Prognostic Performance of RECIP 1.0 Based on [18F]PSMA-1007 PET in Prostate Cancer Patients Treated with [177Lu]Lu-PSMA I&T.

In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on 68Ga- and 18F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [18F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [18F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUVmean, SUVmax, PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 (P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [18F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression.

Prognostic role of quantitative [18F]FDG PET/CT parameters in adrenocortical carcinoma.

PURPOSE: We aimed to evaluate the prognostic potential of baseline [18F]FDG PET/CT for overall survival (OS) in patients with adrenocortical carcinoma (ACC). METHODS: We performed a retrospective analysis of 67 treatment-naïve ACC patients with available [18F]FDG PET/CT at time of initial diagnosis. Pretherapeutic PETs of primary tumors were manually segmented and quantitative parameters (maximum/mean/peak standardized uptake value (SUVmax/mean/peak), metabolic tumor volume (MTV) and tumor lesion glycolysis (TLG, defined as TV*SUVmean) were derived. Based on a visual read, absence (M0) or presence of metastatic disease (M1) were evaluated. Kaplan-Meier and Cox regression analyses were used to determine the prognostic value of the above mentioned markers on overall survival adjusted for established prognostic markers. RESULTS: 24/67 patients (36%) presented with M0 based on PET/CT, while the remaining 43/67 (64%) had M1-status. 32/67 patients died during follow-up and median OS was 48 months. In 12% of patients FDG-PET detected additional metastatic lesion not clearly visible by CT only. In univariable analysis, all quantitatively derived PET parameters failed to reach significance (P ≥ 0.1), and only PET/CT-based M1-status and Ki-67 were associated with increased mortality (M1: HR 13.89, 95% CI 4.15-86.32, P < 0.001; Ki-67 HR 1.29, 95% CI 1.16-1.42; P < 0.0001). Using multivariable Cox regression analyses, M1-status (HR 9.69, 95% CI 2.82-60.99) and Ki-67 index (HR 1.29, 95% CI 1.13-1.04; P < 0.05) remained significant associated with OS. CONCLUSION: In treatment-naïve ACC patients, the quantitative PET parameter failed to predict OS, but presence of metastases detected by [18F]FDG PET/CT and Ki-67 index were independently associated with shorter OS. Therefore, a simple visual PET-based read-out is of prognostic value at initial diagnosis, while time-consuming PET-based quantification can be omitted.

CXCR4-directed PET/CT with [68 Ga]Ga-pentixafor in solid tumors-a comprehensive analysis of imaging findings and comparison with histopathology.

BACKGROUND: C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in various solid cancers and can be targeted by CXCR4-directed molecular imaging. We aimed to characterize the in-vivo CXCR4 expression in patients affected with solid tumors, along with a comparison to ex-vivo findings. METHODS: A total 142 patients with 23 different histologically proven solid tumors were imaged with CXCR4-directed PET/CT using [68 Ga]Ga-pentixafor (total number of scans, 152). A semi-quantitative analysis of the CXCR4-positive tumor burden including maximum standardized uptake values (SUVmax) and target-to-background ratios (TBR) using blood pool was conducted. In addition, we performed histopathological staining to determine the immuno-reactive score (IRS) from patients' tumor tissue and investigated possible correlations with SUVmax (by providing Spearman's rho ρ). Based on imaging, we also assessed the eligibility for CXCR4-targeted radioligand therapy or non-radioactive CXCR4 inhibitory treatment (defined as more than five CXCR4-avid target lesions [TL] with SUVmax above 10). RESULTS: One hundred three of 152 (67.8%) scans showed discernible uptake above blood pool (TBR > 1) in 462 lesions (52 primary tumors and 410 metastases). Median TBR was 4.4 (1.05-24.98), thereby indicating high image contrast. The highest SUVmax was observed in ovarian cancer, followed by small cell lung cancer, desmoplastic small round cell tumor, and adrenocortical carcinoma. When comparing radiotracer accumulation between primary tumors and metastases for the entire cohort, comparable SUVmax was recorded (P > 0.999), except for pulmonal findings (P = 0.013), indicative for uniform CXCR4 expression among TL. For higher IRS, a weak, but statistically significant correlation with increased SUVmax was observed (ρ = 0.328; P = 0.018). In 42/103 (40.8%) scans, more than five TL were recorded, with 12/42 (28.6%) exhibiting SUVmax above 10, suggesting eligibility for CXCR4-targeted treatment in this subcohort. CONCLUSIONS: In a whole-body tumor read-out, a substantial portion of prevalent solid tumors demonstrated increased and uniform [68 Ga]Ga-pentixafor uptake, along with high image contrast. We also observed a respective link between in- and ex-vivo CXCR4 expression, suggesting high specificity of the PET agent. Last, a fraction of patients with [68 Ga]Ga-pentixafor-positive tumor burden were rendered potentially suitable for CXCR4-directed therapy.

