Search

Purpose: This study aimed to determine the effect of model selection on simplified dosimetry for the kidneys using Bayesian fitting (BF) and single-time-point (STP) imaging., Methods: Kidney biokinetics data of [ 177 Lu]Lu-PSMA-617 from mHSPC were collected using SPECT/CT after injection of (3.1 ± 0.1) GBq at time points T1(2.3 ± 0.5), T2(23.8 ± 2.0), T3(47.7 ± 2.2), T4(71.8 ± 2.2), and T5(167.4 ± 1.9) h post-injection. Eleven functions with various parameterizations and a combination of shared and individual parameters were used for model selection. Model averaging of functions with an Akaike weight of >10 % was used to calculate the reference TIAC (TIAC REF ). STP BF method (STP-BF) was performed to determine the STP TIACs (TIAC STP-BF ). The STP-BF performance was assessed by calculating the root-mean-square error (RMSE) of relative deviation between TIAC STP-BF and TIAC REF . In addition, the STP-BF performance was compared to the Hänscheid Method., Results: The function [Formula: see text] with shared parameter λ 2 was selected as the best function (Akaike weight of 57.91 %). STP-BF using the best function resulted in RMSEs of 20.3 %, 9.1 %, 8.4 %, 13.6 %, and 19.3 % at T1, T2, T3, T4, and T5, respectively. The RMSEs of STP-Hänscheid were 22.4 %, 14.6 %, and 21.9 % at T2, T3, and T4, respectively., Conclusion: A model selection was presented to determine the fit function for calculating TIACs in STP-BF. This study shows that the STP dosimetry using BF and model selection performed better than the frequently used STP Hänscheid method., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Aim: The objective of this study was to compare the detection rates of [ 18 F]PSMA-1007 and [ 18 F]Fluciclovine in early biochemical recurrence (BCR) of prostate cancer, i.e. with low prostate-specific antigen (PSA) levels (0.2-5.0 µg/L)., Methods: This was a prospective, single-center (Radboudumc; Nijmegen, The Netherlands), comparative phase II diagnostic imaging study (NCT04239742). The main inclusion criteria were histologically proven adenocarcinoma of the prostate, BCR after radical treatment with two consecutive (rising) PSA values (0.2-5.0 µg/L). Patients underwent both [ 18 F]PSMA-1007 PET/CT and [ 18 F]Fluciclovine PET/CT within two weeks. Both scans were blindly scored by three independent nuclear medicine physicians. Hereafter, a result per scan and region was generated by consensus. The primary outcome was to compare the detection rate on a patient and region level. Secondary objectives were to determine detection rate stratified for PSA value, inter-reader agreement, and SUV measurements. For lesion confirmation a composite reference score was established using follow-up data., Results: Data of fifty patients were included, median age of 71 (IQR: 67-74) years and median PSA value of 0.38 (IQR: 0.30-1.55) µg/L. Detection rates were 68% (34/50) for [ 18 F]PSMA-1007 and 42% (21/50) for [ 18 F]Fluciclovine on a patient level (p < 0.001). Detection rates stratified for PSA value of [ 18 F]PSMA-1007 in comparison with [ 18 F]Fluciclovine were for PSA 0.2-0.5 µg/L; 60.7% versus 25.0% (p = 0.002); and for PSA ≥ 0.5 µg/L; 77.3% versus 63.6% (p = 0.250). There was a trend for higher inter-reader agreement with [ 18 F]PSMA-1007. SUV max (p < 0.001) was significantly higher for [ 18 F]PSMA-1007 in comparison to [ 18 F]Fluciclovine., Conclusion: In patients with early BCR of prostate cancer after radical surgery or radiotherapy, [ 18 F]PSMA-1007 demonstrated a significantly higher detection rate than [ 18 F]Fluciclovine. This is particularly relevant since earlier and more accurate detection of a BCR can guide salvage therapy into a tailored strategy which may improve outcomes., Trial Registration: ClinicalTrials.gov, NCT04239742. Registered 02 January 2020, https://clinicaltrials.gov/study/NCT04239742 ., Competing Interests: Declarations. Ethical approval and consent to participate: This study was performed in line with the principles of the Declaration of Helsinki (version 2013) and approved by the medical ethical committee Arnhem-Nijmegen. All patients provided written informed consent. Consent for publication: Not applicable Competing interests: BP received research support from Novartis, ABX advanced biochemical compounds GmbH, JN received research support from Novartis, ABX advanced biochemical compounds GmbH, MJ received research support from Novartis, ABX advanced biochemical compounds GmbH. RH received consultancy fees from ABX advance biochemical compounds GmbH and Blue Earth Diagnostics. No other potential conflicts of interest relevant to this article exist., (© 2024. The Author(s).)

