In prostate cancer with biochemical failure after therapy, current imaging techniques have a low detection rate at the prostate-specific antigen (PSA) levels at which targeted salvage therapy is effective. ¹¹C-choline and ¹⁸F-fluoromethylcholine, though widely used, have poor sensitivity at low PSA levels. ⁶⁸Ga-PSMA (Glu-NH-CO-NH-Lys-(Ahx)-[⁶⁸Ga-N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid]) has shown promising results in retrospective trials. Our aim was to prospectively compare the detection rates of ⁶⁸Ga-PSMA versus ¹⁸F-fluoromethylcholine PET/CT in men who were initially managed with radical prostatectomy, radiation treatment, or both and were being considered for targeted therapy. Methods: A sample of men with a rising PSA level after treatment, eligible for targeted treatment, was prospectively included. Patients on systemic treatment were excluded. ⁶⁸Ga-PSMA, ¹⁸F-fluoromethylcholine PET/CT, and diagnostic CT were performed sequentially on all patients between January and April 2015, and the images were assessed by masked, experienced interpreters. The findings and their impact on management were documented, together with the results of histologic follow-up when feasible. Results: In total, 38 patients were enrolled. Of these, 34 (89%) had undergone radical prostatectomy and 4 (11%) had undergone radiation treatment. Twelve (32%) had undergone salvage radiation treatment after primary radical prostatectomy. The mean PSA level was 1.74 ± 2.54 ng/mL. The scan results were positive in 26 patients (68%) and negative with both tracers in 12 patients (32%). Of the 26 positive scans, 14 (54%) were positive with ⁶⁸Ga-PSMA alone, 11 (42%) with both ¹⁸F-fluoromethylcholine and ⁶⁸Ga-PSMA, and only 1 (4%) with ¹⁸F-fluoromethylcholine alone. When PSA was below 0.5 ng/mL, the detection rate was 50% for ⁶⁸Ga-PSMA versus 12.5% for ¹⁸F-fluoromethylcholine. When PSA was 0.5–2.0 ng/mL, the detection rate was 69% for ⁶⁸Ga-PSMA versus 31% for ¹⁸F-fluoromethylcholine, and when PSA was above 2.0, the detection rate was 86% for ⁶⁸Ga-PSMA versus 57% for ¹⁸F-fluoromethylcholine. On lesion-based analysis, ⁶⁸Ga-PSMA detected more lesions than ¹⁸F-fluoromethylcholine (59 vs. 29, P < 0.001). The tumor-to-background ratio in positive scans was higher for ⁶⁸Ga-PSMA than for ¹⁸F-fluoromethylcholine (28.6 for ⁶⁸Ga-PSMA vs. 9.4 for ¹⁸F-fluoromethylcholine, P < 0.001). There was a 63% (24/38 patients) management impact, with 54% (13/24 patients) being due to ⁶⁸Ga-PSMA imaging alone. Histologic follow-up was available for 9 of 38 patients (24%), and 9 of 9 ⁶⁸Ga-PSMA–positive lesions were consistent with prostate cancer (⁶⁸Ga-PSMA was true-positive). The lesion positive on ¹⁸F-fluoromethylcholine imaging and negative on ⁶⁸Ga-PSMA imaging was shown at biopsy to be a false-positive ¹⁸F-fluoromethylcholine finding (⁶⁸Ga-PSMA was true-negative). Conclusion: In patients with biochemical failure and a low PSA level, ⁶⁸Ga-PSMA demonstrated a significantly higher detection rate than ¹⁸F-fluoromethylcholine and a high overall impact on management.

⁶⁸Ga-PSMA PET/CT scanning has been shown to be more sensitive than conventional imaging techniques in patients with prostate cancer. This prospective Australian multicenter study assessed whether ⁶⁸Ga-PSMA PET/CT imaging impacts on management intent in patients with primary or recurrent prostate cancer. Methods: Prior to undertaking ⁶⁸Ga-PSMA PET imaging, referring medical specialists completed a questionnaire detailing relevant demographic and clinical data as well as their proposed management plan. A separate follow up questionnaire was completed after the ⁶⁸Ga-PSMA PET/CT scan results were available to determine whether their management plan would change. Results: A total of 431 patients with prostate cancer from four Australian centers had pre- and post-⁶⁸Ga-PSMA management plans completed. Scans were performed for primary staging of intermediate and high risk disease in 25% patients and for restaging/biochemical recurrence in 75% of patients. Overall, ⁶⁸Ga-PSMA PET/CT scanning led to a change in planned management in 51% of patients. The impact was greater in the group of patients with biochemical failure post definitive surgery and /or radiation treatment (62% change in management intent) compared with patients undergoing primary staging (21% change). Imaging with ⁶⁸Ga-PSMA PET/CT revealed unsuspected disease in the prostate bed in 27% of patients, locoregional lymph nodes in 39% and distant metastatic disease in 16% of patients. Conclusion: ⁶⁸Ga-PSMA PET/CT scans detect previously unsuspected disease and may influence planned clinical management in a high proportion of patients with prostate cancer. The impact was greater in patients with biochemical recurrence. This demonstrates the potential clinical value of ⁶⁸Ga-PSMA PET/CT in management of prostate cancer.

Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors; however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n = 13) and -negative (n = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or amplified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell–infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities. Cancer Res; 75(24); 5228–34. ©2015 AACR.

Prostate specific membrane antigen (PSMA) may be targeted for both diagnostic and therapeutic purposes in the management of prostate cancer (PCa). In pre-clinical models, androgen blockade (AB) increases expression of PSMA in both hormone sensitive and castrate resistant xenotypes. The aim of this study was to evaluate the effect of AB treatment on Ga68PSMA-11 PET imaging in hormone naive (Luteinising hormone-releasing hormone (LHRH) ± bicalutamide), and in castrate resistant men (enzalutamide or abiraterone) with metastatic PCa. MATERIALS AND METHODS: Serial ⁶⁸GaPSMA-11 PET were prospectively performed at baseline, days 9, 18 and 28, in 8 men with measurable metastatic hormone sensitive PCa commencing LHRH ± bicalutamide (cohort 1), and 7 men with castrate resistant PCa commencing either enzalutamide or abiraterone (cohort 2). Gleason score (GS), age, time since diagnosis and prior treatments were documented. Testosterone and PSA were measured at baseline and all imaging time points. PET/CT was quantitatively analysed for SUV max, SUV mean and total tumour volume (TTV). RESULTS: Cohort 1: A median 30% (IQR 5-61) reduction in SUV max was recorded by day 9 post AB. A reduction from baseline SUV max occurred in 86.5% (6/7) men by day 9 (P <0.04), with an associated PSA response in 100% men (P < 0.03). TTV reduced in all men by 74.5% (IQR 27- 97) (P <0.02). Following day 9, PSMA response heterogeneity was noted, with persistently high or increasing SUV max in 37.5% (3/8) and marked reduction in 62.5% (5/8). Cohort 2: A median 45% (IQR 12.7-66) increase in intensity of PSMA SUV was recorded by day 9 post AB. All men demonstrated an increase in SUV max and mean on PSMA PET compared to baseline (P < 0.04). This increase at day 9 plateaued by day 28. PSA responses were more delayed in cohort 2 (-15% (IQR 70 -138), with 2/7 men demonstrating PSA progression. Conclusion: There is rapid dichotomous response on ⁶⁸GaPSMA PET imaging to androgen blockade dependent on the presence of a hormone sensitive or castrate resistant PCa phenotype. This has important implications for interpretation of PSMA PET , and in the timing and sequencing of PSMA targeted therapy.