Introduction: Fibroblast activation protein (FAP) is overexpressed in several solid tumors and therefore represents an attractive target for radiotheranostic applications. Recent investigations demonstrated rapid and high uptake of small-molecule inhibitors of FAP ( 68 Ga-FAPI-46) for PET imaging. Here, we report our initial experience in terms of feasibility and safety of 90 Y-labelled FAPI-46 ( 90 Y-FAPI-46) for radioligand therapy (RLT) of extensively pretreated patients with solid tumors. Methods: Patients were considered for 90 Y-FAPI-46 therapy in case of (a) exhaustion of all approved therapies based on multidisciplinary tumor board decision and (b) high FAP expression, defined as SUVmax ≥ 10 in more than 50% of all lesions. If tolerated, posttherapeutic 90 Y-FAPI-46 bremsstrahlung scintigraphy was performed to visually confirm systemic distribution and focal tumor uptake, and 90 Y-FAPI-46 PET scans at multiple timepoints were performed to determine absorbed dose. Blood-based dosimetry was used to determine bone-marrow absorbed dose. Adverse Events were graded using CTCAE v.5.0. Results: Nine patients with either metastatic soft tissue or bone sarcoma (N = 6) and pancreatic cancer (N = 3) were treated between June 2020 and March 2021. Patients received a median of 3.8 (IQR 3.25-5.40) GBq for the first cycle and three patients received subsequent cycles with a median of 7.4 (IQR 7.3-7-5) GBq. Post-therapy 90 Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient 90 Y-FAPI-46 uptake in tumor lesions in 7 of 9 patients (78%). Mean absorbed dose was 0.52 Gy/GBq (IQR 0.41-0.65) in kidney, 0.04 Gy/GBq (IQR 0.03-0.06) in bone marrow and below 0.26 Gy/GBq in the lung and liver. Measured tumor lesions received up to 2.28 Gy/GBq (median 1.28Gy/GBq). Hematologic G3/G4 toxicities were noted in four patients (44%), of which

Aim 68Ga-PSMA PET/CT allows for a superior detection of prostate cancer (PC) tissue, especially in context of a low tumor burden. Digital PET/CT bears the potential of reducing scan time duration / administered tracer activity due to, for instance, its higher sensitivity and improved time coincidence resolution. It might thereby expand 68Ga-PSMA PET/CT that is currently limited by 68Ge/68Ga-generator yield. Our aim was to clinically evaluate the influence of a reduced scan time duration in combination with different image reconstruction algorithms on the diagnostic performance. Methods Twenty PC patients (11 for biochemical recurrence, 5 for initial staging, 4 for metastatic disease) sequentially underwent 68Ga-PSMA PET/CT on a digital Siemens Biograph Vision. PET data were collected in continuous-bed-motion mode with a scan time duration of approximately 17 min (reference acquisition protocol) and 5 min (reduced acquisition protocol). 4 iterative reconstruction algorithms were applied using a time-of-flight (TOF) approach alone or combined with point-spread-function (PSF) correction, each with 2 or 4 iterations. To evaluate the diagnostic performance, the following metrics were chosen: (a) per-region detectability, (b) the tumor maximum and peak standardized uptake values (SUVmax and SUVpeak) and (c) image noise using the liver’s activity distribution. Results Overall, 98% of regions (91% of affected regions) were correctly classified in the reduced acquisition protocol independent of the image reconstruction algorithm. Two nodal lesions (each ≤ 4 mm) were not identified (leading to downstaging in 1/20 cases). Mean absolute percentage deviation of SUVmax (SUVpeak) was approximately 9% (6%) for each reconstruction algorithm. The mean image noise increased from 13–21% (4 iterations) and from 10–15% (2 iterations) for PSF + TOF and TOF images. Conclusions High agreement at 3.5-fold reduction of scan time in terms of per-region detection (98% of regions) and image quantification (mean deviation ≤ 10%) was demonstrated; however, small lesions can be missed in about 10% of patients leading to downstaging (T1N0M0 instead of T1N1M0) in 5% of patients. Our results suggest that a reduction of scan time duration or administered 68Ga-PSMA activities can be considered in metastatic patients, where missing small lesions would not impact patient management.

