A. Sciarra

The Controversial Relationship Between Benign Prostatic Hyperplasia and Prostate Cancer: The Role of Inflammation

CONTEXTnProstate cancer (PCa) is the most common cancer in the adult male, and benign prostatic hyperplasia (BPH) represents the most frequent urologic diagnosis in elderly males. Recent data suggest that prostatic inflammation is involved in the pathogenesis and progression of both conditions.nnnOBJECTIVEnThis review aims to evaluate the available evidence on the role of prostatic inflammation as a possible common denominator of BPH and PCa and to discuss its possible clinical implication for the management, prevention, and treatment of both diseases.nnnEVIDENCE ACQUISITIONnThe National Library of Medicine Database was searched for the following Patient population, Intervention, Comparison, Outcome (PICO) terms: male, inflammation, benign prostatic hyperplasia, prostate cancer, diagnosis, progression, prognosis, treatment, and prevention. Basic and clinical studies published in the past 10 yr were reviewed. Additional references were obtained from the reference list of full-text manuscripts.nnnEVIDENCE SYNTHESISnThe histologic signature of chronic inflammation is a common finding in benign and malignant prostate tissue. The inflammatory infiltrates are mainly represented by CD3(+) T lymphocytes (70-80%, mostly CD4), CD19 or CD20 B lymphocytes (10-15%), and macrophages (15%). Bacterial infections, urine reflux, dietary factors, hormones, and autoimmune response have been considered to cause inflammation in the prostate. From a pathophysiologic standpoint, tissue damage associated with inflammatory response and subsequent chronic tissue healing may result in the development of BPH nodules and proliferative inflammatory atrophy (PIA). The loss of glutathione S-transferase P1 (GSTP1) may be responsible in patients with genetic predisposition for the transition of PIA into high-grade intraepithelial neoplasia (HGPIN) and PCa. Although there is growing evidence of the association among inflammatory response, BPH, and PCa, we can only surmise on the immunologic mechanisms involved, and further research is required to better understand the role of prostatic inflammation in the initiation of BPH and PCa. There is not yet proof that targeting prostate inflammation with a pharmacologic agent results in a lower incidence and progression or regression of either BPH or PCa.nnnCONCLUSIONSnEvidence in the peer-reviewed literature suggested that chronic prostatic inflammation may be involved in the development and progression of chronic prostatic disease, such as BPH and PCa, although there is still no evidence of a causal relation. Inflammation should be considered a new domain in basic and clinical research in patients with BPH and PCa.

Evidence that Serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy patients

A double-blind placebo-controlled study was performed in 35 benign prostatic hypertrophy (BPH) patients never treated before. The patients were randomized into two groups, the 1st (18 cases) receiving Serenoa repens extract (160 mg t.d.) for 3 months up to the day before the operation of transvesical adenomectomy and the 2nd (17 cases) receiving placebo. Steroid receptors were evaluated in the nuclear (n) and cytosolic (c) fraction using the saturation analysis technique (Scatchard analysis or single saturating-dose assay) for androgen (AR) and estrogen (ER) receptors and the enzyme immunoassay (EIA) for ER and progesterone receptors (PgR). Scatchard analysis of ERc and ERn revealed the presence of two classes of binding sites, one with high-affinity low-capacity binding and the other with low-affinity high-capacity binding. In the untreated BPH group, ER were higher in the n than in the c fraction: ERn were positive in 14 cases and ERc in 12 of 17 cases. In the BPH group treated with S. repens extract on the contrary, ERn were negative for both binding classes in 17 cases and ERc in 6 of 18 cases. Using EIA, ERn and ERc were detected in all 15 samples examined, but in the treated group, ERn were significantly (p less than 0.01) lower than in the untreated group, whilst ERc remained almost unchanged. Similar results were obtained measuring PgR: the n fraction of the treated group prostatic samples was significantly (p less than 0.01) lower than that of the untreated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased PSA expression on prostate cancer exosomes in in vitro condition and in cancer patients

