Prostatic Intraepithelial Neoplasia Research Articles

Comparative Analysis of Repeat Biopsies in Patients with Isolated High-grade Prostatic Intraepithelial Neoplasia in Their First Prostate Needle Biopsies of 6 Versus 12 Cores and Systematic Literature Review

Comparative Analysis of Repeat Biopsies in Patients with Isolated High-grade Prostatic Intraepithelial Neoplasia in Their First Prostate Needle Biopsies of 6 Versus 12 Cores and Systematic Literature Review

Leelamine suppresses cMyc expression in prostate cancer cells in vitro and inhibits prostate carcinogenesis in vivo.

Leelamine (LLM) inhibits growth of human prostate cancer cells but the underlying mechanism is not fully understood. The present study was undertaken to determine the effect of LLM on cMyc, which is overexpressed in a subset of human prostate cancers. The effect of LLM on cMyc expression and activity was determined by western blotting/confocal microscopy and luciferase reporter assay, respectively. A transgenic mouse model of prostate cancer (Hi-Myc) was used to determine chemopreventive efficacy of LLM. Exposure of androgen sensitive (LNCaP) and castration-resistant (22Rv1) human prostate cancer cells to LLM resulted in downregulation of protein and mRNA levels of cMyc. Overexpression of cMyc partially attenuated LLM-mediated inhibition of colony formation, cell viability, and cell migration in 22Rv1 and/or PC-3 cells. LLM treatment decreased protein levels of cMyc targets (e.g., lactate dehydrogenase), however, overexpression of cMyc did not attenuate these effects. A trend for a decrease in expression level of cMyc protein was discernible in 22Rv1 xenografts from LLM-treated mice compared with control mice. The LLM treatment (10 mg/kg body weight, 5 times/week) was well-tolerated by Hi-Myc transgenic mice. The incidence of high-grade prostatic intraepithelial neoplasia, adenocarcinoma in situ, and microinvasion was lower in LLM-treated Hi-Myc mice but the difference was not statistically significant. The present study reveals that LLM inhibits cMyc expression in human prostate cancer cells in vitro but concentrations higher than 10 mg/kg may be required to achieve chemoprevention of prostate cancer.

Correlation of serum PSA level with histomorphologic study in prostatic diseases

Correlation of serum PSA level with histomorphologic study in prostatic diseases - IJPO- Print ISSN No: - 2394-6784 Online ISSN No:- 2394-6792 Article DOI No:- 10.18231/2394-6792.2018.0117, Indian Journal of Pathology and Oncology-Indian J Pathol Oncol

Men1 disruption in Nkx3.1-deficient mice results in ARlow/CD44+ microinvasive carcinoma development with the dysregulated AR pathway.

Dysregulated androgen receptor (AR) plays a crucial role in prostate cancer (PCa) development, though further factors involved in its regulation remain to be identified. Recently, paradoxical results were reported on the implication of the MEN1 gene in PCa. To dissect its role in prostate luminal cells, we generated a mouse model with inducible Men1 disruption in Nkx3.1-deficient mice in which mouse prostatic intraepithelial neoplasia (mPIN) occur. Prostate glands from mutant and control mice were analyzed pathologically and molecularly; cellular and molecular analyses were carried out in PCa cell lines after MEN1 knockdown (KD) by siRNA. Double-mutant mice developed accelerated mPIN and later displayed microinvasive adenocarcinoma. Markedly, early-stage lesions exhibited a decreased expression of AR and its target genes, accompanied by reduced CK18 and E-cadherin expression, suggesting a shift from a luminal to a dedifferentiated epithelial phenotype. Intriguingly, over 60% of menin-deficient cells expressed CD44 at a later stage. Furthermore, MEN1 KD led to the increase in CD44 expression in PC3 cells re-expressing AR. Menin bound to the proximal AR promoter and regulated AR transcription via the H3K4me3 histone mark. Interestingly, the cell proliferation of AR-dependent cells (LNCaP, 22Rv1, and VCaP), but not of AR-independent cells (DU145, PC3), responded strongly to MEN1 silencing. Finally, menin expression was found reduced in some human PCa. These findings highlight the regulation of the AR promoter by menin and the crosstalk between menin and the AR pathway. Our data could be useful for better understanding the increasingly reported AR-negative/NE-negative subtype of PCa and the mechanisms underlying its development.

