Correlations of PTEN and ERG Immunoexpression in Prostate Carcinoma and Lesions Related to Its Natural History: Clinical Perspectives.

Purpose: The aim of our study was to observe the associations between the ETS-related gene (ERG) and the phosphatase and tensin homolog gene (PTEN) immunoexpression in prostate cancer and related lesions and highlight the clinical significance of these findings. Methods: We evaluated the immunohistochemical expression of ERG and PTEN in a series of 151 invasive prostate adenocarcinomas, including low-grade (Gleason grade pattern 3) and high-grade (Gleason grade patterns 4, 5) morphological patterns which corresponded to 45.5% and 54.4% of the cases, respectively. Additionally, we evaluated the immunoexpression of the two markers both in foci of high-grade prostatic intraepithelial neoplasia (HGPIN), as a precursor lesion of cancer, and in foci of intraductal carcinoma of the prostate (IDCP). Finally, to ensure the malignant nature of the prostate glands examined, we employed p63 and alpha-methylacyl-CoA racemase (AMACR) expression. Results: We found that PTEN loss was observed in 50.7%, and ERG positivity was detected in 41.8% of our cancerous samples. In HGPIN, PTEN loss appeared to be linked with a high-grade adjacent invasive carcinoma component which also displayed PTEN loss. As far as IDCP is concerned, ERG immunonegativity was correlated with adjacent high-grade invasive cancer, which was also ERG immunonegative. Conclusions: Our findings suggest that the clonal expansion of invasive cancer appears to be associated with distinct immunophenotypic cellular alterations of both early and late cancer-related histological lesions. Patients with PTEN loss in HGPIN in prostate biopsies should be closely monitored due to the increased likelihood of having an associated invasive high-grade carcinoma that may have not been sampled. Given the clinical significance that derives from PTEN expression in HGPIN lesions, we suggest the routine use of PTEN immunohistochemistry in prostate cancer biopsies in which HGPIN is the only finding.

In-Depth Comparison of Genetic Variants Demonstrates a Close Relationship Between Invasive and Intraductal Components of Prostate Cancer.

Intraductal carcinoma (IDC) of the prostate is often associated with concurrent high-grade invasive prostate cancer (PCa) and poor clinical outcomes. In this context, IDC is thought to represent the retrograde spread of invasive prostatic adenocarcinoma into the acini and ducts. Prior studies have demonstrated a concordance of PTEN loss and genomic instability between the IDC and high-grade invasive components of PCa, but larger genomic association studies to solidify our understanding of the relationship between these 2 lesions are lacking. Here, we evaluate the genomic relationship between duct-confined (high-grade prostatic intraepithelial neoplasia and IDC) and invasive components of high-grade PCa using genetic variants generated by whole exome sequencing. High-grade prostatic intraepithelial neoplasia and IDC were laser-microdissected, and PCa and nonneoplastic tissue was manually dissected from 12 radical prostatectomies. A targeted next-generation sequencing panel was used to identify disease-relevant variants. Additionally, the degree of overlap between adjacent lesions was determined by comparing exome-wide variants detected using whole exome sequencing data. Our results demonstrate that IDC and invasive high-grade PCa components show common genetic variants and copy number alterations. Hierarchical clustering of genome-wide variants suggests that in these tumors, IDC is more closely related to the high-grade invasive components of the tumor compared with high-grade prostatic intraepithelial neoplasia. In conclusion, this study reinforces the concept that, in the context of high-grade PCa, IDC likely represents a late event associated with tumor progression.

P2X4 purinergic receptors offer a therapeutic target for aggressive prostate cancer.

