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Abstract The current prostate cancer (PCa) screen test, prostate-specific antigen (PSA), has a high sensitivity for PCa but low specificity for high-risk, clinically significant PCa (csPCa), resulting in overdiagnosis and overtreatment of non-csPCa. Early identification of csPCa while avoiding unnecessary biopsies in men with non-csPCa is challenging. We built an optimized machine learning platform (ClarityDX) and showed its utility in generating models predicting csPCa. Integrating the ClarityDX platform with blood-based biomarkers for clinically significant PCa and clinical biomarker data from a 3448-patient cohort, we developed a test to stratify patients’ risk of csPCa; called ClarityDX Prostate. When predicting high risk cancer in the validation cohort, ClarityDX Prostate showed 95% sensitivity, 35% specificity, 54% positive predictive value, and 91% negative predictive value, at a ≥ 25% threshold. Using ClarityDX Prostate at this threshold could avoid up to 35% of unnecessary prostate biopsies. ClarityDX Prostate showed higher accuracy for predicting the risk of csPCa than PSA alone and the tested model-based risk calculators. Using this test as a reflex test in men with elevated PSA levels may help patients and their healthcare providers decide if a prostate biopsy is necessary.

Abstract Background There is an unmet clinical need for minimally invasive diagnostic tests to improve the detection of grade group (GG) ≥3 prostate cancer relative to prostate antigen‐specific risk calculators. We determined the accuracy of the blood‐based extracellular vesicle (EV) biomarker assay (EV Fingerprint test) at the point of a prostate biopsy decision to predict GG ≥3 from GG ≤2 and avoid unnecessary biopsies. Methods This study analyzed 415 men referred to urology clinics and scheduled for a prostate biopsy, were recruited to the APCaRI 01 prospective cohort study. The EV machine learning analysis platform was used to generate predictive EV models from microflow data. Logistic regression was then used to analyze the combined EV models and patient clinical data and generate the patients' risk score for GG ≥3 prostate cancer. Results The EV‐Fingerprint test was evaluated using the area under the curve (AUC) in discrimination of GG ≥3 from GG ≤2 and benign disease on initial biopsy. EV‐Fingerprint identified GG ≥3 cancer patients with high accuracy (0.81 AUC) at 95% sensitivity and 97% negative predictive value. Using a 7.85% probability cutoff, 95% of men with GG ≥3 would have been recommended a biopsy while avoiding 144 unnecessary biopsies (35%) and missing four GG ≥3 cancers (5%). Conversely, a 5% cutoff would have avoided 31 unnecessary biopsies (7%), missing no GG ≥3 cancers (0%). Conclusions EV‐Fingerprint accurately predicted GG ≥3 prostate cancer and would have significantly reduced unnecessary prostate biopsies.

Abstract Background Studies have suggested a positive association between bladder cancer (BC) outcome and comedication use, including nonsteroidal anti-inflammatory drugs (NSAID), metformin, and prednisone use. To validate these associations, we evaluated whether these medications were associated with clinical outcome in a Canadian cohort of BC patients. Methods This is a retrospective cohort study on BC patients undergoing radical cystectomy (RC) in Québec province in 2000–2015, as registered in the provincial health administration databases. Medication use was considered chronic when prescribed for ≥ 1 year. Overall (OS), disease-specific (DSS) and recurrence-free (RFS) survival were compared using multivariable Cox proportional hazards models. Covariates included age, Charlson’s comorbidity index, region of residence, year of RC, distance to hospital, hospital type, hospital and surgeon annual RC volume, neoadjuvant chemotherapy use, and type of bladder diversion, as well as mutual adjustment for concomitant comedication use (statins, NSAIDs, metformin, and prednisone). Results Of 3742 patients included, 293, 420, and 1503 patients chronically used prednisone, metformin, and NSAIDs before surgery, respectively. In multivariable analyses, preoperative prednisone use was associated with improved OS (HR 0.67, 95%CI 0.55–0.82), DSS (HR 0.58, 95%CI 0.45–0.76), and RFS (HR 0.61, 95%CI 0.47–0.78). Patients who chronically used metformin preoperatively had a worse OS (HR 1.29, 95%CI 1.07–1.55), DSS (HR 1.38, 95%CI 1.10–1.72), and RFS (HR 1.41, 95%CI 1.13–1.74). Preoperative, chronic NSAID use was not significantly associated with all clinical outcomes, with adjusted HRs for OS, DSS, and RFS of 1.10 (95%CI 0.95–1.27), 1.24 (95%CI 1.03–1.48), and 1.22 (95%CI 1.03–1.45), respectively. Directionality of findings was similar when stratifying by comedication use in the year following surgery. Results were similar after propensity-score matching too. Conclusions In our Canadian cohort of BC undergoing RC, chronic prednisone use was associated with improved clinical outcomes, while metformin and NSAID were not.