Rationale: Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. A growing number of local and systemic therapies are available, and accurate staging is critical for management decisions. We assessed the impact of neovasculature imaging by 68 Ga-Ga-PSMA-11 PET/CT on disease staging, prognostic groups and management of patients with HCC compared to staging with computed tomography (CT).Methods: Forty patients who received imaging with 68 Ga-Ga-PSMA-11 PET/CT for HCC staging between September 2018 and September 2019 were retrospectively included.Management pre-and post-PET scan was assessed by standardized surveys. Presence of HCC was evaluated by three blinded readers on a per-patient and per-region basis for PET/CT (PET criteria) and multi-phase contrast-enhanced CT (CT criteria) in separate sessions. Lesions were validated by follow-up imaging or histopathology, and progression-free survival (PFS) was recorded. Endpoints were detection rate and positive predictive value (PPV) for 68 Ga-Ga-PSMA-11 PET vs. CT, inter-reader reproducibility, and changes in stage, prognostic groups and management plans.Results: Median age was 65 years (range, 37-81), median Child-Pugh score was 5 (range, 5-9). Most patients were treatment naïve (27 of 40, 67.5%). The sensitivity of PET vs. CT to identify liver lesions for patients with lesion validation was 31/32 (97%) for both modalities, while it was 6/6 (100%) vs. 4/6 (67%) for extra-hepatic lesions. PET and CT each had a PPV of 100% at the liver level. PET vs. CT stage was congruent in 30/40 (75%) patients; upstaging was seen in 8/40 patients (20%), while 2/40 (5%) had downstaging by PET. Intended management changed in 19/40 patients (47.5%); 9/19 of these patients were found to have detectable distant metastases (47.4%) and assigned stage 4 disease, the majority of whom were shifted to systemic therapy (8 of 9, 89%).Two patients underwent 177 Lu-Lu-PSMA-617 radioligand therapy. Median PFS was 5.2 months for the entire cohort; 5.3 months for PET M0, and 4.7 months for PET M1 patients, respectively. Conclusion:68 Ga-Ga-PSMA-11 PET demonstrated higher accuracy than CT in the detection of HCC metastases and was associated with management change in about half of the patient cohort.

Objective: To assess the feasibility and accuracy of Cerenkov Luminescence Imaging (CLI) for assessment of surgical margins intraoperatively during radical prostatectomy (RPE). Methods:A single centre feasibility study included 10 patients with high-risk primary prostate cancer (PC). 68 Ga-PSMA PET/CT scans were performed followed by RPE and intraoperative CLI of the excised prostate. In addition to imaging the intact prostate, in the first two patients the prostate gland was incised and imaged with CLI to visualise the primary tumour. We compared the tumour margin status on CLI to postoperative histopathology. Measured CLI intensities were determined as tumour to background ratio (TBR).Results: Tumour cells were successfully detected on the incised prostate CLI images as confirmed by histopathology. 3 of 10 men had histopathological positive surgical margins (PSMs), and 2 of 3 PSMs were accurately detected on CLI. Overall, 25 (72%) out of 35 regions of interest (ROIs) proved to visualize a tumour signal according to standard histopathology. The median tumour radiance in these areas was 11301 photons/s/cm 2 /sr (range 3328 -25428 photons/s/cm 2 /sr) and median TBR was 4.2 (range 2.1 -11.6).False positive signals were seen mainly at the prostate base with PC cells overlaid by benign tissue. PSMA-immunohistochemistry (PSMA-IHC) revealed strong PSMA staining of benign gland tissue, which impacts measured activities.Conclusions: This feasibility showed that 68 Ga-PSMA CLI is a new intraoperative imaging technique capable of imaging the entire specimen's surface to detect PC tissue at the resection margin. Further optimisation of the CLI protocol, or the use of lower-energetic imaging tracers such as 18 F-PSMA, are required to reduce false positives. A larger study will be performed to assess diagnostic performance.

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Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) prolongs overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, men with low PSMA expression are excluded from RLT. We explored the effect of androgen receptor blockade with enzalutamide on PSMA expression. Assessment of PSMA and androgen receptor (AR) expression on the human PC cell lines 22Rv1, C4-2, and LNCaP by immunohistochemistry and flow cytometry revealed low (22Rv1) and high (C4-2 and LNCaP) PSMA expression, and high, comparable AR positivity. Treatment with enzalutamide increased PSMA levels in 22Rv1, C4-2, and LNCaP (2.2/2.3/2.6-fold, p = 0.0005/0.03/0.046) after one week compared to DMSO-treated controls as assessed by flow cytometry. NOD/Scid mice bearing 22Rv1 tumors were treated with enzalutamide for two weeks. Positron emission tomography/computed tomography (PET/CT) demonstrated higher tumor uptake of 68Ga-PSMA after enzalutamide treatment (p = 0.004). Similarly, a clinical case with low baseline PSMA avidity demonstrated increased uptake of 68Ga-PSMA after enzalutamide on PET/CT and post-therapeutic 177Lu-PSMA scintigraphy in a patient with mCRPC. Enzalutamide induced PSMA expression in the 22Rv1 xenograft model and in an mCRPC patient, both with low baseline tumoral PSMA levels. Therefore, enzalutamide pre-treatment might render patients with low PSMA expression eligible for 177Lu-PSMA RLT.

