Serum Prostate-specific Antigen Measurement Research Articles

Does ejaculation have an effect on urinary flow rates?

The primary objective of this investigation is to explore the impact of ejaculation on urinary flow rates in men experiencing lower urinary tract symptoms. This study involved the enrollment of 55 male patients who presented with lower urinary tract symptoms. An assessment encompassed components, including medical history, questionnaires related to sexual activity and lower urinary tract symptoms, bladder diary, physical examination, urinalysis, urine culture, ultrasound examination and measurements of serum prostate-specific antigen, free flow uroflowmetry, and post-void residual urine volume. All participants were instructed to abstain from ejaculation for 3 days before undergoing uroflowmetry (UF1). Subsequently, they were required to ejaculate. Subsequent uroflowmetry assessments were conducted at 2 to 4 h (UF2) and 48 to 50 h (UF3) after ejaculation. No further ejaculations were permitted during this timeframe. The patients had a mean age of 50.97 ± 1.47 years. Statistically significant differences were observed in the mean values of Qmax and corrected Qmax (cQmax) between UF1 and UF2 measurements (p < 0.05). These differences were only in patients with benign prostatic enlargement (BPE) (p < 0.05). Furthermore, the number of patients with Qmax <15 mL/s showed a statistically significant difference between UF1 and UF2 measurements, specifically in the BPE group (p = 0.016). In this study, we have observed a significant and temporary increase in the Qmax following ejaculation, particularly among patients with BPE. This indicates that ejaculation can potentially complicate the interpretation of uroflowmetry results. Therefore, further research is necessary to gain a more comprehensive understanding of this phenomenon.

Prediction of Prostate Cancer Risk Stratification Based on A Nonlinear Transformation Stacking Learning Strategy.

Prostate cancer (PCa) is an epithelial malignancy that originates in the prostate gland and is generally categorized into low, intermediate, and high-risk groups. The primary diagnostic indicator for PCa is the measurement of serum prostate-specific antigen (PSA) values. However, reliance on PSA levels can result in false positives, leading to unnecessary biopsies and an increased risk of invasive injuries. Therefore, it is imperative to develop an efficient and accurate method for PCa risk stratification. Many recent studies on PCa risk stratification based on clinical data have employed a binary classification, distinguishing between low to intermediate and high risk. In this paper, we propose a novel machine learning (ML) approach utilizing a stacking learning strategy for predicting the tripartite risk stratification of PCa. Clinical records, featuring attributes selected using the lasso method, were utilized with 5 ML classifiers. The outputs of these classifiers underwent transformation by various nonlinear transformers and were then concatenated with the lasso-selected features, resulting in a set of new features. A stacking learning strategy, integrating different ML classifiers, was developed based on these new features. Our proposed approach demonstrated superior performance, achieving an accuracy of 0.83 and an area under the receiver operating characteristic curve value of 0.88 in a dataset comprising 197 PCa patients with 42 clinical characteristics. This study aimed to improve clinicians' ability to rapidly assess PCa risk stratification while reducing the burden on patients. This was achieved by using artificial intelligence-related technologies as an auxiliary method for diagnosing PCa.

Clinical significance of atypical 68Ga-DOTATOC prostatic uptake on PET/CT: A ten-year review.

Gallium-68-DOTA-D-Phe1-Try3-Octreotide (68Ga-DOTATOC) is a radiolabeled somatostatin receptor (SSTR) analog that is widely used in the imaging of neuroendocrine tumors (NET). Benign and malignant prostate tumors have been observed to express SSTR. Diffuse symmetric DOTATOC uptake in the prostate is a normal positron emission tomography (PET) finding. The aim of this study was to evaluate the frequency and clinical significance of incidental atypical prostatic uptake in men undergoing 68Ga-DOTATOC PET/computed tomography(CT). A retrospective review of consecutive male patients who underwent 68Ga-DOTATOC PET/CT studies at Aalborg University Hospital, Denmark, from November 2010 to April 2020 was performed. Positron emission tomography/CT reports were searched for text words or phrases indicating incidental atypical prostatic uptake. In the resulting cohort, PET/CT were re-evaluated, and DOTATOC uptake in the prostate gland was categorized as focal, diffuse or mixed. The intensity of the uptake was visually graded using the Krenning visual score. Follow-up was based on all available clinical, biochemical, imaging, and pathology follow-up. A total of 178 male patients underwent 193 68Ga-DOTATOC PET/CT scans. Incidental atypical uptake of 68Ga-DOTATOC on PET/CT in the prostatic bed was observed in eight patients (4.5%) (mean age 67 years, range 58-85 years). Six patients (75%) had diffuse uptake; two (25%) patients had focal uptake. Four patients out of eight with incidental findings (50%) had uptake less than or equal to that of the liver (Krenning score 2); four patients (50%) had uptake greater than that of the liver (score 3). All patients had measurements of serum prostate-specific antigen and were referred for urological evaluation. Five patients (62%) underwent a transrectal ultrasound, and three required a biopsy of the prostate. No cases of prostate malignancy (including prostatic cancer) were diagnosed. During a 10-year period, we found that 4.5% of men exhibited prostate incidentalomas on 68Ga-DOTATOC PET/CT. No malignancy was found in the prostate in this population. Our data indicate absent malignancy among incidental 68Ga-DOTATOC findings in the prostate.

