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Overdiagnosis and overtreatment of Grade Group 1 (GG 1) prostate cancer remains a significant health care problem despite of its improved risk assessment and uptake in conservative management. Removing the cancer label from these non-lethal cancers has been proposed as an expedient way to reduce potential physical, psychological and financial harm to patients. Such a nomenclatural change necessitates a multidisciplinary team effort by clinicians and pathologists. Genitourinary Pathology Society recently conducted a survey of its members, gauging their awareness of this controversy and their position on whether GG 1 prostate cancer should be reclassified. Most respondents (196, 81.7%) opposed removing the cancer label from GG 1 cancer, 33 (13.8%) supported a change in nomenclature, while 11 (4.6%) responded that they were uncertain. Of those who supported the reclassification, 17 (51.5%) supported the change for radical prostatectomy only, 4 (12.1%) for biopsy only, and 12 (36.4%) for both biopsy and radical prostatectomy. This survey results highlight the gap between pathologists and clinicians in whether GG 1 prostate cancer should be labeled as "non-cancer," and calls for continued debates and conversations between pathologists and clinicians, and further studies on the biology, diagnostic reproducibility, and ideal management of GG 1 prostate cancer in order to make a more evidence-based decision for patients. [ABSTRACT FROM AUTHOR]

Since its initial description in 1966 by Dr Donald Gleason, Gleason grading has become the cornerstone in the management of prostate cancer (PCa). With widespread use of Prostate Specific Antigen (PSA) screening and needle core biopsy, the diagnosis and management of PCa have dramatically evolved. In addition, better understanding of the morphological spectrum of prostate cancer and its clinical significance have prompted the refinement of the grading criteria and reporting guidelines commensurate to contemporary practice. The modification of the Gleason grading system implemented by the International Society of Urological Pathology in 2005 and subsequent revision in 2014 has profoundly impacted how PCa is graded and managed. This review aims to provide a concise update on the refinement of the histological criteria for various Gleason patterns and problem areas of Gleason grading, and provide recommendations on how to improve the grading reproducibility. The new proposal to group Gleason scores into clinically meaningful 'grade groups' will also be discussed. Finally, we will discuss how magnetic resonance imaging (MRI)-targeted biopsy and emerging genetic markers may help improve the Gleason grading accuracy and risk stratification currently based on clinicopathological parameters. [ABSTRACT FROM AUTHOR]

Background: Studies on single-target PET imaging of gastrin-releasing peptide receptor (GRPR), prostate-specific membrane antigen (PSMA), or neurotensin receptor 1(NTR1) have been reported. However, the performance of these three targets in the progression of PCa remains unclear. Our study aims to compare the expression of GRPR, PSMA, and NTR1 in patients with prostatic intraepithelial neoplasia (PIN), prostate cancer (PCa), and lymph node metastasis. We synthesized molecular probes targeting the markers to achieve a non-invasive precise detection of PCa patients with PET/CT imaging. Methods: In this study, the expression of GRPR, PSMA, and NTR1 was evaluated by immunohistochemistry in 34 PIN, 171 PCa, and 22 lymph node metastasis tissues of patients. The correlation between their expression and the clinicopathological parameters of PCa patients was assessed. Sixteen PCa patients with different Gleason scores (GS) underwent dual-tracer (68Ga-NOTA-RM26 and 68Ga-NOTA-PSMA617) PET/CT. Results: In the PIN stage, the expression of GRPR was significantly higher than that of PSMA and NTR1 (P < 0.001), while NTR1 expression was significantly higher than PSMA and GRPR expression in primary PCa (P = 0.001). High PSMA expression in PCa patients was associated with shorter progression-free survival (P = 0.037) and overall survival (P = 0.035). PCa patients with high GS had higher tumor uptake of 68Ga-NOTA-PSMA617 than those with low GS (P = 0.001), while PCa patients with low GS had higher tumor uptake of 68Ga-NOTA-RM26 than those with high GS (P = 0.001). Conclusions: This study presents three novel biomarkers (PSMA, GRPR, and NTR1) as imaging agents for PET/CT, and may offer a promising approach for non-invasive precise detection and Gleason grade prediction of PCa patients. [ABSTRACT FROM AUTHOR]

