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.

Precise prostate cancer diagnosis using fluorescent nanoprobes for detecting PSA and PSMA in serum.

Novel Au-Se bond-based nanoprobes were designed for concurrent detection of PSA and PSMA in serum samples, aiming to enhance the early diagnosis of prostate cancer. These probes demonstrate robust stability, specificity and accuracy, underscoring their potential as non-invasive tools for diagnosis.

Limited prognostic role of routine serum markers (AP, CEA, LDH and NSE) in oligorecurrent prostate cancer patients undergoing PSMA-radioguided surgery.

INTRODUCTION: We evaluated the prognostic role of pre-salvage prostate-specific membrane antigen-radioguided surgery (PSMA-RGS) serum levels of alkaline phosphatase (AP), carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH), and neuron-specific enolase (NSE). MATERIALS AND METHODS: Patients who consecutively underwent PSMA-RGS for prostate cancer (PCa) oligorecurrence between January 2019 and January 2022 were selected. Biomarkers were assessed one day before surgery. Cox regression and logistic regression models tested the relationship between biochemical recurrence-free survival (BFS), 6- and 12-month biochemical recurrence (BCR), and several independent variables, including biomarkers. RESULTS: 153 consecutive patients were analyzed. In the univariable Cox regression analysis, none of the biomarkers achieved predictor status (AP: hazard ratio [HR] = 1.03, 95% CI 0.99, 1.01; p = 0.19; CEA: HR = 1.73, 95% CI 0.94, 1.21; p = 0.34; LDH: HR = 1.01, 95% CI 1.00, 1.01; p = 0.05; NSE: HR = 1.02, 95% CI 0.98, 1.06; p = 0.39). The only independent predictor of BFS was the number of positive lesions on PSMA PET (HR = 1.17, 95% CI 1.02, 1.30; p = 0.03). The number of positive lesions was confirmed as independent predictor for BCR within 6 and 12 months (BCR < 6 months: odds ratio [OR] = 1.1, 95% CI 1.0, 1.3; p = 0.04; BCR < 12 months: OR = 1.1, 95% CI 1.0, 1.3; p = 0.04). CONCLUSION: The assessment of AP, CEA, LDH, and NSE before salvage PSMA-RGS showed no prognostic impact. Further studies are needed to identify possible predictors that will optimize patient selection for salvage PSMA-RGS.

Imaging Prostate Cancer: Clinical Utility of Prostate-Specific Membrane Antigen.

PURPOSE: Our goal was to review the pathway and pertinent materials leading to approval of prostate-specific membrane antigen (PSMA) scanning by the U.S. Food and Drug Administration (FDA). MATERIALS AND METHODS: Beginning with the pivotal trials and working backward, we summarize the evolution of PSMA scanning, beginning with the discovery of the molecule, the mechanism of action to identify prostate cancer, the route to the present-day test and some of the major publications leading to each step of the sequence. From the thousands of PSMA articles listed on PubMed®, the present review is focused on the 4 large U.S. trials incorporating university studies of the gallium-68 compound and commercial studies of the fluorine-18 compound. The review further focuses on the role of PSMA scanning for both initial staging of prostate cancer and diagnosis of recurrent prostate cancer. RESULTS: PSMA is a transmembrane-bound glycoprotein which is overexpressed by 100-1,000-fold in prostate cancer cells. Preclinical PSMA studies at Cornell and Johns Hopkins in the 1990s were followed by early human studies in Germany in the early 2010s, then pivotal clinical trials at University of California, Los Angeles and University of California, San Francisco, leading to the first FDA approval in December 2020 (68Ga-PSMA-11). In January 2021, a commercially available product (18F-DCFPyL) was approved on the basis of multisite registration trials (CONDOR and OSPREY). Sensitivity and specificity of PSMA scanning exceeds that of any other imaging method currently available for initial staging of prostate cancer and diagnosis of recurrent disease. The accuracy of PSMA scanning is attributed to the great image contrast (high signal-to-noise ratio), a property deriving from the high PSMA tracer uptake by prostate cancer cells. That property can be estimated quantitatively by a metric, the standardized uptake value. A follow-on PSMA compound, the theranostic lutetium-177, is currently pending FDA approval for treatment of metastases. CONCLUSIONS: PSMA scanning is a disruptive technology that promises to transform the way prostate cancer is initially staged, recurrence is diagnosed and some advanced cases are treated.

