The relationship between clinical phenotype and kallikrein-kinin bioregulation in different forms of arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have shown increased levels of neutrophils generating kallikrein-kinin peptides in blood which are potent mediators of inflammation. This study investigated the association between the bioregulation of kinin-mediated inflammation with the clinical, quality of life, and imaging characteristics (e.g. ultrasonography) of different arthritides. METHODS: Patients with osteoarthritis (OA, n = 29), gout (n = 10) and RA (n = 8) were recruited and screened for clinical symptoms, quality of life, and ultrasonographical assessment of arthritis. Blood neutrophils were assessed for the expression of bradykinin receptors (B1R and B2R), kininogens and kallikreins by immunocytochemistry with visualization by bright field microscopy. Levels of plasma biomarkers were measured by ELISA and cytometric bead array. RESULTS: Quality of life (SF-36 domains and summary scores; including pain; and, HAQ) was similar across OA, gout and RA patients; with the exception of worse physical functioning scores between OA and gout patients. Synovial hypertrophy (on ultrasound) differed between groups (p = 0.001), and the dichotomised Power Doppler (PD) score of greater than or equal to 2 (PD-GE2) was marginally significant (p = 0.09). Plasma IL-8 were highest in patients with gout followed by RA and OA (both, P < 0.05). Patients with RA had higher plasma levels of sTNFR1, IL-1ß, IL-12p70, TNF and IL-6, compared to OA and gout patients (all, P < 0.05). Patients with OA had higher expression of K1B and KLK1 on blood neutrophils followed by RA and gout patients (both, P < 0.05). Bodily pain correlated with B1R expression on blood neutrophils (r = 0.334, p = 0.05), and inversely with plasma levels of CRP (r = -0.55), sTNFR1 (r = -0.352) and IL-6 (r = -0.422), all P < 0.05. Expression of B1R on blood neutrophils also correlated with Knee PD (r = 0.403) and PD-GE2 (r = 0.480), both P < 0.05. CONCLUSIONS: Pain levels and quality of life were similar between patients with OA, RA and gout with knee arthritis. Plasma inflammatory biomarkers and B1R expression on blood neutrophils correlated with pain. Targeting B1R to modulate the kinin-kallikrein system may pose as a new therapeutic target in the treatment of arthritis.

Development and preliminary evaluation of an integrin α2ß1-targeted PET probe as a supplement and alternative of PSMA imaging for prostate cancer.

An integrin α2ß1-targeted PET probe (68Ga-IABtP) was developed to serve as a supplement and alternative of PSMA imaging for prostate cancer. 68Ga-IABtP was synthesized by labeling the precursor peptide with 68Ga with 93% labeling yield and 4.14 MBq/µg specific radioactivity. 68Ga-IABtP showed no specific uptake in LNCaP prostate cancer cell with low integrin α2ß1 expression but significantly increased uptake in PC-3 prostate cancer cell with high integrin α2ß1 expression, which could be specifically blocked by the integrin α2ß1 monoclonal antibody. The efflux experiments demonstrated that 68Ga-IABtP could rapidly penetrate into PC-3 cell after cell binding, thereby prolonging the residence time in the tumor and allow enough time for probe clearance from the circulation and non-specific organs. The biodistribution study indicated that 68Ga-IABtP showed no specific accumulation in non-target organs and was quickly cleared from the kidney. The in vivo PET-CT imaging demonstrated that 68Ga-IABtP showed no specific uptake in LNCaP tumor but could specifically accumulate in the PC-3 tumor, and was rapidly cleared from spleen, intestine, kidney and liver, resulting in excellent contrast effect with low background signal and high target to non-target ratios.

Number of screening rounds attended and incidence of high-risk prostate cancer in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC).

