Prognostic significance of a negative PSMA PET/CT in biochemical recurrence of prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is becoming standard of care for men with biochemical recurrence (BCR) of prostate cancer. The implications of a negative PSMA PET/CT scan in this population remain unclear. This study aims to assess the outcome of patients with BCR post radical prostatectomy (RP) who have negative [18F]DCFPyL PET/CT scan at relapse. METHODS: This is a post-hoc subgroup analysis of a prospective non randomized clinical trial. One hundred and one patients (median age, 75 years) with BCR after RP, who tested negative on [18F]DCFPyL PET/CT and subsequently either underwent salvage radiotherapy (sRT) with or without androgen deprivation therapy (ADT) or were followed without active treatment, were included. Freedom from progression (FFP) after negative PSMA PET/CT was determined based on follow-up imaging selected as per clinical practice. Uni- and multivariate Cox regression analyses were performed to examine the association of patients' characteristics, tumor-specific variables, and treatment with clinical progression at the last follow-up. FFP at 1-, 2-, and 3-year were reported using Kaplan Meier analysis. RESULTS: The median PSA level at PET/CT was 0.56 ng/mL (range, 0.4-11.3). Sixty five (64%) patients were followed without receiving further treatment, and 36 (36%) received sRT (18% to the prostate bed only and 18% to the prostate bed and pelvic lymph nodes) within 3 months of the PSMA PET. Seventeen of the sRT patients (17 of 36, 47%) received concomitant androgen deprivation therapy (ADT). Median follow-up was 39 months. Subsequent clinical progression was detected in 21 patients (21%), with 52% in pelvic lymph nodes, 52% in the prostatic fossa, 19% in distant lymph nodes, 14% in lungs, and 10% in bones. The FFP was 95% (95% CI: 91%-99%) at 12 months, 87% (95% CI: 81%-94%) at 24 months, and 79% (95% CI: 71%-88%) at 36 months. Multivariate Cox regression analysis revealed that an initial International Society of Urological Pathology (ISUP) grade 5 was significantly associated with clinical progression at the last follow-up (hazard ratio, 5.1, P value, 0.04). Furthermore, the receipt of sRT correlated significantly with lower clinical progression at the last follow-up (hazard ratio, 0.2, P value, 0.03), whereas other clinical and tumor-specific parameters did not. Following surveillance-only and sRT, 29% (19 of 65) and 6% (2 of 36) of patients, respectively, showed clinical progression. In the sRT group, no significant difference was observed in FFP between patients who underwent sRT to the prostatic fossa versus those who received sRT to the prostatic fossa and pelvic lymph nodes, although the numbers in these groups were small. CONCLUSIONS: This study suggests that salvage radiotherapy is associated with a decreased or delayed clinical progression in patients with biochemical recurrence following radical prostatectomy who have negative PSMA PET/CT scan results. The analysis also underscores the prognostic significance of the initial ISUP grade, with ISUP grade 5 being associated with worse outcomes. TRIAL REGISTRATION: Registered September 14, 2016; NCT02899312 .

Preclinical Evaluation of a PSMA Aptamer-Based Bifunctional PET and Fluorescent Probe.

Prostate cancer is the most prevalent malignant tumor affecting male individuals worldwide. The accurate early detection of prostate cancer is crucial to preventing unnecessary diagnosis and subsequent excessive treatment. Prostate-specific membrane antigen (PSMA) has emerged as a promising biomarker for the diagnosis of prostate cancer. In this study, a dual-modality imaging probe utilizing aptamer technology was developed for positron emission tomography/near-infrared fluorescence (PET/NIRF) imaging, and the specificity and sensitivity of the probe toward PSMA were evaluated both in vitro and in vivo. The probe precursor NOTA-PSMA-Cy5 was synthesized via automated solid-phase oligonucleotide synthesis. Subsequently, the PET/NIRF dual-modality probe [68Ga]Ga-NOTA-PSMA-Cy5 was successfully prepared and exhibited favorable fluorescence properties and stability in vitro. The binding specificity of [68Ga]Ga-NOTA-PSMA-Cy5 to PSMA was assessed through flow cytometry, fluorescence imaging, and cellular uptake experiments in LNCaP cells and PC-3 cells. In vivo PET/NIRF imaging studies demonstrated the sensitive and specific binding of [68Ga]Ga-NOTA-PSMA-Cy5 to PSMA. Overall, the PET/NIRF dual-modality probe [68Ga]Ga-NOTA-PSMA-Cy5 shows promise for the diagnosis of prostate cancer and for the fluorescence-guided identification of PSMA-positive cancer lesions during surgical procedures.

