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Backround: Inflammation characterized by the presence of T and B cells is often observed in prostate cancer, but it is unclear how T‐ and B‐cell levels change during carcinogenesis and whether such changes influence disease progression. Methods: The study used a retrospective sample of 73 prostate cancer cases (45 whites and 28 African Americans) that underwent surgery as their primary treatment and had a benign prostate biopsy at least 1 year before diagnosis. CD3+, CD4+, and CD20+ lymphocytes were quantified by immunohistochemistry in paired pre‐ and post‐diagnostic benign prostate biopsy and tumor surgical specimens, respectively. Clusters of similar trends of expression across two different timepoints and three distinct prostate regions—benign biopsy glands (BBG), tumor‐adjacent benign glands (TAG), and malignant tumor glandular (MTG) regions—were identified using Time‐series Anytime Density Peaks Clustering (TADPole). A Cox proportional hazards model was used to estimate the hazard ratio (HR) of time to biochemical recurrence associated with region‐specific lymphocyte counts and regional trends. Results: The risk of biochemical recurrence was significantly reduced in men with an elevated CD20+ count in TAG (HR = 0.81, p = 0.01) after adjusting for covariates. Four distinct patterns of expression change across the BBG‐TAG‐MTG regions were identified for each marker. For CD20+, men with low expression in BBG and higher expression in TAG compared to MTG had an adjusted HR of 3.06 (p = 0.03) compared to the reference group that had nominal differences in CD20+ expression across all three regions. The two CD3+ expression patterns that featured lower CD3+ expression in the BBG compared to the TAG and MTG regions had elevated HRs ranging from 3.03 to 4.82 but did not reach statistical significance. Conclusions: Longitudinal and spatial expression patterns of both CD3+ and CD20+ suggest that increased expression in benign glands during prostate carcinogenesis is associated with an aggressive disease course. [ABSTRACT FROM AUTHOR]

Distal-less homeobox-1 (DLX1) is a well-established non-invasive biomarker for prostate cancer (PCa) diagnosis, however, its mechanistic underpinnings in disease pathobiology are not known. Here, we reveal the oncogenic role of DLX1 and show that abrogating its function leads to reduced tumorigenesis and metastases. We observed that ~60% of advanced-stage and metastatic patients display higher DLX1 levels. Moreover, ~96% of TMPRSS2-ERG fusion-positive and ~70% of androgen receptor (AR)-positive patients show elevated DLX1, associated with aggressive disease and poor survival. Mechanistically, ERG coordinates with enhancer-bound AR and FOXA1 to drive transcriptional upregulation of DLX1 in ERG-positive background. However, in ERG-negative context, AR/AR-V7 and FOXA1 suffice to upregulate DLX1. Notably, inhibiting ERG/AR-mediated DLX1 transcription using BET inhibitor (BETi) or/and anti-androgen drugs reduce its expression and downstream oncogenic effects. Conclusively, this study establishes DLX1 as a direct-target of ERG/AR with an oncogenic role and demonstrates the clinical significance of BETi and anti-androgens for DLX1-positive patients. Distal-less homeobox 1 (DLX1) is reported as a prostate cancer (PCa) diagnostic biomarker, but the mechanism for its upregulation in PCa is unclear. Here the authors show that ERG, AR and FOXA1 transcriptionally regulates DLX1 expression in PCa, and the inhibition of this ERG/AR transcriptional circuitry with a BET inhibitor reduces the oncogenic effects of DLX1. [ABSTRACT FROM AUTHOR]

Systemic inflammation may increase risk for prostate cancer progression, but the role it plays in prostate cancer susceptibility is unknown. From a cohort of over 10,000 men who had either a prostate biopsy or transurethral resection that yielded a benign finding, we analyzed 517 incident prostate cancer cases identified during follow-up and 373 controls with one or more white blood cell tests during a follow-up period between one and 18 years. Multilevel, multivariable longitudinal models were fit to two measures of systemic inflammation, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), to determine NLR and MLR trajectories associated with increased risk for prostate cancer. For both measures, we found no significant differences in the trajectories by case/control status, however in modeling NLR trajectories there was a significant interaction between race (white or Black and case-control status. In race specific models, NLR and MLR values were consistently higher over time among white controls than white cases while case-control differences in NLR and MLR trajectories were not apparent among Black men. When cases were classified as aggressive as compared to non-aggressive, the case-control differences in NLR and MLR values over time among white men were most apparent for non-aggressive cases. For NLR among white men, significant case-control differences were observed for the entire duration of observation for men who had inflammation in their initial prostate specimen. It is possible that, among white men, monitoring of NLR and MLR trajectories after an initial negative biopsy may be useful in monitoring prostate cancer risk. [ABSTRACT FROM AUTHOR]

