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Approximately 40–70% of biochemically persistent or recurrent prostate cancer (PCa) patients after radical prostatectomy (RPE) are oligo-metastatic in 68gallium-prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET). Those lesions are frequently located outside the prostate bed, and therefore not cured by the current standards of care like external-beam radiotherapy (EBRT) of the prostatic fossa. This retrospective study analyzes the influence of oligo-metastases’ site on outcome after metastasis-directed radiotherapy (MDR). Retrospectively, 359 patients with PET-positive PCa recurrences after RPE were analyzed. Biochemical recurrence-free survival (BRFS) (prostate-specific antigen (PSA)

The impact of prostate-specific membrane antigen (PSMA) PET/CT on management of prostate cancer (PCa) patients with biochemical recurrence (BCR) is well established. However, whether and how PSMA PET/CT affects the management of patients undergoing scans for other clinical indications remains unknown. The goal of this study was to determine the impact of 68Ga-PSMA-11 PET/CT on initial and subsequent management decisions in a cohort of PCa patients referred for various indications (i.e., a basket trial) excluding the 2 main classic indications: BCR and presurgical staging. Methods: This was a prospective study of 197 patients that aimed to determine the impact of 68Ga-PSMA-11 PET/CT on PCa stage and management. The indications for PSMA PET/CT were initial staging of nonsurgical candidates (30 patients) and restaging after definitive treatment (167 patients). The restaging cohort comprised patients restaged with known advanced metastatic disease (n = 103), after androgen deprivation therapy only (n = 16), after surgery and with serum prostate-specific antigen levels lower than 0.2 ng/mL (n = 13), after radiation therapy and not meeting the Phoenix criteria (n = 22), and after other primary local treatments (i.e., high-intensity focused ultrasound, focal laser ablation, cryoablation, hyperthermia, or irreversible electroporation) (n = 13). Patients with BCR and candidates for curative surgery were excluded. Impact on management was assessed using pre- and post-PET questionnaires completed by referring physicians, electronic chart review, or patient telephone calls. Results: PSMA PET/CT changed the disease stage in 135 of 197 (69%) patients (upstaging in 38%, downstaging in 30%, and no change in stage in 32%). Management was affected in 104 of 182 (57%) patients. Specifically, PSMA PET/CT impacted the management of patients who were restaged after radiation therapy without meeting the Phoenix criteria for BCR, after other definitive local treatments, and with advanced metastatic disease in 13 of 18 (72%), 8 of 12 (67%), and 59 of 96 (61%), respectively. Conclusion: PSMA PET/CT has a profound impact on stage and management of PCa patients outside the 2 main classic indications (BCR and presurgical staging) across all examined clinical scenarios.

We aimed to systematically determine the impact of tumor burden on (68)Ga-prostate-specific membrane antigen-11 ((68)Ga-PSMA) PET biodistribution by the use of quantitative measurements. Methods: This international multicenter, retrospective analysis included 406 men with prostate cancer who underwent (68)Ga-PSMA PET/CT. Of these, 356 had positive findings and were stratified by quintiles into a very low (quintile 1, ≤25 cm(3)), low (quintile 2, 25–189 cm(3)), moderate (quintile 3, 189–532 cm(3)), high (quintile 4, 532–1,355 cm(3)), or very high (quintile 5, ≥1,355 cm(3)) total PSMA-positive tumor volume (PSMA-VOL). PSMA-VOL was obtained by semiautomatic segmentation of total tumor lesions using qPSMA software. Fifty prostate cancer patients with no PSMA-positive lesions (negative scan) served as a control group. Normal organs, which included salivary glands, liver, spleen, and kidneys, were semiautomatically segmented using (68)Ga-PSMA PET images, and SUV(mean) was obtained. Correlations between the SUV(mean) of normal organs and PSMA-VOL as continuous and categoric variables by quintiles were evaluated. Results: The median PSMA-VOL was 302 cm(3) (interquartile range [IQR], 47–1,076 cm(3)). The median SUV(mean) of salivary glands, kidneys, liver, and spleen was 10.0 (IQR, 7.7–11.8), 26.0 (IQR, 20.0–33.4), 3.7 (IQR, 3.0–4.7), and 5.3 (IQR, 4.0–7.2), respectively. PSMA-VOL showed a moderate negative correlation with the SUV(mean) of the salivary glands (r = −0.44, P

In a subset of patients with recurrent oligometastatic prostate cancer (PCa) salvage surgery with prostate-specific membrane antigen (PSMA)-targeted radioguidance (PSMA-RGS) might be of value.To evaluate the oncological outcomes of salvage PSMA-RGS and determine the predictive preoperative factors of improved outcomes.A cohort study of oligorecurrent PCa patients with biochemical recurrence (BCR) after radical prostatectomy and imaging with PSMA positron emission tomography (PET), treated with PSMA-RGS in two tertiary care centers (2014-2020), was conducted.PSMA-RGS.Kaplan-Meier and multivariable Cox regression models were used to assess BCR-free (BFS) and therapy-free (TFS) survival. Postoperative complications were classified according to Clavien-Dindo.Overall, 364 patients without concomitant treatment were assessed. At PSMA-RGS, metastatic soft-tissue PCa lesions were removed in 343 (94%) patients. At 2-16 wk after PSMA-RGS, 165 patients reached a prostate-specific antigen (PSA) level of0.2 ng/ml. Within 3 mo, 24 (6.6%) patients suffered from Clavien-Dindo complications grade III-IV. At 2 yr, BFS and TFS rates were 32% and 58%, respectively. In multivariable analyses, higher preoperative PSA (hazard ratio [HR]: 1.07, 95% confidence interval [CI]: 1.02-1.12), higher number of PSMA-avid lesions (HR: 1.23, CI: 1.08-1.40), multiple (pelvic plus retroperitoneal) localizations (HR: 1.90, CI: 1.23-2.95), and retroperitoneal localization (HR: 2.04, CI: 1.31-3.18) of lesions in preoperative imaging were independent predictors of BCR after PSMA-RGS. The main limitation is the lack of a control group.As salvage surgery in oligorecurrent PCa currently constitutes an experimental treatment approach, careful patient selection is mandatory based on life expectancy, low PSA values, and low number of PSMA PET-avid lesions located in the pelvis.We looked at the outcomes from prostate cancer patients with recurrent disease after radical prostatectomy. We found that surgery may be an opportunity to prolong treatment-free survival, but patient selection criteria need to be very narrow.

To compare the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the adapted Prostate Cancer Working Group Criteria 3 (aPCWG3), the adapted Positron Emission Tomography Response Criteria in Solid Tumors (aPERCIST), the PSMA PET Progression (PPP), and the Response Evaluation Criteria In PSMA-Imaging (RECIP) 1.0 for response evaluation using prostate-specific membrane antigen (PSMA)-PET/CT in men with metastatic castration-resistant prostate cancer (mCRPC) treated withA total of 124 patients were included in this multicenter retrospective study. All patients receivedA total of 43 (35%) of patients had non-measurable disease according to RECIST 1.1. Sixteen (13%), 66 (52%), 72 (58%), 69 (56%), and 39 (32%) of 124 patients had PD according to RECIST 1.1, aPCWG3, aPERCIST, PPP, and RECIP, respectively. PD vs no-PD had significantly higher risk of death according to aPCWG3 (HR = 2.37; 95%CI, 1.62-3.48; p 0.001), aPERCIST (HR = 2.48; 95%CI, 1.68-3.66; p 0.001), PPP (HR = 2.72; 95%CI, 1.85-4.01; p 0.001), RECIP 1.0 (HR = 4.33; 95%CI, 2.80-6.70; p 0.001), but not according to RECIST 1.1 (HR = 1.29; 95%CI, 0.73-2.27; p = 0.38). The κ index of RECIST 1.1, aPCWG3, aPERCIST 1.0, PPP, and RECIP 1.0 for identifying PD vs no-PD were 0.50 (95%CI, 0.32-0.76), 0.72 (95%CI, 0.63-0.82), 0.68 (95%CI, 0.63-0.73), 0.73 (95%CI, 0.63-0.83), and 0.83 (95%CI, 0.77-0.88), respectively.PSMA-PET-specific criteria for early response evaluation in men with mCRPC treated with