There is an urgent need for novel systemic therapies for recurrent/systemic salivary gland cancer, as current treatment options are scarce. [ 68 Ga]Ga-PSMA-11 PET/CT revealed relevant uptake of prostate-specific membrane antigen (PSMA) in adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC). Therefore, we assessed the safety, feasibility, efficacy and radiation dosimetry of [ 177 Lu]Lu-PSMA-I&T treatment in AdCC and SDC patients in a prospective pilot study. Methods: This single-center, single-arm study intended to include 10 recurrent/metastatic AdCC patients and five recurrent/metastatic SDC patients. AdCC patients could only participate in case of progressive and/or symptomatic disease. Patients required ≥ 1 lesion ≥ 1.5 cm with an SUV max on [ 68 Ga]Ga-PSMA-11 PET/CT above liver SUV mean . Patients were planned to receive four cycles ~ 7.4 GBq [ 177 Lu]Lu-PSMA-I&T. In case of progressive disease per RECIST 1.1 at mid-treatment evaluation after two cycles, treatment was discontinued. Safety was the primary endpoint. Secondary endpoints included objective response rate (ORR), tumor- and organ-absorbed radiation doses and progression-free survival. Results: After screening, 10 out of 15 (67%) AdCC and two out of 10 (20%) SDC patients were eligible. Two patients (17%) demonstrated grade 3 treatment-related toxicity: lymphocytopenia (8%) and hyponatremia (8%). No dose-limiting toxicities occurred. In the AdCC cohort, six patients (60%) completed the four treatment cycles. Due to progressive disease, treatment was discontinued after two cycles in three patients (30%) and after one cycle in one patient (10%). No objective responses were observed (ORR: 0%). Three AdCC patients (30%) showed stable disease ≥ 6 months (7, 17 and 23 months). None of the two SDC patients completed the treatment: one patient deteriorated after the first cycle, while the other had progressive disease after two cycles. The high screen failure rate due to insufficient PSMA uptake resulted in premature closure of the SDC cohort. Dosimetry revealed low tumor-absorbed doses (median 0.07 Gy/GBq, range 0.001-0.63 Gy/GBq). Conclusions: [ 177 Lu]Lu-PSMA-I&T in AdCC and SDC patients was safe and generally well-tolerated. However, efficacy was limited, likely due to low tumor-absorbed doses. For SDC, [ 177 Lu]Lu-PSMA-I&T appears unfeasible due to insufficient PSMA uptake., Competing Interests: Competing Interests: NvR, MU, CD, SP, BP, AvEvG, MK, MK: nothing to declare. JN: has received research grants from ABX and Novartis, and has received consulting and teaching fees from ITM, POINT biopharma, CURIUM, Novartis and Bayer. CvH: has been member of advisory boards for Bayer, Bristol-Myers Squibb, Elevar, Ipsen, MSD and Regeneron, and has received research grants from Astra Zeneca, Bristol-Myers Squibb, MSD, Merck, Ipsen, Novartis and Sanofi., (© The author(s).)

Rationale: PSMA-targeting radioligand therapy (PSMA-RLT) has shown promise in metastatic castration-resistant prostate cancer (mCRPC), particularly in PSMA-avid tumours. However, predicting response remains challenging. Preclinical data suggests aberrant p53-signalling as a predictor of poor response. Methods: The patient population of this pre-planned retrospective cohort study consists of 96 patients with mCRPC who underwent treatment with PSMA-RLT and were molecularly profiled by whole-genome sequencing and or targeted next-generation sequencing. Response to PSMA-RLT was assessed per molecular subtype, including TP53 -mutational status. Results: Patients with TP53 loss-of-function alterations had a shorter median progression-free survival (3.7 versus 6.2 months, P <0.001), a lower median PSA change (-55% vs. -75%, P =0.012) and shorter overall survival from initiation of PMSA-RLT (7.6 vs. 13.9 months, P =0.003) compared to TP53 -wildtype patients. Pathogenic alterations in AR , MYC , BRCA1 , or BRCA2 as well as in genes linked to the PI3K or MAPK pathways or genes involved in homologous recombination repair, were not associated with response. Only lactate dehydrogenase was, alongside TP53 -status, significantly associated with response. Transcriptome analysis of 21 patients, identified six p53 signalling genes whose low expression was associated to a shorter progression-free survival ( P <0.05). Conclusion: TP53 loss-of-function may serve as a prognostic factor for PSMA-RLT outcomes in patients with mCRPC., Competing Interests: Competing Interests: Maarten J. van der Doelen: Research support: 'Bayer, Janssen-Cilag'. Travel support: 'Astellas'. James Nagarajah: Research support: 'ABX, Novartis'. Advisory role: 'ITM, POINT biopharma, CURIUM, Novartis, Bayer'. Inge M. van Oort: Advisory role: 'Bayer, Astellas, Janssen, MSD/AstraZeneca'. Research support: 'Astellas, Janssen, Bayer'. Jack. A. Schalken: Speaker honorarium: 'Astellas, Bayer'. Niven Mehra: Advisory role: 'Roche, MSD, BMS, Bayer, Astellas, Janssen'. Research support: 'Astellas, Janssen, Pfizer, Roche and Sanofi' Genzyme'. Travel support: 'Astellas, MSD'. The remaining authors declare no conflict of interest., (© The author(s).)

Background Multiparametric MRI (mpMRI) is effective for detecting prostate cancer (PCa); however, there is a high rate of equivocal Prostate Imaging Reporting and Data System (PI-RADS) 3 lesions and false-positive findings. Purpose To investigate whether fluorine 18 ( 18 F) prostate-specific membrane antigen (PSMA) 1007 PET/CT after mpMRI can help detect localized clinically significant PCa (csPCa), particularly for equivocal PI-RADS 3 lesions. Materials and Methods This prospective study included participants with elevated prostate-specific antigen (PSA) levels referred for prostate mpMRI between September 2020 and February 2022. 18 F-PSMA-1007 PET/CT was performed within 30 days of mpMRI and before biopsy. PI-RADS category and level of suspicion (LOS) were assessed. PI-RADS 3 or higher lesions at mpMRI and/or LOS 3 or higher lesions at 18 F-PSMA-1007 PET/CT underwent targeted biopsies. PI-RADS 2 or lower and LOS 2 or lower lesions were considered nonsuspicious and were monitored during a 1-year follow-up by means of PSA testing. Diagnostic accuracy was assessed, with histologic examination serving as the reference standard. International Society of Urological Pathology (ISUP) grade 2 or higher was considered csPCa. Results Seventy-five participants (median age, 67 years [range, 52-77 years]) were assessed, with PI-RADS 1 or 2, PI-RADS 3, and PI-RADS 4 or 5 groups each including 25 participants. A total of 102 lesions were identified, of which 80 were PI-RADS 3 or higher and/or LOS 3 or higher and therefore underwent targeted biopsy. The per-participant sensitivity for the detection of csPCa was 95% and 91% for mpMRI and 18 F-PSMA-1007 PET/CT, respectively, with respective specificities of 45% and 62%. 18 F-PSMA-1007 PET/CT was used to correctly differentiate 17 of 26 PI-RADS 3 lesions (65%), with a negative and positive predictive value of 93% and 27%, respectively, for ruling out or detecting csPCa. One additional significant and one insignificant PCa lesion (PI-RADS 1 or 2) were found at 18 F-PSMA-1007 PET/CT that otherwise would have remained undetected. Two participants had ISUP 2 tumors without PSMA uptake that were missed at PET/CT. Conclusion 18 F-PSMA-1007 PET/CT showed good sensitivity and moderate specificity for the detection of csPCa and ruled this out in 93% of participants with PI-RADS 3 lesions. Clinical trial registration no. NCT04487847 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Turkbey in this issue.

