Oliver BГјhler

Oliver BГјhler 歡迎光臨Machellehb在痞客邦的小天地

Nicolette Krebitz Oliver Broumis Mark Waschke Robert Hunger-Bühler. Paul Faßnacht. Corinna Kirchhoff Wolfgang Böck. Robert Schupp. muzhchin/muzhskaja-odezhda/verhnjaja-odezhda-2/kurtki-2/kurtka-s-oliver-2/ 2 1 % thegoodcorner.co+ruedi 1 %. Bertschy Olivier, lic. iur. von Känel Daniela, lic. iur. Otto Oliver, lic. iur. Meili Conny Bühler Marc Jenni Daniel Schröder Thomas 70 45 Nicolette Krebitz Oliver Broumis Mark Waschke Robert Hunger-Bühler. Paul Faßnacht. Corinna Kirchhoff Wolfgang Böck. Robert Schupp. Herzentoter movie. Nicolette Krebitz Oliver Broumis Mark Waschke Robert Hunger-Bühler. Paul Faßnacht. Corinna Kirchhoff Wolfgang Böck. Robert Schupp.

Nicolette Krebitz Oliver Broumis Mark Waschke Robert Hunger-Bühler. Paul Faßnacht. Corinna Kirchhoff Wolfgang Böck. Robert Schupp. Nicolette Krebitz Oliver Broumis Mark Waschke Robert Hunger-Bühler. Paul Faßnacht. Corinna Kirchhoff Wolfgang Böck. Robert Schupp. Nicolette Krebitz Oliver Broumis Mark Waschke Robert Hunger-Bühler. Paul Faßnacht. Corinna Kirchhoff Wolfgang Böck. Robert Schupp. Herzentoter movie. muzhchin/muzhskaja-odezhda/verhnjaja-odezhda-2/kurtki-2/kurtka-s-oliver-2/ 2 1 % thegoodcorner.co+ruedi 1 %. Bertschy Olivier, lic. iur. von Känel Daniela, lic. iur. Otto Oliver, lic. iur. Meili Conny Bühler Marc Jenni Daniel Schröder Thomas 70 45

Since the s mortality declined in several developed countries as a consequence of decreased diagnosis of distant-stage disease and improved treatment Parkin et al.

In the European Union mortality for prostate cancer increased from to from These trends were mainly observed in the elderly and rates in the EU have remained stable for men below age 65 Levi et al.

The effect of the demographic shifts towards the elderly outweighs that of decreasing trends in mortality rates in the predictions of mortality towards Quinn et al.

For prostate cancer, which mainly involves the elderly, these trends will be important. Prostate Cancer Risk Factors Large clues on risk factors for prostate cancer are still to be found.

Notions on this subject are, however, important because they offer the possibility for primary prevention of the disease.

Prostate cancer is probably the result of a combination of factors. One of them is age. Pros- Vera Nelen tate cancer rates increase with age faster than many other cancers.

Although the incidence of clinical prostate cancer varies greatly around the world, this is not the case for histological cancer.

The age-specific incidence of histological cancer is the same in the United States and Japan, while clinical incidence differs largely.

These data suggest that the initiation of prostate cancer is the same around the world, and related to age. Differences between countries exist in progression to clinical cancer, which is related to other risk factors.

Migration from low-risk to high-risk areas in the world evokes a marked increase in incidence in these populations and supports this theory.

Prostate cancer incidence in Chinese and Japanese men respectively rose from 1. Other risk factors include genetic factors.

African Americans have higher incidence rates than white Americans of similar education and socioeconomic background Baquet et al.

Environmental risk factors in the widest sense were suggested: cigarette smoking, alcohol consumption, cadmium exposure, occupation, infectious agents, ionising radiation, ultraviolet light, physical activity, body mass index and dietary factors Stanford et al.

Most arguments are found for the relation with dietary fat. High intake of dietary fat seems to be related to a higher risk for prostate cancer Sonn et al.

Phyto-oestrogens, present in a soy-rich diet, have been associated with a decreased risk of prostate cancer.

The low incidence in Asian countries may partly be explained by effects of a low animal fat and a soy-rich diet Denis et al.

Positive effects of other dietary factors such as vitamins, minerals and anti-oxidants were suggested but need 1 Epidemiology of Prostate Cancer further confirmation Sonn et al.

Molecular mechanisms implicated in inflammation of the prostate may provoke adverse cell proliferation and play a role in carcinogenesis Naber et al.

One study found that the risk of prostate cancer increased with the lifetime number of female sexual partners and with prior infection with gonorrhoea, supporting the influence of infectious agents Rosenblatt et al.

Studies have shown that prostate cancer is more frequent in regions with less exposure to sunlight. This may be in agreement with vitamin D being protective against cancer Hanchette and Schwartz ; Polek and Weigel Several studies report the interaction of endogenous hormones and prostate cancer.

Higher levels of serum testosterone are associated with an increased risk of prostate cancer Parsons et al.

Altered androgynous hormone metabolism may be the cause of the evolution of histological to clinical prostate cancer.

Oestrogens are also believed to play a role in the regulatory mechanisms of molecular growth in the prostate. The steroid hormone system is a complex regulatory system that is influenced by genetic mechanisms as well as environmental influences such as dietary fat, phyto-oestrogens, vitamins and smoking and plays a role in inflammation.

Other hormones, such as the insulin-like growth factor IGF family, have also been described in the regulation of physiological and pathological processes in the prostate and may play a role in prostate cancer development Gennigens et al.

The involvement of endogenous hormones would explain why unravelling the risk factors that interact with the development of prostate cancer has been so difficult Naber et al.

Conclusion Clues, derived from risk factors, for primary prevention of prostate cancer remain to be found.

Final level arguments, effect on mortality, for the use of screening in the prevention of pros- 7 tate cancer are expected from the large randomised screening trials to be completed in the near future.

Meanwhile prostate cancer remains a large and, through evolutions in incidence and demography, growing health problem.

Evidence for a protective effect of ultraviolet radiation. Int J Cancer. Part I: International comparisons. Proceedings of the 2nd International Consultation on Prostate Cancer.

Bethesda: National Cancer Institute. Between these cells and the final secretory cells, different intermediate or transit cells can be observed, and every one of them can evolve into malignant cells, explaining the biological variability of prostatic cancer.

The exact changes between normal gland and prostatic intraepithelial neoplasia PIN are not yet known, but a post-inflammatory atrophy lesion is being studied in this respect.

The PIN lesion is considered the pre-invasive change of prostatic cancer and its presence in needle biopsy is clinically used for follow-up of the patient.

Introduction Prostate cancer is a glandular malignant neoplasia adenocarcinoma , mostly of secretory or luminal cells. According to the current notion, the origin of such neoplasia is not to be searched for in the secretory cells that are final differentiation cells that will disappear after serving their purpose but in the precursor or stem cells with secretory differentiation.

This hypothesis hierarchical or stem cell model [1] opposes the theory that all neoplastic cells may be tumour-initiating cells stochastic model , but some isolated evidence exists that questions the hierarchical model [2].

Morphological and Molecular Structure of Normal Prostate Glands The histological structure of acini and ducts is identical, probably because the prostate is a sparsely secreting gland, whereas the whole of it should be secretory.

The cells that form the gland are arranged in two layers, basal and luminal Fig. The cells of the basal layer basal cells have little cytoplasm and show no microscopic differences between each other.

Most of them have growth factor receptors of the growth factors produced by the stromal prostate cells, they lack androgen receptors and they express Bcl These cells are considered the stem cells.

A small sub-population of these cells have androgen receptors, which has suggested the possibility that transit intermediate amplifying cells bearing stem cell characteristics exist, but the sensitivity to androgen enable them to differentiate to luminal cells secretory cells , with androgen receptors in all of them [3].

This model is probably an over-simplistic definition of basal and luminal compartments, since the currently existing immunohistochemical tests are capable of stratifying the transit intermediate amplifying cells in early progenitors of intermediate stem cells CK5 and CK18 positive, c-met positive, without androgen receptors , as well as in late progenitors of intermediate stem cells K5 negative, CK18 with irregular expression, c-met positive and irregular expression of androgenic receptors [4] Fig.

Basal and luminal cells Fig. Every one of these cells can be the final differentiation of the prostate cancer, and for this reason the prostate cancer has different phenotypes Molecular Definition of Tumoural Stem Cells of the Prostate The problem that arises in the prostate cancer stem cell model is identifying which cells are the target of carcinogenics.

It is possible that the early and late progenitors of the intermediate stem cells, rather than the stem cells themselves, justify the heterogeneity of prostate cancer, both regarding the expression of androgen receptors and the phenotypic characteristics [4].

It is quite difficult to recognise them using the classical methods, and they present with a differential phenotype with high clonogenicity and therapeutic resistances [5] Fig.

Pre-malignant Changes of Prostate Glands The exact changes between a normal gland and a neoplastic one are not yet known.

There is increasing evidence that predisposing genetic factors, oxidative damage and dietary or environmental factors may play a role in this step of the neoplastic transformation [6].

Very recent observations correlate phagocytic inflammatory cells and cancer with the release of oxygen- and ni- trogen-based radicals.

Together with dietary factors, this leads to oxidative stress and causes cell injury and regeneration with potential expansion of early or late progenitor intermediate cells [7].

The above-mentioned observations have suggested that gland dilatations with flattening of the secretory epithelium, previously considered secretory cell atrophy unrelated to the hormonal status Fig.

Together, these factors have led to high-grade PIN being considered the most likely precursor of prostatic carcinoma.

Even though the patterns often merge with each other, the possibility of a progressive transformation of the flat pattern into a micropapillary one and a cribriform one is a tempting thought.

All of these observations have been the reason why some authors consider the possibility that some of these changes indicate an intraductal carcinoma [21].

