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Most Prostate Specific Membrane Antigens (PSMAs) targeting small molecules accumulate in the salivary glands (SGs), raising concerns about SG toxicity, especially after repeated therapies or therapy with 225 Ac-labeled ligands. SG toxicity is assessed clinically by the severity of patient-reported xerostomia, but this parameter can be challenging to objectively quantify. Therefore, we explored the feasibility of using SG volume as a biomarker for toxicity. In 21 patients with late-stage metastatic resistant prostate cancer (mCRPC), the PSMA volume and ligand uptake of SG were analyzed retrospectively before and after two cycles of 177 Lu-PSMA (LuPSMA; cohort A) and before and after one cycle of 225 Ac-PSMA-617 (AcPSMA, cohort B). Mean Volume-SG in cohort A was 59 ± 13 vs. 54 ± 16 mL (-10%, p = 0.4), and in cohort B, it was 50 ± 13 vs. 40 ± 11 mL (-20%, p = 0.007), respectively. A statistically significant decrease in the activity concentration in the SG was only observed in group B (SUV mean : 9.2 ± 2.8 vs. 5.3 ± 1.8, p < 0.0001; vs. A: SUV mean : 11.2 ± 3.3 vs. 11.1 ± 3.5, p = 0.8). SG volume and PSMA-ligand uptake are promising markers to monitor the SG toxicity after a PSMA RLT.

177 Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new treatment option for metastatic castration-resistant prostate cancer (mCRPC). Its low toxicity profile favors use in elderly patients or in patients with critical comorbidities. The purpose of this analysis was to evaluate the efficacy and safety of [ 177 Lu]-PSMA RLT in mCRPC patients at least 80 y old. Methods: Eighty mCRPC patients at least 80 y old underwent [ 177 Lu]-PSMA-I&T RLT and were retrospectively selected. The patients were previously treated by androgen receptor-directed therapy, received taxane-based chemotherapy, or were chemotherapy-ineligible. The best prostate-specific antigen (PSA) response was calculated, as well as clinical progression-free survival (cPFS) and overall survival (OS). Toxicity data were acquired until 6 mo after the last treatment cycle. Results: Of 80 patients, 49 (61.3%) were chemotherapy-naïve and 16 (20%) had visceral metastases. The median number of previous mCRPC treatment regimens was 2. In total, 324 cycles (median, 4 cycles; range, 1-12) with a median cumulative activity of 23.8 GBq (interquartile range, 14.8-42.2) were applied. A PSA decline of 50% was achieved in 37 (46.3%) patients. Chemotherapy-naïve patients showed higher 50% PSA response rates than chemotherapy-pretreated patients (51.0% vs. 38.7%, respectively). Overall, median cPFS and OS were 8.7 and 16.1 mo, respectively. The median cPFS and OS of chemotherapy-naïve patients were significantly longer than those of chemotherapy-pretreated patients (10.5 vs. 6.5 mo and 20.7 vs. 11.8 mo, respectively, P < 0.05). A lower hemoglobin level and higher lactate dehydrogenase level at baseline were independent predictors of shorter cPFS and OS. Treatment-emergent grade 3 toxicities were anemia in 4 patients (5%), thrombocytopenia in 3 patients (3.8%), and renal impairment in 4 patients (5%). No nonhematologic grade 3 and no grade 4 toxicities were observed. The most frequent clinical side effects were grade 1-2 xerostomia, fatigue, and inappetence. Conclusion: [ 177 Lu]-PSMA-I&T RLT in mCRPC patients at least 80 y old is safe and effective, comparable to previously published data on non-age-selected cohorts with a low rate of high-grade toxicities. Chemotherapy-naïve patients showed a better and longer response to therapy than taxane-pretreated patients. [ 177 Lu]-PSMA RLT seems to be a meaningful treatment option for older patients., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

