Should We Investigate Prostatic Inflammation for the Management of Benign Prostatic Hyperplasia?

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1 EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) available at journal homepage: Should We Investigate Prostatic Inflammation for the Management of Benign Prostatic Hyperplasia? Grégoire Robert a,b, Aurélien Descazeaud a,c, Yves Allory a,d, Francis Vacherot a, Alexandre de la Taille a,e, * a INSERM U955 Eq07, Créteil, France b Pellegrin University Hospital, Bordeaux-2 Victor Segalen University, Department of Urology, Bordeaux, France c Dupuytren Hospital, CHU of Limoges, Department of Urology, Limoges, France d Henri-Mondor Hospital, AP-HP, Department of Pathology, Créteil, France e Henri-Mondor Hospital, AP-HP, Department of Urology, Créteil, France Article info Keywords: Benign prostatic hyperplasia Biomarker Inflammation Risk factor Abstract Context: Although benign prostatic hyperplasia (BPH) is the most frequent disease in elderly men, only a few predictive factors have been identified. Recently, prostatic inflammation has emerged as one of them. Objective: This review describes the relationship between inflammation and BPH prognosis that emerges from the literature. Evidence acquisition: Publications relating to the role of inflammation in BPH were identified by searching PubMed Medline database. Basic science and clinical studies were reviewed. Evidence synthesis: At 12-wk gestation, few inflammatory cells can be observed in the prostatic gland. This amount progressively increases and is more frequent in surgery-derived specimens than in young normal prostates. In fact, almost 80% of surgery-derived specimens show signs of inflammation. Microscopic and immunohistochemical analysis of the inflammatory infiltrate has shown a vast majority of antigen-presenting cells; these immune cells could ensure the sterility of the genitourinary tract. However, immune cells are also releasing numerous cytokines and growth factors that recruit other cells that promote the growth of epithelial and stromal prostatic cells. This process finally results in prostate enlargement. Because of the relationship between BPH and inflammation, antiinflammatory treatments have been tested in BPH and have been shown to improve urinary symptoms. They could therefore be proposed to treat BPH patients with prostatic inflammation. Although inflammation can be diagnosed on prostate biopsy, noninvasive biomarkersthatcouldbeusedtomonitorbph treatment are still needed. Conclusions: Chronic prostatic inflammation is a risk factor for prostate enlargement, BPH symptoms, or acute urinary retention. For BPH patients with inflammation, close surveillance and therapies that exert anti-inflammatory effects could therefore be proposed. However, reliable biomarkers have not yet been validated to detect prostatic inflammation in routine clinical practice. # 2009 Published by Elsevier B.V. on behalf of European Association of Urology. * Corresponding author. INSERM U955 Eq07, CHU Henri-Mondor, Department of Urology, 51, avenue du Maréchal de Lattre de Tassigny, Créteil, France. Tel ; Fax: address: adelataille@hotmail.com (A. de la Taille) /$ see front matter # 2009 Published by Elsevier B.V. on behalf of European Association of Urology. doi: /j.eursup

2 880 EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) Introduction 2. Evidence acquisition Benign prostatic hyperplasia (BPH) predominantly affects men aged >50 yr and represents the most common urologic disease among elderly males [1]. Clinical BPH is defined as a combination of lower urinary tract symptoms (LUTS) with benign prostatic enlargement and bladder outlet obstruction. BPH symptoms range from minimal bother to urinary retention and renal failure. Some patients even experience no symptoms, although BPH is diagnosed at histologic examination. The histologic diagnosis of BPH refers to an overgrowth of the epithelial and stromal components of the transition zone and periurethral area. The prevalence of histologic BPH could be >70% at 60 yr of age and >90% at 70 yr of age [2]. Although androgens and estrogens have been involved in the development of BPH, the cellular and molecular