This notion, however, was rejected by consensus on many occasions owing to lack of reproducible criteria. Another feature to be highlighted is the interrelation between HGPIN and the initial invasive carcinoma.

Molecular Pathology of Stromal Invasion in Prostate Cancer Stromal invasion requires cellular detachment, basal membrane degradation and the ability of the cells to grow in a stromal environment.

Amongst these, E-cadherin and N-cadherin play the leading roles. It is expressed in the prostatic normal secreting cells. N-cadherin is coded at 18q The loss of E-cadherin seems to play quite an important role in the invasive ability of prostate carcinoma Fig.

This loss of expression of E-cadherin is accompanied by a progressive N-cadherin expression, which in turn evolves from a membrane pattern towards a dotted pattern, with intermediate stages of co-expression of both cadherins in a same cell [25].

These changes correlate with the progressive glandular pattern loss Gleason model. The progressive appearance of N-cadherin in the prostate cancer cell membrane brings about a mesenchymal-like transformation of the malignant cells [27], as if such mimesis favoured the metastatic ability by means of adherence to the stromal cells.

We may thus consider E-cadherin a tumoursuppressing gene, and its cellular recovery could have great significance as a treatment of cancer, which looks possible [26, 28].

The loss of cell-stromal adhesion is associated with loss of hemidesmosome-forming proteins and related adhesive molecules as integrins [29].

Such independence requires a false message to the nucleus that the cell is properly attached when actually it is not; this message is probably sent by the malignant cell with expression of laminin and collagen receptors through the synthesis of the basal membrane material [31].

Gleason Grading System of Prostate Cancer as a Model of Evolution When the carcinoma becomes invasive, its aggressiveness increases with the increase of genetic chromosomal changes, evaluable through the changes of the nuclear matrix increased size, contour abnormalities and nuclear chromatin irregularity.

All of these changes are included within the notion of nuclear degree of differentiation; however, because the nuclear matrix, the cytoplasmatic filaments and the intercellular adhesion molecules are closely inter-related, the above-mentioned nuclear changes may also be expressed by means of changes in the architectural arrangement of the neoplastic cells [32].

In prostate cancer the most widely internationally accepted grading model is the Gleason score [33] based on the progressive loss of the gland pattern and the increased peritumoural stroma invasion Fig.

This grading system can be considered a model of the invasive prostate cancer progress, since close relationship has been shown with the progressive loss of E-cadherin expression, and also the abnormal expression of other adhesion molecules [34].

These findings are concurrent with those published by other authors, who found the average Gleason score of the tumours of the transition area to be 5, whereas those of the peripheral area are 7, and they correlate to indicators of lower cell activity and lower aggressiveness in the tumours of the transition area than in those of the peripheral area Mib1-Ki67 expression in 1.

The reason for these differences is unknown. One possible explanation could be the existence of different precursory lesions at each of the areas.

We should remember that the transition area is the one that develops benign prostate hyperplasia, and so the carcinomas in this area coincide with hyperplasia changes.

There has been some speculation that certain forms of microglandular hyperplasia with atypia atypical adenomatous hyperplasia, AAH may play a role as cancer precursors [36].

Molecular Pathology of Prostate Cancer Progression In prostate cancer, progression does not only mean distant metastases but also the hormone independence of its cells hormone refractory prostate cancer.

Metastasis For a long time bone metastasis preference of prostate cancer was thought to be caused by a retrograde flow from the Batson plexus into the pelvic area during the Valsalva manoeuvre, but currently other metastatic factors are considered more important.

Other metastasis-associated genes are: KAI1 11p Nm23H1 and CD44 are less solid factors [42]. Hormone-Refractory Prostate Cancer The lack of response to hormone blockade may be due to many causes.

The stem cell model, discussed above, explains the possibility that, according to the transformed cell being either the early or the late intermediate cell, the tumour may be less or more sensitive, respectively, to anti-androgen therapy [4].

Likewise, the extensive and multifocal neuroendocrine differentiation of prostate adenocarcinoma may represent a different path to androgen independence because these cells can maintain cell proliferation through a paracrine androgen-independent pathway [43].

Another explanation for hormone therapy resistance is the multifocality and heterogeneity of prostate carcinomas.

Amplification of 8q24 through c-myc amplification? It is possible as well to find androgen receptor mutations leading to oestrogen sensitivity, and also overexpression of non-androgenic steroid androgen receptor coactivators [47, 48].

Bcl-2 could also play a role in the hormonal independence mechanism because it is more frequent in these tumours than in hormone-sensitive neoplasias [49].

All of them are able to induce a series or morphological variations that modify the characteristics of prostate cancer and make their interpretation difficult when biopsy specimens are taken.

Hormone therapy causes progressive atrophy of cells with hormone receptors luminal or secretory cells , be them neoplastic or not, leading to an atrophic aspect of the whole glandular structure, with special emphasis on the basal cells.

Treatments with radiation therapy, either external beam radiotherapy or brachytherapy, induce variations similar to those of hormone therapy, but with far more prominent nuclear atypia Fig.

In view of all these variations, particularly those that modify the gland structure, recommendation has been issued not to evaluate the degree of differentiation Gleason model as we do not know the biological significance of such models after treatment [56].

Clinical Application of the Pathological Natural History of Prostate Cancer The body of observations commented upon above is useful as an introduction to understanding the natural history of prostate cancer; however, not 20 Fig.

The PIA lesion may represent an interesting preventive therapy target, provided it is shown to be a usual step between a normal gland and intra-epithelial neoplasia, and particularly if an efficacious anti-inflammatory treatment without side-effects is attained.

Furthermore, adhesion molecules enable us to know the dynamics of invasion and metastasis, but we still do not have the methods that allow us to affect progression.

But the most common clinical factor still associated with prognosis is the stage or level of ex- 21 tension of the carcinoma.

This confirms that tumour volume remains quite reliable in terms of prognostic value the incidence of lymph node metastases is the same in T1b tumours, i.

For this reason, one of the primary roles of the pathologist is to determine extension T stage.

As a refinement of local extension evaluation, microvascular invasion can be an important marker.

Intraprostatic peri- Fig. The neuroendocrine differentiation somewhat implies a poor prognosis, and in some cases it explains hormone independence [64], probably through the correlation with vascular endothelial growth factor VEGF and transforming growth factor TGF -alpha angiogenic factors [65], and the absence of androgenic receptors.

From all of the above we may conclude that currently we are in front of the identification of a series of molecular markers, some of which may be of prognostic and therapeutic use.

To date, the refinement in grade and stage evaluation, as well as hormone sensitivity determination, are the most widely used methods to identify and assess the severity of prostate cancer.

References 1. Prostate cancer. Putzi MJ, De Marzo AM Morphologic transitions between proliferativo inflammatory atrophy and high-grade prostatic intraepithelial neoplasia.

Postma R, Schroder FH, van der Kwast TH Atrophy in prostate needle biopsy cores and its relationship to prostate cancer incidence in screened men.

Montironi R, Mazzucchelli R, Algaba F, et al Morphological identification of the patterns of Prostatic intraepithelial Neoplasia and their importance.

Wilcox G, Soh S, Chakraborty S, Scardino PT, et al Patterns of high-grade prostatic intraepithelial neoplasia associated with clinically aggressive prostate cancer.

Weinstein MH Digital image analysis of proliferativo index: two distinct populations of high grade Prostatic intraepithelial Neoplasia in close proximity to adenocarcinoma of the prostate.

Bonkhoff H, Remberger K Morphogenic concepts of normal and abnormal growth in the human prostate. Bonkhoff H, Wenert N, Dhom G, et al Distribution of basement membranes in primary and metastatic carcinomas of the prostate.

Erbersdobler A, Fritz H, Schnoger S, et al Tumour grade, proliferation, apoptosis, microvessel density, p53, and bcl-2 in prostate cancers: differences between tumours located in the transition zone and in the peripheral zone.

Algaba F, Trias I Diagnostic limits in precursor lesions of prostatic cancer. Isaacs JT Molecular markers for prostate cancer metastasis.

Am J Clin Pathol. Nupponen N, Visakorpi T Molecular biology of progression of prostate cancer.

J Urol Montironi R, Scarpelli M, Lopez Beltran A Carcinoma of the prostate: inherited susceptibility, somatic gene defects and androgen receptors.

Isaacs JT The biology of hormone refractory prostate cancer Why does it develop? Gaudin PB, Zelefsky MJ, Leibel SA, et al Histopathologic effects of three-dimensional conformal external beam radiation therapy on benign and malignant prostate tissues.

Results for patients. Sebo TJ, Bock BJ, Cheville JC, et al The percent of cores positive for cancer in prostate needle biopsy specimens is strongly predictive of tumor stage and volume at radical prostatectomy.

Algaba F, Arce Y, Oliver A, et al Prognostic parameters other than Gleason score for the daily evaluation of prostate cancer in needle biopsy.

Bahnson RR, Dresner SM, Gooding W, et al Incidence and prognostic significance of lymphatic and vascular invasion in radical prostatectomy specimens.

Egan AJM, Bostwick DG Prediction of extraprostatic extension of prostate cancer based on needle biopsy findings: perineural invasion lacks independent significance.

Today the effort has shifted to cure the disease. Since the twentieth century, the word prognosis has also been used in nonmedical contexts, for example in corporate finance or elections.

The most accurate form of prognosis is achieved statistically. Based on different prognostic factors it should be possible to tell patients how they are expected to do after prostate cancer has been diagnosed and how different treatments may change this outcome.

A prognosis is a prediction. In the nineteenth century this was the main goal of medicine: diagnose the disease and achieve a satisfying prognosis of the patient's chances.

Today the effort has shifted towards seeking a cure. Prognostic factors are not only essential to understand the natural history and the course of the disease, but also to predict possible different outcomes of different treatments or perhaps no treatment at all.