Growth and differentiation factor 15 (GDF‐15), also known as macrophage inhibitory cytokine 1 (MIC‐1), may act as both a tumor suppressor and promotor and, by regulating NF‐κB and macrophage signaling, promote early prostate carcinogenesis. To determine whether expression of these two inflammation‐related proteins affect prostate cancer susceptibility, dual immunostaining of benign prostate biopsies for GDF‐15 and NF‐κB was done in a study of 503 case‐control pairs matched on date, age, and race, nested within a historical cohort of 10,478 men. GDF‐15 and NF‐κB expression levels were positively correlated (r = 0.39; p < 0.0001), and both were significantly lower in African American (AA) compared with White men. In adjusted models that included both markers, the odds ratio (OR) for NF‐κB expression was statistically significant, OR =0.87; p = 0.03; 95% confidence interval (CI) =0.77–0.99, while GDF‐15 expression was associated with a nominally increased risk, OR =1.06; p = 0.27; 95% CI =0.96–1.17. When modeling expression levels by quartiles, the highest quartile of NF‐κB expression was associated with almost a fifty percent reduction in prostate cancer risk (OR =0.51; p = 0.03; 95% CI =0.29–0.92). In stratified models, NF‐κB had the strongest negative association with prostate cancer in non‐aggressive cases (p = 0.03), older men (p = 0.03), and in case‐control pairs with longer follow‐up (p = 0.02). Risk associated with GDF‐15 expression was best fit using nonlinear regression modeling where both first (p = 0.02) and second (p = 0.03) order GDF‐15 risk terms were associated with significantly increased risk. This modeling approach also revealed significantly increased risk associated with GDF‐15 expression for subsamples defined by AA race, aggressive disease, younger age, and in case‐control pairs with longer follow‐up. Therefore, although positively correlated in benign prostatic biopsies, NF‐κB and GDF‐15 expression appear to exert opposite effects on risk of prostate tumor development. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the molecular underpinnings of the rare aggressive prostate cancer variants adenosquamous carcinoma, pleomorphic giant‐cell carcinoma, and sarcomatoid carcinoma. Methods and results: We retrieved 19 tumours with one or more variant(s), and performed ERG immunohistochemistry, a next‐generation sequencing assay targeting recurrent gene fusions, and fluorescence in‐situ hybridisation (FISH) for ERG and BRAF. Divergent differentiation included: sarcomatoid carcinoma (n = 10), adenosquamous carcinoma (n = 7), and pleomorphic giant‐cell carcinoma (n = 7). Five patients had more than one variant. Four had variants only in metastases. ERG rearrangement was detected in nine (47%, seven via sequencing, showing TMPRSS2–ERG fusions and one GRHL2–ERG fusion, and two via FISH, showing rearrangement via deletion). ERG was immunohistochemically positive in the adenocarcinoma in eight of nine (89%) patients, but was immunohistochemically positive in the variant in only five of nine patients (56%, typically decreased). One patient had a false‐positive ERG immunohistochemical result in the sarcomatoid component despite a negative FISH result. Two (11%) harboured BRAF fusions (FAM131A–BRAF and SND1–BRAF). Conclusions: ERG fusions are present in these rare prostate cancer variants with a frequency close to that in conventional prostate cancer (9/19, 47%). ERG immunohistochemistry usually detects rearrangement in the adenocarcinoma, but is less sensitive for the variant histology, with weak to negative staining. Adenosquamous and sarcomatoid variants can, particularly, occur together. Molecular assessment may be an additional tool in selected cases to confirm the prostatic origin of unusual tumours. The presence of two BRAF rearrangements suggests that this gene fusion may be enriched in this setting, as RAF kinase fusions have been previously reported in 1–2% of prostate cancers. [ABSTRACT FROM AUTHOR]