Prostate cancer (PCa) remains a leading cause of cancer-related deaths in American men and treatment options for metastatic PCa are limited. There is a critical need to identify new mechanisms that contribute to PCa progression, that distinguish benign from lethal disease, and that have potential for therapeutic targeting. P2X4 belongs to the P2 purinergic receptor family that is commonly upregulated in cancer and is associated with poorer outcomes. We observed P2X4 protein expression primarily in epithelial cells of the prostate, a subset of CD66+ neutrophils, and most CD68+ macrophages. Our analysis of tissue microarrays representing 491 PCa cases demonstrated significantly elevated P2X4 expression in cancer- compared with benign-tissue spots, in prostatic intraepithelial neoplasia, and in PCa with ERG positivity or with PTEN loss. High-level P2X4 expression in benign tissues was likewise associated with the development of metastasis after radical prostatectomy. Treatment with the P2X4-specific agonist cytidine 5'-triphosphate (CTP) increased Transwell migration and invasion of PC3, DU145, and CWR22Rv1 PCa cells. The P2X4 antagonist 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD) resulted in a dose-dependent decrease in viability of PC3, DU145, LNCaP, CWR22Rv1, TRAMP-C2, Myc-CaP, BMPC1, and BMPC2 cells and decreased DU145 cell migration and invasion. Knockdown of P2X4 attenuated growth, migration, and invasion of PCa cells. Finally, knockdown of P2X4 in Myc-CaP cells resulted in significantly attenuated subcutaneous allograft growth in FVB/NJ mice. Collectively, these data strongly support a role for the P2X4 purinergic receptor in PCa aggressiveness and identify P2X4 as a candidate for therapeutic targeting. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Characterization of stage-specific tumor progression in TMPRSS2-ERG (fusion)-driven and non-fusion-driven prostate cancer in GEM models.

In the present study, we performed a comparative stage-specific pathological and molecular marker evaluation of TMPRSS2-ERG fusion and PTEN loss-driven (TMPRSS2-ERG. Ptenflox/flox ) versus non-fusion-driven prostate tumorigenesis (Hi-Myc) in mice. Anterior, ventral, and dorsolateral prostates were collected from mice at different ages (or time points post-Cre induction). Results indicated that growth and progression of prostatic intraepithelial lesions to adenocarcinoma stages occurred in both mice models albeit at different rates. In the TMPRSS2-ERG. Ptenflox/flox mice, the initiation of tumorigenesis was slow, but subsequent progression through different stages became increasingly faster. Adenocarcinoma stage was reached early on; however, no high-grade undifferentiated tumors were observed. Conversely, in the Hi-Myc+/- mice, tumorigenesis initiation was rapid; however, progression through different stages was relatively slower and it took a while to reach the more aggressive phenotype stage. Nevertheless, at the advanced stages in the Hi-Myc+/- mice, high-grade undifferentiated tumors were observed compared to the later stage tumors observed in the fusion-driven TMPRSS2-ERG. Ptenflox/flox mice. These results were corroborated by the stage specific-pattern in the molecular expression of proliferation markers (PCNA and c-Myc); androgen receptor (AR); fusion-resultant overexpression of ERG; Prostein (SLC45-A3); and angiogenesis marker (CD-31). Importantly, there was a significant increase in immune cell infiltrations, which increased with the stage of tumorigenesis, in the TMPRSS2-ERG fusion-positive tumors relative to fusion negative tumors. Together, these findings are both novel and highly significant in establishing a working preclinical model for evaluating the efficacy of interventions during different stages of tumorigenesis in TMPRSS2-ERG fusion-driven PCa.

[The role of angiotensin-converting enzyme and angiotensin ii receptors of the second type in the pathogenesis of proliferative diseases of the prostate].

Angiotensin converting enzyme, angiotensin II, angiotensin II receptors of the first and second types represent the "classical" axis of regulation of the renin-angiotensin system. OBJECTIVE: to analyze the role of the components of the renin-angiotensin system in the pathogenesis of proliferative lesions of the prostate glan MATERIALS AND METHODS: The study included 63 patients who underwent transrectal prostate biopsy. The first group consisted of 19 patients with benign prostatic hyperplasia, the second group consisted of 19 men whose prostate cancer was detected during repeated biopsy, the third group consisted of 25 men with prostate cancer detected during primary prostate biopsy. The expression of angiotensin II type II (AT2-R) receptors in prostate tissue was evaluated using primary polyclonal antibodies Angiotensin II Type 2 Receptor and the EnVision FLEX imaging system (Dako, Denmark) according to a standard technique. The activity of angiotensin converting enzyme (ACE) was determined in the secret of the prostate gland, RESULTS: It was found that the activity of ACE in the secret of the prostate gland in proliferative diseases is significantly higher than in the "healthy" prostate. The highest activity of ACE was noted for benign prostatic hyperplasia, and the minimum - for prostate cancer. The expression of AT2-R in prostate tissues in proliferative diseases of the prostate gland has its own characteristics. The expression of AT2-R in the prostate stroma turned out to be the same, in the nuclei of epithelial cells, the level of expression of AT2-R decreased in the range of BPH-PIN-CP. Thus, an increase in the activity of ACE, the accumulation of angiotensin II in prostate secretions in proliferative prostate diseases against the background of a deficiency of AT2-R is the metabolic basis of malignant transformation of the prostate gland. CONCLUSION: The levels of ACE activity in prostate secretion and the expression of AT2-R in prostate tissue during primary prostate biopsy can be considered as promising prognostic tools for early detection of prostate malignancy.

