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Advancement in prostate cancer


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Chronic prostatitis and cap: actuality and clinical implication

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Advancement in prostate cancer

  2. 2. CHRONIC INFECTION AND CANCER• Some virus induce cancers by acting directly on target cells: • Human papillomaviruses • Epstein-Barr virus• For most of the infectious agents, included those of STIs, the disease appears by an indirect mechanism: • Long-standing chronic inflammation leads to prolonged exposure of tissues to cancer-causing agents produced in response to infection or toxins
  3. 3. CHRONIC INFLAMMATION AND CANCER• Inflammation may contribute to carcinogenesis by several potential mechanisms, including: 1. Elaboration of cytokines and growth factors that favor tumor cell growth (TNF-alfa, VEGF, etc) 2. Induction of cyclooxygenase-2 (COX-2) in macrophages and epithelial cells 3. Generation of mutagenic reactive oxygen species (ROS) and reactive nitrogen species (RNS)• The processes are interrelated
  4. 4. PROLIFERATIVE INFLAMMATORY ATROPHY (PIA)• Described by Angelo De Marzo in 1999 (Am J Pathol )• Focal atrophic lesions containing activated inflammatory cells and proliferating epithelial cells are often directly adjacent to HGPIN, PCa or to both• Somatic genomic abnormalities are similar to those in cells with HGPIN and PCa
  5. 5. NEJM 349: 366, 2003
  6. 6. Meta-analysis of 11 case-control studies revealed a statistically significantsummary OR of prostate cancer of 1.57 for ever having had prostatitis. Urology2002;60:78-83A recent medical records review vs age-matched controls confirms this risk:Any type of prostatitis: OR 1.7 Acute prostatitis: OR 2.5Chronic bacterial prostatitis: OR 1.6 Chronic pelvic pain syndrome: OR 0.9 (Robert et Al. Epidemiology, 2004)Infections may represent one mechanism through which prostate cancerdevelops. However, casuality is unclear, because recall bias and detection
  7. 7. HISTOPATHOLOGIC CLASSIFICATION SYSTEM FOR CHRONIC PROSTATIC INFLAMMATION• Anatomic localisation glandular periglandular stromal• Extension focal multifocal diffuse• Grading 1 2 3 Nickel et Al. BJU Int., 2001
  8. 8. CHRONIC BACTERIAL PROSTATITIS –The most important cause of recurrent UTI inadult man –Frequently asymptomatic between an UTIepisode and the next one –5-10% of the patients with CP/CPPS have aCBP Krieger JN 1998 J New Rem Clin 47:4-15; Schaeffer AJ 1999 IJAA 11: 205-211
  9. 9. ISOLATED BACTERIA FROM CBP IN RECENT CLINICAL TRIALS (USA and EUROPE) Trial Ciproflox. Lomeflox 400mg od Trovaflox. 200mg Levoflox. 500 mg od 500 mg bid vs od vs 28 days Ciproflox 500mg bid Vs Ciproflox 500 mg bid. 28 days Ofloxac.300 mg bid 28 days 42 days Isolated 70 190 395 406 bacteria Gram + 16 (23%) 76 (40%) 322 (81.5%) 344 (85%) Gram - 54 (77 %) 114 (60 %) 73 (18.5%) 62 (15%) Study 1990-1992 1993-1996 1995-1996 2000-2001 PeriodReferences Naber & al., Naber & al., 2002 FDA web site Bundrick(2003) 2000
  10. 10. FLUORQUINOLONS ARE THE CHOISE DRUGS FOR TREATMENT OF CHRONIC BACTERIAL PROSTATITIS• Good activity vs Gram + and Gram – usually isolated in CBP• Favourable pharmacocynetic proprieties and elevated diffusion into prostatic tissue• Clinical and microbiological efficacy widely tested• Long time period treatment (not less than 4-6 weeks)• Best results with NSAIDs’ association