Prostate specific antigen (PSA) test is the most common, clinically validated test for the diagnosis of prostate cancer (PCa). While neoplastic lesions of the prostate may cause aberrant levels of PSA in the blood, the quantitation of free or complexed PSA poorly discriminates cancer patients from those developing benign lesions, often leading to invasive and unnecessary surgical procedures. Microenvironmental acidity increases exosome release by cancer cells. In this study we evaluated whether acidity, a critical phenotype of malignancy, could influence exosome release and increase the PSA expression in nanovesicles released by PCa cells. To this aim, we exploited Nanoparticle Tracking Analysis (NTA), an immunocapture-based ELISA, and nanoscale flow-cytometry. The results show that microenvironmental acidity induces an increased release of nanovesicles expressing both PSA and the exosome marker CD81. In order to verify whether the changes induced by the local selective pressure of extracellular acidity may correspond to a clinical pathway we used the same approach to evaluate the levels of PSA-expressing exosomes in the plasma of PCa patients and controls, including subjects with benign prostatic hypertrophy (BPH). The results show that only PCa patients have high levels of nanovesicles expressing both CD81 and PSA. This study shows that tumor acidity exerts a selective pressure leading to the release of extracellular vesicles that express both PSA and exosome markers. A comparable scenario was shown in the plasma of prostate cancer patients as compared to both BPH and healthy controls. These results suggest that microenvironmental acidity may represent a key factor which determines qualitatively and quantitatively the release of extracellular vesicles by malignant tumors, including prostate cancer. This condition leads to the spill-over of nanovesicles into the peripheral blood of prostate cancer patients, where the levels of tumor biomarkers expressed by exosomes, such as PSA-exosomes, may represent a novel, non-invasive clinical tool for the screening and early diagnosis of prostate cancer.

2D and 3D T2-weighted MR sequences for the assessment of neurovascular bundle changes after nerve-sparing radical retropubic prostatectomy with erectile function correlation

The aim of this study was to assess the capability of a 3D isotropic MRI T2-weighted sequence (3D T2 ISO) in the depiction of changes of neurovascular bundles (NVBs) after bilateral nerve-sparing radical retropubic prostatectomy (RRP). Furthermore, our aim was also to introduce a new MRI classification score of the NVB alteration patterns using the International Index Erectile Function Five-Item (IIEF-5) score as standard of reference. Fifty-three consecutive patients were postoperatively submitted to two MR examinations, including both 2D TSE T2-weighted (2D T2) and 3D T2 ISO sequences. Image findings were scored using a relative five-point classification and correlated with the postoperative IIEF-5 score. Radiologists attributed 13.2% of patients to class 0, 11.3% to class I, 34% to class II, 24.5% to class III, and 16.9% to class IV. With 3D T2 ISO images, the same radiologists determined 43.3% class 0, 32% class I, 11.4% class II, 7.5% class III, and 5.7% class IV. In all cases, the correlation and regression analysis between the 3D T2 ISO and IIEF-5 score resulted in higher coefficients values. The 3D sequence correlated most closely with patients’ grading of erectile function.

Role of magnetic resonance spectroscopic imaging ([1H]MRSI) and dynamic contrast-enhanced MRI (DCE-MRI) in identifying prostate cancer foci in patients with negative biopsy and high levels of prostate-specific antigen (PSA)