BACKGROUND: The European Randomized Study of Screening for Prostate Cancer has shown a 20% reduction in prostate cancer (PC) mortality by prostate-specific antigen-based screening. In addition, screening has been shown to reduce the risk of advanced PC. The objective of the current study was to analyze the impact of screening participation on the incidence of PC by risk group. METHODS: The participants in the screening arm of the Finnish trial (31,867 men) were classified according to screening attendance in a time-dependent fashion. Initially, all men in the screening arm were regarded as nonattenders until the first screening attendance; they then remained in the once-screened group until the second screen and similarly for the possible third round. The control arm formed the reference group. Follow-up started at randomization and ended at the time of diagnosis of PC, emigration, or the end of 2015. PC cases were divided into risk groups according to European Association of Urology definitions. RESULTS: The incidence of low-risk PC increased with the number of screens, whereas no clear relation with participation was noted in the intermediate-risk and high-risk cases. For patients with advanced PC, attending screening at least twice was associated with a lower risk. CONCLUSIONS: Screening reduces the risk of advanced PC after only 2 screening cycles. A single screen demonstrated no benefit in terms of PC incidence. Repeated screening is necessary to achieve screening advantages.

Impact of health literacy on shared decision making for prostate-specific antigen screening in the United States.

BACKGROUND: Current guidelines endorse shared decision making (SDM) for prostate-specific antigen (PSA) screening. The relationship between a patient's health literacy (HL) and SDM remains unclear. In the current study, the authors sought to identify the impact of HL on the rates of PSA screening and on the relationship between HL and SDM following the 2012 US Preventive Services Task Force recommendations against PSA screening. METHODS: Using data from the 2016 Behavioral Risk Factor Surveillance System, the authors examined PSA screening in the 13 states that administered the optional "Health Literacy" module. Men aged ≥50 years were examined. Complex samples multivariable logistic regression models were computed to assess the odds of undergoing PSA screening. The interactions between HL and SDM were also examined. RESULTS: A weighted sample of 12.249 million men with a rate of PSA screening of 33.4% were identified. Approximately one-third self-identified as having optimal HL. Rates of PSA screening were found to be highest amongst the highest HL group (42.2%). Being in this group was a significant predictor of undergoing PSA screening (odds ratio, 1.214; 95% confidence interval, 1.051-1.403). There was a significant interaction observed between HL and SDM (P for interaction, <.001) such that higher HL was associated with a lower likelihood of undergoing PSA screening when SDM was present. CONCLUSIONS: In the uncertain environment of multiple contradictory screening guidelines, men who reported higher levels of HL were found to have higher levels of screening. The authors demonstrated that increased HL may reduce the screening-promoting effect of SDM. These findings highlight the dynamic interplay between HL and SDM that should inform the creation and promulgation of SDM guidelines, specifically when considering patients with low HL.

Abrogation of survival disparity between Black and White individuals after the USPSTF's 2012 prostate-specific antigen-based prostate cancer screening recommendation.

BACKGROUND: In May 2012, the US Preventive Services Task Force (USPSTF) recommended against prostate-specific antigen (PSA)-based screening for prostate cancer (PCa), assigning it a grade D. This decision then was modified in 2018 to a grade C for men aged 55 to 69 years. The authors hypothesized that changes in screening practices would reduce survival outcomes for both Black and White men but maintain racial discrepancies in outcomes. METHODS: Using the Surveillance, Epidemiology, and End Results database, the authors examined PCa-specific survival based on race and year of diagnosis. The period between January 2010 and December 2012 was categorized as the pre-USPSTF era, whereas the period between January 2014 and December 2016 was classified as the post-USPSTF era. The year 2013 was considered the transition year and was excluded from the analysis. RESULTS: A total of 49,388 men were identified in the pre-USPSTF era who were diagnosed with PCa, approximately 83.7% of whom were White and 16.3% of whom were Black. In the post-USPSTF era, a total of 41,829 men were diagnosed with PCa, approximately 82.7% of whom were White and 17.3% of whom were Black. When compared with the pre-USPSTF era, men diagnosed in the post-USPSTF era were found to have more adverse clinical features. In the pre-USPSTF era, White men were less likely to die of PCa than Black men. This survival disparity between White and Black men was no longer observed in the post-USPSTF era. CONCLUSIONS: In men diagnosed with PCa between 2014 and 2016, a survival disparity between White and Black men was not observed due to a decrease in survival among White men while the survival of Black men remained steady.