This is extremely important in a disease like prostate cancer where there is clear evidence that a substantial number of cases discovered by prostatespecific antigen PSA testing are unlikely ever to become clinically significant, not to mention mortal [3].

Furthermore, prognostic factors are of paramount importance for correct interpretation of clinical trials and for the construction of future trials.

Finally, according to WHO national screening committee criteria for implementing a national screening programme, widely accepted prognostic factors must be defined before assessing screening [4].

Not surprisingly, the post radical prostatectomy RP margin status is also a very strong independent prognostic factor [6].

TNM stage, PSA, Gleason score and post prostatectomy margin status are strong, independent and tumour-related prognostic factors. Serum PSA level should be obtained, and depending on the risk category Table 3.

In patients with low risk of metastases the imaging studies are not mandatory, although one might have them done anyway, perhaps to obtain reference documents to compare with possible later positive studies in a given patient.

Standard treatment approaches for localized and locally advanced disease include active monitoring, RP, brachytherapy, external beam radiotherapy EBRT , hormone therapy or a combination of EBRT and hormones depending on the tumour and patient characteristics.

Estimated life expectancy is an important factor in determining whether local treatment should be utilized in management. Randomized clinical trials have shown the efficacy of adjunctive hormonal therapy in patients with high-risk disease treated with radiation therapy.

In metastatic disease hormonal therapy is the mainstay of treatment and chemotherapy has recently been shown to prolong survival in patients with hormone refractory disease [1].

Anatomical Extent of Disease The local extent of disease in the prostate has been demonstrated in multiple studies to be an independent marker of prognosis in prostate cancer [5].

Other methods include magnetic resonance imaging MRI with endorectal coil, ProstaScint Cytogen, Princeton [8] and positron emission tomography [9].

Each is being evaluated, but to date the results are inconclusive. The volume of the tumour itself does not seem to provide much useful prognostic information [10].

Certainly in the choice for brachytherapy and sometimes also for RP, the total prostate volume may be restrictive and then also becomes a prognostic factor.

Pretreatment N and M categories can be assessed by cross-sectional and skeletal imaging. The sensitivity of both investigations depends on serum PSA and Gleason score.

Low PSA values and Gleason scores are rarely associated with extraprostatic disease and in many countries the imaging studies are not performed when the odds are low.

In Europe, increasing numbers of centres no longer perform bone scans in asymptomatic patients with PSA levels below The presence and extent of pelvic lymph node disease correlates clearly with outcome [11].

In more advanced disease, increased tumour involvement on bone scan or visceral organs is of prognostic importance [12]. Histology The histological tumour grade plays a key role in predicting progression and overall survival.

Over the past two decades the Gleason system has become the preferred pathological grading system for prostate cancer [13].

Studies by Albertsen et al. The second study states that aggressive treatment is not recommended for low-grade localized prostate cancer.

Other histopathological factors such as DNA ploidy, microvascularization, perineural invasion and the percentage of positive cores on needle biopsy have been assessed and confronted with the outcome.

Only the percentage of positive cores has been shown to be of independent prognostic significance in one study [17].

In another study both the number of positive biopsy sites and the highest percentage of adenocarcinoma at any biopsy site were significant predictors of small volume cancer in RP specimens [18].

Lymphovascular invasion, identified on the RP specimen, is an independent predictor of PSA relapse and cancer specific survival [19].

New histological assays are currently under investigation. PSA variables have been proposed in order to increase its sensitivity to diagnose localized disease.

These have met with limited success, with the possible exception of the measurement of percentage of free PSA. The prediction of the behaviour of prostate cancer with gene expression transcript profiles looks promising but has to be validated in upcoming clinical trials.

It is appreciated as an independent prognostic factor, both at diagnosis and relapse, either for localized or advanced disease [21, 22].

But as PSA is not cancer specific, one must be somewhat cautious, especially with lower PSA values in the early stages of the disease.

A recent study found that PSA was only weakly associated with prostate cancer volumes in men treated with RP [23].

However, it is helpful to predict the risk of marginally positive disease at RP in conjunction with their T-stage and the Gleason score [24, 25].

In men with clinically localized disease selected for RP, PSA is Although age is a well-known prognostic factor for survival in prostate cancer in general, there is considerable controversy regarding its effect on outcome in patients with localized disease [34].

The controversy is highest in older patients. Life expectancy is a much better parameter in this situation. In more advanced disease older age at presentation and poor performance status are adverse prognostic features [12].

The presence of significant co-morbidity has a definite impact on outcome both in early and advanced stages [35]. Race Race is also a well-known risk factor for developing prostate cancer, but surprisingly this disease also behaves differently in men of different races.

Whether this is due to patient-related factors or to external factors is not clear yet. A study from Dayal et al. One should first check the true incidence of prostate cancer in both groups, define the stage distributions and compare the treatments offered to the patients.

Meanwhile, it has been shown that in more educated populations a majority of even the elderly patients with low-risk prostate cancer receive some form of treatment [38].

It is clear that access to quality care, possibly influenced by socio-economics but also by demography and national health-care politics, has an important impact on prognosis.

This is especially applicable in early disease, where the ability to achieve free surgical margins or to propose appropriate radiation has shown to be of significance [39, 40].

In the first paper [39], Eastham et al. Combined Prognostic Factors The obvious way to improve the usefulness of prognostic factors is to combine them.

Today nomograms like the Partin tables [25], for the prediction of the pathological stage, the margin status and possible lymph node involvement based on the biopsy Gleason score, the clinical stage and the PSA, are widely used in everyday urological Johan Braeckman, Dirk Michielsen practice.

In the late s Kattan et al. They found that the components of the nomogram were not significant, but still useful in helping to direct adjuvant therapy.

Recently Kattan et al. In the future, much is expected from artificial neural networks that may be useful for simultaneous incorporation of the many different prognostic variables associated with prostate cancer [50].

In localized disease, low-, intermediate- and high-risk groupings have been proposed based upon these factors Table 3. The groupings have been shown to predict for prostate cancer specific mortality [6].

The widespread introduction of PSA screening in many counties caused an important diagnostic shift towards early stage, low-risk prostate cancer.

It is clear that more and refined prognostic factors are necessary in order to select the proper patients for the proper treatments.

Recent collaborative initiatives addressed this issue in an attempt to categorize different prognostic factors. Proliferation markers and apoptosis Nuclear morphometry and karyometric analysis Androgen receptors Neuroendocrine markers Genetic markers All other factors that do not appear in categories I and II 29 CAP , seven international conferences were at least partly organized with that intent [52].

The most recent meeting of the WHO in Paris classified the prognostic factors [53] as category I factors that have been proved to be prognostic or predictive based on evidence from multiple published trails and that are recommended for routine screening , category II factors that show promise as predictive factors based on evidence from multiple published studies but that require further evaluation before recommendation or are recommended despite incomplete data as diagnostic or prognostic markers and category III factors awaiting further study to clarify their value in the prognostic arena.

The selected factors are listed in Table 3. The benefit of any treatment with curative intent in patients with localized low- and intermediate-risk disease remains controversial and is being addressed in ongoing trials.

A refinement of prognostic factors for disease progression will be critical in resolving this therapeutic dilemma. In high-risk disease and advanced disease, the role and the timing of adjunctive treatment to improve progression-free and overall survival need to be evaluated.

Ongoing and future trials should not only focus on the therapeutic outcomes but also on the identification of more useful prognostic factors to tell us which patient needs which treatment at what time.

The health provider can also be a prognostic factor. This was already hinted at when we mentioned the relation between the skills of the surgeon performing a RP and the chance of margin-free disease.

But it is clear that optimal guide counselling and commitment of treatment should only be done by people who know their business. Health Publications, Paris 2.

Wilson JM Principles and practice of screening for diseases. World Health Organization, Geneva 5. Picchio M, Messa C, Landoni C, et al Value of C choline positron emission tomography for re-staging prostate cancer : a comparison with F fluorodeoxyglucose positron emission tomography.

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A contemporary approach. Lippincott, Williams and Wilkins, Philadelphia Cheng L, Poulos CK, Pan C, et al Preoperative prediction of small volume cancer less than 0,5 ml in radical prostatectomy specimens.

Fossa SD, Paus E, Lindegaard M, et al Prostate-specific antigen and other prognostic factors in patients with hormone-resistant prostate cancer undergoing experimental treatment.

Moul JW Angiogenesis, p53, bcl-2 and Ki in the progression of prostate cancer after radial prostatectomy. Eastham JA, Kattan MW, Riedel E, et al Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens.

Gleason DF, Mellinger GT The veterans administration cooperative urological research group: prediction of prognosis for prostatic carcinoma by combined histological grading and clinical staging.

A multi-institutional update. JAMA J Clin Oncol Kattan MW, Potters L, Blasko JC, et al Pretreatment nomograms for predicting freedom from recurrence after permanent prostate brachytherapy in prostate cancer.

Urology Rubin MA Using molecular markers to predict outcome. Kattan MW, Shariat SF, Andrews B, et al The addition of interleukine-6 soluble receptor and transforming growth factor beta 1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer.

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Prostate cancer has become a major healthcare problem worldwide, as life expectancy increases. This review provides a simple overview of the endocrinology of prostate cancer and discusses some of the pharmaceutical agents that have been or are being tested to restrain, possibly arrest, the progression of this slowly growing cancer.

Also discussed are many of the dietary factors that may influence the molecular or endocrine events implicated in its development. Dietary factors are considered responsible for the geographical differences in prostate cancer incidence and mortality.

Until recently the concept that dietary variability could influence the pathogenesis of cancer was considered with scepticism, but now interest centres on whether worldwide variability is caused by dietary factors such as the high intake of fat in the West, or prevented by particular constituents of the Asian diet.