PurposeThe purpose of this study was to evaluate the role of magnetic resonance spectroscopic imaging (MRSI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in detecting tumour foci in patients with elevated prostate-specific antigen (PSA) and negative transrectal ultrasonography (TRUS)-guided biopsy.Materials and methodsThis prospective randomised trial was conducted on 150 patients who underwent [1H]MRSI and DCE-MRI and targeted biopsies of suspicious areas on MRI associated with random biopsies.ResultsAfter the second biopsy, the diagnosis of prostate adenocarcinoma was made in 64/150 cases. On a perpatient basis, MRSI had 82.8% sensitivity, 91.8% specificity, 88.3% positive predictive value (PPV), 87.8% negative predictive value (NPV) and 85.7% diagnostic accuracy. The sensitivity, specificity, PPV, NPV and accuracy for DCE-MRI was 76.5%, 89.5%, 84.5%, 83.7% and 82%, respectively. The combination of MRSI and DCE-MRI yielded 93.7% sensitivity, 90.7% specificity, 88.2% PPV, 95.1% NPV and 90.9% accuracy in detecting prostate carcinoma.ConclusionsThe combined study with [1H]MRSI and DCE-MRI showed promising results in guiding the biopsy of cancer foci in patients with an initial negative TRUS-guided biopsy.RiassuntoObiettivoScopo del nostro lavoro è stato valutare il ruolo della risonanza magnetica (RM) con spettroscopia (MRSI) e studio dinamico (DCEMR) nell’individuazione di foci tumorali in pazienti con elevati valori di antigene prostatico specifico (PSA) e biopsia prostatica guidata tramite TRUS (trans-rectal-ultrasound)-guidata negativa.Materiali e metodiLo studio è stato di tipo prospettico randomizzato. Abbiamo esaminato 150 pazienti. Tutti sono stati sottoposti ad esame di 1H-MRSI e DCEMR ed a prelievi mirati nelle zone sospette alla RM, associate a biopsie random.RisultatiDopo la seconda biopsia, la diagnosi di adenocarcinoma prostatico è stata effettuata in 64/150 casi. Nella nostra popolazione, su una base patient by patient, l’MRSI ha mostrato i seguenti valori: sensibilità 82,8%; specificità 91,8%; valore predittivo positivo (PPV) 88,3%; valore predittivo negativo (NPV) 87,8%; accuratezza 85,7%. La DCEMR ha mostrato i seguenti valori: sensibilità 76,5%; specificità 89,5%; PPV 84,5%; NPV 83,7%; accuratezza 82%. L’associazione delle due metodiche, MRSI e DCEMR, aumenta la sensibilità (93,7%), la specificità (90,7%), il PPV (88,2%), il PNV (95,1%) e l’accuratezza (90,9%) nel predire l’individuazione del carcinoma prostatico se paragonata alla sola metodica MRSI o DCEMR.ConclusioniLo studio combinato ha mostrato risultati promettenti nella guida alla biopsia dei foci tumorali in pazienti con prima biopsia TRUS-guidata negativa.

A Novel Therapeutic Option for Castration-resistant Prostate Cancer: After or Before Chemotherapy?

Prostate cancer (PCa) is the most common noncutaneous malignancy and a leading cause of cancer mortality in men in the Western world, accounting for an estimated 94 000 deaths in Europe in 2008 and 32 050 deaths in the United States in 2010 [1]. Although <5% of patients present with metastatic disease, up to 40% of men eventually develop metastases despite local therapy. Metastatic castration-resistant PCa (mCRPC) represents a stage in the natural history of PCa in which only a few therapeutic options are available in addition to chemotherapy [2]. The high frequency of PCa-related metastatic bone disease has led to consideration of this pathway as a therapeutic target. Several bone-targeted agents have been investigated. Zoledronic acid has been evaluated in several trials and has showed effectiveness in stabilizing the bone and preventing skeletal complications [3]. More recently, a nuclear factor-kB ligand (RANKL) inhibitor, denosumab, has been developed for the treatment of bone metastases. A randomized double-blind multicenter study on 1901 men with mCRPC assigned to denosumab or zoledronic acid showed that denosumab was superior in delaying the time to first skeletal-related events (20.7 mo compared with 17.1 mo) [4]. Even more recently [5], a large, multicenter, double-blind, randomized, placebocontrolled study on men with nonmetastatic castrationresistant PCa (CRPC) at high risk of bone metastasis assigned to denosumab compared with placebo showed that targeting the bone microenvironment can delay bone metastasis. Several targets, related or not to the androgen pathway, have been used to develop novel strategies for the treatment of CRPC [6]. Our knowledge of the mechanisms involved in androgen independence remains incomplete. In

