Absence Of Prostate-specific Antigen Research Articles

Real-world analysis of metastatic prostate cancer demonstrates increased frequency of PSA-imaging discordance with visceral metastases and upfront ARAT/docetaxel therapy.

The objective of this study was to evaluate the background and treatment course of patients with metastatic prostate cancer (PC), with a particular focus on radiographic progression in the absence of prostate-specific antigen (PSA) progression. The study population consisted of 229 patients with metastatic hormone-sensitive PC (HSPC), who received prostate biopsy and androgen deprivation therapy at Kobe University Hospital between January 2008 and June 2022. Clinical characteristics were retrospectively evaluated using medical records. PSA progression-free status was defined as ≤1.05 times greater than that from 3 months before. Multivariate analyses were performed using the Cox proportional hazards regression model to identify parameters associated with time to progression on imaging without PSA elevation. A total of 227 patients with metastatic HSPC without neuroendocrine PC were identified. The median follow-up period was 38.0 months, with a median overall survival of 94.9 months. Six patients exhibited disease progression on imaging without PSA elevation during HSPC treatment, three during first-line castration-resistant PC (CRPC) treatment, and two during late-line CRPC treatment. The rate of disease progression without PSA elevation at 3 years after treatment initiation was 7.4%. Multivariate analysis revealed that organ metastases and upfront treatment with docetaxel or androgen receptor axis-targeted therapy were independent prognostic factors for imaging progression without PSA elevation. Disease progression on imaging without PSA elevation occurred not only during HSPC treatment and first-line CRPC treatment, but also during late-line CRPC treatment. Patients with visceral metastases or those treated with upfront androgen receptor axis-targeted or docetaxel may be more prone to such progression.

Radiographic progression in the absence of prostate-specific antigen (PSA) progression in patients with metastatic hormone-sensitive prostate cancer (mHSPC): Post hoc analysis of ARCHES.

5072 Background: Enzalutamide (ENZA) + androgen deprivation therapy (ADT) significantly reduced the risk of radiographic progression and increased overall survival in men with mHSPC, regardless of baseline PSA levels (ARCHES; NCT02677896). This post hoc analysis investigated concordance between PSA progression and radiographic progression in patients with mHSPC. Methods: Patients with mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or placebo (PBO) + ADT. The concordance between radiographic progression and PSA progression, as defined by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria, and between any rise in PSA above nadir was assessed. Results: In total, 267/1150 patients in ARCHES had radiographic progression (ENZA + ADT, n=79; PBO + ADT, n=188). At radiographic progression, the median (range) PSA for ENZA + ADT-treated patients was 2.25 ng/mL (0–1062.3 ng/mL) and 17.47 ng/mL (0–1779.5 ng/mL) for PBO + ADT-treated patients. Most patients (67%) treated with ENZA + ADT did not have PCWG2-defined PSA progression at radiographic progression, compared with 43% of those treated with PBO + ADT (Table). The median absolute and percentage rise in PSA from nadir to radiographic progression was 0.77 ng/mL and 200%, respectively, with ENZA + ADT compared with 12.23 ng/mL and 367%, respectively, with PBO + ADT. Conclusions: In this post hoc analysis of ARCHES, we found frequent discordance between radiographic progression and PSA progression by PCWG2 criteria or any PSA rise over nadir in patients with mHSPC treated with ENZA + ADT. Thus, regular imaging is recommended to detect radiographic progression among patients treated with potent androgen receptor pathway inhibitors, such as ENZA + ADT, as serial PSA monitoring alone may not be sufficient to detect radiographic progression in many patients. Clinical trial information: NCT02677896. [Table: see text]

Electrochemiluminescence immunoassay for the prostate-specific antigen by using a CdS/chitosan/g-C3N4 nanocomposite.