This study was performed to assess the prognostic utility of conventional biochemical and imaging response criteria and 68 Ga-PSMA11 PET-adapted or -specific systems regarding overall survival (OS) in men with metastatic hormone-sensitive and castration-resistant prostate cancer (PC) treated with taxane-based chemotherapy. Methods: A total of 103 patients (metastatic hormone-sensitive PC, n = 57; castration-resistant PC, n = 46) underwent taxane-based chemotherapy. All patients had a minimum of 2 prostate-specific membrane antigen (PSMA) PET scans (at baseline and up to 3 mo after treatment). PSMA PET response was assessed by RECIST 1.1, adapted Prostate Cancer Working Group Criteria 3 (using PSMA PET instead of bone scan), aPERCIST, and PSMA PET progression (PPP) criteria. Response by each criterion was stratified by either progressive disease (PD) or non-PD. For aPERCIST, stratification by PD, stable disease (SD), and partial/complete remission (PR/CR) was performed. Biochemical response was determined by a prostate-specific antigen decrease of at least 50%. Subgroup analyses were performed by castration status. Univariable Cox proportional hazards regression analyses including Harrell's concordance indices were calculated to investigate the association of PD by response criteria and OS. Kaplan-Meier tests including log-rank statistics were calculated for survival analyses. Results: Twenty-six (25%) patients had unmeasurable disease by RECIST 1.1. PD by any response criterion was associated with an at least 2.5-fold increased risk of death and was highest for PD versus CR/PR by aPERCIST (hazard ratio, 11.4) on univariable regression. Stratified by castration status, a similar pattern was observed. PD by any criterion as associated with significantly shortened OS across overall and subgroup analyses. PR/CR by aPERCIST identified patients with lower risk of death and longer OS compared with patients with PD or SD. Conclusion: PSMA PET-based response criteria (PPP, aPERCIST, adapted Prostate Cancer Working Group Criteria 3) have high prognostic utility in men with metastatic PC undergoing taxane-based chemotherapy. PPP is simple to use, identified most patients with PD, and showed best prognostic utility regarding OS. PR/CR by aPERCIST identifies a subgroup of responders (PR/CR) showing better outcomes than patients with PD or SD. Future studies are warranted to amend the current paradigm relying on mere differentiation of PD versus non-PD in metastatic PC and to identify true treatment responders by imaging criteria., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

18 F-rhPSMA-7.3, the lead compound of a new class of radiohybrid prostate-specific membrane antigen (rhPSMA) ligand, is currently in phase III trials for prostate cancer (PCa) imaging. Here, we describe our experience in primary PCa staging. Methods: We retrospectively identified 279 patients with primary PCa who underwent 18 F-rhPSMA-7.3 PET/CT (staging cohort). A subset of patients (83/279) subsequently underwent prostatectomy with lymph node (LN) dissection without prior treatment (efficacy cohort). The distribution of tumor lesions was determined for the staging cohort and stratified by National Comprehensive Cancer Network risk score. Involvement of pelvic LNs was assessed retrospectively by 3 masked independent central readers, and a majority rule was used for analysis. Standard surgical fields were rated on a 5-point scale independently for PET and for morphologic imaging. Results were compared with histopathologic findings on a patient, right-vs.-left, and template basis. Results: For the staging cohort, 18 F-rhPSMA-7.3 PET was positive in 275 of 279 (98.6%), 106 of 279 (38.0%), 46 of 279 (16.5%), 65 of 279 (23.3%), and 5 of 279 (1.8%) patients for local, pelvic nodal, extrapelvic nodal, metastatic bone, and visceral metastatic disease, respectively. In the efficacy cohort, LN metastases were present in 24 of 83 patients (29%) and were located in 48 of 420 (11%) resected templates and in 33 of 166 (19.9%) hemipelvic templates in histopathology. The majority vote results showed that patient-level sensitivity, specificity, and accuracy for pelvic nodal metastases were 66.7% (95% CI, 44.7%-83.6%), 96.6% (95% CI, 87.3%-99.4%), and 88.0% (95% CI, 78.5%-93.8%), respectively, for 18 F-rhPSMA-7.3 PET and 37.5% (95% CI, 19.6%-59.2%), 91.5% (95% CI, 80.6%-96.8%), and 75.9% (95% CI, 65.0%-84.3%), respectively, for morphologic imaging. 18 F-rhPSMA-7.3 showed higher interobserver agreement than morphologic imaging (patient-level Fleiss κ = 0.54 [95% CI, 0.47-0.62] vs. 0.24 [95% CI, 0.17-0.31]). A mean SUV ratio of 6.6 (95% CI, 5.2-8.1) documented a high image contrast between local tumors and adjacent low urinary tracer retention. Conclusion: 18 F-rhPSMA-7.3 PET offers diagnostic performance superior to morphologic imaging for primary N-staging of newly diagnosed PCa, shows lower interreader variation, and offers good distinction between primary-tumor activity and bladder background activity. With increasing National Comprehensive Cancer Network risk group, an increasing frequency of extraprostatic tumor lesions was observed., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: PSMA-targeted radioligand therapy (PRLT) is a promising treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, a high uptake of the radiopharmaceutical in the salivary glands (SG) can lead to xerostomia and becomes dose-limiting for 225Ac-PSMA-617. This study investigated the sialotoxicity of 177Lu-PSMA-I&T/-617 monotherapy and co-administered 225Ac-PSMA-617 and 177Lu-PSMA-617 (Tandem-PPRLT). Methods: Three patient cohorts, that had undergone 177Lu-PSMA-I&T/-617 monotherapy or Tandem-PRLT, were retrospectively analyzed. In a short-term cohort (91 patients), a xerostomia assessment (CTCAE v.5.0), a standardized questionnaire (sXI), salivary gland scintigraphy (SGS), and SG SUVmax and the metabolic volume (MV) on 68Ga-PSMA-11-PET/CT were obtained before and after two cycles of 177Lu-PSMA-I&T/-617. In a long-term cohort, 40 patients were similarly examined. In a Tandem cohort, the same protocol was applied to 18 patients after one cycle of Tandem-PRLT. Results: Grade 1 xerostomia in the short-term follow-up was observed in 22 (24.2%) patients with a worsening of sXI from 7 to 8 at (p < 0.05). In the long-term cohort, xerostomia grades 1 to 2 occurred in 16 (40%) patients. SGS showed no significant changes, but there was a decline of the MV of all SGs. After Tandem-PRLT, 12/18 (66.7%) patients reported xerostomia grades 1 to 2, and the sXI significantly worsened from 9.5 to 14.0 (p = 0.005), with a significant reduction in the excretion fraction (EF) and MV of all SGs. Conclusion: 177Lu-PSMA-I&T/-617 causes only minor SG toxicity, while one cycle of Tandem-PRLT results in a significant SG impairment. This standardized protocol may help to objectify and quantify SG dysfunction.