The fifth edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems encompasses several updates to the classification and diagnosis of prostatic carcinoma as well as incorporating advancements in the assessment of its prognosis, including recent grading modifications. Some of the salient aspects include: (1) recognition that prostatic intraepithelial neoplasia (PIN)‐like carcinoma is not synonymous with a pattern of ductal carcinoma, but better classified as a subtype of acinar adenocarcinoma; (2) a specific section on treatment‐related neuroendocrine prostatic carcinoma in view of the tight correlation between androgen deprivation therapy and the development of prostatic carcinoma with neuroendocrine morphology, and the emerging data on lineage plasticity; (3) a terminology change of basal cell carcinoma to "adenoid cystic (basal cell) cell carcinoma" given the presence of an underlying MYB::NFIB gene fusion in many cases; (4) discussion of the current issues in the grading of acinar adenocarcinoma and the prognostic significance of cribriform growth patterns; and (5) more detailed coverage of intraductal carcinoma of prostate (IDC‐P) reflecting our increased knowledge of this entity, while recommending the descriptive term atypical intraductal proliferation (AIP) for lesions falling short of IDC‐P but containing more atypia than typically seen in high‐grade prostatic intraepithelial neoplasia (HGPIN). Lesions previously regarded as cribriform patterns of HGPIN are now included in the AIP category. This review discusses these developments, summarising the existing literature, as well as the emerging morphological and molecular data that underpins the classification and prognostication of prostatic carcinoma. [ABSTRACT FROM AUTHOR]

Purpose: To assess 68Ga-PSMA PET/CT for detection of low- and intermediate-risk prostate cancer (PCa), high-risk PCa in comparison with mpMRI, respectively, and to determine which of low- and intermediate-risk PCa are more likely to be detected by 68Ga-PSMA PET/CT. Methods: We conducted a retrospective analysis of patients who had undergone a prostate biopsy and/or radical prostatectomy and who were scanned with 68Ga-PSMA PET/CT and mpMRI between June 2019 and March 2021. The mpMRI images were scored with the Prostate Imaging-Reporting and Data System Version 2.1 (PI-RADS) and were classified as either negative (PI-RADS 1–3) or positive (PI-RADS 4–5). Suspicious 68Ga-PSMA PET/CT lesions were reviewed for each relevant patient and classified by double-trained board-certified nuclear medicine physicians. The results were evaluated with the histopathological outcome. All patients were classified according to the D'Amico classification, and the clinical data were combined for stratified analysis. Result: A total of 101 patients who were pathologically diagnosed with PCa were analyzed. Of the 101 patients, 88 (80.6%) patients presented with a pathologic mpMRI, and 85 (79.1%) with a pathologic 68Ga-PSMA PET/CT. In the high-risk PCa cohort, 68Ga-PSMA PET/CT was positive in 64/66 (97.0%) patients and yielded a higher detection rate than that for the mpMRI patients (58/66, 87.9%; p < 0.05). However, mpMRI provided superior diagnostic confidence in identifying low- and intermediate-risk PCa (30/35, 85.7% vs. 21/35, 60.0%; p < 0.05). When the age threshold exceeded 62.5 years and the serum prostate specific antigen (PSA) threshold exceeded 9.4 ng/ml, a higher uptake of PSMA was more likely to occur in the lesions of low- and intermediate-risk PCa. Conclusion: The diagnostic performance of 68Ga-PSMA PET/CT was superior to that of mpMRI in the high-risk PCa cohort, which was consistent with prior studies. Furthermore, in the initial diagnosis of low- and intermediate-risk PCa, we found that mpMRI showed a higher diagnostic accuracy than 68Ga-PSMA PET/CT did. Low- and intermediate-risk PCa patients with a PSA ≥ 9.4 ng/ml and age ≥ 62.5 years were more likely to have a positive 68Ga-PSMA PET/CT result. [ABSTRACT FROM AUTHOR]