5040 Background: 223Ra and 177Lu-PSMA both prolong overall survival (OS) in different mCRPC settings. Previous data from the observational REASSURE (Sartor O, et al. 2021) and WARMTH (Ahmadzadehfar H, et al. 2021) studies suggested the feasibility of sequencing 223Ra and 177Lu-PSMA therapies. Here we used data from the observational, retrospective RALU study to further examine the safety and clinical outcomes of sequential 223Ra/177Lu-PSMA therapy in pts with mCRPC. Methods: This interim analysis investigated the baseline characteristics, safety (primary endpoint) and OS (secondary endpoint) in pts who received 177Lu-PSMA after 223Ra using retrospective data collected in German centers. Results: Data from 49 pts were available for this interim analysis. At baseline, before the start of 177Lu-PSMA, 73% of pts were Eastern Cooperative Oncology Group performance status (ECOG PS) 1 and 27% ECOG PS 2. Visceral metastases were present in 31% of pts. Median prostate-specific antigen (PSA) and alkaline phosphatase (ALP) were 287 ng/ml and 142 U/L, respectively (Table). 70% of pts received ≥4 life-prolonging therapies prior to 177Lu-PSMA, with abiraterone acetate (80%), enzalutamide (67%) and docetaxel (92%) being the most frequently used. 74% of pts received ≥5 223Ra injections. Pts received either PSMA-617 (67%) or PSMA I&T (33%): 65% of pts received 1–4 cycles and 33% received 5–6 cycles. Median duration of 177Lu-PSMA therapy was 4.9 months (m) (0–57.1). Median time from the last 223Ra dose to first 177Lu-PSMA dose was 9.3 m (0.9–41.9). Any grade treatment-emergent adverse events (TEAEs) from the start of 177Lu-PSMA therapy to 30 days of follow-up occurred in 91.8% of pts, and serious TEAEs in 20% of pts. Grade 3-4 hematologic laboratory abnormalities up to 90 days post-177Lu-PSMA occurred in 34.7% of pts for anemia, 12.8% for thrombocytopenia and 2.0% for neutropenia. No grade 5 toxicities occurred. 39% of pts had ≥30% decline in PSA during 177Lu-PSMA treatment. Median OS was 12.6 m (95% CI 8.8–16.1) from the start of 177Lu-PSMA therapy. Conclusions: In this real-world retrospective analysis of selected pts with advanced mCRPC, the 223Ra/177Lu-PSMA treatment sequence was clinically feasible and well tolerated. [Table: see text]

97 Background: The phase 3 VISION trial (NCT03511664) evaluated the efficacy and safety of the radioligand [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) in patients with metastatic castration-resistant prostate cancer. 177Lu-PSMA-617 plus protocol-permitted standard of care (SOC) significantly improved overall survival and radiographic progression-free survival of patients compared with SOC alone. The incidence of adverse events (AEs) of grade 3 or above was higher with 177Lu-PSMA-617 than without, but quality of life was not adversely affected. This dosimetry sub-study aimed to quantify the absorbed dose of 177Lu-PSMA-617 in organs at risk of radiotoxicity due to exposure levels or radiosensitivity. Methods: In a sub-study of VISION, dosimetry was performed in a separate cohort of 29 non-randomized participants at four German sites. Eligible patients received 177Lu-PSMA-617 (7.4 GBq per cycle) plus SOC every 6 weeks for a maximum of 6 cycles. Patients underwent planar whole-body scintigraphy scans and single-photon emission computed tomography/computed tomography (SPECT/CT) scans of the upper and lower abdomen at 2, 24, 48 and 168 hours after first administration. Blood and urine samples were collected throughout cycle 1. 177Lu-PSMA-617 dosimetry outcomes were based on biodistribution, assessed using whole-body conjugate planar-image data, SPECT/CT image data, blood assay data and urinary excretion data. Radiation exposure was estimated using Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM) software code version 2.2. Results were expressed as absorbed dose per unit activity (Gy/GBq) and cumulative estimated absorbed dose (Gy) over all 6 cycles (44.4 GBq cumulative activity) extrapolated from cycle 1 data. Results: Radiation-absorbed doses per unit activity were highest in the lacrimal glands, followed by the salivary glands, with mean values of 2.1 Gy/GBq (standard deviation [SD], 0.47) and 0.63 Gy/GBq (0.36), respectively. The kidneys received 0.43 Gy/GBq (SD, 0.16) and the blood-based red marrow dose was 0.035 Gy/GBq (0.02). The 6-cycle cumulative estimated absorbed dose was 92 Gy (SD, 21) in the lacrimal glands, 28 Gy (16) in the salivary glands, 19 Gy (7.3) in the kidneys and 1.5 Gy (0.90) in the red marrow. In cycle 1, 20% of patients had at least one hematological AE of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2; no patient experienced any renal AE of CTCAE grade ≥ 2 or any lacrimal gland toxicity, and 2 patients had a grade 1 salivary gland AE. Conclusions: 177Lu-PSMA-617 dosimetry results in this sub-study were consistent with the published ranges, and cycle 1 AEs affecting at-risk organs were infrequent and of low-to-moderate severity. These findings indicate that patients with metastatic castration-resistant prostate cancer receiving 177Lu-PSMA-617 should be at low risk of radiation-induced AEs. Clinical trial information: NCT03511664.

Purpose Although treatment planning and individualized dose application for emerging prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) are generally recommended, it is still difficult to implement in practice at the moment. In this study, we aimed to prove the concept of pretherapeutic prediction of dosimetry based on imaging and laboratory measurements before the RLT treatment. Methods Twenty-three patients with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA I&T RLT were included retrospectively. They had available pre-therapy 68 Ga-PSMA-HEBD-CC PET/CT and at least 3 planar and 1 SPECT/CT imaging for dosimetry. Overall, 43 cycles of 177Lu-PSMA I&T RLT were applied. Organ-based standard uptake values (SUVs) were obtained from pre-therapy PET/CT scans. Patient dosimetry was calculated for the kidney, liver, spleen, and salivary glands using Hermes Hybrid Dosimetry 4.0 from the planar and SPECT/CT images. Machine learning methods were explored for dose prediction from organ SUVs and laboratory measurements. The uncertainty of these dose predictions was compared with the population-based dosimetry estimates. Mean absolute percentage error (MAPE) was used to assess the prediction uncertainty of estimated dosimetry. Results An optimal machine learning method achieved a dosimetry prediction MAPE of 15.8 ± 13.2% for the kidney, 29.6% ± 13.7% for the liver, 23.8% ± 13.1% for the salivary glands, and 32.1 ± 31.4% for the spleen. In contrast, the prediction based on literature population mean has significantly larger MAPE (p Conclusion The preliminary results confirmed the feasibility of pretherapeutic estimation of treatment dosimetry and its added value to empirical population-based estimation. The exploration of dose prediction may support the implementation of treatment planning for RLT.

The original version of this article unfortunately contained a mistake. The copyright holder for this article was incorrectly given as “© Springer-Verlag GmbH Germany, part of Springer Nature 2021,” but should have been “© The Author(s) 2021.” The original article has been corrected.