Screening Asymptomatic Men for Prostate Cancer Using Prostate-Specific Antigen as An Early Detection Tool: A Review of Existing Literature

Prostate cancer remains the most common non-skin cancer in men. Prostate-specific antigen (PSA) is recognized as a biomarker for the diagnosis, monitoring, and risk prediction of prostate cancer. However, its role in prostate cancer screening has been controversial. While some authorities have recommended its use for screening, others have stated otherwise. Some clarity is required about its precise role in clinical practice. There need to be more consistent recommendations surrounding using PSA screening in clinical practice. Serum PSA measurements show variable reliability when screening for Prostate cancer, given the dynamics of PSA physiology and the conflicting results from two large, randomized control trials that sought to determine its role in prostate cancer screening and early detection. Hence surrogate measures like PSA density, PSA velocity, free-to-complexed PSA ratio, and percentage Pro-PSA among others, have been used to improve the predictive utility of this assay for Prostate cancer diagnosis. However, the debate on screening still lingers. The current review aims to highlight the controversies and objectively outline the current recommendations. This literature review examined scholarly papers and recommendations about the use of PSA for prostate cancer screening with the aim to rationalize the pros and cons of such approaches. We concluded that although more recent guidelines from the USPSTF recommend that screening be based on individual preference and professional judgment by the healthcare provider, differences in the specific details on how to best employ a PSA screening program still exist and require further review.

Diagnostic Efficacy of PSMA and PSCA mRNAs Combined to PSA in Prostate Cancer Patients.

Serum Prostate-specific antigen (PSA) has been used for screening and diagnosis of prostate cancer (PCa) but it is burdened by its low accuracy, creating a need for reliable diagnostic markers. Despite prostate-specific membrane antigen (PSMA) and prostate stem cell antigen (PSCA) being widely expressed in the tissue of PCa, no definite conclusion regarding their use as clinical biomarkers due to their lacking organ specificity. Therefore, this study aimed to evaluate the peripheral blood levels of PSMA and PSCA mRNAs and examine their diagnostic significance as non-invasive integrated markers.<br /><br />Materials and Methods: 125 subjects were enrolled in this study. They were divided into 25 healthy controls, 25 BPH patients, and 75 PCa patients. The expression levels of PSMA and PSCA were determined using quantitative RT- PCR, in addition to measuring serum PSA.<br /><br />Results: Levels of PSMA and PSCA were over-expressed in PCa patients compared to controls and BPH patients and were found to be associated with increased susceptibility to PCa. Moreover, the diagnostic values of PSMA and PSCA to distinguish PCa patients from BPH patients and controls were inferior to that of PSA. However, the combination of PSMA and PSCA with PSA enhanced the efficacy of the latter.<br /><br />Conclusion: This study suggests that these genes were associated with malignant susceptibility. Concerning the duality of PSMA-PSA or PSCA-PSA, this implies the significance of their investigation together in peripheral blood of prostate patients.

Prognostic Evaluation of Metastatic Castration Resistant Prostate Cancer and Neuroendocrine Prostate Cancer with [68Ga]Ga DOTATATE PET-CT.

Objectives: Prostate cancer is well known to express high levels of somatostatin receptors and preliminary data suggests that PET imaging with the somatostatin analog, [68Ga]Ga-DOTATATE, may allow for whole body staging of patients with metastatic castration resistant prostate cancer (mCRPC) and neuroendocrine prostate cancer (NePC). This study explores the utility of [68Ga]Ga-DOTATATE PET-CT to identify metastatic deposits in men with mCRPC and NePC and prognosticate disease progression. Methods: [68Ga]Ga-DOTATATE PET-CT was performed in 17 patients with mCRPC and of those, 2/17 had NePC. A semiquantitative analysis with standardized uptake values (SUV) (e.g., SUVmax, SUVmean) was performed for each metastatic lesion and reference background tissues. [68Ga]Ga-DOTATATE uptake in metastatic deposits was further classified as: mild (less than liver), moderate (up to liver average), or marked (greater than liver). Serial prostate-specific antigen measurements and patient survival were followed up to 3 years after PET imaging to assess response to standard of care treatment. Results: All patients had at least one metastatic lesion with identifiable [68Ga]Ga-DOTATATE uptake. Marked [68Ga]Ga-DOTATATE uptake was found in 7/17 patients, including both NePC patients, and all were non-responders to systemic therapy and died within the follow up period, with a mean time to death of 8.1 months. Three patients had mild [68Ga]Ga-DOTATATE uptake, and all were responders to systemic therapy and were alive 36 months after [68Ga]Ga-DOTATATE imaging. Conclusions: [68Ga]Ga-DOTATATE is able to identify mCRPC and NePC metastatic deposits, and lesions with [68Ga]Ga-DOTATATE uptake > liver may portend poor outcomes in patients with mCRPC.