Genetic ablation of FASN attenuates the invasive potential of prostate cancer driven by Pten loss.

Loss of the tumor suppressor gene Pten in murine prostate recapitulates human carcinogenesis and causes stromal proliferation surrounding murine prostate intraepithelial neoplasia (mPIN), which is reactive to microinvasion. In turn, invasion has been shown to be regulated in part by de novo fatty acid synthesis in prostate cancer. We therefore investigated the effects of genetic ablation of Fasn on invasive potential in prostate‐specific Pten knockout mice. Combined genetic ablation of Fasn and Pten reduced the weight and volume of all the prostate lobes when compared to single knockouts. The stromal reaction to microinvasion and the cell proliferation that typically occurs in Pten knockout were largely abolished by Fasn knockout. To verify that Fasn knockout indeed results in decreased invasive potential, we show that genetic ablation and pharmacologic inhibition of FASN in prostate cancer cells significantly inhibit cellular motility and invasion. Finally, combined loss of PTEN with FASN overexpression was associated with lethality as assessed in 660 prostate cancer patients with 14.2 years of median follow‐up. Taken together, these findings show that de novo lipogenesis contributes to the aggressive phenotype induced by Pten loss in murine prostate and targeting Fasn may reduce the invasive potential of prostate cancer driven by Pten loss. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Inhibitory Effect of Orally Administered 5-Aminolevulinic Acid on Prostate Carcinogenesis in the FVB-Transgenic Adenocarcinoma of a Mouse Prostate (FVB-TRAMP) Model.

Background:5-aminolevulinic acid (5-ALA) is a constituent of mitochondrial electron carriers, heme and cytochrome c, which are crucial for aerobic energy metabolism and cell apoptosis. We investigated the chemopreventive efficacy of 5-ALA against prostate cancer using the FVB-transgenic adenocarcinoma of mouse prostate (FVB-TRAMP) model. Methods: Samples were collected from 24 FVB-TRAMP mice at 12 and 20 weeks of age (named the first and second sets, respectively). Sixteen mice (from the first set) were randomly allocated into 3 treatment groups: 1) control (no treatment), 2) low dose of 5-ALA (30 mg/kg/day), and 3) high dose of 5-ALA (300 mg/kg/day). Similarly, 8 mice were divided into 2 treatment groups: 1) control and 2) high dose of 5-ALA (300 mg/kg/day). 5-ALA was orally administered to mice before cancer onset, from 6 weeks of age. Results:In the control group, prostate cancer was pathologically detected in 33 and 50 % of mice at 12 and 20 weeks, respectively, while 25% of 12-week old mice in the low-dose group were affected and none of the high-dose group mice developed prostate cancer. Immunohistochemical analysis showed higher expression of cytochrome c oxidase subunit 4 (COX4) in the prostate gland of the high-dose group compared to the control (P = 0.018). Similarly, enzyme-linked immunosorbent assay using lysed prostate tissue revealed higher amounts of cytochrome c in the prostate of the high-dose group compared to the control (P = 0.021). Furthermore, western blot analysis showed higher level of cleaved caspase-3 in mice in the high-dose group diagnosed with high-grade prostatic intraepithelial neoplasia. Conclusion:Our results suggest that oral 5-ALA may support the functional expression of mitochondrial cytochrome c and COX4, leading to caspase 3-dependent apoptosis in carcinogenesis in FVB-TRAMP mice. Future clinical studies are warranted to confirm the chemopreventive value of 5-ALA in prostate carcinogenesis.

Centrosomal Localization of RXRα Promotes PLK1 Activation and Mitotic Progression and Constitutes a Tumor Vulnerability.