CHD1 and SPOP synergistically protect prostate epithelial cells from DNA damage.

BACKGROUND: Recent genomic profiling has identified a subtype of prostate cancer (PCa) characterized by two key genetic alterations: missense mutation of speckle-type POZ protein (SPOP) and homozygous deletion of chromodomain helicase DNA-binding protein 1 (CHD1). Mutually exclusive with E26 transformation-specific (ETS) rearrangements, this subtype displays high genomic instability. Previous studies indicate that deficient SPOP or CHD1 alone leads to feeble prostate abnormalities and each protein is involved in DNA damage response (DDR). It remains to be determined whether CHD1 and SPOP cooperate to suppress prostate tumorigenesis and DDR. METHODS: Prostate-specific single or double knockout of Spop and Chd1 was generated with the Cre/loxP system in mice. Wild-type or mutant SPOP (F102C, F133V) overexpression and CHD1 knockdown with short hairpin RNA were created in human benign prostatic hyperplasia cell line BPH1. The levels of DNA damage and homologous recombination repair were measured by immunofluorescence staining of γH2AX and RAD51, respectively. RESULTS: Spop/Chd1 double-knockout mice displayed prostatic intraepithelial neoplasia at both young (3 months) and old (12 months) ages and failed to generate prostate adenocarcinoma. Compared with wild-type or single-knockout mice, the double-knockout prostate harbored moderately higher proliferating cells and dramatically augmented the level of γH2AX staining, although androgen receptor-positive cells and apoptotic cells remained at a similar level. In BPH1 cell line, SPOP mutant overexpression and CHD1 silencing synergistically sensitized the cells to DNA damage by camptothecin, an inducer of double-strand breaks. CONCLUSIONS: Our results indicate that SPOP and CHD1 can synergistically promote repair of naturally occurring or chemically induced DNA damages in prostate epithelial cells. Regarding the progression of the SPOP/CHD1 subtype of PCa, other functionally complementary drivers warrant further identification. The clinical implication is that this subtype of PCa may be particularly sensitive to poly(ADP-ribose) polymerase inhibitors or DNA-damaging agents.

TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands.

Androgens stimulate the proliferation of epithelial cells in the prostate by activating topoisomerase 2 (TOP2) and regulating the transcription of target genes. TOP2 resolves the entanglement of genomic DNA by transiently generating double-strand breaks (DSBs), where TOP2 homodimers covalently bind to 5' DSB ends, called TOP2-DNA cleavage complexes (TOP2ccs). When TOP2 fails to rejoin TOP2ccs generating stalled TOP2ccs, tyrosyl DNA phosphodiesterase-2 (TDP2) removes 5' TOP2 adducts from stalled TOP2ccs prior to the ligation of the DSBs by nonhomologous end joining (NHEJ), the dominant DSB repair pathway in G0 /G1 phases. We previously showed that estrogens frequently generate stalled TOP2ccs in G0 /G1 phases. Here, we show that physiological concentrations of androgens induce several DSBs in individual human prostate cancer cells during G1 phase, and loss of TDP2 causes a five times higher number of androgen-induced chromosome breaks in mitotic chromosome spreads. Intraperitoneally injected androgens induce several DSBs in individual epithelial cells of the prostate in TDP2-deficient mice, even at 20 hr postinjection. In conclusion, physiological concentrations of androgens have very strong genotoxicity, most likely by generating stalled TOP2ccs.

Reduced cytoplasmic expression of MAGE-A2 predicts tumor aggressiveness and survival: an immunohistochemical analysis.