Background: Bone marrow toxicity in advanced prostate cancer patients who receive [ 177 Lu]Lu-PSMA-617 is a well-known concern. In early stage patients; e.g. low volume metastatic hormone sensitive prostate cancer (mHSPC) patients, prevention of late bone marrow toxicity is even more crucial due to longer life expectancy. To date, bone marrow dosimetry is primarily performed using blood sampling. This method is time consuming and does not account for possible active bone marrow uptake. Therefore other methodologies are investigated. We calculated the bone marrow absorbed dose for [ 177 Lu]Lu-PSMA-617 in mHSPC patients using SPECT/CT imaging and compared it to the blood sampling method as reference., Methods: Eight mHSPC patients underwent two cycles (3 and 6 GBq) of [ 177 Lu]Lu-PSMA-617 therapy. After each cycle, five time point (1 h, 1 day, 2 days, 3 days, 7 days) SPECT/CT was performed at kidney level. Bone marrow dosimetry was performed using commercial software by drawing ten 1.5 cm diameter spheres in the lowest ten vertebrae to determine the time-integrated activity. Simplified protocols using only 2 imaging time points and 3 vertebrae were also compared. Blood-based dosimetry was based on the blood sampling method according to the EANM guideline., Results: Mean bone marrow absorbed dose was significantly different (p < 0.01) for the imaging based method (25.4 ± 8.7 mGy/GBq) and the blood based method (17.2 ± 3.4 mGy/GBq), with an increasing absorbed dose ratio between both methods over time. Bland Altman analysis of both simplification steps showed that differences in absorbed dose were all within the 95% limits of agreement., Conclusion: This study showed that bone marrow absorbed dose after [ 177 Lu]Lu-PSMA-617 can be determined using an imaging-based method of the lower vertebrae, and simplified using 2 time points (1 and 7 days) and 3 vertebrae. An increasing absorbed dose ratio over time between the imaging-based method and blood-based method suggests that there might be specific bone marrow binding of [ 177 Lu]Lu-PSMA-617., (© 2024. The Author(s).)

Introduction: Prostate specific membrane antigen (PSMA) directed radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) patients. However, it is still poorly understood why approximately 40% of the patients does not respond to PSMA-RLT. The aims of this study were to evaluate the pretreatment PSMA expression on immunohistochemistry (IHC) and PSMA uptake on PET/CT imaging in mCRPC patients who underwent PSMA-RLT. We correlated these parameters and a cell proliferation marker (Ki67) to the therapeutic efficacy of PSMA-RLT., Patients and Methods: In this retrospective study, mCRPC patients who underwent PSMA-RLT were analyzed. Patients biopsies were scored for immunohistochemical Ki67 expression, PSMA staining intensity and percentage of cells with PSMA expression. Moreover, the PSMA tracer uptake of the tumor lesion(s) and healthy organs on PET/CT imaging was assessed. The primary outcome was to evaluate the association between histological PSMA protein expression of tumor in pre-PSMA-RLT biopsies and the PSMA uptake on PSMA PET/CT imaging of the biopsied lesion. Secondary outcomes were to assess the relationship between PSMA expression and Ki67 on IHC and the progression free survival (PFS) and overall survival (OS) following PSMA-RLT., Results: In total, 22 mCRPC patients were included in this study. Nineteen (86%) patients showed a high and homogenous PSMA expression of >80% on IHC. Three (14%) patients had low PSMA expression on IHC. Although there was limited PSMA uptake on PET/CT imaging, these 3 patients had lower PSMA uptake on PET/CT imaging compared to the patients with high PSMA expression on IHC. Yet, no correlation was found between PSMA uptake on PET/CT imaging and PSMA expression on IHC (SUVmax: R 2  = 0.046 and SUVavg: R 2  = 0.036). The 3 patients had a shorter PFS compared to the patients with high PSMA expression on IHC (HR: 4.76, 95% CI: 1.14-19.99; P = .033). Patients with low Ki67 expression had a longer PFS and OS compared to patients with a high Ki67 expression (HR: 0.40, 95% CI: 0.15-1.06; P = .013) CONCLUSION: The PSMA uptake on PSMA-PET/CT generally followed the PSMA expression on IHC. However, heterogeneity may be missed on PSMA-PET/CT. Immunohistochemical PSMA and Ki67 expression in fresh tumor biopsies, may contribute to predict treatment efficacy of PSMA-RLT in mCRPC patients. This needs to be further explored in prospective cohorts., Competing Interests: Disclosure The authors have declared that no competing interest exists., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Studies to evaluate and optimize [ 177 Lu]Lu-PSMA treatment focus primarily on individual patient data. A population pharmacokinetic (PK) dosimetry model was developed to explore the potential of using imaging data as input for population PK models and to characterize variability in organ and tumor uptake of [ 177 Lu]Lu-PSMA-617 in patients with low volume metastatic prostate cancer. Simulations were performed to identify the effect of dose adjustments on absorbed doses in salivary glands and tumors. A six-compartment population PK model was developed, consisting of blood, salivary gland, kidneys, liver, tumor, and a lumped compartment representing other tissue (compartment 1-6, respectively), based on data from 10 patients who received [ 177 Lu]Lu-PSMA-617 (2 cycles, ~ 3 and ~ 6 GBq). Data consisted of radioactivity levels (decay corrected) in blood and tissues (9 blood samples and 5 single photon emission computed tomography/computed tomography scans). Observations in all compartments were adequately captured by individual model predictions. Uptake into salivary glands was saturable with an estimated maximum binding capacity (B max ) of 40.4 MBq (relative standard error 12.3%) with interindividual variability (IIV) of 59.3% (percent coefficient of variation [CV%]). IIV on other PK parameters was relatively minor. Tumor volume was included as a structural effect on the tumor uptake rate constant (k 15 ), where a two-fold increase in tumor volume resulted in a 1.63-fold increase in k 15 . In addition, interoccasion variability on k 15 improved the model fit (43.5% [CV%]). Simulations showed a reduced absorbed dose per unit administered activity for salivary glands after increasing radioactivity dosing from 3 to 6 GBq (0.685 Gy/GBq vs. 0.421 Gy/GBq, respectively). All in all, population PK modeling could help to improve future radioligand therapy research., (© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Fibroblast activation protein (FAP) is highly overexpressed in stromal tissue of various cancers. While FAP has been recognized as a potential diagnostic or therapeutic cancer target for decades, the surge of radiolabeled FAP-targeting molecules has the potential to revolutionize its perspective. It is presently hypothesized that FAP targeted radioligand therapy (TRT) may become a novel treatment for various types of cancer. To date, several preclinical and case series have been reported on FAP TRT using varying compounds and showing effective and tolerant results in advanced cancer patients. Here, we review the current (pre)clinical data on FAP TRT and discuss its perspective towards broader clinical implementation.  METHODS: A PubMed search was performed to identify all FAP tracers used for TRT. Both preclinical and clinical studies were included if they reported on dosimetry, treatment response or adverse events. The last search was performed on July 22 2022. In addition, a database search was performed on clinical trial registries (date 15 th of July 2022) to search for prospective trials on FAP TRT., Results: In total, 35 papers were identified that were related to FAP TRT. This resulted in the inclusion of the following tracers for review: FAPI-04, FAPI-46, FAP-2286, SA.FAP, ND-bisFAPI, PNT6555, TEFAPI-06/07, FAPI-C12/C16, and FSDD., Conclusion: To date, data was reported on more than 100 patients that were treated with different FAP targeted radionuclide therapies such as [ 177 Lu]Lu-FAPI-04, [ 90 Y]Y-FAPI-46, [ 177 Lu]Lu-FAP-2286, [ 177 Lu]Lu-DOTA.SA.FAPI and [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 . In these studies, FAP targeted radionuclide therapy has resulted in objective responses in difficult to treat end stage cancer patients with manageable adverse events. Although no prospective data is yet available, these early data encourages further research., (© 2023. The Author(s).)

