1. Inflammation may play a role in the development and progression of benign prostatic hyperplasia (BPH) and prostate cancer. 2. Evidence from histological, clinical, and epidemiological studies suggests that chronic prostatic inflammation is associated with larger prostate volume and an increased risk of BPH progression. 3. Drugs that inhibit prostatic inflammation, such as Serenoa repens extract, may help prevent BPH progression when used alone or in combination with other BPH drugs. Treatment should be tailored based on a patient's symptoms, prostate size, and inflammation markers.

1. Inflammation and Prostate
Diseases Progression
Alessandro Sciarra
Chairman Prostate Unit
Policlinico Umberto I
University La Sapienza
- Rome, Italy

2. BPH: long period before clinical evidence

3. Prostate Cancer: long period before clinical evidence
Normal LGPIN HGPIN Carcinoma
10-20 years 1-10 years

4. Question 1 ?
May inflammation significantly
condition the development and future
progression of prostate diseases ?

5. Question 2 ?
May inflammation be considered
a risk factor so to be integrated
in risk stratification analyses
for prostate diseases ?

6. Association infiammation – prostatic diseases
Evidences: • Epidemiologic
• Genetic
• Mechanism of action
• Histologic
• Clinical

8. 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

9. Association between inflammation and BPH
Urology 71: 475-479, 2008. ©2008 Elsevier

10. Association infiammation – prostatic diseases
Evidences • Epidemiologic
:
• Genetic
• Mechanism of action
• Histologic
• Clinical

14. Association infiammation – prostatic diseases
Evidences • Epidemiologic
:
• Genetic
• Mechanism of action
• Histologic
• Clinical

15. Inflammation and BPH
Linfocita
Macrofago Citochine
Neutrofilo Radicali ossigeno

16. Cytokines and inflammation in the prostate
Kramer et al, Eur Urol, 2007; 51:1202-16

17. Inflammation: possible pathogenesis
 repeated tissue damage
 excessive production of
oxidative damages
 post-translational DNA
modifications
 increased cell proliferation
and angiogenesis

18. Inflammation:two possible actors
NOS and COX

21. Increased apoptosis (TUNEL) with rofecoxib

22. 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 progression
Lucia et al, Curr Urol Rep, 2008; 9:272-78

26. Which inflammation induces prostatic progression?
Evidences: • Histological data – PSA
• Clinical data

27. 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

29. Infiammation: precancerous prostatic lesions
PIA PIN CARCINOMA
(proliferative (prostatic
inflammatory atrophy) intraepithelial neoplasia)
Prostata infiammata

30. Inflammation: potential precursor
lesions ?

31. Which inflammation induces prostatic progression?
Evidences • Histological data – PSA
:
• Clinical data:
- Frequency of the process
- Association with progression

32. • 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

33. 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

34. Infiammation and BPH
Distribution of infiammation Inflammation association with age
CONCLUSIONs: Chronic inflammation was commonly found during autopsies.
Inflammation was directly associated with BPH
Delongchamps et al, J Urol 2008, 179:1736-40

35. A. Sciarra et al. Eur Urol 2000

36. 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
cc
A. Sciarra et al. Eur Urol 2000

37. 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 progression
Roehrborn CG,. AUA meeting 2005, Abstract No. 1277

38. Impact of inflammation on BPH progression
No infiammation
Infiammation
C. Roehrborn, 2005. Studio MTOPS

39. Inflammation:
risk factor for BPH progression or PC development
Roehrborn C. 2006

40. Inflammation as precursor of Prostate Cancer:
Rationale for Preventive Strategies ?

44. How to select patients with BPH and inflammation ?
Evidences: • Symtoms
• Imaging
• Markers

45. How to select patients ?
Histology, no very often available
Different stages for prostatic inflammation
No inflammation Low
Moderate Severe

46. How to select patients ? LUTS and IPSS
Relationship between inflammation and symptoms in BPH

47. 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

48. 1
2
3
4
G PC
H
LGPC
PIN
tio
n HG
mma
in fla
l
r ma
No

49. 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
study
Shenk et al, Am J Epidemiol, 2010; 171:571-82

50. 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/mL
Liangren et al, Urology, 2009; 74:340-4

51. 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 infiammation
Robert et al, Prostate, 2011, in press

52. Mean level of genes expression in 90 samples from BPH
cases on the basis of inflammation score
Robert G et al Nijmegen med Centre

53. 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

54. 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

55. Serenoa Repens exane: specific for prostate tissue
o 2
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Fi b Fi b Te Te Ep Ep Te Te
CELL TYPE

56. 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

57. RESULTS
CELL COUNT INFLAMMATORY PATTERNS
IL-6, CCL-5, COX-2
Apoptosis-prolifetion NF-KB ANALYSIS

58. 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

59. Increased apoptosis (TUNEL) using the combination of rofecoxib - finasteride

60. 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 PSA
No treatments 5 ARI preventive α-blocker Combination 5 ARI –
treatment alpha blocker
Anti-inflammatory Anti-inflammatory on
on the prostate the prostate
Modificato da Roehrborn C.G., BJU 2004