  11. 11. EFFICACY OF QUINOLONES IN PCB TREATMENTQuinolone Dosage Duration evaluable Bacteriol. Follow Pub.-year per day therapy Patients Eradication upAuthor(s) ( mg) (days) (number) (%) (Months)Norfloxacin 800 28 14 64 6 1990Schaeffer et alNorfloxacin 4-800 174 42 60 8 1991Petrikkos et alOfloxacin 400 14 21 67 12 1989 Pustet alCiprofloxacin 1000 14 15 60 12 1987Weidner et alCiprofloxacin 1000 28 16 63 21-36 1991Weidner et alCiprofloxacin 1000 28 34 76 6 2000Naber et alCiprofloxacin vs. 1000 28 78 72 6 2001Naber et al Lomefloxacin 400 28 75 63 6 2001Diagnosis according Meares & Stamey Nickel, Naber & Lobel, WHO Consultation, Paris 2005
  12. 12. LVX 500 mg od vs CIP 500 mg bid for 28 days (Bundrick et al., Urology,2003)Primary endpoint Levofloxacina Ciprofloxacina [IC](5-18 days >EOT)Eradication 102/106 96/125 [-8.98;12.58]in PPb population (75 %) (76.8%)(Primary efficacyvariable)Clinical success 102/136 91/125 [-13.27;8.87]In PPb population (75%) (73%)
  13. 13. CATECHIN : SINERGY EFFECT TO QUINOLONES• Catechin, an extract of green tea, has antimicrobial effect against various bacteria and synergy effect to antibiotics• Combination treatment of catechin and ciprofloxacin showed a statistically significant decrease in bacterial growth and improvements in prostate inflammation compared with ciprofloxacin group (p<0.05) in an experimental CBP models induced in Wistar rats. ( Lee et Al, Int J Urol, 2005)
  14. 14. ROLE OF CHLAMYDIA T. AND UREAPLASMA U. IN CBP• Only one systematic review (Weidner et al 2002)• The simple checking of U. urealyticum and/or C. trachomatis with the 4-glass test is not sufficient to consider these organisms as aetiological agents of CP/ CPPS• The microbiological techniques now available cannot diversify urethral contamination from prostatic infection Anderson & Weidner, WHO Consultation, Paris 2005
  15. 15. CHOISE DRUGS FOR CHLAMYDIA T.Comparative analysis of azithromycin and ciprofloxacin in the treatment of chronic prostatitis caused by Chlamydia trachomatis. (Skerk et All. Int J Antimicrob Agents. 2003)Azytromicin 3 day therapy of 1x500 mg weekly for 3 weeks vs Ciprofloxacin 500 mg b.i.d. for 20 days Significantly higher eradication (36/45 vs 17/44; p=0.0002) and significantly higer clinical cure (31/45 vs 15/44; p=0,0021) were achieved in the group of patients treated with AZITHROMICINE than in the ciprofloxacin group.Comparative randomized pilot study of azythromicin and doxycycline efficacy in the treatment of prostate infection caused by Chlamydia trachomatis ((Skerk et All. Int J Antimicrob Agents. 2004)Azythromicin 1x1000mg (single dose) weekly for 4 weeks vs Doxycycline 100 mg b.i.d. for 28 days There was no significant difference between the eradication rates (A 65/82; D 33/43; p= 0.82) and the clinical cure rate (A 56/82, D 30/43 p= 0.94) of the two antimicrobials
  16. 16. HISTOPATHOLOGICAL STUDIES IN CP/CPPS• Only few studies (4) on this subject have been conducted• Infiltrates of chronic inflammatory cells were found from 33% to 88% of the cases• Predominantly periglandular and stromal lymphocytes• Many bias are related to the different biopsy’s techniques and to the small number of cores (Schmidt et Al., J Urol, 1966; Nielsen et Al, J Urol,1973; Doble et Al, Br. J Urol, 1989; True et Al. J Urol ,1999)
  17. 17. CP/CPPS: BACTERIAL ETIOLOGY?• Bacterial etiology may be invoked even if an organism is not isolated but WBCs count is positive in EPS/VB3• Nonspecific bacterial ribosomal RNA encoding (16S rRNA) shows positive bacterial signals in EPS though negative microbiological cultures in high % of cases• Some studies with PCR prove bacterial implication in prostatic patterns that are negative at microbiological examinations (Hochreiter et Al., J Urol. 2000; Tanner et Al. J Clin Microbiol,1999)