BACKGROUND: Melanoma antigen gene A2 (MAGE-A2) is one of the most cancer-testis antigens overexpressed in various types of cancers. Silencing the MAGE-A2 expression inhibited the proliferation of prostate cancer (PCa) cells and increased the chemosensitivity. However, the expression pattern of MAGE-A2 in PCa tissue samples and its prognostic and therapeutic values for PCa patients is still unclear. METHODS: In this study, for the first time, the staining pattern and clinical significance of MAGE-A2 were evaluated in 166 paraffin-embedded prostate tissues, including 148 cases of PCa and 18 cases of high-grade prostatic intraepithelial neoplasia (HPIN), by immunohistochemical analysis. RESULTS: The simultaneous expression of both nuclear and cytoplasmic patterns of MAGE-A2 with different staining intensities was observed among studied cases. Increased expression of MAGE-A2 was significantly found in PCa tissues compared to HPIN cases (P < 0.0001). Among PCa samples, the strong staining intensity of nuclear expression was predominantly observed in comparison with cytoplasmic expression in PCa tissues (P < 0.0001). A significant and inverse correlation was found between the cytoplasmic expression of MAGE-A2 and increased Gleason score (P = 0.002). Increased cytoplasmic expression of MAGE-A2 was associated with longer biochemical recurrence-free survival (BCR-FS) and disease-free survival (DFS) of patients (P = 0.002, P = 0.001, respectively). In multivariate analysis, Gleason score and cytoplasmic expression of MAGE-A2 were independent predictors of the BCR-FS (P = 0.014; P = 0.028, respectively). CONCLUSIONS: Taken together, cytoplasmic expression of MAGE-A2 was inversely proportional to the malignant grade and duration of recurrence of the disease in patients with PCa.

[Significance of atypical small acinar proliferation and high-grade prostatic intraepithelial neoplasia in prostate biopsy in China].

OBJECTIVE: To assess the rates of atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN) detected in prostate biopsy in China and the risk of PCa found in subsequent repeat biopsy. METHODS: A total of 2,456 patients underwent TRUS-guided prostate biopsy with the samples of ASAP and/or HGPIN tissues in our hospital at least twice between July 2014 and June 2019. We analyzed the findings of digital rectal examination, prostate volumes, PSA levels, and the results of prostate biopsies. RESULTS: Initial prostate biopsies revealed 737 cases of PCa (30.0%), 215 cases of ASAP (8.8%), 98 cases of HGPIN (4.0%), and 18 cases of ASAP+HGPIN (0.7%). Totally, 313 of the patients met the inclusion criteria and included in this study. Of the 215 cases of ASAP confirmed in the first biopsy, 72 and 25 were diagnosed with PCa in the second and third biopsies, respectively, 83 with Gleason score (GS) 6, 14 with GS7, 57 with T1c and 40 with T2a tumors. Of the 98 cases of HGPIN confirmed in the first biopsy, 1 was diagnosed with PCa in the second and another 1 in the third biopsy, both with GS6 and T1c tumors. Of the 18 cases of ASAP+HGPIN confirmed in the first biopsy, 7 and 3 were diagnosed with PCa in the second and third biopsies, respectively, 7 with GS6, 3 with GS7, 6 with T1c and 4 with T2a tumors. CONCLUSIONS: ASAP is a significant risk factor for PCa and repeat prostate biopsy should be performed for patients diagnosed with ASAP in the first biopsy. Whether repeat biopsy is necessary for those diagnosed with HGPIN depends on other related clinical parameters./.

Activation of hepatocyte growth factor/MET signaling initiates oncogenic transformation and enhances tumor aggressiveness in the murine prostate.

Emerging evidence has shown that the hepatocyte growth factor (HGF) and its receptor, MET proto-oncogene, receptor tyrosine kinase (MET), promote cell proliferation, motility, morphogenesis, and angiogenesis. Whereas up-regulation of MET expression has been observed in aggressive and metastatic prostate cancer, a clear understanding of MET function in prostate tumorigenesis remains elusive. Here, we developed a conditional Met transgenic mouse strain, H11Met/+:PB-Cre4, to mimic human prostate cancer cells with increased MET expression in the prostatic luminal epithelium. We found that these mice develop prostatic intraepithelial neoplasia after HGF administration. To further assess the biological role of MET in prostate cancer progression, we bred H11Met/+/PtenLoxP/LoxP:PBCre4 compound mice, in which transgenic Met expression and deletion of the tumor suppressor gene Pten occurred simultaneously only in prostatic epithelial cells. These compound mice exhibited accelerated prostate tumor formation and invasion as well as increased metastasis compared with PtenLoxP/LoxP:PB-Cre4 mice. Moreover, prostatic sarcomatoid carcinomas and lesions resembling the epithelial-to-mesenchymal transition developed in tumor lesions of the compound mice. RNA-Seq and qRT-PCR analyses revealed a robust enrichment of known tumor progression and metastasis-promoting genes in samples isolated from H11Met/+/PtenLoxP/LoxP:PB-Cre4 compound mice compared with those from PtenLoxP/LoxP:PB-Cre4 littermate controls. HGF-induced cell proliferation and migration also increased in mouse embryonic fibroblasts (MEFs) from animals with both Met transgene expression and Pten deletion compared with Pten-null MEFs. The results from these newly developed mouse models indicate a role for MET in hastening tumorigenesis and metastasis when combined with the loss of tumor suppressors.