Abstract The androgen receptor (AR) plays a crucial role in the development and homeostasis of the prostate and is a key therapeutic target in prostate cancer (PCa). The gold standard therapy for advanced PCa is androgen deprivation therapy (ADT), which targets androgen production and AR signaling. However, resistance to ADT develops via AR‐dependent and AR‐independent mechanisms. As reports on AR expression patterns in PCa have been conflicting, we performed cell‐by‐cell AR quantification by immunohistochemistry in the benign and malignant prostate to monitor changes with disease development, progression, and hormonal treatment. Prostates from radical prostatectomy (RP) cases, both hormone‐naïve and hormone‐treated, prostate tissues from patients on palliative ADT, and bone metastases were included. In the normal prostate, AR is expressed in >99% of luminal cells, 51% of basal cells, and 61% of fibroblasts. An increase in the percentage of AR negative (%AR−) cancer cells along with a gradual loss of fibroblastic AR were observed with increasing Gleason grade and hormonal treatment. This was accompanied by a parallel increase in staining intensity of AR positive (AR+) cells under ADT. Staining AR with N‐ and C‐terminal antibodies yielded similar results. The combination of %AR− cancer cells, %AR− fibroblasts, and AR intensity score led to the definition of an AR index, which was predictive of biochemical recurrence in the RP cohort and further stratified patients of intermediate risk. Lastly, androgen receptor variant 7 (ARV7)+ cells and AR− cells expressing neuroendocrine and stem markers were interspersed among a majority of AR+ cells in ADT cases. Altogether, the comprehensive quantification of AR expression in the prostate reveals concomitant changes in tumor cell subtypes and fibroblasts, emphasizing the significance of AR− cells with disease progression and palliative ADT.

Abstract Background Prostate cancer (PCa) patients receiving radiotherapy may be predisposed to secondary malignancies. This study aimed to determine the association between PCa treatments, including radical prostatectomy (RP), external beam radiation therapy (EBRT), brachytherapy (BT) and androgen deprivation therapy (ADT); and secondary bladder and colorectal cancer. Methods A cohort study was constructed using Quebec administrative databases (Med‐Echo and RAMQ). Included men were diagnosed and treated for PCa between 2000 and 2016. Patients with bladder or colorectal cancer prior to PCa were excluded. Follow‐up ended at the earliest of the following: incidence of bladder or colorectal cancer, death, or December 31, 2016. EBRT, BT, EBRT+ADT, RP + ADT or ADT only were compared individually to RP. The incidence of secondary bladder and colorectal cancer were computed. Inverse probability of treatment weighting (IPTW) based on a propensity score was used to control for potential confounding. IPTW‐Cox proportional hazards models were used. Results A significant association was found between secondary bladder cancer and EBRT (HR: 1.84, 95%CI: 1.60;2.13), and also EBRT+ADT (HR: 2.08, 95%CI: 1.67;2.56), but not with BT (HR: 1.36, 95%CI: 0.68;2.74). Secondary colorectal cancer was significantly associated to either EBRT (HR: 1.36, 95%CI: 1.21;1.53); or BT (HR: 2.46, 95%CI: 1.71;3.54). The association between ADT alone and both secondary cancers was also significant (HR: 1.98, 95%CI: 1.69;2.31 and HR: 1.69, 95%CI: 1.49;1.92, respectively). Conclusions Compared to PCa patients undergoing RP, the secondary bladder cancer was associated with EBRT, ADT, alone or in combination. The secondary colorectal cancer was also associated with receiving either EBRT, BT or ADT.

