scale, or with consideration to the potential impacts of local adaptation. Using species-wide sampling across heterogeneous environments, and high-density genome-wide markers (SNPs and PAVs), we show that most koala populations display levels of diversity comparable to other outbred species, except for those populations impacted by population reductions. Genetic clustering analysis and phylogenetic reconstruction reveals a lack of support for current taxonomic classification of three koala subspecies, with only a single evolutionary significant unit supported. Furthermore, ~70% of genetic variance is accounted for at the individual level. The Sydney Basin region is highlighted as a unique reservoir of genetic diversity, having higher diversity levels (i.e., Blue Mountains region; AvHecorr=0.20, PL% = 68.6). Broad-scale population differentiation is primarily driven by an isolation by distance genetic structure model (49% of genetic variance), with clinal local adaptation corresponding to habitat bioregions. Signatures of selection were detected between bioregions, with no single region returning evidence of strong selection. The results of this study show that although the koala is widely considered to be a dietary-specialist species, this apparent specialisation has not limited the koala's ability to maintain gene flow and adapt across divergent environments as long as the required food source is available.

Exploring the relationship between examination pass rates and eligibility pathways among pharmacist candidates for initial board certification.

OBJECTIVES: To compare examination pass rates among different eligibility cohorts for initial board certification in 6 recognized pharmacy practice specialties. DESIGN: Retrospective observational cohort study. SETTING AND PARTICIPANTS: Practicing U.S. pharmacists who were approved candidates for initial board certification examinations in the following Board of Pharmacy Specialties (BPS)-recognized specialties: ambulatory care pharmacy, critical care pharmacy, oncology pharmacy, pediatric pharmacy, pharmacotherapy, and psychiatric pharmacy. OUTCOME MEASURES: The number and percentage of BPS-approved candidates that pass initial board certification examinations differentiated by specialty and eligibility pathway (i.e., completion of postgraduate residency training or demonstration of postlicensure specialized practice experience). RESULTS: Initial board certification examination outcome (i.e., pass or fail) was assessed for a total of 15,171 candidates from Fall 2015 to Fall 2018. Pass rates for that period based on eligibility pathway (e.g., completion of a PGY-2 specialty residency, completion of a PGY-1 residency plus 1-2 years of postlicensure specialized practice experience, or 3-4 years of postlicensure specialized practice experience) were, respectively as follows: ambulatory care pharmacy (n = 2081): 94%, 84%, and 55% (P < 0.0001); critical care pharmacy (n = 2111): 99%, 94%, and 79% (P < 0.0001); oncology pharmacy (n = 1195) 93%, 75%, and 50% (P < 0.0001); pediatric pharmacy (n = 1119): 87%, 73%, and 57%; (P < 0.0001); pharmacotherapy (n = 8368): 88%, 59% (P < 0.0001); and psychiatric pharmacy (n = 477): 93%, 72%, 49% (P < 0.0001). CONCLUSION: From 2015 to 2018, the percentage of BPS-approved candidates that passed initial board certification examinations in ambulatory care pharmacy, critical care pharmacy, oncology pharmacy, pediatric pharmacy, pharmacotherapy, and psychiatric pharmacy was significantly higher for cohorts deemed to be board eligible based on completion of postgraduate residency training.

Vascular anatomical considerations and clinical decision making during insertion of the Avalon® Elite Dual Lumen single-site veno-venous ECMO cannula in children weighing less than 20 kg.

The correct selection and placement of a single-site Avalon® Elite Dual Lumen Cannula for veno-venous extracorporeal membrane oxygenation (ECMO) in children weighing less than 20 kg is dependent on both the mechanical characteristics of the catheter, including length and diameter, as well as the unique vascular anatomic considerations of the patient. This manuscript describes the development of a clinical strategy, over a four-year period from 2012-2016, for cannula selection to reduce the risk of migration and malposition in 20 critically ill children weighing less than 20 kg who presented for veno-venous ECMO.

Timing of Adverse Prostate Cancer Reclassification on First Surveillance Biopsy: Results from the Canary Prostate Cancer Active Surveillance Study.

