Introduction and objectives

Wound healing after myocardial infarction (MI) is a dynamic and complex multiple phase process, and a coordinated cellular response is required for proper scar formation. The current paradigm suggests that pro-inflammatory monocytes infiltrate the MI zone during the initial pro-inflammatory phase and differentiate into inflammatory macrophages, and then switch their phenotypes to anti-inflammatory during the reparative phase. Visualization of the reparative phase post-MI is of great interest because it may reveal delayed resolution of inflammation, which in turn predicts adverse cardiac remodeling. Imaging of anti-inflammatory macrophages may also be used to assess therapy approaches aiming to modulate the inflammatory response in order to limit MI size. Reparative macrophages can be distinguished from inflammatory macrophages by the surface marker mannose receptor (MR, CD206). In this study we evaluated the feasibility of ⁶⁸Ga-NOTA-anti-MMR Nb for imaging of MR on alternatively activated macrophages in murine MI models.

Methods

Wildtype and MR-knockout mice and Wistar rats were subjected to MI via permanent ligation of the left coronary artery. Non-operated or sham-operated animals were used as controls. MR expression kinetics on cardiac macrophages was measured in mice using flow cytometry. PET/CT scans were performed 1 h after intravenous injection of ⁶⁸Ga-NOTA-anti-MMR Nb. Mice and rats were euthanized and hearts harvested for ex vivo PET/MRI, autoradiography, and staining. As a non-targeting negative control, ⁶⁸Ga-NOTA-BCII10 was used.

Results

In vivo-PET/CT scans showed focal radioactivity signals in the infarcted myocardium for ⁶⁸Ga-NOTA-anti-MMR Nb which were confirmed by ex vivo-PET/MRI scans. In autoradiography images, augmented uptake of the tracer was observed in infarcts, as verified by the histochemistry analysis. Immunofluorescence staining demonstrated the presence and co-localization of CD206- and CD68-positive cells, in accordance to infarct zone. No in vivo or ex vivo signal was observed in the animals injected with control Nb or in the sham-operated animals. ⁶⁸Ga-NOTA-anti-MMR Nb uptake in the infarcts of MR-knockout mice was negligibly low, confirming the specificity of ⁶⁸Ga-NOTA-anti-MMR Nb to MR.

Conclusion

This exploratory study highlights the potential of ⁶⁸Ga-NOTA-anti-MMR Nb to image MR-positive macrophages that are known to play a pivotal role in wound healing that follows acute MI.

The aim of this study was to analyze patterns of persistent versus recurrent or new PET lesions in a selected patient cohort with prostate-specific antigen (PSA) persistence after salvage lymph node dissection (SLND) and pre-procedure and post-procedure prostate-specific membrane antigen (PSMA) ligand PET. Methods: Sixteen patients were included in this multicenter study. The inclusion criteria were PSMA PET performed for biochemical recurrence before SLND (pre-SLND PET) and repeat PSMA PET performed for a persistently elevated PSA level (≥0.1 ng/mL) at least 6 wk after SLND (post-SLND PET). Image analysis was performed by 3 independent nuclear medicine physicians applying the molecular imaging TNM system PROMISE. Lesions were confirmed by histopathology, presence on correlative CT/MRI/bone scanning, or PSA response after focal therapy. Results: Post-SLND PET identified prostate cancer lesions in 88% (14/16) of patients with PSA persistence after SLND. Median PSA was 1.2 ng/mL (interquartile range, 0.6-2.8 ng/mL). Disease was confined to the pelvis in 56% of patients (9/16), and most of these men had common iliac (6/16, 38%) and internal iliac lymph node metastases (6/16, 38%). Extrapelvic disease was detected in 31% of patients (5/16). In pre- and post-SLND PET comparison, 10 of 16 had at least one lesion already detected at baseline (63% PET persistence), 4 of 16 had new lesions only (25% PET recurrence), and 2 had no disease on post-SLND PET. All validated regions (11 regions in 9 patients) were true-positive. Nine of 14 (64%) patients underwent repeat local therapies after SLND (7/14 radiotherapy, 2/14 surgery). Conclusion: SLND of pelvic nodal metastases was often not complete according to PSMA PET. About two thirds of patients had PET-positive nodal disease after SLND already seen on pre-SLND PSMA PET. Notably, about one quarter of patients had new lesions, not detected by presurgical PSMA PET.

Background

National Comprehensive Cancer Network guidelines consider ¹⁸F-fluciclovine PET-CT for prostate cancer biochemical recurrence localisation after radical prostatectomy, whereas European Association of Urology guidelines recommend prostate-specific membrane antigen (PSMA) PET-CT. To the best of our knowledge, no prospective head-to-head comparison between these tests has been done so far. The aim of this study was to compare prospectively paired ¹⁸F-fluciclovine and PSMA PET-CT scans for localising biochemical recurrence of prostate cancer after radical prostatectomy in patients with low prostate-specific antigen (PSA) concentrations (<2·0 ng/mL).

Methods

This was a prospective, single-centre, open-label, single-arm comparative study done at University of California Los Angeles (Los Angeles, CA, USA). Patients older than 18 years of age with prostate cancer biochemical recurrence after radical prostatectomy and PSA levels ranging from 0·2 to 2·0 ng/mL without any prior salvage therapy and with a Karnofsky performance status of at least 50 were eligible. Patients underwent ¹⁸F-fluciclovine (reference test) and PSMA (index test) PET-CT scans within 15 days. Detection rate of biochemical recurrence at the patient level and by anatomical region was the primary endpoint. A statistical power analysis demonstrated that a sample size of 50 patients was needed to show a 22% difference in detection rates in favour of PSMA (test for superiority). Each PET scan was interpreted by three independent masked readers and a consensus majority interpretation was generated (two vs one) to determine positive findings. This study is registered with ClinicalTrials.gov, number NCT02940262, and is complete.

Findings

Between Feb 26, 2018, and Sept 20, 2018, 143 patients were screened for eligibility, of whom 50 patients were enrolled into the study. Median follow-up was 8 months (IQR 7-9). The primary endpoint was met; detection rates were significantly lower with ¹⁸F-fluciclovine PET-CT (13 [26%; 95% CI 15-40] of 50) than with PSMA PET-CT (28 [56%; 41-70] of 50), with an odds ratio (OR) of 4·8 (95% CI 1·6-19·2; p=0·0026) at the patient level; in the subanalysis of the pelvic nodes region (four [8%; 2-19] with ¹⁸F-fluciclovine vs 15 [30%; 18-45] with PSMA PET-CT; OR 12·0 [1·8-513·0], p=0·0034); and in the subanalysis of any extrapelvic lesions (none [0%; 0-6] vs eight [16%; 7-29]; OR non-estimable [95% CI non-estimable], p=0·0078).

Interpretation

With higher detection rates, PSMA should be the PET tracer of choice when PET-CT imaging is considered for subsequent treatment management decisions in patients with prostate cancer and biochemical recurrence after radical prostatectomy and low PSA concentrations (≤2·0 ng/mL). Further research is needed to investigate whether higher detection rates translate into improved oncological outcomes.

Funding

None.