Background: The introduction of novel hormonal agents (NHAs) such as abiraterone acetate (ABI) and enzalutamide (ENZ) for metastatic castration-resistant prostate cancer (mCRPC) was an important milestone given their survival benefits, tolerability, and ease of administration relative to taxane chemotherapies. This descriptive study sought to describe the utilization trends of ABI and ENZ in patients with mCRPC in the early years after their approval in the province of Quebec in Canada. Methods: A retrospective population-based cohort was extracted from Quebec public healthcare administrative databases. The cohort included first-time users of NHAs (ABI or ENZ) from 2011 to 2016. The primary analyses aimed to describe the overall temporal trends (2011–2016) of NHA initiators by chemotherapy status (chemotherapy-naïve versus post-chemotherapy), and prescribing specialty (medical oncology versus urology versus others). Results: The cohort comprised 2183 patients, with 1562 (72%) in the chemotherapy-naïve group and 621 (28%) in the post-chemotherapy group. While the majority of patients were post-chemotherapy NHA initiators in 2012, this proportion decreased over time and accounted for only 13% of NHA initiators by the end of 2016. Medical oncologists were the most frequent prescribers of NHAs (upwards of 60%) throughout 2012 but fell to 45% by the end of 2016. Conversely, the proportion of prescriptions by urologists increased from 22% in 2012 to 42% in 2016. Conclusion: Over time, there was an increasing proportion of (1) patients who initiated NHAs without prior chemotherapy treatment, (2) NHA prescribing by urologists, and (3) ENZ users. Taken together, this implies that the introduction of NHAs has altered the management of mCRPC and urologists quickly adopted NHAs into their practice.

Abstract Prostate cancer (PCa) clinical heterogeneity underscores tumor heterogeneity, which may be best defined by cell subtypes. To test if cell subtypes contributing to progression can be assessed noninvasively, we investigated whether 14 genes representing luminal, neuroendocrine, and stem cells are detectable in whole blood RNA of patients with advanced PCa. For each gene, reverse transcription quantitative polymerase chain reaction assays were first validated using RNA from PCa cell lines, and their traceability in blood was assessed in cell spiking experiments. These were next tested in blood RNA of 40 advanced PCa cases and 40 healthy controls. Expression in controls, which was low or negative, was used to define stringent thresholds for gene overexpression in patients to account for normal variation in white blood cells. Thirty‐five of 40 patients overexpressed at least one gene. Patients with more genes overexpressed had a higher risk of death (hazard ratio 1.42, range 1.12–1.77). Progression on androgen receptor inhibitors was associated with overexpression of stem (odds ratio [OR] 7.74, range 1.68–35.61) and neuroendocrine (OR 13.10, range 1.24–142.34) genes, while luminal genes were associated with taxanes (OR 2.7, range 1.07–6.82). Analyses in PCa transcriptomic datasets revealed that this gene panel was most prominent in metastases of advanced disease, with diversity among patients. Collectively, these findings support the contribution of the prostate cell subtypes to disease progression. Cell‐subtype specific genes are traceable in blood RNA of patients with advanced PCa and are associated with clinically relevant end points. This opens the door to minimally invasive liquid biopsies for better management of this deadly disease.