Abstract 3318: PSMA-targeted thorium-227 conjugate (PSMA-TTC) inhibits tumor growth and abnormal bone changes in the intratibial LNCaP xenograft model of bone-metastatic prostate cancer

Abstract Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein specifically overexpressed on the cell membrane of prostate cancer cells. PSMA-targeted thorium-227 conjugate (PSMA-TTC, BAY 2315497) consists of a human PSMA-targeting antibody covalently linked to a 3,2-HOPO (hydroxypyridinone) chelator moiety, radiolabeled with alpha-particle emitting thorium-227. Previous studies have demonstrated PSMA-TTC to be an attractive therapy option for patients with metastatic castration-resistant prostate cancer (mCRPC). In this study, we investigated the efficacy of PSMA-TTC in the LNCaP intratibial model mimicking prostate cancer metastasized to bone. LNCaP prostate cancer cells were inoculated into the right tibiae of male NOD.scid mice. The mice were randomized to treatment groups (n=12/group) based on serum prostate-specific antigen (PSA) and treated with a single dose of vehicle or PSMA-TTC (300 kBq/kg, 0.75 mg/kg, i.v.). Tumor growth was followed by biweekly serum PSA measurements for 42 days. Tumor-induced abnormal bone growth, PSMA-TTC uptake, bone microarchitecture, bone formation rate and tumor area in tumor-bearing tibiae were determined by radiography, gamma counter, microCT, and dynamic and static histomorphometry, respectively. A single injection of PSMA-TTC efficiently inhibited intratibial tumor growth (p&amp;lt;0.001) as evidenced by a 82.6% decrease from baseline PSA value in the treatment group at the end of the study, whereas the vehicle group increased by 380% from baseline. Furthermore, the tumor-bearing tibiae were heavier (138%) than the non-tumor-bearing tibiae in the vehicle group, whereas in the PSMA-TTC-treated mice no such difference was observed (103%). PSMA-TTC decreased tumor-induced abnormal bone area in the tumor-bearing tibiae (43.5% of the vehicle). PSMA-TTC uptake relative to tibia weight was higher in the tumor-bearing tibiae compared with the non-tumor-bearing tibiae, resulting in higher levels of thorium-227 and its daughter isotype radium-223 both 3 days and 3 weeks post injection. In this preclinical study, PSMA-TTC showed robust antitumor efficacy, for the first time, in a model mimicking prostate cancer metastasized to bone as evidenced by a decrease in serum PSA levels, tumor-induced abnormal bone changes, and tumor-bearing tibia weights in the PSMA-TTC-treated mice. PSMA-TTC binds to PSMA-expressing cancer cells, delivering a cytotoxic dose of alpha radiation. The decay product of thorium-227, radium-223 binds to bone matrix and this could also contribute to the antitumor efficacy in this bone-metastatic model. Taken together, our data indicate activity of PSMA-TTC in bone-metastatic CRPC. PSMA-TTC as a monotherapy as well as in combination with darolutamide is currently being investigated in patients with mCRPC in a phase 1 clinical trial (NCT03724747). Citation Format: Christoph Schatz, Mari I. Suominen, Matias Knuuttila, Sabine Zitzmann-Kolbe, Jukka Rissanen, Sanna-Maria Käkönen, Urs Hagemann, Arne Scholz. PSMA-targeted thorium-227 conjugate (PSMA-TTC) inhibits tumor growth and abnormal bone changes in the intratibial LNCaP xenograft model of bone-metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3318.

1.5T Magnetic Resonance-Guided Stereotactic Body Radiotherapy for Localized Prostate Cancer: Preliminary Clinical Results of Clinician- and Patient-Reported Outcomes.