Purpose: For prostate-specific membrane antigen-directed radioligand therapy (PSMA-RLT), [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T are the currently preferred compounds. Recent preclinical studies suggested ~30x higher kidney absorbed dose for [ 177 Lu]Lu-PSMA-I&T compared to [ 177 Lu]Lu-PSMA-617, which may lead to an increased risk of kidney toxicity. We performed two single-centre, prospective dosimetry studies with either [ 177 Lu]Lu-PSMA-617 or [ 177 Lu]Lu-PSMA-I&T, using an identical dosimetry protocol. We evaluated the absorbed doses of both 177 Lu-labelled radioligands in human kidneys., Methods: 3D SPECT/computed tomography (CT) imaging of the kidneys was performed after PSMA-RLT in cancer patients with PSMA-positive disease and an adequate glomerular filtration rate (≥50 mL/min). Ten metastatic hormone-sensitive prostate cancer patients (mHSPC) were treated with [ 177 Lu]Lu-PSMA-617 and 10 advanced salivary gland cancer (SGC) patients were treated with [ 177 Lu]Lu-PSMA-I&T. SPECT/CT imaging was performed at five timepoints (1 h, 24 h, 48 h, 72 h, and 168 h post-injection). In mHSPC patients, SPECT/CT imaging was performed after cycles 1 and 2 (cumulative activity: 9 GBq) and in SGC patients only after cycle 1 (activity: 7.4 GBq). Kidney absorbed dose was calculated using organ-based dosimetry., Results: The median kidney absorbed dose was 0.49 Gy/GBq (range: 0.34-0.66) and 0.73 Gy/GBq (range: 0.42-1.31) for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T, respectively (independent samples t test; P  = 0.010)., Conclusion: This study shows that the kidney absorbed dose for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T differs, with a ~1.5x higher median kidney absorbed dose for [ 177 Lu]Lu-PSMA-I&T. This difference in the clinical setting is considerably smaller than observed in preclinical studies and may not hamper treatments with [ 177 Lu]Lu-PSMA-I&T., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Dosimetry in [ 177 Lu]Lu-PSMA therapy is a valuable tool to assess treatment efficacy and toxicity. This study aims to develop a clinically implementable protocol to determine the absorbed dose in organs and tumor lesions after [ 177 Lu]Lu-PSMA-617 therapy, by reducing the imaging time points and utilizing population-based kinetics with a single scan, with evaluation of its influence on the uncertainty in absorbed dose., Methods: Ten patients with metastatic hormone-sensitive prostate cancer received two cycles of [ 177 Lu]Lu-PSMA-617. Post-treatment imaging was performed at 1 h, 24 h, 48 h, 72 h and 168 h, consisting of three-bed positions SPECT/CT and a whole-body planar scan. Five-time point SPECT dosimetry was performed for lesions and organs with physiological uptake (kidneys, liver and salivary glands) and used as the reference standard. Absorbed dose values for various simplified protocols were compared to the reference standard., Results: Accurate lesion dosimetry is possible using one-time point SPECT imaging at 168 h, with an increase in uncertainty (20% vs. 14% for the reference standard). By including a second time point, uncertainty was comparable to the reference standard (13%). Organ dosimetry can be performed using a single SPECT at 24 h or 48 h. Dosimetry based on planar scans did not provide accurate dose estimations., Conclusion: Accurate lesion dosimetry in [ 177 Lu]Lu-PSMA therapy can be performed using a one- or two-time point protocol, making dosimetry assessments more suitable for routine clinical implementation, although dosimetry based om multiple time points is more accurate. Clinical trial registration This study was approved by the Medical Review Ethics Committee Region Arnhem-Nijmegen on January 23, 2018 and was registered on clinicaltrials.gov (NCT03828838)., (© 2023. The Author(s).)

Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a novel treatment for patients with castration-resistant prostate cancer (CRPC). Given the mode of action, patients in an earlier disease stage, such as hormone-sensitive prostate cancer (HSPC), are also likely to benefit from [ 177 Lu]Lu-PSMA- ( 177 Lu-PSMA) or [ 225 Ac]Ac-PSMA-radioligand treatment ( 225 Ac-PSMA). In this retrospective study, we analyzed the safety and efficacy of PSMA-RLT in early-stage and hormone-sensitive metastatic prostate cancer patients., Methods: A retrospective study was performed in patients who received 177 Lu-PSMA and/or 225 Ac-PSMA with early-stage metastatic prostate cancer. The primary outcome parameter evaluated in this study was the progression-free survival (PFS) after PSMA-RLT and toxicity according to the Common Terminology Criteria for Adverse Events. Secondary outcome parameters were prostate-specific antigen (PSA) response and the date of onset of CRPC state., Results: In total, 20 patients were included of which 18 patients received 177 Lu-PSMA radioligand and two patients received tandem treatment with both 177 Lu-PSMA and 225 Ac-PSMA radioligands. Patients received a median of 2 treatment cycles (range 1-6) and a median activity of 6.2 GBq 177 Lu-PSMA per cycle (interquartile range (IQR) 5.2-7.4 GBq). PSMA-RLT was overall well-tolerated. The most common grade 1-2 side effects were xerostomia ( n = 6) and fatigue ( n = 8), which were only temporarily reported. One patient that received 225 Ac-PSMA developed grade 3-4 bone marrow toxicity. The median PFS was 12 months (95% confidence interval (CI), 4.09-19.9 months). Seventeen (85%) patients had a ≥50% PSA response following PSMA-RLT. One patient developed CRPC 9 months following PSMA-RLT., Conclusions: In this small cohort study, PSMA-RLT appeared safe and showed encouraging efficacy for (metastasized) early-stage and hormone-sensitive prostate cancer patients. Prospective studies are awaited and should include long-term follow-up.

Purpose: Prostate-specific membrane antigen (PSMA)-targeted PET/CT has become increasingly important in the management of prostate cancer, especially in localization of biochemical recurrence (BCR). PSMA-targeted PET/CT imaging with long-lived radionuclides as 89 Zr (T 1/2  = 78.4 h) may improve diagnostics by allowing data acquisition on later time points. In this study, we present our first clinical experience including preliminary biodistribution and dosimetry data of [ 89 Zr]Zr-PSMA-617 PET/CT in patients with BCR of prostate cancer., Methods: Seven patients with BCR of prostate cancer who revealed no (n = 4) or undetermined (n = 3) findings on [ 68 Ga]Ga-PSMA-11 PET/CT imaging were referred to [ 89 Zr]Zr-PSMA-617 PET/CT. PET/CT imaging was performed 1 h, 24 h, 48 h, and 72 h post injection (p.i.) of 111 ± 11 MBq [ 89 Zr]Zr-PSMA-617 (mean ± standard deviation). Normal organ distribution and dosimetry were determined. Lesions visually considered as suggestive of prostate cancer were quantitatively analyzed., Results: Intense physiological uptake was observed in the salivary and lacrimal glands, liver, spleen, kidneys, intestine and urinary tract. The parotid gland received the highest absorbed dose (0.601 ± 0.185 mGy/MBq), followed by the kidneys (0.517 ± 0.125 mGy/MBq). The estimated overall effective dose for the administration of 111 MBq was 10.1 mSv (0.0913 ± 0.0118 mSv/MBq). In 6 patients, and in particular in 3 of 4 patients with negative [ 68 Ga]Ga-PSMA-11 PET/CT, at least one prostate cancer lesion was detected in [ 89 Zr]Zr-PSMA-617 PET/CT imaging at later time points. The majority of tumor lesions were first visible at 24 h p.i. with continuously increasing tumor-to-background ratio over time. All tumor lesions were detectable at 48 h and 72 h p.i., Conclusion: [ 89 Zr]Zr-PSMA-617 PET/CT imaging is a promising new diagnostic tool with acceptable radiation exposure for patients with prostate cancer especially when [ 68 Ga]Ga-PSMA-11 PET/CT imaging fails detecting recurrent disease. The long half-life of 89 Zr enables late time point imaging (up to 72 h in our study) with increased tracer uptake in tumor lesions and higher tumor-to-background ratios allowing identification of lesions non-visible on [ 68 Ga]Ga-PSMA-11 PET/CT imaging., (© 2022. The Author(s).)

177 Lu-PSMA-617 radioligand therapy is a novel treatment for end-stage prostate cancer, which could also be applied to patients with hormone-sensitive prostate cancer with high expression levels of prostate-specific membrane antigen (PSMA). In this perspective, we review the recent results of toxicity, radiation doses, and treatment effect of 177 Lu-PSMA in patients with low volume metastatic hormone-sensitive prostate cancer. Moreover, we present long-term follow-up data, such as toxicity and time without androgen deprivation therapy (ADT), of the patients who participated in this trial. Overall, 177 Lu-PSMA appeared to be a feasible and safe treatment modality in this setting, as well as in long-term follow-up. We observed that men with a prostate-specific antigen (PSA) response of more than 50% seemed to especially benefit from this therapy by postponing ADT and thus preserving the quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Privé, Muselaers, van Oort, Janssen, Peters, van Gemert, Uijen, Schilham, Sedelaar, Westdorp, Mehra, Gotthardt, Barentsz, Gerritsen, Witjes and Nagarajah.)