5043 Background: PSMA-targeted radioligand therapy can improve the outcome of patients with advanced mCRPC. However, patients do not respond uniformly and a PSA decline of ≥50% (PSA50) was achieved only in 46% of the patients in the VISION trial. We hypothesized that using the parotid glands instead of the liver as the reference organ enables more selective stratification. The aim of this study was to test PSMA PET tumor-to-Salivary Glands ratio (PSG score) to predict outcomes after Lu-177 PSMA. Methods: This was an international multicenter retrospective study using the established dataset consisting of 270 men with mCRPC treated with Lu-177 PSMA (Gafita A, Lancet Oncol 2021). First, we assessed baseline PSMA PET quantitatively (qPSG score) to calculate the tumor-to-salivary gland ratio (qPSG = SUVmean whole-body-tumor / SUVmean parotid glands) using a semi-automatic segmentation software (qPSMA). Patients were divided into three groups: high (qPSG > 1.5), intermediate (qPSG = 0.5 - 1.5), and low (qPSG < 0.5). Second, we assessed the reproducibility and the predictive value of the PSG score visually (vPSG score) graded by ten nuclear medicine physicians. Each reader read the baseline PSMA PET 3D maximum intensity projection (MIP) images, and classified the patients into three groups: (high) most of the lesions (> 80%) show higher uptake than parotid glands; (intermediate) neither “low” nor “high”; (low) most of the lesions (> 80%) show lower uptake than parotid glands. In case of disagreement, a majority vote was used. Outcome measures were PSA-progression free-survival (PSA-PFS), overall survival (OS), and PSA50. Results: 237 men were analyzed after excluding 33 men whose parotid glands were out of the scan range. The number of the patients in the high, intermediate, and low groups were 56/237 (23.6%), 163 (68.8%), and 18 (7.6%) for qPSG score, and 106/237 (44.7%), 96 (40.5%), and 35 (14.8%) for vPSG score, respectively. The inter- and intra-readers reproducibility of the vPSG score showed substantial (Fleiss’ weighted Kappa: 0.68) and almost perfect (Cohen's weighted Kappa (mean): 0.83) agreement, respectively. The median PSA-PFS of high, intermediate, and low groups were 7.2, 4.0, and 1.9 months (p < 0.001) for qPSG score and 6.7, 3.8, and 1.9 months (p < 0.001) for vPSG score, respectively. Higher PSA50 rate was observed in the high group followed by the intermediate and low groups (high vs intermediate vs low: [qPSG] 69.6% vs 38.7% vs 16.7%; [vPSG] 63.2% vs 33.3% vs 16.1%). The median OS was longer in the high group than in the intermediate + low (i.e., non-high) group by qPSG (15.0 vs. 11.7 months (p = 0.013)) and vPSG score (14.3 vs.11.0 months (p = 0.038)). Conclusions: The PSG score is a valuable predictive biomarker for response to Lu-177 PSMA. The vPSG score yielded substantial reproducibility and comparable predictive value to the qPSG score.

73 Background: 223Ra and 177Lu-PSMA-617 both prolong overall survival (OS) in different mCRPC settings. The observational, retrospective study, RALU, investigated safety and clinical outcomes of sequential 223Ra/177Lu-PSMA therapy in patients (pts) with mCRPC. This analysis evaluated the association of time interval between 223Ra and 177Lu-PSMA treatments and safety and OS outcomes of 177Lu-PSMA. Methods: Retrospective data were collected from 2021–22 in German nuclear medicine centers for all pts receiving 177Lu-PSMA with prior history of 223Ra therapy. Time intervals were 223Ra dose to first 177Lu-PSMA dose. Results: 42 pts received 177Lu-PSMA within 6 mo after 223Ra (Grp 1) and 90 pts received 223Ra ≥6 mo prior to 177Lu-PSMA (Grp 2). Baseline characteristics prior to 177Lu-PSMA therapy were, respectively: median ages 72 and 74 years; 57% and 63% with Eastern Cooperative Oncology Group performance status (ECOG PS) 1, 43% and 37% with ECOG PS 2; median prostate-specific antigen (PSA) values were 366 and 268 ng/ml, and median alkaline phosphatase (ALP) values were 133 and 149 U/L; 40% and 64% received ≥4 life prolonging therapies before starting 177Lu-PSMA. All pts had prior 223Ra; 57% and 77% received 6 223Ra injections; other prior therapies were abiraterone (60%, 77%), enzalutamide (50%, 78%), docetaxel (71%, 76%) and cabazitaxel (17%, 26%). Prior to 177Lu-PSMA, 24% and 29% of pts had visceral metastases. 45% and 52% of pts received ≥4 177Lu-PSMA cycles. From 177Lu-PSMA start to ≤30 days post last dose, 71% and 82% of pts had treatment-emergent adverse events (TEAEs) of any grade; most common were fatigue (12%, 7%), nausea (12%, 8%) and dry mouth (7%, 18%); 36% and 24% of pts had grade 3–4 TEAEs; excluding laboratory abnormalities, osteonecrosis of the jaw was the most frequent grade 3–4 TEAE (5%, 2%). Grade 3–4 laboratory abnormalities (177Lu-PSMA start to ≤90 days post last dose) are shown; treatment-related deaths were reported for 2% and 4% of pts. AEs led to treatment delays in 10% and 9% of pts. Median OS from start of 177Lu-PSMA was 12.0 mo (95% CI, 8.8–19.9) in Grp 1 and 13.2 mo (95% CI, 10.0–15.9) in Grp 2. During 177Lu-PSMA therapy, PSA response ≥50% occurred in 53% and 39% and ALP response ≥30% in 28% and 14% of pts, respectively. Conclusions: In this real-world setting, treating pts with 177Lu-PSMA within 6 mo of completing 223Ra was clinically feasible and well tolerated: no safety signals or concerns were seen. OS outcomes were similar in pts receiving 177Lu-PSMA 223Ra. [Table: see text]

146 Background: Our purpose was to investigate the adoption and current trends of Lutetium-177 PSMA radioligand therapy (RLT) for metastatic castration-resistant prostate cancer (mCRPC) in Germany. Methods: We analyzed the nationwide German hospital billing database (Destatis) and the hospitals’ quality reports for 177Lutetium PSMA RLT from 2016 to 2020 using the reimbursement.INFO tool. For detection of trends over time we applied linear regression models. For validation of these billing data, we included a total of 1239 177Lu-PSMA RLT cycles from 392 patients within the WARMTH multicenter study from 2016 to 2018. Additionally, we included the 177Lu-PSMA RLT cycles from two participating institutions from 2016 to 2020 for further validation. Results: We identified 12553 cases which were treated with 177Lu-PSMA RLT. The number of 177Lu-PSMA RLTs steadily increased from 1077 to 3640 therapies during the study period (+641 RLT/year; p177Lu-PSMA RLTs, which increased to 36% (16/44) in 2020 (p177Lu-PSMA RLTs were performed at a university hospital, which decreased to 70% (31/44) in 2020. The proportion of patients older than 65 years receiving 177Lu-PSMA RLT increased from 78% in 2016 to 81% in 2020. Conclusions: Treatment of mCRPC with 177Lu-PSMA RLT has been rapidly increasing in Germany in the recent years providing an additional therapy option. Most of the therapies are performed at academic hospitals.

Radiohybrid PSMA (rhPSMA) ligands, a new class of theranostic prostate-specific membrane antigen (PSMA)-targeting agents, feature fast 18F synthesis and utility for labeling with radiometals. Here, we assessed the biodistribution and image quality of 18F-rhPSMA-7 to determine the best imaging time point for patients with prostate cancer. Methods: In total, 202 prostate cancer patients who underwent a clinically indicated 18F-rhPSMA-7 PET/CT were retrospectively analyzed, and 12 groups based on the administered activity and uptake time of PET scanning were created: 3 administered activities (low, 222-296 MBq; moderate, 297-370 MBq; and high, 371-444 MBq) and 4 uptake time points (short, 50-70 min; intermediate, 71-90 min; long, 91-110 min; and extra long, ≥111 min). For quantitative analyses, SUVmean and organ- or tumor-to-background ratio were determined for background, healthy organs, and 3 representative tumor lesions. Qualitative analyses assessed overall image quality, nonspecific blood-pool activity, and background uptake in bone or marrow using 3- or 4-point scales. Results: In quantitative analyses, SUVmean showed a significant decrease in the blood pool and lungs and an increase in the kidneys, bladder, and bones as the uptake time increased. SUVmean showed a trend to increase in the blood pool and bones as the administered activity increased. However, no significant differences were found in 377 tumor lesions with respect to the administered activity or uptake time. In qualitative analyses, the overall image quality was stable along with the uptake time, but the proportion rated to have good image quality decreased as the administered activity increased. All other qualitative image parameters showed no significant differences for the administered activities, but they showed significant trends with increasing uptake time: less nonspecific blood activity, more frequent background uptake in the bone marrow, and increased negative impact on clinical decision making. Conclusion: The biodistribution of 18F-rhPSMA-7 was similar to that of established PSMA ligands, and tumor uptake of 18F-rhPSMA-7 was stable across the administered activities and uptake times. An early imaging time point (50-70 min) is recommended for 18F-rhPSMA-7 PET/CT to achieve the highest overall image quality.