This bicentric, retrospective analysis investigated the efficacy of PET/CT with a novel theranostic prostate-specific membrane antigen (PSMA)--targeting ligand, 18 F-rhPSMA-7, in patients with biochemical recurrence (BCR) of prostate cancer after curative-intent primary radiotherapy. Methods: Datasets from patients with BCR of prostate cancer after external-beam radiation therapy or brachytherapy who underwent 18 F-rhPSMA-7 PET/CT at either Technical University Munich or Ludwig-Maximilians-University Munich were retrospectively reviewed by experienced nuclear medicine physicians and radiologists at both centers. The median injected activity was 299 MBq (range, 204-420 MBq), and the median uptake time was 77 min (range, 46-120 min). All lesions suggestive of recurrent prostate cancer were noted. Detection rates were correlated with patients' prostate-specific antigen (PSA) level, primary Gleason score, and prior use of androgen-deprivation therapy (ADT). Results: Ninety-seven patients were included (65 at Technical University Munich and 32 at Ludwig-Maximilians-University Munich). The median prescan PSA was 4.19 ng/mL (range, 0.1-159 ng/mL). The primary Gleason score was ≤6 in 19 patients, 7 in 25, ≥8 in 33, and unknown in 20. Thirty patients received ADT in the 6 mo preceding PET/CT. 18 F-rhPSMA-7 identified lesions in 91 of 97 (94%) patients. Detection rates stratified by PSA were 88% (22/25), 97% (30/31), 90% (19/21), and 100% (20/20) for a PSA of <2, 2-<5, 5-<10, and ≥10 ng/mL, respectively. Detection rates in the subgroup of patients not meeting the Phoenix criteria for BCR were 80% (4/5), 90% (9/10), 100% (4/4), and 83% (5/6) for a PSA of <0.5, 0.5-<1, 1-<1.5, and 1.5-2 ng/mL, respectively. There were no significant differences in detection rates between patients with and without prior ADT (100% vs. 91%, P = 0.173) or patients with a Gleason score of ≤7 and a Gleason score of ≥8 (98% vs. 91%, P = 0.316). 18 F-rhPSMA-7 revealed local recurrence in 80% (78/97); pelvic lymph node metastases in 38% (37/97); retroperitoneal and supradiaphragmatic lymph node metastases in 9% (9/97) and 4% (4/97), respectively; bone metastases in 27% (26/97); and visceral metastases in 3% (3/97). In the subgroup of patients with a PSA of <2 ng/mL above nadir, local recurrence occurred in 76% (19/25) and pelvic lymph node metastases in 36% (9/25). Conclusion: 18 F-rhPSMA-7 PET/CT demonstrates high detection rates in prostate cancer patients with BCR after primary radiation therapy, even at low PSA values. Its diagnostic efficacy is comparable to published data for other PSMA ligands., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