Chemokine receptor-targeted PET/CT provides superior diagnostic performance in newly diagnosed marginal zone lymphoma patients: a head-to-head comparison with [18F]FDG.

BACKGROUND: In patients with marginal zone lymphoma (MZL), [18F]FDG PET/CT provided inconsistent diagnostic accuracy. C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in MZL and thus, may emerge as novel theranostic target. We aimed to evaluate the diagnostic performance of CXCR4-targeting [68Ga]Ga-PentixaFor when compared to [18F]FDG PET/CT in MZL. METHODS: Thirty-two untreated MZL patients (nodal, n = 17; extranodal, n = 13; splenic, n = 2) received [68Ga]Ga-PentixaFor and [18F]FDG PET/CT within median 2 days. We performed a visual and quantitative analysis of the total lymphoma volume by measuring maximum/peak standardized uptake values (SUVmax/peak), and calculating target-to-background ratios (TBR, defined as lesion-based SUVpeak divided by SUVmean from blood pool). Visual comparisons for both radiotracers were carried out for all target lesions (TL), and quantitative analysis of concordant TL evident on both scans. Last, MZL subtype analyses were also conducted. RESULTS: On a patient-based level, [68Ga]Ga-PentixaFor identified MZL manifestations in 32 (100%) subjects (vs. [18F]FDG, 25/32 [78.1%]). Of the 256 identified TL, 127/256 (49.6%) manifestations were evident only on CXCR4-directed imaging, while only 7/256 (2.7%) were identified on [18F]FDG but missed by [68Ga]Ga-PentixaFor. In the remaining 122/256 (47.7%) concordant TL, [68Ga]Ga-PentixaFor consistently provided increased metrics when compared to [18F]FDG: SUVmax, 10.3 (range, 2.53-37.2) vs. 5.72 (2.32-37.0); SUVpeak, 6.23 (1.58-25.7) vs. 3.87 (1.54-27.7); P < 0.01, respectively. Concordant TL TBR on [68Ga]Ga-PentixaFor (median, 3.85; range, 1.05-16.0) was also approximately 1.8-fold higher relative to [18F]FDG (median, 2.08; range, 0.81-28.8; P < 0.01). Those findings on image contrast, however, were driven by nodal MZL (P < 0.01), and just missed significance for extranodal MZL (P = 0.06). CONCLUSIONS: In newly diagnosed MZL patients, [68Ga]Ga-PentixaFor identified more sites of disease when compared to [18F]FDG, irrespective of MZL subtype. Quantitative PET parameters including TBR were also higher on [68Ga]Ga-PentixaFor PET/CT, suggesting improved diagnostic read-out using chemokine receptor-targeted imaging.

Long-Term Nephrotoxicity of 177Lu-PSMA Radioligand Therapy.

ß-emitting 177Lu targeting prostate-specific membrane antigen (PSMA) is an approved treatment option for metastatic castration-resistant prostate cancer. Data on its long-term nephrotoxicity are sparse. This study aimed to retrospectively evaluate post-177Lu-PSMA estimated glomerular filtration rate (eGFR) dynamics for at least 12 mo in a cohort of metastatic castration-resistant prostate cancer patients. Methods: The institutional databases of 3 German tertiary referral centers identified 106 patients who underwent at least 4 cycles of 177Lu-PSMA and had at least 12 mo of eGFR follow-up data. eGFR (by the Chronic Kidney Disease Epidemiology Collaboration formula) at 3, 6, and 12 mo after 177Lu-PSMA radioligand therapy was estimated using monoexponentially fitted curves through available eGFR data. eGFR changes were grouped (≥15%-<30%, moderate; ≥30%-<40%, severe; and ≥40%, very severe). Associations between eGFR changes (%) and nephrotoxic risk factors, prior treatment lines, and number of 177Lu-PSMA cycles were analyzed using multivariable linear regression. Results: At least moderate eGFR decreases were present in 45% (48/106) of patients; of those, nearly half (23/48) had a severe or very severe eGFR decrease. A higher number of risk factors at baseline (-4.51, P = 0.03) was associated with a greater eGFR decrease. Limitations of the study were the retrospective design, lack of a control group, and limited number of patients with a follow-up longer than 1 y. Conclusion: A considerable proportion of patients may experience moderate or severe decreases in eGFR 1 y from initiation of 177Lu-PSMA. A higher number of risk factors at baseline seems to aggravate loss of renal function. Further prospective trials are warranted to estimate the nephrotoxic potential of 177Lu-PSMA.

