In this study, we investigated upregulation of prostate-specific membrane antigen (PSMA) by enzalutamide in a cohort (n = 30) of patients with advanced metastatic castration-resistant prostate cancer (mCRPC). Patients were examined by [⁶⁸Ga]Ga-PSMA-11 PET/CT pre- and post-enzalutamide medication (mean 13 ± 7 days). Imaging results were compared based on quantification of whole-body PSMA tumor burden: total lesion PSMA (TLP) and normalized TLP values to liver (TLP-LR) and to parotid gland (TLP-PR). In addition, lesion-based analyses were performed. The median (mean) increases in TLP, TLP-LR and TLP-PR after enzalutamide medication were 10.1% (20.2%), 29.5% (34.8%) and 27.6% (24.4%), respectively. These increases were statistically significant (p = 0.002, p < 0.001, and p < 0.001), while prostate-specific antigen (PSA) serum values did not change significantly (p = 0.483). The increase was independent of prior patient exposure to enzalutamide. SUV_max increased substantially (>10%) in 49.6% of target lesions. The relative change was significantly higher in the subgroup of lesions with SUV_max < 10 (p < 0.001). In conclusion, short-term enzalutamide medication significantly increases PSMA expression in patients with mCRPC, irrespective of prior enzalutamide exposure. The relative PSMA upregulation effect seems to be more pronounced in lesions with only moderate baseline PSMA expression. Enzalutamide may provide a potential enhancer medication for PSMA-targeted radioligand therapy.

This study aimed to compare the diagnostic performance of [¹⁸F]PSMA-1007 positron emission tomography/computed tomography (PET/CT) (¹⁸F-PSMA) and [⁶⁸Ga]Ga-PSMA-11 PET/CT (⁶⁸Ga-PSMA) by identifying prostate-specific antigen (PSA) threshold levels for optimal detecting recurrent prostate cancer (PC) and to compare both methods. Retrospectively, the study included 264 patients. The performances of ¹⁸F-PSMA and ⁶⁸Ga-PSMA in relation to the pre-scan PSA were assessed by receiver operating characteristic (ROC) curve. ¹⁸F-PSMA showed PC-lesions in 87.5% (112/128 patients), while ⁶⁸Ga-PSMA identified them in 88.9% (121/136). For ¹⁸F-PSMA biochemical recurrent (BCR) patients treated with radical prostatectomy (78/128, patient group: F-RP), a PSA of 1.08 ng/mL was found to be the optimal cut-off level for predicting positive and negative scans (AUC = 0.821; 95%, CI: 0.710–0.932), while for prostatectomized ⁶⁸Ga-PSMA BCR-patients (89/136, patient group: Ga-RP), the cut-off was 1.84 ng/mL (AUC = 0.588; 95%, CI: 0.410–0.766). In patients with PSA < 1.08 ng/mL (F-RP) 76.3% and <1.84 ng/mL (Ga-RP) 78.6% scans were positive, whereas patients with PSA ≥ 1.08 ng/mL (F-RP) or 1.84 ng/mL (Ga-RP) had positive scan results in 100% and 91.5% (p < 0.001/p = 0.085). The identified PSA thresholds for PSMA-mappable PC lesions in BCR-patients (RP) showed a better separation for ¹⁸F-PSMA with regard to the distinguishing of positive and negative PC-lesions compared to ⁶⁸Ga-PSMA. However, the two PSMA PET/CT tracers gave similar overall findings.

Despite the promising results of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) in metastatic castration-resistant prostate cancer (mCRPC), some patients show worsening disease during PSMA-RLT. We investigated the value of combined [¹⁸F]FDG and [⁶⁸Ga]Ga-PSMA-11 PET imaging in this setting. In n = 29 mCRPC patients with worsening disease after a median of four cycles of [¹⁷⁷Lu]Lu-PSMA-617 RLT, combined [¹⁸F]FDG and [⁶⁸Ga]Ga-PSMA-11 PET imaging was performed to detect [¹⁸F]FDG-avid lesions with low or no PSMA expression (mismatch lesions). To evaluate prognostic implication of mismatch, survival analyses regarding presence, location, and [¹⁸F]FDG PET-derived parameters such as SUV_max, metabolic tumor volume (MTV_m), and total lesion glycolysis (TLG_m) of mismatch findings were performed. Seventeen patients (59%) showed at least one mismatch metastasis. From the time point of combined PET imaging, the median overall survival (OS) of patients with mismatch findings was significantly (p = 0.008) shorter than those without (3.3 vs. 6.1 mo). Patients with a high MTV_m revealed a significantly (p = 0.034) shorter OS of 2.6 mo than patients with low MTV_m (5.3 mo). Furthermore, patients with hepatic mismatch showed a significantly (p = 0.049) shorter OS than those without (2.9 vs. 5.3 mo). Difference in OS regarding SUV_max and TLG_m was not significant. In mCRPC patients with worsening disease during PSMA-RLT, combined [¹⁸F]FDG and [⁶⁸Ga]Ga-PSMA-11 PET imaging is essential to identify mismatch findings, as these are associated with poor outcomes requiring a change in therapy management.

