The Prostate. Supplement最新文献

Background: Our objective was to compare expected survival benefits when screening for prostate cancer with PSA, using an age-specific bound relative to a cutoff of 4.0 ng/ml.

Methods: We used a decision analysis modeling the cancer yield in a cohort screened by both screening tests, and the survival of cancer cases given screen detection and in the absence of screening. Expected cancer yields and positive predictive values were from an ultrasound-guided biopsy series. Stage distributions of screen-detected cases were obtained from the literature. For localized causes, survival given screen detection was assumed to be equal to normal life expectancy for the population. For these cases, survival in the absence of screening was modeled as time from clinical diagnosis to death added to time remaining after time of screen and before clinical diagnosis was made (lead time). For nonlocalized cases at screen detection, survival given screen detection was assumed to be equal to survival in the absence of screening. The average difference between expected survival with and without screening as calculated for age-specific PSA and for PSA > 4.0 ng/ml and compared.

Results: Average years of life saved per subject screened using PSA > 4.0 ng/ml were comparable to those using the age-specific bound. Average years of life saved per cancer case, however, appeared to be potentially greater for PSA > 4.0 ng/ml than for age-specific. PSA. PSA > 4.0 ng/ml detected markedly more prostate cancer cases than age-specific PSA.

Conclusions: Using a bound of 4.0 ng/ml for all ages appears to be more efficient in identifying men with cancer in a screening cohort, which translates into a greater expected survival benefit per cancer case.

Background: The total prostate-specific antigen (t-PSA) in serum measured by PSA assays represents the sum of free (f-PSA) and PSA complexed with alpha 1-antichymotrypsin. The f-PSA/t-PSA (F/T) ratio in prostate cancer (PCA) patients is lower than in patients suffering from benign prostatic hyperplasia (BPH). This review summarizes the current literature on the clinical relevance of measurement of the F/T PSA ratio.

Methods: Discussed are: physiology of PSA, assays for t-PSA and F/T ratio, factors which bias the F/T PSA ratio, use of F/T PSA ratio in the detection of PCA, correlation with histological features, and pathological stage.

Results: Using the F/T ratio in the intermediate t-PSA range, a reduction of approximately 30% in biopsies can be accomplished in the detection of prostate cancer.

Conclusions: The F/T PSA ratio could become a valuable tool in the differentiation of BPH from PCA. To accomplish this goal, an international standardization not only for the t-PSA measurement but also for the F/T PSA ratio must be a priority for manufacturers of PSA assays.

The availability of numerous different assays for the determination of prostate-specific antigen (PSA) has created substantial problems in the interpretation of PSA concentrations. Currently over 60 assays are commercially offered on the European market. The majority of the recently marketed assays are based on the commonly used reference range (< 4 ng/ml), although this rarely has been verified. Some manufacturers avoid specifying the range altogether, while others derive the data from very small collectives. Reference ranges established with sera of young males or even with an unspecified proportion of sera of females are not suitable for assessing the specificity of PSA assays for detecting prostate cancer among males older than age 50 years. Most manufacturers recommend that their assays not be used for diagnostic purposes but only for following up patients previously diagnosed with prostate cancer. Usually the physician remains unaware of this warning as well as of the name of the assay used. Since PSA concentrations may vary in identical samples by a factor of two depending on the assay used, the clinician in charge of interpreting the results needs to be aware of the method used and must have detailed information on the assay-specific reference range.

Prostate cancer has become one of the most important national health problems, as its incidence increases yearly. Conventionally, single-modality local therapy has been the standard of care for clinically localized stage disease and systemic therapy, in the form of primary or combined androgen deprivation, is reserved for advanced, usually metastatic, prostate cancer. Despite improvements in local therapy, a significant number of patients with clinically localized prostate cancer will suffer a systemic relapse after potentially curative local therapy and, despite 50 years of experience in hormone therapy, significant survival prolongation for patients with metastatic prostate cancer remains a challenge. This paper explores potential future systemic therapy strategies in the treatment of prostate cancer. Specifically, the role of adjuvant systemic therapy as part of a multimodality treatment approach for localized prostate cancer and alternative applications of hormone and chemohormone therapies for patients with metastatic disease are discussed.

There is new scientific information on the relationship between androgenic hormones and prostate cancer. In spite of a plausible association between androgenic hormones and the development of prostate cancer, precise mechanisms are lacking. Racial variability in the incidence of prostate cancer may be related to hormonal influences but suggestive observations were noted in studies with a small sample size. Currently, a serum hormone profile will not identify groups or individuals at higher risk of prostate cancer. The earlier integration of hormonal therapy into treatment plans for prostate cancer will substantially alter the model. Early treatment may be vastly more expensive, and the long-term benefit is uncertain. The aggregate costs of hormonal treatment for prostate cancer to the health care system will require a re-evaluation of less expensive, traditional methods for androgen deprivation.

Androgen action differs from that of most hormones in the testosterone, the major androgen secreted from the testes and the most abundant androgen in the circulation of men, is not the principal androgen within target cells. Indeed, abundant evidence indicates that most androgen actions are mediated by the 5alpha-reduced metabolite dihydrotestosterone that is formed in target tissues. The conversion of testosterone to dihydrotestosterone is mediated by two isoenzymes; mutations in the steroid 5alpha-reductase 2 gene cause a rare autosomal-recessive form of male pseudohermaphroditism, and inhibition of this enzyme causes regression of the prostate gland. Dihydrotestosterone binds more tightly to the androgen receptor that does testosterone, but it is not clear whether this property is the sole explanation for its essential role in androgen action. Nor is it clear whether some androgenic effects may be mediated by circulating dihydrotestosterone acting as a hormone.