An electrochemiluminescence (ECL) biosensor was fabricated for the evaluation of prostate specific antigen (PSA). The sensor was developed by successively modifying glassy carbon electrode (GCE) electrodes with CdS/Chito/g-C3N4 nanocomposites and DNA1 was labeled at the 5' end with thiol. The aptamer DNA was labeled at the 3' end with a quencher ferrocene (Fc) was ligated to DNA1 by the principle of complementary base pairing. In the absence of PSA, the ECL intensity signal is effectively quenches through the energy transfer and photoexcitation electron transfer between CdS/Chito/g-C3N4 emitter and quencher Fc. After incubation with target PSA, the aptamer DNA interacts with PSA and then moved away from the electrode surface together, which will recover the ECL intensity. Under the optimal conditions, the ECL intensity increases linearly with the logarithm of PSA concentration in the range of 1pg·mL-1 to 100ng·mL-1, and the detection limit is 0.14pg·mL-1 (S/N = 3). The biosensor has been successfully applied to the determination of PSA in serum sample. Graphical abstractSchematic representation of the electrochemiluminescence sensor based on a CdS/chitosan/g-C3N4 nanocomposite, which can be applied to the determination of prostate specific antigen in serum.

A novel fluorescent assay based on DNAzyme-assisted detection of prostate specific antigen for signal amplification

Prostate specific antigen (PSA) is one of the most common biomarkers for the management of prostate cancer. However, it still remains urgent to develop highly sensitive, cost-effective and selective strategies for PSA assay. In this paper, we developed a low-cost, highly sensitive and specific analytical strategy for the detection of PSA by using a fluorescence sensor based on Pb2+-dependent DNAzyme. We designed a DNA sequence called cmMB with a hairpin structure, containing PSA-specific aptamers and Pb2+-dependent DNAzyme chains. Also, a fluorophore-labelled DNA sequence called Sub-FAM, which contains a cleavage site of Pb2+-dependent DNAzyme and serves as substrate, is also designed for the signal generation. In the presence of PSA, interaction between aptamer and PSA blocks the hairpin structure of cmMB, resulting in the formation of Pb2+-dependent DNAzyme with Pb2+. Then, Pb2+-dependent DNAzyme can cleavage Sub-FAM and produce a high fluorescence. In the absence of PSA, since Sub-FAM remains to be ssDNA and can be absorbed by GO, only low fluorescence can be detected. Under optimal experimental conditions, a good linear relationship in the range of 1–100 pg mL−1 was exhibited, with a limit of detection (LOD) of 0.76 pg mL−1. In addition, the proposed method has potential value in the diagnosis and monitoring of prostate cancer because of its good selectivity and practical application in biological samples.

Peptide cleavage-mediated photoelectrochemical signal on-off via CuS electronic extinguisher for PSA detection

In this work, a peptide-based photoelectrochemical (PEC) biosensor was constructed based on CdTe/TiO2 sensitized structure as electrode and CuS nanocrystals as signal amplifier for the ultrasensitive detection of protein. After peptide was fixed to the CdTe/TiO2 electrode surface, the double-helix DNA (dsDNA) was immobilized at the end of the peptide and used as a carrier to immobilize the doxorubicin-copper sulfide nanocrystals (Dox-CuS) conjugates. As a proof of concept, prostate specific antigen (PSA) has been chosen as the model. In absence of PSA, CuS nanocrystals could consume electron donors and exciting light energy. Additionally, the steric hindrance effect of biomacromolecules hindered the movement of electron donors to the photoelectrode. Eventually, the photoelectric response signal was reduced, and the biosensor was in a "signal off" state. When PSA existed, the PSA specifically cleaved the peptide, and DNA/Dox-CuS probes were released from the electrode surface, resulting in a "signal on" state. The PEC biosensor revealed good specificity, stability, and reproducibility, and it exhibited excellent application in PSA analysis with a linear range from 0.005 to 20ngmL-1 and a low detection limit of 0.0015ngmL-1. This PEC biosensor may have potential applications in bioanalysis, disease diagnostics, and clinical biomedicine.

A label-free fluorescence method based on terminal deoxynucleotidyl transferase and thioflavin T for detecting prostate-specific antigen.