  18. 18. CP/CPPS : A CHALLENGE• Dyssynergic voiding patterns?• Inflammatory disregulation of the injury response leading to persistent chemokine upregulation, oxidant stress, and cellular damage ?• Neurogenic inflammation? (Kaplan et Al. J Urol, 1997) ( Satyanarayana & Shoskes, Mol Med Today, 1997)
  19. 19. URINARY TRACT INNERVATION Detrusor contraction Ach Para- sympathetic Ach Trigone and M sphyncter neurons relaxation Sympathetic Trigone contraction neurons NA α1 Sphyncter contraction Neurogenic Inflammation Primary Symptoms perception (LUTS) sensitive SP neuron CGRP Irritation-Pain TRPV1 CapsaicineTRPV1: vanilloide receptor subtype1, tipical pain receptor, to which irritant substances as Capsaicine bindoneself CGRP = calcitonine gene related peptide  mastcells activation  inflammation
  20. 20. NEUROGENIC INFLAMMATION AND CPPS• The transient receptor potential vanilloid subtype 1 (TRPV1) is an ion channel activated by capsaicin that is involved in pain’s perception and in bladder’s contractions frequency (Avelino and Cruz, Naunyn SchmeiedebergArch Pharmas 2006)• Recent discovery in normal prostatic tissue of a rich TRPV1 sensory innervation may open new therapeutical perspectives for treatment of pain in CPPS (Dinis et Al, Eur. Urol.,2005)• The expression in urothelial and prostatic cancer cells of TRPV1 raises the exciting hypothesis that this receptor is also involved in cell differentiation (Sanchez et Al, Eur J Pharmacol, 2005)
  21. 21. PRIMARY SENSITIVE NEURON (NOCICEPTOR) Bladder Urethra Prostate Irritative stimula (capsaicin) Dorsal Marrow SP SP c-fos CGRP CGRP Irritation- Neurogenic Glutammate/Aspartate pain Inflammation Irritation - Pain The peripheric effect is the beginning of all inflammmatory phenomena’s fall(oedema, parvicellular infiltration, cytokynes production etc.)The central effect is the sending of painful informations to upper centers by the c-fos  pain sensation  starting-signal of the efferent mechanisms as contractionsetc.
  22. 22. ALFA-1 ADRENOCEPTORS IS EXPRESSED IN PRIMARY SENSITIVE NEURONS- α1-adrenoceptor produces excitation -neurosecretion. - α1-adrenoceptor produces irritatation/pain α1-adrenoceptor produces Neurogenic Inflammation
  23. 23. MANAGEMENT OF CHRONIC PROSTATITIS• Antibiotics such as Fluoroquinolones• Alpha-blockers with or without antibiotics• NSAIDs• Allopurinol• Finasteride• Pentosan• Mepartricin• Amitryptiline• Analgesics, including centrally effective drugs• Muscle relaxants such as Valium or Baclofen• Phytotherapy• Physiotherapy with biofeedback• Thermotherapy and TUNA• Prostatic massage• Perineal skin application of Capsaicin• Sacral and pudendal neuromodulation
  24. 24. MANAGEMENT OF CP/CPPS: ANEVIDENCE BASED APPROACH (Dimitrakov et Al,Urology,2006)
  25. 25. MANAGEMENT OF CP/CPPS: AN EVIDENCE BASED APPROACH (Dimitrakov et Al,Urology,2006)
  26. 26. ALPHA-BLOCKERS IN CP/CPPS• Block of alfa-1 receptors in bladder neck (theory of bladder neck hypertrophy) or block of alfa-1 receptors in sensitive neurons (theory of neurogenic inflammation)? (Hruz et Al, Eur Urol,2003); (Wesselmann,World J Urol,2001)• Three of four trials RCTs showed statistically significant benefits on symptoms control and modest clinical efficacy (Mehik et Al, Urology, 2003; Cheah et Al., J urol, 2003; Nickel et al, J Urol, 2004)• One study failed to show benefit from alpha-blocker therapy (it enrolled men with long-standing and refractory symptoms) ( Alexander et Al, Ann Intern Med., 2004)
  27. 27. ΑLPHA1-ADRENOCEPTORS AND NEUROGENIC INFLAMMATION IN CP/CPPS Bladder Urethra Irritative stimulus Prostate (Cyclophosphamide) Dorsal Marrow Alpha-blocker α1 SP SP c-fos Neurogenic CGRP CGRP Irritation Inflammation Glutammato/aspartato pain Restoration of physiological conditionAlfa-1 receptors are not only present on bladder neck but also on the primarysensitive neurons of the bladder and of the prostate too  the action in CP/CPPSseems indipendent by the hydraulic fact (Kindly by Geppetti, 2006)
