Mesothelin antigen density influences anti-mesothelin chimeric antigen receptor T cell cytotoxicity.

BACKGROUND AIMS: Several anti-mesothelin (MSLN) chimeric antigen receptor (CAR) T cells are in phase 1/2 clinical trials to treat solid-organ malignancies. The effect of MSLN antigen density on MSLN CAR cytotoxicity against tumor cells has not been examined previously, nor are there data regarding the effect of agents that increase MSLN antigen density on anti-MSLN CAR T cell efficacy. METHODS: MSLN antigen density was measured on a panel of pancreatic cancer and mesothelioma cell lines by flow cytometry. In parallel, the cytotoxicity and specificity of two anti-MSLN CAR T cells (m912 and SS1) were compared against these cell lines using a real-time impedance-based assay. The effect of two MSLN 'sheddase' inhibitors (lanabecestat and TMI-1) that increase MSLN surface expression was also tested in combination with CAR T cells. RESULTS: SS1 CAR T cells were more cytotoxic compared with m912 CAR T cells against cell lines that expressed fewer than ∼170 000 MSLN molecules/cell. A comparison of the m912 and amatuximab (humanized SS1) antibodies identified that amatuximab could detect and bind to lower levels of MSLN on pancreatic cancer and mesothelioma cell lines, suggesting that superior antibody/scFv affinity was the reason for the SS1 CAR's superior cytotoxicity. The cytotoxicity of m912 CAR T cells was improved in the presence of sheddase inhibitors, which increased MSLN antigen density. CONCLUSIONS: These data highlight the value of assessing CAR constructs against a panel of cells expressing varying degrees of target tumor antigen as occurs in human tumors. Furthermore, the problem of low antigen density may be overcome by concomitant administration of drugs that inhibit enzymatic shedding of MSLN.

Pretreatment prostate-specific antigen density as a predictor of biochemical recurrence in patients with prostate cancer: a meta-analysis.

BACKGROUND: A consensus has not been reached on the value of prostate-specific antigen density (PSAD) as a predictor of biochemical recurrence of prostate cancer. This meta-analysis aimed to evaluate the association between PSAD and biochemical recurrence of prostate cancer after primary treatment. METHODS: Two authors systematically searched PubMed, Web of Science, and Embase databases (up to August September 10, 2023) to identify studies that assessed the value of pretreatment PSAD in predicting biochemical recurrence after primary treatment (radical prostatectomy or radiotherapy) of prostate cancer. A random effect model was used to pool adjusted hazard ratios (HR) with 95% confidence intervals (CI) for biochemical recurrence. RESULTS: Nine studies with 4963 patients were eligible for the meta-analysis. The reported prevalence of biochemical recurrence ranged from 4 to 55.1%. For patients with higher PSAD compared to those with low PSAD, the pooled HR of biochemical recurrence was 1.59 (95% CI 1.21-2.10). Subgroup analysis showed that the pooled HR of biochemical recurrence was 1.80 (95% CI 1.34-2.42) for patients who received radical prostatectomy, and 0.98 (95% CI 0.66-1.45) for patients who received radiotherapy. CONCLUSIONS: Elevated pretreatment PSAD may be an independent predictor for biochemical recurrence of prostate cancer after radical prostatectomy. Determining PSAD could potentially improve the prediction of biochemical recurrence in patients with prostate cancer.

Utility of Prostate Health Index Density for Biopsy Strategy in Biopsy-Naïve Patients With PI-RADS v2.1 Category 3 Lesions.

BACKGROUND: Category 3 lesions in PI-RADSv2.1 pose diagnostic challenges, complicating biopsy decisions. Recent biomarkers like prostate health index (PHI) have shown higher specificity in detecting clinically significant prostate cancer (csPCa) than prostate-specific antigen (PSA). Yet their integration with MRI remains understudied. PURPOSE: To evaluate the utility of PSA and PHI with its derivatives for detecting csPCa in biopsy-naïve patients with category 3 lesion on initial prostate MRI scan. STUDY TYPE: Retrospective. POPULATION: One hundred ninety-three biopsy-naïve patients who underwent MRI, PSA, and PHI testing, followed by both targeted and systematic biopsies. FIELD STRENGTH/SEQUENCE: Turbo spin-echo T2-weighted imaging, diffusion-weighted single-shot echo-planar imaging, and dynamic contrast-enhanced T1-weighted fast field echo sequence imaging in 3 T. ASSESSMENT: PHI density (PHID) and PSA density (PSAD) derived by dividing serum PHI and PSA with prostate volume (MRI based methodology suggested by PI-RADSv2.1). Risk-stratified models to evaluate the utility of markers in triaging patients for biopsy, including low-, intermediate-, and high-risk groups. STATISTICAL TESTS: Independent t-test, Mann-Whitney U test, Mantel-Haenszel test, generalized estimating equation, and receiver operating characteristic (ROC) curve analysis were used. Statistical significance defined as P < 0.05. RESULTS: CsPCa was found in 16.6% (32/193) of patients. PHID had the highest area under the ROC curve (AUROC) of 0.793, followed by PHI of 0.752, PSAD of 0.750, and PSA of 0.654. PHID with two cut-off points (0.88/mL and 1.82/mL) showed the highest potential biopsy avoidance of 47.7% (92/193) with 5% missing csPCa, and the lowest intermediate-risk group (borderline decision group) at 38.9% (75/193), compared to PSA and PHI. DATA CONCLUSION: PHID demonstrated better potential in triaging patients with category 3 lesions, possibly aiding more selective and confident biopsy decisions for csPCa detection, than traditional markers. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 5.