This study proposes an automated prostate cancer (PC) lesion characterization method based on the deep neural network to determine tumor burden on 68Ga-PSMA-11 PET/CT to potentially facilitate the optimization of PSMA-directed radionuclide therapy. We collected 68Ga-PSMA-11 PET/CT images from 193 patients with metastatic PC at three medical centers. For proof-of-concept, we focused on the detection of pelvis bone and lymph node lesions. A deep neural network (triple-combining 2.5D U-Net) was developed for the automated characterization of these lesions. The proposed method simultaneously extracts features from axial, coronal, and sagittal planes, which mimics the workflow of physicians and reduces computational and memory requirements. Among all the labeled lesions, the network achieved 99% precision, 99% recall, and an F1 score of 99% on bone lesion detection and 94%, precision 89% recall, and an F1 score of 92% on lymph node lesion detection. The segmentation accuracy is lower than the detection. The performance of the network was correlated with the amount of training data. We developed a deep neural network to characterize automatically the PC lesions on 68Ga-PSMA-11 PET/CT. The preliminary test within the pelvic area confirms the potential of deep learning methods. Increasing the amount of training data should further enhance the performance of the proposed method and may ultimately allow whole-body assessments.

Vaccine-associated lymphadenopathy (VAL) is a common finding on

(18)F-rhPSMA-7, and its single diastereoisomer form, (18)F-rhPSMA-7.3, are prostate-specific membrane antigen (PSMA)–targeting radiopharmaceuticals. Here, we investigated their accuracy for the assessment of lymph node (LN) metastases validated by histopathology. Methods: Data from 58 patients with biochemical recurrence of prostate cancer after radical prostatectomy receiving salvage surgery after PET imaging with (18)F-rhPSMA-7 or (18)F-rhPSMA-7.3 were retrospectively reviewed. Two nuclear medicine physicians reviewed all PET scans and morphologic imaging in consensus. Readers were masked from the results of histopathology. PET and morphologic imaging were correlated with histopathology from resected LNs. Results: In 75 of 150 resected regions in 54 of 58 patients, tumor lesions were present in histopathology. The template-based specificity of PET ((18)F-rhPSMA-7 and (18)F-rhPSMA-7.3 combined) and morphologic imaging was 93.3% and 100%, respectively. However, (18)F-rhPSMA-7 and (18)F-rhPSMA-7.3 PET detected metastases in 61 of 75 histopathologically proven metastatic LN fields (81.3%) whereas morphologic imaging was positive in only 9 of 75 (12.0%). The positive predictive value was 92.4% for (18)F-rhPSMA-7 and (18)F-rhPSMA-7.3 PET and 100% for morphologic imaging. (18)F-rhPSMA-7 and (18)F-rhPSMA-7.3 PET performance was significantly superior to morphologic imaging (difference in the areas under the receiver-operating-characteristic curves, 0.222; 95% CI, 0.147–0.298; P < 0.001). The mean size of PET-positive and histologically confirmed LN metastases was 6.3 ± 3.1 mm (range, 2–15 mm) compared with a mean size of 9.8 ± 2.5 mm (range, 7–15 mm) on morphologic imaging. Conclusion: (18)F-rhPSMA-7 and (18)F-rhPSMA-7.3 PET offer a high positive predictive value comparable to that reported for (68)Ga-PSMA-11 and represent a valuable tool for guiding salvage lymphadenectomy.

Purpose: Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are a new class of 18F-labeled PSMA-targeting agents. 18F-rhPSMA-7.3 is a lead compound which is currently under investigation in two multicenter phase III trials for PET-imaging. Here, we report the first retrospective data on its detection efficacy and potential impact on clinical management in a homogeneous cohort of patients with biochemical recurrence after radical prostatectomy, and prior to any salvage therapy. Methods: 242 patients (median [range] PSA, 0.60 [0.2-60.8] ng/mL) who underwent 18F-rhPSMA-7.3 PET/CT were retrospectively selected from the institutions' database. Images were re-read by an experienced nuclear medicine physician. Lesion detection rates were stratified by PSA. Further, potential management before and after PET was assessed by an interdisciplinary simulated tumor board and categorized (major vs. minor vs. no therapeutic change). The distribution of management change identified in each PSA subgroup was determined. Results: In total, 176/242 (72.7%) patients showed PSMA-ligand positive findings. 18F-rhPSMA-7.3 detection rates were 61.8% (63/102), 67.9% (38/56), 81.1% (30/37) and 95.7% (45/47) for PSA-levels of 0.2

Cloning of the sodium iodide symporter (NIS) in 1996 has provided an opportunity to use NIS as a powerful theranostic transgene. Novel gene therapy strategies rely on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of therapeutic radionuclides. This review highlights the remarkable progress during the last two decades in the development of the NIS gene therapy concept using selective non-viral gene delivery vehicles including synthetic polyplexes and genetically engineered mesenchymal stem cells. In addition, NIS is a sensitive reporter gene and can be monitored by high resolution PET imaging using the radiotracers sodium [124I]iodide ([124I]NaI) or [18F]tetrafluoroborate ([18F]TFB). We performed a small preclinical PET imaging study comparing sodium [124I]iodide and in-house synthesized [18F]TFB in an orthotopic NIS-expressing glioblastoma model. The results demonstrated an improved image quality using [18F]TFB. Building upon these results, we will be able to expand the NIS gene therapy approach using non-viral gene delivery vehicles to target orthotopic tumor models with low volume disease, such as glioblastoma.Trial registration not applicable.

The purpose of this analysis was to report the safety evaluation of 177Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177Lu-PSMA-617 in the RESIST-PC trial NCT03042312. Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive metastatic castration-resistant prostate cancer after ≥ 1 novel androgen-axis drug, either chemotherapy naive or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET, and no PSMA-negative soft-tissue lesions were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 wk. The primary safety endpoint was assessed by collecting and grading adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, study termination by sponsor, patient withdrawal, lost to follow-up, or 24 mo after the first cycle. Results: The study was closed at enrollment of 71 of 200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least 1 cycle of 177Lu-PSMA-617: 28 (36%) in arm 1 (6.0 GBq) and 41 (64%) in arm 2 (7.4 GBq). There were 10 (43.5%), 19 (46.5%), and 29 (45.3%) patients who completed 4 cycles of 177Lu-PSMA-617 in the 6.0-GBq arm, 7.4-GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0-GBq arm, the 7.4-GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%, respectively), nausea (52.2%; 43.9%; 46.9%, respectively), and diarrhea (13.0%; 31.7%; 25.0%, respectively). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): 1 subdural hematoma grade 4, 1 anemia grade 3, 1 thrombocytopenia grade 4, 1 gastrointestinal hemorrhage grade 3, and 1 acute kidney injury grade 3. There were no clinically significant changes in vital signs in electrocardiograms in the 2 treatment groups. No trend to creatinine increase or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion:177Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-wk intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.