Many constituents could impinge on the molecular events implicated in prostate carcinogenesis to provide health benefit [3, 4], and interest in chemoprevention has increased spectacularly.

The Natural History of Prostate Cancer Prostate cancer is a disease of middle-aged men which presents clinically beyond 50 years of age and involves a slowly growing tumour that takes Some Introductory Perspectives The concept that prostate cancer is preventable is by no means new.

Questions posed by Huggins [1] at one of the earliest meetings to specifically discuss the biology of the gland are still relevant. He highlighted certain unresolved problems Fig.

The disease is prev- Fig. Once outside the confines of the capsule, the disease is incurable. Its natural history is characterised by a year development phase, followed by a year preclinical, asymptomatic period.

Secondary prevention through early diagnosis using serum prostate-specific antigen PSA analysis and prostate biopsy has dramatically increased incidence rates during the preclinical period, creating interest in population screening.

The results of international randomised screening trials are awaited [11]. Particularly important, however, is that the preclinical period offers the potential for primary chemoprevention, which will probably not prevent initiation but certainly could suppress the rate of cancer growth and progression.

The natural history highlights phases where preventive strategies can be focussed. Since this enhanced oestrogenic status is considered responsible for the stromal hyperplasia characteristic of BPH, it is not unreasonable to consider that oestrogens may also be implicated in the molecular events that support cancer progression [9, 12, 27, 30].

Pragmatically, of all the reported risk factors, nutrition presents the most reasonable means of rationalising the global variability of the disease.

Of interest are studies [31] of Asian migrants to North America; within two generations they assume an incidence closer to that of indigenous males Fig.

Moreover, as Asians acquire Western dietary habits, changes in cancer incidence must be monitored [32, 33]. Mitchell Philip Eng Philip E.

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A small sub-population of these cells have androgen receptors, which has suggested the possibility that transit intermediate amplifying cells bearing stem cell characteristics exist, but the sensitivity to androgen enable them to differentiate to luminal cells secretory cells , with androgen receptors in all of them [3].

This model is probably an over-simplistic definition of basal and luminal compartments, since the currently existing immunohistochemical tests are capable of stratifying the transit intermediate amplifying cells in early progenitors of intermediate stem cells CK5 and CK18 positive, c-met positive, without androgen receptors , as well as in late progenitors of intermediate stem cells K5 negative, CK18 with irregular expression, c-met positive and irregular expression of androgenic receptors [4] Fig.

Basal and luminal cells Fig. Every one of these cells can be the final differentiation of the prostate cancer, and for this reason the prostate cancer has different phenotypes Molecular Definition of Tumoural Stem Cells of the Prostate The problem that arises in the prostate cancer stem cell model is identifying which cells are the target of carcinogenics.

It is possible that the early and late progenitors of the intermediate stem cells, rather than the stem cells themselves, justify the heterogeneity of prostate cancer, both regarding the expression of androgen receptors and the phenotypic characteristics [4].

It is quite difficult to recognise them using the classical methods, and they present with a differential phenotype with high clonogenicity and therapeutic resistances [5] Fig.

Pre-malignant Changes of Prostate Glands The exact changes between a normal gland and a neoplastic one are not yet known.

There is increasing evidence that predisposing genetic factors, oxidative damage and dietary or environmental factors may play a role in this step of the neoplastic transformation [6].

Very recent observations correlate phagocytic inflammatory cells and cancer with the release of oxygen- and ni- trogen-based radicals.

Together with dietary factors, this leads to oxidative stress and causes cell injury and regeneration with potential expansion of early or late progenitor intermediate cells [7].

The above-mentioned observations have suggested that gland dilatations with flattening of the secretory epithelium, previously considered secretory cell atrophy unrelated to the hormonal status Fig.

Together, these factors have led to high-grade PIN being considered the most likely precursor of prostatic carcinoma. Even though the patterns often merge with each other, the possibility of a progressive transformation of the flat pattern into a micropapillary one and a cribriform one is a tempting thought.

All of these observations have been the reason why some authors consider the possibility that some of these changes indicate an intraductal carcinoma [21].

This notion, however, was rejected by consensus on many occasions owing to lack of reproducible criteria.

Another feature to be highlighted is the interrelation between HGPIN and the initial invasive carcinoma.

Molecular Pathology of Stromal Invasion in Prostate Cancer Stromal invasion requires cellular detachment, basal membrane degradation and the ability of the cells to grow in a stromal environment.

Amongst these, E-cadherin and N-cadherin play the leading roles. It is expressed in the prostatic normal secreting cells. N-cadherin is coded at 18q The loss of E-cadherin seems to play quite an important role in the invasive ability of prostate carcinoma Fig.

This loss of expression of E-cadherin is accompanied by a progressive N-cadherin expression, which in turn evolves from a membrane pattern towards a dotted pattern, with intermediate stages of co-expression of both cadherins in a same cell [25].

These changes correlate with the progressive glandular pattern loss Gleason model. The progressive appearance of N-cadherin in the prostate cancer cell membrane brings about a mesenchymal-like transformation of the malignant cells [27], as if such mimesis favoured the metastatic ability by means of adherence to the stromal cells.

We may thus consider E-cadherin a tumoursuppressing gene, and its cellular recovery could have great significance as a treatment of cancer, which looks possible [26, 28].

The loss of cell-stromal adhesion is associated with loss of hemidesmosome-forming proteins and related adhesive molecules as integrins [29].

Such independence requires a false message to the nucleus that the cell is properly attached when actually it is not; this message is probably sent by the malignant cell with expression of laminin and collagen receptors through the synthesis of the basal membrane material [31].

Gleason Grading System of Prostate Cancer as a Model of Evolution When the carcinoma becomes invasive, its aggressiveness increases with the increase of genetic chromosomal changes, evaluable through the changes of the nuclear matrix increased size, contour abnormalities and nuclear chromatin irregularity.

All of these changes are included within the notion of nuclear degree of differentiation; however, because the nuclear matrix, the cytoplasmatic filaments and the intercellular adhesion molecules are closely inter-related, the above-mentioned nuclear changes may also be expressed by means of changes in the architectural arrangement of the neoplastic cells [32].

In prostate cancer the most widely internationally accepted grading model is the Gleason score [33] based on the progressive loss of the gland pattern and the increased peritumoural stroma invasion Fig.

This grading system can be considered a model of the invasive prostate cancer progress, since close relationship has been shown with the progressive loss of E-cadherin expression, and also the abnormal expression of other adhesion molecules [34].

These findings are concurrent with those published by other authors, who found the average Gleason score of the tumours of the transition area to be 5, whereas those of the peripheral area are 7, and they correlate to indicators of lower cell activity and lower aggressiveness in the tumours of the transition area than in those of the peripheral area Mib1-Ki67 expression in 1.

The reason for these differences is unknown. One possible explanation could be the existence of different precursory lesions at each of the areas.

We should remember that the transition area is the one that develops benign prostate hyperplasia, and so the carcinomas in this area coincide with hyperplasia changes.

There has been some speculation that certain forms of microglandular hyperplasia with atypia atypical adenomatous hyperplasia, AAH may play a role as cancer precursors [36].

Molecular Pathology of Prostate Cancer Progression In prostate cancer, progression does not only mean distant metastases but also the hormone independence of its cells hormone refractory prostate cancer.

Metastasis For a long time bone metastasis preference of prostate cancer was thought to be caused by a retrograde flow from the Batson plexus into the pelvic area during the Valsalva manoeuvre, but currently other metastatic factors are considered more important.

Other metastasis-associated genes are: KAI1 11p Nm23H1 and CD44 are less solid factors [42].

Hormone-Refractory Prostate Cancer The lack of response to hormone blockade may be due to many causes. The stem cell model, discussed above, explains the possibility that, according to the transformed cell being either the early or the late intermediate cell, the tumour may be less or more sensitive, respectively, to anti-androgen therapy [4].

Likewise, the extensive and multifocal neuroendocrine differentiation of prostate adenocarcinoma may represent a different path to androgen independence because these cells can maintain cell proliferation through a paracrine androgen-independent pathway [43].

Another explanation for hormone therapy resistance is the multifocality and heterogeneity of prostate carcinomas. Amplification of 8q24 through c-myc amplification?

It is possible as well to find androgen receptor mutations leading to oestrogen sensitivity, and also overexpression of non-androgenic steroid androgen receptor coactivators [47, 48].

Bcl-2 could also play a role in the hormonal independence mechanism because it is more frequent in these tumours than in hormone-sensitive neoplasias [49].

All of them are able to induce a series or morphological variations that modify the characteristics of prostate cancer and make their interpretation difficult when biopsy specimens are taken.

Hormone therapy causes progressive atrophy of cells with hormone receptors luminal or secretory cells , be them neoplastic or not, leading to an atrophic aspect of the whole glandular structure, with special emphasis on the basal cells.

Treatments with radiation therapy, either external beam radiotherapy or brachytherapy, induce variations similar to those of hormone therapy, but with far more prominent nuclear atypia Fig.

In view of all these variations, particularly those that modify the gland structure, recommendation has been issued not to evaluate the degree of differentiation Gleason model as we do not know the biological significance of such models after treatment [56].

Clinical Application of the Pathological Natural History of Prostate Cancer The body of observations commented upon above is useful as an introduction to understanding the natural history of prostate cancer; however, not 20 Fig.

The PIA lesion may represent an interesting preventive therapy target, provided it is shown to be a usual step between a normal gland and intra-epithelial neoplasia, and particularly if an efficacious anti-inflammatory treatment without side-effects is attained.

Furthermore, adhesion molecules enable us to know the dynamics of invasion and metastasis, but we still do not have the methods that allow us to affect progression.

