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Simple Summary: 18F-FDG PET/MRI is superior in nodal staging in patients with newly diagnosed breast cancer compared to conventional imaging by sonography, CT and bone scintigraphy and compared to MRI alone. 18F-FDG PET/MRI correctly detects not only nodal positive status in significantly more patients, but also classifies this positive nodal status into the correct clinical lymph node stage more often than conventional imaging and than MRI alone. 18F-FDG PET/MRI may be a future tool as a potential alternative to invasive staging procedures for assessing the N stage. In terms of the detection of distant metastases, there is a trend towards a higher sensitivity of MRI and 18F-FDG PET/MRI, which, however, did not show significant differences compared with conventional staging by CT and bone scintigraphy. This demonstrates that the imaging currently recommended by multiple guidelines seems to be sufficient for the staging of distant metastases. Background: This study compares the diagnostic potential of conventional staging (computed tomography (CT), axillary sonography and bone scintigraphy), whole-body magnetic resonance imaging (MRI) and whole-body 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/)MRI for N and M staging in newly diagnosed breast cancer. Methods: A total of 208 patients with newly diagnosed breast cancer were prospectively included in this study and underwent contrast-enhanced thoracoabdominal CT, bone scintigraphy and axillary sonography as well as contrast-enhanced whole-body 18F-FDG PET/MRI. The datasets were analyzed with respect to lesion localization and characterization. Histopathology and follow-up imaging served as the reference standard. A McNemar test was used to compare the diagnostic performance of conventional staging, MRI and 18F-FDG PET/MRI and a Wilcoxon test was used to compare differences in true positive findings for nodal staging. Results: Conventional staging determined the N stage with a sensitivity of 80.9%, a specificity of 99.2%, a PPV (positive predictive value) of 98.6% and a NPV (negative predictive value) of 87.4%. The corresponding results for MRI were 79.6%, 100%, 100% and 87.0%, and were 86.5%, 94.1%, 91.7% and 90.3% for 18F-FDG PET/MRI. 18F-FDG PET/MRI was significantly more sensitive in determining malignant lymph nodes than conventional imaging and MRI (p < 0.0001 and p = 0.0005). Furthermore, 18F-FDG PET/MRI accurately estimated the clinical lymph node stage in significantly more cases than conventional imaging and MRI (each p < 0.05). Sensitivity, specificity, PPV and NPV for the M stage in conventional staging were 83.3%, 98.5%, 76.9% and 98.9%, respectively. The corresponding results for both MRI and 18F-FDG PET/MRI were 100.0%, 98.5%, 80.0% and 100.0%. No significant differences between the imaging modalities were seen for the staging of distant metastases. Conclusions:18F-FDG PET/MRI detects lymph node metastases in significantly more patients and estimates clinical lymph node stage more accurately than conventional imaging and MRI. No significant differences were found between imaging modalities with respect to the detection of distant metastases. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA)-targeting radio-ligand therapy with beta-emitting 177Lutetium has already been investigated in several early phase dosimetry studies, demonstrated promising results in phase-2, and recently the first phase-3 trial finished recruitment. In contrast, PSMA-targeting alpha-particle therapy (TAT) has only been evaluated in few preclinical experiments, preliminary dosimetry attempts and some retrospective observational studies, yet. First clinical experience with 225Ac-PSMA-617 demonstrates promising antitumor activity with a 63%-70% PSA>50%-response rate, 10-15 months duration of response and complete remissions in approximately ten percent of patients, some of them with enduring relapse-free survival. Nevertheless, without comparative trials there is no prove whether, applied in identical clinical situations, 225Ac-PSMA-617 is really more efficiently than 177Lu-PSMA-617 or vice versa. However, there is some good rationale, that PSMA-TAT might have advantages in particular clinical indications. This includes patients with diffuse type red-marrow infiltration by reducing off-target radiation to surrounding cells; ablation of micrometastases after favorable response to other previous therapy or someday in early stage disease. Also treatment escalation of patients, either with poor response to 177Lu-PSMA or harboring adverse prognostic biomarkers, appears promising. In preclinical research, alpha-radiation demonstrated stronger induction of abscopal effects than beta-radiation; favoring its usage as a combination partner with immunotherapies. So, further evaluation of PSMA-TAT is definitely warranted. Recently, de-escalated treatment protocols and application of 225Ac/177Lu-PSMA "cocktail"-regimens improved the tolerability of 225Ac-PSMA-617 TAT, reducing the risk for development dry-mouth syndrome. This opens new avenues for future application in earlier stage disease. [ABSTRACT FROM AUTHOR]