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 18 F-rhPSMA-7.3 in patients with prostate cancer. Methods: The biodistribution of 18 F-rhPSMA-7.3 on PET/CT scans obtained with a high specific activity (median, 178.9 MBq/µg; n  = 42) and a low specific activity (median, 19.3 MBq/µg; n  = 42) was compared. Results: Tracer uptake by the parotid gland, submandibular gland, and spleen was moderately but significantly lower in the low-specific-activity group than in the high-specific-activity group (median SUV mean , 16.7 vs. 19.2; 18.1 vs. 22.3; and 7.8 vs. 9.6, respectively). No other statistically significant differences were found for normal organs or tumor lesions. Conclusion: A 10-fold decrease in specific activity has only minor effects on the biodistribution of 18 F-rhPSMA-7.3. These findings suggest that 18 F-labeled PSMA ligands can be centrally produced and shipped to PET clinics in a similar way to 18 F-FDG., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Botulinum Toxin injections into salivary glands (SG) up to a total dose of 100 units IncobotulinumtoxinA (IncoA) represent the treatment of choice for sialorrhea. However, BTX might also protect SG against sialotoxic radioligand cancer therapies. The radioligand Actinium-225-PSMA effectively targets Prostate Cancer (PCa) metastases but inevitably destroys SG due to unintended gland uptake. A preliminary case series with regular-dose IncoA failed to reduce SG PSMA-radioligand uptake. We therefore increased IncoA dosage in combination with transdermal scopolamine until a clinically relevant SG PSMA-radioligand uptake reduction was achieved. Ten consecutive men with metastasized PCa refractory to all other cancer therapies received gradually increasing IncoA dosages as part of a compassionate use PSMA-radioligand-therapy trial. The parotid gland received six and the submandibular gland three injection points under ultrasound control, up to a maximum of 30 units IncoA per injection point. A maximum total dose of 250 units IncoA was applied with up to 170 units per parotid and 80 units per submandibular gland. Treatment was well tolerated and all side-effects were non-serious. The most frequent side-effect was dry mouth of mild severity. No dysphagia, facial weakness, chewing difficulties or systemic side-effects were observed. SG injections with IncoA up to a total dose of 250 units are safe when distributed among several injection-points under ultrasound control by an experienced physician. These preliminary findings lay the basis for future trials including BTX as major component for SG protection in established as well as newly emerging radioligand cancer therapies.

Purpose: In PSMA-ligand PET/CT imaging, standardized evaluation frameworks and image-derived parameters are increasingly used to support prostate cancer staging. Clinical applicability remains challenging wherever manual measurements of numerous suspected lesions are required. Deep learning methods are promising for automated image analysis, typically requiring extensive expert-annotated image datasets to reach sufficient accuracy. We developed a deep learning method to support image-based staging, investigating the use of training information from two radiotracers., Methods: In 173 subjects imaged with 68 Ga-PSMA-11 PET/CT, divided into development (121) and test (52) sets, we trained and evaluated a convolutional neural network to both classify sites of elevated tracer uptake as nonsuspicious or suspicious for cancer and assign them an anatomical location. We evaluated training strategies to leverage information from a larger dataset of 18 F-FDG PET/CT images and expert annotations, including transfer learning and combined training encoding the tracer type as input to the network. We assessed the agreement between the N and M stage assigned based on the network annotations and expert annotations, according to the PROMISE miTNM framework., Results: In the development set, including 18 F-FDG training data improved classification performance in four-fold cross validation. In the test set, compared to expert assessment, training with 18 F-FDG data and the development set yielded 80.4% average precision [confidence interval (CI): 71.1-87.8] for identification of suspicious uptake sites, 77% (CI: 70.0-83.4) accuracy for anatomical location classification of suspicious findings, 81% agreement for identification of regional lymph node involvement, and 77% agreement for identification of metastatic stage., Conclusion: The evaluated algorithm showed good agreement with expert assessment for identification and anatomical location classification of suspicious uptake sites in whole-body 68 Ga-PSMA-11 PET/CT. With restricted PSMA-ligand data available, the use of training examples from a different radiotracer improved performance. The investigated methods are promising for enabling efficient assessment of cancer stage and tumor burden., (© 2021. The Author(s).)