Background: Orally administrated agents play a key role in the management of prostate cancer, providing a convenient and cost-effective treatment option for patients. However, they are also associated with adherence issues which can compromise therapeutic outcomes. This scoping review identifies and summarizes data on adherence to oral hormonal therapy in advanced prostate cancer and discusses associated factors and strategies for improving adherence. Methods: PubMed (inception to 27 January 2022) and conference databases (2020–2021) were searched to identify English language reports of real-world and clinical trial data on adherence to oral hormonal therapy in prostate cancer using the key search terms ‘prostate cancer’ AND ‘adherence’ AND ‘oral therapy’ OR respective aliases. Results: Most adherence outcome data were based on the use of androgen receptor pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Self-reported and observer-reported adherence data were used. The most common observer-reported measure, medication possession ratio, showed that the vast majority of patients were in possession of their medication, although proportion of days covered and persistence rates were considerably lower, raising the question whether patients were consistently receiving their treatment. Study follow-up for adherence was generally around 6 months up to 1 year. Studies also indicate that persistence may drop further with longer follow-up, especially in the non-mCRPC setting, which may be a concern when years of therapy are required. Conclusions: Oral hormonal therapy plays an important role in the treatment of advanced prostate cancer. Data on adherence to oral hormonal therapies in prostate cancer were generally of low quality, with high heterogeneity and inconsistent reporting across studies. Short study follow-up for adherence and focus on medication possession rates may further limit relevance of available data, especially in settings that require long-term treatment. Additional research is required to comprehensively assess adherence.

Background: Health economic evaluations are needed to assess the impact on the healthcare system of emerging treatment patterns for advanced prostate cancer. The objective of this study is to review the scientific literature identifying cost-effectiveness and cost analyses that are assessing treatments for metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC). Methods: On 29 June 2021, we searched the scientific (MEDLINE, Embase, and EBSCO) and grey literature for health economic studies targeting mHSPC and nmCRPC. We used the CHEC-extended checklist and the Welte checklist for risk-of-bias assessment and transferability analysis, respectively. Results: We retained 20 cost-effectiveness and 4 cost analyses in the mHSPC setting, and 14 cost-effectiveness and 6 cost analyses in the nmCRPC setting. Docetaxel in combination with androgen deprivation therapy (ADT) was the most cost-effective treatment in the mHSPC setting. Apalutamide, darolutamide, and enzalutamide presented similar results vs. ADT alone and were identified as cost-effective treatments for nmCRPC. An increase in costs as patients transitioned from nmCRPC to mCRPC was noted. Conclusions: We concluded that there is an important unmet need for health economic evaluations in the mHSPC and nmCRPC setting incorporating real-world data to support healthcare decision making.

Background: The role of serum lymphocyte-based biomarkers, such as the neutrophil-to-lymphocyte (NLR), lymphocyte-to-monocyte (LMR), and platelet-to-lymphocyte (PLR) ratios, was previously studied in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy but remains underexplored in patients treated with trimodal therapy (TMT). Objective: To analyze the impact of serum lymphocyte-based biomarkers on main oncological outcomes after TMT for MIBC. Design, setting, and participants: A retrospective study, including 176 patients treated with TMT for nonmetastatic MIBC (cT2–4/cN0–2) between 2001 and 2017 at a tertiary academic center, was conducted. Intervention: TMT, consisting of initial maximal transurethral resection of the bladder tumor, followed by radiotherapy with concurrent chemotherapy. Outcome measurements and statistical analysis: Clinicopathological characteristics, serum laboratory tests, and imaging reports were collected. NLR, LMR, and PLR were calculated before and at the end of TMT. Dynamic patterns of NLR, LMR, and PLR during TMT were studied. Multivariable regression models were performed to estimate the effect of these biomarkers on complete response (CR) to TMT and survival. Results and limitations: The median age was 75 yr (interquartile range 66–82). Staging was cT2 in 156 (89%) and cN0 in 159 (90%) patients. A pretreatment NLR (pre-NLR) of ≥4.0 was independently associated with lower CR rates (odds ratio 0.32; p = 0.013). In addition, a pre-NLR of ≥4.0 was associated with worse cancer-specific survival (hazard ratio [HR] 1.88; p = 0.032) and overall survival (OS; HR 1.61; p = 0.033) together with other factors such as hydronephrosis, Eastern Cooperative Oncology Group performance status, and cT stage 3-4a. When both pre- and post-treatment variables were considered, an increase in NLR beyond 75% during TMT (HR 1.63; p = 0.035) was associated with worse OS. This study was limited by its retrospective design. Conclusions: A high pre-NLR value was independently associated with lower rates of CR and worse survival in MIBC patients undergoing TMT. Prospective validation is needed to implement NLR into clinical practice. Patient summary: In this study, we reported the oncological outcomes of patients with muscle-invasive bladder cancer treated with trimodal therapy. We found that the neutrophil-to-lymphocyte ratio, a cheap and available blood-derived biomarker, was associated with response to trimodal therapy and survival outcomes.