Reduction of false positives using zone-specific prostate-specific antigen density for prostate MRI-based biopsy decision strategies.

OBJECTIVES: To develop and test zone-specific prostate-specific antigen density (sPSAD) combined with PI-RADS to guide prostate biopsy decision strategies (BDS). METHODS: This retrospective study included consecutive patients, who underwent prostate MRI and biopsy (01/2012-10/2018). The whole gland and transition zone (TZ) were segmented at MRI using a retrained deep learning system (DLS; nnU-Net) to calculate PSAD and sPSAD, respectively. Additionally, sPSAD and PI-RADS were combined in a BDS, and diagnostic performances to detect Grade Group ≥ 2 (GG ≥ 2) prostate cancer were compared. Patient-based cancer detection using sPSAD was assessed by bootstrapping with 1000 repetitions and reported as area under the curve (AUC). Clinical utility of the BDS was tested in the hold-out test set using decision curve analysis. Statistics included nonparametric DeLong test for AUCs and Fisher-Yates test for remaining performance metrics. RESULTS: A total of 1604 patients aged 67 (interquartile range, 61-73) with 48% GG ≥ 2 prevalence (774/1604) were evaluated. By employing DLS-based prostate and TZ volumes (DICE coefficients of 0.89 (95% confidence interval, 0.80-0.97) and 0.84 (0.70-0.99)), GG ≥ 2 detection using PSAD was inferior to sPSAD (AUC, 0.71 (0.68-0.74)/0.73 (0.70-0.76); p < 0.001). Combining PI-RADS with sPSAD, GG ≥ 2 detection specificity doubled from 18% (10-20%) to 43% (30-44%; p < 0.001) with similar sensitivity (93% (89-96%)/97% (94-99%); p = 0.052), when biopsies were taken in PI-RADS 4-5 and 3 only if sPSAD was ≥ 0.42 ng/mL/cc as compared to all PI-RADS 3-5 cases. Additionally, using the sPSAD-based BDS, false positives were reduced by 25% (123 (104-142)/165 (146-185); p < 0.001). CONCLUSION: Using sPSAD to guide biopsy decisions in PI-RADS 3 lesions can reduce false positives at MRI while maintaining high sensitivity for GG ≥ 2 cancers. CLINICAL RELEVANCE STATEMENT: Transition zone-specific prostate-specific antigen density can improve the accuracy of prostate cancer detection compared to MRI assessments alone, by lowering false-positive cases without significantly missing men with ISUP GG ≥ 2 cancers. KEY POINTS: • Prostate biopsy decision strategies using PI-RADS at MRI are limited by a substantial proportion of false positives, not yielding grade group ≥ 2 prostate cancer. • PI-RADS combined with transition zone (TZ)-specific prostate-specific antigen density (PSAD) decreased the number of unproductive biopsies by 25% compared to PI-RADS only. • TZ-specific PSAD also improved the specificity of MRI-directed biopsies by 9% compared to the whole gland PSAD, while showing identical sensitivity.

Estimated Prostate Volume by Semiautomatic Segmentation of MRI Is More Accurately Correlated with Radical Prostatectomy Specimen Weight than the Volume Calculated by Ellipsoid Formula.

INTRODUCTION: Accurate in vivo prostate volume (PV) estimation is important for obtaining prostate-specific antigen density (PSAD) and further predicting clinically significant prostate cancer (csPCa). We aimed to evaluate the accuracy of multiparametric magnetic resonance imaging (mpMRI)-estimated PV compared to both volume and weight of radical prostatectomy (RP). METHODS: We identified 310 PCa patients who underwent RP following combined targeted and systematic biopsy in our institution from September 2019 to February 2021. The MRI PV was determined using a semiautomated segmentation algorithm. RP PV was calculated using the prolate ellipsoid formula (length × width × height × π/6). Formula (prostate weight = [actual weight-3.8 g]/1.05 g/mL) was applied, and the resulting volume was used in further analysis. RESULTS: The median PV from MRI, RP, and RP weight were 39 mL, 38 mL, and 44 mL, respectively. Spearman's rank correlation coefficients (ρ) were 0.841 (MRI PV vs. RP weight), 0.758 (RP PV vs. RP weight), and 0.707 (MRI PV vs. RP PV) (all p < 0.001). Decreased correlation between the MRI PV and RP PV was observed in the larger (more than 55 mL) prostate. The PSAD derived from MRI PV showed most efficient to detect csPCa in RP specimen (57.9% vs. 57.6% vs. 45.4%). CONCLUSION: MRI PV is correlated better with RP weight than calculated RP PV, especially in larger prostate. The high csPCa detection rate in final pathology suggested that PSAD derived from MRI PV can be confidently used in clinical practice.