Rationale: Prolonged in vivo evaluation of PSMA tracers could improve tumor imaging and patient selection for 177 Lu-PSMA-617 and 177 Lu-PSMA-I&T. In this study, we present the radiolabeling method of PSMA-617 and PSMA-I&T with the long-lived positron emitter 89 Zr to enable PET imaging up to 7 days post-injection. We compared the biodistribution of 89 Zr-PSMA-617 and 89 Zr-PSMA-I&T to those of 177 Lu-PSMA-617 and 177 Lu-PSMA-I&T, respectively, in a PSMA + xenograft model. Moreover, we provide the first human 89 Zr-PSMA-617 images., Materials and Methods: PSMA ligands were labeled with 50-55 MBq [ 89 Zr]ZrCl 4 using a two-step labeling protocol. For biodistribution, BALB/c nude mice bearing PSMA + and PSMA - xenografts received 0.6 µg (0.6-1 MBq) of 89 Zr-PSMA-617, 89 Zr-PSMA-I&T, 177 Lu-PSMA-617, or 177 Lu-PSMA-I&T intravenously. Ex vivo biodistribution and PET/SPECT imaging were performed up to 168 h post-injection. Dosimetry was performed from the biodistribution data. The patient received 90.5 MBq 89 Zr-PSMA-617 followed by PET/CT imaging., Results: 89 Zr-labeled PSMA ligands showed a comparable ex vivo biodistribution to its respective 177 Lu-labeled counterparts with high tumor accumulation in the PSMA + xenografts. However, using a dose estimation model for 177 Lu, absorbed radiation dose in bone and kidneys differed among the 177 Lu-PSMA and 89 Zr-PSMA tracers. 89 Zr-PSMA-617 PET in the first human patient showed high contrast of PSMA expressing tissues up to 48 h post-injection., Conclusion: PSMA-617 and PSMA-I&T were successfully labeled with 89 Zr and demonstrated high uptake in PSMA + xenografts, which enabled PET up to 168 h post-injection. The biodistribution of 89 Zr-PSMA-I&T and 89 Zr-PSMA-617 resembled that of 177 Lu-PSMA-I&T and 177 Lu-PSMA-617, respectively. The first patient 89 Zr-PSMA-617 PET images were of high quality warranting further clinical investigation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: For localization of biochemical recurrence of prostate cancer, 68Ga-PSMA-11 PET/CT imaging was performed in a 66-year-old man with no suspicious findings at 1 hour p.i. Additional 89Zr-PSMA-617 PET/CT revealed a small local recurrence in the prostate bed, facilitating consecutive local therapy. This interesting image points to the potential of PET/CT with 89Zr-labeled PSMA ligands, for example, 89Zr-PSMA-617, for identifying the source of biochemical recurrence despite otherwise negative imaging including conventional PSMA PET/CT., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) allows for accurate diagnosis and staging of prostate cancer (PCa). Compared to other PSMA PET tracers available, [18F]PSMA-1007 is predominantly excreted via the hepatobiliary tract resulting in low renal excretion which improves evaluation of the pelvic area. However, some patients do show high urinary uptake of [18F]PSMA-1007. The present study aimed to investigate this sudden high urinary uptake of [18F]PSMA-1007 by evaluating [18F]PSMA-1007 PET scans from PCa patients. In this single-center retrospective study, patients that underwent [18F]PSMA-1007 PET imaging between July 2018 and January 2021 were included. Data regarding the individual patient characteristics, scan acquisition and batch production were analyzed. To determine the urinary excretion of [18F]PSMA-1007, a region of interest was drawn in the bladder, and standardized uptake values (SUVs) were calculated and compared to SUVs in the prostate. An SUVmax of >10 was considered high urinary excretion, an SUVmax 7.5−10 intermediate and an SUVmax < 7.5 low urinary excretion. A total of 344 patients underwent [18F]PSMA-1007 PET/CT imaging, with 37 patients receiving three or more [18F]PSMA-1007 PET/CT scans. The mean SUVmean and SUVmax of the bladder were 3.9 (SD 2.9) and 5.9 (SD 4.2), respectively. Fourteen percent of patients showed high urinary uptake of [18F]PSMA-1007. Twelve of the thirty-seven patients (32.4%) that had multiple scans showed a varying urinary uptake of [18F]PSMA-1007 per PSMA PET/CT scan. In terms of patient characteristics, risk factors, medication and blood laboratory results, no significant influencing variables were found. Nor was there a difference observed in the batch size and the mean radiochemical purity of PSMA-1007 for high- and low-excreting patients. However, the bladder volume affected the mean SUVmax in the bladder significantly, with higher SUVs in lower bladder volumes. In this study, we observed that a higher SUV in the urinary tract seemed to occur in patients with low bladder volume. A prospective study is needed to corroborate this hypothesis.

Purpose: Prostate-specific membrane antigen radioligand therapy (PSMA-RLT) is a novel treatment for castration-resistant prostate cancer (mCRPC). While the majority of patients responds to PSMA-RLT, with 10-15% having an exceptional response, approximately 30% of patients is unresponsive to PSMA-RLT. The molecular underpinning may in part explain these varying responses. This study investigated alterations in DNA damage repair (DDR) genes in tumour biopsies and their association with response to PSMA-RLT., Methods: A predefined retrospective cohort study was performed in mCRPC patients of whom the tumours had undergone next-generation sequencing of 40 DDR genes and received Lu-177-PSMA and/or Ac-225-PSMA-RLT. The primary outcome of this study was to compare the progression free survival (PFS) after PSMA-RLT for patients with and without pathogenic DDR aberrations in their tumour. Secondary outcomes were prostate-specific antigen (PSA) response and overall survival (OS)., Results: A total of 40 patients were included of which seventeen had a tumour with a pathogenic DDR aberration (DDR+), of which eight had defects in BRCA1/2. DDR+ patients had an equal varying response to PSMA-RLT compared to those without pathological DDR anomalies (DDR-) in terms of PFS (5.9 vs. 6.4 months, respectively; HR 1.14; 95% CI 0.58-2.25; p = 0.71), ≥50% PSA response (59% vs. 65%, respectively; p = 0.75) or OS (11.1 vs. 10.7 months, respectively; HR 1.40; 95% CI: 0.68-2.91; p = 0.36)., Conclusion: In this study of a selected cohort, pathogenic DDR aberrations were not associated with exceptional responsiveness to PSMA-RLT. Translational studies in larger prospective cohorts are warranted to associate DDR gene defects with differential responses to PSMA-RLT., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Patient eligibility for [ 177 Lu]Lu-PSMA therapy remains a challenge, with only 40-60% response rate when patient selection is done based on the lesion uptake (SUV) on [ 68 Ga]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 [ 68 Ga]Ga-PSMA-11 PET/CT, followed by 3 GBq [ 177 Lu]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 [ 68 Ga]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 [ 68 Ga]Ga-PSMA-PET scan can be used to predict the absorbed dose of [ 177 Lu]Lu-PSMA therapy to organs, and (to a limited extent) to lesions. This strategy facilitates in treatment management and could increase the personalization of [ 177 Lu]Lu-PSMA therapy., (© 2021. The Author(s).)

