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Prostatitis-Cancer
 
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  • L ’aspettativa di vita media prevista è in continuo aumento
  • … mostrano evidenze cliniche per cui l ’ infiammazione cronica è direttamente correlabile in maniera statisticamente significativa con lo sviluppo di un tumore di alterazioni istopatologiche com il PIN di alto grado nella prostata
  • È nota già da tempo la catena di geni coinvolti nella trscrizione dei fattori dell ’ infiammazione…
  • L ’infiltrato infiammatorio produce citochine proinfiammatorie e radicali dell’ossigeno che danneggiano sia l’epitelio che lo stroma.
  • E ’ già stato dimostrato che l’infiammazione cronica è un fattore prognostico sfavorevole per l’IPB… in presenza di infiammazione cronica infatti aumenta la probabilità di progressione della patologia, l’aggravamento dei sintomi, la necessità di intervento chirurgico e la ritenzione urinaria acuta. L ’analisi istopatologica dettagliata dei tessuti prostatici di pazienti affetti da IPB sintomatica, inoltre, ha dimostrato la presenza di focolai di infiammazione cronica in elevate percentuali. _____________________________________________________________________ L ’infiammazione può essere anche un fattore di rischio per lo sviluppo del cancro prostatico in alcuni pazienti. Ovviamente per la complessità che contraddistingue lo sviluppo del CaP, sono necessarie ulteriori evidenze per dimostrare il reale impatto dell ’infiammazione cronica su questa patologia. In base alle conoscenze che abbiamo fino ad ora, dove si può agire per prevenire? Monitorare lo stato di PIA permetterebbe di tenere il paziente sotto controllo, ma in Europa sono ancora pochi i laboratori di anatomia patologica in grado di evidenziarlo. Il passaggio da PIN di alto grado a Ca prostatico è solitamente molto rapido e anche molto probabile (70-80%). Quindi è necessario e fattibile intervenire sull ’infiammazione per prevenire tutto il resto.
  • L ’infiammazione è molto importante per la prognosi dell’IPB. Non solo… molti autori ipotizzano che l'infiammazione possa avere un ruolo nello sviluppo e la progressione delle patologie prostatiche.
  • Istopatologia di prostatite batterica cronica. L ’infiammazione è meno pronunciata e più focalizzata di quella che si vede nelle forme acute. I neutrofili appaiono sparsi o assenti. C ’è un’infiltrazione focale di linfociti, plasmacellule e macrofagi dentro e attorno agli acini prostatici
  • Ugualmente un farmaco per bloccare infiammazione cronica come fattore di progressione IPB deve poter essere usato a lungo termine (maggiore 6 mesi)
  • Servono evidenze sperimentali e cliniche
  • Permixon prostata specifico COSA NE PENSI? PUO ’ GENERARE DUBBI; VISTO CHE STIAMO PARLANDO DELL?ATTIVITA ’ ANTIINFIAMMATORIA DI PERMIXON E NON DI APOPTOSI??GRAZIE
  • Servono evidenze sperimentali e cliniche

Prostatitis-Cancer Prostatitis-Cancer Presentation Transcript

  • Inflammation and Prostate Diseases ProgressionAlessandro SciarraChairman Prostate UnitPoliclinico Umberto IUniversity La Sapienza- Rome, Italy
  • BPH: long period before clinical evidence
  • Prostate Cancer: long period before clinical evidence Normal LGPIN HGPIN Carcinoma 10-20 years 1-10 years
  • Question 1 ? May inflammation significantlycondition the development and future progression of prostate diseases ?
  • Question 2 ?May inflammation be considered a risk factor so to be integrated in risk stratification analyses for prostate diseases ?