PSA density does not improve predictive accuracy of the UCSF-CAPRA score.

INTRODUCTION: The University of California, San Francisco Cancer of the Prostate Risk Assessment (CAPRA) score is a validated tool using factors at diagnosis to predict prostate cancer outcomes after radical prostatectomy (RP). This study evaluates whether substitution of prostate-specific antigen (PSA) density for serum PSA improves predictive performance of the clinical CAPRA model. METHODS: Participants were diagnosed in 2000-2019 with stage T1/T2 cancer, underwent RP, with at least a 6-month follow-up. We computed standard CAPRA score using diagnostic age, Gleason grade, percent positive cores, clinical T stage, and serum PSA, and an alternate score using similar variables but substituting PSA density for PSA. We reported CAPRA categories as low (0-2), intermediate (3-5), and high (6-10) risk. Recurrence was defined as two consecutive PSA ≥ 0.2 ng/mL or receipt of salvage treatment. Life table and Kaplan-Meier analysis evaluated recurrence-free survival after prostatectomy. Cox proportional hazards regression models tested associations of standard or alternate CAPRA variables with recurrence risk. Additional models tested associations between standard or alternate CAPRA score with recurrence risk. Cox log-likelihood ratio test (-2 LOG L) assessed model accuracy. RESULTS: A total of 2880 patients had median age 62 years, GG1 30% and GG2 31%, median PSA 6.5, and median PSA density 0.19. Median postoperative follow-up was 45 months. Alternate CAPRA model was associated with shifts in risk scores, with 16% of patients increasing and 7% decreasing (p < 0.01). Recurrence-free survival after RP was 75% at 5 years and 62% at 10 years. Both CAPRA component models were associated with recurrence risk after RP on Cox regression. Covariate fit statistics showed better fit for standard CAPRA model versus alternate (p < 0.01). Standard (hazard ratio [HR]: 1.55; 95% confidence interval [CI]: 1.50-1.61) and alternate (HR: 1.50; 95% CI: 1.44-1.55) CAPRA scores were associated with recurrence risk, with better fit for standard model (p < 0.01). CONCLUSIONS: In a 2880 patient cohort followed for median 45 months after RP, alternate CAPRA model using PSA density was associated with higher biochemical recurrence (BCR) risk, but performed inferior to standard CAPRA at predicting BCR. While PSA density is an established prognostic variable in prediagnostic settings and sub-stratifying low-risk disease, it does not improve BCR model predictive accuracy when applied across a range of cancer risk.

Preclinical development and evaluation of nanobody-based CD70-specific CAR T cells for the treatment of acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) treatment remains challenging. CD70 was reported as a promising AML-specific antigen. Preclinically, CAR T-cell with single-chain-variable fragment (scFv) or truncated CD27 targeting CD70 has been reported to treat AML. However, various disadvantages including spontaneous exhaustion, proteinase-mediated loss of functional receptors, and high immunogenicity, limited its further application to clinical settings. Alternatively, the single-variable domain on heavy chain (VHH), also known as nanobodies, with comparable binding ability and specificity, provides an optional solution. METHOD: We generated CD70 knocked-out novel nanobody-based anti-CD70-CAR T-cells (nb70CAR-T) with two different VHHs for antigen detection. Next, we detected the CD70 expression on primary AML blasts by flow cytometry and associated the efficacy of nb70CAR-T with the target antigen density. Finally, epigenetic modulators were investigated to regulate the CD70 expression on AML cells to promote the functionality of nb70CAR-T. RESULTS: Our nb70CAR-T exhibited expected tumoricidal functionality against CD70-expressed cell lines and primary AML blasts. However, CD70 expression in primary AML blasts was not consistently high and nb70CAR-T potently respond to an estimated 40.4% of AML patients when the CD70 expression level was over a threshold of 1.6 (MFI ratio). Epigenetic modulators, Decitabine and Chidamide can up-regulate CD70 expression on AML cells, enhancing the treatment efficacy of nb70CAR-T. CONCLUSION: CD70 expression in AML blasts was not fully supportive of its role in AML targeted therapy as reported. The combinational use of Chidamide and Decitabine with nb70CAR-T could provide a new potential for the treatment of AML.

A novel clinically significant prostate cancer prediction system with multiparametric MRI and PSA: P.Z.A. score.