But the most common clinical factor still associated with prognosis is the stage or level of ex- 21 tension of the carcinoma. This confirms that tumour volume remains quite reliable in terms of prognostic value the incidence of lymph node metastases is the same in T1b tumours, i.

For this reason, one of the primary roles of the pathologist is to determine extension T stage. As a refinement of local extension evaluation, microvascular invasion can be an important marker.

Intraprostatic peri- Fig. The neuroendocrine differentiation somewhat implies a poor prognosis, and in some cases it explains hormone independence [64], probably through the correlation with vascular endothelial growth factor VEGF and transforming growth factor TGF -alpha angiogenic factors [65], and the absence of androgenic receptors.

From all of the above we may conclude that currently we are in front of the identification of a series of molecular markers, some of which may be of prognostic and therapeutic use.

To date, the refinement in grade and stage evaluation, as well as hormone sensitivity determination, are the most widely used methods to identify and assess the severity of prostate cancer.

References 1. Prostate cancer. Putzi MJ, De Marzo AM Morphologic transitions between proliferativo inflammatory atrophy and high-grade prostatic intraepithelial neoplasia.

Postma R, Schroder FH, van der Kwast TH Atrophy in prostate needle biopsy cores and its relationship to prostate cancer incidence in screened men.

Montironi R, Mazzucchelli R, Algaba F, et al Morphological identification of the patterns of Prostatic intraepithelial Neoplasia and their importance.

Wilcox G, Soh S, Chakraborty S, Scardino PT, et al Patterns of high-grade prostatic intraepithelial neoplasia associated with clinically aggressive prostate cancer.

Weinstein MH Digital image analysis of proliferativo index: two distinct populations of high grade Prostatic intraepithelial Neoplasia in close proximity to adenocarcinoma of the prostate.

Bonkhoff H, Remberger K Morphogenic concepts of normal and abnormal growth in the human prostate. Bonkhoff H, Wenert N, Dhom G, et al Distribution of basement membranes in primary and metastatic carcinomas of the prostate.

Erbersdobler A, Fritz H, Schnoger S, et al Tumour grade, proliferation, apoptosis, microvessel density, p53, and bcl-2 in prostate cancers: differences between tumours located in the transition zone and in the peripheral zone.

Algaba F, Trias I Diagnostic limits in precursor lesions of prostatic cancer. Isaacs JT Molecular markers for prostate cancer metastasis.

Am J Clin Pathol. Nupponen N, Visakorpi T Molecular biology of progression of prostate cancer. J Urol Montironi R, Scarpelli M, Lopez Beltran A Carcinoma of the prostate: inherited susceptibility, somatic gene defects and androgen receptors.

Isaacs JT The biology of hormone refractory prostate cancer Why does it develop? Gaudin PB, Zelefsky MJ, Leibel SA, et al Histopathologic effects of three-dimensional conformal external beam radiation therapy on benign and malignant prostate tissues.

Results for patients. Sebo TJ, Bock BJ, Cheville JC, et al The percent of cores positive for cancer in prostate needle biopsy specimens is strongly predictive of tumor stage and volume at radical prostatectomy.

Algaba F, Arce Y, Oliver A, et al Prognostic parameters other than Gleason score for the daily evaluation of prostate cancer in needle biopsy.

Bahnson RR, Dresner SM, Gooding W, et al Incidence and prognostic significance of lymphatic and vascular invasion in radical prostatectomy specimens.

Egan AJM, Bostwick DG Prediction of extraprostatic extension of prostate cancer based on needle biopsy findings: perineural invasion lacks independent significance.

Today the effort has shifted to cure the disease. Since the twentieth century, the word prognosis has also been used in nonmedical contexts, for example in corporate finance or elections.

The most accurate form of prognosis is achieved statistically. Based on different prognostic factors it should be possible to tell patients how they are expected to do after prostate cancer has been diagnosed and how different treatments may change this outcome.

A prognosis is a prediction. In the nineteenth century this was the main goal of medicine: diagnose the disease and achieve a satisfying prognosis of the patient's chances.

Today the effort has shifted towards seeking a cure. Prognostic factors are not only essential to understand the natural history and the course of the disease, but also to predict possible different outcomes of different treatments or perhaps no treatment at all.

This is extremely important in a disease like prostate cancer where there is clear evidence that a substantial number of cases discovered by prostatespecific antigen PSA testing are unlikely ever to become clinically significant, not to mention mortal [3].

Furthermore, prognostic factors are of paramount importance for correct interpretation of clinical trials and for the construction of future trials.

Finally, according to WHO national screening committee criteria for implementing a national screening programme, widely accepted prognostic factors must be defined before assessing screening [4].

Not surprisingly, the post radical prostatectomy RP margin status is also a very strong independent prognostic factor [6].

TNM stage, PSA, Gleason score and post prostatectomy margin status are strong, independent and tumour-related prognostic factors.

Serum PSA level should be obtained, and depending on the risk category Table 3. In patients with low risk of metastases the imaging studies are not mandatory, although one might have them done anyway, perhaps to obtain reference documents to compare with possible later positive studies in a given patient.

Standard treatment approaches for localized and locally advanced disease include active monitoring, RP, brachytherapy, external beam radiotherapy EBRT , hormone therapy or a combination of EBRT and hormones depending on the tumour and patient characteristics.

Estimated life expectancy is an important factor in determining whether local treatment should be utilized in management. Randomized clinical trials have shown the efficacy of adjunctive hormonal therapy in patients with high-risk disease treated with radiation therapy.

In metastatic disease hormonal therapy is the mainstay of treatment and chemotherapy has recently been shown to prolong survival in patients with hormone refractory disease [1].

Anatomical Extent of Disease The local extent of disease in the prostate has been demonstrated in multiple studies to be an independent marker of prognosis in prostate cancer [5].

Other methods include magnetic resonance imaging MRI with endorectal coil, ProstaScint Cytogen, Princeton [8] and positron emission tomography [9].

Each is being evaluated, but to date the results are inconclusive. The volume of the tumour itself does not seem to provide much useful prognostic information [10].

Certainly in the choice for brachytherapy and sometimes also for RP, the total prostate volume may be restrictive and then also becomes a prognostic factor.

Pretreatment N and M categories can be assessed by cross-sectional and skeletal imaging. The sensitivity of both investigations depends on serum PSA and Gleason score.

Low PSA values and Gleason scores are rarely associated with extraprostatic disease and in many countries the imaging studies are not performed when the odds are low.

In Europe, increasing numbers of centres no longer perform bone scans in asymptomatic patients with PSA levels below The presence and extent of pelvic lymph node disease correlates clearly with outcome [11].

In more advanced disease, increased tumour involvement on bone scan or visceral organs is of prognostic importance [12]. Histology The histological tumour grade plays a key role in predicting progression and overall survival.

Over the past two decades the Gleason system has become the preferred pathological grading system for prostate cancer [13].

Studies by Albertsen et al. The second study states that aggressive treatment is not recommended for low-grade localized prostate cancer.

Other histopathological factors such as DNA ploidy, microvascularization, perineural invasion and the percentage of positive cores on needle biopsy have been assessed and confronted with the outcome.

Only the percentage of positive cores has been shown to be of independent prognostic significance in one study [17]. In another study both the number of positive biopsy sites and the highest percentage of adenocarcinoma at any biopsy site were significant predictors of small volume cancer in RP specimens [18].

Lymphovascular invasion, identified on the RP specimen, is an independent predictor of PSA relapse and cancer specific survival [19].

New histological assays are currently under investigation. PSA variables have been proposed in order to increase its sensitivity to diagnose localized disease.

These have met with limited success, with the possible exception of the measurement of percentage of free PSA.

The prediction of the behaviour of prostate cancer with gene expression transcript profiles looks promising but has to be validated in upcoming clinical trials.

It is appreciated as an independent prognostic factor, both at diagnosis and relapse, either for localized or advanced disease [21, 22].

But as PSA is not cancer specific, one must be somewhat cautious, especially with lower PSA values in the early stages of the disease.

A recent study found that PSA was only weakly associated with prostate cancer volumes in men treated with RP [23].

However, it is helpful to predict the risk of marginally positive disease at RP in conjunction with their T-stage and the Gleason score [24, 25].

In men with clinically localized disease selected for RP, PSA is Although age is a well-known prognostic factor for survival in prostate cancer in general, there is considerable controversy regarding its effect on outcome in patients with localized disease [34].

The controversy is highest in older patients. Life expectancy is a much better parameter in this situation. In more advanced disease older age at presentation and poor performance status are adverse prognostic features [12].

The presence of significant co-morbidity has a definite impact on outcome both in early and advanced stages [35].

Race Race is also a well-known risk factor for developing prostate cancer, but surprisingly this disease also behaves differently in men of different races.

Whether this is due to patient-related factors or to external factors is not clear yet. A study from Dayal et al. One should first check the true incidence of prostate cancer in both groups, define the stage distributions and compare the treatments offered to the patients.

Meanwhile, it has been shown that in more educated populations a majority of even the elderly patients with low-risk prostate cancer receive some form of treatment [38].

It is clear that access to quality care, possibly influenced by socio-economics but also by demography and national health-care politics, has an important impact on prognosis.

This is especially applicable in early disease, where the ability to achieve free surgical margins or to propose appropriate radiation has shown to be of significance [39, 40].

In the first paper [39], Eastham et al. Combined Prognostic Factors The obvious way to improve the usefulness of prognostic factors is to combine them.

Today nomograms like the Partin tables [25], for the prediction of the pathological stage, the margin status and possible lymph node involvement based on the biopsy Gleason score, the clinical stage and the PSA, are widely used in everyday urological Johan Braeckman, Dirk Michielsen practice.

In the late s Kattan et al. They found that the components of the nomogram were not significant, but still useful in helping to direct adjuvant therapy.