Prostate-specific antigen (PSA) is the only biomarker for the diagnosis of prostate cancer. So the PSA screening test is very important due to the high occurrence of prostate cancer in men. In this work, a label-free fluorescent method was developed based on terminal deoxynucleotidyl transferase (TdT) and G-quadruplex-thioflavin T complex for detecting PSA. In the absence of PSA, the PSA aptamer can be used as the primer for TdT extension reactions, resulting in the formation of G-quadruplexes and generation of strong fluorescent signals. After the addition of PSA, the PSA-aptamer complex prevented the TdT extension reaction due to steric hindrance, thus resulting in a poor fluorescent signal. The assay showed a wide linear range (0.1 to 80pg/mL) and a detection limit of 0.086pg/mL (S/N = 3). It also has good specificity for PSA determination and gives satisfactory results when applied to biological samples. Conceivably, its merits such as good selectivity and high sensitivity indicate that the proposed method has a promising application potential in the clinical diagnosis and treatment of prostate cancer. Graphical abstract.

Multicolor and photothermal dual-readout biosensor for visual detection of prostate specific antigen

Developing a facile and reliable approach for tumor marker detection is crucial in early diagnosis of cancer. Here, a multicolor and photothermal dual signal readout immunosensor was proposed based on a nanoparticle-mediated transformation strategy and used for sensitive detection of prostate specific antigen (PSA). To construct such a platform, Fe3O4 nanoparticles (NPs) -functionalized graphene oxide was modified with partially complementary DNA and served as the signal probes. In the absence of PSA, the signal probes were captured via hybridization reaction between DNA and PSA aptamer. Subsequently, Fe3O4 NPs anchored on the probes were transformed into a photothermal agent, Prussian blue NPs, which converted biological signal into heat via the near-infrared laser irradiation, and thus sensitive quantitative detection of PSA was realized by using a thermometer with a lower detection limit of 0.31 ng/mL. Meanwhile, Prussian blue NPs displayed multiply colors by mixing with potassium ferricyanide, and rapid qualitative detection by naked eyes was realized. The two sets of data mutually validate each other, which greatly improved the accuracy and reliability of PSA detection. More strikingly, graphene oxide as the enrichment carrier of Fe3O4 NPs significantly enhanced the accumulation of Prussian blue NPs in situ, and thus the signal amplification was effectively accomplished. Besides, the sensing strategy avoided the use of enzyme and simplified analysis process. Such a cost-effective and sensitive dual-readout visual protocol opens up new perspectives for personalized diagnosis and on-site detection.

Who Dies From Prostate Cancer? An Analysis of the Surveillance, Epidemiology and End Results Database

AimsTo characterise the presenting features of those who ultimately die from prostate cancer (PCa). Materials and methodsThe study population consisted of patients in the Surveillance, Epidemiology and End Results (SEER) Program database diagnosed with PCa between 1990 and 2015. Patients were assigned to the following clinical risk groups: low-risk localised (LRL), intermediate-risk localised (IRL), high-risk localised (HRL), node-positive and metastatic (M1). Before 2004, in the absence of prostate-specific antigen (PSA) and Gleason score data, patients with cT1-T2aN0M0 and low-grade PCa were classified as LRL, those with cT3-4N0M0 or high-grade PCa were classified as HRL and all others with N0M0 disease were classified as IRL. The primary aim was to describe the risk group distribution of those who ultimately died from PCa compared with those who were diagnosed with PCa over the study period. A secondary aim was to estimate PCa-specific survival (PCSS) and evaluate the association of risk group with PCSS. ResultsAmong a total of 811 487 patients who were diagnosed with PCa, data sufficient for risk group determination were present in 635 733 patients. The median follow-up was 83 months. The overall risk group distribution at diagnosis was as follows: LRL 10.5%, IRL 49.7%, HRL 34.8%, node-positive 1.5% and M1 3.5%. The risk group distribution of those who died from PCa was 3.9%, 29.4%, 40.9%, 3.2% and 22.8%, respectively. Compared with LRL PCa, the adjusted hazard ratio (95% confidence interval) for PCSS was 1.40 (1.33–1.46) in IRL, 3.76 (3.60–3.93) in HRL, 11.87 (11.14–12.65) in node-positive and 37.12 (35.43–38.88) in M1. ConclusionsIn this large contemporary cohort, patients with M1, node-positive and HRL disease accounted for two-thirds of all deaths from PCa. De novo metastatic PCa was associated with an approximately 40-fold increased risk of death from PCa compared with LRL PCa. Efforts to improve PCSS will therefore depend largely on improvements in therapy in those with M1, node-positive and HRL disease.