PURPOSE: This study aims to establish and validate a new diagnosis model called P.Z.A. score for clinically significant prostate cancer (csPCa). METHODS: The demographic and clinical characteristics of 956 patients were recorded. Age, prostate-specific antigen (PSA), free/total PSA (f/tPSA), PSA density (PSAD), peripheral zone volume ratio (PZ-ratio), and adjusted PSAD of PZ (aPSADPZ) were calculated and subjected to receiver operating characteristic (ROC) curve analysis. The nomogram was established, and discrimination abilities of the new nomogram were verified with a calibration curve and area under the ROC curve (AUC). The clinical benefits of P.Z.A. score were evaluated by decision curve analysis and clinical impact curves. External validation of the model using the validation set was also performed. RESULTS: The AUCs of aPSADPZ, age, PSA, f/tPSA, PSAD and PZ-ratio were 0.824, 0.672, 0.684, 0.715, 0.792 and 0.717, respectively. The optimal threshold of P.Z.A. score was 0.41. The nomogram displayed excellent net benefit and better overall calibration for predicting the occurrence of csPCa. In addition, the number of patients with csPCa predicted by P.Z.A. score was in good agreement with the actual number of patients with csPCa in the high-risk threshold. The validation set provided better validation of the model. CONCLUSION: P.Z.A. score (including PIRADS(P), aPSADPZ(Z) and age(A)) can increase the detection rate of csPCa, which may decrease the risk of misdiagnosis and reduce the number of unnecessary biopsies. P.Z.A. score contains data that is easy to obtain and is worthy of clinical replication.

Antigen-specific IgG subclass composition in recipient mice can indicate the degree of red blood cell alloimmunization as well as discern between primary and secondary immunization.

BACKGROUND: Despite the vast antigen disparity between donor and recipient red blood cells (RBCs), only 2%-6% of transfusion patients mount an alloantibody response. Recently, RBC antigen density has been proposed as one of the factors that can influence alloimmunization, however, there has been no characterization of the role of antigen density along with RBC dose in primary and secondary immunization. STUDY DESIGN AND METHODS: To generate RBCs that express distinct antigen copy numbers, different quantities of hen egg lysozyme (HEL) were coupled to murine RBCs. The HEL-RBCs were subsequently transfused into recipient mice at different RBC doses and their HEL-specific IgM, IgG, and IgG subclass response was evaluated. RESULTS: Productive immune responses could be generated through a high copy number antigen transfused at low RBC doses or a low copy number transfused at high RBC doses. Further, primary but submaximal humoral immunization predominantly induced the IgG2b and IgG3 subclasses. In contrast, a maximal primary immunization or a secondary immunization induced all four IgG subclasses. DISCUSSION: Our results confirm the existence of an antigen threshold for productive immune responses but indicate that a high antigen copy number alone might not be enough to induce a response, but rather a combination of both antigen copy number and cell dosage may determine the outcome of immunization. Further, this study provides a proof of concept that the IgG subclass composition can be an indicator of the level of RBC alloimmunization as well as discern between primary and secondary immunization at least in this murine model.

Antigen copy number and antibody dose can determine the outcome of erythrocyte alloimmunization inducing either antibody-mediated immune suppression or enhancement in a murine model.

BACKGROUND: The administration of anti-D for the prevention of hemolytic disease of the fetus and newborn is one of the most successful clinical uses of the phenomenon of antibody-mediated immune suppression (AMIS). However, despite adequate prophylaxis, failures can still occur in the clinic and are poorly understood. Recently, the copy number of red blood cell (RBC) antigens has been shown to influence immunogenicity in the context of RBC alloimmunization; however, its influence on AMIS remains unexplored. STUDY DESIGN AND METHODS: RBCs expressing approximately 3,600 and approximately 12,400 copy numbers of surface-bound hen egg lysozyme (HEL), named respectively HELmed -RBCs and HELhi -RBCs, and selected doses of a polyclonal HEL-specific IgG were transfused into mice. Recipient HEL-specific IgM, IgG, and IgG subclass responses were evaluated by ELISA. RESULTS: Antigen copy number affected the antibody dose required for AMIS induction with higher antigen copy numbers requiring larger doses of antibody. For instance, 5 µg of antibody caused AMIS for HELmed -RBCs but not HELhi -RBCs, while 20 µg induced significant suppression for both HEL-RBCs. Overall, increasing amounts of the AMIS-inducing antibody were associated with a more complete AMIS effect. In contrast, the lowest tested doses of the AMIS-inducing IgG led to evidence of enhancement at the IgM and IgG levels. DISCUSSION: The results demonstrate that the relationship between antigen copy number and antibody dose can influence the outcome of AMIS. Further, this work suggests that the same antibody preparation can induce both AMIS and enhancement but that the outcome may depend on the quantitative interrelationship of antigen-antibody binding.

Clinical value of prostate health index as an indicator for recommending magnetic resonance imaging in patients with gray-zone prostate-specific antigen level.