Emergence of an aggressive androgen receptor (AR)-independent neuroendocrine prostate cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Nevertheless, the majority of advanced-stage prostate cancer patients, including those with SPINK1-positive subtype, are treated with AR-antagonists. Here, we show AR and its corepressor, REST, function as transcriptional-repressors of SPINK1, and AR-antagonists alleviate this repression leading to SPINK1 upregulation. Increased SOX2 expression during NE-transdifferentiation transactivates SPINK1, a critical-player for maintenance of NE-phenotype. SPINK1 elicits epithelial-mesenchymal-transition, stemness and cellular-plasticity. Conversely, pharmacological Casein Kinase-1 inhibition stabilizes REST, which in cooperation with AR causes SPINK1 transcriptional-repression and impedes SPINK1-mediated oncogenesis. Elevated levels of SPINK1 and NEPC markers are observed in the tumors of AR-antagonists treated mice, and in a subset of NEPC patients, implicating a plausible role of SPINK1 in treatment-related NEPC. Collectively, our findings provide an explanation for the paradoxical clinical-outcomes after ADT, possibly due to SPINK1 upregulation, and offers a strategy for adjuvant therapies. SPINK1 upregulation is found in ~10–25% of prostate cancers. Here, they show that whilst SPINK1 is transcriptionally repressed by androgen receptor and its co-repressor REST, it is upregulated after androgen-deprivation therapy, which leads to neuroendocrine differentiation of prostate cancer cells. [ABSTRACT FROM AUTHOR]

Aims: Comedonecrosis in prostate cancer has always been Gleason pattern 5. However, we aimed to evaluate how intraductal carcinoma (not graded) with comedonecrosis should be considered. Methods and results: From 52 radical prostatectomy patients, 40 were informative and evaluated with immunohistochemistry for basal cells. Clinical outcome was assessed for biochemical recurrence, metastatic disease and the need for adjuvant therapy. Comedonecrosis was predominantly located in intraductal carcinoma (24, 60%). However, nine (23%) had comedonecrosis within invasive cancer and seven (18%) within both invasive and intraductal carcinoma. Extraprostatic extension rarely showed comedonecrosis (5, 13%), but rather perineural invasion within cribriform glands. Tumours were largely high‐stage (15, 38% pT3a and 19, 48% pT3b), with 15 (37%) having positive lymph nodes and four distant metastases. Most cases (25, 63%) had other patterns of Gleason pattern 5 (single cells, solid), although 10 were reclassified as containing no invasive pattern 5. Of these, most were pT3 (eight of 10), but none had positive lymph nodes. Lymph node metastases were more common in patients with invasive cancer containing comedonecrosis (P = 0.02), and the need for androgen deprivation was near significance (P = 0.07), but biochemical recurrence was not significantly different (P = 0.58). Conclusions: Prostate cancer with comedonecrosis is often intraductal; however, these tumours are largely high‐stage, showing a higher rate of positive lymph nodes with invasive comedonecrosis. Immunohistochemistry may be considered when comedonecrosis may significantly change the tumour grade. However, it is not clear at present that excluding intraductal carcinoma from the grade is superior to including it in grading when it is associated with high‐grade invasive cancer. [ABSTRACT FROM AUTHOR]

Cadmium is a known carcinogen that has been implicated in prostate cancer, but how it affects prostate carcinogenesis in humans remains unclear. Evidence from basic science suggests that cadmium can bind to the androgen receptor causing endocrine disruption. The androgen receptor is required for normal prostate development and is the key driver of prostate cancer progression. In this study, we examined the association between cadmium content and androgen receptor protein expression in prostate cancer tissue of African American (N = 22) and European American (N = 30) men. Although neither overall tumor cadmium content (log transformed) nor androgen receptor protein expression level differed by race, we observed a race-cadmium interaction with regard to androgen receptor expression ( P  = 0.003) even after accounting for age at prostatectomy, smoking history, and Gleason score. African American men had a significant positive correlation between tumor tissue cadmium content and androgen receptor expression (Pearson correlation = 0.52, P  = 0.013), while European Americans showed a non-significant negative correlation between the two (Pearson correlation = −0.19, P  = 0.31). These results were unchanged after further accounting for tissue zinc content or dietary zinc or selenium intake. African American cases with high-cadmium content (>median) in tumor tissue had more than double the androgen receptor expression (0.021 vs. 0.008, P  = 0.014) of African American men with low-cadmium level. No difference in androgen receptor expression was observed in European Americans by cadmium level (high 0.015 vs. low 0.011, P  = 0.30). Larger studies are needed to confirm these results and if upheld, determine the biologic mechanism by which cadmium increases androgen receptor protein expression in a race-dependent manner. Our results suggest that cadmium may play a role in race disparities observed in prostate cancer. [ABSTRACT FROM AUTHOR]