[Place of molecular imaging in the management of prostate cancer]. / Place de l'imagerie moléculaire dans la prise en charge du cancer de la prostate.

In the management of prostate cancer in recent years, innovative therapies have appeared requiring precise and reliable disease detection. In 2021, new generation imaging (PET/CT, multiparametric MRI, PET/MRI) have their place at all stages of the prostate cancer natural history to help target the lesion(s) and guide therapy and improve the results obtained. PSMA PET/CT is currently the leader in this type of imaging with a complete offer during the disease: both from diagnosis, to recurrence or in the oligo-metastatic and metastatic stage resistant to castration with a pivotal role in the PSMA theranostic approach. However, multiparametric MRI also has many detection advantages when the prostate is left in place, which suggests the potential major benefit of hybrid PSMA PET/MRI imaging.

Molecular analysis of circulating tumor cells of metastatic castration-resistant Prostate Cancer Patients receiving 177Lu-PSMA-617 Radioligand Therapy.

Rationale: Lu-177-PSMA-617 radioligand therapy (RLT) is currently under approval for treatment of metastatic castration resistant prostate cancer (mCRPC) patients with late stage disease. However, previous studies demonstrated both heterogeneity of prostate specific membrane antigen (PSMA) expression, as well as response to PSMA treatment among mCRPC patients. Thus, there is an unmet need for identifying predictive parametres prior or under PSMA-RLT treatment. We therefore aimed to correlate several clinical and molecular parameters with response to PSMA treatment in a cohort of mCRPC patients undergoing PSMA RLT followed by a detailed analysis of promising candidates. Methods: Nineteen patients, median age 68.8 years (range: 56.9 - 83.3) with mCRPC were included in this study. We performed baseline analysis of clinical parameters based on PSMA PET/CT, (metabolic tumor volume (MTV), total tumor volume (TTV)), serum PSA, ALP, LDH and gene expression analysis of circulating tumor cells (expression of AR full length (AR-FL), AR splice variant 7 (AR-V7), PSA and PSMA) as well as common markers for neuroendocrine differentiation (NED). Results: Patients presented with bone, lymph node, and visceral metastases (89%, 68%, and 21%, respectively). All patients were pretreated with docetaxel, either abiraterone or enzalutamide, or both. Biochemical response in terms of PSA decline ≥50 or ≥30% was observed in 42% and 63%, respectively. There were significant correlations between PSA and PSMA mRNA expression, as well as tumor volumes (both MTV and TTV), AR-FL and AR-V7 mRNA expression. However, there was no correlation with response to PSMA treatment. Furthermore, none of these parameters was significantly correlated with baseline serum PSA values. Common NED markers were shown to be specifically high expressed and revealed impact on OS independent from AR-V7 gene expression. Conclusion: We demonstrate that AR-FL and its splice variant AR-V7 might serve as prognostic biomarkers displaying high tumor burden in mCRPC patient prior to PSMA-RLT. Contrary, PSMA, which has been discussed as a biomarker for PSMA targeted treatment, does not display strong prognostic ability - at least on the mRNA level. Surprisingly, none of these parameters correlates to response to PSMA treatment. In contrast, commom NED markers such as SYP and ENO2 as well as FOXA1 expression level seem to predict OS, but not PFS, more reliably. We admit that a limitation of our study is the focus on mRNA expression of potential biomarkers only. Further investigations analyzing the potential role of protein expression of these markers are therefore warranted.

Interim Results of a Prospective Prostate-Specific Membrane Antigen-Directed Focal Stereotactic Reirradiation Trial for Locally Recurrent Prostate Cancer.

