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Background: To develop and validate a novel administration device for holmium-166 transarterial radioembolisation (TARE) with the purpose of facilitating controlled fractional microsphere administration for a more flexible and image-guided TARE procedure., Methods: A Controlled Administration Device (CAD) was developed using MR-conditional materials. The CAD contains a rotating syringe to keep the microspheres in suspension during administration. Different rotational speeds were tested ex vivo to optimise the homogeneity of microsphere fractions administered from the device. The technical performance, accuracy, and safety was validated in three patients in a clinical TARE setting by administering a standard clinical dose in 5 fractions (identifier: NCT05183776). MRI-based dosimetry was used to validate the homogeneity of the given fractions in vivo, and serious adverse device event ((S)A(D)E) reporting was performed to assess safety of the CAD., Results: A rotational speed of 30 rpm resulted in the most homogeneous microsphere fractions with a relative mean deviation of 1.1% (range: -9.1-8.0%). The first and last fraction showed the largest deviation with a mean of -26% (std. 16%) and 7% (std. 13%). respectively. In the three patient cases the homogeneity of the microsphere fractions was confirmed given that MRI-based dosimetry showed near linear increase of mean absorbed target liver dose over the given fractions with R 2 values of 0.98, 0.97 and 0.99. No (S)A(D)E's could be contributed to the use of the CAD., Conclusions: The newly developed CAD facilitates safe and accurate fractional microsphere administration during TARE, and can be used for multiple applications in the current and future workflows of TARE., (© 2024. 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.

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.)

Background: Radium-223 is a registered treatment option for symptomatic bone metastatic castration-resistant prostate cancer (mCRPC). Aim of this multicenter, prospective observational cohort study was to evaluate health-related quality of life (HR-QoL), psychological distress and fatigue in mCRPC patients treated with radium-223., Methods: Primary endpoint was cancer-specific and bone metastases-related HR-QoL, as measured by the EORTC QLQ-C30 and BM-22 questionnaires. Secondary endpoints were psychological distress and fatigue, evaluated by the HADS and CIS-Fatigue questionnaires. Outcomes were analyzed for the total cohort and between subgroups (1-3 versus 4-5 versus 6 radium-223 injections). A trajectory analysis was performed to explore HR-QoL patterns over time., Results: In total, 122 patients were included for analysis. Baseline HR-QoL, pain intensity, psychological distress and fatigue were worse in patients who did not complete radium-223 therapy. In patients who completed therapy, stabilization of HR-QoL was perceived and psychological distress and fatigue remained stable, whereas clinically meaningful and statistically significant deterioration of HR-QoL, psychological distress and fatigue over time was observed in patients who discontinued radium-223 therapy. Trajectory analysis revealed that HR-QoL deterioration over time was more likely in patients with baseline opioid use, low hemoglobin and high alkaline phosphatase levels., Conclusions: Patients who discontinued radium-223 therapy showed worse HR-QoL, psychological distress and fatigue at baseline and more frequent deterioration of HR-QoL, psychological distress and fatigue over time when compared to patients who completed therapy. Specific attention with regard to HR-QoL during follow-up is indicated in patients with opioid use, low hemoglobin and high alkaline phosphatase levels before radium-223 therapy initiation., Clinical Trial Registration Number: NCT04995614., (© 2022. The Author(s).)