Prostate-specific antigen testing after the US Preventive Services Task Force recommendation: a population-based analysis of electronic health data.

PURPOSE: This study describes longitudinal trends in the use of prostate-specific antigen (PSA)-based testing in two geographically distinct healthcare systems following the 2011 US Preventive Services Task Force (USPSTF) recommendations against routine PSA screening. METHODS: We analyzed population-based health claims data from 253,139 men aged 40-80 who were enrolled at two US healthcare systems. We assessed trends in the percentage of eligible men receiving ≥ 1 PSA test per year by time period (2000-2008, 2009-2011, 2012-2014), age (40-54, 55-69, 70-80), and race (white, black, other, unknown), and conducted a joinpoint regression analysis. RESULTS: Men aged 55-69 and 70-80 years of all races had similar use of PSA testing between 2000 and 2011, ranging between 47 and 56% of eligible men by year, while only 22-26% of men aged 40-54 had a PSA test per year during this period. Overall, the percentage of men receiving at least one PSA test per year decreased by 26% between 2009-2011 and 2012-2014, with similar trends across race and age groups. PSA testing declined significantly after 2011 (annual percent change = - 11.28). CONCLUSIONS: Following the 2011 USPSTF recommendations against routine PSA screening, declines in PSA testing were observed among men of all races and across all age groups in two large US healthcare systems.

Failure to achieve castrate level of serum testosterone during luteinizing hormone-releasing hormone agonist therapy in a patient with prostate cancer.

We report the failure to achieve castrate level of serum testosterone during luteinizing hormone-releasing hormone agonist therapy in a patient with prostate cancer. A 76-year-old man was admitted to our hospital for evaluation of an elevated serum prostate specific antigen (PSA) level (191.10 ng/ml) in August 2011. He was diagnosed with T3aN0M1b prostate adenocarcinoma. A combined androgen blockade using luteinizing hormone-releasing hormone agonist (the 1-month depot of leuprorelin acetate) and antiandrogen was administered. Due to liver dysfunction, antiandrogens, both bicalutamide and flutamide, were stopped. The 1-month depot was switched to the 3-month depot in May 2013, but the patient complained of induration and abscess at the infection site. Leuprorelin acetate was replaced by goserelin acetate. Because no adverse event appeared after injection of the 1-month depot of goserelin acetate, the 3-month depot was administered in October 2013. The PSA level increased gradually, and the testosterone level was greater than 50 ng/dl, that is, above castrate range. The 3-month depot of both leuprorelin acetate and goserelin acetate was not effective for this patient. For this reason, the 1-month depot of leuprorelin acetate was started resulting in a rapid decrease in PSA and testosterone levels. Thereafter, androgen depriving therapy could be continued. Androgen deprivation therapy is the standard treatment for patients with advanced prostate cancer and luteinizing hormone-releasing hormone aims to suppress serum testosterone to castrate range. We recommend assessing the serum testosterone levels during luteinizing hormone-releasing hormone agonist therapy for monitoring treatment efficacy and verifying progression when the PSA level increases.

How to make clinical decisions to avoid unnecessary prostate screening in biopsy-naïve men with PI-RADs v2 score ≤ 3?