Approximately 4%–10% of patients with renal cell carcinoma (RCC) have tumoral vascular invasion with resultant thrombi in the renal vein and in the inferior vena cava (IVC). The authors describe an interesting case of IVC tumor thrombus that migrated to the right cardiac chambers during RCC resection. The diagnosis was made by intraoperative transesophageal echocardiography (TEE), which revealed the presence of a free-floating thrombus between the right atrium (RA) and right ventricle (RV). The patient required an urgent sternotomy with cardiopulmonary bypass (CPB) for atrial thrombus removal prior to the completion of the nephrectomy. The patient made a full recovery and was discharged to a rehabilitation facility. These findings illustrate the importance of intraoperative TEE monitoring during nephrectomy and IVC thrombectomy. In this case, TEE allowed for the diagnosis of an unexpected complication necessitating prompt cardiac surgical management.

Abstract Background To define a new coefficient to be used in the formula (Volume = L x H x W x Coefficient) that better estimates prostate volume using dimensions of fresh prostates from patients who had transrectal ultrasound (TRUS) imaging prior to prostatectomy. Methods The prostate was obtained from 153 patients, weighed and measured to obtain length (L), height (H), and width (W). The density was determined by water displacement to calculate volume. TRUS data were retrieved from patient charts. Linear regression analyses were performed to compare various prostate volume formulas, including the commonly used ellipsoid formula and newly introduced bullet-shaped formula. Results By relating measured prostate volumes from fresh prostates to TRUS-estimated prostate volumes, 0.66 was the best fitting coefficient in the (L x H x W x Coefficient) equation. This newfound coefficient combined with outlier removal yielded a linear equation with an R2 of 0.64, compared to 0.55 and 0.60, for the ellipsoid and bullet, respectively. By comparing each of the measured vs. estimated dimensions, we observed that the mean prostate height and length were overestimated by 11.1 and 10.8% using ultrasound (p 0.05). Overall, the ellipsoid formula underestimates prostate volumes by 18%, compared to an overestimation of 4.6 and 5.7% for the bullet formula and the formula using our coefficient, respectively. Conclusions This study defines, for the first time, a coefficient based on freshly resected prostates as a reference to estimate volumes by imaging. Our findings support a bullet rather than an ellipsoid prostate shape. Moreover, substituting the coefficient commonly used in the ellipsoid formula by our calculated coefficient in the equation estimating prostate volume by TRUS, provides a more accurate value of the true prostate volume.

The purpose of this study was to evaluate the impact of augmented prophylaxis (ciprofloxacin augmented with an aminoglycoside) compared with that of empirical prophylaxis (ciprofloxacin alone) on transrectal post-prostate biopsy infectious complication (PBIC) rates. A retrospective cohort study evaluated 2835 patients receiving either augmented or empirical prophylactic regimen before undergoing a transrectal ultrasound-guided prostate biopsy between January 2010 and October 2018. The patients were compared according to prophylactic regimen received. The incidence of PBICs and the impact of risk factors were evaluated. A total of 1849 patients received the empirical regimen, and 986 patients received the augmented regimen. The composite PBIC rate was 2.1% (n = 39) and 0.9% (n = 9) (p = 0.019), respectively, and the SIRS rate was 1.9% and 0.8% (p = 0.020), respectively. Of the 50 patients presenting with a PBIC, 29 (58%) had positive cultures (blood and/or urine) for Escherichia coli, of which 28 (97%) were ciprofloxacin-resistant. Taking a fluoroquinolone in the previous 6 months and having a previous urinary tract infection within 1 year prior to the biopsy had significant impact on PBIC rates (p = 0.009 and p = 0.011, respectively). Compared with ciprofloxacin alone, augmented prophylaxis was associated with significantly lower PBICs.