PURPOSE: To report the feasibility, toxicity, and preliminary outcomes (metabolic and biochemical) of 68Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-directed focal prostate reirradiation using linear accelerator (LINAC)-based stereotactic body radiation treatment (SBRT). METHODS AND MATERIALS: From March 2016 to March 2019, 25 patients were enrolled in a prospective single institution trial (ACTRN12617000035325). Eligibility criteria included patients with biopsy proven isolated prostate recurrence after definitive irradiation, with concordant multiparametric MRI and 68Ga-PSMA PET/CT findings, and a prostate-specific antigen of less than 15 ng/mL at the time of recurrence. The study included a sequential dose escalation component with the first 18 patients receiving 36 Gy in 6 fractions on alternate days with subsequent patients receiving 38 Gy in 6 fractions assuming acceptable toxicity. RESULTS: Median age was 72 years (range, 62-83) with a median time between first radiation treatment and salvage SBRT of 8.3 years (range, 4.5- 13.6). Median prostate-specific antigen at reirradiation was 4.1 (range, 1.1-16.6). The median follow-up was 25 months (range, 13-46). Acute grade 1 and 2 genitourinary (GU) toxicity occurred in 6 (24%) and 1 (4%) men, respectively. Acute grade 1 gastrointestinal (GI) toxicity occurred in 8% with one acute grade 3 GI toxicity (4%) due to a rectal ulcer overlying the hydrogel. Late grade 1 and 2 GU toxicity occurred in 28% and 4%. Late grade 1 GI toxicity occurred in 8% with no grade 2 or greater toxicity. Twenty-four patients have undergone per-protocol 12-month 68Ga-PSMA PET/CT, of which 23 (92%) demonstrated a complete metabolic response. Biochemical freedom from failure was 80% at 2 years with 3 out of 4 of the biochemical failures exhibiting recurrent local disease. CONCLUSIONS: PSMA-directed salvage focal reirradiation to the prostate using linear accelerator-based SBRT is feasible and safe. Toxicity was low, with very favorable short term local and biochemical control in a carefully selected cohort of patients.

Multidisciplinary total eradication therapy (TET) in men with newly diagnosed oligometastatic prostate cancer.

To evaluate the outcomes of total eradication therapy (TET), designed to eradicate all sites of visible cancer and micrometastases, in men with newly diagnosed oligometastatic prostate cancer (OMPCa). Men with ≤ 5 sites of metastases were enrolled in a prospective registry study, underwent neoadjuvant chemohormonal therapy, followed by radical prostatectomy, adjuvant radiation (RT) to prostate bed/pelvis, stereotactic body radiation therapy (SBRT) to oligometastases, and adjuvant hormonal therapy (HT). When possible, the prostate-specific membrane antigen targeted 18F-DCFPyL PET/CT (18F-DCFPyL) scan was obtained, and abiraterone was added to neoadjuvant HT. Twelve men, median 55 years, ECOG 0, median PSA 14.7 ng/dL, clinical stages M0-1/12 (8%), M1a-3/12 (25%) and M1b-8/12 (67%), were treated. 18F-DCFPyL scan was utilized in 58% of cases. Therapies included prostatectomy 12/12 (100%), neoadjuvant [docetaxel 11/12 (92%), LHRH agonist 12/12 (100%), abiraterone + prednisone 6/12 (50%)], adjuvant radiation [RT 2/12 (17%), RT + SBRT 4/12 (33%), SBRT 6/12 (50%)], and LHRH agonist 12/12 (100%)]. 2/5 (40%) initial patients developed neutropenic fever (NF), while 0/6 (0%) subsequent patients given modified docetaxel dosing developed NF. Otherwise, TET resulted in no additive toxicities. Median follow-up was 48.8 months. Overall survival was 12/12 (100%). 1-, 2-, and 3-year undetectable PSA's were 12/12 (100%), 10/12 (83%) and 8/12 (67%), respectively. Median time to biochemical recurrence was not reached. The outcomes suggest TET in men with newly diagnosed OMPCa is safe, does not appear to cause additive toxicities, and may result in an extended interval of undetectable PSA.

Assessment of the role of Ga-68 PSMA I&T PET/CT in response evaluation to docetaxel therapy in castration resistant prostate cancer patients. / Evaluación del papel de la PET/TC con [68Ga]Ga-PSMA I&T en la evaluación de la respuesta a la terapia con docetaxel en pacientes con cáncer de próstata resistente a la castración.