Objectives: Prostate cancer screening algorithms and preoperative nomograms do not include patients' body mass index (BMI). We evaluated outcomes at radical prostatectomy (RP) adjusted to BMI. Methods: Serum prostate-specific antigen (PSA) levels, PSA mass, PSA density (PSAD), and RP findings were analyzed with respect to BMI in 4,926 men who underwent RP between 2005 and 2014. Results: In total, 1,001 (20.3%) men were normal weight, 2,547 (51.7%) were overweight, and 1,378 (28%) were obese. Median PSA levels (ng/mL) were normal weight, 5.0; overweight, 5.1; and obese, 5.2 (P = .094). Median PSA mass increased with increasing BMI: 15.9 vs 17.4 vs 19.4 µg (P < .001). Median PSAD was not significantly different: 0.11 vs 0.11 vs 0.11 ng/mL/g (P = .084). Median prostate weight increased with increasing BMI: 44 vs 45 vs 49 g (P < .001). Median prostatectomy tumor volume increased with increasing BMI: 3.9 vs 4.7 vs 5.9 cm³ (P < .001). Overweight and obese patients had a higher Gleason score and more locally advanced cancer (P < .001). Frequency of positive surgical margins increased with higher BMIs (P < .001). Frequency of lymph node metastasis did not differ significantly (P = .088). Conclusions: While BMI correlates with tumor volume, Gleason score, and extent of disease at RP, there is no routinely measured clinical parameter reflecting this. Only PSA mass highlights this correlation. Thus, BMI and potentially PSA mass should be taken into account in predictive algorithms pertaining to prostate cancer and its surgical treatment. [ABSTRACT FROM AUTHOR]

Pelvic lymph node dissection (PLND) is currently the most accurate staging modality for lymph node metastases in prostate adenocarcinoma. There is no consensus on the optimal sampling method of PLND specimens among pathologists. This study analyzed the effectiveness of the submission of entire adipose tissue in 451 cases and its impact on total lymph node yield and detection of positive lymph nodes. The sizes of metastatic foci and positive lymph nodes in 83 cases were also studied. Submission of entire adipose tissue increased the lymph node yield and positive lymph node detection by 36.7 % and 1.99 %, respectively. Three cases had positive lymph nodes exclusively in adipose tissue. Of the patients examined, 68% had the largest positive lymph node, <1 cm. In conclusion, it was noted that metastases from prostate cancer were frequently small and seen within small lymph nodes. Submission of entire adipose tissue substantially increased the lymph node yield, but its impact on the detection of additional positive lymph nodes was low. Submission of the entire adipose tissue may be considered as an option in patients with high-risk factors for lymph node metastases. [ABSTRACT FROM AUTHOR]

We analyzed 5 features on 12-core transrectal ultrasound-guided prostate needle biopsy (TRUS) to predict the extent of cancer at radical prostatectomy (RP). In 388 TRUS-RP pairs, number of positive cores (NPC), percentage of each core involved (%PC), perineural invasion (PNI), Gleason score (GS), distribution of positive cores (DPC), and preoperative prostate-specific antigen (PSA) were correlated with extraprostatic extension (EPE), seminal vesicle invasion (SVI), positive surgical margin (R1), positive lymph nodes (N1), and tumor volume. All features predicted EPE and SVI. NPC, GS, %PC, and PNI strongly predicted R1 status. RP tumor volume was directly proportional to the NPC and %PC. PSA alone and with selected biopsy findings correlated with tumor volume, stage, SVI, and N1 (P < .0001). Contiguous DPC was a significant risk for EPE and SVI (P < .0001) compared with isolated positive cores. Findings at 12-core TRUS along with preoperative PSA reliably predict advanced local disease and have practical value as guides to effective planning for surgical resections. [ABSTRACT FROM AUTHOR]