Clinical/methodological Issue: 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)., Standard Radiological Procedures: 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., Methodological Innovations: Hybrid imaging provides higher diagnostic accuracy for lymph node and bone metastases compared to conventional imaging and has a significant impact on clinical management., Performance: 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., Purpose: 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., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: The prostate-specific membrane antigen (PSMA) is a relevant target in prostate cancer, and immunohistochemistry studies showed associations with outcome. PSMA-ligand positron emission tomography (PET) is increasingly used for primary prostate cancer staging, and the molecular imaging TNM classification (miTNM) standardizes its reporting. We aimed to investigate the potential of PET-imaging to serve as a noninvasive imaging biomarker to predict disease outcome in primary prostate cancer after radical prostatectomy (RP)., Methods: In this retrospective analysis, 186 primary prostate cancer patients treated with RP who had undergone a 68 Ga-PSMA-11 PET up to three months prior to the surgery were included. Maximum standardized uptake value (SUV max ), SUV mean , tumor volume (TV) and total lesion (TL) were collected from PET-imaging. Moreover, clinicopathological information, including age, serum prostate-specific antigen (PSA) level, and pathological characteristics, was assessed for disease outcome prediction. A stage group system for PET-imaging findings based on the miTNM framework was developed., Results: At a median follow-up after RP of 38 months (interquartile range (IQR) 22-53), biochemical recurrence (BCR) was observed in 58 patients during the follow-up period. A significant association between a positive surgical margin and miN status (miN1 vs. miN0, odds ratio (OR): 5.428, p = 0.004) was detected. miT status (miT ≥ 3a vs. miT < 3, OR: 2.696, p = 0.003) was identified as an independent predictor for Gleason score (GS) ≥ 8. Multivariate Cox regression analysis indicated that PSA level (hazard ratio (HR): 1.024, p = 0.014), advanced GS (GS ≥ 8 vs. GS < 8, HR: 3.253, p < 0.001) and miT status (miT ≥ 3a vs. miT < 3, HR: 1.941, p = 0.035) were independent predictors for BCR. For stage I disease as determined by PET-imaging, a shorter BCR-free survival was observed in the patients with higher SUV max (IA vs. IB stage, log-rank, p = 0.022)., Conclusion: Preoperative miTNM classification from 68 Ga-PSMA-11 PET correlates with postoperative GS, surgical margin status and time to BCR. The association between miTNM staging and outcome proposes 68 Ga-PSMA-11 PET as a novel non-invasive imaging biomarker and potentially serves for ancillary pre-treatment stratification., (© 2021. The Author(s).)

An inherent challenge to clinical trials that aim to test the efficacy of experimental therapeutics for patients with amyotrophic lateral sclerosis (ALS) is the relative rarity of the disease. A promising solution to this problem is a multi-center approach that ideally includes sites distributed across a broad geographic area. In support of such an approach, the European E-RARE program and the United States National Institutes of Health (NIH) partnered to support the investigator-initiated ROCK-ALS trial (Eudra-CT-Nr.: 2017-003676-31, NCT03792490) as a multi-national collaboration between centers in Europe and North America that is led by European investigators. During the set-up of this international trial, however, a number of unanticipated legal, administrative, and financial complexities emerged that required significant adaptation of the proposed trial scheme. Here, we report our experience navigating these obstacles and describe the potential solutions that we explored. Our experience may inform future efforts to implement multi-national investigator-initiated trials that involve both European and United States centers.

The objective of this retrospective study was to assess the detection rate (DR), positive predictive value (PPV), and correct detection rate (CDR) of 18 F-rhPSMA-7 PET/CT in biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) using composite validation. Methods: 18 F-rhPSMA-7 PET/CT scans of patients with BCR between July 2017 and June 2018 were retrospectively reviewed. All suspicious lesions were recorded. The reference standard was histopathology or combinations of histopathology, imaging, or prostate-specific antigen (PSA) follow up, defined as composite reference standard. DR was calculated as the proportion of PSMA PET-positive patients to all patients independent of the reference standard, whereas the CDR was the percentage of patients who had at least 1 true-positive PSMA PET lesion localized that corresponded with the reference standard. The PPV was defined as the proportion of patients who had true-positive to all positive findings. The correlation between DR and patient characteristics was evaluated. Results: A total of 532 patients with a median PSA level of 0.97 ng/mL (interquartile range: 0.41-2.46 ng/mL) were included. Of these, 162 patients had composite follow-up at a median duration of 5.6 mo (range: 1.1-14.2 mo). The proportion of patients who had no lesion visualized on PET/CT, localized disease, and any distant metastases (M1) were 20%, 43%, and 37%, respectively. PET DR among all patients was 80%. On a per-patient basis, the PPV of 18 F-rhPSMA-7 PET/CT in the composite cohort was 88%, and the CDR was 70%. The PPV in the histopathology-proven cohort was 91%, and the CDR in this subgroup was 73%. In patients with PSA levels ≥ 1 ng/mL the DR and PPV were 90% and 91%, respectively, resulting in a CDR of 82%. In patients with PSA levels < 1 ng/mL, the DR and PPV were 69% and 85%, respectively, resulting in a CDR of 59%. There was a significant positive correlation between 18 F-rhPSMA-7 PET/CT detection efficacy and stratified PSA levels ( P = 0.005), as well as PSA nadir after prostatectomy ( P < 0.001). Conclusion: 18 F-rhPSMA-7 PET/CT offers high PPV in BCR after RP. Its CDR is dependent on the prescan PSA value with excellent CDR in patients with PSA ≥ 1 ng/mL., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