Routine [⁶⁸Ga]Ga-PSMA-11 PET/CT (one hour post-injection) has been shown to accurately detect prostate cancer (PCa) lesions. The goal of this study is to evaluate the benefit of a dual-time point imaging modality for the staging and restaging of PCa patients. Biphasic [⁶⁸Ga]Ga-PSMA-11 PET/CT of 233 patients, who underwent early and late scans (one/three hours post-injection), were retrospectively studied. Tumor uptake and biphasic lesion detection for 215 biochemically recurrent patients previously treated for localized PCa (prostatectomized patients (P-P)/irradiated patients (P-I) and 18 patients suspected of having primary PCa (P-T) were separately evaluated. Late [⁶⁸Ga]Ga-PSMA-11 PET/CT imaging detected 554 PCa lesions in 114 P-P patients, 187 PCa lesions in 33 P-I patients, and 47 PCa lesions in 13 P-T patients. Most patients (106+32 P-P/P-I, 13 P-T) showed no additional PCa lesions. However, 11 PSMA-avid lesions were only detected in delayed images, and 33 lesions were confirmed as malignant by a SUVmax increase. The mean SUVmax of pelvic lymph node metastases was 25% higher (p < 0.001) comparing early and late PET/CT. High positivity rates from routine [⁶⁸Ga]Ga-PSMA-11 PET/CT for the staging and restaging of PCa patients were demonstrated. There was no decisive influence of additional late imaging with PCa lesion detection on therapeutic decisions. However, in a few individual cases, additional delayed scans provided an information advantage in PCa lesion detection due to higher tracer uptake and improved contrast.

[¹⁸F]Fluoro-2-deoxy-2-d-glucose positron emission tomography (FDG-PET) is commonly used in the clinic for diagnosis of cancer and for follow-up of therapy outcome. Additional to the well-established value in tumor imaging, it bears potential to depict immune processes in modern immunotherapies. T cells enhance their glucose consumption upon activation and are crucial effectors for the success of such novel therapies. In this study, we analyzed the T cell immunity in spleen after antigen-specific stimulation of T cells via highly innovative RNA-based vaccines using FDG-PET/MRI. For this purpose, we employed systemic administration of RNA-lipoplexes encoding the endogenous antigen of Moloney murine leukemia virus (gp70) which have been previously shown to induce potent innate as well as adaptive immune mechanisms for cancer immunotherapy. Feasibility of clinical imaging of increased splenic FDG uptake was demonstrated in a melanoma patient participating in a clinical phase 1 trial of a tetravalent RNA-lipoplex cancer vaccine. We observed exclusive increase of glucose uptake in spleen compared to other organs thanks to liposome-mediated RNA targeting to this immune-relevant organ. In vivo and ex vivo FDG uptake analysis in the spleen of vaccinated mice correlated well with antigen-specific T cell activation. Moreover, the use of an irrelevant (antigen non-specific) RNA also resulted in enhanced FDG uptake early after vaccination through the activation of several other splenic cell populations. The glucose uptake was also dependent on the dose of RNA administered in line with the activation and frequencies of proliferating antigen-specific T cells as well as the general activation pattern of splenic cell populations. Our preclinical results show rapid and transient vaccination-induced increase of FDG uptake within the spleen reflecting immune activation preceding T cell proliferation. FDG-PET/CT in patients is also capable to image this immune activation resulting in a new potential application of FDG-PET/CT to image immune processes in new immunological therapies.

In biochemical recurrence of prostate cancer (BCR), prompt tumor localization guides early treatment, potentially improving patient outcomes. Gallium-68 prostate-specific membrane antigen-11 positron emission tomography/computed tomography (⁶⁸Ga-PSMA-11 PET/CT) detection rates of lesions suspicious for prostate cancer are well known to rise along with prostate-specific antigen (PSA) concentration. However, published data are limited regarding very low values (≤0.2 ng/mL). We retrospectively analyzed ~7-year “real-world” experience in this setting in a large post-prostatectomy cohort (N = 115) from two academic clinics. Altogether 44 lesions were detected in 29/115 men (25.2%) (median [minimum–maximum] 1 [1–4]/positive scan). The apparent oligometastatic disease was found in nine patients (7.8%) at PSA as low as 0.03 ng/mL. Scan positivity rates were highest when PSA was >0.15 ng/mL, PSA doubling time was ≤12 months, or the Gleason score was ≥7b (in 83 and 107 patients, respectively, with available data); these findings were statistically significant (p ≤ 0.04), except regarding PSA level (p = 0.07). Given the benefits of promptly localizing recurrence, our observations suggest the potential value of ⁶⁸Ga-PSMA-11 PET/CT in the very low PSA BCR setting, especially in cases with more rapid PSA doubling time or with high-risk histology.