Introduction: In the Netherlands, the sentinel lymph node procedure protocol consists of preoperative lymphoscintigraphy combined with intraoperative blue dye for identifying sentinel lymph nodes in early vulvar squamous cell carcinoma. This study aimed at investigating the role of early and late lymphoscintigraphy., Material and Methods: From January 2015 to January 2019, early and late lymphoscintigraphies of 52 women were retrospectively analyzed. Lymphoscintigraphy was performed 30 minutes (early) and 2.5-4 hours (late) after vulvar injection of 99m Tc-labeled nanocolloid. We calculated the concordance correlation coefficient (CCC) between number of sentinel lymph nodes detected on both images using the Lins concordance coefficient and correlated with clinicopathological data., Results: Thirty-four women had a midline tumor and 18 had a lateral tumor. Detection rates with early and late scintigraphy were 88.5% and 98.1%, respectively. Median number of detected nodes was 1.0 (0-7) and 2.0 (0-7). Good statistical correlation between number of sentinel lymph nodes detected on early and late imaging was found (CCC = 0.76) in most patients. In 18 women (35%) a mismatch occurred: a higher number of nodes was detected on late imaging. In 11 of 18 women re-injection was performed because no sentinel lymph nodes were visualized on early images. Late imaging and intraoperative detection showed a good statistical correlation (CCC = 0.61). One woman showed an isolated groin recurrence despite negative sentinel lymph nodes., Conclusions: This study showed good statistical correlations between early and late scintigraphy in most patients. However, in 35% of women late scintigraphy detected more nodes. In case of poor visualization after the first scintigraphy, re-injection should be considered. Late scintigraphy is probably helpful in confirming successful re-injection and in showing deviating lymph flow in women with failed mapping after the first injection and successful re-injection. Because missing metastatic sentinel lymph nodes often leads to a poor prognosis, we prefer optimal correlations between imaging and intraoperative identification. Hence, late scintigraphy cannot be safely omitted., (© 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

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: Transarterial radioembolization (TARE) is a treatment for liver tumours based on injection of radioactive microspheres in the hepatic arterial system. It is crucial to achieve a maximum tumour dose for an optimal treatment response, while minimizing healthy liver dose to prevent toxicity. There is, however, no intraprocedural feedback on the dose distribution, as nuclear imaging can only be performed after treatment. As holmium-166 ( 166 Ho) microspheres can be quantified with MRI, we investigate the feasibility and safety of performing 166 Ho TARE within an MRI scanner and explore the potential of intraprocedural MRI-based dosimetry., Methods: Six patients were treated with 166 Ho TARE in a hybrid operating room. Per injection position, a microcatheter was placed under angiography guidance, after which patients were transported to an adjacent 3-T MRI system. After MRI confirmation of unchanged catheter location, 166 Ho microspheres were injected in four fractions, consisting of 10%, 30%, 30% and 30% of the planned activity, alternated with holmium-sensitive MRI acquisition to assess the microsphere distribution. After the procedures, MRI-based dose maps were calculated from each intraprocedural image series using a dedicated dosimetry software package for 166 Ho TARE., Results: Administration of 166 Ho microspheres within the MRI scanner was feasible in 9/11 (82%) injection positions. Intraprocedural holmium-sensitive MRI allowed for tumour dosimetry in 18/19 (95%) of treated tumours. Two CTCAE grade 3-4 toxicities were observed, and no adverse events were attributed to treatment in the MRI. Towards the last fraction, 4/18 tumours exhibited signs of saturation, while in 14/18 tumours, the microsphere uptake patterns did not deviate from the linear trend., Conclusion: This study demonstrated feasibility and preliminary safety of a first in-human application of TARE within a clinical MRI system. Intraprocedural MRI-based dosimetry enabled dynamic insight in the microsphere distribution during TARE. This proof of concept yields unique possibilities to better understand microsphere distribution in vivo and to potentially optimize treatment efficacy through treatment personalization., Registration: Clinicaltrials.gov, identifier NCT04269499, registered on February 13, 2020 (retrospectively registered)., (© 2022. The Author(s).)