Purpose: The main side effect of prostate-specific membrane antigen targeting alpha therapy (PSMA TAT) is dry mouth syndrome. Inflammation of the salivary glands and consequent reduced salivary function have been reported in patients after radioiodine therapy. The beneficial effects of sialendoscopy on radiation-induced inflammation in tissue are well known. Thus sialendoscopy with dilatation, saline irrigation and steroid injections (prednisolone) was performed before and after 225Ac-PSMA-617 TAT to reduce inflammatory effects in the salivary glands and to improve or prevent xerostomia.Methods: Eleven men with metastatic castration-resistant prostate cancer (mean age 68.5 years, range 58-80 years) underwent sialendoscopy, dilatation, saline irrigation and steroid injection of both submandibular and both parotid glands before or after every cycle of 225Ac-PSMA-617 TAT. Sialendoscopy and steroid injection were performed by a senior ENT physician. Quality of life was evaluated using two health-related quality of life (HRQOL) questionnaires, the Xerostomia Questionnaire (XQ) and the Xerostomia Inventory (XI) before and 3 months after the intervention.Results: In all 11 patients both parotid and both submandibular glands were affected by radiation sialadenitis and sialendoscopy was performed. The patients experienced no complications after sialendoscopy, and showed a significant improvement in HRQOL as measured using the XQ and XI. After sialendoscopy the XQ score decreased significantly from 77.7 ± 13.6 to 42.7 ± 14.8 (p = 0.003) and the XI score decreased from 44.5 ± 6.9 to 25.8 ± 12.8 (p = 0.003). Due to the limited number of patients we only report tendencies.Conclusion: Sialendoscopy with dilatation, saline irrigation and steroid injection had beneficial effects on salivary gland function and HRQOL in patients undergoing 225Ac-PSMA-617 RLT. However, even with sialadenoscopic support after multiple cycles of TAT, salivary gland function was reduced and xerostomia was present. Therefore, not only inflammation but also the direct effect of radiation is a putative cause of dry mouth. Further research is necessary to determine the main side effects of PSMA TAT. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor-associated macrophages (TAMs) play numerous roles in cancer biology and are an important component of the relationship between immune system response and tumor progression. Several new immunotherapy techniques have been developed that target TAMs and are under investigation in both clinical and preclinical settings. Despite this surge of new immunotherapy techniques, a means to specifically and quantifiably measure the presence of TAMs to ensure the viability of these therapies, has yet to be widely investigated. The development of molecular imaging agents that target TAMs provides a path to noninvasively gain valuable insight into the molecular and functional characteristics of the tumor microenvironment and how the immune response facilitates the progression of cancer or therapy response. This article reviews published preclinical and clinical research in the imaging of TAMs through Positron Emission Tomography (PET). Macrophages are large phagocytic cells that can be classified as a type of white blood cell and may be either mobile or stationary in tissues. The presence of macrophages in essentially every major disease makes them attractive candidates to serve as therapeutic targets and diagnostic biomarkers. Macrophages that are found in the microenvironment of solid tumors are referred to as tumor-associated macrophages (TAMs) and have been shown to influence chemoresistance, immune regulation, tumor initiation and tumor growth. The imaging of TAMs through Positron Emission Tomography (PET) has the potential to provide valuable information on cancer biology, tumor progression, and response to therapy. This review will highlight the versatility of macrophage imaging in cancer through the use of PET. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeted radionuclide therapy (TRT) aims to selectively deliver radioactive molecules to tumor cells. For this purpose, we deliver iodine-131 ([131I]) to melanoma cells by using our laboratory-developed melanin specific radiotracer, the ICF01012. Approximately 50% and 20%–30% of human melanomas have activating mutation in BRAF or NRAS genes, respectively. These mutations lead to a constitutive activation of the MAPK/ERK pathway, which is known to be involved in tumor cells' radioresistance. In this work, we showed using 3D in vitro tumor models, an additive efficiency of combining [131I]ICF01012-TRT and MAPK/ERK inhibitors in BRAF- and NRAS-mutant melanoma cells. In mice bearing NRASQ61K-mutated melanoma, TRT induced an impressive decrease in tumor growth, as well as a highly extended survival. Additionally, we showed that TRT reduces the metastatic capacity of melanoma, especially through lymph-node dissemination. These results are therefore of great interest, especially for patients with NRAS-mutant metastatic melanoma who currently lack specific efficient therapies. Purpose: To assess the efficiency of targeted radionuclide therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor radioresistance. Methods: For TRT, we used a melanin radiotracer ([131I]ICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAFV600E SK-MEL-3, murine NRASQ61K 1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRASQ61K 1007 syngeneic model. Results: TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. In mice bearing NRASQ61K 1007 melanoma, [131I]ICF01012 induced a significant extended survival (92 vs. 44 days, p < 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation. Conclusion: Our data suggest that [131I]ICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that [131I]ICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: NeoB is undergoing evaluation as a novel theragnostic agent—that is, that it can be employed either for the diagnosis of tumor expressing gastrin-releasing peptide receptor (GRPR) using nuclear imaging, or for the therapy of such GRPR positive tumors using internal radiotherapy. The switch from diagnosis to therapy simply rely on the choice of the radioisotope that is coupled to NeoB. The aim of our study was to investigate—for the first time—the potency of NeoB for tumor therapy once labeled with the beta- emitter Lu-177. This study has been conducted in mice bearing human Gastrointestinal Stromal Tumors (GIST). [177Lu]Lu-NeoB was found to accumulate in the tumor, with only minimal retention in off-target organs. Consequently, mice treated with therapeutic doses of [177Lu]Lu-NeoB (37MBq/week for three weeks) exhibited tumor regression and therefore long term survival in comparison to the control untreated mice. NeoB is a radiotracer targeting the gastrin-releasing peptide receptor (GRPR), a G-protein–coupled receptor expressed in various cancers. The aim of the present study was to evaluate the biodistribution and efficacy of this new therapeutic agent in Gastrointestinal Stromal Tumors (GIST). Eighty-two SCID mice bearing GIST-882 tumors were employed. [177Lu]Lu-NeoB biodistribution was evaluated up to seven days by organ sampling (200 pmol/0.8 MBq, i.v.). For efficacy evaluation, mice received either saline, 400 pmol or 800 pmol of [177Lu]Lu-NeoB (37MBq, 1/w, 3 w, i.v.). SPECT/CT imaging was performed at 24 h, and tumor volume was determined up to 100 days. Elevated and specific [177Lu]Lu-NeoB uptake was found in the GIST tumor, as demonstrated by in vivo competition (19.1 ± 3.9 %ID/g vs. 0.3 ± 0.1 %ID/g at 4h). [177Lu]Lu-NeoB tumor retention (half-life of 40.2 h) resulted in elevated tumor-to-background ratios. Tumor volumes were significantly reduced in both treated groups (p < 0.01), even leading to complete tumor regression at the 400 pmol dose. [177Lu]Lu-NeoB exhibited excellent pharmacokinetics with elevated and prolonged tumor uptake and low uptake in non-target organs such as pancreas. The potential of this new theragnostic agent in different indications, including GIST, is under evaluation in the FIH [177Lu]Lu-NeoB clinical trial. [ABSTRACT FROM AUTHOR]

Competing Interests: All authors declare that they have no conflicts of interest regarding this article. Disclosures: Frederik L. Giesel is a consultant at ABX, SOFIE Biosciences and Telix and holds small patent interests in F18-PSMA-1007 and FAP ligands.