Simple SummaryThe combination of stereotactic body radiotherapy (SBRT) and magnetic resonance-guided radiation therapy (MRgRT) offers the potential for achieving better tumor control and lower toxicities for prostate cancer (PC) patients. This study reports for the first time preliminary longitudinal clinical results of 1.5T MR-guided SBRT (MRgSBRT) in a cohort of 51 localized PC patients (median follow-up: 199 days; range: 41–424 days), based on both clinician-reported outcome measurement (CROM) and patient-reported outcome measurement (PROM). The maximum cumulative clinician-reported grade ≥ 2 (Common Terminology Criteria for Adverse Events Scale v. 5.0) acute genitourinary (GU) and gastrointestinal (GI) toxicities were 11.8% (6/51) and 2.0% (1/51), respectively, while grade ≥ 2 subacute GU and GI toxicities were 2.3% (1/43) each. Patient-reported urinary, bowel, and hormonal domain summary scores were reduced at 1 month, then gradually returned to baseline levels, with the exception of the sexual domain. The finding of low toxicity supports the accumulation of clinical evidence for 1.5T MRgSBRT in localized PC.Background: Magnetic resonance-guided stereotactic body radiotherapy (MRgSBRT) offers the potential for achieving better prostate cancer (PC) treatment outcomes. This study reports the preliminary clinical results of 1.5T MRgSBRT in localized PC, based on both clinician-reported outcome measurement (CROM) and patient-reported outcome measurement (PROM). Methods: Fifty-one consecutive localized PC patients were prospectively enrolled with a median follow-up of 199 days. MRgSBRT was delivered in five fractions of 7.25–8 Gy with daily online adaptation. Clinician-reported gastrointestinal (GI) and genitourinary (GU) adverse events based on the Common Terminology Criteria for Adverse Events (CTCAE) Scale v. 5.0 were assessed. The Expanded Prostate Cancer Index Composite Questionnaire was collected at baseline, 1 month, and every 3 months thereafter. Serial prostate-specific antigen measurements were longitudinally recorded. Results: The maximum cumulative clinician-reported grade ≥ 2 acute GU and GI toxicities were 11.8% (6/51) and 2.0% (1/51), respectively, while grade ≥ 2 subacute GU and GI toxicities were 2.3% (1/43) each. Patient-reported urinary, bowel, and hormonal domain summary scores were reduced at 1 month, then gradually returned to baseline levels, with the exception of the sexual domain. Domain-specific subscale scores showed similar longitudinal changes. All patients had early post-MRgSBRT biochemical responses. Conclusions: The finding of low toxicity supports the accumulation of clinical evidence for 1.5T MRgSBRT in localized PC.

PREDICTIVE VALUE OF SERUM PROSTATE SPECIFIC ANTIGEN IN DETECTING BONE METASTASIS IN PROSTATE CANCER

Objective: We determine the utility of Prostate Specific Antigen (PSA) for predicting the presence of skeletal metastasis on Bone Scan (BS) in prostate cancer patients. Material &amp; Methods: Retrospective analysis of medical records of 70 consecutive prostate cancer patients subjected to bone scan during the last 2 years was done. 5 cases were excluded due to the following reasons: Serum PSA not available, hormonal or other therapy given prior to serum PSA measurement, and/or Bone Scan, and symptomatic for bone metastasis. In remaining 65 cases, PSA value and bone scan were evaluated. Results: BS was found to be positive in 20/65 (31%) and negative in 45(69%) patients. 24 (37%) had serum PSA &gt; 100 ng/ml, 25 (38.5%) had PSA of 20‐100 ng/ml and only 16 (24.5%) had PSA &lt; 20 ng/ml. Conclusion: Serum PSA &lt; 20 ng/ml have high predictive value in ruling out skeletal metastasis. Our data are in corroboration with results from previous studies that BS should be performed only if PSA &gt; 20 ng/ml. Using this cut‐off, unnecessary investigation can be avoided. Avoiding BS asymptomatic in this group of patients would translate into a significant cost‐saving and reduction in their psychological and physical burden.

ERECTILE DYSFUNCTION AFTER TRANSURETHRAL PROSTATE RESECTION (TURP) IN PATIENTS WITH LOWER URINARY TRACT SYMPTOMS AT KOJA HOSPITAL, JAKARTA