Objectives: To perform a Phase II trial of docetaxel administered on a weekly schedule for 6 weeks before radical prostatectomy (RP) in patients with locally advanced prostate cancer.Methods: Treatment consisted of six doses of docetaxel 40 mg/m2 intravenously administered weekly for 6 weeks followed by RP. Eligibility criteria included clinical Stage T2b, prostate-specific antigen (PSA) level 15 ng/mL or greater or Gleason sum 8 or greater, and no evidence of metastatic disease. The primary endpoint was feasibility and drug-related and surgical-related toxicities. Secondary endpoints included pre-RP PSA level, local response, pathologic outcomes, and time to PSA failure.Results: Twenty-nine patients were entered; 80% completed all 6 weeks of therapy and 97% underwent RP. The median PSA level was 12 ng/mL (range 2.5 to 43.3), the median Gleason sum was 8 (range 6 to 9), and all had Stage T2b or greater disease. A statistically significant reduction in the prechemotherapy versus postchemotherapy mean PSA level was observed (12.00 ± 1.86 ng/mL versus 8.42 ± 1.63 ng/mL, P <0.03), with 79% of patients experiencing some reduction and 24% a more than 50% reduction in PSA level in response to docetaxel alone. No unexpected toxicities and no intraoperative complications occurred. Pathologic analysis demonstrated residual carcinoma in all cases. Three patients (11%) had organ-confined disease, and 26 (93%) had achieved an undetectable PSA postoperatively. At a median follow-up of 23 months (range 1.5 to 36), 20 patients were disease free with no additional therapy.Conclusions: This trial establishes the baseline effect of short-course high-dose docetaxel alone on locally advanced prostate cancer. Additional study of this paradigm with other agents alone and in combination with docetaxel seems warranted. [Copyright &y& Elsevier]

Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable. Here we show, through gene expression profiling, that the polycomb group protein enhancer of zeste homolog 2 (EZH2) is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes targeted against EZH2 reduce the amounts of EZH2 protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression. [ABSTRACT FROM AUTHOR]

Purpose: To prospectively assess the feasibility of diffusional kurtosis (DK) imaging for distinguishing prostate cancer(PCa) from benign prostate hyperplasia (BPH) in comparison with standard diffusion-weighted (DW) imaging, as well as low-from high-grade malignant regions.Materials and Methods: 147 consecutive patients with suspected PCa underwent multi-parametric 1.5-TMR. Diffusion kurtosis imaging was acquired with with 5 b values (0,600,800,1600,and 2400sec/mm2).Region of interest (ROI)-based measurements were performed on ADC, D, and K map by two radiologists. Data were analyzed by using mixed-model analysis of variance and receiver operating characteristic curves. Correlations among the three parameters (ADC,D and K) in all patients, and correlations between three parameters with the tumor Gleason score (GS) in PCa group were analyzed using Pearson's correlation coefficient in peripheral zone(PZ) and transiton zone(TZ).Results: 58 patients were proved with PCa (9 GS 3 + 3[PZ/TZ = 4/5], 49 GS ≥ 7 [PZ/TZ = 26/23]), and 89 patients were with BPH. ADC,D and K were able to distinguish benignance from tumor tissue both in PZ and TZ(P＜0.01), but performed poorly in neither differentiating low-(GS 3 + 3) from high-grade (GS≥3 + 4) disease, nor GS(3 + 4) from GS(4 + 3).There was a weak correlation between the GS and ADC, D (PZ:ADC r=-0.113, D r=-0.139; TZ:ADC r=-0.104,D r=-0.103), while a moderate correlation between the GS and K(PZ:K r = 0.492; TZ:K r = 0.433, P＜0.01).K had significantly greater area under the curve for differentiating PCa from BHP than ADC both in PZ and TZ.Conclusion: DK model may add value in PCa detection and diagnosis, but none can differentiate low-from high-grade PCas (including GS=3+4 from GS=4+3). [ABSTRACT FROM AUTHOR]

Objective: To determine if multiparametric (mp) magnetic resonance imaging (MRI) can identify significant apical disease, thereby informing decisions regarding preservation of the membranous urethra. Materials and Methods: Men undergoing radical prostatectomy (RP) between January 2012 and June 2016, who underwent a 12‐core transrectal ultrasonography‐guided systematic biopsy (SB), preoperative 3‐Tesla MRI, and sectioning of the prostate specimen with tumour foci mapping, were extracted from a single surgeon's prospective longitudinal outcomes database. Apical SB and mpMRI lesion results were compared with regard to their ability to predict aggressive tumours in the prostatic apex (PA), defined as prostate cancer grade group >1. Results: Of the 100 men who met the eligibility criteria, 43 (43%) exhibited aggressive prostate cancer in the distal 5 mm of the apex. A Likert score >2 in the apical one‐third of the prostate was found to be more reliable than any cancer found on apical SB at detecting aggressive cancer in the apex. On multivariate regression analysis, which included Likert score in the apex, age, prostate‐specific antigen (PSA) level, prostate size and presence of any cancer on apical biopsy, only Likert score (P = 0.005) and PSA level (P = 0.025) were significant and independent predictors of aggressive cancer in the distal apex. Conclusion: The results of the study showed that MRI was superior to SB at identifying aggressive prostate cancer within the distal PA and may be useful for planning the extent of apical preservation during RP. [ABSTRACT FROM AUTHOR]