Importance: The presence of pelvic nodal metastases at radical prostatectomy is associated with biochemical recurrence after prostatectomy. Objective: To assess the accuracy of prostate-specific membrane antigen (PSMA) 68Ga-PSMA-11 positron emission tomographic (PET) imaging for the detection of pelvic nodal metastases compared with histopathology at time of radical prostatectomy and pelvic lymph node dissection. Design, Setting, and Participants: This investigator-initiated prospective multicenter single-arm open-label phase 3 imaging trial of diagnostic efficacy enrolled 764 patients with intermediate- to high-risk prostate cancer considered for prostatectomy at University of California, San Francisco and University of California, Los Angeles from December 2015 to December 2019. Data analysis took place from October 2018 to July 2021. Interventions: Imaging scan with 3 to 7 mCi of 68Ga-PSMA-11 PET. Main Outcomes and Measures: The primary end point was the sensitivity and specificity for the detection pelvic lymph nodes compared with histopathology on a per-patient basis using nodal region correlation. Each scan was read centrally by 3 blinded independent central readers, and a majority rule was used for analysis. Results: A total of 764 men (median [interquartile range] age, 69 [63-73] years) underwent 1 68Ga-PSMA-11 PET imaging scan for primary staging, and 277 of 764 (36%) subsequently underwent prostatectomy with lymph node dissection (efficacy analysis cohort). Based on pathology reports, 75 of 277 patients (27%) had pelvic nodal metastasis. Results of 68Ga-PSMA-11 PET were positive in 40 of 277 (14%), 2 of 277 (1%), and 7 of 277 (3%) of patients for pelvic nodal, extrapelvic nodal, and bone metastatic disease. Sensitivity, specificity, positive predictive value, and negative predictive value for pelvic nodal metastases were 0.40 (95% CI, 0.34-0.46), 0.95 (95% CI, 0.92-0.97), 0.75 (95% CI, 0.70-0.80), and 0.81 (95% CI, 0.76-0.85), respectively. Of the 764 patients, 487 (64%) did not undergo prostatectomy, of which 108 were lost to follow-up. Patients with follow-up instead underwent radiotherapy (262 of 379 [69%]), systemic therapy (82 of 379 [22%]), surveillance (16 of 379 [4%]), or other treatments (19 of 379 [5%]). Conclusions and Relevance: This phase 3 diagnostic efficacy trial found that in men with intermediate- to high-risk prostate cancer who underwent radical prostatectomy and lymph node dissection, the sensitivity and specificity of 68Ga-PSMA-11 PET were 0.40 and 0.95, respectively. This academic collaboration is the largest known to date and formed the foundation of a New Drug Application for 68Ga-PSMA-11. Trial Registration: ClinicalTrials.gov Identifiers: NCT03368547, NCT02611882, and NCT02919111.

Simple Summary Visceral involvement in prostate cancer (PCa) represents a negative prognostic factor. Liver metastases typically occur in systemic, late-stage, castration-resistant prostate cancer (CRPC). The diagnostic performance of [68Ga]Ga-PSMA-11-PET for visceral metastases of CRPC patients has never been systematically assessed. Our aim was to evaluate the diagnostic performance of PSMA-PET compared to conventional imaging, i.e., CT or MRI, or liver biopsy in the detection of liver metastases in CRPC patients. The secondary aim was to assess the ability of radiomics to predict the presence of liver metastases. Regarding liver metastases assessment in CRPC patients, [68Ga]-PSMA-11-PET demonstrated moderate sensitivity while high specificity, positive predictive value, and reproducibility compared to conventional imaging and liver biopsy. However, nuclear medicine physicians should carefully assess the liver parenchyma on PET images, especially in patients at higher risk for liver metastases and with high PSA values. Moreover, radiomic features may aid in recognizing higher-risk patients to develop them. Background: To evaluate the diagnostic performance of PSMA-PET compared to conventional imaging/liver biopsy in the detection of liver metastases in CRPC patients. Moreover, we evaluated a PSMA-PET/CT-based radiomic model able to identify liver metastases. Methods: Multicenter retrospective study enrolling patients with the following inclusion criteria: (a) proven CRPC patients, (b) PSMA-PET and conventional imaging/liver biopsy performed in a 6 months timeframe, (c) no therapy changes between PSMA-PET and conventional imaging/liver biopsy. PSMA-PET sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for liver metastases were calculated. After the extraction of radiomic features, a prediction model for liver metastases identification was developed. Results: Sixty CRPC patients were enrolled. Within 6 months before or after PSMA-PET, conventional imaging and liver biopsy identified 24/60 (40%) patients with liver metastases. PSMA-PET sensitivity, specificity, PPV, NPV, and accuracy for liver metastases were 0.58, 0.92, 0.82, 0.77, and 0.78, respectively. Either number of liver metastases and the maximum lesion diameter were significantly associated with the presence of a positive PSMA-PET (p < 0.05). On multivariate regression analysis, the radiomic feature-based model combining sphericity, and the moment of inverse difference (Idm), had an AUC of 0.807 (95% CI:0.686-0.920). Conclusion: For liver metastases assessment, [68Ga]Ga-PSMA-11-PET demonstrated moderate sensitivity while high specificity, PPV, and inter-reader agreement compared to conventional imaging/liver biopsy in CRPC patients.

Radioligand therapy (RLT) targeting prostate specific-membrane antigen (PSMA) is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). It administrates 225Ac- or 177Lu-labeled ligands for the targeted killing of tumor cells. Differently from X- or γ-ray, for the emitted α or β particles the ionization of the DNA molecule is less dependent on the tissue oxygenation status. Furthermore, the diffusion range of electrons in a tumor is much larger than the volume typically spanned by hypoxic regions. Therefore, hypoxia is less investigated as an influential factor for PSMA-directed RLT, in particular with β emitters. This study proposes an in silico approach to theoretically investigate the influence of tumor hypoxia on the PSMA-directed RLT. Based on mice histology images, the distribution of the radiopharmaceuticals was simulated with an in silico PBPK-based convection–reaction–diffusion model. Three anti-CD31 immunohistochemistry slices were used to simulate the tumor microenvironment. Ten regions of interest with varying hypoxia severity were analyzed. A kernel-based method was developed for dose calculation. The cell survival probability was calculated according to the linear-quadratic model. The statistical analysis performed on all the regions of interest (ROIs) shows more heterogeneous dose distributions obtained with 225Ac compared to 177Lu. The higher homogeneity of 177Lu-PSMA-ligand treatment is due to the larger range covered by the emitted β particles. The dose-to-tissue histogram (DTH) metric shows that in poorly vascularized ROIs only 10% of radiobiological hypoxic tissue receives the target dose using 177Lu-PSMA-ligand treatment. This percentage drops down to 5% using 225Ac. In highly vascularized ROIs, the percentage of hypoxic tissue receiving the target dose increases to more than 85% and 65% for the 177Lu and 225Ac-PSMA-ligands, respectively. The in silico study demonstrated that the reduced vascularization of the tumor strongly influences the dose delivered by PSMA-directed RLT, especially in hypoxic regions and consequently the treatment outcome.