Simultaneous targeting and monitoring of free antigen and in-situ membrane antigen in prostate cancer cells via an aggregation-induced emission-based bifunctional probe.

The precise clinical diagnosis of prostate cancer still presents inherent challenges, and usually a monitoring of multiple biomarkers is required. In this study, a new aggregation-induced emission (AIE)-based bifunctional strategy was developed for the simultaneous detection of prostate cancer-specific in situ membrane antigens (PSMA) and free antigens (PSA). First, a bifunctional fluorescent probe with double sensing sites (a PSA-specific sensing site and a PSMA-targeted ligand) was constructed. In the presence of PSA, it specifically binds to the PSA-specific sensing site of the probe, resulting in the restoration of the fluorescence signal, enabling linear sensing of PSA. For the detection of PSMA, the PSMA-targeted ligand modified on the probe can specifically recognize PSMA, inducing the aggregation of the AIE material and resulting in an enhanced fluorescence signal. Moreover, a liposome-based artificial cell was developed to simulate the real prostate cancer cell, and it was used to investigate the feasibility of monitoring the two types of antigens. Utilizing this bifunctional fluorescent strategy, a dual-analysis of free serum antigen biomarker of PSA and in-situ membrane antigen of PSMA was achieved. The assay exhibited a wide linearity range for PSA detection from 0.0001 to 0.1 µg/mL, with a low limit of detection (LOD) of 6.18 pg/mL. For PSMA, the obtained LOD is 8.79 pg/mL, with a linearity range from 0.0001 to 0.1 µg/mL. This strategy allows us to simultaneously assess the levels of two types of biomarkers in living human prostatic cancer cells, providing a highly accurate and selective tool for early screening and monitoring of prostatic cancer.

Expression of PSMA in Tumor-Associated Vasculature Predicts Poorer Survival in Patients With Hepatocellular Carcinoma and Is Likely Associated With PD-L1.

BACKGROUND: PSMA (prostate-specific membrane antigen) is a type II transmembrane glycoprotein recently found to be expressed in hepatocellular carcinoma (HCC). We aimed to characterize the expression pattern of PSMA in HCC and its association with clinicopathologic parameters and other biomarkers. METHODS: Immunohistochemical studies for PSMA were performed on a previously established tissue microarray of 103 surgically resected HCC. RESULTS: Conceivable PSMA expression in ≥5% tumor-associated vasculature (TAV) was considered positive, and was identified in 56 (54.4%) tumors. Eight (7.8%) tumors also showed membranous/cytoplasmic and/or canalicular staining in tumor cells. By chi-square tests, only PSMA-positive TAV was associated with moderate-to-poorly differentiated HCC and the modified higher tumor stage (P < .05). PSMA-positive TAV was not associated with age, sex, or expression of glypican-3, keratin 7, CD3, CD8, HHLA-2, but marginally correlated with programmed death-ligand 1 (PD-L1) expression (P = .052). Kaplan-Meier survival analysis revealed PSMA-positive TAV as an independent risk factor for poorer disease-specific survival (P = .008). Co-expression of PD-L1 did not ameliorate the adverse prognostication of PSMA-positive TAV. Membranous/cytoplasmic/canalicular expression of PSMA alone was not prognostically significant. CONCLUSIONS: Our study confirmed that PSMA-positive TAV is a prospective diagnostic and prognostic biomarker for HCC. Co-expression of PSMA with PD-L1 may suggest potential crosstalk between the 2 proteins, likely regulating the tumor microenvironment.

68 Ga-Prostate-Specific Membrane Antigen PET/CT in Ovarian Tumors : Potential to Differentiate Benign and Malignant Tumors Before Surgery: A Preliminary Report.