Comparison of PET/CT-based eligibility according to VISION and TheraP trial criteria in end-stage prostate cancer patients undergoing radioligand therapy.

BACKGROUND: Two randomized clinical trials demonstrated the efficacy of prostate-specific membrane antigen (PSMA) radioligand therapy (PSMA RLT) in metastatic castration-resistant prostate cancer (mCRPC). While the VISION trial used criteria within PSMA PET/CT for inclusion, the TheraP trial used dual tracer imaging including FDG PET/CT. Therefore, we investigated whether the application of the VISION criteria leads to a benefit in overall survival (OS) or progression-free survival (PFS) for men with mCRPC after PSMA RLT. METHODS: Thirty-five men with mCRPC who had received PSMA RLT as a last-line option and who had undergone pretherapeutic imaging with FDG and [68Ga]Ga-PSMA I&T or [18F]PSMA-1007 were studied. Therapeutic eligibility was retrospectively evaluated using the VISION and TheraP study criteria. RESULTS: 26 of 35 (74%) treated patients fulfilled the VISION criteria (= VISION+) and only 17 of 35 (49%) fulfilled the TheraP criteria (= TheraP+). Significantly reduced OS and PFS after PSMA RLT was observed in patients rated VISION- compared to VISION+ (OS: VISION-: 3 vs. VISION+: 12 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.0-9.1, p < 0.01; PFS: VISION-: 1 vs. VISION+: 5 months, HR 2.7, 95% CI 1.0-7.8, p < 0.01). For patients rated TheraP-, no significant difference in OS but in PFS was observed compared to TheraP+ patients (OS: TheraP-: 5.5 vs. TheraP+: 11 months, HR 1.6, 95% CI 0.8-3.3, p = 0.2; PFS: TheraP-: 1 vs. TheraP+: 6 months, HR 2.2, 95% CI 1.0-4.5, p < 0.01). CONCLUSION: Retrospective application of the inclusion criteria of the VISION study leads to a benefit in OS and PFS after PSMA RL, whereas TheraP criteria appear to be too strict in patients with end-stage prostate cancer. Thus, performing PSMA PET/CT including a contrast-enhanced CT as proposed in the VISION trial might be sufficient for treatment eligibility of end-stage prostate cancer patients.

PSMA PET/CT for Response Assessment of 177Lu-PSMA Therapy.

Prostate-specific membrane antigen (PSMA) PET/CT has been widely integrated into the management of prostate cancer (PCa) patients with biochemical recurrence, is increasingly used for initial staging in high-risk patients prior to surgery or to identify candidates for PSMA-targeted radioligand therapy (RLT). To date, monitoring response in PCa patients in prospective studies remains the domain of conventional imaging, such as magnetic resonance/CT or bone scintigraphy. With the increasing use of PSMA-targeted PET/CT in PCa, however, varying criteria based on molecular imaging have been established to define progressive disease, including "PSMA PET Progression Criteria," "Response evaluation criteria in PSMA PET/CT (RECIP 1.0)" or consensus statements of respective societies. In the present review, we will discuss the current status of PSMA PET/CT for response monitoring, focusing on PSMA RLT with [177Lu]Lu-labeled PSMA ligands, along with a head-to-head comparison of recently published response criteria.

Complete loss of E-cadherin expression in a rare case of metastatic malignant meningioma: a case report.