Myeloid cells, crucial players in antitumoral defense, are affected by tumor-derived factors and treatment. The role of myeloid cells and their progenitors prior to tumor infiltration is poorly understood. Here we show single-cell transcriptomics and functional analyses of the myeloid cell lineage in patients with non-medullary thyroid carcinoma (TC) and multinodular goiter, before and after treatment with radioactive iodine compared to healthy controls. Integrative data analysis indicates that monocytes of TC patients have transcriptional upregulation of antigen presentation, reduced cytokine production capacity, and overproduction of reactive oxygen species. Interestingly, these cancer-related pathological changes are partially removed upon treatment. In bone marrow, TC patients tend to shift from myelopoiesis towards lymphopoiesis, reflected in transcriptional differences. Taken together, distinct transcriptional and functional changes in myeloid cells arise before their infiltration of the tumor and are already initiated in bone marrow, which suggests an active role in forming the tumor immune microenvironment., (© 2022. The Author(s).)

Patients diagnosed with locally advanced esophageal cancer are often treated with neoadjuvant chemoradiotherapy followed by surgery. This study explored whether detection of circulating tumor DNA (ctDNA) in plasma can be used to predict residual disease during treatment. Diagnostic tissue biopsies from patients with esophageal cancer receiving neoadjuvant chemoradiotherapy and surgery were analyzed for tumor-specific mutations. These tumor-informed mutations were used to measure the presence of ctDNA in serially collected plasma samples using hybrid capture-based sequencing. Plasma samples were obtained before chemoradiotherapy, and prior to surgery. The association between ctDNA detection and progression-free and overall survival was measured. Before chemoradiotherapy, ctDNA was detected in 56% (44/78) of patients and detection was associated with tumor stage and volume ( p = 0.05, Fisher exact and p = 0.02, Mann-Whitney, respectively). After chemoradiotherapy, ctDNA was detected in 10% (8/78) of patients. This preoperative detection of ctDNA was independently associated with recurrent disease (hazard ratio 2.8, 95% confidence interval 1.1-6.8, p = 0.03, multivariable Cox-regression) and worse overall survival (hazard ratio 2.9, 95% confidence interval 1.2-7.1, p = 0.02, multivariable Cox-regression).Ultradeep sequencing-based detection of ctDNA in preoperative plasma of patients with locally advanced esophageal cancer may help to assess which patients have a high risk of recurrence after neoadjuvant chemoradiotherapy and surgery.

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.)

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.)

Selective internal radiation therapy (SIRT) is a treatment modality for liver tumours during which radioactive microspheres are injected into the hepatic arterial tree. Holmium-166 ( 166 Ho) microspheres used for SIRT can be visualized and quantified with MRI, potentially allowing for MRI guidance during SIRT. The purpose of this study was to investigate the MRI compatibility of two angiography catheters and a microcatheter typically used for SIRT, and to explore the detectability of 166 Ho microspheres in a flow phantom using near real-time MRI. MR safety tests were performed at a 3 T MRI system according to American Society for Testing of Materials standard test methods. To assess the near real-time detectability of 166 Ho microspheres, a flow phantom was placed in the MRI bore and perfused using a peristaltic pump, simulating the flow in the hepatic artery. Dynamic MR imaging was performed using a 2D FLASH sequence during injection of different concentrations of 166 Ho microspheres. In the safety assessment, no significant heating (ΔT max 0.7 °C) was found in any catheter, and no magnetic interaction was found in two out of three of the used catheters. Near real-time MRI visualization of 166 Ho microsphere administration was feasible and depended on holmium concentration and vascular flow speed. Finally, we demonstrate preliminary imaging examples on the in vivo catheter visibility and near real-time imaging during 166 Ho microsphere administration in an initial patient case treated with SIRT in a clinical 3 T MRI. These results support additional research to establish the feasibility and safety of this procedure in vivo and enable the further development of a personalized MRI-guided approach to SIRT.