We present a 78-year-old man with suspicion of prostate cancer due to a PSA of 200 ng/mL, who underwent F-PSMA-1007 (prostate specific membrane antigen) PET/CT for primary staging. Besides heterogeneous uptake to the prostate, an increased PSMA uptake in the cecum was observed, located in the thickened cecal wall with suspicion of a secondary malignancy. Colonoscopic biopsy followed by hemicolectomy confirmed the diagnosis of colon adenocarcinoma. This case demonstrates the importance of bioptic workup of suspicious findings on PSMA PET/CT, which are unlikely to be related to prostate cancer as PSMA ligand uptake is not exclusively prostate cancer specific.

Radiohybrid PSMA (rhPSMA) ligands, a new class of theranostic prostate-specific membrane antigen (PSMA)-targeting agents, feature fast 18 F synthesis and utility for labeling with radiometals. Here, we assessed the biodistribution and image quality of 18 F-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 18 F-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, SUV mean 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, SUV mean showed a significant decrease in the blood pool and lungs and an increase in the kidneys, bladder, and bones as the uptake time increased. SUV mean 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 18 F-rhPSMA-7 was similar to that of established PSMA ligands, and tumor uptake of 18 F-rhPSMA-7 was stable across the administered activities and uptake times. An early imaging time point (50-70 min) is recommended for 18 F-rhPSMA-7 PET/CT to achieve the highest overall image quality., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

18 F-labeled prostate-specific membrane antigen (PSMA) PET tracers are increasingly used in preference to 68 Ga-PSMA-11 for restaging biochemical recurrence (BCR) of prostate cancer. They are associated with longer half-lives, larger-scale production, and lower positron range than their 68 Ga-labeled counterparts. Here, we describe the efficacy of an 18 F-labeled radiohybrid PSMA, rhPSMA-7, a novel theranostic PSMA-targeting agent for imaging BCR of prostate cancer. Methods: Datasets from 261 consecutive patients with noncastrate BCR after radical prostatectomy who underwent 18 F-rhPSMA-7 PET/CT at our institution between June 2017 and March 2018 were reviewed retrospectively. All lesions suspected of being recurrent prostate cancer were recorded. The detection rate for sites of presumed recurrence was correlated with patients' prostate-specific antigen (PSA) level, primary Gleason score, and prior therapy (androgen deprivation therapy and external-beam radiation therapy). Results: The 261 patients had a median PSA level of 0.96 ng/mL (range, 0.01-400 ng/mL). The median injected activity of 18 F-rhPSMA-7 was 336 MBq, with a median uptake time of 76 min. In total, 211 patients (81%) showed pathologic findings on 18 F-rhPSMA-7 PET/CT. The detection rates were 71% (42/59), 86% (44/51), 86% (42/49), and 95% (76/80) at PSA levels of 0.2 to <0.5 ng/mL, 0.5 to <1 ng/mL, 1 to <2 ng/mL, and ≥2 ng/mL, respectively. In 32% patients (7/22) with a PSA of less than 0.2 ng/mL, suggestive lesions were present. 18 F-rhPSMA-7 PET/CT revealed local recurrence in 43% of patients (113). Lymph node metastases were present in the pelvis in 42% of patients (110), in the retroperitoneum in 17% (45), and in a supradiaphragmatic location in 8.0% (21). Bone and visceral metastases were detected in 21% (54) and 3.8% (10), respectively. Detection efficacy was not influenced by prior external-beam radiation therapy (79.1% vs. 82.1%, P = 0.55), androgen deprivation therapy within the 6 mo preceding imaging (80.6% vs. 80.9%, P = 0.54), or primary Gleason score (77.9% for ≤7 vs. 82.6% for ≥8, P = 0.38). Conclusion: 18 F-rhPSMA-7 PET/CT offers high detection rates in early BCR after radical prostatectomy, especially among patients with low PSA values., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