Purpose: We report efficacy and safety of 90Y-FAPI-46-RLT in patients with advanced sarcoma, pancreatic cancer (PDAC) and other cancer entities. Experimental Design: Up to four cycles of RLT were offered to patients with (a) progressive metastatic malignancy, (b) exhaustion of approved therapies, and (c) high fibroblast activation protein (FAP) expression, defined as SUVmax≥10 in more than 50% of tumor. Primary endpoint was RECIST response after RLT. Secondary endpoints included PET response (PERCIST), overall survival, dosimetry and safety of FAP-RLT. Results: Among n=119 screened patients, n=21 (18%) were found eligible (n=16/3/1/1 sarcoma/PDAC/prostate/gastric cancer; 38% ECOG≥2) and received n=47 90Y-FAPI-46-RLT cycles; n=16/21 (76%) patients underwent repeat RLT. By RECIST disease control was confirmed in n=8/21 patients (38%; 8/16 [50%] of evaluable patients). There were 1 partial response and 7 stable diseases after RLT. Disease control was associated with prolonged overall survival (p=0.013). PERCIST response was noted in n=8/21 patients (38%; 8/15 [53%] of evaluable patients). Dosimetry was acquired in n=19 (90%) patients. Mean absorbed dose was 0.53Gy/GBq in kidney, 0.04Gy/GBq in bone marrow and <0.14Gy/GBq in liver and lung. Treatment-related grade 3 or 4 adverse events were observed in n=8 (38%) patients with thrombocytopenia (n=6) and anemia (n=6) being most prevalent. Conclusion: 90Y-FAPI-46-RLT was safe and led to RECIST partial response in one case as well as stable disease in about one third of patients with initially progressive sarcomas, PDAC and other cancers. Discontinuation after the first cycle and a low rate of partial response require for future improvement of FAP-RLT.

Introduction Patient eligibility for [177Lu]Lu-PSMA therapy remains a challenge, with only 40–60% response rate when patient selection is done based on the lesion uptake (SUV) on [68Ga]Ga-PSMA-PET/CT. Prediction of absorbed dose based on this pre-treatment scan could improve patient selection and help to individualize treatment by maximizing the absorbed dose to target lesions while adhering to the threshold doses for the organs at risk (kidneys, salivary glands, and liver). Methods Ten patients with low-volume hormone-sensitive prostate cancer received a pre-therapeutic [68Ga]Ga-PSMA-11 PET/CT, followed by 3 GBq [177Lu]Lu-PSMA-617 therapy. Intra-therapeutically, SPECT/CT was acquired at 1, 24, 48, 72, and 168 h. Absorbed dose in organs and lesions (n = 22) was determined according to the MIRD scheme. Absorbed dose prediction based on [68Ga]Ga-PSMA-PET/CT was performed using tracer uptake at 1 h post-injection and the mean tissue effective half-life on SPECT. Predicted PET/actual SPECT absorbed dose ratios were determined for each target volume. Results PET/SPECT absorbed dose ratio was 1.01 ± 0.21, 1.10 ± 0.15, 1.20 ± 0.34, and 1.11 ± 0.29 for kidneys (using a 2.2 scaling factor), liver, submandibular, and parotid glands, respectively. While a large inter-patient variation in lesion kinetics was observed, PET/SPECT absorbed dose ratio was 1.3 ± 0.7 (range: 0.4–2.7, correlation coefficient r = 0.69, p < 0.01). Conclusion A single time point [68Ga]Ga-PSMA-PET scan can be used to predict the absorbed dose of [177Lu]Lu-PSMA therapy to organs, and (to a limited extent) to lesions. This strategy facilitates in treatment management and could increase the personalization of [177Lu]Lu-PSMA therapy.