Prostate Restored
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Is PSA always high with BPH?

The PSA level also tends to rise in men with benign prostatic hyperplasia (BPH) and is a good marker for prostate volume. PSA levels are usually elevated in men with acute bacterial prostatitis.

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Human glandular kallikrein–2

Human glandular kallikrein (hK)-2 is a serine protease that has approximately 80% structural homology with prostate-specific antigen (PSA; ie, hK-3). It is responsible for the conversion of the inactive pro-PSA zymogen to the enzymatically active PSA in vitro, which is a prerequisite for formation of PSA–alpha 1 -antichymotrypsin (ACT) and other complexes. As prostate cancer cells become more anaplastic, hK-2 levels rise, whereas PSA levels tend to fall. Concentrations of PSA and hK-2 are high in prostatic and seminal fluid but low in the blood. The Goteborg screening study evaluated 604 men with a total PSA (tPSA) higher than 3. These men underwent digital rectal examination (DRE), transrectal ultrasonography (TRUS), and sextant prostate biopsies. Cancer was identified in 144 men (23.8%). Significantly higher levels of hK-2 and tPSA were found in those with cancer, whereas the ratio of free PSA (fPSA) to tPSA was lower. The optimum equation predicting the presence of cancer was as follows:

hK-2 × tPSA/fPSA

The receiver operating characteristic (ROC) was 0.81. At a sensitivity of 75%, the specificity of tPSA was 47%, the sensitivity of tPSA/fPSA was 63%, and the sensitivity of hK-2 × tPSA/fPSA was 74%. At any higher sensitivity, the tPSA consistently had decreasing specificity, whereas the other 2 measures produced similar results. Men with localized cancer who were treated with radical prostatectomy had lower hK-2 levels if the cancer was confined to the organ, as compared with men who had extraprostatic extension of cancer. The tPSA levels in this same cohort were not different.

Prostate-specific membrane antigen

Prostate-specific membrane antigen (PSMA) is a selective antigenic marker of prostate epithelial cells that can be found in the serum. Bostwick et al found that this marker is expressed in 70% of benign epithelial cells, 78% of prostate intraepithelial neoplastic cells, and 80% of invasive cancer cells. [18] PSMA is expressed to a greater extent than PSA in higher-grade cancers. PSMA is a 100-kd type II membrane protein. The gene for PSMA is located on the short arm of chromosome 11. The gene has been fully sequenced and cloned and encodes for a glycoprotein consisting of 3 domains: an intracellular domain, a transmembrane region, and a large 707-amino-acid extracellular sequence making up the bulk of the molecule. Two variations of the PSMA gene have been identified and characterized, but their individual roles have not been elucidated. Nonprostate expression of PSMA occurs in the proximal tubule cells of the kidney, the salivary glands, and the small bowel (particularly the duodenum); PSMA has high folate hydrolase activity that is essential for absorbing ingested folates. Anti-PSMA monoclonal antibodies react to the endothelium of malignant tissue but not to normal endothelium. Various carcinomas express PSMA consistently and strongly in their tumor-associated neovasculature; however, similar expression has not been found in prostate cancer neovasculature. The development of immunoassays and Western blot–based assays for PSMA has permitted an increasing number of studies. PSMA levels seem to correlate with stage and tumor volume. After radical prostatectomy, PSMA levels become undetectable, but they rise if the tumor recurs. Reverse transcriptase polymerase chain reaction (RT-PCR) testing with PSMA primers has been used to detect circulating prostate cancer cells. This method detects tumor cells at concentrations as low as 1 per 10 million lymphocytes.

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The use of this method for clinical decision-making has been limited. With this technology, cancer cells can be identified in the circulation and in the bone marrow of patients with all stages of prostate cancer. This indicates that cancer cells begin leaving the prostate early in the development of the disease, but most of them do not survive, and their identification does not correlate with patient prognosis or survival. Ferrari et al demonstrated that PSMA RT-PCR technology was superior to standard histologic techniques for detecting micrometastases in lymph nodes removed during radical prostatectomy. [19] In this study, lymph nodes were obtained from 33 patients with Gleason scores of 7 or higher and serum PSA levels of 10 or higher who were undergoing radical prostatectomy. Routine pathology examinations identified cancer cells in 4 (12%) of these patients. [19] PSA or PSMA expression occurred in 27 (82%) of the patients. The 4 patients with positive lymph node findings also had positive results for both PSA and PSMA. Among the 29 patients with no histologic evidence of disease, 23 (79%) tested positive with RT-PCR. In these 23 patients, PSMA was detected more frequently than PSA, though in 2 patients, only PSA was found. Although these findings demonstrate that prostate cancer cells or fragments of these cells can be found in pelvic lymph nodes, the status of these cells and their viability cannot be ascertained. This observation is another indication of the early egress of cancer cells from the prostate, but there is not necessarily any correlation with patient prognosis and survival. PSMA serves as the basis for the ProstaScint scan. This is an imaging study used to detect metastatic cancer. Its primary use has been to identify prostate cancer cells in lymph nodes and in the prostate base. PSMA is being evaluated as a means of providing therapy. When PSMA is used as an immunotherapeutic agent, dendritic cells are primed with PSMA and infused into the patient. This is intended to produce a specific immune response to prostate cells. With PSMA used as a guide to identify and target prostate cells, radioactive isotopes and cytotoxic agents can be delivered to these cells.

Cell cycle inhibitor p27

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The cell cycle inhibitor p27 is a putative tumor suppressor gene. Loss of p27 is associated with a poor prognosis in patients with breast, colorectal, and prostate carcinoma. In men treated with radical prostatectomy, loss of p27 expression correlates with an increased probability of cancer recurrence and lower survival rates. Decreased p27 expression also is associated with high-grade cancer cells, positive surgical margins, seminal vesicle invasion, and lymph node metastases.

Serum insulinlike growth factor

Insulinlike growth factor (IGF)-1, its binding protein (IGF-binding protein [IGFBP]), and its receptor (IGF receptor [IGFR]) have been implicated in the development of prostate cancer. PSA cleaves IGF-1 from its binding protein, allowing this potent growth factor to act on prostate epithelial cells. Plasma concentrations of IGF-1 have been associated with an increased risk of prostate cancer. In the Physicians’ Health Study, 152 cases of prostate cancer were matched with 152 controls from the population of 14,916 physicians. Serum samples assayed for IGF-1 at the outset of the study found a positive association with the subsequent development of prostate cancer. Men in the highest quartile for IGF-1 had a relative risk of 2.4 as compared with men in the lowest quartile. The predominant IGF-1 binding protein, IGFBP-3, has growth-inhibiting properties that diminish the effect of IGF-1. After correcting for IGFBP-3 levels, the risk of developing prostate cancer was 4.5 times greater for the highest quartile than for the lowest quartile. The clinical usefulness of this assay has yet to be demonstrated, because alternative explanations for these findings may exist. Prostate size and a large overlap in actual values limit the utility of the test but do provide additional information regarding the biology of prostate cancer.

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