Inflammation and Prostate       Diseases ProgressionAlessandro SciarraChairman Prostate UnitPoliclinico Umberto IUniversit...
BPH: long period before clinical evidence
Prostate Cancer: long period before clinical evidence    Normal       LGPIN      HGPIN        Carcinoma             10-20 ...
Question 1              ?  May inflammation significantlycondition the development and future  progression of prostate dis...
Question 2                 ?May inflammation be considered a risk factor so to be integrated  in risk stratification analy...
Association infiammation – prostatic diseases  Evidences:    • Epidemiologic                • Genetic                • Mec...
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° b...
Association between inflammation and BPHUrology 71: 475-479, 2008. ©2008 Elsevier
Association infiammation – prostatic diseases   Evidences    • Epidemiologic   :                • Genetic                •...
Association infiammation – prostatic diseases   Evidences    • Epidemiologic   :                • Genetic                •...
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 ...
Inflammation:two possible actors       NOS and COX
Increased apoptosis (TUNEL) with rofecoxib
The role of inflammation in the human prostate                                                                         FGF...
Which inflammation induces prostatic progression?    Evidences:     • Histological data – PSA                   • Clinical...
Histopathological aspects of BPH            Inflammatory aspects      Histological aggressiveness• 0 = no contact between ...
Infiammation: precancerous prostatic lesions                                   PIA                       PIN              ...
Inflammation: potential precursor           lesions ?
Which inflammation induces prostatic progression? Evidences    • Histological data – PSA :              • Clinical data:  ...
• Prospective analysis on 167 prostate during autopsy. • Pathologic analysis identified all carcinoma focus, BPH nodule an...
Inflammation and BPH              67.6%                                                                        88         ...
Infiammation and BPH           Distribution of infiammation                     Inflammation association with age CONCLUSI...
A. Sciarra et al. Eur Urol 2000
Inflammation and prostate volume:                                       who influences the other ?                        ...
Inflammation and progression risk: MTOPS 544 patients from MTOPS study with acute (only 31) or chronic inflammation at bas...
Impact of inflammation on BPH progression                                                No infiammation                  ...
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                ...
How to select patients ?Histology, no very often available Different stages for prostatic inflammation No inflammation    ...
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...
1                                                         2                                                         3     ...
Systemic Markers for infiammation                                                 Case-control nested study (4971 cases)  ...
IL-8 as marker of inflammation in BPH                                          IL-8 levels in prostatic secretion Sensibil...
Urinary markers for inflammation • 90 tissue prostatic samples obtained from BPH patients waiting for surgery • Urinary sa...
Mean level of genes expression in 90 samples from BPH        cases on the basis of inflammation scoreRobert G et al Nijmeg...
Possible results from a long term block of prostatic                      inflammation• Improvement of LUTS correlated to ...
Which drug for prostatic inflammation - BPHEvidences:   • Experimental             – Studies on primary cultures          ...
Serenoa Repens exane: specific for prostate tissue                                                  o     2               ...
Serenoa Repens exane: Hypothesis for a mechanism of action                   Stromal and epithelial human prostate cells  ...
RESULTS                 CELL COUNT         INFLAMMATORY PATTERNS                                          IL-6, CCL-5, COX...
Which drug for prostatic inflammation - BPHEvidences   • Experimental:            – Studies on primary cultures           ...
Increased apoptosis (TUNEL) using the combination of rofecoxib - finasteride
How to treat BPH- inflammation                                                        Patient                        IPSS≤...
Prostatitis-Cancer
Prostatitis-Cancer
Prostatitis-Cancer
Prostatitis-Cancer
Prostatitis-Cancer
Prostatitis-Cancer
Prostatitis-Cancer
Prostatitis-Cancer
Prostatitis-Cancer
Prostatitis-Cancer
Prostatitis-Cancer
Prostatitis-Cancer
Prostatitis-Cancer
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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

    1. 1. Inflammation and Prostate Diseases ProgressionAlessandro SciarraChairman Prostate UnitPoliclinico Umberto IUniversity La Sapienza- Rome, Italy
    2. 2. BPH: long period before clinical evidence
    3. 3. Prostate Cancer: long period before clinical evidence Normal LGPIN HGPIN Carcinoma 10-20 years 1-10 years
    4. 4. Question 1 ? May inflammation significantlycondition the development and future progression of prostate diseases ?
    5. 5. Question 2 ?May inflammation be considered a risk factor so to be integrated in risk stratification analyses for prostate diseases ?
    6. 6. Association infiammation – prostatic diseases Evidences: • Epidemiologic • Genetic • Mechanism of action • Histologic • Clinical
    7. 7. 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
    8. 8. Association between inflammation and BPHUrology 71: 475-479, 2008. ©2008 Elsevier
    9. 9. Association infiammation – prostatic diseases Evidences • Epidemiologic : • Genetic • Mechanism of action • Histologic • Clinical
    10. 10. Association infiammation – prostatic diseases Evidences • Epidemiologic : • Genetic • Mechanism of action • Histologic • Clinical
    11. 11. Inflammation and BPHLinfocitaMacrofago CitochineNeutrofilo Radicali ossigeno
    12. 12. Cytokines and inflammation in the prostateKramer et al, Eur Urol, 2007; 51:1202-16
    13. 13. Inflammation: possible pathogenesis  repeated tissue damage  excessive production of oxidative damages  post-translational DNA modifications  increased cell proliferation and angiogenesis
    14. 14. Inflammation:two possible actors NOS and COX
    15. 15. Increased apoptosis (TUNEL) with rofecoxib
    16. 16. 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
    17. 17. Which inflammation induces prostatic progression? Evidences: • Histological data – PSA • Clinical data
    18. 18. 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
    19. 19. Infiammation: precancerous prostatic lesions PIA PIN CARCINOMA (proliferative (prostatic inflammatory atrophy) intraepithelial neoplasia)Prostata infiammata
    20. 20. Inflammation: potential precursor lesions ?
    21. 21. Which inflammation induces prostatic progression? Evidences • Histological data – PSA : • Clinical data: - Frequency of the process - Association with progression
    22. 22. • 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
    23. 23. 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
    24. 24. 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
    25. 25. A. Sciarra et al. Eur Urol 2000
    26. 26. 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
    27. 27. 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
    28. 28. Impact of inflammation on BPH progression No infiammation InfiammationC. Roehrborn, 2005. Studio MTOPS
    29. 29. Inflammation:risk factor for BPH progression or PC development Roehrborn C. 2006
    30. 30. Inflammation as precursor of Prostate Cancer: Rationale for Preventive Strategies ?
    31. 31. How to select patients with BPH and inflammation ? Evidences: • Symtoms • Imaging • Markers
    32. 32. How to select patients ?Histology, no very often available Different stages for prostatic inflammation No inflammation Low Moderate Severe
    33. 33. How to select patients ? LUTS and IPSSRelationship between inflammation and symptoms in BPH
    34. 34. 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
    35. 35. 1 2 3 4 G PC H LGPC PIN tio n HG mma in fla l r maNo
    36. 36. 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
    37. 37. 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
    38. 38. 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
    39. 39. Mean level of genes expression in 90 samples from BPH cases on the basis of inflammation scoreRobert G et al Nijmegen med Centre
    40. 40. 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
    41. 41. 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
    42. 42. 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
    43. 43. 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
    44. 44. RESULTS CELL COUNT INFLAMMATORY PATTERNS IL-6, CCL-5, COX-2Apoptosis-prolifetion NF-KB ANALYSIS
    45. 45. 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
    46. 46. Increased apoptosis (TUNEL) using the combination of rofecoxib - finasteride
    47. 47. 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

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