There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.

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Detection of unique oncogenic alterations encoded by the sequence or biochemical modification in cancer-associated transforming macromolecules has revolutionized diagnosis, classification and management of human cancers. While these signatures were traditionally regarded as largely intracellular and confined to the tumor mass, oncogenic mutations and actionable cancer-related molecular alterations can also be accessed remotely through their recovery from biofluids of either rare circulating tumor cells (CTCs), or of more abundant non-cellular carriers, such as extracellular vesicles (EVs), protein complexes, or cell-free tumor DNA (ctDNA). Tumor-related macromolecules may also accumulate in circulating platelets. Collectively, these approaches are known as liquid biopsy and hold promise as non-invasive, real-time opportunities to access to the evolving molecular landscape of human malignancies. More recently, a possibility of recovering cancer-specific DNA sequences from circulating leukocytes has also been postulated using experimental models. While it is often assumed that these and other liquid biopsy approaches rely on material passively shed from the tumor mass or its debris, recent evidence suggests that several regulated processes contribute to the abundance, nature, half-life, and turnover of different circulating cancer-related molecular signals. Moreover, many of these signals possess biological activity and may elicit local and systemic regulatory responses. Thus, a better understanding of the biology of liquid biopsy platforms and analytes may enable achieving improved performance of this promising and emerging diagnostic strategy in cancer.

Abstract Background Refinement of parameters defining prostate cancer (PC) prognosis are urgently needed to identify patients with indolent versus aggressive disease. The Canadian Prostate Cancer Biomaker Network (CPCBN) consists of researchers from four Canadian provinces to create a validation cohort to address issues dealing with PC diagnosis and management. Methods A total of 1512 radical prostatectomy (RP) specimens from five different biorepositories affiliated with teaching hospitals were selected to constitute the cohort. Tumoral and adjacent benign tissues were arrayed on tissue microarrays (TMAs). A patient clinical database was developed and includes data on diagnosis, treatment and clinical outcome. Results Mean age at diagnosis of patients in the cohort was 61 years. Of these patients, 31% had a low grade (≤6) Gleason score (GS), 55% had GS 7 (40% of 3 + 4 and 15% of 4 + 3) and 14% had high GS (≥8) PC. The median follow-up of the cohort was 113 months. A total of 34% had a biochemical relapse, 4% developed bone metastasis and 3% of patients died from PC while 9% died of other causes. Pathological review of the TMAs confirmed the presence of tumor and benign tissue cores for > 94% of patients. Immunohistochemistry and FISH analyses, performed on a small set of specimens, showed high quality results and no biorepository-specific bias. Conclusions The CPCBN RP cohort is representative of real world PC disease observed in the Canadian population. The frequency of biochemical relapse and bone metastasis as events allows for a precise assessment of the prognostic value of biomarkers. This resource is available, in a step-wise manner, for researchers who intend to validate prognostic biomarkers in PC. Combining multiple biomarkers with clinical and pathologic parameters that are predictive of outcome will aid in clinical decision-making for patients treated for PC.