PURPOSE: To evaluate the usefulness of prostate health index (PHI) as an indicator for recommending magnetic resonance imaging (MRI) in patients with prostate-specific antigen (PSA) gray zone level < 10 ng/mL. METHODS: 443 patients who underwent prostate biopsy (PB) after serum PHI test and MRI between April 2019 and December 2022 were enrolled. For patients with visible lesion on MRI with Prostate Imaging Reporting and Data System Score (PI-RADS) ≥ 3, MRI-targeted PB was performed in addition to systematic 12-core PB. RESULTS: The optimal cutoff value of PHI for predicting PI-RADS ≥ 3 lesions was 39.6, which was significantly associated with overall prostate cancer (OR 3.07, p = 0.018) and clinically significant prostate cancer (csPCa) (OR 4.15, p = 0.006) at MRI-targeted PB cores. When MRI was restricted to patients with PHI ≥ 39.6 alone, 28.7% of unnecessary MRI could be saved at the cost of missing 13.6% of csPCa. When omitting MRI for patients with PHI < 39.6 and PSAD < 0.12 ng/mL2, unnecessary MRI could be reduced by 20.1% with the risk of missing 6.2% of csPCa. With addition of systematic PB, 21.0% of patients with negative MRI-targeted PB were diagnosed as csPCa. CONCLUSIONS: For patients in PSA gray zone, PHI of 39.6 might be an indicator for MRI and further MRI-targeted PB in additional to PSAD of 0.12 ng/mL2, reducing 20.1% of unnecessary MRI with the minimal risk of missing 6.2% of csPCa. To maximize csPCa detection, combining both MRI-targeted and systematic PB should be also considered.

The Value of Prostate-Specific Antigen Density in Combination with Lesion Diameter for the Accuracy of Prostate Cancer Prediction in Prostate Imaging-Reporting and Data System 3 Prostate Lesions.

INTRODUCTION: The aim of the study was to investigate the value of prostate-specific antigen density (PSAD) and lesion diameter (LD) combination in prostate cancer (PCa) detection. METHODS: 181 patients who were detected to have prostate imaging-reporting and data system (PI-RADS) 3 lesions in mpMRI and underwent prostate biopsies were included in the study. Demographic, clinical, and pathological data of all patients were evaluated. The patients were divided into four groups according to PSAD and LD status (PSAD <0.15 ng/mL/cc + LD <1 cm, PSAD <0.15 ng/mL/cc + LD ≥1 cm, PSAD ≥0.15 ng/mL/cc + LD <1 cm, and PSAD ≥0.15 ng/mL/cc + LD ≥1 cm). Diagnostic ability for PCa and clinical significant PCa (csPCa) was evaluated by PSAD and LD. RESULTS: PSAD ≥0.15 ng/mL/cc (OR = 6; 95% Cl = 2.847-12.647; p < 0.001), LD ≥1 cm (OR = 7.341; 95% confidence interval [CI] = 2.91-18.52; p < 0.001), and combination of PSAD ≥0.15 ng/mL/cc and LD ≥1 cm (OR = 10.023; 95% CI = 4.32-23.252; p < 0.001) were associated with PCa detection rates. The most sensitivity, specificity, negative, and positive predictive values were found in PSAD ≥0.15 ng/mL/cc + LD ≥1 cm group for both PCa and csPCa detection (48.8%, 92%, 85.2%, and 65.6% for any PCa detection; 66.7%, 85.2%, 97.3%, and 24.2% for csPCa detection, respectively). CONCLUSION: The presence of PSAD ≥0.15 ng/mL/cc or LD ≥1 cm in mpMRI of patients with PI-RADS 3 lesions is associated significantly with the finding of PCa and particularly with the detection of csPCa.

Pseudotyping Improves the Yield of Functional SARS-CoV-2 Virus-like Particles (VLPs) as Tools for Vaccine and Therapeutic Development.

Virus-like particles (VLPs) have been proposed as an attractive tool in SARS-CoV-2 vaccine development, both as (1) a vaccine candidate with high immunogenicity and low reactogenicity and (2) a substitute for live virus in functional and neutralization assays. Though multiple SARS-CoV-2 VLP designs have already been explored in Sf9 insect cells, a key parameter ensuring VLPs are a viable platform is the VLP spike yield (i.e., spike protein content in VLP), which has largely been unreported. In this study, we show that the common strategy of producing SARS-CoV-2 VLPs by expressing spike protein in combination with the native coronavirus membrane and/or envelope protein forms VLPs, but at a critically low spike yield (~0.04-0.08 mg/L). In contrast, fusing the spike ectodomain to the influenza HA transmembrane domain and cytoplasmic tail and co-expressing M1 increased VLP spike yield to ~0.4 mg/L. More importantly, this increased yield translated to a greater VLP spike antigen density (~96 spike monomers/VLP) that more closely resembles that of native SARS-CoV-2 virus (~72-144 Spike monomers/virion). Pseudotyping further allowed for production of functional alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2), and omicron (B.1.1.529) SARS-CoV-2 VLPs that bound to the target ACE2 receptor. Finally, we demonstrated the utility of pseudotyped VLPs to test neutralizing antibody activity using a simple, acellular ELISA-based assay performed at biosafety level 1 (BSL-1). Taken together, this study highlights the advantage of pseudotyping over native SARS-CoV-2 VLP designs in achieving higher VLP spike yield and demonstrates the usefulness of pseudotyped VLPs as a surrogate for live virus in vaccine and therapeutic development against SARS-CoV-2 variants.