Peptide cleavage-based electrochemical biosensor coupling graphene oxide and silver nanoparticles

Herein, a novel electrochemical biosensor for sensitive analysis of prostate specific antigen (PSA) is demonstrated. A specific peptide is employed on the gold electrode as a molecular recognition element for target induced cleavage. In the absence of PSA, graphene oxide (GO) is directly immobilized on the peptide modified electrode, which triggers the aggregation of silver ions and subsequent reduction reaction to form silver nanoparticles (AgNPs). Well defined sharp silver stripping peak can thus be achieved, which stands for a highly characteristic solid-state Ag/AgCl reaction. However, in the presence of PSA, the peptide is specifically recognized and cleaved. The resulted product on the electrode surface cannot aid the immobilization of GO and subsequent formation of AgNPs. Therefore, electrochemical response is decreased remarkably, which can be used to indicate the concentration of PSA. This work demonstrates that the combination of the transduction of peptide cleavage event with GO/AgNPs nanocomposites is a promising attempt for PSA analysis with high sensitivity and selectivity.

Novel electrochemical biosensor based on cationic peptide modified hemin/G-quadruples enhanced peroxidase-like activity

This work designed an artificial substrate peptide to synthesize peptide-hemin/G-quadruplex (peptide-DNAzyme) conjugates. In addition to enhancing catalytic activity of hemin/G-quadruplex, the peptide could also be induced and cleaved by prostate specific antigen (PSA). It was the first report on peptide-DNAzyme conjugates in application of the peptide biosensor. The polyethyleneimine-reduced graphene oxide@hollow platinum nanotubes (PEI-rGO@PtNTs) nanocomposites were cast on the glassy carbon electrode in order to form the interface of biocompatibility and huge surface area for bioprobes immobilization. In absence of PSA, the peptide-DNAzyme conjugates retained intact on the surface of the electrode to produce a strong response signal. But in presence of PSA, the peptide-DNAzyme conjugates were destroyed to release electron mediators, resulting in dramatical decrease of the electrochemicl signal. Therefore, the method had high sensitivity and super selectivity with the limit of detection calculated as 2.0 fg/mL. Furthermore, the strategy would be promising to apply for other proteases by transforming the synthetic peptide module of target.

Graphene oxide@gold nanorods-based multiple-assisted electrochemiluminescence signal amplification strategy for sensitive detection of prostate specific antigen

A novel and competitive electrochemiluminescence (ECL) aptasensor for prostate specific antigen (PSA) assay was constructed using gold nanorods functionalized graphene oxide (GO@AuNRs) multilabeled with glucose oxidase (GOD) and streptavidin (SA) toward luminol-based ECL system. A strong initial ECL signal was achieved by electrodeposited gold (DpAu) on the electrode because of gold nanoparticles (AuNPs) motivating the luminol ECL signal. The signal probes prepared by loading GOD and SA-biotin-DNA on GO@AuNRs were used for achieving multiple signal amplification. In the absence of PSA, the signal probes can be attached on the electrode by hybridization reaction between PSA aptamer and biotin-DNA. In this state, the GOD loaded on the probe could catalyze glucose to in situ produce H2O2 and then AuNRs catalyze H2O2 to generate abundant reactive oxygen species (ROSs) in luminol ECL reaction. Both the high-content GOD and AuNRs in the signal probe amplified the ECL signal in the ECL system. Moreover, the combination of SA with biotin-DNA further expands ECL intensity. The integration of such amplifying effects in this protocol endows the aptasensor with high sensitivity and good selectivity for PSA detection. This aptasensor exhibits a linear relation in the range of 0.5pgmL−1 to 5.0ngmL−1 with the detection limit of 0.17pgmL−1 (S/N = 3). Besides, the strategy was successfully applied in determination of human serum samples with recovery of 81.4–116.0%.

An efficient method for native protein purification in the selected range from prostate cancer tissue digests.