Abstract Background The benefits of PSA-based screening for prostate cancer (PCa) are controversial. The Canadian and American Task Forces on Preventive Health Care (CTFPHC & USPSTF) have released recommendations against the use of routine PSA-based screening for any men. We thought to assess the impact of these recommendations on the outcomes and trends of prostate needle biopsies. Methods A complete chart review was conducted for all men who received prostate needle biopsies at McGill University Health Center between 2010 and 2016. Of those, we included 1425 patients diagnosed with PCa for analysis. We Compared 2 groups of patients (pre and post recommendations’ release date) using Welch’s t-tests and Chi-square test. A multivariate logistic regression model was used to analyze variables predicting worse pathological outcomes. Results When the release date of the USPSTF draft (October 2011) was used as a cut-off, we found an average annual decrease of 10.6% in the total number of biopsies. The median (IQR) baseline PSA levels were higher in post-recommendations group (n = 977) when compared to pre-recommendations group (n = 448) [8 ng/ml (5.7–12.9) versus 6.4 ng/ml (4.9–10.1), respectively. P = 0.0007]. Also, post-recommendations group’s patients had higher Gleason score (G7: 35.4% versus 28.4% and G8-G10: 31.2% versus 18.1%, respectively. P

BACKGROUND:The identification of patients with high-risk prostate cancer (PC) is a major challenge for clinicians, and the improvement of current prognostic parameters is an unmet clinical need. We and others have identified an association between the nuclear localization of NF-κB p65 and biochemical recurrence (BCR) in PC in small and/or single-centre cohorts of patients. METHODS AND FINDINGS:In this study, we accessed 2 different multi-centre tissue microarrays (TMAs) representing cohorts of patients (Test-TMA and Validation-TMA series) of the Canadian Prostate Cancer Biomarker Network (CPCBN) to validate the association between p65 nuclear frequency and PC outcomes. Immunohistochemical staining of p65 was performed on the Test-TMA and Validation-TMA series, which include PC tissues from patients treated by first-line radical prostatectomy (n = 250 and n = 1,262, respectively). Two independent observers evaluated the p65 nuclear frequency in digital images of cancer tissue and benign adjacent gland tissue. Kaplan-Meier curves coupled with a log-rank test and univariate and multivariate Cox regression models were used for statistical analyses of continuous values and dichotomized data (cutoff of 3%). Multivariate analysis of the Validation-TMA cohort showed that p65 nuclear frequency in cancer cells was an independent predictor of BCR using continuous (hazard ratio [HR] 1.02 [95% CI 1.00-1.03], p = 0.004) and dichotomized data (HR 1.33 [95% CI 1.09-1.62], p = 0.005). Using a cutoff of 3%, we found that this biomarker was also associated with the development of bone metastases (HR 1.82 [95% CI 1.05-3.16], p = 0.033) and PC-specific mortality (HR 2.63 [95% CI 1.30-5.31], p = 0.004), independent of clinical parameters. BCR-free survival, bone-metastasis-free survival, and PC-specific survival were shorter for patients with higher p65 nuclear frequency (p < 0.005). As the small cores on TMAs are a limitation of the study, a backward validation of whole PC tissue section will be necessary for the implementation of p65 nuclear frequency as a PC biomarker in the clinical workflow. CONCLUSIONS:We report the first study using the pan-Canadian multi-centre cohorts of CPCBN and validate the association between increased frequency of nuclear p65 frequency and a risk of disease progression.

Purpose: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. Materials and Methods: Low- and intermediate-risk prostate cancer patients were assigned to training (n[333) and validation (n[202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with crossvalidation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. Results: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P <.001). Conclusions: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance. [ABSTRACT FROM AUTHOR]

Few studies have addressed racial differences in prostate cancer (PCa) detection between Western and Arabian countries, although PCa has a significantly lower prevalence in Arabic populations compared to Western populations. Therefore, an explanation of this difference is lacking. Serum prostate-specific antigen (PSA) is a valuable marker used to select patients who should undergo prostate biopsies, although the manner in which it is used may require adjustments based on the ethnic population in question. We investigated racial differences in the PCa detection rate between Canadian and Saudi populations. A retrospective analysis was performed of data collected prospectively over 5 consecutive years in urology clinics at the McGill University Health Center (MUHC) and King Saud University Hospital (KSUH). Men who had high (>4'ng/mL) or rising PSA levels and a negative digital rectal examination were eligible. A total of 1403 Canadian and 414 Saudi patients were evaluated for the study; 717 and 158 men, median age 64 and 68 years, were included in the MUHC and KSUH cohorts, respectively, P

Renal angiomyolipoma with inferior vena caval venous extension is rare with only 40 cases reported in the literature. We report a case of a 35-year-old lady with angiomyolipoma with inferior vena caval thrombus that was managed surgically with robotic-assisted radical nephrectomy.

