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In this retrospective observational study we focused on the failure of prostate specific membrane antigenradioligand therapy. Therefore we evaluated the correlation between PSMA uptake on positron emission tomography/computed tomography and PSMA protein expression on IHC on fresh biopsy leasion of mCRPC-patients. Secondly we PSMA uptake on PET/CT, protein expression of PSMA and Ki67 were associated with the therapeutic outcome of PSMA-RLT. 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 PSMARLT 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. [ABSTRACT FROM AUTHOR]

Background: Transarterial radioembolization (TARE) is a treatment modality for liver tumors during which radioactive microspheres are injected into the hepatic arterial system. These microspheres distribute throughout the liver as a result of the blood flow until they are trapped in the arterioles because of their size. Holmium-166 (166Ho)-loaded microspheres used for TARE can be visualized and quantified with MRI, as holmium is a paramagnetic metal and locally increases the transverse relaxation rate R*2. The current 166Ho quantification method does not take regional differences in baseline R*2 values (such as between tumors and healthy tissue) into account, which intrinsically results in a systematic error in the estimated absorbed dose distribution. As this estimated absorbed dose distribution can be used to predict response to treatment of tumors and potential toxicity in healthy tissue, a high accuracy of absorbed dose estimation is required. Purpose: To evaluate pre-existing differences in R*2 distributions between tumor tissue and healthy tissue and assess the feasibility and accuracy of voxelwise subtraction-based ΔR*2 calculation for MRI-based dosimetry of holmium-166 transarterial radioembolization (166Ho TARE). Methods: MRI data obtained in six patients who underwent 166Ho TARE of the liver as part of a clinical study was retrospectively evaluated. Pretreatment differences in R*2 distributions between tumor tissue and healthy tissue were characterized. Same-day pre- and post-treatment R*2 maps were aligned using a deformable registration algorithm and subsequently subtracted to generate voxelwise R*2 maps and resultant absorbed dose maps. Image registration accuracy was quantified using the dice similarity coefficient (DSC), relative overlay (RO), and surface dice (=4 mm; SDSC). Voxelwise subtraction-based absorbed dose maps were quantitatively (root-mean-square error, RMSE) and visually compared to the current MRI-based mean subtraction method and routinely used SPECT-based dosimetry. Results: Pretreatment R*2 values were lower in tumors than in healthy liver tissue (mean 36.8 s-1 vs. 55.7 s-1, P = 0.004). Image registration improved the mean DSC of 0.83 (range: 0.70-0.88) to 0.95 (range: 0.92-0.97), mean RO of 0.71 (range 0.53-0.78) to 0.90 (range: 0.86-0.94), and mean SDSC =4 mm of 0.47 (range: 0.28-0.67) to 0.97 (range: 0.96-0.98). Voxelwise subtractionbased absorbed dose maps yielded a higher tumor-absorbed dose (median increase of 9.0%) and lower healthy liver-absorbed dose (median decrease of 13.8%) compared to the mean subtraction method. Voxelwise subtractionbased absorbed dose maps corresponded better to SPECT-based absorbed dose maps, reflected by a lower RMSE in three of six patients. Conclusions: Voxelwise subtraction presents a robust alternative method for MRI-based dosimetry of 166Ho microspheres that accounts for pre-existing R*2 differences, and appears to correspond better with SPECT-based dosimetry compared to the currently implemented mean subtraction method. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate-specific membrane antigen-direct radioligand therapy is a novel treatment for patients with castration-resistant prostate cancer. Yet, given the mode of action of PSMA-RLT, it is postulated that in early disease prostate cancer settings, e.g. hormone-sensitive, can also benefit from this treatment. In this retrospective study, the safety and efficacy was investigated of two PSMA-RLT schemes: monotherapy with 177Lu-PSMA and 177Lu-PSMA in combination with 225Ac-PSMA in twenty patients with early stage metastatic prostate cancer. The treatment appeared safe with limited and mainly transient side effects, also on a longer term follow-up, with encouraging efficacy for twenty early-stage metastatic prostate cancer. 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 [177Lu]Lu-PSMA- (177Lu-PSMA) or [225Ac]Ac-PSMA-radioligand treatment (225Ac-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 177Lu-PSMA and/or 225Ac-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 177Lu-PSMA radioligand and two patients received tandem treatment with both 177Lu-PSMA and 225Ac-PSMA radioligands. Patients received a median of 2 treatment cycles (range 1–6) and a median activity of 6.2 GBq 177Lu-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 225Ac-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. [ABSTRACT FROM AUTHOR]

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 99mTc‐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. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to determine the diagnostic value of 18F-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 18F-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. 18F-FDG-PET/CT and MRI were compared to the clinical diagnosis according to international guidelines. Results For 18F-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 18F-FDG-PET/CT is the detection of metastatic infection (16 patients, 50.0%). Conclusion 18F-FDG-PET/CT and MRI are both necessary techniques in diagnosing vertebral osteomyelitis. An important advantage of 18F-FDG-PET/CT is the visualization of metastatic infection, especially in patients with bacteremia. MRI is more sensitive in detection of small epidural abscesses. [ABSTRACT FROM AUTHOR]

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.

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.)

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.)