Introduction: Targeted alpha-radiation therapy (TAT) with 225 Ac-labeled prostate-specific membrane antigen (PSMA) ligands is a promising novel treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients. However, limited data are available on efficacy, quality of life (QoL), and pretherapeutic biomarkers. The aim of this study was to evaluate the efficacy of 225 Ac-PSMA TAT and impact on QoL in advanced mCRPC, and to explore predictive biomarkers on pretherapeutic metastatic tissue biopsies., Methods: Observational cohort study including consecutive patients treated with 225 Ac-PSMA TAT between February 2016 and July 2018. Primary endpoint was overall survival (OS). Furthermore, prostate-specific antigen (PSA) changes, radiological response, safety, QoL, and xerostomia were evaluated. Biopsies were analyzed with immunohistochemistry and next-generation sequencing., Results: Thirteen patients were included. Median OS was 8.5 months for the total cohort and 12.6 months for PSMA radioligand therapy-naïve patients. PSA declines of ≥90% and ≥50% were observed in 46% and 69% of patients, respectively. Six patients were radiologically evaluable; 50% showed partial response. All patients showed >90% total tumor volume reduction on PET imaging. Patients experienced clinically relevant decrease of pain and QoL improvement in physical and role functioning domains. Xerostomia persisted during follow-up. Patients with high baseline immunohistochemical PSMA expression or DNA damage repair alterations tended to have longer OS., Conclusions: TAT with 225 Ac-PSMA resulted in remarkable survival and biochemical responses in advanced mCRPC patients. Patients experienced clinically relevant QoL improvement, although xerostomia was found to be nontransient. Baseline immunohistochemical PSMA expression and DNA damage repair status are potential predictive biomarkers of response to 225 Ac-PSMA TAT., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

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: Radium-223 improves overall survival (OS) in men with bone metastatic castration-resistant prostate cancer (mCRPC). While the exact mechanism behind this survival benefit remains unclear, radium-induced immunological mechanisms might contribute to the OS advantage. We performed a comprehensive evaluation of the immunological changes in mCRPC patients by phenotyping the peripheral blood mononuclear cells (PBMCs) during radium-223 therapy., Materials and Methods: In this prospective, single-arm, exploratory study, PBMCs of 30 mCRPC patients were collected before, during, and after treatment with radium-223. Lymphocyte and monocyte counts were analyzed to get insight into general immune cell trends. Next, we analyzed changes in T cell subsets, myeloid-derived suppressor cells (MDSCs), and immune checkpoint expression using linear regression models. Per subset, the 6-month change (% of baseline) was determined. Bootstrapped 95% confidence intervals were used to measure the degree of uncertainty of our findings., Results: We observed a substantial decrease in absolute lymphocyte counts (-0.12 * 10^9 cells/L per injection, 95% CI: -0.143 - -0.102). Simultaneously, an increase was observed in the proportion of T cells that expressed costimulatory (ICOS) or inhibitory (TIM-3, PD-L1, and PD-1) checkpoint molecules. Moreover, the fraction of two immunosuppressive subsets - the regulatory T cells and the monocytic MDSCs - increased throughout treatment. These findings were not more pronounced in patients with an alkaline phosphatase response during therapy., Conclusion: Immune cell subsets in patients with mCRPC changed during radium-223 therapy, which warrants further research into the possible immunological consequences of these changes., Competing Interests: MD received research grants form Bayer (to institution) during the conduct of the study, travel expenses from Bayer, research grants from Janssen Pharmaceuticals, and personal fees from Astellas outside the submitted work. RH is member of the advisory board of Bayer, and received personal fees and travel expenses from Bayer outside the submitted work. DS is a member of the advisory boards of Janssen Pharmaceuticals, Astellas and Bayer, and received research grants from Astellas outside the submitted work. NM is a member of the advisory boards of Bayer, Bristol Myers Squibb, Roche, Merck Sharp and Dome, Astellas and Janssen Pharmaceuticals, and reports personal fees from Bayer, research grants and personal fees from Janssen Pharmaceuticals, Merck Sharp and Dohme, Roche, Astellas, AstraZeneca and Sanofi, and research grants from Pfizer and Genzyme outside the submitted work. The remaining 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 © 2021 Creemers, van der Doelen, van Wilpe, Hermsen, Duiveman-de Boer, Somford, Janssen, Sedelaar, Mehra, Textor and Westdorp.)