The emergence of castrate-resistant prostate cancer (CRPC) contributes to the high mortality of patients diagnosed with prostate cancer (PCa), which in part could be attributed to the existence and the emergence of cancer stem cells (CSCs). Recent studies have shown that deregulated expression of microRNAs (miRNAs) contributes to the initiation and progression of PCa. Among several known miRNAs, let-7 family appears to play a key role in the recurrence and progression of PCa by regulating CSCs; however, the mechanism by which let-7 family contributes to PCa aggressiveness is unclear. Enhancer of Zeste homolog 2 (EZH2), a putative target of let-7 family, was demonstrated to control stem cell function. In this study, we found loss of let-7 family with corresponding over-expression of EZH2 in human PCa tissue specimens, especially in higher Gleason grade tumors. Overexpression of let-7 by transfection of let-7 precursors decreased EZH2 expression and repressed clonogenic ability and sphere-forming capacity of PCa cells, which was consistent with inhibition of EZH2 39UTR luciferase activity. We also found that the treatment of PCa cells with BR-DIM (formulated DIM: 3,39- diindolylmethane by Bio Response, Boulder, CO, abbreviated as BR-DIM) up-regulated let-7 and down-regulated EZH2 expression, consistent with inhibition of self-renewal and clonogenic capacity. Moreover, BR-DIM intervention in our ongoing phase II clinical trial in patients prior to radical prostatectomy showed upregulation of let-7 consistent with downregulation of EZH2 expression in PCa tissue specimens after BR-DIM intervention. These results suggest that the loss of let-7 mediated increased expression of EZH2 contributes to PCa aggressiveness, which could be attenuated by BR-DIM treatment, and thus BR-DIM is likely to have clinical impact. [ABSTRACT FROM AUTHOR]

Objective To describe a novel method of achieving pelvic hypothermia during robot-assisted radical prostatectomy ( RARP) and a modification of technique allowing immediate organ retrieval for intraoperative examination and targeted frozen-section biopsies. Patients and Methods Intracorporeal cooling and extraction ( ICE) consists of a modification of the standard RARP technique with the use of the GelPOINT™ ( Applied Medical, Rancho Santa Margarita, CA, USA), a hand access platform, which allows for delivery of ice-slush and rapid specimen extraction without compromising pneumoperitoneum. Results The ICE technique reproducibly achieves a temperature of 15 °C in the pelvic cavity with no obvious body temperature change. Adopting this technique during RARP, there was an absolute risk reduction by 26.6% in positive surgical margin rate in patients with pT3a disease when compared with similar patients undergoing conventional RARP ( P = 0.04). Conclusions The ICE technique eliminates the potential handicap of decreased tactile sensation for oncological margins, especially in the high-risk patients. This technique allows the surgeon to immediately examine the surgical specimen after resection, and with the aid of frozen-section pathology determine if further resection is required. A prospective trial is underway in our centre to evaluate the effects of this novel technique on postoperative outcomes. [ABSTRACT FROM AUTHOR]

Precision prostatectomy is a new form of focal therapy that appears to be safe and efficacious, and adds to the growing armamentarium of risk-adapted therapies for treatment of localized prostate cancer that avoid the functional side effects of whole-gland treatments. The existing treatment options for men with intermediate- or high-volume low-risk prostate cancer (PCa) are associated with a substantial risk of over- or undertreatment. The development of risk-adjusted therapies is an unmet need for these patients. To describe our novel technique of precision prostatectomy, a form of surgical focal therapy that allows radical excision of the index PCa lesion along with >90% prostatic tissue extirpation while preserving the prostatic capsule and seminal vesicle/vas deferens complex on the side contralateral to the dominant cancer lesion, and to report on medium-term functional and oncologic outcomes in the first 88 consecutive men who underwent this procedure between December 2016 and January 2020. Men with (1) prostate-specific antigen (PSA) ≤20 ng/ml, (2) clinical T stage ≤cT2, (3) a dominant unilateral lesion with Gleason ≤ 4 + 3 disease with any number or percentage of cores involved ipsilaterally on prostate biopsy, (4) no primary Gleason ≥4 lesion contralaterally, and (5) a preoperative Sexual Health Inventory of Men (SHIM) score of ≥17 (out of 25) with/without phosphodiesterase type-5 inhibitor use who consented to undergo precision prostatectomy were included in this single-arm, single-center, IDEAL stage 2b prospective development study. Robotic precision prostatectomy. The safety and urinary, sexual, and oncologic outcomes of the precision prostatectomy technique were studied. Descriptive statistics and Kaplan-Meier analyses were used to assess 12-mo urinary continence (0–1 pad), 12-mo sexual potency (SHIM score ≥17), 36-mo freedom from clinically significant PCa (grade group ≥2), secondary treatments, metastatic disease, and mortality. At study entry, the median age, PSA, and SHIM score were 60.0 yr (interquartile range [IQR] 54.2–65.9), 5.7 ng/ml (IQR 4.2–7.1), and 22 points (IQR 19–24), respectively. The median follow-up was 25 mo (IQR 14–38). At 12 mo, all patients were continent (0–1 pads), with 90.9% of patients using 0 pads. The median time to urinary continence was 1 mo (IQR 1–4). At 12 mo, 85% of all-comers and 90.2% of the preoperatively potent men were potent. The median time to sexual potency was 4 mo (IQR 4–12). From an oncologic standpoint, at 36 mo an estimated 93.4% of the patients were free from clinically significant residual PCa and 91.7% had not undergone any additional treatment. All patients were alive and free of metastatic disease at 36 mo. Precision prostatectomy is technically safe and reproducible and offers excellent postoperative functional results. At 36-mo follow-up, the oncologic outcomes and secondary treatment rates appear to be superior to existing ablative focal therapy results. Pending long-term data, a risk-stratified surgical approach to PCa may avoid whole-gland therapy and preserve functional quality of life in men with localized PCa. Precision prostatectomy is a new form of focal therapy for intermediate-risk prostate cancer in which a 5–10-mm rim of prostate capsule is left on the opposite side of the gland to where the dominant cancer is located. The technique appears to be safe and efficacious and adds to the growing armamentarium of risk-adapted therapies for treatment of localized prostate cancer that avoid the adverse effects on urinary and erectile function of whole-gland treatments. [ABSTRACT FROM AUTHOR]