Recently Kattan et al. In the future, much is expected from artificial neural networks that may be useful for simultaneous incorporation of the many different prognostic variables associated with prostate cancer [50].

In localized disease, low-, intermediate- and high-risk groupings have been proposed based upon these factors Table 3. The groupings have been shown to predict for prostate cancer specific mortality [6].

The widespread introduction of PSA screening in many counties caused an important diagnostic shift towards early stage, low-risk prostate cancer.

It is clear that more and refined prognostic factors are necessary in order to select the proper patients for the proper treatments. Recent collaborative initiatives addressed this issue in an attempt to categorize different prognostic factors.

Proliferation markers and apoptosis Nuclear morphometry and karyometric analysis Androgen receptors Neuroendocrine markers Genetic markers All other factors that do not appear in categories I and II 29 CAP , seven international conferences were at least partly organized with that intent [52].

The most recent meeting of the WHO in Paris classified the prognostic factors [53] as category I factors that have been proved to be prognostic or predictive based on evidence from multiple published trails and that are recommended for routine screening , category II factors that show promise as predictive factors based on evidence from multiple published studies but that require further evaluation before recommendation or are recommended despite incomplete data as diagnostic or prognostic markers and category III factors awaiting further study to clarify their value in the prognostic arena.

The selected factors are listed in Table 3. The benefit of any treatment with curative intent in patients with localized low- and intermediate-risk disease remains controversial and is being addressed in ongoing trials.

A refinement of prognostic factors for disease progression will be critical in resolving this therapeutic dilemma.

In high-risk disease and advanced disease, the role and the timing of adjunctive treatment to improve progression-free and overall survival need to be evaluated.

Ongoing and future trials should not only focus on the therapeutic outcomes but also on the identification of more useful prognostic factors to tell us which patient needs which treatment at what time.

The health provider can also be a prognostic factor. This was already hinted at when we mentioned the relation between the skills of the surgeon performing a RP and the chance of margin-free disease.

But it is clear that optimal guide counselling and commitment of treatment should only be done by people who know their business. Health Publications, Paris 2.

Wilson JM Principles and practice of screening for diseases. World Health Organization, Geneva 5. Picchio M, Messa C, Landoni C, et al Value of C choline positron emission tomography for re-staging prostate cancer : a comparison with F fluorodeoxyglucose positron emission tomography.

Daneshmand S, Ouek ML, Stein JP, et al Prognosis of patients with lymph node positive prostate cancer following radical prostatectomy: long-term results.

Amin M, Boccon-Gibod L, Egevad L, et al Prognostic and predictive factors and reporting of prostate carcinoma in prostate needle biopsy specimens.

A contemporary approach. Lippincott, Williams and Wilkins, Philadelphia Cheng L, Poulos CK, Pan C, et al Preoperative prediction of small volume cancer less than 0,5 ml in radical prostatectomy specimens.

Fossa SD, Paus E, Lindegaard M, et al Prostate-specific antigen and other prognostic factors in patients with hormone-resistant prostate cancer undergoing experimental treatment.

Moul JW Angiogenesis, p53, bcl-2 and Ki in the progression of prostate cancer after radial prostatectomy.

Eastham JA, Kattan MW, Riedel E, et al Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens.

Gleason DF, Mellinger GT The veterans administration cooperative urological research group: prediction of prognosis for prostatic carcinoma by combined histological grading and clinical staging.

A multi-institutional update. JAMA J Clin Oncol Kattan MW, Potters L, Blasko JC, et al Pretreatment nomograms for predicting freedom from recurrence after permanent prostate brachytherapy in prostate cancer.

Urology Rubin MA Using molecular markers to predict outcome. Kattan MW, Shariat SF, Andrews B, et al The addition of interleukine-6 soluble receptor and transforming growth factor beta 1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer.

Srigley JR, Mahul A, Boccon-Gibod L, et al Prognostic and predictive factors in prostate cancer: histological perspectives and recent international consensus initiatives.

Prostate cancer has become a major healthcare problem worldwide, as life expectancy increases. This review provides a simple overview of the endocrinology of prostate cancer and discusses some of the pharmaceutical agents that have been or are being tested to restrain, possibly arrest, the progression of this slowly growing cancer.

Also discussed are many of the dietary factors that may influence the molecular or endocrine events implicated in its development.

Dietary factors are considered responsible for the geographical differences in prostate cancer incidence and mortality. Until recently the concept that dietary variability could influence the pathogenesis of cancer was considered with scepticism, but now interest centres on whether worldwide variability is caused by dietary factors such as the high intake of fat in the West, or prevented by particular constituents of the Asian diet.

Many constituents could impinge on the molecular events implicated in prostate carcinogenesis to provide health benefit [3, 4], and interest in chemoprevention has increased spectacularly.

The Natural History of Prostate Cancer Prostate cancer is a disease of middle-aged men which presents clinically beyond 50 years of age and involves a slowly growing tumour that takes Some Introductory Perspectives The concept that prostate cancer is preventable is by no means new.

Questions posed by Huggins [1] at one of the earliest meetings to specifically discuss the biology of the gland are still relevant. He highlighted certain unresolved problems Fig.

The disease is prev- Fig. Once outside the confines of the capsule, the disease is incurable.

Its natural history is characterised by a year development phase, followed by a year preclinical, asymptomatic period. Secondary prevention through early diagnosis using serum prostate-specific antigen PSA analysis and prostate biopsy has dramatically increased incidence rates during the preclinical period, creating interest in population screening.

The results of international randomised screening trials are awaited [11]. Particularly important, however, is that the preclinical period offers the potential for primary chemoprevention, which will probably not prevent initiation but certainly could suppress the rate of cancer growth and progression.

The natural history highlights phases where preventive strategies can be focussed. Since this enhanced oestrogenic status is considered responsible for the stromal hyperplasia characteristic of BPH, it is not unreasonable to consider that oestrogens may also be implicated in the molecular events that support cancer progression [9, 12, 27, 30].

Pragmatically, of all the reported risk factors, nutrition presents the most reasonable means of rationalising the global variability of the disease.

Of interest are studies [31] of Asian migrants to North America; within two generations they assume an incidence closer to that of indigenous males Fig.

Moreover, as Asians acquire Western dietary habits, changes in cancer incidence must be monitored [32, 33].

Already in Japan a rising prostate cancer incidence [35] is seen to relate to a rising intake of dietary fat.

Prostate cancer is a major health-care problem, now exacerbated by increasing life expectancy worldwide. Preventive strategies are being considered [34, 35, 36] through reviews of closed and on-going trials of various dietary and hormonal factors that were established to assess efficacy and associated adverse effects.

Few of these have been completed and analysed. Some Dietary Factors for Chemoprevention Isoflavonoids and Lignans Phyto-oestrogens, certain isoflavonoids and lignans offer an exciting approach to prevention [3, 4].

They are bioactive Fig. The presence of non-steroidal oestrogens in plants has long been known, with legumes such as soybean, lentils, beans and chickpeas being major sources of isoflavonoids [40].

These foodstuffs contain glycoside conjugates of 36 Keith Griffiths et al. The formation of equol from daidzein is illustrated, together with reported biological effects and structural relationships with oestrogens 4 The Prevention of Prostate Cancer genistein and daidzein, which are metabolised by normal gut microflora to produce the isoflavonoids.

Soybean is a dietary staple in Asia, and many traditional diets of India, Africa, Mediterranean countries, and South America have a similar high legume content.

The intake of legumes has fallen in Western countries over the last century [41]. Plant lignans, matairesinol and secoisolariciresinol, are similarly metabolised to produce enterolactone and enterodiol, which are also oestrogenic [4].

Flaxseed is a rich source of lignans, as are other seeds such as sesame and whole grain cereals like rye, fruits, berries and vegetables.

Although their oestrogenic properties could influence prostate cancer progression, they also demonstrate an imposing array of other biological effects [4, 9].

Enterolactone concentrations are high in urine of vegetarians [42], and interestingly, substantial amounts are found in expressed prostatic 37 fluid of Portuguese men [43].

The plasma isoflavonoid content in Japan is high [44] relative to levels in the United Kingdom Fig. Daily supplementation with a cereal bar containing the soy protein appropriate to the daily Japanese intake shows the rapid elevation of plasma concentrations of genistein and daidzein compared to those consistently sustained by Asian people Fig.

Flavonoids Certain health benefits of polyphenolic flavonoids have also been known for a long time.

Unlike the isoflavonoids, however, flavonoids are ubiquitous in nature and their influence on health could be profound.

Their complex chemistry is well studied [45, 46] and Fig. Onions are a source of apigenin, apples of quercetin, Fig. The levels of these isoflavonoids in Japanese subjects are illustrated for comparison green tea of catechins and various anthocyanidins and resveratrol are constituents of red wine.

In ancient times, herbs and spices were synonymous with medicines, including the well-recognized thyme and parsley, garlic and chives and the cruciferous vegetables [47].

Cinnamon may suppress inflammatory disease. Curcumin, the yellow pigment of turmeric, as well as capsaicin in chilli pepper, are reported [48] to have cancerrestraining activity.

Others exercise a range of biological actions, such as the inhibition of angiogenesis or promotion of apoptosis [50, 51]. An inhibitory effect on various experimental tumours was reported 40 Keith Griffiths et al.

Flavonoids have a 2-phenylchroman nucleus, and isoflavonoids such as genistein have a 3-phenylchroman nucleus. Also illustrated are the structures of resveratrol, a constituent of red wine, and one of the catechins present in tea [54, 55], together with an ability to promote apoptosis in prostate cancer cell lines [56].

A recent study [57] indicated that men with a high long-term intake of selenium, as reflected in toenail paring levels, were at lower risk of developing prostate cancer.