The aim of this work is to evaluate our clinical real-world data obtained with 225 Ac-PSMA-617 (AcPSMA), which were acquired under compassionate care regulations in patients with advanced-stage prostate cancer. The objective parameters that could be derived from this evaluation are compared with previous literature about AcPSMA and 177 Lu-PSMA-617 (LuPSMA). Methods: The medical files of all patients who had received AcPSMA on an individual patient basis at the Heidelberg University Hospital since January 2014 were analyzed retrospectively. Previously published patients were excluded. The remaining patients were tailored into 2 subgroups with different treatment strategies: group 1 received AcPSMA as a deescalated monotherapy, and group 2 received LuPSMA plus AcPSMA as a cocktail regimen. Baseline characteristics, serum prostate-specific antigen (PSA) response, and overall survival were compared with the most appropriate historical controls. Results: Of 287 patients treated, 54 were excluded because of previous publication and 233 were evaluated, 104 of whom received AcPSMA monotherapy (median, 6 MBq). In this group, 55 patients (53%) presented with a best PSA response of at least 50%. The other 129 patients received a cocktail therapy of AcPSMA (median, 4 MBq) plus LuPSMA (4 GBq). In this group, a best PSA response of at least 50% was observed in 74 patients (57%). The median overall survival in the monogroup was 9 mo and in the cocktail group was 15 mo. If adjusted for prognostic baseline characteristics, the efficacy of both regimens was not significantly different. Conclusion: Deescalated treatment activities of AcPSMA or AcPSMA and LuPSMA cocktail regimens present better tolerability with regard to xerostomia than previous regimens of at least 100 kBq/kg while retaining high antitumor activity in poor-prognosis prostate cancer patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Purpose: In patients with malignant lymphoma, disease activity is recommended to be assessed by FDG-PET/CT and the Deauville five-point scale (5-PS). The purpose of this study was to explore the potential of iodine concentration measured in contrast-enhanced dual-layer spectral detector CT (SDCT) as an alternative surrogate parameter for lymphoma disease activity by investigating its correlation with maximum standardized uptake values (SUV max ) and 5-PS., Materials and Methods: 25 patients were retrospectively analyzed. Contrast-enhanced SDCT and FDG-PET/CT were performed in the same treatment interval within at most 3 months. CT attenuation values (AV), absolute iodine concentrations (aIC), and normalized iodine concentrations (nIC) of lymphoma lesions were correlated with SUV max using Spearman's rank correlation coefficient. The performance of aIC and nIC to detect lymphoma activity (defined as 5-PS > 3) was determined using ROC curves., Results: 60 lesions were analyzed, and 31 lesions were considered active. AV, aIC, and nIC all correlated significantly with SUV max . The strongest correlation (Spearman ρ = 0.71; p < 0.001) and highest area under the ROC curve (AUROC) for detecting lymphoma activity were observed for nIC normalized to inferior vena cava enhancement (AUROC = 0.866). The latter provided sensitivity, specificity, and diagnostic accuracy of 87 %, 75 %, and 80 %, respectively, at a threshold of 0.20. ROC analysis for AV (AUROC = 0.834) and aIC (AUROC = 0.853) yielded similar results., Conclusion: In malignant lymphomas, there is a significant correlation between metabolic activity as assessed by FDG-PET/CT and iodine concentration as assessed by SDCT. Iodine concentration shows promising diagnostic performance for detecting lymphoma activity and may represent a potential imaging biomarker., Key Points: · Iodine concentration correlates significantly with SUVmax in lymphoma patients. · Iodine concentration may represent a potential imaging biomarker for detecting lymphoma activity. · Normalization of iodine concentration improves diagnostic performance of iodine concentration., Citation Format: · Gehling K, Mokry T, Do TD et al. Dual-Layer Spectral Detector CT in Comparison with FDG-PET/CT for the Assessment of Lymphoma Activity. Fortschr Röntgenstr 2022; 194: 747 - 754., Competing Interests: The authors of this manuscript declare relationships with the following companies:K. Gehling: NoneT. Mokry: NoneT. D. Do: Speakers’ bureau Philips HealthcareF. L. Giesel: NoneS. Dietrich: NoneU. Haberkorn: NoneH.-U. Kauczor: Research grant and speakers’ bureau Philips HealthcareT. F. Weber: None, (Thieme. All rights reserved.)