Retinoid X receptor alpha (RXRα), a nuclear receptor of transcription factor, controls various physiological and pathological pathways including cellular growth, proliferation, differentiation, and apoptosis. Here, we report that RXRα is phosphorylated at its N-terminal A/B domain by cyclin-dependent kinase 1 (Cdk1) at the onset of mitosis, triggering its translocation to the centrosome, where phosphorylated-RXRα (p-RXRα) interacts with polo-like kinase 1 (PLK1) through its N-terminal A/B domain by a unique mechanism. The interaction promotes PLK1 activation, centrosome maturation, and mitotic progression. Levels of p-RXRα are abnormally elevated in cancer cell lines, during carcinogenesis in animals, and in clinical tumor tissues. An RXRα ligand XS060, which specifically inhibits p-RXRα/PLK1 interaction but not RXRα heterodimerization, promotes mitotic arrest and catastrophe in a tumor-specific manner. These findings unravel a transcription-independent action of RXRα at the centrosome during mitosis and identify p-RXRα as a tumor-specific vulnerability for developing mitotic drugs with improved therapeutic index.

Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer

Chemoprevention trials for prostate cancer by androgen receptor or androgen synthesis inhibition have proven ineffective. Recently, it has been demonstrated that the histone methlytransferase, EZH2 is deregulated in mouse and human high-grade prostatic intraepithelial neoplasia (HG-PIN). Using preclinical mouse and human models of prostate cancer, we demonstrate that genetic and chemical disruption of EZH2 expression and catalytic activity reversed the HG-PIN phenotype. Furthermore, inhibition of EZH2 function was associated with loss of cellular proliferation and induction of Tp53-dependent senescence. Together, these data provide provocative evidence for EZH2 as an actionable therapeutic target toward prevention of prostate cancer.

FRMD6 has tumor suppressor functions in prostate cancer.

Available tools for prostate cancer (PC) prognosis are suboptimal but may be improved by better knowledge about genes driving tumor aggressiveness. Here, we identified FRMD6 (FERM domain-containing protein 6) as an aberrantly hypermethylated and significantly downregulated gene in PC. Low FRMD6 expression was associated with postoperative biochemical recurrence in two large PC patient cohorts. In overexpression and CRISPR/Cas9 knockout experiments in PC cell lines, FRMD6 inhibited viability, proliferation, cell cycle progression, colony formation, 3D spheroid growth, and tumor xenograft growth in mice. Transcriptomic, proteomic, and phospho-proteomic profiling revealed enrichment of Hippo/YAP and c-MYC signaling upon FRMD6 knockout. Connectivity Map analysis and drug repurposing experiments identified pyroxamide as a new potential therapy for FRMD6 deficient PC cells. Finally, we established orthotropic Frmd6 and Pten, or Pten only (control) knockout in the ROSA26 mouse prostate. After 12 weeks, Frmd6/Pten double knockouts presented high-grade prostatic intraepithelial neoplasia (HG-PIN) and hyperproliferation, while Pten single-knockouts developed only regular PIN lesions and displayed lower proliferation. In conclusion, FRMD6 was identified as a novel tumor suppressor gene and prognostic biomarker candidate in PC.

Prediction of clinically significant prostate cancer after negative prostate biopsy: The current value of microscopic findings