Prostate cancer (CP) cells differ from their normal counterpart in gene expression. Genes encoding secreted or extracellular proteins with increased expression in CP may serve as potential biomarkers. For their detection and quantification, assays based on monoclonal antibodies are best suited for development in the clinical setting. One approach to obtain antibodies is to use recombinant proteins as immunogen. However, the synthesis of recombinant protein for each identified candidate is time-consuming and expensive. It is also not practical to generate high quality antibodies to all identified candidates individually. Furthermore, non-native forms (e.g., recombinant) of proteins may not always lead to useful antibodies. Our approach was to purify a subset of proteins from CP tissue specimens for use as immunogen. In the present investigation, ten cancer specimens obtained from cases scored Gleason 3+3, 3+4 and 4+3 were digested by collagenase to single cells in serum-free tissue culture media. Cells were pelleted after collagenase digestion, and the cell-free supernatant from each specimen were pooled and used for isolation of proteins in the 10-30 kDa molecular weight range using a combination of sonication, dialysis and Amicon ultrafiltration. Western blotting and mass spectrometry (MS) proteomics were performed to identify the proteins in the selected size fraction. The presence of cancer-specific anterior gradient 2 (AGR2) and absence of prostate-specific antigen (PSA)/KLK3 were confirmed by Western blotting. Proteomics also detected AGR2 among many other proteins, some outside the selected molecular weight range, as well. Using this approach, the potentially harmful (to the mouse host) exogenously added collagenase was removed as well as other abundant prostatic proteins like ACPP/PAP and AZGP1 to preclude the generation of antibodies against these species. The paper presents an optimized scheme for convenient and rapid isolation of native proteins in any desired size range with minor modifications.

Patterns of Declining Use and the Adverse Effect of Primary Androgen Deprivation on All-cause Mortality in Elderly Men with Prostate Cancer

BackgroundPrimary androgen deprivation therapy (pADT) is commonly used to treat elderly men diagnosed with localized prostate cancer (CaP), despite the lack of evidence supporting its use. ObjectiveTo examine the effect of pADT on mortality and to assess contemporary trends of pADT use in elderly men with CaP. Design, setting, and participantsMen older than 65 yr residing in Surveillance, Epidemiology, and End Results (SEER) registry areas diagnosed with localized or locally advanced CaP between 1992 and 2009 and not receiving definitive therapy. Outcome measurements and statistical analysisPropensity score (PS)-weighted Cox proportional hazards models were used to estimate the effect of pADT use on overall survival among patients receiving pADT. The interaction between comorbidity-adjusted life expectancy (LE) and pADT use was assessed within the Cox and PS-weighted models. Contemporary (2004–2009) trends for pADT use were analyzed by linear regression. Results and limitationsThe primary cohort included 46 376 men, of whom 17 873 received pADT (39%). Patients with >10 yr LE had lower pADT utilization rates than patients with short LE. Between 2004 and 2009, the use of pADT in men with localized CaP decreased by 14% (from 36% to 22%). Relative to observation, pADT was associated with a survival disadvantage, with a hazard ratio for all-cause mortality of 1.37 (95% confidence interval 1.20–1.56). Limitations included biases not accounted for by the PS-weighted model, changes in CaP staging over the study period, the absence of prostate-specific antigen (PSA) data prior to 2004, and the limits of retrospective analysis to demonstrate causality. ConclusionsThe use of pADT in elderly men with localized CaP has decreased over time. For men forgoing primary definitive therapy, the use of pADT is not associated with a survival benefit compared to observation, and denies men an opportunity for cure with definitive therapy. The deleterious effect of pADT is most pronounced in men with prolonged LE. Patient summaryIn this report, we assessed the effect of primary androgen deprivation (pADT) on prostate cancer mortality and determined current trends in the use of pADT. We showed that use of pADT in men aged >65 yr with localized prostate cancer has decreased over time. We also found that pADT is detrimental to men with localized prostate cancer, and particularly men with longer life expectancy. Therefore, we conclude that ADT should not be used as a primary treatment for men with prostate cancer that has not spread beyond the prostate.