PURPOSE: To determine whether patients can avoid systematic prostate biopsy (PBx) if their Prostate Imaging Reporting and Data System version 2 (PI-RADs v2) score is ≤ 3 and how we clinicians make decisions that can maximize benefit. MATERIALS AND METHODS: We reviewed our prospectively maintained database of consecutive men who received transrectal ultrasound-guided 24-core biopsy as well as pre-biopsy multi-parametric magnetic resonance imaging (mp-MRI). Of the 1276 men who were performed PBx in our institution from 2012 to July 2018, 491 patients conformed to the criteria. Negative predictive value (NPV) of negative mp-MRI (defined as PI-RADs < 3) combined prostate-specific antigen density (PSAD) were calculated. Models based on PI-RADs v2 were developed to predict the absence of clinically significant prostate cancer (CSPCa) and prostate cancer (PCa). Nomograms as well as receiver operating curves (ROC) were established to estimate the discrimination. Calibration curves were used to assess the concordance between predictive value and true risk. Decision curves were made to measure the overall net benefit. RESULTS: Prostate cancer and CSPCa detection rates were 21.6%, 7.3% and 36.7%, 23.4% in PIRADs v2 < 3 cohort and PIRADs v2 = 3 cohort, respectively. Men with biopsy-proved CSPCa had higher prostate-specific antigen (PSA), lower prostate volume (PV) and higher PSAD (all p < 0.05 in the two cohorts) than patients with clinically insignificant prostate cancer (CIPCa) or negative results. NPV of negative mp-MRI for detection of PCa was much higher when the PSAD was less than 0.15 (p < 0.001) and 0.2 for CSPCa (p = 0.007). According to multivariate analysis, we developed the model comprising Age, PSAD and PI-RADs v2 to predict the absence of CSPCa and PCa. The area under the curve (AUC) of the model for non-CSPCa was 0.75 (95% CI 0.68-0.80, PSAD cutoff 0.20), better than 0.71 (95% CI 0.65-0.80, PSAD cutoff 0.15). As for model for non-PCa, the AUC was 0.76 (95% CI 0.70-0.80, PSAD cutoff 0.15), higher than 0.71(95% CI 0.67-0.78, PSAD cutoff 0.20). Internally validated calibration curves showed that the model might overestimated the risk of the absence of CSPCa when the threshold was between 53 and 72%, and if the threshold was between 72 and 87%, it might underestimate the risk. As for the absence of PCa, the model might overestimate the risk between 52 and 76%. Decision curves showed that a better clinical net benefit was met when the threshold was 55% for non-PCa and 70% for non-CSPCa. CONCLUSIONS: NPV of negative mp-MRI for detection of CSPCa and PCa was improved with decreasing PSAD. The nomograms based on PI-RADs v2, age and PSAD showed internally validated high discrimination and calibration for the absence of PCa and CSPCa. When the predictive value was greater than 70% for the absence of CSPCa and 55% for the absence of PCa, we could avoid unnecessary PBx to maximize net benefit.

Upregulation of CRISP-3 and kallikrein in stallion seminal plasma is associated with poor tolerance of cooled storage.

For unknown reasons, stallion fertility and sperm longevity during cooled storage of semen vary markedly between individuals. Spermatozoa from individual stallions react differently to the presence, or the removal, of seminal plasma (SP). The aim was to evaluate differences in protein content in stallion seminal plasma with either a positive or a negative effect on sperm chromatin integrity during storage. Stallion semen samples from different ejaculate fractions were stored at 5°C for 24 hr. Sperm survival was assessed after storage using a sperm chromatin structure assay. Protein expression in SP with either positive or negative effects on sperm survival during storage was studied using two-dimensional differential gel electrophoresis and liquid chromatography-mass spectrometry. Lower sperm chromatin integrity was associated with upregulation of the proteins kallikrein, CRISP-3 and HSP-1, while higher chromatin integrity was associated with upregulation of TIMP-2. In the sperm-rich fractions, kallikrein and CRISP-3 differed significantly between SP samples with differing effects on sperm chromatin integrity. In the sperm-poor fractions, TIMP-2 and HSP-1 differed significantly between the two SP groups. Differences in the seminal plasma proteome are associated with sperm longevity during cooled storage.

Ultrasensitive amperometric immunosensor for the prostate specific antigen by exploiting a Fenton reaction induced by a metal-organic framework nanocomposite of type Au/Fe-MOF with peroxidase mimicking activity.