OBJECTIVE: There have been only few studies investigating the role of PSMA ligands in the therapy response assessment of metastasized castration resistant prostate cancer (mCRPC) cases. In this study we aimed at evaluating the capability of 68Ga- prostate-specific membrane antigen (PSMA) I&T positron emission tomography/computerized tomography (PET/CT) in the assessment of therapeutic response in patients under docetaxel therapy for prostate cancer (PCa). MATERIAL AND METHODS: The clinical records of all mCRPC patients treated with docetaxel and referred to our department for 68Ga-PSMA I&T PET/CT imaging were retrospectively analysed. Sixteen patients (mean age 69 years, range 52-82 years) with castration-resistant prostate cancer patients receiving palliative docetaxel therapy and had undergone 68Ga-PSMA I&T PET/CT scan were included in the study. 68Ga-PSMA I&T PET/CT imaging was done and prostate specific antigen (PSA) levels were measured at baseline before administration of docetaxel (PET1) and after at least 3 cycles (range 4-12) of chemotherapy (PET2). Patient-based as well as lesion-based comparison of PET2 findings with PET1 findings were done. RESULTS: The change (decrease) observed in lymph node and prostate gland/prostatic bed SUVmax values after treatment compared to pretreatment was found to be statistically significant (P=.033). 3/16 patients (19%) were classified as progressive disease (PD), 4/16 (25%) as stable disease (SD), 9/16 (56%) as partial remission (PR) radiologically. An increasing PSA trend (IT) was observed in 4 patients (25%) and a decreasing PSA trend (DT) in 3 patients (18%). Nine patients showed a PSA response of ≥ 50% (56%). Of the 4 patients showing SD, 3 had IT, 3 had BR. Of the 9 patients who showed PR on PET studies, 8 patients showed BR and 1 patient showed DT. CONCLUSION: Imaging with 68Ga-PSMA PET/CT showed great concordance with biochemical response evaluation in terms of PSA levels, especially in patients showing good response to therapy. 68Ga-PSMA PET/CT was also successful in identifying progressive disease in patients showing paradoxical decline in PSA levels.

EV-Ident: Identifying Tumor-Specific Extracellular Vesicles by Size Fractionation and Single-Vesicle Analysis.

Tumor-derived extracellular vesicles (EVs) have emerged as a promising source of circulating biomarkers for liquid biopsies. However, understanding the heterogeneous physical and biochemical properties of EVs originating from multiple complex biogenesis pathways remains a major challenge. Here, we introduce EV-Ident for preparation of subpopulations of EVs in three different size fractions: large EVs (EV200 nm; 200-1 000 nm), medium EVs (EV100 nm; 100-200 nm), and small EVs (EV20 nm; 20-100 nm). Furthermore, this technology enables the in situ labeling of fluorescence markers for the protein profiling of individual EVs. As a proof-of-concept, we analyzed the presence of human epidermal growth factor receptor 2 (HER2) and prostate-specific membrane antigen (PSMA) in breast cancer and prostate cancer cell-derived EVs, respectively, using three different size fractions at the single-EV level. By reducing the complexity of EV heterogeneity in each size fraction, we found that HER2-positive breast cancer cells showed the greatest expression of HER2 in EV20 nm, whereas PSMA expression was the highest in EV200 nm derived from PSMA-expressing prostate cancer cells. This increase in HER2 expression in EV20 nm and PSMA expression in EV200 nm was further confirmed in plasma-derived nanoparticles (PNPs) obtained from breast and prostate cancer patients, respectively. Our study demonstrates that single-EV analysis using EV-Ident provides a practical way to understand EV heterogeneity and to successfully identify potent subpopulation of EVs for breast and prostate cancer, which has promising translational implications for cancer theranostics. Furthermore, these findings have the potential to address fundamental questions surrounding the biology and clinical applications of EVs.

Prostate-specific membrane antigen in circulating tumor cells is a new poor prognostic marker for castration-resistant prostate cancer.