Diagnostic value of 18F-PSMA-1007 PET/CT combined with prostate specific antigen derived indicators in gray area prostate cancer. / 18F-PSMA-1007 PET/CTè”åˆå‰åˆ—è ºç‰¹å¼‚æ€§æŠ—åŽŸè¡ç”ŸæŒ‡æ ‡å¯¹ç°åŒºå‰åˆ—è ºç™Œçš„è¯Šæ–­ä»·å€¼.

OBJECTIVES: The incidence of prostate cancer is increasing every year, and precision diagnosis and treatment can help reduce unnecessary prostate punctures for prostate cancer patients in the gray area. This study aims to investigate the diagnostic value of 18F-prostate specific membrane antigen (PSMA) imaging combined with prostate specific antigen (PSA)-derived indicators for gray zone prostate cancer. METHODS: A total of 107 patients who underwent 18F-PSMA PET/CT imaging for suspicious prostate cancer with tPSA of 4 to 10 µg/L (PSA gray zone) in a hospital were retrospectively included, and were divided into a prostate cancer group and a non-prostate cancer group based on pathological findings. Patients underwent PSA testing, 18F-PSMA, and abdominal ultrasound, and age, tPSA, fPSA, f/tPSA, prostate volume, PSA density (PSAD), maximum standardized uptake value (SUVmax), and molecular imaging prostate specific membrane antigen (miPSMA) score were compared between the 2 groups. Multivariate logistic regression was used to analyze the influencing factors the diagnosis of gray zone prostate cancer. Receiver operating characteristic (ROC) curves were constructed to evaluate the efficacy of PSAD and SUVmax alone and in combination in diagnosing gray zone prostate cancer. RESULTS: The volume of the prostate cancer group [42.00(34.00, 58.00) cm3 vs 49.00(41.27, 60.41) cm3] was smaller than that of the non-prostate cancer group (Z=-2.376, P=0.017), and the PSAD [(0.18±0.06) µg/(L·cm3) vs 0.15±0.05 µg/(L·cm3)] and SUVmax [18.63(8.03, 28.57) vs 9.33(5.90, 13.52)] were higher than those in the non-prostate cancer group (both P<0.05). The percentage of miPSMA score ≥2 in the prostate cancer group was higher than that in the non-prostate cancer group (χ2=40.987, P<0.001). PSAD (OR=22.154, 95% CI 1.430 to 873.751, P=0.042) and SUVmax (OR=1.301, 95% CI 1.034 to 1.678, P=0.009) were independent influential factors for the diagnosis of prostate cancer in the gray zone. The optimal cut-off values of PSAD and SUVmax were 0.22 µg/(L·cm3) and 8.02, respectively, and the AUCs for the diagnosis of prostate cancer in the gray zone alone and in combination were 0.628 (95% CI 0.530 to 0.720, P<0.05) and 0.806 (95% CI 0.718 to 0.876, P<0.05), 0.847 (95% CI 0.765 to 0.910, P<0.05), with sensitivities of 41.03%, 76.92%, and 74.36% and specificities of 79.41%, 89.71%, and 92.65%, respectively. CONCLUSIONS: PSAD and SUVmax are increased in patients with gray zone prostate cancer, and the combination of PSAD and SUVmax is of high value in diagnosing gray zone prostate cancer.

Diagnostic evaluation and incorporation of PSA density and the prostate imaging and data reporting system (PIRADS) version 2 classification in risk-nomograms for prostate cancer.

PURPOSE: The diagnostic approach for prostate cancer still depends on PSA and DRE. OBJECTIVES: to evaluate the diagnostic validity of PSA-Density and PIRADSv2 as diagnostic tests regarding biopsy results, and to design nomograms that include all diagnostic variables for malignancy, significant tumor (ST) and high-grade tumor. METHODS: Cross-sectional study which included men with PSA ≥ 4 ng/ml and/or suspicious DRE, PIRADSv2 ≥ 3 lesions on multiparametric MRI and prostate biopsy. The gold standard test was the maximum ISUP of the targeted biopsy per patient (malignancy: ISUP ≥ 1, ST: ISUP ≥ 2, high-grade tumor: ISUP ≥ 4). Association and logistic regression tests were used and diagnostic validity parameters using PSA-Density and PIRADSv2 classification was analyzed. Nomograms were designed for malignancy, ST, and high-grade tumor using the best model selection procedure from all possible equations. RESULTS: 336 men with median age, PSA and PSA-Density of 67.7 years (IQR:12.6), 6.3 ng/ml (IQR:3.3) and 0.12 ng/ml/cc (IQR:0.10), respectively; 63 index lesions were PIRADS3, 204 PIRADS4, and 69 PIRADS5. 65.8% and 37.8% were malignant and ST, respectively. The significant positive association highlighted between malignancy and ST with age, DRE, PSA-Density and PIRADSv2. PSA-Density and PIRADSv2 ≥ 3 presented the highest sensitivity to detect malignancy, and their combination showed sensitivity nearly 95% (AUC:0.803). Nomograms for malignancy and ST included the variables age, DRE, PSA-Density, and PIRADSv2 with a sensitivity closely 91% (AUC:0.833), and a specificity of almost 85% for ST, exposing risk < 5% for ST when PSA-Density is < 0.15, not suspicious DRE and PIRADS3. CONCLUSION: PSA-Density and PIRADSv2 classification in risk nomograms can provide highly relevant information to increase the accuracy in the diagnosis of PC and ST.