To increase the sensitivity of electrochemical sensor, Fe-MIL-88B-NH2 (Fe-MOF) with peroxidase-like activity is designed for the construction of immunoprobe. The Fe-MOF was prepared by one-step hydrothermalf method using 2-aminoterephthalic acid and iron(III) chloride. For the immunoprobe, it was fabricated by gold nanocomposite/Fe-MOF (Au/Fe-MOF) for the immobilization of labeling antibody (the antibody was used to conjuncting with label materials). The thin layer of Methylene Blue (MB) covered by reduced graphene oxide-gold nanocomposites (Au-rGO) serves as a substrate to covalently fix coating antibodies. The MB as a redox-active species was modified on the glass carbon electrode that can give a strong amperometric signal at 0.18 V (vs. Ag/AgCl). With the participation of H2O2, Fe-MOF can induce the Fenton reaction which degrades MB covered by Au-rGO on the substrate. The rest of MB on the surface of electrode becomes oxidized thereby generating a current signal. Square wave voltammetry (SWV) was used to quantify PSA. Under optimal conditions, the immunoassay is stable, specific and reproducible. It has a lower detection limit of 0.13 pg mL-1 (S/N = 3) and a wide analytical range that extends from 0.001 to 100 ng mL-1. Graphical abstractA sandwich-type amperometric immunoassay based on Fe-MOF-induced Fenton reaction was designed for sensitive determination of prostate specific antigen.

Beyond PSA: The Role of Prostate Health Index (phi).

BACKGROUND: Widespread use of prostate specific antigen (PSA) in screening procedures allowed early identification of an increasing number of prostate cancers (PCas), mainly including indolent cancer. Availability of different therapeutic strategies which have a very different impact on the patient's quality of life suggested a strong need for tools able to identify clinically significant cancer at diagnosis. Multi-parametric magnetic resonance showed very good performance in pre-biopsy diagnosis. However, it is an expensive tool and requires an experienced radiologist. In this context, a simple blood-based test is worth investigating. In this context, researchers focused their attention on the development of a laboratory test able to minimize overdiagnosis without losing the identification of aggressive tumors. RESULTS: Recent literature data on PCa biomarkers revealed a clear tendency towards the use of panels of biomarkers or a combination of biomarkers and clinical variables. Phi, the 4Kscore, and Stockholm3 as circulating biomarkers and the Mi-prostate score, Exo DX Prostate, and Select MD-X as urinary biomarker-based tests have been developed. In this scenario, phi is worthy of attention as a noninvasive test significantly associated with aggressive PCa. CONCLUSIONS: Literature data showed that phi had good diagnostic performance to identify clinically significant (cs) PCa, suggesting that it could be a useful tool for personalized treatment decision-making. In this review, phi potentialities, limitations, and comparisons with other blood- and urinary-based tests were explored.

Triplexed CEA-NSE-PSA Immunoassay Using Time-Gated Terbium-to-Quantum Dot FRET.

Time-gated Förster resonance energy transfer (TG-FRET) between Tb complexes and luminescent semiconductor quantum dots (QDs) provides highly advantageous photophysical properties for multiplexed biosensing. Multiplexed Tb-to-QD FRET immunoassays possess a large potential for in vitro diagnostics, but their performance is often insufficient for their application under clinical conditions. Here, we developed a homogeneous TG-FRET immunoassay for the quantification of carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and prostate-specific antigen (PSA) from a single serum sample by multiplexed Tb-to-QD FRET. Tb-IgG antibody donor conjugates were combined with compact QD-F(ab')2 antibody acceptor conjugates with three different QDs emitting at 605, 650, and 705 nm. Upon antibody-antigen-antibody sandwich complex formation, the QD acceptors were sensitized via FRET from Tb, and the FRET ratios of QD and Tb TG luminescence intensities increased specifically with increasing antigen concentrations. Although limits of detection (LoDs: 3.6 ng/mL CEA, 3.5 ng/mL NSE, and 0.3 ng/mL PSA) for the triplexed assay were slightly higher compared to the single-antigen assays, they were still in a clinically relevant concentration range and could be quantified in 50 µL serum samples on a B·R·A·H·M·S KRYPTOR Compact PLUS clinical immunoassay plate reader. The simultaneous quantification of CEA, NSE, and PSA at different concentrations from the same serum sample demonstrated actual multiplexing Tb-to-QD FRET immunoassays and the potential of this technology for translation into clinical diagnostics.

Bias-corrected estimates of effects of PSA screening decisions on the risk of prostate cancer diagnosis and death: Analysis of the Finnish randomized study of screening for prostate cancer.