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 .

Our purpose was to prospectively investigate optimal evaluation of qualitative and quantitative 18 F-FDG PET/CT in response evaluations 12-14 wk after neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer patients. Methods: This was a side study of the prospective diagnostic pre-SANO trial. 18 F-FDG PET/CT scans at baseline and at 12-14 wk after nCRT were qualitatively assessed for the presence of tumor. Maximum SUVs normalized for lean body mass (SUL max ) were measured in all scans. The primary endpoint was the proportion of false-negative patients with tumor regression grade (TRG) 3-4 (>10% vital residual tumor) in qualitative and quantitative analyses. Receiver-operating-characteristic curve analysis for TRG1 versus TRG3-4 using SUL max , SUL max tumor-to-esophagus ratio, and Δ%SUL max was performed to define optimal cutoffs. Secondary endpoints were sensitivity, specificity, negative predictive value, and positive predictive value for TRG1 versus TRG2-4. Results: In total, 129 of 219 patients were analyzed. Qualitative 18 F-FDG PET/CT was unable to detect TRG3-4 in 15% of patients. Sensitivity, specificity, negative predictive value, and positive predictive value in qualitative analysis for detecting TRG1 versus TRG2-4 was 80%, 37%, 42%, and 77%, respectively. In 18 of 190 patients (10%) with follow-up scans after nCRT, 18 F-FDG PET/CT identified new interval metastases. Quantitative parameters did not detect TRG3-4 tumor in 27%-61% of patients. The optimal cutoff for detecting TRG1 versus TRG2-4 was a post-nCRT SUL max of 2.93 (area under receiver-operating-characteristic curve, 0.70). Conclusion: Qualitative and quantitative analyses of 18 F-FDG PET/CT are unable to accurately detect TRG3-4 and to discriminate substantial residual disease from benign inflammation-induced 18 F-FDG uptake after nCRT. However, 18 F-FDG PET/CT is useful for the detection of interval metastases and might become useful in an active surveillance strategy with serial 18 F-FDG PET/CT scanning., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Disturbances in adipose tissue glucose uptake may play a role in the pathogenesis of type 2 diabetes, yet its examination by 2-deoxy-2-[ 18 F]fluorodeoxyglucose ([ 18 F]FDG) PET/CT is challenged by relatively low uptake kinetics. We tested the hypothesis that performing [ 18 F]FDG PET/CT during a hypoglycaemic clamp would improve adipose tissue tracer uptake to allow specific comparison of adipose tissue glucose handling between people with or without type 2 diabetes., Design: We enrolled participants with or without diabetes who were at least overweight, to undergo a hyperinsulinaemic hypoglycaemic clamp or a hyperinsulinaemic euglycaemic clamp (n = 5 per group). Tracer uptake was quantified using [ 18 F]FDG PET/CT., Results: Hypoglycaemic clamping increased [ 18 F]FDG uptake in visceral adipose tissue of healthy participants (P = 0.002). During hypoglycaemia, glucose uptake in visceral adipose tissue of type 2 diabetic participants was lower as compared to healthy participants (P < 0.0005). No significant differences were observed in skeletal muscle, liver or pancreas., Conclusions: The present findings indicate that [ 18 F]FDG PET/CT during a hypoglycaemic clamp provides a promising new research tool to evaluate adipose tissue glucose metabolism. Using this method, we observed a specific impairment in visceral adipose tissue [ 18 F]FDG uptake in type 2 diabetes, suggesting a previously underestimated role for adipose tissue glucose handling in type 2 diabetes., (© 2019 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Static single-time-frame 18 F-FDG PET/CT is useful for the localization and functional characterization of pheochromocytomas and paragangliomas (PPGLs). 