Abstract: Background: There is a paucity of data on long-term oncologic outcomes for patients undergoing robot-assisted radical prostatectomy (RARP) for prostate cancer (PCa). Objective: To evaluate oncologic outcomes in patients undergoing RARP at a high-volume tertiary center, with a focus on 5-yr biochemical recurrence–free survival (BCRFS). Design, setting, and participants: The study cohort consisted of 1384 consecutive patients with localized PCa who underwent RARP between September 2001 and May 2005 and had a median follow-up of 60.2 mo. No patient had secondary therapy until documented biochemical recurrence (BCR). BCR was defined as a serum prostate-specific antigen ≥0.2 ng/ml with a confirmatory value. BCRFS was estimated using the Kaplan-Meier method. Event–time distributions for the time to failure were compared using the log-rank test. Univariable and multivariable Cox proportional hazards regression models were used to determine variables predictive of BCR. Intervention: All patients underwent RARP. Measurements: BCRFS rates were measured. Results and limitations: This cohort of patients had moderately aggressive PCa: 49.0% were D’Amico intermediate or high risk on biopsy; however, 60.9% had Gleason 7–10 disease, and 25.5% had ≥T3 disease on final pathology. There were 189 incidences of BCR (31 per 1,000 person years of follow-up) at a median follow-up of 60.2 mo (interquartile range [IQR]: 37.2–69.7). The actuarial BCRFS was 95.1%, 90.6%, 86.6%, and 81.0% at 1, 3, 5, and 7 yr, respectively. In the patients who recurred, median time to BCR was 20.4 mo; 65% of BCR incidences occurred within 3 yr and 86.2% within 5 yr. On multivariable analysis, the strongest predictors of BCR were pathologic Gleason grade 8–10 (hazard ratio [HR]: 5.37; 95% confidence interval [CI], 2.99–9.65; p <0.0001) and pathologic stage T3b/T4 (HR: 2.71; 95% CI, 1.67–4.40; p <0.0001). Conclusions: In a contemporary cohort of patients with localized PCa, RARP confers effective 5-yr biochemical control. [Copyright &y& Elsevier]

Objectives: We present postprostatectomy pathology results from a series of prostate cancer (Pca) Gleason grade group ≥2 patients who did not have findings suggestive of cancer on preoperative pelvic magnetic resonance imaging (MRI).Methods: We performed an institutional retrospective study of prostate magnetic resonance imaging (MRI) examinations done from October 2015 to February 2018. We identified patients who underwent prostatectomy for Pca Gleason ≥3 + 4 diagnosed on prostate biopsy with no associated MRI findings suggestive of malignancy and analyzed their postprostatectomy pathologic findings and MRI imaging results.Results: At our institution, 850 men with Pca received MRI between 2015 and 2018, and 156/850 patients received robotic-assisted radical prostatectomy. Thirty-three patients (33/156 = 21%) had negative MRI for PIRAD 3 or greater but had a biopsy showing significant Pca. Their mean (range) age was 62.7 (50-86) years. Their median (interquartile range) PSA, and PSA density were, 4.6 (3.7) ng/mL and 0.12 (0.05) ng/mL/cm2, respectively; all not significantly different from patients with visible lesions on MRI who underwent surgery. On post prostatectomy pathology, 27/33 (82%) men had Pca Gleason score 7 or greater. The most common pattern was infiltrative growth with cancer glands intermingling between benign glands.Conclusion: We describe the pathologic and imaging findings in an extensive series of men with clinically significant Pca with no significant lesions on preoperative MRI. Our results support the importance of patient counseling on the risk of missing significant Pca on MRI in isolation from other clinical variables. [ABSTRACT FROM AUTHOR]