PURPOSE: During active surveillance for localized prostate cancer, the timing of the first surveillance biopsy varies. We analyzed the Canary PASS (Prostate Cancer Active Surveillance Study) to determine biopsy timing influence on rates of prostate cancer adverse reclassification at the first active surveillance biopsy. MATERIALS AND METHODS: Of 1,085 participants in PASS, 421 had fewer than 34% of cores involved with cancer and Gleason sum 6 or less, and thereafter underwent on-study active surveillance biopsy. Reclassification was defined as an increase in Gleason sum and/or 34% or more of cores with prostate cancer. First active surveillance biopsy reclassification rates were categorized as less than 8, 8 to 13 and greater than 13 months after diagnosis. Multivariable logistic regression determined association between reclassification and first biopsy timing. RESULTS: Of 421 men, 89 (21.1%) experienced reclassification at the first active surveillance biopsy. Median time from prostate cancer diagnosis to first active surveillance biopsy was 11 months (IQR 7.8-13.8). Reclassification rates at less than 8, 8 to 13 and greater than 13 months were 24%, 19% and 22% (p = 0.65). On multivariable analysis, compared to men biopsied at less than 8 months the OR of reclassification at 8 to 13 and greater than 13 months were 0.88 (95% CI 0.5,1.6) and 0.95 (95% CI 0.5,1.9), respectively. Prostate specific antigen density 0.15 or greater (referent less than 0.15, OR 1.9, 95% CI 1.1, 4.1) and body mass index 35 kg/m2 or greater (referent less than 25 kg/m2, OR 2.4, 95% CI 1.1,5.7) were associated with increased odds of reclassification. CONCLUSIONS: Timing of the first active surveillance biopsy was not associated with increased adverse reclassification but prostate specific antigen density and body mass index were. In low risk patients on active surveillance, it may be reasonable to perform the first active surveillance biopsy at a later time, reducing the overall cost and morbidity of active surveillance.

Docetaxel and mitoxantrone before radical prostatectomy in men with high-risk prostate cancer: 10-year follow-up and immune correlates.

The aims of this study were to report the clinical outcomes in a cohort of men with high-risk prostate cancer treated with neoadjuvant docetaxel and mitoxantrone 10 years after treatment, identify pretreatment clinical parameters that may be predictors of recurrence, and describe tumor-infiltrating leukocytes present in radical prostatectomy specimens. We conducted a phase I/II study of neoadjuvant docetaxel and mitoxantrone before radical prostatectomy in high-risk localized prostate cancer to determine the feasibility of this combination and predictors of prostate cancer recurrence after cytotoxic chemotherapy. After 10 years of follow-up, 34 (63%) of 54 participants experience a recurrence. In univariate analysis, prostate-specific antigen (PSA) density (P=0.01), pathological stage (P=0.03), lymph node status (P<0.0001), seminal vesicle invasion (P=0.003), and tissue vascular endothelial growth factor (VEGF) expression (P=0.016) were significantly associated with recurrence. In multivariate analysis, only lymph node status, PSA density, and VEGF expression were significant predictors of disease recurrence. We used a tissue microarray for the first 50 participants to characterize the tumor-infiltrating lymphocytes and evaluate them for association with recurrence. We measured CD3, CD4, CD8, FoxP3, CD20, CD15, CD68, and CD163 by immunohistochemistry in both tumor and normal prostate specimens, but did not find an association between immunophenotype and recurrence. There was a significantly different density of CD68 and CD163 cells between normal and tumor tissue. Lymph node status, PSA density, and tissue VEGF expression predict recurrence after chemotherapy for high-risk prostate cancer. Additional studies are needed to determine the potential benefit of chemotherapy in the neoadjuvant setting.

Outcomes of Active Surveillance for Clinically Localized Prostate Cancer in the Prospective, Multi-Institutional Canary PASS Cohort.

PURPOSE: Active surveillance represents a strategy to address the overtreatment of prostate cancer, yet uncertainty regarding individual patient outcomes remains a concern. We evaluated outcomes in a prospective multicenter study of active surveillance. MATERIALS AND METHODS: We studied 905 men in the prospective Canary PASS enrolled between 2008 and 2013. We collected clinical data at study entry and at prespecified intervals, and determined associations with adverse reclassification, defined as increased Gleason grade or greater cancer volume on followup biopsy. We also evaluated the relationships of clinical parameters with pathology findings in participants who underwent surgery after a period of active surveillance. RESULTS: At a median followup of 28 months 24% of participants experienced adverse reclassification, of whom 53% underwent treatment while 31% continued on active surveillance. Overall 19% of participants received treatment, 68% with adverse reclassification, while 32% opted for treatment without disease reclassification. In multivariate Cox proportional hazards modeling the percent of biopsy cores with cancer, body mass index and prostate specific antigen density were associated with adverse reclassification (p=0.01, 0.04, 0.04, respectively). Of 103 participants subsequently treated with radical prostatectomy 34% had adverse pathology, defined as primary pattern 4-5 or nonorgan confined disease, including 2 with positive lymph nodes, with no significant relationship between risk category at diagnosis and findings at surgery (p=0.76). CONCLUSIONS: Most men remain on active surveillance at 5 years without adverse reclassification or adverse pathology at surgery. However, clinical factors had only a modest association with disease reclassification, supporting the need for approaches that improve the prediction of this outcome.

Animal leptospirosis.

Leptospirosis is a global disease of animals, which can have a major economic impact on livestock industries and is an important zoonosis. The current knowledge base is heavily biased towards the developed agricultural economies. The disease situation in the developing economies presents a major challenge as humans and animals frequently live in close association. The severity of disease varies with the infecting serovar and the affected species, but there are many common aspects across the species; for example, the acute phase of infection is mostly sub-clinical and the greatest economic losses arise from chronic infection causing reproductive wastage. The principles of, and tests for, diagnosis, treatment, control and surveillance are applicable across the species.