BACKGROUND: Hematogenous tumor spread of malignant meningiomas occurs very rarely but is associated with very poor prognosis. CASE PRESENTATION: We report an unusual case of a patient with a malignant meningioma who developed multiple metastases in bones, lungs and liver after initial complete resection of the primary tumor. After partial hepatic resection, specimens were histologically analyzed, and a complete loss of E-cadherin adhesion molecules was found. No oncogenic target mutations were found. The patient received a combination of conventional radiotherapy and peptide receptor radionuclide therapy (PRRT). Due to aggressive tumor behavior and rapid spread of metastases, the patient deceased after initiation of treatment. CONCLUSIONS: E-cadherin downregulation is associated with a higher probability of tumor invasion and distant metastasis formation in malignant meningioma. Up to now, the efficacy of systemic therapy, including PRRT, is very limited in malignant meningioma patients.

Chemokine Receptor PET/CT Provides Relevant Staging and Management Changes in Marginal Zone Lymphoma.

Because of gastral and extranodal manifestations, guideline-compatible diagnostic work-up of marginal zone lymphoma is challenging. We aimed to determine the diagnostic performance of C-X-C motif chemokine receptor 4 (CXCR4)-directed PET/CT compared with routine diagnostics, along with PET/CT-based retrospective changes in therapeutic management. The predictive potential of the PET signal was also investigated, and the number of patients eligible for CXCR4-directed radioligand therapy in a theranostic setting was determined. Methods: For this study, 100 marginal zone lymphoma patients underwent CXCR4-directed PET/CT. We compared staging results and treatment decisions from molecular imaging with respective results from guideline-compatible work-up (CT, esophagogastroduodenoscopy, and bone marrow-derived biopsy). Prognostic performance of the in vivo CXCR4 PET signal for progression-free survival (PFS) was evaluated (using log-rank test and Kaplan-Meier curves). Results: Relative to CT, CXCR4-directed imaging led to Ann Arbor (AA) staging changes for 27 of 100 patients (27.0%). Among those, clinically relevant upstaging from AA I or AA II to AA III or AA IV was observed for 23 patients (85.2%), along with respective changes in therapeutic management (escalation, 6/23 [26.1%]; deescalation, 17/23 [73.9%]). CXCR4 PET/CT yielded diagnostic accuracy of 94.0% relative to esophagogastroduodenoscopy and 76.8% relative to bone marrow-derived biopsy. An increased CXCR4 PET signal was linked to shorter PFS (707 d vs. median PFS not reached; hazard ratio, 3.18; 95% CI, 1.37-7.35; P = 0.01). CXCR4-directed radioligand therapy would have been feasible for 18 of 100 patients (18.0%). Conclusion: Relative to CT, CXCR4-directed PET/CT led to AA changes for 27 of 100 patients. Chemokine receptor PET/CT may improve current diagnostic algorithms and influence management relative to CT alone, potentially obviating some biopsies.

Somatostatin Receptor-Directed PET/CT Can Differentiate Between Different Subtypes of Head and Neck Paragangliomas.

BACKGROUND: Given their neuroendocrine origin, head and neck paragangliomas (HNPGLs) can be imaged with somatostatin receptor (SSTR)-directed PET/CT. We aimed to determine whether the in vivo PET signal can differentiate between varying HNPGL subtypes. PATIENTS AND METHODS: Fourteen patients with HNPGL received pretherapeutic SSTR-PET/CTs using 68 Ga-DOTATOC. Six (42.9%) patients had a jugular paraganglioma (PGL-J), 5 (35.7%) were diagnosed with carotid paraganglioma (PGL-Cs), and the remaining 3 patients (21.4%) had PGL-C with pathogenic SDHx germline variants (PGL-C-SDH). A visual and quantitative assessment of the primary tumor on SSTR-PET was performed, including SUV max and target-to-background ratio (TBR). Quantitative values were then compared between subgroups of patients affected with different HNPGL entities. RESULTS: On visual assessment, all primary HNPGLs could be identified on SSTR-PET/CT. Quantification of HNPGL revealed substantially elevated SUV max in PGL-J (101.7 ± 58.5) when compared with PGL-C-SDH (13.4 ± 5.6, P < 0.05), but not when compared with PGL-C (66.7 ± 27.3, P = 0.4; PGL-C vs PGL-C-SDH, P = 0.2). TBR of PGL-J (202.9 ± 82.2), however, further differentiated between PGL-C (95.7 ± 45.4, P < 0.05) and PGL-C-SDH (20.4 ± 12.2, P < 0.01; PGL-C vs PGL-C-SDH, P = 0.3). Moreover, whole-body readout revealed metastases in 2/3 (66.7%) of PGL-C-SDH patients, with a single SSTR-expressing skeletal lesion in one subject and bipulmonary lesions in the other patient. CONCLUSIONS: In patients with HNPGL, SSTR-PET/CT identified the primary and metastatic disease and provides substantially elevated TBR, indicating excellent image contrast. PET-based quantification can also differentiate between varying HNPGL subtypes.