The aim of this study is to elucidate the clinical significance of prostate-specific membrane antigen (PSMA) expression in circulating tumor cells (CTCs) from castration-resistant prostate cancer (CRPC) patients. We analyzed a total of 203 CTC samples from 79 CRPC patients to investigate the proportion of positive mRNA expressions at different treatment phases. Among them, we elected to focus on specimens from 56 CRPC patients who progressed on therapy and were subsequently provided a new treatment (treatment-switch cohort). In this cohort, we investigated the association between PSMA expression in CTCs and treatment response. CTCs were detected in 55/79 patients and median serum PSA in CTC-positive patients was 67.0 ng/ml. In the treatment-switch cohort of 56 patients, 20 patients were positive for PSMA in CTCs. PSMA expression was inversely associated with percentage of change in prostate-specific antigen (PSA). The median PSA progression-free survival and overall survival were significantly shorter in the PSMA-positive cohort. Furthermore, PSMA expression was predictive of poorer treatment response, shorter PSA progression-free survival and overall survival. PSMA expression in circulating tumor cells may be a novel poor prognostic marker for CRPC.

Interfacial charge regulation of protein blocking layers in transistor biosensor for direct measurement in serum.

Ion-sensitive field-effect transistor (ISFET) as a biosensor facilitates a process of data-acquisition through label-free and real-time monitoring. Direct quantification of a biomarker in serum is challenging in ISFET biosensor since charged proteins in serum interfere transduction to electrical signals. Here, we report the fabrication of protein blocking layers (PBLs) with intended interfacial charges to minimize non-specific protein bindings on ISFET. Use of charged protein precursors enables to regulate the interfacial charge of PBLs, preserving their intrinsic electric features (neutral: hemoglobin, positively charged: lysozyme, negatively charged: BSA). The effect of this interfacial charge on the signal was demonstrated through PSMA (prostate cancer biomarker) sensing using a dual-gate ISFET biosensor. The neutral PBL showed the minimum noise compared to the negatively and positively charged PBLs, enabling the ISFET to exhibit the same detection range in untreated serum as with pre- or post-treatment (1 fg/ml to 100 ng/ml). The introduction of neutral PBLs to ISFET biosensors would allow the application of the ISFET biosensor as a point-of-care device.

A Prospective Study of 18F-DCFPyL PSMA PET/CT Restaging in Recurrent Prostate Cancer following Primary External Beam Radiotherapy or Brachytherapy.

PURPOSE: Radio-recurrent prostate cancer is typically detected by a rising prostate-specific antigen and may reflect local or distant disease. Positron emission tomography (PET) radiotracers targeting prostate-specific membrane antigen, such as 18F-DCFPyL have shown promise in restaging men with recurrent disease postprostatectomy but are less well characterized in the setting of radio-recurrent disease. METHODS AND MATERIALS: A prospective, multi-institutional study was conducted to evaluate the effect of 18F-DCFPyL PET/computed tomography (CT) when added to diagnostic imaging (DI; CT abdomen and pelvis, bone scan, multiparametric magnetic resonance imaging pelvis) for men with radio-recurrent prostate cancer. All men were imaged with DI and subsequently underwent 18F-DCFPyL PET/CT with local and central reads. Tie break reads were performed as required. Management questionnaires were completed after DI and again after 18F-DCFPyL PET/CT. Discordance in patterns of disease detected with 18F-DCFPyL PET/CT versus DI and changes in management were characterized. RESULTS: Seventy-nine men completed the study. Most men had T1 disease (62%) and Gleason score <7 (95%). Median prostate-specific antigen at diagnosis was 7.4 ng/mL and at relapse was 4.8 ng/mL. DI detected isolated intraprostatic recurrence in 38 out of 79 men (48%), regional nodal recurrence in 9 out of 79 (11%), distant disease in 12 out of 79 (15%), and no disease in 26 out of 79 (33%). 18F-DCFPyL PET/CT detected isolated intraprostatic recurrence in 38 out of 79 men (48%), regional nodal recurrence in 21 out of 79 (27%), distant disease in 24 out of 79 (30%), and no disease in 10 out of 79 (13%). DI identified 8 out of 79 (10%) patients to have oligometastatic disease, compared with 21 out of 79 (27%) with 18F-DCFPyL PET/CT. 18F-DCFPyL PET/CT changed proposed management in 34 out of 79 (43%) patients. CONCLUSIONS: 18F-DCFPyL PET/CT identified extraprostatic disease in twice as many men with radio-recurrent prostate cancer compared with DI and detected a site of recurrence in 87% of men compared with 67% with DI. Furthermore, 18F-DCFPyL PET/CT identified potentially actionable disease (prostate only recurrence or oligometastatic disease) in 75% of men and changed proposed management in 43% of men.

