The role of prostate specific antigen in screening and management of clinically localized prostate cancer

International Urology and Nephrology -     

The effects of cellular telephone use on serum PSA levels in men

BACKGROUND: The increasing use of cellular telephones is known to have harmful effects on human health. The aim of this prospective study was to determine whether cellular telephone use affected serum PSA levels in men. METHODS: Participants included 20 men with ages ranging from 22 to 65 years who had never previously used cellular telephones. Blood samples were taken prior to and 30 days after the beginning of cellular telephone use. Serum was separated from the blood samples and stored in a deep freezer until the end of the study, at which time serum free and total PSA levels were determined by tandem radioimmunoassay. The results were statistically analyzed by the Wilcoxon Paired Signed Rank Test. RESULTS: Average free and total PSA values were 2.070 ng/ml and 0.500 ng/ml before the study, and 2.0 ng/ml and 0.505 ng/ml at the end of the study, respectively. No significant difference was determined between the initial and final values (p > 0.05). CONCLUSIONS: The results indicate that cellular telephone use does not significantly affect PSA values in the short term. Nevertheless, we think that there is a need for longer-term studies on this subject.     

Direct evidence for the activation of phospholipase C gamma 1 by in vivo treatment with morphine in the mouse periaqueductal gray matter

The aim of the present study was to investigate whether in vivo morphine treatment could participate in the activation of phospholipase Cgamma1 (PLCgamma1) isoform in the mouse periaqueductal gray matter (PAG) which can be accompanied by antinociceptive responses induced by morphine. As well as mu-opioid receptor-like immunoreactivity (MOR-IR), moderate PLCgamma1-like immunoreactivity (PLCgamma1-IR) was noted in the mouse PAG section. After s.c. treatment with morphine, the intensive PLCgamma1-IR was detected in the cell surface of the positive cells. Treatment s.c. with morphine produced a robust increase in the number of phosphorylated-PLCgamma1 (p-PLCgamma1) expressing cells in the PAG. Deletion of PLCgamma1 gene by i.c.v. pretreatment with antisense oligodeoxynucleotide against PLCgamma1 revealed a significant inhibition of supraspinal antinociception induced by a selective mu-opioid receptor agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin (DAMGO). Furthermore, i.c.v. pretreatment with a specific antibody to PLCgamma1 caused a concentration-dependent attenuation of antinociception produced by i.c.v. treatment with either morphine or DAMGO. These findings suggest that in vivo morphine treatment can activate PLCgamma1 isoform in the mouse PAG which can be, at least in part, associated with the expression of supraspinal antinociception induced by mu-opioid receptor agonists in the mouse.     

Membrane and synaptic effects of corticotropin-releasing factor on periaqueductal gray neurons of the rat

Corticotropin-releasing factor (CRF) has been identified as a major component of the hypothalamic-pituitary-adrenal (HPA) axis. By stimulating the release of adrenocorticotropin hormone (ACTH), CRF acts as a key mediator of the stress response. However, CRF receptors and neuronal elements are present in many extrahypothalamic regions of the brain. A region that contains both CRF-ergic neurons and CRF receptors is the midbrain periaqueductal gray (PAG). The physiological effects of CRF in the PAG are unknown. In this study, an in vitro preparation, extracellular and intracellular patch-clamp recordings, were used to examine the effects of CRF, applied through an injecting electrode, on PAG neurons. Recordings were made from 147 neurons in the PAG. CRF injecting electrode concentrations of 0.05 and 1 microM were tested. At the higher concentration, CRF had a predominant excitatory effect on the neurons, and at the lower concentration, CRF produced no significant effect on the neurons. The excitatory effect was dose dependent and was often associated with a depolarization in membrane potential in intracellular recordings. Application of the CRF antagonist, alpha-helical CRF, blocked this excitatory effect. It is concluded that CRF has a predominant excitatory effect on PAG neurons. It is also concluded that CRF is not acting presynaptically. This excitatory effect of CRF on PAG neurons may lead to activation of a descending analgesic pathway.     