The aim of this study was to assess the safety, tolerability, and effects on renal function as well as therapeutic efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) using 177 Lu-labeled PSMA-617 in patients with metastatic castration-resistant prostate cancer and a single functioning kidney before PRLT. Methods: Sixteen patients (aged 53-78 y; mean age, 64.7 ± 6.5 y) with a single functioning kidney received PRLT with 177 Lu-PSMA-617 between March 2015 and October 2018. All parameters of renal function (serum creatinine, blood urea nitrogen, and electrolytes) were prospectively documented in a structured database and analyzed before each PRLT cycle and in follow-up. Renal function was further quantified by measuring tubular extraction rate (TER) using 99m Tc-mercaptoacetyltriglycine renal scintigraphy. Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Kaplan-Meier analysis was performed to obtain the progression-free survival and overall survival. Results: The median administered activity was 22.1 GBq (range, 15.4-33.8 GBq). The calculated absorbed radiation dose to the kidney per cycle was 5.3 ± 2.1 Gy (0.81 ± 0.32 Gy/GBq). Renal function was already impaired at baseline in 43.7% of patients, including CTCAE grade 1 renal impairment in 25.0% and CTCAE grade 2 in 18.8%. Grade 1 and 2 renal impairment, respectively, were present in 37.5% and 6.3% of the patients after the first PRLT cycle and in 31.3% and 12.5% after the second cycle. No CTCAE grade 3 or 4 nephrotoxicity was observed during or after treatment. There was no significant change in either TER or the ratio of TER to lower-limit TER after the last cycle of treatment ( P > 0.05). The median PFS was 8.1 mo based on both the criteria of the European Organization for Research and Treatment of Cancer and RECIST. The median overall survival has yet to be reached with a median follow-up time of 19.3 mo (range, 5.8-45.3 mo). Conclusion: In patients with a single functioning kidney, 177 Lu-PSMA-617 PRLT is feasible, seems to be effective, and is well tolerated, without any signs of acute or subacute nephrotoxicity during a mean follow-up of nearly 2 y (and up to 45.3 mo). Further long-term follow-up of this special patient group is warranted., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Molecular alterations in malignant disease result in the expression or upregulations of various targets that can be used for imaging and treatment with radiopharmaceuticals. This theranostic principle has acquired greater importance in personalized medicine in recent years, particularly in oncology, where advanced tumors can be treated effectively with low side effects. Since the pioneering use of 131 I in differentiated thyroid cancer in the 1940s, remarkable achievements in nuclear medicine endoradiotherapy have been demonstrated, mainly in the treatment of neuroendocrine neoplasms by using 177 Lu-labeled somatostatin analogs or in the treatment of advanced prostate cancer using prostate-specific membrane antigen-directed radionuclide therapy. Besides that, this review focuses on promising novel radiopharmaceuticals and describes their preclinical and clinical status. Radiolabeled antibodies, such as 131 I-omburtamab directed against the B7-H3 protein on the surface of neuroblastoma cells; HuMab-5B1, a 89 Zr/ 177 Lu-labeled antibody for the treatment of CA19-9-expressing malignancies; and 177 Lu-lilotomab, a CD37 antibody for the treatment of B-cell lymphomas, are being highlighted. The neurotensin receptor ligand 111 In/ 177 Lu-3B-227 has demonstrated high potential in imaging and therapy for several malignancies (e.g., pancreatic adenocarcinomas). Targeting of the fibroblast activation protein is currently being explored for different tumor entities using PET imaging with the fibroblast activation protein inhibitor (FAPI) 68 Ga-FAPI-04, and the first therapeutic applications of 90 Y-FAPI-04 have been applied. After 2 decades of rapid development in theranostics, a variety of new targets are available for further clinical investigation., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Patients with neuroendocrine tumors (NETs) of the gastrointestinal tract suffer frequently from chronic diarrhea. A well characterized medical advice containing zeolite (Detoxsan ® powder) was applied to patients suffered from therapy-refractory diarrhea either by its frequency or by watery stool, despite receiving standard pharmacotherapy according to the guidelines for carcinoid syndrome and comorbidities. Detoxsan ® powder acts as an adsorbent and might reduce significantly symptoms of diarrhea in patients suffering from NETs., Aim: To overcome the therapy-refractory diarrhea of patients with NETs by the zeolite containing medical advice Detoxsan ® powder., Methods: A total of 20 patients (12 female and 8 male) suffering from diarrhea either by its frequency or from watery stool caused by NETs were included. In each patient, the diagnosis had been confirmed by histology and somatostatin receptors expression proven by positron emission tomography/computed tomography using Ga-68-labeled somatostatin analogs. All patients received standard-of-care pharmacotherapy and were additionally given Detoxsan ® powder as an extemporaneous drug containing 90% natural Cuban zeolite and 10% magnesium aspartate. Recommended daily dosage ranges between 3 g once to three times per day. Each day dose and bowel movements were documented by the patients themselves in a pre-defined table. Additionally to the bowel movements quantitative determinations of serotonin, urea, creatinine and single ions were performed within the serum of the patients by commercially available equipment used as a matter of routine in the clinic., Results: All patients enrolled in this pilot study did not only suffer from NETs, but also from comorbidities and treatment-resistant diarrhea. There was insufficient control of diarrhea, most probably due to the secretion of hormones like serotonin produced by the slowly growing and highly differentiated NETs. All patients only took Detoxsan ® powder as an antidiarrheal drug. In general, response effects need several days to become perceptible and require an intake of Detoxsan ® powder for an extended time period or intermittently, if persisting stabilization of bowel movements could not be achieved. A correlation between NET grade, part and size of bowel resection and functionality of the tumor could not be demonstrated. Therefore, diarrhea seemed to be based on the metabolic activity of the well-differentiated NETs, which eventually led to treatment resistance. In summary, 14 out of the 20 patients (70%) declared to be very content with using Detoxsan ® powder and observed a significant reduction of diarrhea, while the effective dose and intake period that resulted in a symptom relief varied individually., Conclusion: Detoxsan ® powder is able to reduce significantly symptoms of NET-related diarrhea in the majority of patients. The duration of taking Detoxsan ® powder and its dosage vary individually., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest. Dathe W is an external advisor for Heck Bio-Pharma GmbH and licenser for Detoxsan®.