Objective: To provide insights into the role of multiparametric magnetic resonance imaging (mpMRI) in predicting oncological control following 2 focal ablation (FA) templates for selective cases of prostate cancer.Materials and Methods: A total of 59 radical prostatectomies were performed between 2012 and 2016 on cases that fulfilled criteria for FA. The Gleason score (GS), extent of Gleason pattern (GP) 4, maximum linear cross-sectional length (MLCSL), and location of tumor foci were recorded and related to scale on corresponding 3-mm transverse slice prostate maps. Gleason pattern 4 extra-focal disease (GP4EFD) was defined as prostate cancer with any GP 4 not detected by mpMRI and transrectal ultrasound systematic biopsy observed outside a specified ablation zone. The location of these GP4EFD relative to the MRI lesion (MRI-L) (contralateral or ipsilateral) was recorded and used to predict oncological control following a hypothetical margin and ipsilateral hemi-ablation templates.Results: Overall, 15 of 59 (25.4%) of the prostate specimens had at least 1 GP4EFD. Of the total 20 GP4EFD, 7 of 20 (35%) were ipsilateral and 13 of 20 (65%) were contralateral to the MRI-L. Of the GP4EFD, 16 of 20 (80%), 2 of 20 (10%), and 2 of 20 (10%) were GS 3 + 4, GS 4 + 3, and GS 4 + 4, respectively. Of these GP4EFD, 10 of 20 (50%) exhibited an MLCSL <5 mm. Ablating only the MRI-L+10 mm or performing an ipsilateral hemi-ablation would leave residual GP4 in 14 of 59 (23.7%) and 11 of 59 (18.6%) of cases, respectively.Conclusion: Because a significant proportion of candidates for FA based on mpMRI and systematic biopsy will have pre-existing GP4EFD outside ablation templates, active surveillance of the untreated prostate is mandatory. [ABSTRACT FROM AUTHOR]

Objective: To determine whether a combination of prostate cancer gene 3 (PCA3) and magnetic resonance imaging (MRI) suspicion score (mSS) could further optimize detection of prostate cancer on MRI fusion-targeted biopsy (MRF-TB) among men with no history of biopsy.Materials and Methods: We included in this study 187 men presenting to our institution between June 2012 and August 2014 who underwent multiparametric MRI (mpMRI) and PCA3 before MRF-TB. Biopsy results, stratified by biopsy indication and PCA3 score, were recorded. Receiver operating characteristics curves and multivariable logistic regressions were used to model the association of PCA3 and mSS with cancer detection on MRF-TB.Results: PCA3 is associated with cancer detection on MRF-TB for men with no prior biopsies (area under the curve: 0.67, 95% confidence interval: 0.59-0.76). Using a cutoff of ≥35, PCA3 was associated with cancer risk among men with mSS 2-3 (P = .004), but not among those with mSS 4-5 (P = .340). The interaction of PCA3 and mSS demonstrated significantly higher discrimination for cancer than mSS alone (area under the curve: 0.83 vs 0.79, P = .0434).Conclusion: Urinary PCA3 is associated with mSS and the detection of cancer on MRF-TB for men with no prior biopsies. PCA3 notably demonstrates a high negative predictive value among mSS 2-3. However, in the case of high-suspicion mpMRI, PCA3 is not associated with cancer detection on MRF-TB, adding little to cancer diagnosis. Further studies are needed to evaluate the utility of PCA3 in predicting cancer among men with normal mpMRI. [ABSTRACT FROM AUTHOR]

Significant differences, including epidemiologic, clinical, pathologic and genetic, exist between Asian and Caucasian prostate cancer. Detailed pathologic data are, however, scarce. We studied in detail and compared the pathological features of prostate cancer in radical prostatectomy specimens in 228 patients (117 Japan, 111 US). Japanese prostate cancer had a higher Gleason grade group (mean 2.67 vs. 2.42 US, P < 0.05), but lower pathological stage (72 % pT2 and 28 % pT3 vs 55 % pT2 and 45 % pT3 US, P < 0.05). Japanese cancer showed significantly more tumor foci (3.8 vs 2.9 US, P < 0.05), and higher incidence of bilateral significant disease (81.3 % vs. 66.7 % US, P < 0.05). The dominant tumor nodules in Japanese cases had higher Gleason grade group (mean 2.73 vs. 2.40 US, P < 0.05). The incidence of intraductal carcinoma was significantly higher in Japanese patients (35.3 % vs. 12.6 % US, P < 0.01), which was independent of Gleason score (7: 30.9 % Japan vs 11.8 % US, P < 0.01; ≥ 8: 87.5 % Japan vs 28.6 % US, P < 0.01) and tumor stage (pT2: 24.1 % Japan vs 6.6 % US, P < 0.01; pT3: 62.9 % Japan vs 20 % US, P < 0.01). These findings demonstrate distinct pathological features in prostate cancer between Japanese and Caucasian patients, and may have important diagnostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