Molecular evidence supporting the precursor nature of atypical adenomatous hyperplasia of the prostate.

Atypical adenomatous hyperplasia (AAH) of the prostate is characterized by lobular proliferation of closely packed small acini. It is hypothesized that AAH is a precursor lesion for low-grade prostate cancer arising from the transition zone. Telomere dysfunction is common during malignant transformation of epithelia. In this study, we investigate telomere shortening in AAH (n = 93), high-grade prostatic intraepithelial neoplasia (HGPIN) ( n = 68), and prostatic adenocarcinoma (PCA) ( n = 70) using quantitative fluorescence in situ hybridization. Twenty percent (19 of 93) of AAH specimens, 68% (46 of 68) of HGPIN, and 83% (58 of 70) of PCA showed significant telomere shortening. Thirty-two percent of AAH lesions had α-methylacyl-CoA racemase (AMACR) expression, a sensitive and specific marker for HGPIN and PCA. AMACR expression in AAH was seen more frequently in AAH foci with telomere shortening or coexisting PCA. Our findings indicate that a subset of AAH lesions have telomere shortening and AMACR expression, suggesting that these foci may be precursors for PCA.

Co-expression of TLR-9 and MMP-13 is associated with the degree of tumour differentiation in prostate cancer.

In vitro experiments demonstrated that stimulation of Toll-like receptor 9 (TLR-9) by synthetic TLR-9 ligands induces the invasion of TLR-9-expressing prostate cancer cells through matrix metalloproteinase 13 (MMP-13). However, the clinical value of TLR-9 and MMP-13 co-expression in the pathophysiology of the prostate is unknown. In the study, we evaluated the expression levels and clinical significance of the TLR-9 and MMP-13 in a series of prostate tissues. One hundred and eighty prostate tissues including prostate cancer (PCa) (n = 137), high-grade prostatic intraepithelial neoplasia (HPIN) (n = 18) and benign prostatic hyperplasia (BPH) (n = 25) were immunostained for the TLR-9 and MMP-13 markers. Subsequently, the correlation between the TLR-9 and MMP-13 staining scores and clinicopathological parameters was obtained. Higher expressions of TLR-9 and MMP-13 were found in PCa and high-grade prostatic intraepithelial neoplasia compared to benign prostatic hyperplasia tissues. Among PCa samples, a positive relationship was revealed between the MMP-13 expression and Gleason score (P < 0.001). There was a significant correlation between TLR-9 expression and regional lymph node involvement (P = 0.04). The expression patterns of TLR-9 and MMP-13 markers demonstrated a reciprocal significant correlation between the two markers in the same series of prostate samples (P < 0.001). Furthermore, the Gleason score of TLR-9high /MMP-13high and TLR-9low /MMP-13low phenotypes showed a significant difference (P = 0.002). Higher expressions of TLR-9 and MMP-13 can confer aggressive behaviour to PCa. Therefore, these markers may be used as a valuable target for tailored therapy of PCa.

Chronic prostatitis alters the prostatic microenvironment and accelerates preneoplastic lesions in C57BL/6 mice.

BACKGROUND: Chronic prostatitis has been supposed to be associated with preneoplastic lesions and cancer development. The objective of this study was to examine how chronic inflammation results in a prostatic microenvironment and gene mutation in C57BL/6 mice. METHODS: Immune and bacterial prostatitis mouse models were created through abdominal subcutaneous injection of rat prostate extract protein immunization (EAP group) or transurethral instillation of uropathogenic E. coli 1677 (E. coli group). Prostate histology, serum cytokine level, and genome-wide exome (GWE) sequences were examined 1, 3, and 6 months after immunization or injection. RESULT: In the EAP and E. coli groups, immune cell infiltrations were observed in the first and last months of the entire experiment. After 3 months, obvious proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN) were observed accompanied with fibrosis hyperplasia in stroma. The decrease in basal cells (Cytokeratin (CK) 5+/p63+) and the accumulation of luminal epithelial cells (CK8+) in the PIA or PIN area indicated that the basal cells were damaged or transformed into different luminal cells. Hic1, Zfp148, and Mfge8 gene mutations were detected in chronic prostatitis somatic cells. CONCLUSION: Chronic prostatitis induced by prostate extract protein immunization or E. coli infection caused a reactive prostatic inflammation microenvironment and resulted in tissue damage, aberrant atrophy, hyperplasia, and somatic genome mutation.