mechanisms underlying the pathogenesis of BPH and leading to a symptomatic disease are still not fully known [3]. Basic science and clinical studies suggest that inflammation may be a central mechanism in prostate enlargement and BPH progression. The findings of in vitro and in vivo studies indicate that chronic inflammation may influence the development of histologic BPH. Consistently, the Medical Therapy of Prostatic Symptoms (MTOPS) and Reduction by Dutasteride of Prostate Cancer Events (REDUCE) clinical trials have recently shown a relationship between prostatic inflammation and LUTS [4,5]. This review therefore aims to describe the relationship between inflammation and BPH prognosis that emerges from the literature. We identified publications relating to the role of inflammation in BPH by searching the PubMed Medline database. Search terms were benign prostatic hyperplasia (BPH), inflammation, chemokines, cytokines, and lymphocytes. In addition, we found references in the reference sections of the publication identified. Publications were limited to those in English. There was no time limit in the Medline search; however, publications presented in this review were selected because they were the most recent and the most relevant in supporting the implication of prostatic inflammation in BPH development. 3. Evidence synthesis 3.1. Presence of inflammatory infiltrates in prostatic tissues The presence of inflammatory cells is a well-known histologic feature of prostatic tissue. Histologic inflammation has been reported in most surgery-derived specimens, even if patients have no history or symptoms of prostatitis [6,7]. Fig. 1 illustrates different stages of inflammatory infiltration of the prostatic gland. In 2003, Di Silverio et al published the largest histologic study of inflammation on BPH specimens [8]. In this study, the type of inflammation acute or chronic and the severity of the inflammation were analysed on 3942 surgery-derived BPH specimens collected over a 20-yr Fig. 1 Different stages of prostatic inflammation: (a) no inflammation, (b) mild, (c) moderate, and (d) severe.

3 EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) period. Inflammation was observed in 43% of BPH specimens. In these specimens, the main type of inflammation was chronic inflammation (69% of the cases). Severity of the chronic inflammation was described as mild in the vast majority of the cases (78%). Furthermore, comparison of histologic findings with clinical data showed that inflammation was significantly associated with age and prostate size. Even though more than half of prostates (61%) that measured ml exhibited signs of chronic inflammation, only 8.5% of prostates that measured ml presented these signs ( p < 0.001). These results indicate that inflammation and BPH are closely related. Because baseline prostate size can be considered a predictor of BPH progression, such as acute urinary retention [5], the relationship between prostate size and chronic inflammation suggests that inflammation could induce worsening of clinical parameters Composition of prostatic inflammatory infiltrates Because inflammatory cells are reported in most surgeryderived specimens, the pattern of the inflammatory infiltrate has been well defined. Nickel et al investigated 80 patients with diagnosed BPH but no history or symptoms of prostatitis [7]. This study assessed the location and the density of the inflammatory infiltrate in prostate obtained by transurethral resection of the prostate (TURP). The inflammatory cell density was graded from 1 to 3, and its location was defined as glandular, periglandular, stromal, or periurethral by leukocyte common antigen immunostaining and morphometric analysis of histologic sections. Although inflammation was observed in all patients, the mean tissue area involved constituted 1.1% of the total specimen. The inflammation was mainly periglandular. Irrespective of the localisation, the grade 1 inflammation Fig. 2 Standard coloration (a) and immunostaining of a benign prostatic hyperplasia sample with CD3 (b), CD4 (c), CD8 (d), CD20 (e), and CD163 (f) antibodies showing evidences of moderate inflammatory infiltrate with a majority of CD4 + T lymphocytes.