ObjectiveTo assess the current ability of atypical small acinar proliferation (ASAP), multifocal high-grade prostatic intraepithelial neoplasia (mHGPIN), HGPIN with atypia (PINATYP) and other non-malignant lesions to predict clinically significant prostate cancer (csPCa) in repeat prostate biopsies. MethodsThis retrospective study analyzed 377 repeat prostate biopsies, carried out between 2.014 and 2.017, and excluding those with previous PCa or 5-alpha reductase inhibitors treatment. ASAP, mHGPIN, PINATYP, prostatic atrophy, prostatic hyperplastic atrophy, proliferative inflammatory atrophy (PIA), chronic prostatitis, acute prostatitis, or granulomatous prostatitis, were prospectively reported after 12-core transrectal ultrasound (TRUS) systematic negative previous biopsies. 3T-multiparametric magnetic resonance imaging (mpMRI) was performed previous repeat biopsies. At least 2-core TRUS targeted biopsies of Prostate Imaging-Reporting and Data Systemv2 lesions ≥3, and/or 12-core TRUS systematic biopsy were performed in repeat prostate biopsies. The main outcome measurements were csPCa detection, which was defined when the International Society of Uro-Pathology group grade >1 and avoided biopsies. After logistic regression analysis the most efficient model was selected, nomogram was designed with internal validation, and clinical utility was analyzed. ResultsNormal benign tissue alone was present in less than 2% of previous negative biopsies. mHGPIN (39.7%), ASAP (4.3%) and PINATYP (3.7%) failed to predict csPCa risk in repeat biopsies. The finding of PIA (38.2%) associated with a decreased the risk of csPCa with an Odd ratio of 0.54 (95% confidence interval: 0.31–0.95), P= 0.031. The area under the curve, to predict csPCa, of mpMRI was 0.736, increasing up to 0.860 (95% confidence internal:0.82–0.90) when PSA density, age, digital rectal examination, and differential PSA between biopsies and PIA finding were integrated in a predictive model. At 6% threshold, more than 20% of repeat prostate biopsies were saved without missing csPCa. ConclusionCurrently, mHGPIN in negative prostate biopsy seems not able to predict the risk of future csPCa. The low incidence of ASAP and PINATYP, in our series, did not allow us to draw conclusions. PIA finding associated with a reduced risk of csPCa, and it could be integrated in a useful based-mpMRI predictive nomogram.

Multiparametric MR imaging of the prostate at 1.5-T without endorectal coil using an 8 channel pelvic phased array: Is it still a viable option?

IntroductionThe purpose of our work was to evaluate the feasibility of prostate multiparametric MR imaging at 1.5-T without endorectal coil using an 8 channel pelvic phased array coil. Material and methodsA total of 154 patients who underwent mp-MRI were retrospectively included. Patients received a standardized mp-MRI, compliant with 2012 European Society of Uro-Radiology guidelines, with 1·5 T magnetic field strength and an 8 channel pelvic phased-array coil.Two blinded readers graded the image quality of mp-MRI on a three-point scale and they scored the prostate lesions according to PI-RADS v2. All PI-RADS of 4 or 5 underwent biopsy. A third radiologist and a pathologist verified the correspondence between the MRI images and the results of the biopsy. Results64 (41.6%) patients showed a Pi-rads of 4 or 5. At biopsy, 79.7% showed a Gleason score ≥7, 12.5% showed a Gleason score of 6 and 7.8% showed a negative biopsy. In the group of Pi-rads ≤ 3, 12 patients underwent a biopsy with the following results: negative biopsy in 33.3%, atypical Small Acinar Proliferation in 16.7%, prostatic intraepithelial neoplasia in 25% and indolent PCa 25%. Mp-MRI in the identification of clinically significant cancer provided a low percentage of false positive (7.8%) while in 79.7% of cases it was capable to detect clinically significant prostate cancer. In 92.2% of patients mp-MRI identified a prostate cancer with a Gleason score ≥6. The inter-reader agreement was excellent in defining both the quality of the examination and the PI-RADS category (k = 0.83 and k = 0.70, respectively). Conclusionsmp-MRI at 1.5-T without endorectal coil using an 8 channel phased array is an appropriate tool for early detection of clinically significant prostate cancer. Implications for practice8 channel pelvic phased array is still an appropriate tool for early detection of clinically significant prostate cancer and for obtaining a reduction in overdiagnosis of indolent PCa.

Perils of hidden depths

A man in his 60s presented with lower urinary tract symptoms. His serum prostate-specific antigen level was 6 ng/mL. A prostate biopsy was performed (figure 1). Figure 1 Prostate biopsy...