The impact of metformin use on the risk of prostate cancer after prostate biopsy in patients with high grade intraepithelial neoplasia.

PURPOSE: We report our experience on metformin use in diabetic patients and its impact on prostate cancer (PCa) after a high-grade prostatic intraepithelial neoplasia (HGPIN) diagnosis. MATERIALS AND METHODS: We retrospectively analyzed 551 patients with a diagnosis of HGPIN without PCa in a first prostate biopsy. The cohort of the study consisted of 456 nondiabetic subjects, and 95 diabetic patients. Among the patients with diabetes 44 were treated with metformin, and 51 with other antidiabetic drugs. A transrectal ultrasound prostate biopsy scheme with 22 cores was carried out 4-6 months after the first diagnosis of HGPIN. RESULTS: Among 195 (35.4%) patients with cancer, there were statistically significant differences in terms of PCa detection (p<0.001), Gleason score distribution (p<0.001), and number of positive biopsy cores (pv0.002) between metformin users and non-users. Metformin use was associated with a decreased risk of PCa compared with neveruse (p<0.001). Moreover, increasing duration of metformin assumption (≥2 years) was associated with decreasing incidence of PCa and higher Gleason score ≥7 compared with assumption <2 years. CONCLUSIONS: This preliminary experience suggests that metformin use may have some beneficial effects in patients with diabetes and HGPIN; metformin should not be overlooked in these patients because it is neither new nor expensive.

Repeat Prostate Biopsy Practice Patterns in a Statewide Quality Improvement Collaborative.

PURPOSE: We examined rebiopsies in MUSIC (Michigan Urological Surgery Improvement Collaborative) to understand adherence to guidelines recommending repeat prostate biopsy in patients with multifocal high grade prostatic intraepithelial neoplasia or atypical small acinar proliferation. MATERIALS AND METHODS: We analyzed data on men undergoing repeat biopsy, practice patterns and cancer detection rates. Multivariate regression modeling was used to calculate the proportion of patients undergoing rebiopsy. We used claims data to validate the treatment classification in MUSIC. To understand reasons for not performing rebiopsy we reviewed records of a sample of patients with atypical small acinar proliferation. RESULTS: We identified 5,375 men with a negative biopsy, of whom 411 (7.6%) underwent repeat biopsy. In 718 men with high grade prostatic intraepithelial neoplasia, 350 with atypical small acinar proliferation and 587 with high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation or atypical small acinar proliferation alone at initial biopsy the rebiopsy rate was 20.7%, 42.5% and 55.6%, respectively. The adjusted proportion of patients with rebiopsy in each practice ranged from 0% to 17.2% (p <0.001). The overall cancer detection rate at rebiopsy was 39.3%. It was highest after atypical small acinar proliferation (adjusted probability 0.39, 95% CI 0.30-0.48), and after high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation (adjusted probability 0.50, 95% CI 0.35-0.65). The greatest Gleason 7 or greatest detection rate of 41.1% was found in patients with high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation. Chart review revealed that 45.5% of patients with atypical small acinar proliferation underwent prostate specific antigen testing instead of rebiopsy while 36% failed to undergo rebiopsy despite a recommendation. CONCLUSIONS: Rebiopsy rates vary in Michigan practices with relatively low use in men with high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation or atypical small acinar proliferation alone. Quality improvement strategies should target patients with atypical small acinar proliferation and high grade prostatic intraepithelial neoplasia as they have the highest likelihood of cancer detection.

Dutasteride for the prevention of prostate cancer in men with high-grade prostatic intraepithelial neoplasia: results of a phase III randomized open-label 3-year trial.