More information is needed about effects of prostate-specific antigen (PSA) screening for informed decision making. The objective of our study is to evaluate the effects of an implemented screening decision on the risk of prostate cancer (PC) diagnosis and PC death. In a randomized trial, 31,867 Finnish men aged 55-67 years were allocated to the screening arm and 48,282 to the control arm during 1996-1999. Two to three screening rounds were offered to the screening arm with a PSA cut-off of 4.0 ng/ml. A counterfactual exclusion method was used to adjust for the effects of screening noncompliance and PSA contamination on risk of PC death and PC incidence by prognostic group at 15 years of follow up. After correcting for noncompliance and contamination, PSA screening led to 32.4 (95% CI 26.4, 38.6) more PC diagnoses per 1,000 men after 15 years and 1.4 (95% CI 0.0, 2.8) fewer PC deaths compared to the control arm. The corresponding results of an intention-to-screen analysis were 16.5 (95% CI 12.3, 20.7) and 0.8 (95% CI 0.5, 2.0), respectively. These results can be used for patient counseling in informed decision making about PC screening. A limitation of the study was the lack of comprehensive data on contamination.

Immunoreactivity for prostate specific antigen and Ki67 differentiates subgroups of prostate cancer related to outcome.

Based on gene-expression profiles, prostate tumors can be subdivided into subtypes with different aggressiveness and response to treatment. We investigated if similar clinically relevant subgroups can be identified simply by the combination of two immunohistochemistry markers: one for tumor cell differentiation (prostate specific antigen, PSA) and one for proliferation (Ki67). This was analyzed in men with prostate cancer diagnosed at transurethral resection of the prostate 1975-1991 (n = 331) where the majority was managed by watchful waiting. Ki67 and PSA immunoreactivity was related to outcome and to tumor characteristics previously associated with prognosis. Increased Ki67 and decreased PSA were associated with poor outcome, and they provided independent prognostic information from Gleason score. A combinatory score for PSA and Ki67 immunoreactivity was produced using the median PSA and Ki67 levels as cut-off (for Ki67 the upper quartile was also evaluated) for differentiation into subgroups. Patients with PSA low/Ki67 high tumors showed higher Gleason score, more advanced tumor stage, and higher risk of prostate cancer death compared to other patients. Their tumor epithelial cells were often ERG positive and expressed higher levels of ErbB2, phosphorylated epidermal growth factor receptor (pEGF-R) and protein kinase B (pAkt), and their tumor stroma showed a reactive response with type 2 macrophage infiltration, high density of blood vessels and hyaluronic acid, and with reduced levels of caveolin-1, androgen receptors, and mast cells. In contrast, men with PSA high/Ki67 low tumors were characterized by low Gleason score, and the most favorable outcome amongst PSA/Ki67-defined subgroups. Men with PSA low/Ki67 low tumors showed clinical and tumor characteristics intermediate of the two groups above. A combinatory PSA/Ki67 immunoreactivity score identifies subgroups of prostate cancers with different epithelial and stroma phenotypes and highly different outcome but the clinical usefulness of this approach needs to be validated in other cohorts.

Electrochemiluminescent immunosensor for prostate specific antigen based upon luminol functionalized platinum nanoparticles loaded on graphene.

A novel label-free electrochemiluminescent (ECL) immunosensor based upon luminol functionalized platinum nanoparticles loaded on graphene sheets (Lu-Pt@GS) as sensing platform was fabricated for highly sensitive and selective determination of prostate specific antigen (PSA). In this work, for the first time luminol was employed as both ECL luminescence reagent and reductants to in-situ reduce H2PtCl6 forming Pt NPs on surface of GS. A great deal of luminol could be attached onto the surface of Pt NPs within the reduction process, which can generate strong ECL emission. Pt NPs not only could enhance ECL signals of luminol but supply active sites for the immobilization of PSA antibodies with micro friendly environment. For preventing the consecutive reaction among luminol and H2O2, single-step cycle pulse was adopted, resulting in stable and strong ECL signals. Under optimized experimental conditions, the proposed ECL immunosensor acquired a wide linear range of 1 pg/mL to 10 ng/mL with a relatively low detection limit of 0.3 pg/mL for PSA. Furthermore, due to high sensitivity, simplicity and cost-effectiveness, the designed immunosensor provides a new method for detecting other important biomarkers in clinical analysis.