4 882 EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) cell density was the predominant grade. However, the inflammation cell density grade 3 was located in the periglandular and stromal areas in 84% and 57% of patients, respectively. Even if investigating the relationship between inflammation characteristics and clinical outcomes was not the primary aim of this study, Nickel et al mentioned that the inflammation pattern did not correlated with urinary catheterisation, prostate-specific antigen (PSA) levels, or urine culture. Several studies have analysed the composition of inflammatory infiltrate in BPH [9 11]. The inflammatory infiltrate is mainly composed of T lymphocytes, which account for about 70% of the inflammatory cells, associated with 15% of B lymphocytes and 15% of macrophages. CD4 lymphocytes (memory helper T cells) represent up to 60% of T lymphocytes in BPH. In contrast to BPH, Di Carlo et al [12] recently described the main features of the normal prostate-associated lymphoid tissue: (1) a majority of T lymphocytes (70% CD8 cells) infiltrating the periglandular area and (2) lymphoid aggregates in the fibromuscular stroma. These aggregates are constituted by B lymphocyte follicles, representing 50% of the whole aggregate surrounded by parafollicular T cells containing two times more CD4 cells than CD8 cells. In accordance with the aforementioned studies, the results of our study show the importance of inflammatory infiltrates in the prostatic gland [13]. We assessed inflammation in 282 patients surgically treated for BPH (Fig. 2). Prostatic inflammation was studied on tissue microarrays after standard coloration and immunohistochemistry. An inflammatory infiltrate constituted by T lymphocytes (CD3 + cells) was found in 80% of the BPH specimens. Antigen-presenting cells such as B lymphocytes (CD20 + cells) and macrophages (CD163 + cells) were also observed in 52% and 82% of cases, respectively. This high prevalence of immune cells and their periglandular organisation in the prostatic gland suggest that the prostate may play an immune role in ensuring the sterility of the genitourinary tract [14]. The prostate could thus be considered an immunocompetent organ, like the intestine or the lung. As previously described for these organs, a deregulation of the immune response may also occur in the prostate, inducing prostatic disease Origins of chronic prostatic inflammation At 12-wk gestation, few inflammatory cells are observed in the prostate [15]. At this stage of development, inflammatory cells are predominantly located in the periglandular area. In addition, the proportion of CD8 + cells is higher than that of CD4 + cells. This organisation is also observed in the normal prostate of young adults [9]. In BPH tissue, the alteration of organisation including composition and localisation of immune cells suggests a deregulation of the immune response. The mechanisms that deregulate the immune response in BPH are still unknown. Two hypotheses have been proposed to explain the development of chronic inflammation in BPH: (1) the role of infectious events and (2) the role of autoimmune response. The infectious origin of the chronic inflammation in BPH has been suggested in several studies. Viruses and bacterial agents are commonly detectable in BPH samples and are often associated with chronic prostatitis [16,17]. To further evaluate the association between prostatitis and the occurrence of clinical BPH, a population-based study was performed in 2447 men in Olmsted County, Minnesota, USA [18]. A history of prostatitis that was recorded in 9.3% of men was significantly associated with the following parameters: BPH diagnosis, BPH treatment, or urinary retention. Compared with men without a history of prostatitis, the odds of a BPH diagnosis were 2.4-fold greater in men with a history of prostatitis. Furthermore, a history of prostatitis conferred a1.7-foldincreaseanda1.33-foldincreaseintheriskof receiving treatment for BPH and of experiencing urinary retention, respectively. Altogether, these results suggest that a history of prostatitis may be considered a risk factor for the development of BPH. The second hypothesis relates to the role of the autoimmune response. Prostate releases products that have a high proteolytic activity to act against microbial agents. However, these proteolytic secretions are also released when an epithelial injury occurs, implicating the subsequent digestion of the connective tissues in the prostatic gland. This phenomenon allows a direct interaction between components of the seminal liquid (eg, spermatozoids and other immunogenic antigens) and the immune cells. This cascade of events may thus induce an autoimmune response Interactions between immune cells and prostatic cells Inflammatory cells release inflammatory mediators, including cytokines and growth factors, to interact with other immune cells. These inflammatory mediators are involved in the regulation of the immune response but may also interact with surrounding prostatic cells. They