The influence of age on prostate cancer screening index.

PURPOSE: This study aimed to identify parameters with a higher diagnostic value for early screening of prostate cancer (PCa) at different ages. MATERIALS AND METHODS: A total of 294 patients were included and divided into two groups according to the age of patients (≤66 and >66 years). Receiver operating characteristic (ROC) curves of total prostate-specific antigen (TPSA), free PSA (FPSA), (F/T)PSA, PSA density (PSAD), PSA-AV score, the ratio of patients' age to prostate volume (AVR) and (F/T)/PSAD were constructed. The area under the ROC curve (AUC) was calculated, and differences in the AUC values among the above-mentioned parameters were compared. RESULTS: There were 121 patients in the ≤66 years age group (benign prostatic hyperplasia BPH, 103 patients; PCa 18 patients) and 173 patients in the >66 years age group (BPH, 100 patients; PCa, 73 patients). In the ≤66 years age group, the AUC value of AVR for PCa diagnosis was the highest; however, there was no statistically significant difference compared with the AUC values of PSAD and (F/T)/PSAD; compared with TPSA, FPSA, (F/T)PSA and PSA-AV, the differences were statistically significant. In the >66 years age group, the AUC values of PSAD and PSA-AV for PCa diagnosis were higher than those of TPSA, FPSA, (F/T)PSA and (F/T)/PSAD, and the difference was statistically significant; however, the difference was not statistically significant when compared with the AUC value of AVR. CONCLUSION: In different age groups, screening indices for PCa diagnosis should be selected according to the age of patients.

The Influence of Endogenous Testosterone Density on Unfavorable Disease and Tumor Load at Final Pathology in Intermediate-Risk Prostate Cancer: Results in 338 Patients Treated with Radical Prostatectomy and Extended Pelvic Lymph Node Dissection.

OBJECTIVE: The aim of this study is to evaluate the influence of endogenous testosterone density (ETD) on features of aggressive prostate cancer (PCa) in intermediate-risk disease treated with radical prostatectomy and extended pelvic lymph node dissection. MATERIALS AND METHODS: Density measurements included the ratio of endogenous testosterone (ET), prostate-specific antigen (PSA), and percentage of biopsy positive cores (BPC) on prostate volume (ETD, PSAD, and BPCD, respectively). The ratio of percentage of cancer invading the gland (tumor load, TL) on prostate weight (TLD) was also calculated. Unfavorable disease (UD) was defined as tumor upgrading (ISUP >3) and/or upstaging (pT >2) and/or lymph node invasion (LNI). Associations of ETD with features of aggressive PCa, including UD and TLD, were evaluated by logistic and linear regression models. RESULTS: Evaluated cases were 338. Subjects with upgrading, upstaging, and LNI were 61/338 (18%), 73/338 (21%), and 25/338 (7.4%), respectively. TLD correlated with UD (Pearson's correlation coefficient, r = 0.204; p < 0.0001), PSAD (r = 0.342; p < 0.0001), BPCD (r = 0.364; p < 0.0001), and ETD (r = 0.214; p < 0.0001), which also correlated with BMI (r = -0.223; p < 0.0001), PSAD (r = 0.391; p < 0.0001), and BPCD (r = 0.407; p < 0.0001). TLD was the strongest independent predictor of UD (OR = 2.244; 95% CI = 1.146-4.395; p = 0.018). In the multivariate linear regression model predicting BPCD, ETD was an independent predictor (linear regression coefficient, b = 0.026; 95% CI: 0.016-0.036; p < 0.0001) together with PSAD (b = 1.599; 95% CI: 0.863-2.334; p < 0.0001) and TLD (b = 0.489; 95% CI: 0.274-0.706; p < 0.0001). According to models, TLD increased as ETD increased accordingly, but mean ET levels were significantly lower for patients with UD. CONCLUSIONS: As ETD measurements incremented, the risk of large tumors extending beyond the prostate increased accordingly, and patients with lower ET levels were more likely to occult UD. The influence of ETD on PCa biology should be addressed by prospective studies.