KDM5B Is Essential for the Hyperactivation of PI3K/AKT Signaling in Prostate Tumorigenesis

KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer. KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to prostate cancer tumorigenesis remain unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and prostate cancer progression in cultured cells and in mouse models of prostate epithelium-specific mutant Pten/Kdm5b. Kdm5b deficiency resulted in a significant delay in the onset of prostate cancer in Pten-null mice, whereas Kdm5b loss alone caused no morphologic abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared with that of Pten mice. Pathologic analysis revealed Pten/Kdm5b mice displayed mild morphologic changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high-grade prostatic intraepithelial neoplasia and prostate cancer. Mechanistically, KDM5B governed PI3K/AKT signaling in prostate cancer in vitro and in vivo. KDM5B directly bound the PIK3CA promoter, and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human prostate cancer cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against prostate cancer. SIGNIFICANCE: This study demonstrates that levels of histone modification enzyme KDM5B determine hyperactivation of PI3K/AKT signaling in prostate cancer and that targeting KDM5B could be a novel strategy against prostate cancer.

Патогенетическая терапия доброкачественной гиперплазии предстательной железы и простатической интраэпителиальной неоплазии

Introduction. Benign prostatic hyperplasia (BPH) is a neoplasm and clinically occurred by progressive enlargement of the prostate. However, prostate neoplasm can also be malignant, which is come out from high-grade prostatic intraepithelial neoplasia (PIN). It is a proven precancerous condition. Purpose. Тo evaluate the data published on September and October 2020 on the prevalence, pathogenesis of BPH and PIN and methods of their treatment. Materials and methods. The search results in scientific databases PubMed, MEDLINE, Embase were analyzed for the queries «BPH», «PIN», «epidemiology of BPH», «pathogenesis», «treatment of PIN». Results. BPH is a very common disease in the elderly population. The pathogenesis of BPH includes age, genetics or hormones disorders, growth factors, inflammation, and lifestyle factors. PIN is the only common precursor of prostatic cancer. The main treatment methods are 5α-reductase inhibitors, phosphodiesterase-5 inhibitors, and surgical methods. In addition, plant active molecules are also widely used in the treatment of BPH and PIN. Conclusions. While 5α-reductase and phosphodiesterase-5 inhibitors treatment, as well as surgical methods have a lot of adverse events and complications, a unique herbal complex Gardaprost was developed, which suppresses hyperplasia of prostate. Curcumin, genistein and epigalocatechin-3- gallate, which are part of the preparation, form a safe agent aimed at combating the growth of the prostate gland in BPH, and also has a significant effect in the prevention of exacerbations of chronic prostatitis and malignancy in patients with PIN.

Effect of Atorvastatin on 7,12-Dimethylbenz (α) Anthracene and Testosterone-induced Prostatic Intraepithelial Neoplasia in the Prostate of Wistar Rats: Role of TRPM7

Effect of Atorvastatin on 7,12-Dimethylbenz (α) Anthracene and Testosterone-induced Prostatic Intraepithelial Neoplasia in the Prostate of Wistar Rats: Role of TRPM7

The Association between Prostate-Specific Antigen Velocity (PSAV), Value and Acceleration, and of the Free PSA/Total PSA Index or Ratio, with Prostate Conditions.