PURPOSE: High-grade prostatic intraepithelial neoplasia (HGPIN) is a potential precursor of prostate cancer (PCa), and patients with HGPIN are at high risk for PCa development. Objective of our study was to evaluate the efficacy of dutasteride 0.5 mg in PCa prevention among men with isolated HGPIN on biopsy. METHODS: This prospective, randomized, phase III, open-label 3-year trial assessed dutasteride versus active surveillance in patients with HGPIN. Patients were randomized to dutasteride 0.5 mg daily or active surveillance. Per-protocol prostate biopsies were performed at 6, 12, 24, and 36 months until cancer detection or study end. The primary end point was cancer-free survival (CFS). An intention-to-treat analysis was done for patients who underwent at least one per-protocol biopsy. An efficacy analysis was done for patients who completed the study. CFS was evaluated using Kaplan-Meier and log-rank analysis. RESULTS: In total, 220 men were randomized (dutasteride, n = 107; surveillance, n = 113). PCa was detected in 47.6: 49.1 % in the surveillance group and 45.9 % in the treatment group (p = 0.66). The detected PCa differentiation by Gleason score (GS) was GS 6 in 76.9 %, GS 7 in 19.8 %, and GS ≥ 8 in 3.3 %, with no difference between groups. The 3-year PCa-free survival was 43.6 % in the surveillance and 49.6 % in the dutasteride group (log rank p = 0.57). Limitations include a relatively high non-adherence rate, open-label design, and baseline sextant biopsy scheme. CONCLUSIONS: Dutasteride 0.5 mg for 3 years did not lower the PCa detection rate but did not worsen detected PCa characteristics in men with HGPIN.

Serum carotenoid and retinol levels in African-Caribbean Tobagonian men with high prostate cancer risk in comparison with African-American men.

Black men are known to have a higher risk for prostate cancer (PC). Carotenoids and retinol, linked to PC, have not been compared in different black populations at risk. We examined serum carotenoid and retinol levels between PC-free African-Caribbean (AC) Tobagonian men with a high PC risk (high-grade prostatic intraepithelial neoplasia, atypical foci or repeated abnormal PC screenings) and African-American (AA) men with elevated serum prostate-specific antigen (PSA) levels (≥4 ng/ml). AC men who participated in the 2003 lycopene clinical trial and AA men who participated in the 2001-2006 National Health and Nutrition Examination Survey were compared. Serum specimens were analysed for carotenoid (ß-carotene, α-carotene, ß-cryptoxanthin, lutein/zeaxanthin and lycopene) and retinol levels by isocratic HPLC. Quantile regression was used to examine the association between serum carotenoid and retinol levels and black ethnicity, overall and among men with elevated serum PSA. There were sixty-nine AC men and sixty-five AA men, aged 41-79 years, included. AC men were associated with lower serum lycopene and retinol levels, and higher serum α- and ß-carotenes and lutein/zeaxanthin levels compared with AA men, after adjusting for age, BMI, ever smoked cigarettes, education and hypertension (P≤0·03). Among men with elevated PSA, serum retinol was no longer statistically significant with ethnicity (P=0·06). Possible differences may be attributed to dietary intake, genetics and/or factors that influence bioavailability of these micronutrients. Prospective studies are warranted that investigate whether these differences in micronutrients between AC Tobagonian and AA men influence PC risk.

Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization.

Prostate cancer often manifests as morphologically distinct tumour foci and is frequently found adjacent to presumed precursor lesions such as high-grade prostatic intraepithelial neoplasia (HGPIN). While there is some evidence to suggest that these lesions can be related and exist on a pathological and morphological continuum, the precise clonal and temporal relationships between precursor lesions and invasive cancers within individual tumours remain undefined. Here, we used molecular genetic, cytogenetic, and histological analyses to delineate clonal, temporal, and spatial relationships between HGPIN and cancer lesions with distinct morphological and molecular features. First, while confirming the previous finding that a substantial fraction of HGPIN lesions associated with ERG-positive cancers share rearrangements and overexpression of ERG, we found that a significant subset of such HGPIN glands exhibit only partial positivity for ERG. This suggests that such ERG-positive HGPIN cells either rapidly invade to form adenocarcinoma or represent cancer cells that have partially invaded the ductal and acinar space in a retrograde manner. To clarify these possibilities, we used ERG expression status and TMPRSS2-ERG genomic breakpoints as markers of clonality, and PTEN deletion status to track temporal evolution of clonally related lesions. We confirmed that morphologically distinct HGPIN and nearby invasive cancer lesions are clonally related. Further, we found that a significant fraction of ERG-positive, PTEN-negative HGPIN and intraductal carcinoma (IDC-P) lesions are most likely clonally derived from adjacent PTEN-negative adenocarcinomas, indicating that such PTEN-negative HGPIN and IDC-P lesions arise from, rather than give rise to, the nearby invasive adenocarcinoma. These data suggest that invasive adenocarcinoma can morphologically mimic HGPIN through retrograde colonization of benign glands with cancer cells. Similar clonal relationships were also seen for intraductal carcinoma adjacent to invasive adenocarcinoma. These findings represent a potentially undervalued indicator of pre-existing invasive prostate cancer and have significant implications for prostate cancer diagnosis and risk stratification.