Purpose: Adrenal 11-oxygenated androgens may support cancer progression in men with prostate cancer owing to their abundance and androgenic potential. We hypothesized that preoperative circulating levels of 11-oxygenated androgens influence clinical outcomes in men with newly diagnosed localized prostate cancer. Materials and Methods: We studied 1,793 treatment-naïve patients and 155 patients who received preoperative treatment with 5α-reductase inhibitors in the prospective PROCURE cohort, for which preoperative plasma samples were obtained prior to radical prostatectomy. Adrenal 11-oxygenated precursors, potent 11-oxygenated androgens and their metabolites (n=7), were quantified using liquid chromatography-tandem mass spectrometry. Circulating levels were evaluated in relation to prognostic factors, disease-free survival, and metastasis-free survival using multivariable Cox proportional hazards models. Results: At a median follow-up of 93.8 months after surgery, 583 patients experienced biochemical recurrence, 104 developed metastatic disease, and 168 deceased. Higher levels of 11-hydroxytestosterone and 11-ketotestosterone were observed in men with PSA >20 ng/mL and positive nodal status (P < .05). In multivariable analyses, no significant association between 11-oxygenated androgens and disease-free survival was observed. Adrenal 11β-hydroxyandrostenedione, the predominant androgenic 11-ketotestosterone, and its metabolite 11-ketoandrosterone, modeled as quartiles, were associated with metastasis-free survival (P = .06, P = .03, and P = .008, respectively). Significant accumulation of 11-oxygenated androgen precursors and bioactive androgens, but reduced metabolite levels, was observed in patients on 5α-reductase inhibitors (P < .001). Conclusions: Preoperative circulating 11-oxygenated androgen levels are associated with metastasis-free survival in men with localized prostate cancer undergoing radical prostatectomy and are affected by 5α-reductase inhibitor treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Prostate cancer (PCa) is the most common non-skin cancer among men in developed countries. Several novel treatments have been adopted by healthcare systems to manage PCa. Most of the observational studies and randomized trials on PCa have concurrently evaluated fewer treatments over short follow-up. Further, preceding decision analytic models on PCa management have not evaluated various contemporary management options. Therefore, a contemporary decision analytic model was necessary to address limitations to the literature by synthesizing the evidence on novel treatments thereby forecasting short and long-term clinical outcomes. OBJECTIVES: To develop and validate a Markov Monte Carlo model for the contemporary clinical management of PCa, and to assess the clinical burden of the disease from diagnosis to end-of-life. METHODS: A Markov Monte Carlo model was developed to simulate the management of PCa in men 65 years and older from diagnosis to end-of-life. Health states modeled were: risk at diagnosis, active surveillance, active treatment, PCa recurrence, PCa recurrence free, metastatic castrate resistant prostate cancer, overall and PCa death. Treatment trajectories were based on state transition probabilities derived from the literature. Validation and sensitivity analyses assessed the accuracy and robustness of model predicted outcomes. RESULTS: Validation indicated model predicted rates were comparable to observed rates in the published literature. The simulated distribution of clinical outcomes for the base case was consistent with sensitivity analyses. Predicted rate of clinical outcomes and mortality varied across risk groups. Life expectancy and health adjusted life expectancy predicted for the simulated cohort was 20.9 years (95%CI 20.5-21.3) and 18.2 years (95% CI 17.9-18.5), respectively. CONCLUSION: Study findings indicated contemporary management strategies improved survival and quality of life in patients with PCa. This model could be used to compare long-term outcomes and life expectancy conferred of PCa management paradigms.