Alterations at the molecular level are a hallmark of cancer. Prostate cancer is associated with the overexpression of prostate-specific membrane antigen (PSMA) in a majority of cases, predominantly in advanced tumors, increasing with the grade or Gleason's score. PSMA can be selectively targeted using radiolabeled PSMA ligands. These small molecules binding the PSMA can be radiolabeled with γ-emitters like 99m Tc and 111 In or positron emitters like 68 Ga and 18 F for diagnosis as well as with their theranostic pairs such as 177 Lu (β-emitter) or 225 Ac (α-emitter) for therapy. This review summarizes the theranostic role of PSMA ligands for molecular imaging and targeted molecular radiotherapy, moving towards precision oncology.

The dose-limiting salivary gland toxicity of 225 Ac-labelled PSMA for treatment of metastatic, castration-resistant prostate cancer remains unresolved. Suppressing the metabolism of the gland by intraparenchymal injections of botulinum toxin appears to be a promising method to reduce off-target uptake. A 68 Ga-PSMA PET/CT scan performed 45 days after injection of 80 units of botulinum toxin A into the right parotid gland in a 63-year-old patient showed a decrease in the SUVmean in the right parotid gland of up to 64% as compared with baseline. This approach could be a significant breakthrough for radioprotection of the salivary glands during PSMA radioligand therapy., Competing Interests: Compliance with Ethical StandardsRichard P. Baum, Thomas Langbein, Aviral Singh, Mostafa Shahinfar, Christiane Schuchardt, Gerd Fabian Volk, Harshad Kulkarni declare that they have no conflict of interest.All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the1964 Declaration of Helsinki and its later amendments or comparable ethical standards.Informed consent was obtained from the patient who was the subject of the study.

In a controlled study, functional-scintigraphic investigations into perfusion and ventilation were performed on 10 dogs with non-damaged and extremely severely damaged lungs. The pulmonary damage was produced by injecting oleic acid (OA) into the right atrium of the heart under controlled ventilation (IPPV). The scintigraphic examinations were carried out using 133Xenon. The study compared HFJV (HFJV100, HFJV300) with IPPV in the non-damaged lung as well as HFJV300 with IPPV and CPPV (PEEP 1 kPa) after damage by OA. With the aid of the present radionuclide investigations, new insights can be gained into the largely unclear regional conditions of the gas exchange under HFJV in both the healthy and the damaged lung. Results from controlled studies on the distribution of ventilation and perfusion under HFJV have not been reported to date. The functional-scintigraphic examination with 133Xe on dogs shows, based on specific conditions of the gas exchange and special anatomic conditions of the lungs, a ventilation distribution that differs fundamentally from all other forms of ventilation, including HFOV, preference being given to apical pulmonary segments. This refers to the normal and the damaged lungs alike. However, ventilation-specific changes in pulmonary perfusion do not occur. The resulting deviating regional VA/Q relationship are obviously not of crucial influence upon the gas exchange. Rather, it is influenced and determined by damage-induced intraregional functional-structural alterations in the lung.