Introduction: Prostate-specific antigen velocity (PSAV) is used to monitor men with clinical suspicion of prostate cancer (PCa), with a normal cut-off point of 0.3–0.5 ng/mL/year. The aim of the study is to establish the predictive capacity of PSAV (value and acceleration) and of the free PSA/total PSA index or ratio. Method: Prospective multicentre observational study in 2035 men of over 47 years of age. Inclusion criteria: men who wished to be informed on the health of their prostate. Exclusion criteria: men with a previously diagnosed prostate condition. Groups: GA: (n = 518): men with serum PSA equal to or greater than 2.01 ng/mL. GB: (n = 775): men with serum PSA greater than or equal to 0.78 ng/mL and less than 2.01 ng/mL. GC: (n = 742): men with serum PSA less than 0.78 ng/mL. Variables: prostate-specific antigen (PSA); age; body mass index (BMI); PSA velocity (PSAV) (ng/mL per year); free PSA/total PSA index (iPSA); PSAV acceleration (increasing: positive, or decreasing: negative); prostate diagnosis (benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), or infectious and non-infectious prostatitis and prostatic adenocarcinoma (PCa)); de novo diagnoses of urinary tract diseases or conditions; concomitant treatments, diseases and conditions; final diagnosis of prostate health. Results: Mean age 62.35 years (SD 8.12), median 61 (47–94); age was lowest in GC. Mean BMI was 27.89 kg/m2 (SD 3.96), median 27.58 (18.56–57.13); no differences between groups. Mean PSAV was 0.69, SD 2.16, median 0.13 (0.001–34.46); PSAV was lowest in GC. Mean iPSA was 27.39 u/L (SD 14.25), median 24.29 (3.7–115); iPSA was lowest in GA. PSAV had more positive acceleration in GA and more negative acceleration in GC. There were 1600 (78.62%) cases of normal prostate or BPH, 322 (15.82%) cases of PIN or non-infectious prostatitis, and 113 (5.55%) cases of PCa. There were more cases of BPH in GC and more cases of PIN or prostatitis and cancer in GA (p = 0.00001). De novo diagnoses: 15 cases of urinary incontinence (UI), 16 discomfort/pain in LUT, 112 cases of voiding disorders, 12 urethral strictures, 19 hematuria, 51 cystitis, 3 pyelonephritis, 4 pelvic inflammatory disease; no differences were found between groups. In the multivariate analysis, PSAV and the direction of PSAV acceleration (positive or negative) were the variables which were correlated most strongly with prostate health. iPSA was associated with the presence of prostatitis, PCa, and BPH. Men in GA had more prostatitis, PCa, treatment with alpha blockers, and history of previous smoking. GB had more cases of BPH and more positive acceleration of PSAV. GC had more normal prostates, more BPH, more use of ranitidine, and more PSAV with negative acceleration. Conclusions: PSAV, direction of PSAV acceleration, and iPSA in PSA cut-off points of 0.78 ng/mL and 2.01 ng/mL in a priori healthy men over 47 predict the probability of benign or malignant pathology of the prostate.

Frequency of Prostate Cancer Among the Prostatic Tissue Samples- Collected From Different Tertiary Level Hospital in Dhaka City

Background: Prostate cancer is the development of cancer in the prostate, a gland in the male reproductive system. The cancer cells may spread from the prostate to other area of the body, particularly the bones and lymph nodes. It may initially cause no symptoms. A disease known as benign prostatic hyperplasiamay produce similar symptoms. Objective: To identify the frequency of prostate cancer in prostatic tissue submitted for histopathological examination in selected hospital of Dhaka City. Method: This analytical observational study consists of review of 3914 histopathological reports of prostatic specimen examined in 13 selected tertiary level hospitals in Dhaka city. This study was carried out from January 2007 to December 2009 (three years). All data were compiled, analyzed and appropriate statistical tests were done to make inference. Results: During the study period, among the 2914 histopathological specimen of prostatic tissue, 637(about 16%) cases were diagnosed as prostate cancer (including PIN), 3221 (about 82%) cases were benign prostatic hyperplasia, 53 (1 .35%) were chronic prostatitis and the remaining 3 cases were other rare disease e.g. lipid storage disease etc. Among the prostate cancer, most common was prostatic adenocarcinoma (about 95%); about 3% was Prostatic Intraepithelial Neoplasia (PIN), 1% squamous cell carcinoma arid I % are primary Transtiona1 cell carcinoma (TCC). Most of the patients diagnosed with prostate cancers are of advanced age - between 70 to 80 years (53.46%), and the second peak age is 60- 70 years (34.57 %). Of the prostate cancer cases 8.78% were well differentiated, 34.84% were moderately differentiated and 64.36% were poorly differentiated. The ratio between benign and malignant prostatic disease was about 5:1. Though all the prostatic diseases are common in elderly people, benign prostatic disease occurs more commonly: in younger patients than the prostate cancer. Conclusion: From this study it is evident that the burden of prostate cancer is still low in our context. But the disease seems to be increasing in recent years mainly due to increasing number of aged population. So in near future, the burden of the disease will be increasing throughout the world including our country. Prostate cancer is a slow growing tumor. It has a very sensitive tumor marker (PSA) also. Early diagnosis and proper management certainly improves the prognosis of the disease. There is a screening program for early diagnosis of the disease though it is relatively a costly program. Screening should be considered in persons who have a strong family history of prostate cancer. Every urologist, health policy makers should be aware of the burden of the disease and appropriate planning, necessary manpower & skill development, resource allocation should be made to combat the situation efficiently. Bangladesh Journal of Urology, Vol. 21, No. 2, July 2018 p.88-92

Followup of Men with PI-RADS™ 4 or 5 Abnormality on Prostate Magnetic Resonance Imaging and Nonmalignant Pathological Findings on Initial Targeted Prostate Biopsy.