Background The risk of biochemical recurrence (BCR) following radical prostatectomy for pathologic Gleason 7 prostate cancer varies according to the proportion of Gleason 4 component. Objective We sought to explore the value of several novel quantitative metrics of Gleason 4 disease for the prediction of BCR in men with Gleason 7 disease. Design, setting, and participants We analyzed a cohort of 2630 radical prostatectomy cases from 1990–2007. All pathologic Gleason 7 cases were identified and assessed for quantity of Gleason pattern 4. Three methods were used to quantify the extent of Gleason 4: a quantitative Gleason score (qGS) based on the proportion of tumor composed of Gleason pattern 4, a size-weighted score (swGS) incorporating the overall quantity of Gleason 4, and a size index (siGS) incorporating the quantity of Gleason 4 based on the index lesion. Outcome measurements and statistical analysis Associations between the above metrics and BCR were evaluated using Cox proportional hazards regression analysis. Results and limitations qGS, swGS, and siGS were significantly associated with BCR on multivariate analysis when adjusted for traditional Gleason score, age, prostate specific antigen, surgical margin, and stage. Using Harrell's c-index to compare the scoring systems, qGS (0.83), swGS (0.84), and siGS (0.84) all performed better than the traditional Gleason score (0.82). Conclusions Quantitative measures of Gleason pattern 4 predict BCR better than the traditional Gleason score. Patient summary In men with Gleason 7 prostate cancer, quantitative analysis of the proportion of Gleason pattern 4 (quantitative Gleason score), as well as size-weighted measurement of Gleason 4 (size-weighted Gleason score), and a size-weighted measurement of Gleason 4 based on the largest tumor nodule significantly improve the predicted risk of biochemical recurrence compared with the traditional Gleason score. [ABSTRACT FROM AUTHOR]

Background Increasing evidence supports the use of magnetic resonance imaging (MRI)-ultrasound fusion–targeted prostate biopsy (MRF-TB) to improve the detection of clinically significant prostate cancer (PCa) while limiting detection of indolent disease compared to systematic 12-core biopsy (SB). Objective To compare MRF-TB and SB results and investigate the relationship between biopsy outcomes and prebiopsy MRI. Design, setting, and participants Retrospective analysis of a prospectively acquired cohort of men presenting for prostate biopsy over a 26-mo period. A total of 601 of 803 consecutively eligible men were included. Interventions All men were offered prebiopsy MRI and assigned a maximum MRI suspicion score (mSS). Men with an MRI abnormality underwent combined MRF-TB and SB. Outcomes Detection rates for all PCa and high-grade PCa (Gleason score [GS] ≥7) were compared using the McNemar test. Results and limitations MRF-TB detected fewer GS 6 PCas (75 vs 121; p < 0.001) and more GS ≥7 PCas (158 vs 117; p < 0.001) than SB. Higher mSS was associated with higher detection of GS ≥7 PCa ( p < 0.001) but was not correlated with detection of GS 6 PCa. Prediction of GS ≥7 disease by mSS varied according to biopsy history. Compared to SB, MRF-TB identified more GS ≥7 PCas in men with no prior biopsy (88 vs 72; p = 0.012), in men with a prior negative biopsy (28 vs 16; p = 0.010), and in men with a prior cancer diagnosis (42 vs 29; p = 0.043). MRF-TB detected fewer GS 6 PCas in men with no prior biopsy (32 vs 60; p < 0.001) and men with prior cancer (30 vs 46; p = 0.034). Limitations include the retrospective design and the potential for selection bias given a referral population. Conclusions MRF-TB detects more high-grade PCas than SB while limiting detection of GS 6 PCa in men presenting for prostate biopsy. These findings suggest that prebiopsy multiparametric MRI and MRF-TB should be considered for all men undergoing prostate biopsy. In addition, mSS in conjunction with biopsy indications may ultimately help in identifying men at low risk of high-grade cancer for whom prostate biopsy may not be warranted. Patient summary We examined how magnetic resonance imaging (MRI)-targeted prostate biopsy compares to traditional systematic biopsy in detecting prostate cancer among men with suspicion of prostate cancer. We found that MRI-targeted biopsy detected more high-grade cancers than systematic biopsy, and that MRI performed before biopsy can predict the risk of high-grade cancer. [ABSTRACT FROM AUTHOR]