  28. 28. CAPSAICIN: TOPICAL APPLICATION TO THE PERINEAL SKIN• Implicated in neurogenic inflammation: interacts with vanilloid receptors (TRPV1)• Pilot study on 22 patients and 6 healthy control subjects.• Topical application of 5 ml CAPSAICIN at a concentration of 10(-5)M to the perineal body skin• The patients with CP/CPPS reported: – heat/burning sensation intensity statistically greater than healthy controls (p<0.001) – shorter time to heat sensation onset (p<0.001) – improvement of symptoms after 7 days in 16/22 patients (NIH- CPSI p<0.01) (Turini et Al, Urology,2006)
  29. 29. ANTIBIOTICS FOR CP/CPPSA) 2 large-scale studies: a) LVX vs placebo b) CIPRO vs placebo (80 + 169 enrolled patients for 6 weeks of treatment) showed no significant difference in the decrease of NIH-CPSI total score from baseline to 6 weeks for the two drugs compared with placebo (Nickel, BJU,2003; Alexander, Ann Intern Med, 2004)B) Preliminary experience with therapy designed to eliminate nanobacteria (comET = tetracycline 500mg + nutriceutical + EDTA suppository) resulted in significant improvement in the symptoms of recalcitrant CPPS in the majority of men with CP/CPPS and prostate stones (Shoskes et Al, J Urol, 2005)
  30. 30. ANTI-INFLAMMATORY TARGETS AND PREVENTION OF PCa• Cytokines Anti-inflammatory cytokines (Interleukin-12)• NF-kB Salicylates• COX-2 Non-steroidal anti-inflammatory drugs Selective COX-2 inhibitors• PPARg Prostaglandins Thiazolidinediones (e.g., troglitazone, etc)• Reactive Oxygen Species Anti-oxidants: vitamin E, b Carotene Phytochemicals/free radical scavengers
  31. 31. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND RISK FOR PROSTATE CANCER• Among the prospective studies the relative risk of prostate cancer for aspirin and non aspirin NSAIDs use ranges from 0.45 for multiple daily use to 1.05 for twice or more per week (Roberts et Al, Mayo Clin Proc, 2002 Leitzmann et al, Cancer Epidemiol Biomarkers Prev,2002; Dasgupta et Al, Cancer J, 2006)• In Baltimore Longitudinal Study of Aging only men < 70 years old who had ever used aspirin or ibuprofen had a statistically significant lower risk of prostate cancer (RR = 0,76 and 0.79 rispecrively). No difference statistically significant in men > 70’ Cancer Epidemiol Biomarkers & Prev, 2005)• In Italian multicentric case control study odds ratio (OR) for regular aspirin use was 1,10 = no protective role of regular aspirin use is observed on prostate cancer risk
  32. 32. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (SELECTIVE COX-2 INHIBITORS ) Rofecoxib, Celecoxib, Valdecoxib, Parecoxib, Etoricoxib and Lumiracoxib• Only one trial with Rofecoxib 25 and 50 mg for six weeks in the treatment of CP/CPPS (161 patients)• Only 50 mg reached statistical significance (symptoms, pain and quality of life) versus placebo (Nickel et Al, J Urol,2003)• Adverse effects on renal events and arrhytmia have been controversial, with suggestion of a class effect (Zhang et Al, JAMA 2006)
  33. 33. ADVERS EFFECTS OF COX-2 INHIBITORS• 14 trial reports with 116094 participants• 6394 composite renal events and 286 arrhythmia events• Compared with controls Rofecoxib was associated with increased risk of arrhythymia ( RR=2,90) and renal events (RR=1,53): removed from the marketplace (2004)• Celecoxib was associated with lower risk of renal dysfunction (RR=0.61) compared with controls but the risk of cardiovascular events may be increased• Valdecoxib: increased risk of cardiovascular adverse events and increased risk of serious skin reactions: removed from marketplace (2005)• Other agents of same family were not significantly associated with risks of adverse events (Zhang et Al. JAMA, 2006)