Reciprocal interactions between the amygdala and ventrolateral periaqueductal gray in mediating of Q/N(1-17)-induced analgesia in the rat

The opioid peptide, Orphanin FQ/nociceptin (OFQ/N(1-17))(,) its active fragments, and a related precursor peptide each produce analgesia following microinjection into the amygdala of rats. OFQ/N(1-17)-induced analgesia elicited from the amygdala is blocked by amygdala pretreatment of either general, mu, kappa, or delta-opioid antagonists even though OFQ/N(1-17) binds poorly to these receptor subtypes, and the antagonists bind poorly to the ORL-1/KOR-3 receptor. Agonists at mu and kappa opioid receptors as well as beta-endorphin each produce analgesia elicited from the amygdala that is blocked by opioid antagonist pretreatment in the ventrolateral periaqueductal gray (vlPAG) of rats. The present study examined whether pretreatment of general and selective opioid antagonists in the vlPAG blocked OFQ/N(1-17)-induced analgesia on the tail-flick test elicited from the amygdala, and whether pretreatment of general and selective opioid antagonists in the amygdala blocked OFQ/N(1-17)-induced analgesia elicited from the vlPAG of rats. OFQ/N(1-17)-induced analgesia elicited from the amygdala was significantly and markedly reduced following vlPAG pretreatment with a dose range of either naltrexone, beta-funaltrexamine (beta-FNA, mu), nor-binaltorphamine (NBNI, kappa) or naltrindole (NTI, delta). In contrast, opioid antagonists administered into misplaced mesencephalic control placements ventral and lateral to the vlPAG actually enhanced OFQ/N(1-17)-induced analgesia elicited from the amygdala. OFQ/N(1-17)-induced analgesia elicited from the vlPAG was significantly and markedly reduced following amygdala pretreatment with naltrexone and NBNI, to a lesser degree by NTI, and was unaffected by beta-FNA. Yet, opioid antagonists administered into misplaced amygdala control placements were generally ineffective in altering OFQ/N(1-17)-induced analgesia elicited from the vlPAG. Latencies were transiently increased by general, but not selective opioid antagonist treatment alone in the amygdala, but not the vlPAG. These data indicate reciprocal and regional interactions between the amygdala and vlPAG in the mediation of OFQ/N(1-17) by classic opioid receptor subtype antagonists in rats.     

Problems with prostate specific antigen screening for prostate cancer in the primary healthcare setting in South Africa

OBJECTIVES: To assess the feasibility of detecting early-stage prostate cancer in the primary healthcare setting, and to investigate whether there is a higher incidence of prostate cancer in Black African men. PATIENTS AND METHODS: The study was a collaboration with registrars in the authors' institutions and primary healthcare centres serving mainly a Black African or mixed ancestry (Coloured) population in the semi-urban Cape Town metropolitan area of South Africa. Men aged 50-70 years attending the clinics were counselled about prostate cancer and invited to have a digital rectal examination (DRE), serum prostate-specific antigen (PSA) assay and transrectal ultrasonography-guided sextant prostate biopsy if the DRE was clinically suspicious of malignancy or the serum PSA was > or = 4.0 ng/mL. An American Urological Association Symptom Index (AUA-SI) was obtained, and urine analysed using dipsticks. RESULTS: From May 2000 to November 2001, 660 men were assessed (mean age 59.4 years, range 30-82); 60.6% were Black African, 37.3% mixed (Coloured), 1.8% White (Caucasian) and 0.2% Asian (Indian). The mean (range) AUA-SI was 5.98 (0-35) in the whole group; the DRE was recorded as clinically suspicious of malignancy in 3.2%. The mean PSA was 20.39 (0.04-10 000) ng/mL in the whole group, but when two outliers (1865 and 10 000 ng/mL) were disregarded, it was 2.4 ng/mL. In Black patients the mean PSA was 31.8 (0.04-10 000) ng/mL, and without the outliers, 2.1 ng/mL; in Coloured patients it was 2.94 (0.05-50) ng/mL. The PSA was > or = 4.0 ng/mL in 9.6% of the whole group, in 7.8% of Black and in 13% of Coloured patients. Prostate biopsies were taken in 21 patients (3.2% of the whole group and a third of those with a PSA of > or = 4.0 ng/mL); in Black patients, biopsies were taken in 1.5% and 19.4%, respectively, and in Coloured patients in 6.1% and 46.9%, respectively. The prostate biopsy showed cancer in 43% of the whole group, in a third of Black and in 47% of Coloured patients; prostate cancer was detected in 1.4%, 0.5% and 2.8%, respectively. CONCLUSIONS: That prostate biopsies were obtained in only 19% of Black and in only 47% of Coloured men with a serum PSA of > or = 4.0 ng/mL is of concern. This indicates that there is a significant problem in getting men with an elevated serum PSA level to undergo a prostate biopsy in the primary healthcare setting in South Africa.     