Objective: To compare the utility of the systematic 12-core prostate biopsy (SB) combined with magnetic resonance imaging (MRI)-targeted lesion biopsy (MRI-TB) vs MRI-TB alone in the diagnosis of high PI-RADS lesions.Materials and Methods: Patients undergoing MRI-TB + SB for suspicious MRI lesions were retrospectively reviewed. These patients had a previous prostate biopsy and were evaluated with MRI to assess the need for a repeat biopsy. Pathologic findings of MRI-TB combined with a SB were compared to those of the patients' previous SB. An upgrade was defined as an increase in the Gleason Score of any prior biopsy. A no-upgrade (NU) MRI-TB was defined as a MRI-TB that did not lead to disease upgrading when compared to SB.Results: A total of 148 patients were analyzed in this study. Of the 255 total lesions (247 lesions with PI-RADS ≥3), 141 were upgraded from the previous biopsy (55.3%). Of these, 104 were upgraded by the MRI-TB (40.8%), and 87 lesions were upgraded by the SB (34.1%). The MRI-TB had a NU rate of 26.2% for all lesions. On subanalysis, the NU rates of PI-RADS 3, 4, and 5 MRI-TBs were 39.3%, 21.2%, and 3.4%, respectively.Conclusion: The NU rate for the MRI-TB in a PIRADS-5 lesion is meager. Men with a PI-RADS 5 lesion may be safely managed with the MRI-TB alone without combining with SB. Men with PI-RADS 3 and 4 lesions should benefit from SB in addition to MRI-TB for accurate management of their disease. [ABSTRACT FROM AUTHOR]

We present the functional characterization of a pseudogene associated recurrent gene fusion in prostate cancer. The fusion gene KLK4-KLKP1 is formed by the fusion of the protein coding gene KLK4 with the noncoding pseudogene KLKP1. Screening of a cohort of 659 patients (380 Caucasian American; 250 African American, and 29 patients from other races) revealed that the KLK4-KLKP1 is expressed in about 32% of prostate cancer patients. Correlative analysis with other ETS gene fusions and SPINK1 revealed a concomitant expression pattern of KLK4-KLKP1 with ERG and a mutually exclusive expression pattern with SPINK1, ETV1, ETV4, and ETV5. Development of an antibody specific to KLK4-KLKP1 fusion protein confirmed the expression of the full-length KLK4-KLKP1 protein in prostate tissues. The in vitro and in vivo functional assays to study the oncogenic properties of KLK4-KLKP1 confirmed its role in cell proliferation, cell invasion, intravasation, and tumor formation. Presence of strong ERG and AR binding sites located at the fusion junction in KLK4-KLKP1 suggests that the fusion gene is regulated by ERG and AR. Correlative analysis of clinical data showed an association of KLK4-KLKP1 with lower preoperative PSA values and in young men (<50 years) with prostate cancer. Screening of patient urine samples showed that KLK4-KLKP1 can be detected noninvasively in urine. Taken together, we present KLK4-KLKP1 as a class of pseudogene associated fusion transcript in cancer with potential applications as a biomarker for routine screening of prostate cancer. [ABSTRACT FROM AUTHOR]