Prostate cancer is the most common malignancy and the second leading cause of cancer-related death in men. Accurate imaging diagnosis and staging are crucial for patient management and treatment. The role of nuclear medicine in the diagnosis of prostate cancer has evolved rapidly in recent years due to the availability of hybrid imaging with radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA).Hybrid imaging provides higher diagnostic accuracy compared to conventional imaging and has a significant impact on clinical management. Numerous radiotracers have been used in clinical applications, with PSMA ligands being the most commonly used.Hybrid imaging provides higher diagnostic accuracy for lymph node and bone metastases compared to conventional imaging and has a significant impact on clinical management.The high accuracy for primary staging in high-risk prostate cancer using PSMA ligands has led to the inclusion of PSMA positron emission tomography (PET)/computed tomography (CT) in the new German S3 guideline for primary staging of prostate cancer.The aim of this article is to provide an overview of the use of PET imaging in the primary diagnosis of prostate cancer, to present the most commonly used radiotracers, and to highlight the results of recent studies.KLINISCHES/METHODISCHES PROBLEM: Das Prostatakarzinom ist die häufigste maligne Erkrankung und die zweithäufigste karzinombedingte Todesursache bei Männern in Deutschland. Eine sichere Diagnose und ein Staging mit präziser Bildgebung sind entscheidend, um den Patienten eine zielgenaue Behandlung zu bieten. Die Rolle der Nuklearmedizin bei der Diagnose des Prostatakarzinoms hat sich in den letzten Jahren durch die Verfügbarkeit der Hybridbildgebung mit prostataspezifischen Radiopharmaka rasant weiterentwickelt.Die Hybridbildgebung bietet eine höhere diagnostische Genauigkeit im Vergleich zur konventionellen Bildgebung und hat einen erheblichen Einfluss auf die klinische Behandlung. In der klinischen Anwendung wurden zahlreiche Radiotracer eingesetzt, wobei PSMA-Liganden am häufigsten verwendet werden.Die Positronen-Emissions-Tomographie/Computertomographie mit dem prostataspezifischen Membranantigen (PSMA-PET/CT) und die PET/Magnetresonanztomographie (MRT) bieten im Vergleich zur konventionellen Bildgebung sowie zu anderen Radiotracern eine höhere Empfindlichkeit für den Nachweis von Lymphknoten- bzw. Fernmetastasen. LEISTUNGSFäHIGKEIT: Aufgrund der hohen Genauigkeit für das primäre Staging beim Hochrisikoprostatakarzinom hat die PSMA-PET/CT Einzug in die neue S3-Leitlinie des Prostatakarzinoms gefunden.Ziel dieses Artikels ist es, einen Überblick über den Einsatz der PET-Bildgebung in der Primärdiagnose des Prostatakarzinoms zu geben, die am häufigsten verwendeten Radiotracer vorzustellen und die Ergebnisse aktueller Studien zu diskutieren.

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands such asPreclinical dosimetry was performed with SCID-mice sacrificed at multiple timepoints (10-300 min) post-injection of 25.6 ± 3.6 MBqPreclinical dosimetry revealed that at 3.5 h and 1 h bladder voiding intervals, the extrapolated total effective doses were 26.6 and 12.2 µSv/MBq forRadiation dosimetry is favourable for both agents. Radiation exposure, assuming a 1 h voiding interval, is less than 5 mSv after injection of 370 MBq.

Since its introduction to the diagnostic pathway for prostate cancer management, prostate-specific membrane antigen (PSMA)–ligand PET has demonstrated great potential. PSMA-ligand imaging is increasingly influencing therapeutic decision making, although its impact on patient outcomes still needs to be defined. One relatively new application, enabled through chemical and engineering efforts, is PSMA-guided surgery. This review highlights the potential of PSMA-guided surgery and discusses its implications in lymph node dissection in primary and recurrent prostate cancer.

Purpose Accurate and precise renal dosimetry during 177 Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy is crucial for therapy decisions. Sampling schedules for estimating the necessary time-integrated activity coefficients (TIACs) are not optimized and standardized for clinical practice. Therefore, a simulation study to determine optimal sampling schedules (OSSs) was performed on 13 virtual 177 Lu-PSMA I&T therapy patients. Method A total of 880 clinically feasible sampling schedules for planar imaging (three time points) were investigated. To simulate the hybrid planar/SPECT method, an additional quantitative SPECT/CT measurement following one planar image was considered. For each sampling schedule and patient, the activity values were generated separately. Measurement noise was modeled by drawing random numbers of log-normal distributions. The used fractional standard deviations (FSD) differed depending on the imaging modality. For activity values assigned to planar imaging, systematic noise between 25% and 75% of the total noise was simulated. After fitting with a mono-exponential function, the root-mean-squared errors of the deviations of the simulated TIACs from the ground truth for 1000 replications were used to determine the OSS. The uncertainties of the TIACs and renal dose coefficients were estimated. Results For the hybrid planar/SPECT method, OSSs were determined to be (3-4, 72-76, 124-144) h post injection (p.i.) with the quantitative SPECT/CT scan shortly after the second measurement. The accuracy and precision of the determined TIACs were in the range of (-3.0 ± 6.2)% and (-1.0 ± 6.5)%. This precision was improved by a factor 2-3 compared to dosimetry based on planar images only. Similar results were obtained for the renal dose coefficients. The virtual patients' renal dose coefficients were (0.68 ± 0.24) Gy/GBq indicating that a population-based method yields an uncertainty of 35%. Conclusions Dosimetry based on the hybrid planar/SPECT method with OSS outperforms dosimetry based on planar images. The high variability in dose coefficients between the virtual patients demonstrates the need for individualized dosimetry.

Background To develop a supervised machine learning (ML) algorithm predicting above- versus below-median overall survival (OS) from diffusion-weighted imaging-derived radiomic features in patients with pancreatic ductal adenocarcinoma (PDAC). Methods One hundred two patients with histopathologically proven PDAC were retrospectively assessed as training cohort, and 30 prospectively accrued and retrospectively enrolled patients served as independent validation cohort (IVC). Tumors were segmented on preoperative apparent diffusion coefficient (ADC) maps, and radiomic features were extracted. A random forest ML algorithm was fit to the training cohort and tested in the IVC. Histopathological subtype of tumor samples was assessed by immunohistochemistry in 21 IVC patients. Individual radiomic feature importance was evaluated by assessment of tree node Gini impurity decrease and recursive feature elimination. Fisher’s exact test, 95% confidence intervals (CI), and receiver operating characteristic area under the curve (ROC-AUC) were used. Results The ML algorithm achieved 87% sensitivity (95% IC 67.3–92.7), 80% specificity (95% CI 74.0–86.7), and ROC-AUC 90% for the prediction of above- versus below-median OS in the IVC. Heterogeneity-related features were highly ranked by the model. Of the 21 patients with determined histopathological subtype, 8/9 patients predicted to experience below-median OS exhibited the quasi-mesenchymal subtype, whilst 11/12 patients predicted to experience above-median OS exhibited a non-quasi-mesenchymal subtype (p < 0.001). Conclusion ML application to ADC radiomics allowed OS prediction with a high diagnostic accuracy in an IVC. The high overlap of clinically relevant histopathological subtypes with model predictions underlines the potential of quantitative imaging in PDAC pre-operative subtyping and prognosis.

Prostate-specific membrane antigen (PSMA) is expressed in most prostate cancers and can be identified by PSMA-ligand imaging, which has already become clinically accepted in several countries in- and outside Europe. PSMA-directed radioligand therapy (PSMA-RLT) with Lutetium-177 (177Lu-PSMA) is currently undergoing clinical validation. Retrospective observational data have documented favourable safety and striking clinical responses. Recent results from a prospective clinical trial (phase II) have been published confirming high response rates, low toxicity and reduction of pain in metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed after conventional treatments. Such patients typically survive for periods less than 1.5 years. This has led some facilities to adopt compassionate or unproven use of this therapy, even in the absence of validation within a randomised-controlled trial. As a result, a consistent body of evidence exists to support efficacy and safety data of this treatment. The purpose of this guideline is to assist nuclear medicine specialists to deliver PSMA-RLT as an "unproven intervention in clinical practice", in accordance with the best currently available knowledge.