may thus contribute to the development of BPH. In accordance with this hypothesis, most of these mediators have been reported to influence the growth of epithelial or stromal prostatic cells [14]. Conversely, BPH epithelial cells have been shown to release by themselves numerous inflammatory mediators [19 21]. Therefore, several molecular pathways have been investigated to explain these interactions between prostatic and inflammatory cells. First, Kramer et al investigated the expression of lymphocyte-derived growth factors and its impact on prostatic stromal cell growth [11]. Lymphokine synthesis was analysed in the following samples: normal prostate tissue, BPH tissue, BPH-derived T cells, BPH-derived stromal cell lines, and prostate cancer tissue by reverse transcriptionpolymerase chain reaction (RT-PCR) and Southern blotting. The effect of interleukins (IL)-2, -4, -7 and interferon-g (IFN-g) on the proliferation of normal and BPH-derived stromal cells was assessed by [3H]thymidine incorporation assay. The results showed that BPH tissues contain infiltrates of T lymphocytes, B lymphocytes, and macrophages that are chronically activated. These infiltrating cells release

5 EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) cytokines (IL-2, IFN-g, and transforming growth factor-b [TGF-b]) that may lead to the fibromuscular growth observed in BPH. Second, toll-like-receptors (TLR) are involved in the innate immune response and are often expressed by antigen-presenting cells. TLRs are activated by lipopolysaccharides or bacterial antigens. This activation results in the production of inflammatory mediators. Because TLRs are expressed on epithelial and stromal prostatic cells, their activation may induce the secretion of inflammatory mediators by prostatic cells themselves [20,22]. These mediators may then recruit inflammatory cells to act against bacterial agents. They also may affect the growth of prostatic cells. Finally, a recent study performed in our laboratory focused on the gene expression level in BPH [23]. Thirtyseven extracted RNA from BPH samples were hybridised to Affymetrix chips containing gene expression probes. Gene expression levels were compared with clinical data and prostate size. In particular, 49 genes involved in the inflammatory process were investigated. Of these, eight genes were upregulated in large prostate (>60 ml), but seven genes were downregulated. Toll-like receptor 1 (TLR1), toll-like receptor 2 (TLR2), toll-like receptor 3 (TLR3), and chemokine (C-X-C motif) receptor 4 (CXCR4) were upregulated with a mean fold change >1.40. Because TLR genes are involved in the first steps of the innate immune response, this upregulation of TLR gene expression could reinforce the hypothesis explaining the development of BPH by the deregulation of immune response Association between prostatic inflammation and lower urinary tract symptoms A relationship between inflammation and prostate volume in BPH has been shown in multicentre studies such as the MTOPS [4] and the REDUCE [5] clinical trials (Table 1). Because these studies were multicentre and included a large number of patients, their results strengthen the hypothesis that prostatic inflammation may play a key role in BPH development. The MTOPS study demonstrated the relationship between inflammation and prostate volume by examining the presence of inflammation in prostate biopsies of 1198 patients [5]. In 544 patients (45.4%), inflammation was observed and described as chronic inflammation in most cases (531 out of 544; 94.3%). Conversely, no signs of inflammation were observed in 653 patients (54.6%). Compared with men without prostatic inflammation, men with inflammation were older (64 vs 62.8 yr, p = 0.001), had a larger gland (41.1 vs 36.8 ml, p = ), and had higher serum PSA levels (3.3 vs 2.5 ng/ml, p < ). In addition, the risk for acute urinary retention was higher in patients with prostatic inflammation (2.4% vs 0.6%, p =0.011). However, the International Prostate Symptom Score (IPSS), the quality of life score, and maximum urinary flow rate were similar in patients with or without prostatic inflammation. Table 1 Relationship between prostatic inflammation and clinical symptoms of benign prostatic hyperplasia Study Design Study population Inflammatory status Age PSA Volume IPSS AUR % Yr p ng/ml p cm 3 p p % p High-grade NS 10.6 NS NS inflammation Low-grade inflammation Acute or chronic < < inflammation No inflammation Chronic < < <0.005 inflammation No inflammation Surgically treated patients Retrospective observational study, tissue microarray, immunostaining techniques Mondor experience [13] n =227 Patients under medical therapy Prospective, randomised, controlled study, prostate biopsy samples, standard coloration MTOPS [4] n =1197 Patients under medical therapy Prospective, randomised, controlled study, prostate biopsy samples, standard coloration REDUCE [39] n =8824 PSA = prostate-specific antigen; IPSS = International Prostate Symptom Score; AUR = acute urinary retention; NS = not significant.