Background Reports on long-term oncologic outcomes for patients who undergo robot-assisted radical prostatectomy (RARP) are scant, as for radical prostatectomy covering only the contemporary prostate-specific antigen (PSA) era. Objective To evaluate cancer control in men who underwent RARP at least 10 yr ago. Design, setting, and participants From 2001 to 2003, we followed 483 consecutive men with localized prostate cancer who underwent RARP at a high-volume tertiary center. Intervention RARP as first-line therapy. Outcome measurements and statistical analysis We calculated biochemical recurrence –free survival (BCRFS), metastasis-free survival (MFS), and cancer-specific survival (CSS). Actuarial rates were estimated via Kaplan-Meier. Cox proportional hazards models were used to identify variables predictive of biochemical recurrence (BCR), receipt of salvage therapy, and metastases. Results and limitations There were 108 patients with BCR at a median follow-up of 121 mo (interquartile range: 97–132). Actuarial BCRFS, MFS, and CSS rates at 10 yr were 73.1%, 97.5%, and 98.8%, respectively. On multivariable analysis, D’Amico risk groups or pathologic Gleason grade, stage, and margins were the strongest predictors of BCR depending on whether preoperative or postoperative variables were considered. The value of the detectable PSAs together with disease severity were independent predictors of receipt of salvage therapy, together with a persistent PSA for metastases. Conclusions In contemporary patients with localized prostate cancer, RARP confers effective 10-yr cancer control. Disease severity and PSA measurements can be used to guide more personalized and cost-effective postoperative surveillance regimens. Patient summary Robot-assisted radical prostatectomy confers effective 10-yr cancer control for men with localized disease, similar to the open approach. Recurrence is best predicted by postoperative disease severity. Persistent disease signals the risk of progression likely requiring early salvage treatment; lower postoperative risk warrants protracted surveillance beyond 5 yr from surgery, and those with higher risk may require follow-up beyond 10 yr. [ABSTRACT FROM AUTHOR]

Purpose: To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. Methods and Materials: Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. Results: Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the 2 arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. Conclusions: Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer. [Copyright &y& Elsevier]

Background and Objective: To determine the effect of multiplicity of prostate imaging reporting and data system assessment category 3 (PI-RADS 3) lesions on cancer detection rate (CDR) of confirmatory targeted biopsy of such lesion in patients diagnosed with prostate cancer and managed with active surveillance.Methods: This study was conducted at a single academic institution. There were 91 men with ≥ 1 PI-RADS 3 lesion detected through magnetic resonance imaging (MRI) after systematic prostate biopsy in the course of management of patients diagnosed with prostate cancer with active surveillance. We compared the CDRs based on targeted biopsy of PI-RADS 3 lesions that occurred (1) as solitary lesions, (2) as 1 of multiple PI-RADS 3 only lesions, or (3) with ≥ 1 higher grade lesion.Results: Median age was 65.0 years (interquartile range 59.5-70.0), median prostate specific antigen was 5.95 ng/ml (interquartile range 4.30-8.83), and median prostate specific antigen density was 0.161 ng/ml2 (0.071-0.194). Forty-three men had solitary PI-RADS 3 lesions, 22 had multiple PI-RADS 3 only lesions, and 26 had multiple lesions with ≥ 1 higher grade lesion. The overall CDR (Gleason score ≥ 3 + 3) based on confirmatory MRI targeted biopsy in a given PI-RADS 3 lesion in each group was 23%, 45%, and 54%, respectively (P = 0.0274). The CDRs for clinically significant disease (Gleason score ≥ 3 + 4) were 16%, 32%, and 35%, respectively (P = 0.1701).Conclusions: Coexisting lesions increase the CDR of confirmatory MRI targeted biopsy of PI-RADS 3 lesions in patients managed with active surveillance. Risk stratification algorithms for PI-RADS 3 lesion to guide biopsy and management decisions may consider including multiplicity of lesions. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the effects of African American (AA) race on the number, location, Prostate Imaging Reporting and Data System (PI-RADS) score, cancer detection rate, and cancer upgrade rate of the regions of interest (ROI) discovered on mltiparametric magnetic resonance imaging (mp-MRI) of the prostate.Methods: We performed an institutional retrospective study of 592 patients who received a prostate mp-MRI. Number of ROI (1-4), their location, and PI-RADS score v2 were evaluated in a matched cohort of Caucasian and AA males. Propensity score matching was performed using the variables of age, prostate specific antigen (PSA) level, and prostate volume. Comparisons utilized chi-square tests and P < 0.05 was considered significant.Results: One hundred and twenty three AA patients were matched with an equal number of Caucasian men of similar characteristics. The AA population's median age was 63 years (57.3-69.3), median PSA 6.6 (4.6-12.1), and median prostate volume 55 ml (33-90.8). The Caucasian population's median age was 66.3 years (60.9-71.1), median PSA 5.4 (3.8-8), and median prostate volume 52.5 ml (33.2-83). The number of ROI was 2 or more in 24% of AA men and 12% of Caucasian men (P = 0.035), and 3 or more in 10% of AA and 2% of Caucasian men (P = 0.034). There was no significant difference in location, PI-RADS scores, cancer detection rate, and cancer upgrade rate of the ROI between the 2 groups.Conclusions: AA patients, as compared to Caucasian counterparts, have a higher number of ROI detected on prostate mp-MRI. [ABSTRACT FROM AUTHOR]