Our purpose was to define a clinically useful lower limit of injected dose for 68Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT imaging of prostate cancer. Methods:68Ga-PSMA-11 PET/CT was performed on 11 patients. PET was acquired in list mode and reconstructed using a 3-min full acquisition, a 2-min acquisition, and a 1-min acquisition to generate images obtained with three thirds (standard dose), two thirds (low dose), and one third (very low dose) of the injected dose, respectively. Overall image quality (5-point scale) was assessed, and the detectability of PSMA-positive lesions was determined by 3 readers and compared with the reference standard. Results: Image quality declined with decreasing dose (mean score of 4.1 ± 0.4 for the standard dose, 3.4 ± 0.7 for the low dose, and 1.9 ± 0.4 for the very low dose; all P

(18)F-labeled prostate-specific membrane antigen (PSMA)–ligand PET has several principal advantages over (68)Ga-PSMA-11. The purpose of this retrospective study was to evaluate the frequency of non–tumor-related uptake and the detection efficacy comparing (68)Ga-PSMA-11 PET/CT and (18)F-PSMA-1007 PET/CT in recurrent prostate cancer (PC) patients. Methods: The study included 102 patients with biochemically recurrent PC after radical prostatectomy undergoing (18)F-PSMA-1007 PET/CT imaging. On the basis of various clinical variables, patients with corresponding (68)Ga-PSMA-11 PET/CT scans were matched. All PET/CT scans (n = 204) were reviewed by 1 nuclear medicine physician. First, all PET-positive lesions were noted. Then, lesions suspected of being recurrent PC were differentiated from lesions attributed to a benign origin on the basis of known pitfalls and information from CT. For each region, the SUV(max) of the lesion with the highest PSMA-ligand uptake was noted. Detection rates were determined, and SUV(max) was compared separately for (68)Ga-PSMA-11 and (18)F-PSMA-1007. Results: In total, (18)F-PSMA-1007 PET and (68)Ga-PSMA-11 PET revealed 369 and 178 PSMA-ligand–positive lesions, respectively. (18)F-PSMA-1007 PET revealed approximately 5 times more lesions attributed to a benign origin than did (68)Ga-PSMA-11 PET (245 vs. 52 lesions, respectively). The benign lesions most frequently observed were ganglia, unspecific lymph node, and bone lesions, at a rate of 43%, 31%, and 24% for (18)F-PSMA-1007 PET and 29%, 42%, and 27% for (68)Ga-PSMA-11 PET, respectively. The SUV(max) of lesions attributed to a benign origin was significantly higher (P < 0.0001) for (18)F-PSMA-1007 PET. Further, a similar number of lesions was attributed to recurrent PC (124/369 for (18)F-PSMA-1007 PET and 126/178 for (68)Ga-PSMA-11 PET). Conclusion: The number of lesions with increased PSMA-ligand uptake attributed to a benign origin is considerably higher for (18)F-PSMA-1007 PET than for (68)Ga-PSMA-11 PET. This finding indicates the need for sophisticated reader training emphasizing known pitfalls and reporting within the clinical context.

Die Diagnostik von Tumoren des Dunndarms ist anspruchsvoll. Eine wichtige Rolle spielt die Schnittbildgebung mittels Computer- und Magnetresonanztomografie. Lesen Sie in dieser kurzen Ubersicht, worauf im Allgemeinen und in den einzelnen Indikationen zu achten ist.

Our aim was to introduce and validate qPSMA, a semiautomatic software package for whole-body tumor burden assessment in prostate cancer patients using 68Ga-prostate-specific membrane antigen (PSMA) 11 PET/CT. Methods: qPSMA reads hybrid PET/CT images in DICOM format. Its pipeline was written using Python and C++ languages. A bone mask based on CT and a normal-uptake mask including organs with physiologic 68Ga-PSMA11 uptake are automatically computed. An SUV threshold of 3 and a liver-based threshold are used to segment bone and soft-tissue lesions, respectively. Manual corrections can be applied using different tools. Multiple output parameters are computed, that is, PSMA ligand-positive tumor volume (PSMA-TV), PSMA ligand-positive total lesion (PSMA-TL), PSMA SUVmean, and PSMA SUVmax Twenty 68Ga-PSMA11 PET/CT data sets were used to validate and evaluate the performance characteristics of qPSMA. Four analyses were performed: validation of the semiautomatic algorithm for liver background activity determination, assessment of intra- and interobserver variability, validation of data from qPSMA by comparison with Syngo.via, and assessment of computational time and comparison of PSMA PET-derived parameters with serum prostate-specific antigen. Results: Automatic liver background calculation resulted in a mean relative difference of 0.74% (intraclass correlation coefficient [ICC], 0.996; 95%CI, 0.989;0.998) compared with METAVOL. Intra- and interobserver variability analyses showed high agreement (all ICCs > 0.990). Quantitative output parameters were compared for 68 lesions. Paired t testing showed no significant differences between the values obtained with the 2 software packages. The ICC estimates obtained for PSMA-TV, PSMA-TL, SUVmean, and SUVmax were 1.000 (95%CI, 1.000;1.000), 1.000 (95%CI, 1.000;1.000), 0.995 (95%CI, 0.992;0.997), and 0.999 (95%CI, 0.999;1.000), respectively. The first and second reads for intraobserver variability resulted in mean computational times of 13.63 min (range, 8.22-25.45 min) and 9.27 min (range, 8.10-12.15 min), respectively (P = 0.001). Highly significant correlations were found between serum prostate-specific antigen value and both PSMA-TV (r = 0.72, P < 0.001) and PSMA-TL (r = 0.66, P = 0.002). Conclusion: Semiautomatic analyses of whole-body tumor burden in 68Ga-PSMA11 PET/CT is feasible. qPSMA is a robust software package that can help physicians quantify tumor load in heavily metastasized prostate cancer patients.

ZusammenfassungGrundlage der systemischen Therapie des fortgeschrittenen oder metastasierten Prostatakarzinoms ist die Hormontherapie. Diese besteht bei in der Regel aus einer Androgendeprivationstherapie mit dem Ziel der Absenkung des Testosteronwerts auf Kastrationsniveau. Bei Patienten mit einer hohen Metastasenlast im hormon-sensiblen Stadium wird die Behandlung initial durch eine Chemotherapie mit Docetaxel ergänzt. Alternativ können Patienten mit einem primär metastasierten, unbehandelten Prostatakarzinom und einem hohen Risikoprofil mit einer erweiterten Hormontherapie mit Abirateron/Prednison und Androgendeprivation therapiert werden. Wenn es zu einer Tumorprogression unter Androgendeprivationstherapie trotz Testosteronwerten im Kastrationsbereich kommt, spricht man von einem kastrationsresistenten Prostatakarzinom. Zur Behandlung des nicht metastasierten, kastrationsresistenten Prostatakarzinoms stehen seit Kurzem die Antiandrogene Enzalutamid und Apalutamid zur Verfügung. Das metastasierte, kastrationsresistente Prostatakarzinoms kann mit folgenden zugelassenen Therapieoptionen behandelt werden: Erweiterte Hormontherapie mit Abirateron/Prednison oder Enzalutamid; Taxan basierte Chemotherapie mit Docetaxel oder Cabazitaxel; Radioisotopentherapie mit Radium-223-Dichlorid. Eine PSMA-Liganden-basierte Radionuklidbehandlung zeigt in ersten Veröffentlichungen vielversprechende Therapieergebnisse und wird in Deutschland bereits im Rahmen eines individuellen Heilversuchs angeboten. Die Auswahl und Sequenz der verschiedenen Therapieoptionen ist u. a. abhängig von den Zulassungskriterien, der Patientenpräferenz und dem Nebenwirkungsprofil. Der folgende Artikel gibt einen Überblick über aktuelle Therapieoptionen zur Systemtherapie im hormonsensiblen und kastrationsresistenten Stadium des metastasierten Prostatakarzinoms.