Objective: To report outcomes of magnetic resonance imaging (MRI)-ultrasound fusion-targeted biopsy (MRF-TB) and 12-core systematic biopsy (SB) over a 26-month period in men with prior negative prostate biopsy.Materials and Methods: Between June 2012 and August 2014, 210 men presenting to our institution for prostate biopsy with ≥1 prior negative biopsy underwent multiparametric MRI followed by MRF-TB and SB and were entered into a prospective database. Clinical characteristics, maximum mpMRI suspicion scores (mSS), and biopsy results were queried from the database, and the detection rates of Gleason ≥7 prostate cancer (PCa) and overall PCa were compared between biopsy techniques using McNemar's test.Results: Forty seven (29%) of 161 men meeting inclusion criteria (mean age, 65 ± 8 years; mean prostate-specific antigen, 8.9 ± 8.9) were found to have PCa. MRF-TB and SB had overall cancer detection rates (CDRs) of 21.7% and 18.6% (P = .36), respectively, and CDR for Gleason score (GS) ≥7 disease of 14.9% and 9.3% (P = .02), respectively. Of 26 men with GS ≥7 disease, MRF-TB detected 24 (92.3%) whereas SB detected 15 (57.7%; P < .01). Using UCSF-CAPRA criteria, only 1 man was restratified from low risk to higher risk based on SB results compared to MRF-TB alone. Among men with mSS <4, 72% of detected cancers were low risk by UCSF-CAPRA criteria.Conclusion: In men with previous negative biopsies and persistent suspicion of PCa, SB contributes little to the detection of GS ≥7 disease by MRF-TB, and avoidance of SB bears consideration. Based on the low likelihood of detecting GS ≥7 cancer and overall low-risk features of PCa in men with mSS <4, limiting biopsy to men with mSS ≥4 warrants further investigation. [ABSTRACT FROM AUTHOR]

Summary Chromobox homolog 7 (CBX7) plays an important role in gene transcription in a wide array of cellular processes, ranging from stem cell self-renewal and differentiation to tumor progression. CBX7 functions through its N-terminal chromodomain (ChD), which recognizes trimethylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. In this study, we report the discovery of small molecules that inhibit CBX7ChD binding to H3K27me3. Our crystal structures reveal the binding modes of these molecules that compete against H3K27me3 binding through interactions with key residues in the methyl-lysine binding pocket of CBX7ChD. We further show that a lead compound, MS37452, derepresses transcription of Polycomb repressive complex target gene p16 / CDKN2A by displacing CBX7 binding to the INK4A/ARF locus in prostate cancer cells. These small molecules have the potential to be developed into high-potency chemical modulators that target CBX7 functions in gene transcription in different disease pathways. [ABSTRACT FROM AUTHOR]

Aims Intraductal carcinoma of the prostate ( IDC- P) is a distinct clinicopathological entity and is associated with aggressive, high-grade and high-volume prostate carcinoma ( PCa). The incidence, clinicopathological characteristics and prognostic significance of IDC- P have not been reported in prostate biopsies ( PBx) that surgical pathologists encounter in their daily practice. Methods and results In 1176 prospectively collected PBx, 33 IDC- P cases were identified (2.8%). The mean age of patients with IDC- P was 65 (range 46-79) years and mean serum prostate-specific antigen was 16.2 (range 0.4-105.6) ng/ml. Three (0.26%) IDC- P cases did not have a concomitant invasive PCa. Of 30 cases with concomitant invasive PCa, Gleason score was 7 in 16 (53.3%), 8 in four (13.3%) and 9 in 10 (33.3%) cases. The mean number of biopsy cores involved by PCa was 7.2 (range 1-14). Nine patients were treated with radical prostatectomy. Seminal vesicle invasion was found in four of nine (44%) cases, significantly higher than the risk of 12% predicted by Partin Tables ( P = 0.016). Conclusions This is the first prospective study that has investigated the incidence and prognostic significance of IDC- P diagnosed in PBx encountered in daily practice. It is critical for surgical pathologists to diagnose and report IDC- P in PBx. [ABSTRACT FROM AUTHOR]

