Prostata Study Analysis

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Treatment decisions after diagnosis of clinically localised prostate cancer are difficult due to variability in tumour behaviour. We therefore examined one of the Prostata Study Analysis promising biomarkers in prostate cancer, Ki, in a cohort of patients diagnosed with prostate cancer between and and treated conservatively.

Ki expression was assessed immunohistochemically, in two laboratories, by two different scoring methods and the results compared with cancer-specific and overall survival. The power of the biomarker was compared with Gleason score and initial serum prostate-specific antigen PSA. Ki is a powerful biomarker in localised prostate cancer and adds to a model predicting the need for radical or conservative therapy. As it is already in widespread use in routine pathology, it is confirmed as the most promising biomarker to be applied into routine practice.

In spite of extensive research, Prostata Study Analysis are very few molecular markers that have been translated Prostata Study Analysis routine use in clinical oncology. Any new Prostata Study Analysis must give further predictive ability beyond that available by using current known, easily measured parameters, and Prostata Study Analysis data must differentiate patients into groups for Prostata Study Analysis different treatment Prostata Study Analysis can be selected.

Biomarker measurement for purely prognostic information has limited Prostata Study Analysis unless it indicates different treatment options. In no area of oncology are new biomarkers more urgently required than in prostate cancer.

The most appropriate treatment for clinically localised prostate Prostata Study Analysis is still unknown. Treatment options vary from radical surgery Bott et alor radiotherapy Parker and Dearnaley, to hormonal treatment alone, or simply active surveillance and watchful waiting Albertsen et al; Parker et al Patients must choose, with little scientific rationale, between these wildly contrasting treatments.

Screening for prostate cancer in the United States has caused an almost doubling incidence, whereas mortality has remained relatively stable McDavid et al Radical treatments have the advantage of a high cure rate. However, this comes with the potential of serious long-term morbidity from sexual dysfunction or incontinence. Although Gleason score and serum PSA have been shown to be strong predictors of prognosis in early prostate cancer, much remains to be done to improve predictions.

The search for biomarkers that can add to the knowledge provided by the known markers is therefore Prostata Study Analysis high importance in future as a guide to therapy. Prostata Study Analysis Ki protein is well known and widely used to assess the tumour proliferation rate.

It is one of the several cell-cycle-regulating proteins, which can be demonstrated by immunohistochemistry Gerdes et al It is a DNA-binding protein that is expressed in all phases of cell cycle but undetectable in resting cells Gerdes et although strangely its function is yet to be clearly elucidated.

Numerous studies have shown Ki to be a prognostic marker in prostate cancer treated by radical prostatectomy, but none in a large conservatively treated cohort of prostate cancers with long-term follow-up in which clear relative risk values can be calculated. Our hypothesis was that measurement of Ki in Prostata Study Analysis a well-defined cohort could provide prognostic information that supplemented the currently known indicators of prognosis Prostata Study Analysis prostate cancer.

The detailed methods of cohort assembly have been described in an earlier paper Cuzick et al In Prostata Study Analysis, men were included in this study if they were under 76 years of age at diagnosis and had clinically localised prostate cancer diagnosed between January and December Patients who had a radical prostatectomy or radiation therapy within 6 months of diagnosis, or clear evidence of metastatic disease by bone scan, X-ray, CT scan, MRI, bone biopsy, lymph node biopsy or pelvic lymph node dissection or clinical indications of metastatic disease including pathologic fracture, soft tissue metastasis, spinal compression Prostata Study Analysis bone pain at or within 6 months of diagnosis, were excluded.

Eligibility was established by review of patient records by registry data-collection officers and trained medical staff. Clinical staging was centrally reviewed. All patients had centralised Gleason grading by Prostata Study Analysis panel of genitourinary pathologists and had initial diagnostic serum PSA available.

Blocks from the trans-urethral resection specimens, which were available, were identified and the corresponding haematoxylin and eosin sections marked for cancerous areas. These were microarrayed in a series of Prostata Study Analysis blocks using 0. Four cores were taken from different areas of tumour to account for tumour heterogeneity in each case, and areas of adjacent normal tissue were also sampled.

These are immunohistochemical markers of prostatic basal cells and are absent in areas of prostatic carcinoma. Normal tonsil was used as a positive control where a high proliferation is seen in germinal centres. A percentage was derived using the number of Kipositive cells as the numerator and the total number of malignant cells invasive carcinoma as the denominator.

In common with other microarray studies, the maximal staining from the sampled cores for Prostata Study Analysis case was Prostata Study Analysis. The results were analysed by dichotomous, grouped and continuous variables and compared with overall and prostate cancer-specific survival. A total of eligible cases were included on the tissue microarray. Their derivation is described in Figure 1. Ki staining results were analysed for both the semi-quantitative and quantitative Prostata Study Analysis.

Analysis included Prostata Study Analysis cancerous cores, corresponding to cases. Characteristics of the cohort are given in Table 1. The mean Ki score was 5. Results were similar to those reported for the total cohort. Significance was maintained whether the results were analysed as a continuous variable or as groups Table 1 ; Figure 3A and B.

A Prostata Study Analysis fully quantitative method assessed by counting cells AG and WG did not improve the predictive value Table 1. A and B Prostate cancer survival and overall survival as predicted by four groups of Ki score.

The three strongest variables, Gleason score, baseline PSA and extent of disease, were included in a multivariate model together with Ki Again, the use of a more fully quantitative method was not better than the semi-quantitative method reported in this table details not shown. ERG—ETV1 rearrangement status has been shown to be an important predictor for prostate cancer cause-specific survival.