Long-Circulating Prostate-Specific Membrane Antigen-Targeted NIR Phototheranostic Agent.

Targeted photodynamic therapy (PDT) combined with image-guided surgical resection is a promising strategy for precision cancer treatment. Prostate-specific membrane antigen (PSMA) is an attractive target due to its pronounced overexpression in a variety of tumors, most notably in prostate cancer. Recently, we reported a pyropheophorbide-based PSMA-targeted agent, which exhibited long plasma circulation time and effective tumor accumulation. To further advance PSMA-targeted photodynamic therapy by harvesting tissue-penetrating properties of the NIR light, we developed a bacteriochlorophyll-based PSMA-targeted photosensitizer (BPP), consisting of three building blocks: (1) a PSMA-affinity ligand, (2) a peptide linker to prolong plasma circulation time and (3) a bacteriochlorophyll photosensitizer for NIR fluorescence imaging and photodynamic therapy (Qy absorption maximum at 750 nm). BPP exhibited excellent PSMA-targeting selectivity in both subcutaneous and orthotopic mouse models. The nine D-peptide linker in BPP structure prolonged its plasma circulation time (12.65 h). Favorable pharmacokinetic properties combined with excellent targeting selectivity enabled effective BPP tumor accumulation, which led to effective PDT in a subcutaneous prostate adenocarcinoma mouse model. Overall, bright NIR fluorescence of BPP enables effective image guidance for surgical resection, while the combination of its targeting capabilities and PDT activity allows for potent and precise image-guided photodynamic treatment of PSMA-expressing tumors.

Prostate Specific Membrane Antigen Targeted Positron Emission Tomography of Primary Prostate Cancer: Assessing Accuracy with Whole Mount Pathology.

PURPOSE: We evaluated which lesions are detected and missed on [68Ga]Ga-PSMA (prostate specific membrane antigen)-11 positron emission tomography in patients with primary prostate cancer. MATERIALS AND METHODS: Patients undergoing radical prostatectomy were enrolled in this prospective observational study. Patients underwent [68Ga]Ga-PSMA-11 positron emission tomography/computerized tomography or positron emission tomography/magnetic resonance imaging prior to surgery and received a dose of [68Ga]Ga-PSMA-11 intraoperatively for positron emission tomography of extirpated specimens. Whole mount pathology was performed with lesion and intralesion based analysis to determine the characteristics of lesions detected or not detected by PSMA positron emission tomography. Lesion volume was determined by planimetry and clinically significant lesion volume was calculated as lesion volume × fraction pattern 4/5. RESULTS: On whole mount analysis 30 cancerous lesions were found in a total of 15 patients, including 4, 15, 4, 1 and 6 which were Grade Group 1, 2, 3, 4 and 5, respectively. PSMA-positron emission tomography detected 100% of primary/index lesions and 8 of 11 (82%) secondary lesions. All Grade Group 3-5 lesions were detected vs 12 of 15 Grade Group 2 lesions. When comparing Grade Group 2 vs 3-5, lesion size was similar (p=0.48) but the standardized uptake value was lower for Grade Group 2 vs 3-5 (5.3 vs 7.9, p=0.03). The 3 missed lesions showed 10% or less of pattern 4 and a Gleason pattern 4/5 volume of less than 0.1 cm3. CONCLUSIONS: PSMA positron emission tomography detected 100% of primary/index lesions in this study. The 3 missed secondary lesions were small and had a low percent of pattern 4. This argues for further study to better understand what defines clinically significant prostate cancer, which would assist in determining whether small lesions that become challenging to detect by [68Ga]Ga-PSMA-11 positron emission tomography confer a risk to the patient.

Does transrectal ultrasonography-guided biopsy of the prostate lead to possible further metastasis via circulating tumor cells?