  • Association infiammation – prostatic diseases Evidences: • Epidemiologic • Genetic • Mechanism of action • Histologic • Clinical
  • 5 years Follow-up In the group with CI at 1° biopsy, 20% of pts developed PC and 6% HPIN In the group without CI at 1° biopsy , 6% of pts developed PC. P<0.05
  • Association between inflammation and BPHUrology 71: 475-479, 2008. ©2008 Elsevier
  • Association infiammation – prostatic diseases Evidences • Epidemiologic : • Genetic • Mechanism of action • Histologic • Clinical
  • Association infiammation – prostatic diseases Evidences • Epidemiologic : • Genetic • Mechanism of action • Histologic • Clinical
  • Inflammation and BPHLinfocitaMacrofago CitochineNeutrofilo Radicali ossigeno
  • Cytokines and inflammation in the prostateKramer et al, Eur Urol, 2007; 51:1202-16
  • Inflammation: possible pathogenesis  repeated tissue damage  excessive production of oxidative damages  post-translational DNA modifications  increased cell proliferation and angiogenesis
  • Inflammation:two possible actors NOS and COX
  • Increased apoptosis (TUNEL) with rofecoxib
  • The role of inflammation in the human prostate FGFs IGFs TGF-β Modification epithelial Cyr61 Epithelial hyperplasia function Citochine ↑ IL-8 ↓ PDF Tissue damage Infiammation Angiogenesis Diseases Progression ↑ IL-8 Modification stromal FGFs IGFs Stromal hyperplasia function TGF-β Cyr61 Citochine Inflammation can stimulate prostatic disease progressionLucia et al, Curr Urol Rep, 2008; 9:272-78
  • Which inflammation induces prostatic progression? Evidences: • Histological data – PSA • Clinical data
  • Histopathological aspects of BPH Inflammatory aspects Histological aggressiveness• 0 = no contact between inflammatory cells and glandular epithelium• 1 = contact between inflammation and epithelium• 2 = interstitial infiltrate with glandular disruption• 3 = glandular disruption on more than 25% Irani; J Urol 1997
  • Infiammation: precancerous prostatic lesions PIA PIN CARCINOMA (proliferative (prostatic inflammatory atrophy) intraepithelial neoplasia)Prostata infiammata
  • Inflammation: potential precursor lesions ?
  • Which inflammation induces prostatic progression? Evidences • Histological data – PSA : • Clinical data: - Frequency of the process - Association with progression
  • • Prospective analysis on 167 prostate during autopsy. • Pathologic analysis identified all carcinoma focus, BPH nodule and acute or chronic inflammation area. • The prevalence of the association between carcinoma, BPH and infiammation, has been evaluated.Delongchamps et al, J Urol 2008, 179:1736-40
  • Inflammation and BPH 67.6% 88 32.4% 16 6 Acuta Cronica Acuta + cronica In BPH areas ,75% were associated with chronic inflammation (p= 0.01).Delongchamps et al, J Urol 2008, 179:1736-40
  • Infiammation and BPH Distribution of infiammation Inflammation association with age CONCLUSIONs: Chronic inflammation was commonly found during autopsies. Inflammation was directly associated with BPHDelongchamps et al, J Urol 2008, 179:1736-40
  • A. Sciarra et al. Eur Urol 2000
  • Inflammation and prostate volume: who influences the other ? Chronic inflammation: F(1,2)=408.64; p=0.002 Acute inflammation: F(1,2)=2.292; p=0.269 50 chronic chronic - trend 40 30 20 acute 10 acute - trend 0 30-39 40-49 50-59 60-69 70-79 80-89 ccA. Sciarra et al. Eur Urol 2000
  • Inflammation and progression risk: MTOPS 544 patients from MTOPS study with acute (only 31) or chronic inflammation at basal prostate biopsy , compared with cases without infiammation Patients with inflammation were elderly (64 vs. 62.8 years, p=0.001), with higher volume prostates (41.1 vs. 36.8 ml; p=0.0002) and higher PSA levels (3.3 vs. 2.5 ng/ml; p<0.0001). In these patients with inflammation a higher risk of acute urinary retention episodes and a positive trend in favour of clinical progression was found (21.0 vs. 13.2%; p=0.083). Inflammation contributes to BPH progressionRoehrborn CG,. AUA meeting 2005, Abstract No. 1277
  • Impact of inflammation on BPH progression No infiammation InfiammationC. Roehrborn, 2005. Studio MTOPS
  • Inflammation:risk factor for BPH progression or PC development Roehrborn C. 2006
  • Inflammation as precursor of Prostate Cancer: Rationale for Preventive Strategies ?