Background: Our objective was to determine the clearance rate of free and total serum PSA following radical retropubic prostatectomy.

Methods: Sera were obtained from 10 men with localized prostate cancer prior to and 1, 4, 8, 24, 48, and 72 hr after radical prostatectomy. No patient received any postoperative blood transfusion. Free and total PSA were measured using the Hybritech Tandem-R (total PSA) and radioimmunometric free PSA assay. Postsurgery serum-free and total PSA concentrations were modeled using a "two-compartment" pharmacokinetic model.

Results: The pharmacokinetic model with an initial constant "infusion" suggests that, following release from the prostate, both free and total PSA are taken up into a second compartment for metabolism. The movement of PSA between these compartments was accurately modeled. Following surgery, there is a shift of both free and total PSA best modeled as a constant infusion into the serum at a rate of 1.97 and 1.60 ng/ml, respectively, for a period of approximately 1 hr. Following this initial constant infusion, the half-life estimations for free and total PSA are initially 1.2 and 0.75 hr, respectively, which then increase to 22 and 33 hr, respectively.

Conclusions: Serum free and total PSA are cleared from the circulation following a "two-compartment" model with an initial constant "infusion." The constant "infusion" is most likely a consequence of surgical manipulation. The initial half-life estimates are < 2 hr for both free and total PSA, and later increase to 22 and 33 hr, respectively.

Background: Prostate-specific membrane antigen (PSMA) has been detected in human prostatic cancer tissues, serum, and seminal fluid based on Western blot data with the monoclonal antibody 7E11.C5. The reactive protein is very similar in size to that from human prostatic carcinoma LNCaP cells and corresponds to a protein with a molecular size of about 110,000 daltons. Given that PSMA is known to be a 750 amino acid protein of about 84,000 daltons, a substantial portion, perhaps 20-25% of the native molecular weight, is composed of carbohydrates.

Methods: In this study, we have begun initial analyses of the glycosylation of the PSMA protein from multiple sources using a variety of exo- and endoglycosidase treatments.

Results: The results indicate that the carbohydrate is primarily N-linked and in each case the deglycosylated protein has an apparent molecular weight of about 86,000 daltons. The glycan present on in vivo-derived PSMA from tumor tissue or serum was found to be primarily N-linked complex type. A small amount of O-linked glycan also appears to be present. In contrast, only high mannose-type N-linked glycans are present on the PSMA from LNCaP cells.

Conclusions: Oligosaccharides present on PSMA derived from both tissue culture LNCaP cells and in vivo specimens are primarily N-linked and comprise about 20-25% of the native molecular weight. N-linked glycans of PSMA derived from in vivo sources were found to be complex type, lacking polylactosamine structures. In contrast, LNCaP cells express only high mannose-type structures. These results will be useful in our ongoing efforts to develop monoclonal antibodies which are specific for protein epitopes present in the extracellular domain of the protein.

To examine the role of human chromosomes in the development of metastatic prostate cancer, we introduced a copy of human chromosomes into highly metastatic Dunning R-3327 rat prostatic cancer cells by microcell-mediated chromosome transfer. Each microcell hybrid clones containing human chromosomes 8, 10, 11, and 17, respectively, showed decreased ability to metastasize to the lung, without any loss of tumorigenicity. This finding demonstrates that these human chromosomes contain metastasis suppressor genes for prostate cancer. Spontaneous deletion of portions of human chromosomes was observed in human chromosome 10, 11, and 17 studies. In the human chromosome 8 study, irradiated microcell-mediated chromosome transfer was performed to enrich chromosomal arm deletions of human chromosome 8. Relationships between the size of human chromosomes introduced into microcell hybrid clones and the number of lung metastases produced by the clones were analyzed to determine which part of human chromosomes contained metastasis suppressor gene(s) for prostate cancer. Molecular and cytogenetic analyses of microcell hybrid clones demonstrated that metastasis suppressor genes on human chromosomes 8, 10, and 11 were located on 8p23-q12, 10q, 11p13-11.2, respectively. Further analyses are proposed to confirm the potentially useful advantage of this assay system to identify metastasis suppressor gene(s) for prostate cancer.

Background: Although prostate-specific antigen (PSA) has aided significantly in the diagnosis of prostate cancer, more sensitive and accurate assays are needed. Presently, we are developing a sensitive immunoassay for hK2 protein for the detection of prostate cancer.

Methods: Polyclonal and monoclonal antibodies specific for hK2 were produced and used for Western blot analysis and immunohistochemistry for detection of hK2 protein in serum and human tissues. The reverse-transcriptase polymerase chain reaction (RT-PCR) was utilized to detect hK2 mRNA from patient blood samples.

Results: Western blot analysis demonstrated that the antibodies used are monospecific for hK2. Immunohistochemistry showed that hK2 is expressed only in prostatic epithelia. An RT-PCR study showed that hK2 mRNA would be a useful candidate for early detection of prostatic micrometastasis.

Conclusions: Monospecific antibodies for hK2 have been developed for detecting hK2 protein. Our studies indicate that hK2 may be a useful marker for prostate cancer.