Study Type - Diagnosis (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? High grade prostatic intraepithelial neoplasia is a pre-malignant lesion to prostate cancer and is associated with 20%-25% risk of prostate cancer in subsequent repeat biopsies. ERG is a highly prostate-cancer-specific marker. Expression of ERG is rare in isolated high grade prostatic intraepithelial neoplasia diagnosed in prostate biopsy and is not associated with cancer risk in subsequent repeat biopsies. OBJECTIVES To evaluate how often ERG, a highly prostate-cancer-specific marker, is expressed in isolated high grade prostatic intraepithelial neoplasia (HGPIN) by immunohistochemistry., To study whether a positive ERG immunostain in HGPIN correlates with prostate cancer (PCa) detection in subsequent repeat biopsies., PATIENTS AND METHODS Patients with initial HGPIN in biopsies and at least one follow-up prostate biopsy were included., Biopsies with HGPIN were immunostained for ERG., The ERG staining results were then correlated with the PCa risk in subsequent biopsies., RESULTS The mean age of 94 patients was 63 years (range 48-78). A mean of 1.8 (range 1-5) repeat biopsy sessions were carried out at a mean interval of 27.4 months (range 1.5-140). The repeat biopsies showed PCa and non-cancer lesions (benign, HGPIN, atypical glands suspicious for cancer) in 36 patients (38%) and 58 patients (62%) respectively., ERG immunostain was positive in five (5.3%) biopsies with HGPIN, in which PCa was found in two (40%) subsequent biopsies. Of 89 biopsies with negative ERG staining, PCa was found in 34 (38%) repeat biopsies. The cancer detection rate was not different between ERG positive and negative cases ( P= 0.299)., CONCLUSIONS This is the first study to investigate the ERG protein expression in prostate biopsy containing HGPIN only and its use to stratify the cancer risk associated with HGPIN. We found that ERG expression is distinctly uncommon in isolated HGPIN (5.3%)., Positive ERG expression is not associated with increased cancer detection in subsequent repeat biopsies. The use of ERG immunostain in the evaluation and cancer risk stratification of HGPIN is of limited value. [ABSTRACT FROM AUTHOR]

Objectives: Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer cells. Recently, PSMA has been found in the neovasculature in association with other solid malignant tumors, including clear cell renal carcinoma (RCC). We studied the expression of PSMA in different primary renal tumors.Methods: A tissue microarray was constructed from 60 normal kidney, 21 clear cell RCC (CCRCC), 20 papillary RCC (PRCC), 16 chromophobe RCC, 19 oncocytoma, 14 transitional cell carcinoma, and 19 angiomyolipoma (AML) specimens. This tissue microarray was then immunostained for a vascular endothelial marker CD34 and PSMA. PSMA expression in CD34-positive tumor-associated neovasculature was scored according to the staining intensity and the percentage of vessels. Only diffuse strong or weak, or focal strong PSMA staining was graded as positive.Results: PSMA was expressed in the proximal tubules of the normal kidney and in the tumor-associated vasculature in the renal tumors. Positive PSMA staining was detected in 76.2% of CCRCC, 31.2% of chromophobe RCC, 52.6% of oncocytoma, 21.4% of transitional cell carcinoma, and 0% of PRCC and AML specimens. Its expression was greater in CCRCC than PRCC, chromophobe RCC, transitional cell carcinoma, and AML (P <0.001), but was not significantly different from the expression in oncocytoma (P = 0.79). PSMA expression did not correlate with the pathologic stage in CCRCC.Conclusions: PSMA is differentially expressed in the tumor-associated neovasculature in different renal tumors. It is most commonly detected in CCRCC and rarely detectable in PRCC and AML. This finding suggests that antibodies against PSMA may potentially be used as a diagnostic marker and therapeutic target for renal neoplasms. [ABSTRACT FROM AUTHOR]

Objectives: No consensus exists regarding the prognostic value of tumor volume (TV) in predicting biochemical recurrence (BCR) of prostate cancer, especially late in the prostate-specific antigen (PSA) era. We assessed this relationship in a large cohort of patients treated at one institution with standardized pathologic assessment from 1998 to 2005. Methods: Data were collected for 1833 patients undergoing radical prostatectomy for clinically localized prostate cancer since 1998. Patients receiving neoadjuvant or adjuvant therapy or with node-positive disease were excluded. Along with the routine pathologic assessment, TV was prospectively assessed in all specimens. BCR was defined as two consecutive PSA levels of 0.2 ng/mL or one PSA level of greater than 0.2 ng/mL. Results: Although a larger TV correlated with lower rates of biochemical relapse-free survival in patients with a surgical Gleason score of 7 (P <0.0001) and surgical Gleason score of 8 or greater (P = 0.0459), the biochemical relapse-free survival rate at 4 years for low, medium, and extensive surgical Gleason score 6 or less tumors was 95%, 96%, and 97%, respectively (P = 0.65). In a multivariate model, including TV, initial PSA, EPE, seminal vesicle invasion, and surgical Gleason score, the TV predicted for BCR (P = 0.0176). Conclusions: The results of this large study suggest that a large TV is an independent predictor of BCR in patients with tumors of specimen Gleason score 7 or higher. In contrast, most grade 6 tumors will be organ confined, even if of high volume, and TV will not predict for BCR in these patients. [Copyright &y& Elsevier]