  • How to select patients with BPH and inflammation ? Evidences: • Symtoms • Imaging • Markers
  • How to select patients ?Histology, no very often available Different stages for prostatic inflammation No inflammation Low Moderate Severe
  • How to select patients ? LUTS and IPSSRelationship between inflammation and symptoms in BPH
  • Multiparametric magnetic resonance with spectroscopic analysis: a modern approach in prostatic imaging Prostate 1H-MRSI (cancer) Ch: Choline = cellular turnover Ci: Citrate = terminal metabolites of Krebs cycle Cr: Creatine = it increases in hypermetabolism
  • 1 2 3 4 G PC H LGPC PIN tio n HG mma in fla l r maNo
  • Systemic Markers for infiammation Case-control nested study (4971 cases) on the association between inflammatory markers and symptomatic BPH based on the placebo arm of PCPT studyShenk et al, Am J Epidemiol, 2010; 171:571-82
  • IL-8 as marker of inflammation in BPH IL-8 levels in prostatic secretion Sensibility and specificity of IL-8 to identify BPH associated ot inflammation versus BPH alone were85.7% and 91.3% respectively, using a cut-off of 3992 pg/mLLiangren et al, Urology, 2009; 74:340-4
  • Urinary markers for inflammation • 90 tissue prostatic samples obtained from BPH patients waiting for surgery • Urinary samples obtained after digital rectal examination • Inflammatory score was classified on the basis of inflammatory cells extension: – 0: no inflammation – 1: mild inflammation – 2: moderate inflammation – 3: severe infiammationRobert et al, Prostate, 2011, in press
  • Mean level of genes expression in 90 samples from BPH cases on the basis of inflammation scoreRobert G et al Nijmegen med Centre
  • Possible results from a long term block of prostatic inflammation• Improvement of LUTS correlated to prostatic inflammation• Prevention of LUTS progression correlated to prostatic inflammation• Reduction of the risk of BPH-related complications (AUR)• Synergic effect with other drugs used to block BPH progression
  • Which drug for prostatic inflammation - BPHEvidences: • Experimental – Studies on primary cultures – Inhibition on inflammatory factors – Effect on proliferation/apoptosis • Clinical – Long term therapy – Combination with alpha1 blockers – Combination with 5 ARI
  • Serenoa Repens exane: specific for prostate tissue o 2 o t ip tic ta os pr lio ite Ep 1% APOPTOSIS t ipo ico 2 stat ipo ro it op t ic eli sta it ro Ep stip o1 ob la i tip r t ic Fi b ta o1 2 os t ip ipo pr a at sti 1 2 ell ell bla ipo ipo am m am m ro ne it it o1 o2 Fi b ta ta ne ll am ll am tip tip 1 2 2 cu cu de de ale ale ipo ipo o1 ti sti ti sti en n t t t ip t ipo la s la s or re mo mo lo lo ob bla ob bla ut to idi idi ico co Fib r ro Fib r ro ss ssu id id st sti Fi b Fi b Te Te Ep Ep Te Te CELL TYPE
  • Serenoa Repens exane: Hypothesis for a mechanism of action Stromal and epithelial human prostate cells Modification lipid-fatty acid asset (1-5) (Ev Lev 2b)Cellular membrane damage-increased permeab. (nuclear, mitochondrial)(1-5) (Ev Lev 2b) antiinflammatory Reduction Effect Chromatin Mitochondrial inhibition 5 lipoxigenase 5AR I-II AR-ER condensation Block/distruction (5)(Ev Lev 2b) (2,3)(Ev. Lev 4) (2,4)(Ev Lev 2b) Reducion ecosanoid prod. = leucotren (5)(Ev Lev 2b) Increased ratio Apoptosis/proliferation (2,6,7)(Ev Lev 2b) 1-Buck J Urol 2004 2-Bayne Prostate 1999,J urol 2000 3-Habib Eur Urol 2009 4-Petrangeli JCP 2009 5-Paubert-Braquet Prostglandin 199897 6-Vacherot Prostate 2009 7-Vela Navarrete J Urol 2005
  • RESULTS CELL COUNT INFLAMMATORY PATTERNS IL-6, CCL-5, COX-2Apoptosis-prolifetion NF-KB ANALYSIS
  • Which drug for prostatic inflammation - BPHEvidences • Experimental: – Studies on primary cultures – Inhibition on inflammatory factors – Effect on proliferation/apoptosis • Clinical – Long term therapy – Combination with alpha1 blockers – Combination with 5 ARI
  • Increased apoptosis (TUNEL) using the combination of rofecoxib - finasteride
  • How to treat BPH- inflammation Patient IPSS≤7 IPSS>7 LUTS moderate- LUTS mild severe Symptoms or parameters correlated to prostatic inflammation Low volume High volume Low volume High volume Low PSA Elevated PSA Low PSA Elevated PSANo treatments 5 ARI preventive α-blocker Combination 5 ARI – treatment alpha blocker Anti-inflammatory Anti-inflammatory on on the prostate the prostateModificato da Roehrborn C.G., BJU 2004