[The use of ProstaDoz in patients with benign prostatic hyperplasia and coexistent high-grade prostatic intraepithelial neoplasia].

INTRODUCTION: In recent years there has been an increasing interest in the drug treatment of benign prostatic hyperplasia (BPH) to improve the patients quality of life without surgical treatment. In this connection, phytotherapeutic drugs and biologically active dietary supplements (BADS), consisting of a combination of microelements, vitamins and plant extracts, have been increasingly used in addition to synthetic preparations. OBJECTIVE: To investigate the clinical effectiveness of dietary supplement ProstaDoz in the treatment of BPH with coexistent high-grade prostatic intraepithelial neoplasia (PIN). MATERIALS AND METHODS: The study group comprised 30 men with BPH and high-grade PIN who were diagnosed with primary biopsy and received ProstaDoz for three months. The control group included 18 patients with the same diagnosis who were treated with Tamsulosin. RESULTS: After a 3-month intake of the ProstaDoz, a statistically significant reduction was observed in symptom scores for BPH and the quality of life index by 18% (p<0.001) and 16.7% (p<0.001), respectively. The residual urine volume and total serum PSA decreased by 28.3% (p<0.001) and 46.8% (p<0.001), respectively. Unlike the control group, the rate of prostate cancer detection was 6.25 times lower in patients taking ProstaDoz, and 16% of them had lower grade PIN compared with baseline or no PIN at all. CONCLUSION: The findings suggest that using ProstaDoz in patients with BPH and high-grade PIN contributes to improving the quality of life (QoL) of patients and the regression of dysplasia.

Clinical Significance of Proliferative Inflammatory Atrophy in Negative Prostatic Biopsies.

PURPOSE: To analyze the association between prostatic proliferative inflammatory atrophy finding in negative prostate biopsies and future detection of prostate cancer (PCa) and its aggressiveness in men subjected to repeat biopsies, due to persistent suspicion of PCa. MATERIALS AND METHODS: Prospective and observational study of 474 men scheduled to repeated PBs. Assessment of PIA and its extension in the previous biopsy. PCa detection rate and tumor aggressiveness. Age, serum total PSA, free PSA, percent free PSA (%fPSA), digital rectal exam (DRE), prostate volume (PV), PSA density (PSAD), PSA kinetics (PSAV and PSADT) findings of PIA and HGPIN, and number of affected cores in previous PBs were included in the univariate and multivariate analysis. Aggressive tumors were considered when any Gleason pattern 4 was found. RESULTS: PCa was detected in 133 men (28.1%). Age, serum total PSA, %fPSA, PV, PSAD, PSAV, PSADT, and PIA finding were significantly associated to PCa detection. However, only age, OR: 1.06 (95%CI: 1.03-1.10), P < 0.01; DRE, OR: 1.76 (95%CI: 1.05-2.92), P = 0.03; %fPSA, OR: 0.96 (95%CI: 0.93-0.99), P = 0.03; PV, OR: 0.98 (95%CI: 0.97-0.99) and PIA finding, OR: 0.49 (95%CI: 0.29-0.83), P < 0.01, were independent predictors of PCa detection. PCa was found in 18% of 159 men with previous PIA finding while in 33% of 315 men without previous PIA (P < 0.01). None of the studied parameters including PIA in the previous biopsy were related with subsequent PCa aggressiveness. CONCLUSIONS: PIA finding in negative biopsies correlates with a decreased frequency of detecting PCa in men with persistent suspicion of PCa. The aggressiveness of future detected tumors was not associated with previous PIA finding. Prostate 76:1501-1506, 2016. © 2016 Wiley Periodicals, Inc.