Introduction: While [ 177 Lu]Lu-PSMA radioligand therapy is currently only applied in end-stage metastatic castrate-resistant prostate cancer (mCRPC) patients, also low-volume hormone-sensitive metastatic prostate cancer (mHSPC) patients can benefit from it. However, there are toxicity concerns related to the sink effect in low-volume disease. This prospective study aims to determine the kinetics of [ 177 Lu]Lu-PSMA in mHSPC patients, analyzing the doses to organs at risk (salivary glands, kidneys, liver, and bone marrow) and tumor lesions < 1 cm diameter., Methods: Ten mHSPC patients underwent two cycles of [ 177 Lu]Lu-PSMA therapy. Three-bed position SPECT/CT was performed at 5 time points after each therapy. Organ dosimetry and lesion dosimetry were performed using commercial software and a manual approach, respectively. Correlation between absorbed index lesion dose and treatment response (PSA drop of > 50% at the end of the study) was calculated and given as Spearman's r and p-values., Results: Kinetics of [ 177 Lu]Lu-PSMA in mHSPC patients are comparable to those in mCRPC patients. Lesion absorbed dose was high (3.25 ± 3.19 Gy/GBq) compared to organ absorbed dose (salivary glands: 0.39 ± 0.17 Gy/GBq, kidneys: 0.49 ± 0.11 Gy/GBq, liver: 0.09 ± 0.01 Gy/GBq, bone marrow: 0.017 ± 0.008 Gy/GBq). A statistically significant correlation was found between treatment response and absorbed index lesion dose (p = 0.047)., Conclusions: We successfully performed small lesion dosimetry and showed that the tumor sink effect in mHSPC patients is of less concern than was expected. Tumor-to-organ ratio of absorbed dose was high and tumor uptake correlates with PSA response. Additional treatment cycles are legitimate in terms of organ toxicity and could lead to better tumor response., (© 2021. The Author(s).)

In the past decade, a growing body of literature has reported promising results for prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy in prostate cancer. First clinical studies evaluating the efficacy of [ 177 Lu]Lu-PSMA radioligand therapy (PSMA-RLT) demonstrated favorable results in prostate cancer patients. [ 177 Lu]Lu-PSMA is generally well tolerated due to its limited side effects. While PSMA is highly overexpressed in prostate cancer cells, varying degrees of PSMA expression have been reported in other malignancies as well, particularly in the tumor-associated neovasculature. Hence, it is anticipated that PSMA-RLT could be explored for other solid cancers. Here, we describe the current knowledge of PSMA expression in other solid cancers and define a perspective towards broader clinical implementation of PSMA-RLT. This review focuses specifically on salivary gland cancer, glioblastoma, thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer, and breast cancer. An overview of the (pre)clinical data on PSMA immunohistochemistry and PSMA PET/CT imaging is provided and summarized. Furthermore, the first clinical reports of non-prostate cancer patients treated with PSMA-RLT are described., (© 2021. The Author(s).)

Accurate assessment of lymph node (LN) metastases in prostate cancer (PCa) patients is critical for prognosis and patient management. Both prostate-specific membrane antigen (PSMA) PET/CT and ferumoxtran-10 nanoparticle-enhanced MRI (nano-MRI) are imaging modalities with high potential to identify LN metastases in PCa patients. The aim of this study was to compare the results of these imaging technologies in terms of characteristics and anatomic localization of suspicious LNs in order to assess the feasibility of their complementary use for imaging in PCa patients. Methods: In total, 45 patients with either primary PCa ( n = 8) or recurrence ( n = 36) were included in this retrospective study. All patients underwent both 68 Ga-PSMA PET/CT and nano-MRI between October 2015 and July 2017 within 3 wk. Both scans were performed at the same institution according to local clinical protocols. All scans were analyzed independently by experienced nuclear medicine physicians and radiologists. The size, anatomic location, and level of suspicion were determined for all visible LNs. Subsequently, the findings from 68 Ga-PSMA PET/CT and nano-MRI were compared without respect to a reference standard. Results: In total, 179 suspicious LNs were identified. Significantly more suspicious LNs per patient were detected by nano-MRI ( P < 0.001): 160 were identified in 33 patients by nano-MRI, versus 71 in 25 patients by 68 Ga-PSMA PET/CT. Of all suspicious LNs, 108 were identified only by nano-MRI (60%), 19 (11%) only by 68 Ga-PSMA PET/CT, and 52 (29%) by both methods. The mean size of the suspicious LNs as identified by nano-MRI was significantly smaller (5.3 mm) than that by 68 Ga-PSMA PET/CT (6.0 mm; P = 0.006). The median level of suspicion did not differ significantly. Both modalities identified suspicious LNs in all anatomic regions of the pelvis. Conclusion: Both modalities identified suspicious LNs that were missed by the other. Both modalities identified suspicious LNs in all anatomic regions of the pelvis; however, nano-MRI appeared to be superior in detecting smaller suspicious LNs. These findings suggest that nano-MRI has a potential role as a complement to PSMA PET/CT. However, since the clinical implications of the different results are not well established yet, further investigation of this complementary use is encouraged., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: [ 177 Lu]Lu-PSMA-617 radioligand therapy ( 177 Lu-PSMA) is a novel treatment for metastatic castration-resistant prostate cancer (mCRPC), which could also be applied to patients with metastatic hormone-sensitive prostate cancer (mHSPC) with PSMA expression. In this prospective study (NCT03828838), we analyzed toxicity, radiation doses, and treatment effect of 177 Lu-PSMA in pateints with low-volume mHSPC., Patients and Methods: Ten progressive patients with mHSPC following local treatment, with a maximum of ten metastatic lesions on [ 68 Ga]Ga-PSMA-11 PET/diagnostic-CT imaging (PSMA-PET) and serum PSA doubling time <6 months received two cycles of 177 Lu-PSMA. Whole-body single-photon emission CT/CT (SPECT/CT) and blood dosimetry was performed to calculate doses to the tumors and organs at risk (OAR). Adverse events (AE), laboratory values (monitoring response and toxicity), and quality of life were monitored until week 24 after cycle 2, the end of study (EOS). All patients underwent PSMA-PET at screening, 8 weeks after cycle 1, 12 weeks after cycle 2, and at EOS., Results: All patients received two cycles of 177 Lu-PSMA without complications. No treatment-related grade III-IV adverse events were observed. According to dosimetry, none of the OAR reached threshold doses for radiation-related toxicity. Moreover, all target lesions received a higher radiation dose than the OAR. All 10 patients showed altered PSA kinetics, postponed androgen deprivation therapy, and maintained good quality of life. Half of the patients showed a PSA response of more than 50%. One patient had a complete response on PSMA-PET imaging until EOS and two others had only minimal residual disease., Conclusions: 177 Lu-PSMA appeared to be a feasible and safe treatment modality in patients with low-volume mHSPC., (©2021 American Association for Cancer Research.)