6 884 EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) The findings of the MTOPS trial are in line with those of the REDUCE trial [5]. In this study, the degree of inflammation was scored as none, mild, moderate, or marked in prostate biopsies of 8824 patients. These patients were aged yr, had serum PSA levels ranging from 2.5 ng/ml to 10 ng/ml, and had an IPSS score < 25. Acute prostatitis was an exclusion criterion. The authors observed 77.6% of patients with chronic inflammation and only 22.6% of patients without inflammation. Prostatic inflammation was associated with higher prostate volume (46.5 vs 43.4 ml, p < ), higher IPSS score (8.8 vs 8.2, p < ), and higher irritative IPSS subscore (4.3 vs 4.1, p < ). A statistically significant correlation was found between average chronic inflammation and IPSS variables (correlation coefficient 0.057, p < for total IPSS). In our laboratory, we investigated the presence of inflammation with regard to the stages of BPH disease [24]. Patients with severe BPH disease (n =282)referredto patients surgically treated, and those with intermediate BPH disease (n = 88) referred to patients undergoing transrectal biopsies because of moderately elevated PSA levels (<10 ng/ ml) without major LUTS. Controls (n = 10) that is, no evidence of prostatic disease were obtained by using cadaver prostates. Prostatic inflammation was observed in 79%, 48%, and 20% of severe, intermediate, and no BPH patients, respectively. In the subgroup of 282 patients with severe BPH disease, we found a significant association between the grade of prostatic inflammation and prostate volume or IPSS score [13]. Mean prostate volume was 62 ml in low-grade inflammation, whereas it was 77 ml in highgrade inflammation ( p = 0.002). Similarly, the mean IPSS score was 12 in low-grade inflammation, whereas it was 21 in high-grade inflammation ( p = 0.02) Prostatic inflammation as a target for medical therapy Because prostatic inflammation is associated with prostate enlargement and symptomatic BPH, inflammation can be considered a therapeutic target in BPH. Consistently, some anti-inflammatory agents have already been tested in vitro and in vivo for the treatment of BPH. Minnery et al have investigated the effects of doxazosin combined with ibuprofen on BPH cell lines [25]. They found that the combination therapy significantly reduced cell viability and induced apoptosis in two different cell lines (BPH-1 and B1). Furthermore, the effect of the combination therapy on BPH-1 cells resulted in a decreased protein expression of JM-27 that is highly upregulated in symptomatic BPH. Di Silverio et al studied the effects of the 5a-reductase inhibitor (5-ARI) and cyclooxygenase-2 (COX-2) inhibitor combination therapy [26]. Intermediate results of this study highlighted the fact that patients receiving the combination therapy had a significant increase in the apoptotic index of prostatic cells compared with patients receiving 5-ARI alone. In addition, the combination therapy was more effective in improving symptom than 5-ARI alone after a 4-wk treatment. However, after a 24-wk treatment, the effectiveness of the combination therapy was similar to that of 5-ARI alone. The authors concluded that the combination therapy with COX-2 inhibitor induced a more rapid clinical improvement. Despite these findings, this study was stopped early because of cardiovascular side-effects of the COX-2-inhibitor. Falahatkar et al studied the effects of celecoxib (a COX-2 inhibitor) on nocturia caused by BPH in a randomised, double blind, placebo-controlled study [27]. Eighty men were randomised to receive celecoxib or placebo for 1 mo. In the celecoxib group, the mean nocturnal frequency decreased from 5.17 to 2.5 ( p < ), and the mean IPSS decreased from 18.2 to 15.5 ( p < ) after 1 mo of follow-up. In contrast, no significant decreases in nocturnal frequency or IPSS were reported in the placebo group. In line with these findings, Addla et al reported a decrease in the nocturnal urine volume and nocturnal frequency in 26 patients with nocturnal polyuria after a single dose of diclofenac [28]. Altogether, these results indicate that antiinflammatory agents are effective for the short-term treatment of BPH symptoms such as nocturia. However, studies investigating the long-term effectiveness of antiinflammatory agents are needed. Phytotherapy seems to be a promising therapeutic approach for chronic prostatic inflammation [29]. Vela Navarette et al studied the effects of Serenoa repens phytotherapy on the prostate inflammatory status [30]. A significant reduction in B lymphocyte count (58.2 vs 91.4 cells per field; p = 0.097) and other inflammatory markers (TNF-a and IL-1b) was observed after treatment with Serenoa repens. The anti-inflammatory effect of Serenoa repens phytotherapy could be mediated by the downregulation of leukotriene B4 [31]. Moreover, we have previously shown that Serenoa repens induced apoptosis and inhibited cell proliferation in BPH patients [32]. Consistently, the addition of Serenoa repens in the culture medium resulted in an accumulation of the lipidosterolic extracts in the cytoplasm of cells (Fig. 3), inducing a significant decrease in the proliferation index. Fig. 3 BPH-1 cells observed 1 h after adjunction of Serenoa repens in the culture medium. The red oil coloration fixes in red the lipidosterolic extracts that are concentrated in the cytoplasm of cells.