Phase 2 Trial of Single-agent Everolimus in Chemotherapy-naive Patients with Castration-resistant Prostate Cancer (SAKK 08/08)

BackgroundThe phosphatase and tensin homolog (PTEN) tumor suppressor gene is deregulated in many advanced prostate cancers, leading to activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway and thus increased cell survival. ObjectiveTo evaluate everolimus, an inhibitor of mTOR, in patients with metastatic castration-resistant prostate cancer (mCRPC), and to explore potentially predictive serum biomarkers by proteomics, the significance of PTEN status in tumor tissue, and the impact of everolimus on immune cell subpopulations and function. Design, setting, and participantsA total of 37 chemotherapy-naive patients with mCRPC and progressive disease were recruited to this single-arm phase 2 trial (ClinicalTrials.gov identifier NCT00976755). InterventionEverolimus was administered continuously at a dose of 10mg daily. Outcome measurements and statistical analysisThe primary end point was progression-free survival (PFS) at 12 wk defined as the absence of prostate-specific antigen (PSA), radiographic progression, or clinical progression. Groups were compared using Wilcoxon rank-sum tests or Fisher exact tests for continuous and discrete variables, respectively. Time-to-event end points were analyzed using the Kaplan-Meier method and univariate Cox regression. Results and limitationsA total of 13 patients (35%; 95% confidence interval, 20–53) met the primary end point. Confirmed PSA response ≥50% was seen in two (5%), and four further patients (11%) had a PSA decline ≥30%. Higher serum levels of carboxypeptidase M and apolipoprotein B were predictive for reaching the primary end point. Deletion of PTEN was associated with longer PFS and response. Treatment was associated with a dose-dependent decrease of CD3, CD4, and CD8 T lymphocytes and CD8 proliferation and an increase in regulatory T cells. Small sample size was the major limitation of the study. ConclusionsEverolimus activity in unselected patients with mCRPC is moderate, but PTEN deletion could be predictive for response. Several serum glycoproteins were able to predict PFS at 12 wk. Prospective validation of these potential biomarkers is warranted. Trial registrationThis study is registered with ClinicalTrials.gov with the identifier NCT00976755.Results of this study were presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology (June 3–7, 2011; Chicago, IL, USA) and the annual meeting of the German, Austrian, and Swiss Societies for Oncology and Hematology (September 30–October 4, 2011; Basel, Switzerland).

Prostate-Specific Antigen-Retargeted Recombinant Newcastle Disease Virus for Prostate Cancer Virotherapy

Oncolytic virus (OV) therapies of cancer are based on the use of replication-competent, tumor-selective viruses with limited toxicity. Newcastle disease virus (NDV), an avian paramyxovirus, is a promising OV and is inherently tumor selective and cytotoxic only to tumor cells. Replication is restricted in normal cells. Despite encouraging phase I/II clinical trials with NDV, further refinements for tumor-specific targeting are needed to enhance its therapeutic index. Systemically delivered NDV fails to reach solid tumors in therapeutic concentrations and also spreads poorly within the tumors due to barriers including complement, innate immunity, and the extracellular matrix. Overcoming these hurdles is paramount to realizing the exceptional oncolytic efficacy of NDV. We engineered the F protein of NDV and generated a recombinant NDV (rNDV) whose F protein is cleavable exclusively by prostate-specific antigen (PSA). The rNDV replicated efficiently and specifically in prostate cancer (CaP) cells and 3-dimensional prostaspheres but failed to replicate in the absence of PSA. Induction of intracellular PSA production by a synthetic androgen analog (R1881) enhanced fusogenicity in androgen-responsive CaP cells. Further, PSA-cleavable rNDV caused specific lysis of androgen-independent and androgen-responsive/nonresponsive CaP cells and prostaspheres, with a half-maximal effective concentration (EC50) ranging from a multiplicity of infection of 0.01 to 0.1. PSA-retargeted NDV efficiently lysed prostasphere tumor mimics, suggesting efficacy in vivo. Also, PSA-cleavable NDV failed to replicate in chicken embryos, indicating no pathogenicity for chickens. Prostate-specific antigen targeting is likely to enhance the therapeutic index of rNDV owing to tumor-restricted replication and enhanced fusogenicity.

