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Transcript of Prostatitis-Cancer
Inflammation and Prostate Diseases Progression
Alessandro SciarraChairman Prostate UnitPoliclinico Umberto IUniversity La Sapienza - Rome, Italy
BPH: long period before clinical evidence
Normal LGPIN HGPIN Carcinoma
10-20 years 1-10 years
Prostate Cancer: long period before clinical evidence
Question 1 ?
May inflammation significantly condition the development and future
progression of prostate diseases ?
Question 2 ?
May inflammation be considered a risk factor so to be integrated
in risk stratification analysesfor 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 BPH
Urology 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 BPH
Linfocita
Macrofago
Neutrofilo
Citochine
Radicali ossigeno
Cytokines and inflammation in the prostate
Kramer 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 actorsNOS and COX
Increased apoptosis (TUNEL) with rofecoxib
The role of inflammation in the human prostate
Lucia et al, Curr Urol Rep, 2008; 9:272-78
Modification epithelial function
Tissue damage
Modification stromal function
Infiammation Angiogenesis
Epithelial hyperplasia
Stromal hyperplasia
FGFsIGFs
TGF-Cyr61
Citochine
FGFsIGFs
TGF-Cyr61
Citochine
Diseases Progression
↑ IL-8 ↓ PDF
↑ IL-8
Inflammation can stimulate prostatic disease progression
Which inflammation induces prostatic progression?
Evidences: • Histological data – PSA
• Clinical data
Histopathological aspects of BPH
Inflammatory aspectsHistological 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
Prostata infiammata
PIA(proliferative
inflammatory atrophy)
PIN(prostatic
intraepithelial neoplasia)
CARCINOMA
Inflammation: potential precursor lesions ?
Which inflammation induces prostatic progression?
Evidences:
• Histological data – PSA
• Clinical data:- Frequency of the process- Association with progression
Delongchamps et al, J Urol 2008, 179:1736-40
• 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.
Inflammation and BPH
Delongchamps et al, J Urol 2008, 179:1736-40
In BPH areas ,75% were associated with chronic inflammation (p= 0.01).
67.6%
32.4%
Infiammation and BPH
Delongchamps et al, J Urol 2008, 179:1736-40
Distribution of infiammation Inflammation association with age
CONCLUSIONs: Chronic inflammation was commonly found during autopsies. Inflammation was directly associated with BPH
A. Sciarra et al. Eur Urol 2000
Inflammation and prostate volume:who influences the other ?
A. Sciarra et al. Eur Urol 2000
50
40
30
20
10
030-39 40-49 50-59 60-69 70-79 80-89
cc
acute - trendacute
chronic - trendchronic
Chronic inflammation: F(1,2)=408.64; p=0.002Acute inflammation: F(1,2)=2.292; p=0.269
Inflammation and progression risk: MTOPS
Roehrborn CG,. AUA meeting 2005, Abstract No. 1277
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 progression
Impact of inflammation on BPH progression
C. Roehrborn, 2005. Studio MTOPS
No infiammationInfiammation
Roehrborn C. 2006
Inflammation: risk factor for BPH progression or PC development
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 IPSS
Relationship between inflammation and symptoms in BPH
Multiparametric magnetic resonance with spectroscopic analysis: a modern approach in prostatic imaging
Prostate 1H-MRSI (cancer)
Cr:Creatine = it increases in hypermetabolism
Ch:Choline = cellular turnover
Ci:Citrate = terminal metabolites of Krebs cycle
1234
Normal inflammation HGPINLGPC
HGPC
Systemic Markers for infiammation
Shenk et al, Am J Epidemiol, 2010; 171:571-82
Case-control nested study (4971 cases) on the association between
inflammatory markers and symptomatic BPH based on the placebo arm of PCPT
study
IL-8 as marker of inflammation in BPH
Liangren et al, Urology, 2009; 74:340-4
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/mL
Urinary markers for inflammation
Robert et al, Prostate, 2011, in press
• 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 infiammation
Mean level of genes expression in 90 samples from BPH cases on the basis of inflammation score
Robert 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 - BPH
Evidences: • 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
Epitelio prosta
tico tipo 2
Epitelio prosta
tico tipo 1
Fibroblasti prostatici tipo 2
Fibroblasti prostatici ti
po 1
Fibroblasti cutanei tipo 1
Fibroblasti cutanei tipo 2
Fibroblasti della mammella tipo 1
Fibroblasti della mammella tipo 2
Tessuto re
nale tipo 1
Tessuto re
nale tipo 2
Epididimo tipo 1
Epididimo tipo 2
Testicolo tipo1
Testicolo tipo 2
Serenoa Repens exane: specific for prostate tissue
CELL TYPE
% A
POPT
OSI
S
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)
Reduction 5AR I-II
Increased ratio Apoptosis/proliferation (2,6,7)(Ev Lev 2b)
Mitochondrial Block/distruction(2,4)(Ev Lev 2b)
1-Buck J Urol 20042-Bayne Prostate 1999,J urol 20003-Habib Eur Urol 20094-Petrangeli JCP 20095-Paubert-Braquet Prostglandin 1998976-Vacherot Prostate 20097-Vela Navarrete J Urol 2005
Cellular membrane damage-increased permeab. (nuclear, mitochondrial)(1-5) (Ev Lev 2b)
Effect AR-ER
Chromatin condensation(2,3)(Ev. Lev 4)
inhibition 5 lipoxigenase (5)(Ev Lev 2b)
Reducion ecosanoid prod.= leucotren (5)(Ev Lev 2b)
antii
nfla
mm
ator
y
RESULTS CELL COUNT INFLAMMATORY PATTERNS
Apoptosis-prolifetion NF-KB ANALYSIS
IL-6, CCL-5, COX-2
Which drug for prostatic inflammation - BPH
Evidences:
• 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
Modificato da Roehrborn C.G., BJU 2004
Anti-inflammatory on the prostate
Anti-inflammatory on the prostate
Low volumeLow PSA
No treatments
High volumeElevated PSA
5 ARI preventive treatment
Low volume Low PSA
-blocker
High volumeElevated PSA
Combination 5 ARI – alpha blocker
IPSS≤7
LUTS moderate-severeLUTS mild
IPSS>7
Patient
Symptoms or parameters correlated to prostatic inflammation