Biochemical disease-free survival in patients with a high prostate-specific antigen level (20-100 ng/mL) and clinically localized prostate cancer after radical prostatectomy

OBJECTIVE: To examine our experience with radical prostatectomy (RP) in patients with a serum prostate-specific antigen (PSA) level of > 20 ng/mL (who are sometimes considered poor candidates for RP) to determine the outcome and possible predictors of a favourable outcome. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 79 patients who underwent RP with an initial PSA of 20-100 ng/mL. Biochemical disease-free survival (BDFS) was assessed using the Kaplan-Meier method and predictors of treatment outcome examined by uni- and multivariate analysis. Patients excluded from the analysis were 11 (14%) whose surgery was aborted after finding cancerous pelvic nodes and who did not undergo RP; four others with normal nodes during RP who had metastatic tumour on permanent sections; and 14 who had follow-up data for < 2 years. RESULTS: The mean (sd) age of the 50 patients in the final study population was 63 (7) years and the mean PSA 37.9 (16.0) ng/mL. The median (range) follow-up was 54 (24-120) months. The BDFS was 60% at 3 years and 48% at 5 years of follow-up. Two patients developed a local recurrence and eight developed metastatic disease. On logistic regression analysis of factors influencing BDFS, only extracapsular extension of disease was predictive of PSA recurrence; no preoperative factor was significant. When time to PSA recurrence was assessed by Cox regression analysis, again only extracapsular extension was predictive, with no preoperative variable a statistically significant predictor. CONCLUSIONS: Patients with a high serum PSA level (20-100 ng/mL) may be appropriate candidates for RP. While the cancer-free survival is not as good as in patients with a lower PSA, a significant percentage of patients achieve BDFS. No preoperative variables were predictive of disease-free survival or time to PSA recurrence.     