Objective: Aim of this study is to identify risk factors associated with erectile dysfunction in post-transurethral prostate resection (TURP) patients for the management of benign prostatic hyperplasia (BPH). Material &amp; Methods: During 2019, 22 patients met the TURP indication criteria in the urology polyclinic of Koja Hospital for symptomatic BPH management. All patients underwent transabdominal ultrasonography to confirm prostate volume and underwent laboratory tests to measure serum prostate-specific antigen (PSA). History of comorbidities such as diabetes mellitus, cardiovascular events, and hypertension was recorded. The patient's sexual function was determined using the International Index of Erectile Function questionnaire (IIEF-5) before surgery and six months postoperatively, where erectile dysfunction was established for scores below 21. Mean comparisons were made to see if there was a significant change in IIEF score six months postoperatively. Results: There were 22 subjects as samples with a mean age of 63 ± 3.8 years, prostate volume 47.64 ± 5.5 mL and a median PSA level of 3.3 [1-47] ng/dL. The comorbidities found in the subjects were diabetes mellitus (22.7%), cardiovascular events (36.4%), and hypertension (27.3%). The mean IIEF-5 score before surgery was 14.55 ± 0.78 and was not significantly different (p= 0.225) with a reevaluation six months after surgery of 14.18 ± 0.76. Conclusion: There was no change in the severity of erectile dysfunction in patients undergoing TURP surgery.

Abstract 358: A prospective study of prostate cancer metastases identifies an androgen receptor activity-low, stemness program associated with resistance to androgen receptor axis inhibitors and unveils mechanisms of clonal evolution

Abstract Background: The androgen receptor axis inhibitors (ARi) (e.g, enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown. Methods: In a prospective trial MATCH-R (NCT02517892), 55 mCRPC patients underwent whole exome sequencing (WES) (n=45) and RNA-sequencing (RNA-seq) (n=52) of metastatic biopsies before starting ARi. Also, 16 mCRPC patients underwent biopsy at time of resistance (WES=14, RNA-seq = 14). The objectives were to identify genomic alterations associated with resistance to ARi as well as to describe clonal evolution. Primary resistance was determined at 4 months of treatment using composite criteria for progression that included serum prostate specific antigen measurements, bone scan, CT imaging and symptom assessments. Acquired resistance was defined by occurrence of progressive disease after initial response or stable disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher's exact tests. Results: At 4 months, 22/55 patients in the cohort had disease progression (primary resistance). No genomic alterations from WES analysis were significantly associated with primary resistance. Analysis of sequential biopsies suggests that mCRPC follows mainly a parallel evolution model and involve DNA-repair related mutational processes. At time of acquired resistance to ARi, most tumors acquired new drivers affecting AR pathway (e.g, AR, NCOR1/2) or lineage switching (e.g, RB1, PTEN, TP53). Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis to identify pathways whose activity state correlated with resistance. AR gene alterations and AR expression were similar between responding and non-responding patients. Transcriptional analysis demonstrated that multiple specific gene sets — including those linked to low AR transcriptional activity, stemness program, RB loss and homologous repair deficiency — were activated in both primary and acquired resistance. Conclusion: Resistance to AR axis inhibitors results from multiple transcriptional programs already activated in pre-treatment samples. Clonal evolution analysis along with RNA-seq data indicate the role of genomic instability and lineage switching in driving acquired resistance Citation Format: Naoual Menssouri, Loic Poiraudeau, Carole Helissey, Ludovic Bigot, Jonathan Sabio, Tony Ibrahim, Claudio Nicotra, Maud Ngocamus, Lambros Tselikas, Thierry De Baere, Etienne Rouleau, Ludovic Lacroix, Anne Chaucherau, Luc Friboulet, Ronan Flippot, Giulia Baciarello, Laurence Albiges, Emeline Colomba, Pernelle Lavaud, Stefan Michiels, Aline Maillard, Antoine Italiano, Fabrice Barlesi, Jean-Charles Soria, Jean-Yves Scoazec, christophe Massard, Benjamin Besse, Fabrice André, Karim Fizazi, Daniel Gautheret, Yohann Loriot. A prospective study of prostate cancer metastases identifies an androgen receptor activity-low, stemness program associated with resistance to androgen receptor axis inhibitors and unveils mechanisms of clonal evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 358.

Whole blood GRHL2 expression as a prognostic biomarker in metastatic hormone-sensitive and castration-resistant prostate cancer.