More recently [58] a decreased incidence of prostate cancer was reported after selenium supplementation. More than 30, North American males are to be recruited, minimal age generally 55, but 50 for African-Americans, valuable therefore, in determining whether they effectively restrain progression to clinical cancer.

Vitamins Much of the epidemiological data relating to the cancer protective value of vitamin supplementation would seem somewhat equivocal.

Conversely, another review [61] of data on vitamins A, C and E, concluded that the association between vitamin C and breast cancer risk was limited, although a modest, protective effect of vitamin A was recognised.

Boyle [63, 64] emphasised caution in accepting conclusions derived from such studies, outlining the need for controlled trials before, for example, vitamin supplementation should be recommended as protective against breast cancer.

The data Fig. Vitamin E had no effect on lung cancer risk. Recent interest has centred on lycopene Fig. Uncooked tomatoes are a less effective source.

Lycopene is another effective anti-oxidant [66, 67], with a recent analysis of anti-oxidants in biopsies of adipose tissue showing [68] it to be the principal constituent.

It restrains the growth of cultured cancer cells [69], possibly by inhibition of IGF-signalling networks [70].

Tomato powder, as distinct from purified lycopene, increased prostate cancer-specific survival, in N-methyl-N-nitrosourea-treated rats [71].

Giovannucci [72] considers that tomato intake 42 Keith Griffiths et al. Illustrated are the numbers of cases of prostate cancer, also seen in relation to the incidence values for cancers of lung and bladder consistently relates to a reduced risk of prostate cancer, which is inversely associated with plasma lycopene concentrations.

The influence of the carotenoids, vitamin A, retinoids and retinoic acid on prostate carcinogenesis would seem complex.

Although vitamin A supports normal cellular differentiation and controls proliferation, it has a limited influence on established cancer.

Various synthetic retinoid analogues have similar characteristics, and despite high toxicity are thought by some to offer anti-cancer properties [73].

Although it seems that vitamin A supplementation may increase the risk of prostate cancer [63, 64], Schroeder [76] reported a significant increased risk associated with a lower serum vitamin A levels.

Possibly relevant are the classical experiments of Lasnitski [77, 78], which demonstrated that methylcholanthrene-induced prostate epithelial hyperplasia was inhibited by retinoic acid as well as vitamin A.

Results of a chemopreventive study [71] of lycopene are also shown. The levels of 1,diOH-VitD3 in stored serum from these men were compared to controls, matched for age, race and for sample storage time.

Noteworthy, however, was that risk was associated only with palpable tumours, not incidental cancer, suggesting that any influence is confined to the later stages of tumour progression.

The skin, the only source of vitamin D3, is where 7-dehydrocholesterol is converted by solar UV irradiation to the provitamin D3.

Thermal isomerisation of provitamin D3 to vitamin D3, occurs in the epidermis from where it enters the blood.

It is hydroxylated at the C position in the liver and then, primarily in the kidney but also by keratinocytes, hydroxylated to 1,diOH-VitD3, the biologically active hormone, the biological effects of which are mediated [96] through VDR.

VDR is associated with enhanced apoptosis, increased expression of Bcl-2 and G1S cell cycle blockade in prostate cancer cell lines. In the USA, prostate cancer mortality is inversely proportional to UV-radiation [99], and in Finland, vitamin D deficiency similarly relates to UV-radiation and cancer.

Levels of plasma OH-VitD3, which have been falling during the past 25 years as prostate cancer incidence has increased, are markedly different between men in the rural north during winter than in the southern region.

The risk that relates to vitamin D deficiency is higher in pre-andropausal men than those over 50, suggesting a risk factor which implicates androgens.

Also illustrated are some effects of retinoic acid on the proliferation of various prostate cell lines in culture. Retinoic acid did not restrain the growth of the human prostate cancer cell lines PC3 and DU Data taken from the Tenovus Institute for Cancer Research [90] Hormonal Aspects of Prevention Prevention with dietary factors offers an exciting prospect, but an anti-hormonal approach is more pragmatic.

Such males did, however, develop acceptable secondary sex characteristics, reasonable libido and a phallus, characteristics promoted by testosterone.

The use of anti-androgens such as flutamide, bicalutamide or cyproterone acetate could offer benefit to men at high risk, but loss of potency, gynaecomastia, nausea and diarrhoea, are unwanted adverse features.

Quite rightly, trials have 46 been instigated [34, 35], although anti-androgen therapy cannot be perceived as an acceptable preventive approach to recommend, for example, to all African-American males over the age of 40, men who must by now believe themselves at risk.

The development of finasteride [, ], a 5AR inhibitor, provided an innovative approach to suppressing intraprostatic DHT levels without compromising sexuality.

Finasteride specifically inhibits 5AR2, whereas alternatives, dutasteride and epristeride, inhibit both 5AR1 and The Prostate Cancer Prevention Trial PCPT involved treating patients for 7 years with either finasteride 5 mg daily or placebo, followed by an end-point prostate biopsy.

Plasma testosterone levels are sustained. Rather than biopsy and its confounding problems, some believe the only acceptable end-points should be survival, metastasis-free survival or disease-specific survival, which is an expensive approach requiring more subjects and longer periods of study, but one that could possibly offer unequivocal results.

Second, there is the question as to whether such a trial should commence at an earlier age than Such issues have been considered recently [].

However, the greater prevalence of high-grade cancer in the finasteride group, with a Gleason score of 7 or more, tends to compromise any unequivocal recommendation regarding the clinical value of finasteride in preventive practise for men over The NCI-P trial, which is evaluating flutamide against the combination of flutamide and the anti-oestrogen toremifene, offers a new approach to preventive therapy.

Since oestrogens play a more significant role in prostate growth regulatory events than hitherto thought [7, 9, 27], the influence of an anti-oestrogen is awaited with interest.

Is There a Genetic Approach to Prevention Recognising the long preclinical phase in the natural history of prostate cancer, the identification of men with a genetic predisposition to develop the disease would clearly be beneficial.

Familial clustering [] and evidence that family history constitutes a greater risk suggests underlying predisposing factors. The search centred on point mutations, deletion or insertion of nucleotides within a gene sequence that result in aberrant messenger m RNA expression and thereby mutant proteins.

Decreased repeats from 24 to 18 relate to elevated AR transactivation activity and prostate cancer [, ], with the prevalence of shorter alleles highest in African-Americans and lowest in Asian men, reflecting the geographical variation in incidence.

Mutant ARs that inappropriately bind an array of ligands [] would seem rare in early prostate cancer, although prevalent in metastatic tissue.

Gene amplification, whereby substantial lengths of nucleotide sequences are copied, sometimes more than a fold, is a common feature of cancer.

If the sequence contains genes encoding for growth regulatory proteins, the effect could support cancer progression.

Gene deletion incurs cellular instability and restricted growth restraint; the loss of growth suppressor retinoblastoma Rb protein, for example, inevitably confers a growth advantage to the cancer cell.

Loss of a p53 gene, which encodes the protein that prevents a damaged cell entering the cell cycle until DNA repair is complete, is 4 The Prevention of Prostate Cancer generally an event related to the later refractory phases of the disease.

Many low-penetrance susceptibility genes, mapped to frequently deleted regions in prostate cancers, are concerned with androgen metabolism.

Genetic aberration of the SRD5A2 gene would influence the prostate, and mutations have been reported, with VL89 reducing enzyme activity, which is common in Asian men, whereas A49T relates to increased activity and poor prognosis [].

The latter mis-sense mutation is associated with a sevenfold greater risk of prostate cancer in African-American men.

Aberrations of the HSD17B2 gene, 16q Gene polymorphisms may identify men at risk, but also support the design of preventive strategies with shorter time-periods and lower costs.

Dietary Factors: Causative or Protective? Some Reflections on Obesity and Fat Intake Possibly of significance is that prostate cancer geographical variability is reflected in a similar pattern for cancers of breast, ovary and endometrium, for which oestrogens are risk factors.

Sound arguments support some degree of homology between breast and prostate cancers [27, ], and evidence has accumulated to suggest a major role for oestrogens in prostate growth control [9, 27, ].

Once again, geographical variability in incidence directs attention to Asian and Western lifestyles, issues outlined by Doll [] three decades ago, since when, after many retrospective and prospective investigations, the consensus viewpoint of three cancer agencies [] was, very simply, that the consumption of vegetables and fruit correlates with reduced risk.

The greater risk associated with red meat, primarily beef, thereby allowed governmental institutions to recommend frequent consumption of vegetables and fruit, with moderation in meat intake.

Broad recommendations, therefore, with the International Agency for Research on Cancer IARC suggest [] that there is little support, at present, for various supplementary cocktails of vitamins and minerals, although the results of the SELECT trial are eagerly anticipated.

The influence of dietary fat on cancer risk remains controversial. Some researchers have not been convinced [] that eating a low-fat diet supports a longer life.

Nonetheless, with greater fat intake in Japan, prostate cancer incidence increases [33]; whether this relates to a decreased consumption of soy protein, however, remains to be determined.

A range of prospective cohort studies on total dietary fat intake and prostate cancer risk [] failed to identify an unequivocal relationship, although a correlation with animal fat intake was recognised, a relationship believed by many to constitute the principal risk factor responsible for geographical variability.

Important, nonetheless, was that obesity did relate to a greater risk of dying from prostate cancer. Any link between risk and obesity, or increased body mass index BMI , does, however, remain controversial [].

Whereas a Norwegian study [] suggested a higher BMI increased risk, Giovannucci [] indicated the contrary. Treatment with an aromatase inhibitor is of clinical value in the management of breast cancer; interestingly, enterolactone, genistein and equol all inhibit the aromatase enzyme in vitro [9, ].

Possibly more important is the relationship of risk to obesity during puberty and the immediate post-pubertal years, with a report [] that adolescent obesity increased the risk of dying from prostate cancer.