PURPOSE OF THE REPORT: Ovarian cancer is usually diagnosed in an advanced stage of disease due to the absence of specific symptoms and a lack of sensitive diagnostic methods. Prostate-specific membrane antigen (PSMA) is expressed on prostate cancer cells but can be found in other tumors such as ovarian cancer.The aim of this pilot study was to evaluate the feasibility of using 68 Ga-PSMA-11 PET/CT in detection of ovarian neoplasm before surgical treatment. PATIENTS AND METHODS: Eight women with mean age of 56.0 ± 16.2 years were included in the study. All patients underwent transvaginal ultrasound followed by CT scan of the chest and abdomen as qualification for surgery. Within a 1-week interval, PET/CT was performed on a Siemens Biograph scanner, 60 minutes after injection of 2 MBq/kg 68 Ga-PSMA-11. RESULTS: In 3 cases (37.5%), the 68 Ga-PSMA-11 PET/CT was positive, whereas histological examination confirmed 2 serous ovarian cancer cases and 1 ovarian borderline tumor. The SUV max in the serous ovarian cancer was 8.7 and 4.1, and in the borderline ovarian tumor, it was 13.8. No correlation was found between antigen CA-125 level and 68 Ga-PSMA expression. Range of tumor SUV max was not correlated with stage of disease. The remaining 62.5% (5/8) were negative in 68 Ga-PSMA-11 PET/CT, and histopathology confirmed benign pelvic tumor. CONCLUSIONS: The initial experience supports the potential to use 68 Ga-PSMA-11 in ovarian cancer to differentiate malignant and benign tumors before surgery.This study was approved by the Ethical Committee of the Medical University of Warsaw (KB/2/A/2018).

68 Ga-prostate-specific membrane antigen (PSMA) PET/CT as a clinical decision-making tool in biochemically recurrent prostate cancer.

OBJECTIVE: PSMA PET/CT has demonstrated superior sensitivity over conventional imaging in the detection of local and distant recurrence in biochemically relapsed (BCR) prostate cancer. We prospectively investigated the management impact of 68 Ga-PSMA PET/CT imaging in men with BCR, with the aim of identifying baseline clinicopathological predictors for management change. PATIENTS AND METHODS: Men with BCR who met eligibility criteria underwent 68 Ga-PSMA-11 PET/CT at Monash Health (Melbourne, Australia). Intended management plans were prospectively documented before and after 68 Ga-PSMA PET/CT imaging. Binary logistic regression analysis was performed to identify potential clinicopathological predictors of management change. Descriptive statistics were used to characterize the nature of these changes. RESULTS: Seventy men underwent 68 Ga-PSMA-11 PET/CT imaging. Median age was 67 years (IQR 63-72) and median PSA was 0.48 ng/ml (IQR 0.21-1.9). PSMA-avid disease was observed in 56% (39/70) of patients. Pre-scan management plan was altered following scanning in 43% (30/70) of patients. Management changes were significantly more common in patients with higher baseline PSA levels (PSA≥2 ng/ml, p = 0.01). 18/36 (50%) of the patients initially planned for watchful waiting had their management changed, including the use of salvage pelvic radiotherapy (n = 7) and stereotactic ablative body radiotherapy to oligometastatic disease (n = 6). CONCLUSION: Management change after 68 Ga-PSMA PET/CT for BCR is common and typically resulted in treatment intensification strategies in those planned for a watchful waiting approach. This study adds to the growing pool of evidence supporting the clinical utility of PSMA PET/CT imaging in the care of patients with BCR after definitive therapy.

Establishment and prospective validation of an SUVmax cutoff value to discriminate clinically significant prostate cancer from benign prostate diseases in patients with suspected prostate cancer by 68Ga-PSMA PET/CT: a real-world study.