Efficacy of Cetuximab in Metastatic Castration-Resistant Prostate Cancer Might Depend on EGFR and PTEN Expression: Results from a Phase II Trial (SAKK 08/07)

The EGF receptor (EGFR) is overexpressed in the majority of metastatic castration-resistant prostate cancers (mCRPC) and might represent a valid therapeutic target. The combination of docetaxel and cetuximab, the monoclonal antibody against EGFR, has not been tested in patients with prostate cancer. Patients with mCRPC progressing during or within 90 days after at least 12 weeks of docetaxel were included in this phase II trial. Treatment consisted of docetaxel (75 mg/m(2) every 3 weeks or 35 mg/m(2) on days 1, 8, 15 every 4 weeks) in combination with cetuximab (400 mg/m(2) on day 1 and then 250 mg/m(2) weekly). The primary endpoint was progression-free survival (PFS) at 12 weeks defined as the absence of prostate-specific antigen (PSA), radiographic, or clinical progression. Evaluation of known biomarkers of response and resistance to cetuximab (EGFR, PTEN, amphiregulin, epiregulin) was conducted. Thirty-eight patients were enrolled at 15 Swiss centers. Median age was 68 years and median PSA was 212 ng/mL. PFS at 12 weeks was 34% [95% confidence interval (CI), 19%-52%], PFS at 24 weeks was 20%, and median overall survival (OS) was 13.3 months (95% CI, 7.3-15.4). Seven patients (20%) had a confirmed ≥ 50% and 11 patients (31%) a confirmed ≥ 30% PSA decline. About 47% of enrolled patients experienced grade 3 and 8% grade 4 toxicities. A significantly improved PFS was found in patients with overexpression of EGFR and persistent activity of PTEN. EGFR inhibition with cetuximab might improve the outcome of patients with mCRPC. A potential correlation between EGFR overexpression, persistent expression of PTEN, and EGFR inhibition should be investigated further.

Recombinant prostate-specific antigen proaerolysin shows selective protease sensitivity and cell cytotoxicity

Native proaerolysin is a channel-forming bacterial protoxin that binds to cell-surface receptors and then is activated by furin or furin-like proteases. We genetically engineered proaerolysin by replacing the furin-cleavage sequence with a prostate-specific antigen-selective sequence. The recombinant modified proaerolysin was expressed and purified from Aeromonas salmonicida in good yields and purity. Recombinant modified proaerolysin had no furin sensitivity and markedly increased prostate-specific antigen sensitivity relative to wild-type proaerolysin. Human prostate cancer cells were significantly more sensitive to recombinant modified proaerolysin in the presence of active prostate-specific antigen when compared with the absence of prostate-specific antigen or the presence of potent prostate-specific antigen inhibitors. Most normal human cells with the exception of prostate and renal epithelial cells showed very low sensitivity to recombinant modified proaerolysin. Our results suggest that recombinant modified proaerolysin is a potent prostate-specific antigen-sensitive protoxin that deserves further development for regional therapy of benign and malignant prostate growths.

THE USE OF PROSTATE-SPECIFIC ANTIGEN AS A CRITERION FOR CONDOM EFFECTIVENESS

A series of articles recently published in the Journal reported on the use of pre- and postcoital levels of prostatespecific antigen (PSA) in vaginal fluid as a criterion for the effectiveness of condoms. The authors of course emphasized and interpreted the absence of PSA in the vagina as proof of the good quality of condoms as well as the reliability of mechanical contraception. However the referenced articles do not deal with female PSA (refer to Zaviacic and Ablin and the references therein) that as by the male prostate is generated by the female prostate. Moreover there is no mention of either a possibility of the presence of PSA in the vagina of a healthy woman or the significance of the female prostate and a woman’s sexual life in this possible vaginal PSA positivity. (excerpt)

Immunoperoxidase localization of prostate-specific antigen.

In instances of metastatic tumor from an unknown primary site, it is important to isolate those cases which are attributable to prostatic carcinoma. Immunoperoxidase localization of human prostate-specific antigen (PSA) would be useful in this regard if it were reliably detectable in prostatic carcinoma. We have studied 15 specimens from 14 patients with carcinoma of the prostate by immunoperoxidase techniques. The presence of PSA correlates with the Gleason grade. All cases of Gleason grade 9 or less demonstrated strong staining for PSA. Of the seven specimens with a Gleason grade 10, only four (57%) demonstrated significant staining, while two were entirely devoid of PSA. PSA is thus useful when it is present, but the absence of PSA in a poorly differentiated tumor of undetermined origin does not unequivocally rule out the possibility of a prostatic carcinoma.