Such a lifestyle would lead to elevated levels of androgens and IGF-I. Since the IGFnetwork supports proliferation and the progression of cells into the cell cycle Fig.

Prostate Cancer: A Multifactorial Process Prostate carcinogenesis is a multi-step process involving multiple interactive factors and endocrine, genetic and nutritional features that impact on growth regulatory events [6] that either support or restrain cancer progression through the continuum from initiation to the invasive phenotype.

Interruption of these events is the basis of prevention. Such a strategy using antihormonal drugs is clearly an important issue.

DHT is a predominant growth-promoting factor in prostate cancer development, and the PCPT trial provided evidence of a beneficial influence of finasteride therapy for part of a group of men treated beyond the age of A controversial issue centres on whether the decline in intraprostatic DHT triggers a compensatory expression of alternative, more aggressive growth-promoting signalling in the more progressive cancerous lesions that will be harboured by a proportion of such males, with the consequent development of high-grade cancer.

There is evidence that chronic, or recurrent intraprostatic inflammation, a feature of asymptomatic prostatitis and PIA, could be implicated in the early phases of prostate carcinogenesis [24, 25, 27].

Moreover, a study by Coffey [27], emphasising a role for isoflavonoids in the suppression of prostatic inflammation induced in rodents by inappropriate intrauterine oestrogen imprinting, highlights the need for trials of soy protein supplementation during the adolescent and post-pubertal years.

Certainly at the andropause, the phyto-oestrogens may well suppress progression of latent cancer to malignant disease, and trials with soy protein would seem appropriate.

Furthermore, soy protein supplements, as opposed to genistein alone, may be relevant, since it appears that only certain males can convert daidzein to equol Fig.

There is evidence that the presentation of a higher-grade prostate cancer is associated with an ability to produce equol. Moreover, infusion of green tea leaves with hot water liberates secoisolariciresinol and matairesinol, precursors of enterolactone.

The proanthocyanidins are more effective antioxidants than vitamins C and E, whereas resveratrol has anti-inflammatory properties and influences ER-signalling.

Statins, tocotrienols and limonene inhibit HMG-reductase. The mevalonic acid 6C-unit is the basic starter molecule of the cholesterol biosynthetic pathway, being converted first to the 5C-isopentyl pyrophosphate through two farnesyl units to lanosterol and then cholesterol study [] provides evidence that they inhibit the progression of HGPIN to clinical cancer.

A recent case control study in south-eastern China [] reports a significant correlation between green tea consumption and the risk of prostate cancer.

There is evidence [] that the tea polyphenols inhibit prostate cancer dissemination by repressing the PSA-triggered activation of matrix metalloproteinases that are concerned with fibronectin and laminin degradation and thereby support cancer cell invasion.

In passing, there is a notion [] that alcohol itself may promote the aromatisation of androgens. The isothiocyanates of cruciferous vegetables, constituents such as sulphoraphane, could also exercise some degree of protection against prostate cancer initiation, possessing the capacity to detoxify particular animal carcinogens such as the heterocyclic aromatic amines produced by the charring of red meat [27, ].

This is somewhat controversial, since risk appears to relate to the intake of red meat [10], despite such amines 4 The Prevention of Prostate Cancer 51 Fig.

Nevertheless, sulphoraphane promotes apoptosis, decreases cyclin B1 expression and induces G2M cell cycle arrest in human prostate cancer cell lines.

Although cancer was simply considered an imbalance between cell proliferation and cell death, more recently, failure of cancer cells to undergo apoptosis has become the major issue [, ].

There is no doubt that the statins decrease serum cholesterol and benefit those with cardiovascular problems, but can they decrease cancer risk?

HMGCoA reductase inhibition will suppress the synthesis of isoprenoid residues, thereby inhibiting isoprenylation of the p21 Ras protein, important for Ras GTP-ase signalling.

Isoprenyl- ation involves the transfer of either Cfarnesyl, or Cgeranylgeranyl isoprene residues to the pprotein, thereby increasing its lipophobic nature that enables GTPase to be anchored, then re-located within the cell membrane.

Ras mutations are a feature of prostate cancer, and repression of isoprenylation of the mutated p21 Ras protein provides growth control.

Transfection of this mutated protein into mouse fibroblasts in the presence of insulin and IGF-I results in transformation and enhanced cell proliferation.

Also interesting is that prenylflavonoids [] such as isopentenyl-naringenin act as oestrogen agonists. The less well known tocotrienols, natural analogues of tocopherol Fig.

Although the precise role of oestrogens within the prostate remains somewhat of a conundrum, they consistently feature in preventive strategies; indolecarbinol, for example, a constituent of cruciferous vegetables such as cabbage, cauliflower, Brussels sprouts and broccoli, influences the metabolism of 2- and hydroxylated oestrogens.

Indolecarbinol is a product of cruciferous vegetables. The indolecarbinol can prevent genotoxic agents from reaching their target site and, second, induce 2-hydroxylase enzyme systems Bradlow [] reports that hydroxylation relates to cancer initiation, whereas 2-hydroxylation is associated with suppression.

Indole-3carbinol induces the 2-hydroxylases Fig. They can be quite distinct, sometimes complementary, but often mutually antagonistic, with differing affinities with various oestrogens [37, 39], and prostate carcinogenesis will be influenced by the cellular specificity and content of ER-isoforms.

Can ge- 4 The Prevention of Prostate Cancer nistein suppress AR levels and thereby epithelial cell proliferation during the early male adult years?

Should year-olds undertake soy protein supplementation? Scientifically credible preventive measures must be inextricably linked to curative medicine, based on a precise understanding of the natural history of a disease.

Second, preventive strategies must be integrated into community screening programmes. As to whether nutritional factors can prevent initiation or extend the time to clinical disease remains to be proved.

Governmental agencies recommend the benefits of a diet rich in fruit and vegetables, a moderate red meat intake and regular exercise.

It is probably disappointing to mention this, but caution is indicated with regard to the efficacy of supplementation with specific dietary constituents on the basis that doseresponses and adverse effects are yet unknown, since few randomised controlled trials have been completed.

The medical community may also believe the preventive concept to be a little premature. Such trials are costly and finances are limited.

The concept that health gain can be derived from diet-related intervention initiatives, even if scientifically sound, could be difficult to finance.

Prevention must, however, be the keystone of medicine in the early decades of the twenty-first century, and discussion must centre on real costs, risks versus benefits of preventive strategies and whether it is a worldwide issue for the entire population, or merely appropriate for AfricanAmerican males, possibly Finns, who are recognised as high risk, or simply complementary to current practise in the management of clinical disease.

Such an approach is not in any way an alternative option to recognised clinical practice. If a preventive strategy could be offered to all men, however, only few would derive benefit, and any specific agent would have to be taken for a considerable period of time.

The use of tamoxifen as intervention therapy for breast cancer requires appropriate North American females to take the drug for a year to prevent one additional case [].

Compelling evidence suggests that isoflavonoids may well provide health benefit to Asian and other ethnic populations worldwide, either through the intake of soy protein by healthy, reproducing Asians, or of other legumes, by the people of India and South America.

A similar influence was recognised by Hirayama [] with regard to all cancers and lung cancer, with an impact even on those who smoked. There were , subjects studied Definitive evidence from controlled trials may not be available for many years, so is it reasonable to suggest that since humans appear not to be adversely affected by exposure to these phytooestrogens, that a greater intake of soybean, or legumes, could be specifically recommended?

A similar argument could prevail for the polyphenols of green tea. Undoubtedly, the importance of a properly balanced diet is now better appreciated by the general public, but any suggestion for the need for specific dietary change must be accompanied by readily assimilated science.

The signal-transduction pathways that convey such salutary messages to the man-in-the-street must be very professional and the information scientifically sound, with consideration given to the renowned inability of the public to reach a consensus on almost any subject.

Open dissent through the media tends to generate scepticism, upholding the view that scientists rarely agree on any such issues.

Sporn [] has most eloquently argued the need for intervention initiatives directed to the early phases of carcinogenesis.

Lots of vegetables and fruit can be recommended for men through their early years and possibly the three post-pubertal decades, but is this sufficient?

The health benefits of statins as effective primary pre- 55 ventive agents against stroke [] and for those with hypercholesterolaemia, or at even moderate risk of coronary or cerebrovascular problems, might support their inclusion in such a capsule.

All this may be facetious comment and, clearly, care is important []. The science is never simple. Moreover, a metaanalysis of 19 trials and , subjects suggested [] that a high vitamin E dose could enhance all-cause mortality.

A goody bag capsule offers a logical way forward. But does society require unequivocal science from expensive and time-consuming, randomised trials, before forms of intervention can be established that do not compromise the credibility of medical science?

Another recent review describes the compelling evidence that dietary nutrients may prevent the development and progression of prostate cancer, with a meta-analysis indicating that consumption of soy food was associated with a lower risk of prostate cancer.

The impact of intervention therapy on the ageing process and mortality, or premature death, could be profound; analysis is therefore necessary on the costs vs benefits of such strategies, which would change social structure.

Research into the impact of dietary constituents on disease processes must be encouraged and appropriate controlled intervention trials quickly established as finance becomes available.

Keith Griffiths et al. Acknowledgements 9. The authors would like to thank Mr. David Griffiths, CompGraphics Services, Cardiff, UK, for the kind use of the illustrations provided for this chapter on prevention of prostate cancer.

Huggins C Introduction. National Cancer Institute, U. Scientific Publications Adlercreutz H Western diet and Western diseases: some hormonal and biochemical mechanisms and associations.

In: J. Grayhack, J. Saherbenske eds Benign prostatic hyperplasia. Sakr WA Prostatic intraepithelial neoplasia: a marker for high-risk groups and a potential target for chemoprevention.

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