Background: PSMA-PET is a novel imaging modality for the staging of prostate cancer (PCa). While there are several PSMA ligands available, F-18-PSMA-1007 is particularly of interest as it is not renally excreted and therefore does not impair the imaging of the pelvic area. Hence, this study aimed to investigate the F-18-PSMA-1007-PET for the primary staging of PCa and compared it to multi-parametric (mp) MRI and histopathology., Methods: A retrospective study was performed of men with intermediate and high-risk PCa patients that underwent a F-18-PSMA-1007-PET after mpMRI with subsequent MR-guided target biopsy (MRGB). Suspicious mpMRI lesions and F-18-PSMA-1007-PET were simultaneously reviewed on both a per patient and per-lesion basis. Results were subsequently evaluated with histopathological outcome of MRGB, and if performed, the radical prostatectomy specimen., Results: A total of 66 suspicious mpMRI lesions were identified in 53 patients and underwent MRGB. Two lesions had a maximum standardized uptake value (SUV max ) less than the mean SUV max of healthy prostate tissue and were considered as non-PSMA-expressing. All PSMA avid tumors had higher SUV max than the mean SUV mean of the bladder/urine, therefore all lesions were clearly distinguishable in the pelvic area. Twenty-three patients received a radical prostatectomy of which the histopathology specimens were evaluated. F-18-PSMA-1007-PET/CT correctly staged seminal vesicle invasion (i.e. pT3b) more often than mpMRI (90 vs. 76%), whereas mpMRI more accurately detected extracapsular extension (i.e. pT3a) compared to F-18-PSMA-1007-PET (90% vs 57%)., Conclusions: The present study of a selected cohort suggest that dual imaging with mpMRI and F-18-PSMA-1007-PET may improve staging of primary PCa. F-18-PSMA-1007-PET/CT had low renal clearance, which could assist the evaluation of tumors in proximity of the bladder.

Background: In recent years, there is increasing evidence showing a beneficial outcome (e.g. progression free survival; PFS) after metastases-directed therapy (MDT) with external beam radiotherapy (EBRT) or targeted surgery for oligometastatic hormone sensitive prostate cancer (oHSPC). However, many patients do not qualify for these treatments due to prior interventions or tumor location. Such oligometastatic patients could benefit from radioligand therapy (RLT) with 177 Lu-PSMA; a novel tumor targeting therapy for end-stage metastatic castration-resistant prostate cancer (mCRPC). Especially because RLT could be more effective in low volume disease, such as the oligometastatic status, due to high uptake of radioligands in smaller lesions. To test the hypothesis that 177 Lu-PSMA is an effective treatment in oHSPC to prolong PFS and postpone the need for androgen deprivation therapy (ADT), we initiated a multicenter randomized clinical trial. This is globally, the first prospective study using 177 Lu-PSMA-I&T in a randomized multicenter setting., Methods & Design: This study compares 177 Lu-PSMA-I&T MDT to the current standard of care (SOC); deferred ADT. Fifty-eight patients with oHSPC (≤5 metastases on PSMA PET) and high PSMA uptake (SUVmax > 15, partial volume corrected) on 18 F-PSMA PET after prior surgery and/or EBRT and a PSA doubling time of < 6 months, will be randomized in a 1:1 ratio. The patients randomized to the interventional arm will be eligible for two cycles of 7.4GBq 177 Lu-PSMA-I&T at a 6-week interval. After both cycles, patients are monitored every 3 weeks (including adverse events, QoL- and xerostomia questionnaires and laboratory testing) at the outpatient clinic. Twenty-four weeks after cycle two an end of study evaluation is planned together with another 18 F-PSMA PET and (whole body) MRI. Patients in the SOC arm are eligible to receive 177 Lu-PSMA-I&T after meeting the primary study objective, which is the fraction of patients who show disease progression during the study follow up. A second primary objective is the time to disease progression. Disease progression is defined as a 100% increase in PSA from baseline or clinical progression., Discussion: This is the first prospective randomized clinical study assessing the therapeutic efficacy and toxicity of 177 Lu-PSMA-I&T for patients with oHSPC., Trial Registration: Clinicaltrials.gov identifier: NCT04443062 .

Complications after intravesicalMycobacterium bovisBCG instillation Intravesical instillation of Mycobacterium bovis BCG is frequently used for non-muscle invasive high-grade urothelial cell carcinoma of the bladder. M. bovisBCG is a mycobacterium and was one of the first cancer immunotherapies. It activates the immune system and so reduces disease recurrence. Although rare, this treatment can lead to mycobacterial infections or systemic immune reactions. Diagnosing these complications is often challenging because the symptoms are non-specific. In addition, M. bovisBCG infections are hard to detect with current diagnostics, i.e. bacterial cultures, PCR and radiological imaging. Thus, proper treatment is often delayed as M. bovis does not respond to conventional broad-spectrum antibiotics. In this article we present three patients with BCG pneumonia, BCG arthritis and BCG cystitis, respectively. Subsequently, we describe the history of M. bovis BCG, its pathophysiology, the clinical presentation of its complications and diagnostics and treatment.