Serummarker in der Früherkennung und dem Staging des Prostatakarzinoms

Zusammenfassung Die Entwicklung des prostataspezifischen Antigens (PSA) erfolgte nach bescheidenem Beginn durch Extraktion aus Seminalplasma als potentieller Marker in der Forensik über die Identifizierung in Prostatagewebe und nachfolgend im Serum. Jedoch konnte erst die Entwicklung von Immunoassays zur Bestimmung der PSA-Konzentration im Serum das einzigartige Potential des PSA in der Behandlung des Prostatakarzinoms offenbaren. Heute ist das PSA der mit Abstand wichtigste Tumormarker in der Urologie, wenn nicht in der gesamten Onkologie und hat Früherkennung, Staging, Behandlung und Nachsorge des Prostatakarzinoms in jeder Beziehung revolutioniert.Trotz dieser Verdienste des PSA treten dessen Unzulänglichkeiten immer deutlicher zutage, die dem PSA das Charakteristikum eines perfekten Tumormarkers verbieten. Erstens ist PSA—trotz hoher Organspezifität—kein Marker für Prostatakarzinome: benigne Prostatahyperplasie, Prostatitis oder prostatische Manipulation beeinflussen die PSA-Serumkonzentration und führen zu einer hohen Anzahl kostspieliger und potentiell morbiditätsbehafteten Biopsien. Weiterhin ist im Gesamt-PSA-Bereich zwischen 4 und 10 ng/ml bei einer erforderlichen Sensitivität von 95% die Spezifität des PSA nicht zufriedenstellend. Darüber hinaus—ein einmaliges Charakteristikum des Prostata-Ca—entwickeln zwar 30–40% aller Männer ein Prostatakarzinom, jedoch nur 9–11% eine klinisch signifikante Tumorlast und noch weniger (2,5–4,3% aller Männer) versterben an einem Prostatakarzinom. Mit anderen Worten sind der überwiegende Teil aller Karzinome für die Lebenserwartung des Betroffenen ohne Bedeutung und müssen daher u. U. weder diagnostiziert, noch behandelt werden. Das PSA ist nicht in der Lage, diese sog. klinisch nichtsignifikanten von den signifikanten Karzinomen zu unterscheiden. Schließlich steigt die Prävalenz des Prostatakarzinoms durch die höhere Lebenserwartung jenseits der 7. Dekade an. Andererseits sind es v. a. die Patienten im Alter von 50–70 Jahren, die ein aggressiv wachsendes Karzinom entwickeln und von früh eingeleiteter invasiver Diagnostik und Therapie profitieren werden.Was generell unter dem Oberbegriff "Gesamt-PSA" subsummiert wird, ist in Wirklichkeit eine komplexe, in der Zusammensetzung der einzelnen Subformen heterogene Mischung aus gebundenen und freien molekularen PSA-Formen. Komplexiertes PSA (cPSA) stellt die dominierende Variante des Gesamt-PSA dar, hiervon besteht wiederum der größte Teil (ca 98%) aus PSA in 1/1 molarem Verhältnis kovalent an 1-Antichymotrypsin gebunden (ACT-PSA). Der kleinere Anteil, das freie PSA (fPSA) im Serum, ist enzymatisch inaktiv ohne mit dem Überschuss an Antiproteasen im Serum zu reagieren. Darüber hinaus existieren verschiedene Isoformen des fPSA, die spezifisch im Serum bestimmt werden können. Neuere Studien unterstützen die Hypothese einer klinischen Verwendung dieser Isoformen des fPSA in der Früherkennung des Prostatakarzinoms.Die klinische Evaluierung des humanen glandulären Kallikrein 2 (hK2) unterstützt eine dem PSA komplementäre Rolle in der Früherkennung des Prostatakarzinoms und als Stagingserummarker für das klinisch lokalisierte Prostatakarzinom eine signifikante Verbesserung gegenüber dem PSA.In dieser Übersicht werden die etablierten und potentiell neuen PSA-Varianten und das hK2 für Diagnostik und Staging des Prostatakarzinoms zusammengefasst.     

The human PC346 xenograft and cell line panel: a model system for prostate cancer progression

OBJECTIVE: Prostate cancer (PC) model systems that reflect the different disease stages are essential for studying the development and progression of PC and for testing new treatment modalities. This review summarizes the establishment and characterization of the PC346 progression model and compares it to other available human PC cell lines and xenografts. METHODS: The PC346 model was derived from the transurethral resection of a primary prostate tumor. Tumor samples were subcutaneously implanted into athymic mice, which resulted in the development of a series of xenografts from which in vitro cell cultures were established. RESULTS: The PC346 panel includes sublines with hormone-response characteristics that range from androgen-sensitive to androgen-independent (AI) growth. In vivo and in vitro selection of androgen-sensitive lines under androgen-depleted conditions replicated the clinically relevant relapse phenomenon, and resulted in a series of modifications in the androgen-receptor (AR) pathway: AR mutation, overexpression, and downregulation. CONCLUSIONS: The PC346 panel reproduces many biological characteristics of the different phases of clinical PC and the most common AR modifications observed in hormone-refractory tumors, being a valuable addition to the limited collection of available model systems.     

Androgen and anti-androgen treatment modulates androgen receptor activity and DJ-1 stability

BACKGROUND: Mechanisms regulating the transition from hormone responsive to hormone refractory prostate cancer (PCa) have remained unclear. METHODS: We analyzed androgen and anti-androgen treatment on endogenous AR activity in primary human prostate epithelial (HPE) cells cultured directly from patient radical prostatectomy specimens utilizing a transiently infected gene reporter (TIGR) assay. RESULTS: Flutamide treatment exhibited agonist activities in HPE cells derived from tumor and non-tumor specimens which contained wild-type AR. After proteomic comparison of these cells to those where flutamide functioned normally as an antagonist, we identified DJ-1, a positive regulator of AR. DJ-1 expression increased in HPE and LNCaP cells during flutamide treatment as a result of DJ-1 protein stabilization. CONCLUSION: Stabilization of AR and its co-regulators in the absence of androgen may partially account for anti-androgen withdrawal syndrome and potentially contribute to the development of hormone refractory PCa.