Significant Diagnostic Value of Free-Serum PSA (FPSA)/Prostate-Specific Antigen Density (PSAD) and (F/T)/PSAD for Prostate Cancer of the Chinese Population in a Single Institution.

BACKGROUND The aim of this study was to investigate the diagnostic value of (F/T)/PSAD for prostate cancer detection in the Chinese population. MATERIAL AND METHODS Data were collected retrospectively from patients with prostate cancer or benign prostatic hyperplasia from July 2009 to September 2014. SPSS 19.0 software was used for the receiver operating characteristic curve (ROC), and calculating sensitivity, specificity, and positive predictive values (PPV) and negative predictive values (NPV), respectively. Comparison of the area under ROC (AUC) was performed using the MedCalc v. 10.4.7.0 software. RESULTS A total of 660 patients (including 251 patients with prostate cancer and 409 patients with prostatic hyperplasia) were included. Prostate volume (PV), prostate-specific antigen density (PSAD), free-serum PSA (FPSA)/PSAD, and free-to-total PSA (F/T)/PSAD had similar AUC (P>0.05), and had significantly higher AUC (P<0.001) than F/T, total-serum PSA (TPSA), and free-serum PSA (FPSA). Based on the optimal cutoff value, the sensitivity of (F/T)/PSAD and FPSA/PSAD was similar (P>0.05), and significantly higher than the PV and PSAD (P<0.05). The logistic regression model using a combination of age, FPSA, PV, PSAD, FPSA/PSAD, and (F/T)/PSAD showed higher AUC than each one alone (P<0.001). CONCLUSIONS (F/T)/PSAD can be used as a predictor for prostate cancer in the Chinese population aged >50 years and has a significantly lower false negative rate than PSAD and PV with a cutoff value of ≤0.731. A new parameter, FPSA/PSAD, has similar diagnostic accuracy comparable to (F/T)/PSAD. The diagnostic value of a combination of age, FPSA, PV, PSAD, FPSA/PSAD, and (F/T)/PSAD needs further investigation.

The Specific Choice of Transrectal Ultrasound-Guided Prostate Biopsy Scheme Based on Prostate Specific Antigen and Prostate Specific Antigen Density.

BACKGROUND Although magnetic resonance imaging (MRI)-targeted biopsy and saturation biopsy can improve the accuracy of prostate biopsy, transrectal ultrasound (TRUS)-guided prostate biopsy is still the cornerstone for diagnosis of prostate cancer. However, it is not clear whether it is necessary to perform the same TRUS-guided biopsy scheme for patients with different prostate specific antigen (PSA) or prostate specific antigen density (PSAD) levels. The purpose of this study was to evaluate the optimal core number for specific suspected prostate cancer patients. MATERIAL AND METHODS There were 398 patients who underwent 12-core biopsy scheme, who were included in this retrospective analysis. The 12-core scheme incorporated a classic sextant scheme and 4-core biopsies from the base and middle regions bilaterally. The cancer detection rates of patients with different PSA or PSAD levels between the 12-core, sextant, 4-core, and 2-core biopsy were compared. RESULTS The differences in cancer detection rates between the 12-core biopsy scheme and the sextant biopsy scheme were significant in patients with PSA <20 ng/mL or PSAD <0.3. There were no differences in the cancer detection rates between the 12-core biopsy scheme and the 4-core biopsy scheme in patients with PSA ≤50 ng/mL or PSAD ≤1.0. There were significant differences between 12-core and 2-core scheme when PSA ≤70 ng/mL or PSAD ≤1.5. CONCLUSIONS We recommend that the 12-core biopsy should be used for patients with PSA <20 ng/mL or PSAD <0.3. The biopsy scheme in patients with PSA 20-50 ng/mL or PSAD 0.3-1.0 should be considered in combination with DRE and MRI. For patients with PSA >50 ng/mL or PSAD >1.0, we recommend 6-core or 4-core biopsy by comprehensively considering multiple factors. The 2-core biopsy is recommended for patients with PSA >70 ng/mL or PSAD >1.5.