BackgroundAs potent systemic therapies transition earlier in the prostate cancer disease course, molecular biomarkers are needed to guide optimal treatment selection for metastatic hormone-sensitive prostate cancer (mHSPC). The value of whole blood RNA to detect candidate biomarkers in mHSPC remains largely undefined.MethodsIn this cohort study, we used a previously optimised whole blood reverse transcription polymerase chain reaction assay to assess the prognostic utility [measured by seven-month undetectable prostate-specific antigen (PSA) and time to castration-resistance (TTCR)] of eight prostate cancer-associated gene transcripts in 43 mHSPC patients. Transcripts with statistically significant associations (P<0.05) were further investigated in a metastatic castration-resistant prostate cancer (mCRPC) cohort (n=119) receiving contemporary systemic therapy, exploring associations with PSA >50% response (PSA50), progression-free survival (PFS) and overall survival (OS). Clinical outcomes were prospectively collected in a protected digital database. Kaplan-Meier estimates and multivariable Cox proportional-hazards models assessed associations between gene transcripts and clinical outcomes (mHSPC covariates: disease volume, docetaxel use and haemoglobin level; mCRPC covariates: prior exposure to chemotherapy or ARPIs, haemoglobin, performance status and presence of visceral disease). Follow-up was performed monthly during ARPI treatment, three-weekly during taxane chemotherapy, and three-monthly during androgen deprivation therapy (ADT) monotherapy. Serial PSA measurements were performed before each follow-up visit and repeat imaging was at the discretion of the investigator.ResultsDetection of circulating Grainyhead-like 2 (GRHL2) transcript was associated with poor outcomes in mHSPC and mCRPC patients. Detectable GRHL2 expression in mHSPC was associated with a lower rate of seven-month undetectable PSA levels (25% vs. 65%, P=0.059), and independently associated with shorter TTCR (HR 7.3, 95% CI: 1.5–36, P=0.01). In the mCRPC cohort, GRHL2 expression predicted significantly lower PSA50 response rates (46% vs. 69%, P=0.01), and was independently associated with shorter PFS (HR 3.1, 95% CI: 1.8–5.2, P<0.001) and OS (HR 2.9, 95% CI: 1.6–5.1, P<0.001). Associations were most apparent in patients receiving ARPIs.ConclusionsDetectable circulating GRHL2 was a negative prognostic biomarker in our mHSPC and mCRPC cohorts. These data support further investigation of GRHL2 as a candidate prognostic biomarker in metastatic prostate cancer, in addition to expanding efforts to better understand a putative role in therapeutic resistance to AR targeted therapies.

Diagnostic performance of 18F-DCFPyL positron emission tomography/computed tomography for biochemically recurrent prostate cancer and change-of-management analysis.

Conventional imaging (CI) performs poorly to identify sites of disease in biochemically recurrent prostate cancer. 68Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) is most studied but has a very short half-life. This study reports the diagnostic performance of the novel prostate-specific membrane antigen (PSMA) radiotracer 18F-DCFPyL using real-life data and tumor board simulation to estimate the impact of 18F-DCFPyL PET on patient management. Ninety-three 18F-DCFPyL PET/CT scans performed for patients previously treated for prostate cancer with a rising prostate-specific antigen (PSA) were retrospectively compared to contemporary CI and clinical imaging and PSA followups. A chart review was performed to document prior imaging, pathology results, serial serum PSA measurements, and other pertinent clinical data. Clinical utility of 18F-DCFPyL PET was measured using a simulated tumor board formed by three physicians with extensive prostate cancer experience deciding on management with and without knowledge of PET/CT results. At median PSA 2.27 (interquartile rage [IQR] 5.27], 82% of 18F-DCFPyL PET/CT demonstrated at least one site of disease: non-regional lymph nodes (37% of scans), regional lymph node metastases (28%), local recurrence (27%), and bone metastases (20%), with higher PET positivity at higher PSA. Compared to 18F-DCFPyL PET/CT, CI showed overall poor performance, with accuracy below 20% for all extent of disease. PET/CT changed management in 44% of cases. The most frequent scenario was a radical change from initiating androgen deprivation therapy (ADT) to stereotactic body radiotherapy (SBRT) of oligo-lesional disease. In univariate and multivariate analysis, no patient characteristic could predict change of management by PET/CT results. 18F-DCFPyL significantly outperforms CI in recurring prostate cancer and is likely to impact management.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.

The summary presented herein represents Part II of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients with castration-resistant disease. Please refer to Part I for discussion of the management of patients with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer. The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1[Figure: see text] and detailed herein. The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.

DEATH DUE TO SEVERE ANEMIA CAUSED BY PROSTATE CANCER: AN AUTOPSY REPORT

The autopsy findings of a 66-year-old man who died of severe anemia caused by undiagnosed prostate cancer are presented. The findings suggested the condition of severe anemia. The infiltration and metastasis of the prostate specific antigen (PSA) positive adenocarcinoma was observed at the bladder, rectum and bone. Blood clot attached to the mucosal surface and trabeculation of the bladder and blood clot in the rectum was observed. Furthermore, the serum PSA level was markedly high, and thought to be valuable for a postmortem diagnosis of prostate cancer. The existence of rectal infiltration of the prostate cancer is a rare complication, and could indicate particularly advanced disease. The anemia found in this case was suspected to be caused by the combination of massive metastasis to the bone and active blood loss from the mucosa of the bladder and rectum. Moreover, the utility of postmortem measurement of serum PSA in the diagnosis of prostate cancer was suggested.