OBJECTIVE To investigate the detection rate and extent of high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical glands (AG) suspicious for prostate cancer, and the cancer risk in subsequent biopsies, diagnosed by a first 24-core saturation biopsy, as although the optimum extent of biopsy is controversial there is a trend to increase the number of cores taken, and apart from detecting prostate cancer, identifying HGPIN and AG is associated with a greater risk of finding cancer in subsequent biopsies, thus warranting a closer follow-up. PATIENTS AND METHODS The study included 100 men with consecutive first-time saturation biopsies; the indications for biopsy were an abnormal digital rectal examination and/or a serum prostate-specific antigen (PSA) level of >2.5 ng/mL. Each biopsy specimen was reviewed retrospectively by two pathologists to confirm the histological diagnosis. The number and percentage of cores positive for HGPIN, bilateral involvement and multifocality (HGPIN involving two or more cores) were recorded in each case. The presence of AG and cancer was also recorded. An extended (10–12 cores) repeat biopsy was available in 23 patients. RESULTS The median (range) age and PSA level of the patients was 63 (41–80) years and 4.9 (1.5–67.0) ng/mL, respectively. Of the 100 patients, 34% had normal findings (benign prostatic tissue, BPT), 39% had cancer, 26% had HGPIN and cancer, 22% had HGPIN alone, and 5% had AG. Repeat biopsies were available in nine of the 22 (41%) patients with HGPIN, four of five with AG, and 10 of the 34 (29%) with BPT. The median (range) interval between the first and second biopsy was 13 (4–36) months. Prostate cancer was detected at the second biopsy in a third of patients with isolated HGPIN on the first biopsy, and one of the four with AG. None of the patients with BPT had cancer on re-biopsy. The cancer detection rate was significantly greater in patients with multifocal than in those with unifocal HGPIN (80% vs none, P = 0.010). The median number of cores and percentage of tissue involved by HGPIN was 3.5 (2–5) and 1.0 (0.5–1.2)%, respectively, in patients with cancer detected in repeat biopsies, compared to 1.0 (1–3) and 0.2 (0.2–0.6)% in patients without cancer on repeat biopsy ( P = 0.023 and 0.015, respectively). CONCLUSION Identifying multifocal HGPIN on first saturation biopsy is associated with an overall cancer detection rate of 80% on repeat 10–12-core biopsy. Although there were few patients, the detection of multifocal HGPIN warrants additional searches for concurrent invasive carcinoma by repeated biopsy. [ABSTRACT FROM AUTHOR]

Purpose: To determine if the presence of perineural invasion (PNI) predicts biochemical recurrence in patients who underwent low-dose-rate brachytherapy for the treatment of localized prostate cancer. Methods and Materials: A retrospective case control matching study was performed. The records of 651 patients treated with brachytherapy between 1996 and 2003 were reviewed. Sixty-three of these patients developed biochemical failure. These sixty-three patients were then matched in a one-to-one ratio to patients without biochemical failure, controlling for biopsy Gleason score, clinical stage, initial prostate-specific antigen, age, and the use of androgen deprivation. The pathology of the entire cohort was then reviewed for evidence of perineural invasion on initial prostate biopsy specimens. The biochemical relapse free survival rates for these two groups were compared. Results: Cases and controls were well matched, and there were no significant differences between the two groups in age, Gleason grade, clinical stage, initial prostate-specific antigen, and the use of androgen deprivation. PNI was found in 19 (17%) patients. There was no significant difference in the rates of PNI between cases and controls, 19.6% and 14.3% respectively (p = 0.45). PNI did not correlate with biochemical relapse free survival (p = 0.40). Conclusion: Perineural invasion is not a significant predictor of biochemical recurrence in patients undergoing brachytherapy for prostate cancer. [Copyright &y& Elsevier]