5009 Background: Prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) allows detection of small and/or atypically localized metastatic prostate cancer (PCa) lesions. In a subset of patients with recurrent oligometastatic PCa salvage surgery with PSMA-targeted radioguidance (PSMA-RGS) may be of value. We aimed to evaluate the oncological outcomes of salvage PSMA-RGS for oligo-recurrent PCa and determine predictive preoperative factors of improved outcomes. Methods: In this cohort study within two tertiary care centers, patients with biochemical recurrence (BCR) after radical prostatectomy (RP) and imaging with PSMA PET receiving salvage PSMA-RGS between 2014 and 2020 were analyzed. Kaplan-Meier and multivariable Cox regression models adjusted for various parameters were used to test for BCR-free survival (BFS) and therapy-free survival (TFS) differences. Postoperative complications were classified according to Clavien-Dindo. Results: Overall, 364 patients were assessed. At PSMA-RGS, median (IQR) age and preoperative PSA was 67 (61-71) years and 1.0 (0.5-1.9) ng/ml. Metastatic soft-tissue lesions from PCa metastases could be removed in 343 (94.2%) patients. Within three months from surgery, 24 (6.6%) patients suffered from Clavien-Dindo complications grade III-IV. During follow-up, 225 patients experienced BCR and 121 patients received further therapy. Median follow-up for patients who did not experience BCR and who did not receive further therapy was 10.8 months and 10.3 months, respectively. Median (IQR) BFS and TFS was 7.8 (5.4-10.5) and 35.5 months (25.9-45.9 months). At two years of follow-up, BFS rate was 31.9% and TFS rate was 58.0%. In multivariable analyses, higher preoperative PSA (HR: 1.1), higher number of PSMA-avid lesions on preoperative imaging (HR: 1.2) and multiple (pelvic plus retroperitoneal) localizations (HR: 1.9), as well as retroperitoneal localization (HR: 2.0) of lesions in PSMA PET imaging were independent predictors of BCR after PSMA-RGS. Limitations are the retrospective design and lack of a control group. Conclusions: As salvage surgery in oligo-recurrent PCa currently constitutes an experimental treatment approach careful patient selection is mandatory based on life expectancy, low PSA values and low number of PSMA PET avid lesions located in the pelvis. Further studies are needed to confirm our findings and define the oncological value of salvage surgical procedures in oligo-recurrent PCa.

Purpose The objective of this study was to evaluate the image degrading factors in quantitative 177Lu SPECT imaging when using both main gamma photopeak energies. Methods Phantom measurements with two different vials containing various calibrated activities in air or water were performed to derive a mean calibration factor (CF) for large and small volumes of interest (VOIs). In addition, Monte Carlo simulations were utilized to investigate the effect of scatter energy window width, scatter correction method, such as effective scatter source estimation (ESSE) and triple energy window (TEW), and attenuation map on the quantification of 177Lu. Results: The measured mean CF using large and small VOIs in water was 4.50 ± 0.80 and 4.80 ± 0.72 cps MBq−1, respectively. Simulations showed a reference CF of 3.3 cps MBq−1 for the water-filled phantom considering all photons excluding scattered events. By using the attenuation map generated for 190 keV photons, the calculated CFs for 113 keV and 208 keV are 10% lower than by using the weighted mean energy of 175 keV for 177Lu. The calculated CF using the TEW correction was 17% higher than using the ESSE method for a water-filled phantom. However, our findings showed that an appropriate scatter window combination can reduce this difference between TEW and ESSE methods. Conclusions The present work implies that choosing a suitable width of scatter energy windows can reduce uncertainties in radioactivity quantification. It is suggested to generate the attenuation map at 113 keV and 208 keV, separately. Furthermore, using small VOIs is suggested in CF calculation.

The purpose of this analysis was to report the safety evaluation of (177)Lu-PSMA-617 derived from the cohort of 64 patients exposed to (177)Lu-PSMA-617 in the RESIST-PC trial NCT03042312. Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive metastatic castration-resistant prostate cancer after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET, and no PSMA-negative soft-tissue lesions were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 wk. The primary safety endpoint was assessed by collecting and grading adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, study termination by sponsor, patient withdrawal, lost to follow-up, or 24 mo after the first cycle. Results: The study was closed at enrollment of 71 of 200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least 1 cycle of (177)Lu-PSMA-617: 28 (36%) in arm 1 (6.0 GBq) and 41 (64%) in arm 2 (7.4 GBq). There were 10 (43.5%), 19 (46.5%), and 29 (45.3%) patients who completed 4 cycles of (177)Lu-PSMA-617 in the 6.0-GBq arm, 7.4-GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0-GBq arm, the 7.4-GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%, respectively), nausea (52.2%; 43.9%; 46.9%, respectively), and diarrhea (13.0%; 31.7%; 25.0%, respectively). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): 1 subdural hematoma grade 4, 1 anemia grade 3, 1 thrombocytopenia grade 4, 1 gastrointestinal hemorrhage grade 3, and 1 acute kidney injury grade 3. There were no clinically significant changes in vital signs in electrocardiograms in the 2 treatment groups. No trend to creatinine increase or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion: (177)Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-wk intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different (177)Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.

Rationale The development of consensus guidelines for interpretation of Prostate-Specific Membrane Antigen (PSMA)-Positron Emission Tomography (PET) is needed to provide more consistent reports in clinical practice. The standardization of PSMA-PET interpretation may also contribute to increasing the data reproducibility within clinical trials. Finally, guidelines in PSMA-PET interpretation are needed to communicate the exact location of findings to referring physicians, to support clinician therapeutic management decisions. Methods A panel of worldwide experts in PSMA-PET was established. Panelists were selected based on their expertise and publication record in the diagnosis or treatment of PCa, in their involvement in clinical guidelines and according to their expertise in the clinical application of radiolabeled PSMA inhibitors. Panelists were actively involved in all stages of a modified, nonanonymous, Delphi consensus process. Results According to the findings obtained by modified Delphi consensus process, panelist recommendations were implemented in a structured report for PSMA-PET. Conclusions The E-PSMA standardized reporting guidelines, a document supported by the European Association of Nuclear Medicine (EANM), provide consensus statements among a panel of experts in PSMA-PET imaging, to develop a structured report for PSMA-PET in prostate cancer and to harmonize diagnostic interpretation criteria.

We investigated whether the time between synthesis and injection and the resulting decrease in specific activity affects the normal-organ and tumor uptake of the PSMA ligand

The role of prostate-specific membrane antigen (PSMA)–targeted PET in comparison to multiparametric MRI (mpMRI) in the evaluation of intraprostatic cancer foci is not well defined. The aim of our study was to compare the diagnostic performance of (68)Ga-PSMA-11 PET/CT (PSMA PET/CT), mpMRI, and PSMA PET/CT + mpMRI using 3 independent masked readers for each modality and with histopathology as the gold standard in the detection, intraprostatic localization, and determination of local extension of primary prostate cancer. Methods: Patients with intermediate- or high-risk prostate cancer who underwent PSMA PET/CT as part of a prospective trial (NCT03368547) and mpMRI before radical prostatectomy were included. Each imaging modality was interpreted by 3 independent readers who were unaware of the other modality result. A central majority rule was applied (2:1). Pathologic examination of whole-mount slices was used as the gold standard. Imaging scans and whole-mount slices were interpreted using the same standardized approach on a segment level and a lesion level. A “neighboring” approach was used to define imaging–pathology correlation for the detection of individual prostate cancer foci. Accuracy in determining the location, extraprostatic extension (EPE), and seminal vesicle invasion (SVI) of prostate cancer foci was assessed using receiver-operating-characteristic curve analysis. Interreader agreement was calculated using intraclass correlation coefficient analysis. Results: The final analysis included 74 patients (14 [19%] with intermediate risk and 60 [81%] with high risk). The cancer detection rate (lesion-based analysis) was 85%, 83%, and 87% for PSMA PET/CT, mpMRI, and PSMA PET/CT + mpMRI, respectively. The change in AUC was statistically significant between PSMA PET/CT + mpMRI and the 2 imaging modalities alone for delineation of tumor localization (segment-based analysis) (P < 0.001) but not between PSMA PET/CT and mpMRI (P = 0.093). mpMRI outperformed PSMA PET/CT in detecting EPE (P = 0.002) and SVI (P = 0.001). In the segment-level analysis, intraclass correlation coefficient analysis showed moderate reliability among PSMA PET/CT and mpMRI readers using a 5-point Likert scale (range, 0.53–0.64). In the evaluation of T staging, poor reliability was found among PSMA PET/CT readers and poor to moderate reliability was found for mpMRI readers. Conclusion: PSMA PET/CT and mpMRI have similar accuracy in the detection and intraprostatic localization of prostate cancer foci. mpMRI performs better in identifying EPE and SVI. For the T-staging evaluation of intermediate to high-risk prostate cancer, mpMRI should still be considered the imaging modality of reference. Whenever available, PSMA PET/MRI or the coregistration or fusion of PSMA PET/CT and mpMRI (PSMA PET/CT + mpMRI) should be used as it improves tumor extent delineation.