Prostate-specific antigen dynamics predict individual responses to intermittent androgen deprivation

Intermittent androgen deprivation therapy (IADT) is an attractive treatment for biochemically recurrent prostate cancer (PCa), whereby cycling treatment on and off can reduce cumulative dose and limit toxicities. We simulate prostate-specific antigen (PSA) dynamics, with enrichment of PCa stem-like cell (PCaSC) during treatment as a plausible mechanism of resistance evolution. Simulated PCaSC proliferation patterns correlate with longitudinal serum PSA measurements in 70 PCa patients. Learning dynamics from each treatment cycle in a leave-one-out study, model simulations predict patient-specific evolution of resistance with an overall accuracy of 89% (sensitivity = 73%, specificity = 91%). Previous studies have shown a benefit of concurrent therapies with ADT in both low- and high-volume metastatic hormone-sensitive PCa. Model simulations based on response dynamics from the first IADT cycle identify patients who would benefit from concurrent docetaxel, demonstrating the feasibility and potential value of adaptive clinical trials guided by patient-specific mathematical models of intratumoral evolutionary dynamics.

Abstract LB-A01: Establishment of a novel prostate cancer bone metastasis model in humanized mice and early efficacy results of pembrolizumab

Abstract Background: Programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) expression is typically low in primary prostate cancer but increases at advanced stages. However, targeting PD-1 or PD-L1 has not proven efficacy in prostate cancer patients, and recent clinical trials are directed to combination therapies. About 85% of advanced prostate cancer patients develop skeletal metastases, and the focus in this context should be addressed to the treatment of these metastases. These efforts have been hindered by the lack of relevant preclinical bone metastasis models in immunocompetent mice. We aimed to establish a prostate cancer bone metastasis model in humanized mice and to assess pembrolizumab efficacy in the established model. Materials and methods: Two million LNCaP human prostate cancer cells were inoculated into tibia bone marrow of male CIEA NOG® mice engrafted with human CD34+ hematopoietic stem cells to generate humanized mice. Serum prostate-specific antigen (PSA) levels were measured at 4 weeks, and the mice were allocated to receive either pembrolizumab (anti-PD-1, Keytruda®, 5 mg/kg, Q5D) or human IgG4 isotype control for 6 weeks. Tumor growth was monitored by measuring serum PSA levels. Tumor-induced bone changes were monitored by measuring serum levels of the bone formation marker N-terminal propeptide of type I procollagen (PINP), and by X-ray imaging of tibia. Changes in quantity of circulating T cells was monitored by flow cytometry. At study termination, tissue samples were collected for histological and immunohistochemical evaluation of tumor-infiltrating lymphocytes (TILs). Results: A tumor take of 90% was observed in the humanized mice evaluated by serum PSA levels at endpoint. No significant differences were observed in serum PSA levels, but in a few mice treated with pembrolizumab, only modest tumor growth was observed. Intratibial LNCaP tumors induced osteoblastic-mixed lesions as evaluated by X-ray imaging. No differences were observed in the bone lesion area or in serum PINP levels between the isotype control and pembrolizumab groups. No changes in circulating levels of CD4+, CD8+, or CD4+CD8+ cells were observed. Histology will be performed to confirm tumor morphology and overall tumor viability, and immunohistochemical analysis will reveal the quantity and location of TILs in the tumor. Conclusions: A novel preclinical model of bone metastasis in humanized mice was established. Intratibial prostate cancer tumors induced osteoblastic mixed bone lesions and increased serum PSA levels, mimicking the clinical situation in patients. Resembling recent clinical findings, no or modest responses with pembrolizumab as monotherapy were observed. Citation Format: Tiina E Kähkönen, Mari I Suominen, Jenni HE Mäki-Jouppila, Azusa Tanaka, Philip Dube, Jussi M Halleen, Jenni Bernoulli. Establishment of a novel prostate cancer bone metastasis model in humanized mice and early efficacy results of pembrolizumab [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A01. doi:10.1158/1535-7163.TARG-19-LB-A01

Plasma extracellular vesicles as phenotypic biomarkers in prostate cancer patients.