18 F-FDG uptake varies between PPGLs with different genotypes, and the highest SUVs are observed in cases of succinate dehydrogenase ( SDH ) mutations, possibly related to enhanced aerobic glycolysis in tumor cells. The exact determinants of 18 F-FDG accumulation in PPGLs are unknown. We performed dynamic PET/CT scanning to assess whether in vivo 18 F-FDG pharmacokinetics has added value over static PET to distinguish different genotypes. Methods: Dynamic 18 F-FDG PET/CT was performed on 13 sporadic PPGLs and 13 PPGLs from 11 patients with mutations in SDH complex subunits B and D, von Hippel-Lindau ( VHL ), RET, and neurofibromin 1 ( NF1 ). Pharmacokinetic analysis was performed using a 2-tissue-compartment tracer kinetic model. The derived transfer rate-constants for transmembranous glucose flux ( K 1 [in], k 2 [out]) and intracellular phosphorylation ( k 3 ), along with the vascular blood fraction (V b ), were analyzed using nonlinear regression analysis. Glucose metabolic rate (MR glc ) was calculated using Patlak linear regression analysis. The SUV max of the lesions was determined on additional static PET/CT images. Results: Both MR glc and SUV max were significantly higher for hereditary cluster 1 ( SDHx, VHL ) tumors than for hereditary cluster 2 ( RET, NF1 ) and sporadic tumors ( P < 0.01 and P < 0.05, respectively). Median k 3 was significantly higher for cluster 1 than for sporadic tumors ( P < 0.01). Median V b was significantly higher for cluster 1 than for cluster 2 tumors ( P < 0.01). No statistically significant differences in K 1 and k 2 were found between the groups. Cutoffs for k 3 to distinguish between cluster 1 and other tumors were established at 0.015 min -1 (100% sensitivity, 15.8% specificity) and 0.636 min -1 (100% specificity, 85.7% sensitivity). MR glc significantly correlated with SUV max ( P = 0.001) and k 3 ( P = 0.002). Conclusion: In vivo metabolic tumor profiling in patients with PPGL can be achieved by assessing 18 F-FDG pharmacokinetics using dynamic PET/CT scanning. Cluster 1 PPGLs can be reliably identified by a high 18 F-FDG phosphorylation rate., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Sufficient thyroid iodine uptake is needed to ensure effective radioactive iodine (RAI) treatment, which is mediated by the sodium-iodide symporter (NIS). Activation of AMP-activated-protein-kinase (AMPK), leads to decreased NIS expression and thyroid iodine uptake in in vitro and animal models. Clinically relevant conditions that lead to AMPK activation include metformin use and hypocaloric conditions. Here, we aim to assess the effects of metformin and hypocaloric diet on thyroid iodine uptake in healthy volunteers. Healthy male volunteers were included and randomized. Group 1 (n = 8) received metformin, group 2 (n = 7) followed a hypocaloric diet (1500 kcal/day), superposed on a moderate iodine restriction diet; Baseline measurements included thyroid iodine-123 (I-123) uptake and TSH, fT4, T3 and rT3 levels. After two weeks, thyroid function and I-123 uptake measurements were repeated. Baseline characteristics were similar between groups. Levels of TSH and fT4 were similar after each intervention. T3 decreased after hypocaloric diet and metformin (-0.2 ± 0.19 nmol/L, p = 0.0327; respectively -0.13 ± 0.13 nmol/L, p = 0.0282), resulting in decreased T3/rT3 ratios. There was no significant difference in thyroid I-123 uptake after each intervention. In conclusion, metformin treatment and hypocaloric diet resulted in a significant decrease in T3 levels and T3/rT3 ratios in healthy volunteers, without significant effects on thyroid iodine uptake. We found no indications that metformin or hypocaloric diet will have clinically relevant effects on RAI uptake.