Thousands of patients undergo radical treatment for prostate cancer every year in Europe and the United States. Many of these patients will have curative and beneficial treatment. However, a significant number of these patients have treatment unnecessarily as their tumours will not progress before death from another cause. They may suffer unnecessary morbidity from their surgery. The greatest uncertainties in managing prostate cancer are around the identification of which cancers are of clinical significance and over the choice of radical treatment, and in which settings they are appropriate.

With the diagnosis of prostate cancer being made more frequently in asymptomatic men, it is of growing importance to know which of these men are likely to benefit from aggressive treatment. Numerous studies have shown Ki to be a prognostic indicator in various stages of prostate cancer. However, to our knowledge, there are no studies conducted on a large conservatively treated cohort with Prostata Study Analysis data, where decisions on future treatment could be indicated, and a very recent paper Laurila et alsuggested that Prostata Study Analysis studies are needed to show the final outcome of proliferative activity in patients with watchful waiting.

Since the initial studies showing the utility and feasibility of immunochemistry on paraffin-embedded formalin-fixed urological material Fontana et al, Ki was shown to be an interesting marker in prostate cancer at an early stage Oomens et al; McLoughlin et al It has been investigated on TURP material Feneley et al, biopsy material Szende et al; Cowen Prostata Study Analysis al; Ojea et aland radical prostatectomy series Bettencourt et al; Moul, ; Zudaire Bergera et al; Inoue et alin large screening programmes Laurila et aland after radiation therapy Li et al Some of these show that Ki is an independent predictor of outcome on multivariate analysis Pollack et al This is the largest series to date with marker analysis and one that utilises the currently used prognostic biomarkers of serum PSA and Gleason score.

This is of great relevance as all of these cancers were treated conservatively at diagnosis, and therefore the Ki score would have given further information on recurrence risk and enhanced the decision making process of radical vs conservative management. Our earlier papers on this cohort have shown the discriminatory value of revised Gleason score and serum PSA at predicting tumour behaviour Cuzick et al; Kattan et al; Eastham et al Ki has a number of advantages as a biomarker.

First, it is widely used by academic and non-academic Histopathology departments, which have the ability to perform immunochemistry, and is used as an adjunct to Prostata Study Analysis and management in a number of other Prostata Study Analysis.

This study shows that semi-quantitative methodologies may produce as much information as more Prostata Study Analysis methods that may not be possible for the average laboratory. However, such assessments can be difficult with small amounts of formalin-fixed material, and the recent discovery of complex rearrangements within single glands raises problems with tumour heterogeneity Clark et Prostata Study Analysis These techniques are not available in most hospitals, and need careful assessment.

Tumour tissue from the prostate is very difficult to identify macroscopically, and therefore assessment in this manner remains by far the simplest technique by which tissue biomarker assessment is likely to become widespread in the assessment of prostatic malignancy.

From a biological point of view, Prostata Study Analysis use Prostata Study Analysis a proliferation marker is also an adjunct to existing methods. Although many grading systems for cancers include mitotic count in the calculation of grade such as the Nottingham method for assessing grade in breast carcinomathe Gleason grading system is purely pattern based.

Therefore, this may be a reason why the estimation Prostata Study Analysis proliferation index appears such Prostata Study Analysis powerful independent predictor of tumour behaviour. The other cardinal advantage of this cohort is the length of follow-up and the use of both cause-specific and overall death outcomes. The natural history of prostate cancer means that such long-term assessments are essential for the validation of new biomarkers. A number of limitations of the study have to be noted.

First, Prostata Study Analysis is a retrospective cohort study dealing with prostate cancer diagnosis, as it was in the s rather than it is presently. Most patients would have presented symptomatically, and the vast increase in prostate cancer diagnosis in the past 20 years is undoubtedly due to an increase in PSA screening. However, in all countries, prostate cancer diagnosis continues to be unscientific in its basis.

Screening is unproven and instituted in relatively Prostata Study Analysis centres. Health-care Prostata Study Analysis in the United States vary from intense screening, with a high cancer detection of clinically insignificant tumours in centres of excellence, to more symptom-based treatments in the disadvantaged parts of the population.

In the United Kingdom, there has been an increase in requests for PSA testing, but many men are only tested after complaining of urinary symptoms. Thus, despite an increase in public health awareness Prostata Study Analysis prostate cancer, the disease is detected by Prostata Study Analysis variety of methods, and we have moved from one unscientifically proven model to another, which is equally unproven. Screening, although popular politically, is not evidence based in prostate cancer.

Hardly one criterion for screening assessment is fulfilled by prostate cancer. The medical community is therefore left with offering patients a variety of drastically different treatments, with no evidence base.

However, the major difference between this study and current practice is that it is an assessment of TURP material only. As biopsy diagnosis of prostate cancer is far more common, especially in developed countries, it could be argued that this study does not represent modern detection methods.

Interestingly, the method of diagnosis had no significant difference on outcome in our cohort Cuzick et al, and Gleason profiles of both limbs were comparable. The assessment of Ki on the biopsy material, which forms the second half of this cohort, is planned to further validate these data, as well as computer-based assessments of Ki index, to attempt validation of systems that can be used in different laboratories.

Despite intense interest, no biomarker is currently routinely utilised for the assessment of the degree of aggressiveness of prostate cancer. We have shown that Ki is Prostata Study Analysis interesting candidate for the routine assessment of suitability for active surveillance treatments and that this Prostata Study Analysis needs to be confirmed in biopsy material.

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