Neuroendocrinelike transdifferentiation of prostate cancer adenocarcinomas correlates with serum levels of chromogranin A (CgA) and drives treatment resistance. The aim of this work was to evaluate whether CgA can serve as a response predictor for 177 Lu-prostate-specific membrane antigen 617 (PSMA) radioligand therapy (RLT) in comparison with the established tumor markers. Methods: One hundred consecutive patients with metastasized castration-resistant prostate cancer scheduled for PSMA RLT were evaluated for prostate-specific antigen (PSA), lactate dehydrogenase (LDH), and CgA at baseline and in follow-up of PSMA RLT. Tumor uptake of PSMA ligand, a known predictive marker for response, was assessed as a control variable. Results: From the 100 evaluated patients, 35 had partial remission, 16 stable disease, 15 mixed response, and 36 progression of disease. Tumor uptake above salivary gland uptake translated into partial remission, with an odds ratio (OR) of 60.265 (95% confidence interval [CI], 5.038-720.922). Elevated LDH implied a reduced chance for partial remission, with an OR of 0.094 (95% CI, 0.017-0.518), but increased the frequency of progressive disease (OR, 2.717; 95% CI, 1.391-5.304). All patients who achieved partial remission had a normal baseline LDH. Factor-2 elevation of CgA increased the risk for progression, with an OR of 3.089 (95% CI, 1.302-7.332). Baseline PSA had no prognostic value for response prediction. Conclusion: In our cohort, baseline PSA had no prognostic value for response prediction. LDH was the marker with the strongest prognostic value, and elevated LDH increased the risk for progression of disease under PSMA RLT. Elevated CgA demonstrated a moderate impact as a negative prognostic marker in general but was explicitly related to the presence of liver metastases. Well in line with the literature, sufficient tumor uptake is a prerequisite to achieve tumor response., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Because of different physical properties, the β-emitters 177 Lu and 90 Y offer specific radiologic-biologic advantages in dedicated clinical situations. Our objective was to introduce 90 Y-labeled prostate-specific membrane antigen (PSMA)-617 to clinical application, providing additional avenues for personalized medicine. Here, we present our dosimetry estimate for 90 Y-PSMA-617, report first clinical experiences, and discuss the advantages and drawbacks of varying the β-emitter in PSMA-targeting radioligand therapy. Methods: To approximate radiation dosimetry, 4 patients with metastatic castration-resistant prostate cancer underwent serially performed imaging up to 1 wk after 177 Lu-PSMA-617 therapy. Time-activity curves were extrapolated to the half-life of 90 Y, and OLINDA was used to calculate the dosimetry estimate. In clinical practice, 11 patients with PSMA-positive lymph-nodal bulk disease were stratified to receive 90 Y-PSMA-617 radioligand therapy (mean, 3.2 GBq; range, 2.8-3.7 GBq); afterward, safety lab tests, prostate-specific antigen (PSA) response, and clinical findings were thoroughly followed. Results: The projected dosimetry for 90 Y-PSMA-617 estimated a mean kidney dose of 3.47 ± 1.40 Gy/GBq, red marrow dose of 0.11 ± 0.04 Gy/GBq, and salivary gland dose of 5.57 ± 1.34 Gy/GBq; randomly chosen metastases were approximated with 22.8 ± 16.10 Gy/GBq. The observed acute hematologic toxicity (5 cases of leukopenia and 2 of thrombocytopenia, all grade 1 or 2) and clinical side effects (2 cases of transient xerostomia and 1 of nausea, all grade 1 or 2), as well as PSA response (any PSA response, 7/11 patients; >50% PSA decline, 5/11 patients), were comparable to 177 Lu-PSMA-617 literature data. Conclusion: A factor 3-4 lower treatment activity for 90 Y-PSMA-617 translates into a comparable dosimetry estimate and clinical findings similar to those of 177 Lu-PSMA-617. However, safety was demonstrated only for patients with oligometastatic disease. Further studies are needed to evaluate its potential in patients with more disseminated bone involvement or visceral metastasis., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

The objective of this study was to evaluate the rate of detection of bone metastases obtained with the prostate-specific membrane antigen (PSMA)-targeting tracer 99m Tc-MIP-1427, as opposed to conventional bone scanning with 99m Tc-methylene diphosphonate ( 99m Tc-MDP), in a collective of patients with known advanced-stage osseous metastasized prostate cancer. Methods: Twenty-one patients with known metastatic disease were staged with both conventional bone scanning and PSMA ligand scintigraphy within a time frame of less than 10 d. Imaging included planar whole-body scanning and SPECT or SPECT/CT with 2 bed positions 3 h after injection of either 500-750 MBq of 99m Tc-MIP-1427 or 600-750 MBq of 99m Tc-MDP. Lesions were scored as typical tumor, equivocal (benign/malignant), or normal within a standard reporting schema divided into defined anatomic regions. Masked and consensus readings were performed with sequential unmasking: planar scans first, then SPECT/CT, the best evaluable comparator (including MRI), PET/CT, and follow-up examinations. Results: Eleven patients had PSMA-positive visceral metastases that were predictably not diagnosed with conventional bone scanning. However, SPECT/CT was required to distinguish between soft-tissue uptake and overlapping bone. Four patients had extensive 99m Tc-MDP-negative bone marrow lesions. Seven patients had superscan characteristics on bone scans; in contrast, the extent of red marrow involvement was more evident on PSMA scans. Only 3 patients had equivalent results on bone scans and PSMA scans. In 16 patients, more suspect lesions were detected with PSMA scanning than with bone scanning. In 2 patients (10%), a PSMA-negative tumor phenotype was present. Conclusion: PSMA scanning provided a clear advantage over bone scanning by reducing the number of equivocal findings in most patients. SPECT/CT was pivotal for differentiating bone metastases from extraosseous tumor lesions., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)