Background/aim: We evaluate whether transrectal ultrasonography (TRUS)-guided prostate biopsy might lead to spillage of tumor cells into peripheral blood as a result of disruption of the epithelial barrier and ultimately result in metastasis. Materials and methods: Eighty-eight patients underwent TRUS-guided prostate needle biopsy due to prostate-specific antigen (PSA) increase or abnormal digital rectal examination at the Samsun Research and Training Hospital (Samsun, Turkey) between April 2016 and September 2018. Approximately 10 mL of whole blood was collected from patients before, 1 week after, and 1 month after biopsy. Samples were analyzed for CD117 positivity and prostate-specific membrane antigen (PSMA) levels using flow cytometry. Patients with pathologically determined prostate cancer and without CD117 positivity before biopsy were included in the study. The study group thus consisted of 55 patients. Results: Subjects' PSA levels ranged from 2.3 to 40.0 ng/mL (median: 7.9 ng/mL), and their Gleason score was a median of 7 (range: 5­9). PSMA levels ranged between 9.3 ng/mL and 118.5 ng/mL and CD117 antigen levels between 0 and 5. We detected no CD117- positive cells in blood samples collected 7 days or 1 month after biopsy. Conclusion: We detected no circulating tumor cells in the peripheral circulation following biopsy. Prostate needle biopsy seems to be a safe method in terms of spillage of tumor cells into blood circulation as a possible cause of further metastasis.

A pilot study of prostate-specific membrane antigen (PSMA) dynamics in men undergoing treatment for advanced prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a rational target for noninvasive detection of recurrent prostate cancer (PCa) and for therapy of metastatic castration-resistant prostate cancer (mCRPC) with PSMA-targeted agents. Here we conducted serial measurements of PSMA expression on circulating tumor cells (CTCs) to evaluate patterns of longitudinal PSMA dynamics over the course of multiple sequential therapies. METHODS: A retrospective investigation of men with mCRPC undergoing evaluation at medical oncology clinics at our institution assessed the dynamics of PSMA expression in the context of different systemic treatments administered sequentially. Eligibility included patients who began systemic therapies with androgen receptor (AR)-directed agents or taxane agents for whom peripheral blood samples were tested for CTC mRNA of AR splice variant-7 (AR-V7), prostate-specific antigen (PSA), and PSMA (with >2 CTC + results) in a CLIA-accredited laboratory. RESULTS: From August 2015 to November 2017, we identified 96 eligible men. Fifteen had greater than or equal to 2 sequential therapies and evaluable CTC samples, greater than or equal to 1 expressing PSMA (PSMA+). Among the 15 patients included in this analysis, a total of 54 PSMA status evaluations were performed in the context of 48 therapies during a median follow-up of 18 months. At baseline, PSMA signal was detected ("positive") in 11 of 15 (73.3%) patients, while for 4 of 15 (26.7%) patients PSMA signal was undetectable ("negative"). In all but two patients, the baseline collection corresponded with a change in treatment. On the second assessment, PSMA increases were detected in all 4/4 (100%) PSMA-negative patients and 8 of 11 (72.7%) PSMA-positive patients. PSMA significantly decreased in a patient treated with 177 Lu-PSMA-617. Serum PSA declines were seen in 7 of 8 (88%) of the treatment periods where PSMA decreased. CONCLUSIONS: PSMA expression in CTCs is a dynamic marker. PSMA transcript declines appear to be associated with concurrent decreases in serum PSA. Sequential CTC sampling could provide a noninvasive response assessment to systemic treatment for mCRPC.