  34. 34. PHYTOTHERAPY: QUERCETINE• Poliphenolic bioflavonoid (red wine, green tea, onions and spices)• Antioxidant and anti-inflammatory properties: inhibits IL-8 and MCP-1 (Monocyte chemoattractant protein-1) and inhibits the activation of NF-kB by TNF-alpha implicated in CPPS pathogenesis• 30 patients vs placebo• 500 mg 2 times daily ( 1 month)• 67% vs 20% had improved more than 25% in symptoms;• Significant improvement in 82% if Quercetine is associated with bromelain and papain (open label)• Interaction with Quinolones (competitive inhibitor of DNA gyrase) (Shoskes et Al. Urology,1999)
  35. 35. ALLOPURINOL FOR CHRONIC PROSTATITIS Reflux of urine into prostatic ducts causes prostatic inflammation via high concetration of purine and pyrimidine base-containing metabolites in prostatic secretions (Persson et al, J Urol. 1996)• Allopurinol is used hoping to lower prostatic levels of uric acid and improving symptoms• Only one trial with 54 men met study inclusion criteria• There was a statistically significant change favoring allopurinol in patient- reported discomfort between the study and control group at follow-up• No side effects in patients receiving allopurinol (McNaughton Collins and Wilt, The Cochrane Librrary, 2006)
  36. 36. MEPARTRICIN• One study examined efficacy of 40 mg of mepartricin, an estrogen-lowerihg agent, versus placebo in 26 CPPS patients• Following 60 days of treatment there was statistically significant decrease in total NIH-CPSI, pain, quality of life and 17-beta estradiol levels• Compared to baseline, the changes in urinary scores and the serum level of LH, FSH and T at the end of the study failed to reach statistical significance (De Rose et Al., Urology, 2004)
  37. 37. PENTOSAN POLYSULFATE• 100 men with CP/CPPS were randomised to 300mg PPS or pacebo 3 times daily for 16 weeks• Clinical Global Improvement (CGI)showed moderate to marked improvement in significantly more PPS-trated patients (18 or 37% vs. 8 or 18%, p=0,04)• At 16 weeks also NIH-CPSI scores were significantly better in the PPS as compared to the placebo group (-2,0 or 22% vs. -1.0 or 12%, p=0,031) ( Nickel et Al., J Urol., 2005)
  38. 38. PHYTOTHERAPY: BEE POLLEN (CERNILTON) Experimental study in rats show inhibitory effect on the prostatic inflammatory cytokynes (Asakawa et Al, Hinyokika Kiyo, 2001) Clinical study on 90 patients• 1 tab 3 times daily for 6 months• If complicating factors: minimal response• If uncomplicated patients: 36% cured and 42%improved, with decrease in complement C3/coeruloplasmine in the ejaculate (Rugendorffet Al. Br.J Urol. 1993)
  39. 39. MULTIMODAL THERAPY FOR CP/CPPS• Monotherapy resulted very often in frustrating answers• The relative efficacy of diverse therapeutical approaches suggests that CP/CPPS is a multifactorial condition with symptoms potentially due to infection, inflammation and/ or neuromuscolar spasm• An approach using stepwise therapy with antibiotics, anti-inflammatories and neuromuscolar agents can be successful in the majority of patients with long-standing chronic prostatitis (Shoskes et Al. J Urol. 2003)
  40. 40. CATEGORY IV PROSTATITIS Finding of leukocytes in EPS/VB3 or inflammation in histhologic specimens• What is its prevalence: - in the context of BPH ? - in prostatic biopsies ? - in the global population ?• Can it influence PSA levels ?• Does it respond to antibiotics ?• Do we need to treat?