Radium-223 therapy was registered in 2013 as a new life-prolonging therapeutic option for patients with symptomatic bone metastatic castration-resistant prostate cancer after the phase 3 ALSYMPCA study. Postregistration reports on the use of radium-223 in real-world populations demonstrate that appropriate selection of patients for radium-223 therapy is challenging. While primarily retrospective and post hoc studies identified prognostic variables associated with overall survival, validated predictive biomarkers are still lacking. Important pretherapeutic prognostic variables include the number of prior therapies, baseline Eastern Cooperative Oncology Group performance status, baseline extent of bone metastatic disease, and baseline alkaline phosphatase, prostate-specific antigen, and lactate dehydrogenase levels. We reviewed the currently available literature to provide recommendations on patient selection for radium-223 therapy in patients with bone metastatic castration-resistant prostate cancer. In addition, the recent evidence from the report of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee regarding the restricted use of radium-223 after interim data analysis of the ERA-223 trial has been incorporated into our recommendations. Future perspectives are also discussed, including radium-223 re-treatment, the use of concomitant therapies, and the implementation of pretherapeutic molecular analysis for treatment stratification., (Copyright © 2018 Elsevier Inc. All rights reserved.)

On successful completion of this activity one should be able to judge the prognosis of patients harboring metastasized differentiated thyroid cancer (DTC); identify suitable treatment regimens, taking into account the characteristics of the tumor and the patient's general condition; and know the basics of radioiodine treatment, tyrosine kinase treatment, and redifferentiation treatment for metastasized DTC., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: The aim of this study was to determine the diagnostic value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT) and magnetic resonance imaging (MRI) in diagnosing vertebral osteomyelitis., Methods: From November 2015 until December 2016, 32 patients with suspected vertebral osteomyelitis were prospectively included. All patients underwent both 18 F-FDG-PET/CT and MRI within 48 h. All images were independently reevaluated by two radiologists and two nuclear medicine physicians who were blinded to each others' image interpretation. 18 F-FDG-PET/CT and MRI were compared to the clinical diagnosis according to international guidelines., Results: For 18 F-FDG-PET/CT, sensitivity, specificity, PPV, and NPV in diagnosing vertebral osteomyelitis were 100%, 83.3%, 90.9%, and 100%, respectively. For MRI, sensitivity, specificity, PPV, and NPV were 100%, 91.7%, 95.2%, and 100%, respectively. MRI detected more epidural/spinal abscesses. An important advantage of 18 F-FDG-PET/CT is the detection of metastatic infection (16 patients, 50.0%)., Conclusion: 18 F-FDG-PET/CT and MRI are both necessary techniques in diagnosing vertebral osteomyelitis. An important advantage of 18 F-FDG-PET/CT is the visualization of metastatic infection, especially in patients with bacteremia. MRI is more sensitive in detection of small epidural abscesses.

Purpose: To identify pre-therapeutic variables associated with overall survival (OS) in patients treated with Ra., Methods: Data from 45 CRPC patients treated with Ra were retrospectively analyzed. All patients who received at least one Ra injection were included in the study. Cox proportional hazard regression models were used to estimate hazard ratio's (HR) and to test for association., Results: Twenty-one patients (47%) received six Ra injections and 24 patients (53%) received one to five Ra injections. Median OS since start of Ra was 13.0 months (95% confidence interval (CI) 8.2-17.8). Patients who completed Ra therapy had a median OS of 19.7 months (95% CI 14.9-24.6), while patients who received one to five Ra injections had a median OS of 5.9 months (95% CI 3.8-8.1; P < 0.001).Univariable analysis showed poor baseline ECOG performance status (PS), baseline opioid use, lowered baseline hemoglobin, and elevated prostate-specific antigen, alkaline phosphatase and lactate dehydrogenase (LD) levels were significantly associated with OS. Multivariable Cox regression analysis demonstrated that poor baseline ECOG PS (HR 10.6) and high LD levels (HR 7.7) were pre-therapeutic variables that predicted poor OS., Conclusions: In a multivariable Cox regression model, good baseline ECOG PS and low LD levels were significantly associated with longer OS in patients treated with Ra. These variables may be used for stratification of CRPC patients for Ra therapy. Prospective studies to evaluate these variables are warranted, to develop a nomogram to select patients properly. In this retrospective study, predictors of overall survival in 45 metastatic castration-resistant prostate cancer patients treated with Ra therapy were evaluated. Baseline ECOG performance status and lactate dehydrogenase levels turned out to be significant in a multivariable prediction model for overall survival.