7 EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) Biomarkers for inflammation in benign prostatic hyperplasia To treat the inflammation associated with BPH, prostatic inflammation has to be diagnosed. Even if many candidate biomarkers are proposed for the diagnosis of prostatic inflammation, few of them have been validated. Serum malondialdehyde (MDA) is a marker of inflammation and oxidative stress. MDA has been tested as a biomarker of inflammation in 22 BPH patients and in 22 healthy donors [33]. MDA levels increased in BPH patients and was correlated to serum PSA values. However, these results have not been confirmed in other studies. Serum C reactive protein (CRP) concentration, a nonspecific marker of inflammation, was measured in 2337 men from the Third National Health and Nutrition Examination Survey [34]. Men with a CRP concentration above 3 mg/l were 1.47 times more likely to have LUTS, although this association was not statistically significant. IL-8 also seems to be a candidate marker for prostatic inflammation diagnosis. IL-8 is secreted by prostatic epithelial cells and is a mediator of neutrophil accumulation and activation [35,36]. The seminal plasma levels of IL-8 were found positively correlated with symptom scores of BPH [37]. Liu et al analysed the IL-8 expression level in prostatic secretion in BPH patients with or without prostatic inflammation [38]. Prostatic fluid was collected from 44 consecutive patients diagnosed with BPH and scheduled for TURP. The IL-8 expression level was measured using enzyme-linked immunosorbent assay kits, and prostatic inflammation was scored on random samples from TURP. The results showed that the IL-8 expression level in prostatic fluid was correlated with the presence of prostatic inflammation. Consequently, IL-8 may be considered a valuable marker for detecting BPH with inflammation (sensitivity: 85.7%; specificity: 91.3%). International research groups are currently evaluating other candidate markers. 4. Conclusions Chronic prostatic inflammation is a key pathway leading to prostate enlargement, increase in IPSS, and greater risk of complications. Although prostatic inflammation is observed in at least 50% of symptomatic BPH patients, physicians usually do not pay any attention to this aspect of the disease. Indeed, when chronic prostatic inflammation is either suspected clinically or proven histologically, the clinician should take it into account in the management of BPH. For these patients, close surveillance and treatment with anti-inflammatory effects could be proposed. Although inflammation can be diagnosed on prostate biopsy, we cannot recommend performing a prostate biopsy in every BPH patient. In future, we could expect that measurement of less invasive biomarkers may help in the diagnosis of prostatic inflammation. Together with other BPH predictive factors, prostatic inflammation could be turned into a predictive tool for BPH progression and complication. However, additional data are needed to turn it into guidelines. Conflicts of interest The authors have nothing to disclose. Funding support Pierre Fabre Médicament provided funding for part of this work. References [1] Garraway WM, Collins GN, Lee RJ. High prevalence of benign prostatic hypertrophy in the community. Lancet 1991;338: [2] Carter HB, Coffey DS. The prostate: an increasing medical problem. Prostate 1990;16: [3] Lee KL, Peehl DM. Molecular and cellular pathogenesis of benign prostatic hyperplasia. J Urol 2004;172: [4] Roehrborn CG, Kaplan SA, Noble WD, Lucia MS, Slawin KM, McVary KT. The impact of acute or chronic inflammation in baseline biopsy on the risk of clinical progression of BPE: results from the MTOPS study. In: Proceedings from the annual meeting of the American Urological Association; May 21 25, 2005; San Antonio, TX. 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