  41. 41. CATEGORY IV PROSTATITISEPS/VB3 32,2 – 42% (Potts, 2000; Carver, 2003)BPH 43,1 – 100% (Nickel et Al. BJU Int. 1999)BIOPSIES 40 - 95% (Stancick,2004; Shattermann et Al, 2003)RADICAL PROSTATECTOMIES 95% (Gerstenbluth et Al, J Urol, 2002) In Japan, where PCa prevalence is very low, only 11,2% of screened population for high PSA has hystologic evidence of NIH IV prostatitis ( Shimomura et Al, 2003)
  42. 42. PATTERNS OF INFLAMMATION IN BPH• 162 consecutive TURP/open prostatectomy• 98.1% focal inflammation• 7 categories of inflammation: - segregated glandular - periglandular - diffuse stromal - isolated stromal - lymphoid nodular - acute necrotizing - granulomatous Kohnen PW et al, J Urol 1979
  43. 43. PATTERNS OF INFLAMMATION IN BPH Segregated glandular prostatitis Periglandular prostatitis Diffuse stromal prostatitisPeriglandular and stromal prostatitis Lymphoid nodular prostatitits Acute necrotizing prostatitis
  44. 44. (TURP) (44% bacterial growth)
  45. 45. PROSTATE INFLAMMATION AND PSA• There is controversy on the grade of influence of prostatitis category IV on the serum PSA levels• Serum PSA levels influenced by: - extension of the prostate inflammation - intensity and grade of epithelial lesion - type of inflammation Schattermman PHF et al. – Eur Urol 2000;37:404-412 Morote J et al. – Eur Urol 2000;37:537-540
  46. 46. PROSTATIC INFLAMMATION AND PSA: THE IRANI’S SCALEExtent Infiltration aggressiveness PSA elevation 0 no phlogistic cells no contact between +/- phlogistic cells and glandular epithelium 1 diffuse stromal contact between infiltration/no inflammatory infiltrate +/- limphoid nodules and glandular epithelium 2 limphoid nodules diffuse stromal infiltration not aggregated with disruption <25% + of glandular epithelium 3 wide inflammatory disruption > 25% ++ areas of aggregated of glandular epithelium infiltration Irani et Al. J Urol. 1997
  47. 47. ASYMPTOMATIC PROSTATITIS NIH-IV Synthesis of clinical studies• 7 clinical studies on more than 450 cases with high PSA and normal DRE and urinalysis• In all of the 7 studies Quinolones were used +/-NSAIDs• Reduction of PSA: > 50% of cases• Mean/median PSA reduction: 16-42%• PSA normalization: 17-46% only in benign conditions• PSA specificity: increased• Number of biopsies reduction: > 20% of cases ( Potts, J Urol, 2000; Carver et Al. J Urol, 2003; Guercio et Al. Arch It Urol Androl, 2004)
  48. 48. ASYMPTOMATIC PROSTATITIS DO WE NEED TO TREAT?Potential benefits: decrease need for prostate biopsies potential to decrease BPH or CaP risk potential to increase fertility (infertile men)Potential disadvantages: no proven therapy potential toxicity of therapy for asymptomatic patients
  49. 49. DIETARY INTAKE OF ANTIOXIDANTSIntake of different antioxidants that might attenuate celland genome damage inflicted by inflammatory oxidants (egsuperoxide, nitric oxide and peroxynitrite) has been foundto protect against prostate cancer developmentRCT of SELENIUM supplementation revealed a decrease in incident prostatecancer (RR 0,51) while ALFA-TOCOFEROL supplementation showed a 32%decrease in PCa incidence and a 41% decrease in PCa mortality ( Duffield-Lillico at Al, BJU Int,2003) (The Alpha- Tocoferol, Beta Carotene Ca Prevention study Group, N Engl J Med, 1994)Consumption of vegetables containing the carotenoid LYCOPENE andconsumption of crociferous vegetables containing isothiocyanates such asSULFORAPHANE reduce prostate cancer risk, acting as antioxidants byinducing a plethora of carcinogen detoxification enzymes (Cohen et Al, J Natl Cancer Inst, 2000; Dinkova-Kostova et Al, Free Radic Biol med, 2000)CURCUMIN showed free radical scavernging ability and antioxidantefficiency in experimental study (Khopde et Al. Biophys Chem. 1999)
  50. 50. ROTATION DIET IN FOOD INTOLERANCE• Minimal persistent prostate inflammation with increased production of endogenous free radicals could be due to daily intaking of intolerant foods. (Sampson, J allergy Clin Immunol, 2004)• IgE studies can be used to detect real allergies while DRIA test (Dinamometric Research Into Allergies) can discovery individual food-intolerance ( Speciani et al, Allergy, 1992)• Rotation diet can re-establish the food tolerance, reduces cholesterol and positively increases the LAG-TIME (an in-vitro test which exprimes the resistance to oxidative stress). This prove the strong relationship between oxidative stress and diet (Perrone et Al, 2003)
  51. 51. CONCLUSIONS• Additional well designed basic, clinical and epidemiological studies are needed to resolve whether intraprostatic chronic inflammation is a rational target for prostate cancer prevention• If so, prostatic infections could be cleared with antibiotics or antiviral agents, inflammation could be inhibited by antiinflammatory agents, and reactive byproducts of the inflammatory response could be quenched by dietary and supplemental antioxidants• Also, novel therapies could be developed that interfere with the intraprostatic production or action of cytokines