342 Use of multiparametric MR with neurovascular bundle evaluation to optimize the oncological and functional management of patients considered for nerve sparing radical prostatectomy

Introduction. To obtain the best results with radical prostatectomy, either from an oncological or a functional point of view, a correct selection of cases and planning of surgery are crucial. Multiparametric magnetic resonance imaging (MRI) promises to make it a successful imaging tool for improving many aspects of prostate cancer management. Aim. The aim of this study is to evaluate whether a modern multiparametric MRI can help either to better select prostate cancer cases for a nerve-sparing radical prostatectomy or to improve the functional evaluation related to neurovascular bundles preservation. Main Outcome Measures. The effect of preoperative MRI on neurovascular bundle management was examined for the frequency and the appropriateness of changes of the surgical plane on the basis of MRI indications. Methods. In a prospective study, 125 consecutive patients with biopsy proven prostate cancer who were scheduled to undergo bilateral nerve-sparing surgery. All patients included into the study were submitted to a preoperative multiparametric MRI. On the basis of MRI evaluation, patients were divided into two groups. Patients in group A were then submitted to a bilateral nerve-sparing (NS) radical prostatectomy (RP), whereas patients in group B were submitted to unilateral NS or non-NS RP. Results. In group A, the confirmation from the MRI study to perform a bilateral NS procedure was appropriate in 70 of 73 cases (95.9%), whereas in group B, the surgical plan was appropriate in 28 of 32 cases (87.5%). On the contrary, MRI findings suggested a change in the initial surgical plan (group B) for 32 of 105 cases (30.5%). Of these 32 cases in group B, MRI suggested to perform a unilateral NS procedure in 21 of 32 cases (65.6%) and a non-NS procedure in 11 of 32 cases (34.4%). Conclusions. Multiparametric MRI analysis can significantly improve the standard selection and management of prostate carcinoma cases considered for an NS RP. Panebianco V, Salciccia S, Cattarino S, Minisola F, Gentilucci A, Alfarone A, Ricciuti GP, Marcantonio A, Lisi D, Gentile V, Passariello R, and Sciarra A. Use of multiparametric MR with neurovascular bundle evaluation to optimize the oncological and functional management of patients considered for nerve-sparing radical prostatectomy. J Sex Med 2012;9:2157-2166.

Rare case of multiple adenomatoid tumors arising from tunica vaginalis of testis and epididymis