A benign magnetic resonance imaging targeted prostate biopsy in the setting of a PI-RADS™ 4/5 abnormality presents a clinical dilemma for future management. We evaluated benign histological features on magnetic resonance imaging targeted prostate biopsy to determine if they predict the likelihood of missed cancer on subsequent biopsy. Between June 2012 and September 2016, 1,595 men were enrolled in a prospective study of magnetic resonance imaging targeted and systematic biopsy outcomes. We re-reviewed pathology from benign biopsies of PI-RADS 4/5 abnormalities and divided them into 5 groups for comparison to outcomes of clinical followup: inflammation (38%), stroma/glandular hyperplasia (9%), normal prostate tissue (28%), atypical small acinar proliferation/high grade prostatic intraepithelial neoplasia (9%) and cancer in adjacent systematic cores (16%). Of 497 men 88 (18%) with PI-RADS 4/5 abnormality prior to initial biopsy had no cancer on magnetic resonance imaging targeted prostate biopsy. On followup, 45 men underwent repeat magnetic resonance imaging: 12 (27%) had persistent PI-RADS 4/5 abnormalities, 17 (38%) had PI-RADS 2/3, 16 (35%) had PI-RADS 1. On repeat magnetic resonance imaging targeted prostate biopsy, cancer was found in 62.5% of men with PI-RADS 4/5 and 23% of men with PI-RADS 2/3. Histological groups on initial biopsy were not predictive of the likelihood of PI-RADS downgrade on repeat magnetic resonance imaging or cancer detection on repeat biopsy. Among men with no cancer on magnetic resonance imaging targeted prostate biopsy performed for PI-RADS abnormality, downgrade of PI-RADS score is noted in 73% on repeat magnetic resonance imaging. Persistence of PI-RADS 4/5 predicts a higher risk of missed cancer, warranting prompt re-biopsy. While histological findings such as inflammation may underlie some PI-RADS 4/5 abnormalities, initial histology is a poor predictor of cancer likelihood on repeat biopsy.

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

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. 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. 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. 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.

Macrophages expedite cell proliferation of prostate intraepithelial neoplasia through their downstream target ERK.

The risk factors for prostate cancer include a high-fat diet and obesity, both of which are associated with an altered cell environment including increased inflammation. It has been shown that chronic inflammation due to a high-fat diet or bacterial infection has the potential to accelerate prostate cancer as well as its precursor, prostatic intraepithelial neoplasia (PIN), development. However, the underlying mechanism of how chronic inflammation promotes prostate cancer development, especially PIN, remains unclear. In this study, we showed that more macrophages were present in PIN areas as compared to the normal areas of human prostate. When co-culturing PIN cells with macrophages in 3D, more PIN cells had nuclear localized cyclin D1, indicating that macrophages enhanced PIN cell proliferation. We identified ICAM-1 and CCL2 as chemoattractants expressed by PIN cells to recruit macrophages. Furthermore, we discovered that macrophage-secreted cytokines including C5a, CXCL1, and CCL2 were responsible for increased PIN cell proliferation. These three cytokines activated ERK and JNK signaling in PIN cells through a ligand-receptor interaction. However, only blockade of ERK abolished macrophage cytokines-induced cell proliferation of PIN. Overall, our results provide a mechanistic view on how macrophages activated through chronic inflammation can expedite PIN progression during prostate cancer development. The information from our work can facilitate a comprehensive understanding of prostate cancer development, which is required for improvement of current strategies for prostate cancer therapy.