Background and Aims: The aims of this study were to establish a maximum standardized uptake value (SUVmax) cutoff to discriminate clinically significant prostate cancer (csPCa) from benign prostate disease (BPD) by 68Ga-labeled prostate-specific membrane antigen (68Ga-PSMA-11) positron emission tomography/computed tomography (PET/CT) in patients with suspected prostate cancer (PCa), and to perform a prospective real-world validation of this cutoff value. Methods: The study included a training cohort to identify an SUVmax cutoff value and a prospective real-world cohort to validate it. A retrospective analysis assessed 135 patients with suspected PCa in a large tertiary care hospital in China who underwent 68Ga-PSMA-11 PET/CT. All patients were suspected of having PCa based on symptoms, digital rectal examination (DRE), total prostate-specific antigen (tPSA) level, and multiparameter magnetic resonance imaging (mpMRI). The 68Ga-PSMA PET/CT results were evaluated using histopathological results from transrectal ultrasound-guided 12-core biopsy with necessary targeted biopsy as references. Patients with Gleason scores (GS) ≥7 from the biopsy results were diagnosed with csPCa, and patients with negative biopsy and follow-up results were diagnosed with BPD. Receiver operating characteristic (ROC) curve analysis was used to identify the optimal SUVmax cutoff value. The cutoff value was prospectively validated in 58 patients with suspected PCa. The diagnostic benefits of the cutoff value for clinical decision making were also evaluated. Results: According to ROC curve analysis, the most appropriate SUVmax cutoff value for discriminating csPCa from BPD was 5.30 (sensitivity, 85.85%; specificity, 86.21%; area under the curve [AUC], 0.893). The cutoff achieved a sensitivity of 83.33%, a specificity of 81.25%, a positive predictive value (PPV) of 92.11%, a negative predictive value (NPV) of 65.00%, and an accuracy of 82.76% in the prospective validation cohort. Metastases were used as an indicator to reduce false negative results in patients with SUVmax ≤ 5.30. In patients without metastases, an SUVmax value of 5.30 was also the best cutoff to diagnose localized csPCa (sensitivity, 80.43%; specificity, 86.21%; AUC, 0.852). The cutoff discriminated localized csPCa from BPD with a sensitivity of 76.19%, a specificity of 81.25%, a PPV of 84.21%, an NPV of 72.22%, and an accuracy of 78.38% in the prospective validation cohort. The cutoff, combined with metastases, achieved an accuracy of 89.12% in all patients, increasing accuracy by 8.29% and reducing equivocal results compared with manual reading. There was a strong correlation between SUVmax and PSMA expression (rs = 0.831, P < 0.001) and a moderate correlation between SUVmax and GS (rs = 0.509, P < 0.001). The PSMA expression and SUVmax values of patients with csPCa were significantly higher than those of patients with BPD (P < 0.001). Conclusion: We established and prospectively validated the best SUVmax cutoff value (5.30) for discriminating csPCa from BPD with high accuracy in patients with suspected PCa. 5.30 is an effective cutoff to discriminate csPCa patients with or without metastases. The cutoff may provide a potential tool for the precise identification of csPCa by 68Ga-PSMA PET/CT, ensuring high accuracy and reducing equivocal results.

Prospective assessment of AR splice variant and PSMA detection on circulating tumor cells of mCRPC patients: preliminary analysis of patients enrolled in PRIMERA trial (NCT04188275).

In our institution, a prospective observational trial testing micro-RNA (miRNA) and ARV7 mutational status in metastatic, castration resistant prostate cancer (mCRPC), is currently recruiting (PRIMERA trial, NCT04188275). A pre-planned interim analysis was performed when 50% of the planned accrual was reached. In this report, we explored the predictive value of Circulating Tumor Cell (CTC) detection in mCRPC patients undergoing 1st line therapy. Moreover, ARV7, ARFL, PSMA and PSA expression on CTC was reported to explore potential correlation with patient prognosis and response to therapy. PRIMERA is a prospective observational trial enrolling mCRPC patients undergoing standard treatment (ARTA + ADT) after I line ADT failure. Clinical and pathological features were collected. Outcomes selected for this preliminary analysis were time to castration resistance (TTCR), PSA at 8 weeks after ARTA therapy start, PSA drop at 8 weeks, Overall PSA drop, PSA nadir. Correlation between these outcomes and CTC detection was tested. Expression of ARV7, ARFL, PSA and PSMA was explored in CTC+ patients to assess their prevalence in this cohort and their impact on selected outcomes. Median TTCR was significantly shorter in CTC+ vs CTC- patients (32.3 vs 75 months, respectively, p = 0.03) and in ARFL+ vs ARFL- patients (30.2 vs 51.1 months, respectively, p = 0.02). ARV7, PSMA and PSA expression on CTC had no impact on median TTCR, nor on biochemical response to therapy. Patients in whom CTC and ARFL expression were detected had significant reduced TTCR. However, PSA response was not influenced by CTCs detection and specific biomarkers expression.