Los tumores adenomatoides suelen presentarse como masas extratesticulares. La mayor parte de estas pequeñas masas paratesticulares, de crecimiento lento, se pueden diagnosticar mediante exploración fı́sica. La ecografı́a también ayuda al diagnóstico de este tumor benigno al demostrar la localización extratesticular de la masa. Los tumores adenomatoides del epidı́dimo se suelen identificar bien y es preciso diferenciarlos de las lesiones parenquimatosas testiculares. Un varón de 40 años acudió a nuestro servicio de urologı́a con antecedentes, desde un año antes, de masa escrotal izquierda, indolora y dura. El paciente negaba antecedentes de trastornos o intervenciones quirúrgicas genitourinarias, traumatismos recientes y sı́ntomas generales. La exploración fı́sica demostró múltiples masas paratesticulares de pequeño tamaño. La ecografı́a de escroto reveló 3 masas paratesticulares sólidas y bien definidas, hipoecoicas, de 5, 6 y 10mm respectivamente, localizadas en la superficie anterior del testı́culo. Todos los marcadores tumorales séricos, como alfafetoproteı́na, gonadotropina coriónica humana beta y lactato deshidrogenasa, estaban dentro de los lı́mites normales. Se realizó una exploración testicular mediante abordaje inguinal con escisión local de las masas paratesticulares (fig. 1). El análisis intraoperatorio de cortes congelados de las muestras no mostró signos de malignidad. El estudio histológico posterior confirmó la presencia de tejido fibroso benigno con elementos celulares reunidos en nidos y cordones sólidos y un moderado estado inflamatorio (fig. 2). El postoperatorio cursó sin incidencias y, hasta la fecha, el paciente se encuentra bien, sin signos de recidiva transcurridos 8 meses. El cáncer de testı́culo suele presentarse como una masa sólida palpable; el 90–95% de las masas testiculares palpables son tumores de células germinativas malignas. La ecografı́a de alta resolución detecta con fiabilidad las masas intratesticulares sólidas, aunque no diferencia entre lesiones benignas y malignas. Las opciones terapéuticas consisten en orquiectomı́a radical, biopsia diagnóstica por escisión y conducta expectante. Los tumores paratesticulares son procesos poco frecuentes y por lo general benignos que, si se diagnostican correctamente, son susceptibles de extirpación local. Los tumores adenomatoides de epidı́dimo son el subgrupo más frecuente y representan el 60–70% de las neoplasias benignas de estas estructuras. Se ha señalado que la inflamación puede intervenir en su aparición, debido a su asociación ocasional con periorquitis e hidroceles, ası́ como a la presencia de células inflamatorias en su interior. Se producen sobre todo en los tejidos paratesticulares en los varones y en el útero y las trompas de Falopio en las mujeres. En su mayor parte proceden del epidı́dimo y, rara vez, de túnica testicular, cordón espermático, conductos eyaculatorios, próstata o zonas suprarrenales. www.elsevier.es/acuro Actas Urológicas Españolas

Clinical evidence of neuroendocrine differentiation in a patient with prostate cancer and bone marrow micrometastases

A 58-year-old man had a biopsy taken in November 1998 and was diagnosed as having prostatic adenocarcinoma of Gleason score 5 (3+2); his serum PSA was 86.7 ng/mL. A DRE revealed a palpable nodule of increased consistency on the left lobe of the prostate; TRUS showed a hypoechoic area 1.5 cm in diameter in the peripheral zone of the left lobe of the prostate, with no evidence of capsular or seminal vesicle in®ltration. CT of the abdomen and pelvis showed no lymphadenopathy, and the bone scan and chest X-rays were normal. Laboratory tests showed a signi®cant reduction in haemoglobin (94 g/L, normal 132±170), platelet count (89 000; normal 150 000±450 000) and neutrophils (33.8%, normal 55±70). In November 1998 the patient underwent an iliac bone marrow biopsy and the histology showed tumour cell clusters; immunohistochemical staining for PSA was positive at the tumour cell sites. Histological sections from the prostate biopsy were assessed for chromogranin A expression by immunohistochemistry [1], and more than one focus with extensive staining for chromogranin A was detectable in the tumour cells (.Fig. 1). Moreover, high

New ultrasensitive assay development by using monoclonal antibodies for detecting prostate-specific antigen

The Serono Maia Clone prostatic-specific antigen (PSA) kit incorporates an immunoradiometric assay for the measurement of PSA in the serum. The method can be used over a range of 0-100 ng/ml without dilution. Standard concentrations are 0, 0.4, 1, 5, 20, and 100 ng/ml. Up to date, 373 normal men, 89 normal women, 117 prostatic carcinoma, 98 other carcinoma, and 85 benign prostatic hypertrophy have been tested. The aim of this study is to evaluate the sensitivity and specificity of a new immunoassay method for the determination of PSA, that could be able to evaluate low levels of PSA, resulted undetectable with other methods. This ability could be useful in patients treated with hormone-suppressive therapy or after radical prostatectomy. We have collected all low values present in samples examined. With the Serono Maia Clone PSA kit only 26.7% of these have been evaluated as out values as opposed to 46.5% with the Hybritech kit.