Combination of biparametric magnetic resonance imaging with prostate-specific antigen density to stratify the risk of significant prostate cancer: Initial biopsy and long-term follow-up results.

OBJECTIVES: To assess whether the combination of biparametric magnetic resonance imaging with prostate-specific antigen density can properly stratify the risk of significant prostate cancer in patients undergoing prostate biopsies and how this approach affects the detection of prostate cancer during follow-up in patients who do not undergo prostate biopsy. METHODS: In total, 411 biopsy-naïve patients who had elevated prostate-specific antigen levels and then underwent biparametric magnetic resonance imaging for suspicious prostate cancer were analyzed: 203 patients underwent prostate biopsies, whereas 208 patients did not. Significant prostate cancer detection rates stratified by the combination of Prostate Imaging Reporting and Data System score and prostate-specific antigen density were assessed in patients who underwent prostate biopsies. The cumulative incidence of prostate cancer detection during the follow-up was assessed in patients who omitted biopsy. RESULTS: The negative predictive value for significant prostate cancer was 89% for Prostate Imaging Reporting and Data System scores 1-3, which increased to 97% when prostate-specific antigen density <0.15 ng/ml/cm3 was combined. Among patients who did not undergo biopsy, patients with Prostate Imaging Reporting and Data System scores 1-3 plus prostate-specific antigen density <0.15 ng/ml/cm3 included significantly less cases in which significant prostate cancer was detected during the follow-up, compared with the others (3.2% versus 17% at 36 months). CONCLUSIONS: Restriction of prostate biopsies to patients with Prostate Imaging Reporting and Data System scores 4-5 or prostate-specific antigen density ≥0.15 ng/ml/cm3 proved to be the good biopsy strategy, effectively balancing risks and benefits.

The efficiency of prostate-specific antigen density measurement using three different methods on the prediction of biochemical recurrence.

BACKGROUND: The aim of this study was to evaluate the efficiency of prostate-specific antigen (PSA) density (PSAD) calculated through prostate volume (PV) obtained via transrectal ultrasound (TRUS) and magnetic resonance imaging (MRI) and actual prostate weight (PW) methods obtained via pathological evaluation on the prediction of biochemical recurrence (BCR) in the follow-ups of patients who had undergone radical prostatectomy (RP). METHODS: A total of 335 clinically localized prostate cancer (PCa) patients who had received open RP between January 2015 and December 2018 were enrolled in the study. Pre and postoperative demographic data, clinical and pathological findings and BCR conditions were recorded. The PSAD was calculated using information obtained through preoperative TRUS examinations, MRI, and collected pathological specimens after RP by dividing the maximum preoperative PSA value and PV/PW. RESULTS: In a mean follow-up duration of 20.2 ± 8.5 months, recurrence was observed in 52 patients (24.4%) and progression was observed in 8 (3.8%) patients. The TRUS-PSAD, MRI-PSAD, and PW-PSAD values were statistically significantly higher in BCR patients compared to non-BCR patients. The International Society of Urologic Pathologists (ISUP) grade 5 and pT3b as a pathological stage were detected as independent variables in the prediction of BCR formation. Actual PW had a high prediction value compared to other PSAD measurements at <40 g prostate weights, but it had a low prediction value in prostates with an actual PW >60 g. CONCLUSIONS: In this study, it was stated that PSAD acquired through different imaging methods does not affect the usability of PSAD in BCR prediction in clinical practice. The ISUP grade 5 and pT3b stage PCa were detected as independent markers in BCR prediction after RP.

Body mass index in relation to prostate-specific antigen-related parameters.

BACKGROUND: Only a few previous studies conducted to assess the association between body mass index (BMI) and prostate-specific antigen (PSA) related parameters have taken prostate volume (PV) and blood volume (BV) into consideration. The objective of this study was to assess the relationship between BMI and parameters of PSA concentrations in Chinese adult men. METHODS: A total of 86,912 men who have received annual physical examination at the First Affiliated Hospital of Army Medical University from 1 January 2011 to 31 December 2018 were included in this study. Linear regression models were performed to assess the relationship between BMI, PV, BV and PSA, and analyze the correlation between BMI and PSA, PSA density and PSA mass. RESULTS: The univariable linear regression showed that PV, BV, systolic pressure (SBP), pulse, fasting blood glucose (FBG) and age were significantly associated with PSA level (P < 0.05). The multivariate linear regression demonstrated that PV, BV, FBG and age were significantly associated with PSA level (P < 0.05). WHR and BMI is negatively associated with PSA and PSA density (P < 0.05), and no statistically significant association was found between PSA mass and WHR and (P = 0.268) or BMI (P = 0.608). CONCLUSIONS: The findings of this large-sample, hospital-based study in China indicate that PV was positively associated with serum PSA concentrations, while BMI and BV were inversely related with PSA levels. PSA mass can be used to estimate the PSA concentration without being affected by obesity in Chinese men.