The development of phenotypic biomarkers to aid the selection of treatment for patients with castrate-resistant prostate cancer (CRPC) is an important priority. Plasma exosomes have excellent potential as real-time biomarkers to characterize the tumor because they are easily accessible in the blood and contain DNA, RNA, and protein from the parent cell. This study aims to investigate the characteristics of putative prostate-specific plasma extracellular vesicle (EV) markers and their relationship with clinical outcomes. We investigated plasma EVs in a total of 89 patients with prostate cancer (PCa) at different stages of disease progression. EVs were isolated using both precipitation and ultracentrifugation methods; physical characterization was performed using dynamic light scattering, acetylcholinesterase (AChE) activity, and velocity gradients. An immunocapture method was developed for the evaluation of prostate-specific membrane antigen (PSMA)-positive exosomes. Exosomal messenger RNA (mRNA) was quantified using droplet digital polymerase chain reaction for the expression of KLK3 and androgen receptor splice variant 7 (AR-V7) genes, which code prostate-specific antigen (PSA) and AR-V7, respectively. Serum sex steroids were measured using liquid chromatography-tandem mass spectroscopy. Isolated exosomes from patients with CRPC had a smaller hydrodynamic size than those isolated from localized patients with PCa, whileAChE activity showed no difference. Moreover, no differences were observed after initiation of androgen deprivation therapy in serial patient samples. Velocity gradients identified that PSMA-positive exosomes occupied a specific fraction of isolated EVs. A total of 35 patients with CRPC had mRNA analyzed from isolated plasma exosomes. Detectable exosomal KLK3 corresponded with higher concomitant serum PSA measurements, as expected (mean, 112.6 vs 26.61 ng/mL; P = .065). Furthermore, detectable levels of AR-V7 mRNA were associated with a shorter time to progression (median, 16.0 vs 28.0 months; P = .0499). Furthermore, detectable exosomal AR-V7 was significantly associated with testosterone levels below the lower limit of quantification (<0.1 nM). Our results suggest that exosomal AR-V7 is correlated with lower sex steroid levels in CRPC patients with a poorer prognosis. PSMA immunocapture does not appear sufficient to isolate PCa-specific exosomes.

Utility of Multiparametric MRI for Predicting Residual Clinically Significant Prostate Cancer After Focal Laser Ablation.

OBJECTIVE. The purpose of this study was to compare in a multireader manner the diagnostic accuracies of 3-T multiparametric MRI interpretation and serial prostate-specific antigen (PSA) measurement in predicting the presence of residual clinically significant prostate cancer after focal laser ablation. MATERIALS AND METHODS. Eighteen men had undergone focal laser ablation for low- or intermediate-risk prostate cancer as part of two National Cancer Institute-funded phase 1 clinical trials. Multiparametric MRI was performed immediately after and 6 and 12 months after focal laser ablation. Serial PSA measurements after focal laser ablation were recorded, and MRI-ultrasound fusion biopsy was performed 6 and 12 months after ablation and served as the reference standard. Multiparametric MRI was performed at 3 T with pelvic phased-array coils. T2-weighted, DW, and dynamic contrast-enhanced MR images were retrospectively assessed by two blinded radiologists using a 3-point Likert scale (0-2). Inter-reader agreement was assessed with the Cohen kappa statistic. The diagnostic accuracies of multiparametric MRI and PSA measurement were compared. RESULTS. Residual clinically significant prostate cancer was identified in 11 of 18 (61%) men. Logistic regression analysis of serial PSA measurements yielded a correct classification rate of 61.1% (p > 0.05). Using a multiparametric MRI threshold score of 4 or greater, both radiologists made correct classifications for 16 of 18 men (89%) at 6 months and 15 of 17 men (88%) at 12 months. Interreader agreement was substantial to excellent for T2-weighted imaging, DWI, and dynamic contrast-enhanced MRI and improved uniformly from 6 to 12 months. Logistic regression analysis of the retrospectively reviewed multiparametric MR images yielded AUCs greater than 0.90 for each radiologist 6 and 12 months after focal laser ablation (p < 0.001). CONCLUSION. Multiparametric MRI 6 and 12 months after focal laser ablation significantly outperformed serial PSA measurements for predicting the presence of residual clinically significant prostate cancer.

Active surveillance in prostate cancer

Prostate cancer remains among the most commonly diagnosed malignancies worldwide in men. In patients with low-risk prostate cancer, the risk of metastasis and mortality is very low; therefore, atumor surveillance strategy can be used. In patients undergoing active surveillance, curative active therapy is postponed without compromising opportunities for cure until there is evidence of progression or the patient desires active therapy. The aim of active surveillance in prostate cancer patients is to minimize treatment-related toxicity without impairing patient survival. To maintain patients under active surveillance, the following criteria should be met: prostate-specific antigen (PSA) ≤10 ng/ml, Gleason score ≤6, cT1 or cT2a, ≤2biopsy cores with <50% cancer involvement of every positive core. Follow-up in active surveillance patients is based on repeat biopsy, serial PSA measurements, and digital rectal examination.