Single Lesion on Prostate-specific Membrane Antigen-ligand Positron Emission Tomography and Low Prostate-specific Antigen Are Prognostic Factors for a Favorable Biochemical Response to Prostate-specific Membrane Antigen-targeted Radioguided Surgery in Recurrent Prostate Cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-ligand positron emission tomography (PET) allows detection of metastatic prostate cancer (PC) lesions at low prostate-specific antigen (PSA) values. To facilitate their intraoperative detection during salvage surgery, we recently introduced PSMA-targeted radioguided surgery (RGS). OBJECTIVE: To describe the outcome of a large cohort of patients treated with PSMA-targeted RGS and to establish prognostic factors. DESIGN, SETTING, AND PARTICIPANTS: A total of 121 consecutive patients with recurrent PC as defined by PSMA-ligand PET (median PSA: 1.13ng/ml) underwent PSMA-targeted RGS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The frequency of a complete biochemical response (cBR; PSA <0.2ng/ml) without additional treatment and the duration of biochemical recurrence-free survival (bRFS, time from PSMA-targeted RGS with PSA <0.2ng/ml without further treatment) were evaluated and correlated with preoperatively available clinical variables. RESULTS AND LIMITATIONS: In almost all patients (120/121, 99%) metastatic tissue could be removed. A cBR was achieved in 77 patients (66%). The chance of cBR was highest in patients with both low preoperative PSA and a single lesion (38/45: 84%). Median bRFS was 6.4mo in the whole patient cohort and 19.8mo for patients with cBR. Significantly longer median bRFS was observed in patients with a low preoperative PSA value (p=0.004, hazard ratio 1.48, 95% confidence interval 1.13-1.93) and with a single lesion in preoperative PSMA-ligand PET (14.0 vs 2.5mo, p=0.002). CONCLUSIONS: PSMA-targeted RGS leads to a remarkable interval of bRFS in a subset of patients. The frequency of cBR and the duration of bRFS were highest in patients with a low preoperative PSA value and a single lesion on PSMA-ligand PET. PATIENT SUMMARY: Prostate-specific membrane antigen radioguided surgery delays disease progression in selected patients with recurrent prostate cancer after radical prostatectomy. Patients with a single lesion of recurrence and a low prostate-specific antigen value had the best outcome.

A Multicenter Prospective Clinical Trial of 68Gallium PSMA HBED-CC PET-CT Restaging in Biochemically Relapsed Prostate Carcinoma: Oligometastatic Rate and Distribution Compared With Standard Imaging.

PURPOSE: The purpose of this study is to assess the utility of 68Gallium prostate-specific membrane antigen (PSMA) Division of Radiopharmaceutical Chemistry (DKFZ)-PSMA-11 positron emission tomography (PET)-computed tomography (CT), compared with standard imaging, in the detection of recurrent prostate carcinoma in patients with biochemical relapse to determine the prevalence of oligometastatic disease recurrence and its distribution. METHODS AND MATERIALS: This is a prospective, multicenter clinical trial of PSMA-HBED PET/CT imaging in patients with early biochemical relapse of prostate carcinoma (median prostate-specific antigen [PSA], 2.55 ng/mL) after definitive prostatectomy (152 patients) or radiation therapy (86 patients) with either no lesions or oligometastatic disease on abdominopelvic CT and bone scan (BS). PSMA-HBED PET/CT scan was performed within 8 weeks of restaging imaging, and all sites of abnormal PSMA-HBED binding determined as probable or definite for prostate carcinoma were included in the analysis. PSMA positivity was assessed for correlation with Gleason Score, PSA level, and PSA doubling time. RESULTS: Two hundred thirty-eight patients underwent PSMA-HBED PET/CT imaging. In 199 patients with no lesions on restaging CT and BS, 148 patients (74%) demonstrated PSMA-positive lesions, with 113 patients (57%) being oligometastatic. In 39 patients with oligometastatic lesions on restaging CT and BS, 19 patients (49%) were confirmed as oligometastatic on PSMA PET/CT and 16 patients (41%) were upstaged to polymetastatic. The 4 remaining patients (10%) with sites of possible metastatic disease were not confirmed as having prostate carcinoma. Combining the overall group, there were 183 patients (77%) with PSMA-HBED-positive lesions (682 lesions), suggesting prostate carcinoma, of whom 132 patients (55%) were oligometastatic. In the oligometastatic group, PSMA positivity was limited to the pelvis in 65% of patients, involving either the prostate or nodes (American Joint Committee on Cancer stage N1). This study found a positive correlation between PSMA-HBED positivity and PSA levels; no other factors were statistically significant. CONCLUSIONS: For patients with biochemical relapse with BS and CT demonstrating either no disease or low-volume disease, there is a high overall prevalence of PSMA PET/CT-positive disease. More than half of the patients were oligometastatic, and of those, disease was confined to the pelvis in nearly two-thirds of patients. This result confirms that PSMA PET/CT is significantly more sensitive than standard restaging imaging, and it may be useful in identifying patients for subsequent targeted therapy.