Summary statement on screening for prostate cancer in Europe.

The European Randomised Study of Screening for Prostate Cancer (ERSPC) showed that Prostate-Specific Antigen (PSA) based screening results in a significant prostate cancer mortality reduction. Although there are concerns on overdiagnosis and overtreatment, it has been shown that the benefits can outweigh the harms if screening is stopped in older ages to prevent overdiagnosis. A limited screening program (for example screening at ages 55-59 years), including active surveillance for men with low-risk tumors, can even be cost-saving, compared with testing in an opportunistic setting in the wrong ages, as currently in Europe. Further improvements are expected in the use of active surveillance and in discrimination between indolent and significant disease due to new biomarkers and magnetic resonance imaging. However, these future developments are no reason to postpone feasibility studies of high-quality PSA screening and reduce opportunistic testing at old ages.

Kallikrein-related peptidases and associated microRNAs as promising prognostic biomarkers in gastrointestinal malignancies.

Gastrointestinal (GI) malignancies represent a wide spectrum of diseases of the GI tract and its accessory digestive organs, including esophageal (EC), gastric (GC), hepatocellular, pancreatic (PC) and colorectal cancers (CRC). Malignancies of the GI system are responsible for nearly 30% of cancer-related morbidity and approximately 40% of cancer-related mortality, worldwide. For this reason, the discovery of novel prognostic biomarkers that can efficiently provide a better prognosis, risk assessment and prediction of treatment response is an imperative need. Human kallikrein-related peptidases (KLKs) are a subgroup of trypsin and chymotrypsin-like serine peptidases that have emerged as promising prognosticators for many human types of cancer, being aberrantly expressed in cancerous tissues. The aberrant expression of KLKs in human malignancies is often regulated by KLK/microRNAs (miRNAs) interactions, as many miRNAs have been found to target KLKs and therefore alter their expression levels. The biomarker utility of KLKs has been elucidated not only in endocrine-related human malignancies, including those of the prostate and breast, but also in GI malignancies. The main purpose of this review is to summarize the existing information regarding the prognostic significance of KLKs in major types of GI malignancies and highlight the regulatory role of miRNAs on the expression levels of KLKs in these types of cancer.

Prostate Cancer Disseminated Tumor Cells are Rarely Detected in the Bone Marrow of Patients with Localized Disease Undergoing Radical Prostatectomy across Multiple Rare Cell Detection Platforms.

PURPOSE: Prostate circulating tumor cells escape into peripheral blood and enter bone marrow as disseminated tumor cells, representing an early step before conventionally detectable metastasis. It is unclear how frequently this occurs in localized disease and existing detection methods rely on epithelial markers with low specificity and sensitivity. We used multiple methodologies of disseminated tumor cell detection in bone marrow harvested at radical prostatectomy. MATERIALS AND METHODS: Bone marrow was harvested from 208 clinically localized cases, 16 controls and 5 metastatic cases with peripheral blood obtained from 37 metastatic cases. Samples were evaluated at 4 centers with 4 distinct platforms using antibody enrichment with the AdnaTest (Qiagen®) or VERSA (versatile exclusion based rare sample analysis), or whole sample interrogation with the RareCyte platform (Seattle, Washington) or HD-SCA (high definition single cell assay) using traditional epithelial markers and prostate specific markers. We investigated the sensitivity and specificity of these markers by evaluating expression levels in control and metastatic cases. RESULTS: EpCAM, NKX3.1 and AR were nonspecifically expressed in controls and in most samples using AdnaTest with no relation to perioperative variables. Only 1 patient with localized disease showed positive results for the prostate specific marker PSA. With the VERSA platform no localized case demonstrated disseminated tumor cells. With the RareCyte and HD-SCA platforms only a single patient had 1 disseminated tumor cell. CONCLUSIONS: Evaluation across multiple platforms revealed that epithelial markers are nonspecific in bone marrow and, thus, not suitable for disseminated tumor cell detection. Using prostate specific markers disseminated tumor cells were typically not detected in patients with localized prostate cancer.