With the largest high-risk prostate cancer (PCa) cohort to date undergoing 68 Ga-prostate-specific membrane antigen (PSMA) PET/CT primary staging, we aimed to 1) characterize the metastatic spread of PCa in relation to tumor 68 Ga-PSMA-uptake and the D'Amico classification, and 2) compare 68 Ga-PSMA PET/CT findings with radical prostatectomy (RP) with pelvic lymph node dissection (PLND) histopathology. Methods A total of 691 consecutive newly diagnosed, biopsy-proven, treatment-naïve, D'Amico high-risk PCa patients primary staged by 68 Ga-PSMA PET/CT were included. PSMA maximum standardized uptake value (SUV max) and metastatic findings were compared to PSA level, International Society of Urologic Pathology (ISUP) grade, and clinical stage as traditional risk stratification parameters. Moreover, 68 Ga-PSMA PET/CT findings were compared with histology in RP patients undergoing PLND. Undetected lymph node metastases (LNMs) underwent immunohistochemical PSMA staining. Results Advanced disease (N1/M1) was observed in 35.3% of patients (244/691) and was associated with increasing PSA levels, ISUP grades, and clinical stages. LNMs (N1/M1a) were detected in 31.4% (217/691) and bone metastases (M1b) in 16.8% (116/691). Advanced disease frequencies in patients with ISUP grade 2 and 3 were 10.8% (11/102) and 37.1% (33/89), respectively. Risk of advanced disease for cT2a/cT2b/cT2c tumors were almost equal (24.2%, 27.9%, and 22.4%, respectively). We observed a weak correlation between SUV max and biopsy ISUP grade (ρ = 0.21; P < 0.001) and a modest correlation between SUV max and post-prostatectomy ISUP grade (ρ = 0.38; P < 0.001). Sensitivity, specificity, positive and negative predictive value, and accuracy for LNMs detection on 68 Ga-PSMA PET/CT in the PLND cohort were 30.6%, 96.5%, 68.8%, 84.5%, and 83.1%, respectively. Undetected LNMs were either micrometastases located in the lymph node border or without PSMA expression. Conclusion In this high-risk PCa cohort, we identified advanced disease in about one-third at diagnosis. ISUP grade was the superior predictor for advanced disease at diagnosis. We found a significant difference in frequency of advanced disease between ISUP grade 2 and 3, which supports the Gleason Score 7 subdivision. Interestingly, we observed no significant differences in risk of advanced disease when comparing the different cT2 stages. The undetected LNMs were either PSMA-negative or micrometastases.

Background Circular RNAs (circRNAs) constitute a largely unexplored source for biomarker discovery in prostate cancer (PC). Here, we characterize the biomarker potential of circRNAs in PC, where the need for novel diagnostic and prognostic tools to facilitate more personalized management is pressing. Methods We profiled the transcriptomic landscape of circRNAs in PC by total RNA sequencing of 31 adjacent-normal and 143 tumor samples from localized (radical prostatectomy (RP)) and metastatic PC patients (cohort 1, training). Diagnostic and prognostic potential was evaluated in cohort 1, and 39 top circRNA candidates were selected for validation in two additional PC cohorts (cohort 2, n = 111; RP cohort 3, n = 191) by NanoString-based expression analysis. Biochemical recurrence (BCR)-free survival was assessed using Kaplan-Meier, univariate, and multivariate Cox regression analyses. The circRNA candidates were further detected in extracellular vesicle (EV)-enriched plasma samples from PC patients and controls (cohort 4, n = 54). Results Expression of circABCC4, circFAT3, circATRNL1, and circITGA7 was highly cancer-specific (area under the curve 0.71–0.86), while low circITGA7 expression was significantly (P < 0.05) associated with BCR in univariate analysis in two RP cohorts. Moreover, we successfully trained and validated a novel 5-circRNA prognostic signature (circKMD1A/circTULP4/circZNF532/circSUMF1/circMKLN1) significantly associated with BCR beyond routine clinicopathological variables (RP cohort 1: P = 0.02, hazard ratio = 2.1; RP cohort 3: P < 0.001, hazard ratio = 2.1). Lastly, we provide proof-of-principle for detection of candidate circRNAs in EV-enriched plasma samples from PC patients. Conclusions circRNAs hold great biomarker potential in PC and display both high cancer specificity and association to disease progression.

In 2 high-risk prostate cancer patients, PET scans revealed focally increased 68Ga–prostate-specific membrane antigen uptake in the distal esophagus. Both patients had hiatus herniation on gastroscopy, and esophageal biopsies revealed acute and chronic inflammation in both patients and a benign hyperplastic polyp in one of the patients. Recently, reports have demonstrated that inflammation can cause false-positive findings on 68Ga–prostate-specific membrane antigen PET/CT, and these cases present this phenomenon in the esophagus as well.