Metastatic infection is an important complication of Staphylococcus aureus bacteremia (SAB). Early diagnosis of metastatic infection is crucial, because specific treatment is required. However, metastatic infection can be asymptomatic and difficult to detect. In this study, we investigated the role of 18 F-FDG PET/CT in patients with SAB for detection of metastatic infection and its consequences for treatment and outcome. Methods: All patients with SAB at Radboud University Medical Center were included between January 2013 and April 2016. Clinical data and results of 18 F-FDG PET/CT and other imaging techniques, including echocardiography, were collected. Primary outcomes were newly diagnosed metastatic infection by 18 F-FDG PET/CT, subsequent treatment modifications, and patient outcome. Results: A total of 184 patients were included, and 18 F-FDG PET/CT was performed in 105 patients, of whom 99 had a high-risk bacteremia. 18 F-FDG PET/CT detected metastatic infectious foci in 73.7% of these high-risk patients. In 71.2% of patients with metastatic infection, no signs and symptoms suggesting metastatic complications were present before 18 F-FDG PET/CT was performed. 18 F-FDG PET/CT led to a total of 104 treatment modifications in 74 patients. Three-month mortality was higher in high-risk bacteremia patients without 18 F-FDG PET/CT performed than in those in whom 18 F-FDG PET/CT was performed (32.7% vs. 12.4%, P = 0.003). In multivariate analysis, 18 F-FDG PET/CT was the only factor independently associated with reduced mortality ( P = 0.005; odds ratio, 0.204; 95% confidence interval, 0.066-0.624). A higher comorbidity score was independently associated with increased mortality ( P = 0.003; odds ratio, 1.254; 95% confidence interval, 1.078-1.457). Conclusion: 18 F-FDG PET/CT is a valuable technique for early detection of metastatic infectious foci, often leading to treatment modification. Performing 18 F-FDG PET/CT is associated with significantly reduced 3-mo mortality., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Objectives: Thyroglobulin (Tg) measurements are used to monitor for residual thyroid tissue in patients with differentiated thyroid cancer (DTC) after thyroidectomy and radioiodine ablative therapy. In recent years highly sensitive Tg assays have been developed. In this study the analytical performance of the new Roche Elecsys Tg II assay was evaluated and compared with the well documented Access2 Tg assay (Beckman-Coulter)., Design and Methods: Analytical performance was examined using various Clinical and Laboratory Standards Institute (CLSI) evaluation protocols. Tg negative patient sera were used to establish an upper reference limit (URL) for the Elecsys Tg II assay., Results: Non-linearity, drift and carry-over according to CLSI EP10 and EP6 in a measuring range of 0.04-500 ng/mL were non-significant. Total precision according to CLSI EP5 was 10% at a Tg concentration of 0.08 ng/mL. A patient serum comparison performed according to a modified CLSI EP9 protocol showed a significant difference of a factor of approximately 1.4, despite using an identical CRM calibrator. The Elecsys Tg II assay measured Tg with a two-fold higher sensitivity than the Access2 assay. Finally, using human sera without Tg, an URL of 0.05 ng/mL was determined., Conclusions: In our hands the highly sensitive Elecsys Tg II assay shows a good analytical performance and a higher sensitivity compared to the Access2 Tg assay. An URL of 0.05 ng/mL for the Elecsys Tg II assay was determined which may improve the clinical utility of the assay for the detection of residual DTC or disease recurrence.