PSMA-PET improves deep learning-based automated CT kidney segmentation.

For dosimetry of radiopharmaceutical therapies, it is essential to determine the volume of relevant structures exposed to therapeutic radiation. For many radiopharmaceuticals, the kidneys represent an important organ-at-risk. To reduce the time required for kidney segmentation, which is often still performed manually, numerous approaches have been presented in recent years to apply deep learning-based methods for CT-based automated segmentation. While the automatic segmentation methods presented so far have been based solely on CT information, the aim of this work is to examine the added value of incorporating PSMA-PET data in the automatic kidney segmentation. METHODS: A total of 108 PET/CT examinations (53 [68Ga]Ga-PSMA-I&T and 55 [18F]F-PSMA-1007 examinations) were grouped to create a reference data set of manual segmentations of the kidney. These segmentations were performed by a human examiner. For each subject, two segmentations were carried out: one CT-based (detailed) segmentation and one PET-based (coarser) segmentation. Five different u-net based approaches were applied to the data set to perform an automated segmentation of the kidney: CT images only, PET images only (coarse segmentation), a combination of CT and PET images, a combination of CT images and a PET-based coarse mask, and a CT image, which had been pre-segmented using a PET-based coarse mask. A quantitative assessment of these approaches was performed based on a test data set of 20 patients, including Dice score, volume deviation and average Hausdorff distance between automated and manual segmentations. Additionally, a visual evaluation of automated segmentations for 100 additional (i.e., exclusively automatically segmented) patients was performed by a nuclear physician. RESULTS: Out of all approaches, the best results were achieved by using CT images which had been pre-segmented using a PET-based coarse mask as input. In addition, this method performed significantly better than the segmentation based solely on CT, which was supported by the visual examination of the additional segmentations. In 80% of the cases, the segmentations created by exploiting the PET-based pre-segmentation were preferred by the nuclear physician. CONCLUSION: This study shows that deep-learning based kidney segmentation can be significantly improved through the addition of a PET-based pre-segmentation. The presented method was shown to be especially beneficial for kidneys with cysts or kidneys that are closely adjacent to other organs such as the spleen, liver or pancreas. In the future, this could lead to a considerable reduction in the time required for dosimetry calculations as well as an improvement in the results.

Prostate-specific Membrane Antigen Reporting and Data System Version 2.0.

Prostate-specific Membrane Antigen Reporting and Data System (PSMA-RADS) was introduced for standardized reporting, and PSMA-RADS version 1.0 allows classification of lesions based on their likelihood of representing a site of prostate cancer on PSMA-targeted positron emission tomography (PET). In recent years, this system has extensively been investigated. Increasing evidence has accumulated that the different categories reflect their actual meanings, such as true positivity in PSMA-RADS 4 and 5 lesions. Interobserver agreement studies demonstrated high concordance among a broad spectrum of 68Ga- or 18F-labeled, PSMA-directed radiotracers, even for less experienced readers. Moreover, this system has also been applied to challenging clinical scenarios and to assist in clinical decision-making, for example, to avoid overtreatment in oligometastatic disease. Nonetheless, with an increasing use of PSMA-RADS 1.0, this framework has shown not only benefits, but also limitations, for example, for follow-up assessment of locally treated lesions. Thus, we aimed to update the PSMA-RADS framework to include a refined set of categories in order to optimize lesion-level characterization and best assist in clinical decision-making (PSMA-RADS version 2.0).

Early biochemical and radiographic response after one cycle of [177Lu]Lu-PSMA I&T radioligand therapy in metastatic castration-resistant prostate cancer patients.

PURPOSE: The aim of this study was to investigate very early radiographic PSMA PET response after one cycle of [177Lu]Lu-PSMA I&T radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) and to assess its role in predicting overall response and survival. METHODS: This retrospective study enrolled 40 mCRPC patients who were treated with a median of 3 (2-9) [177Lu]Lu-PSMA I&T RLT cycles. Biochemical response was based on the relative change of serum PSA according to PCWG3 criteria, while radiographic response referred to the relative change of PSMA-derived total viable tumor volumes expressed as total lesion PSMA (TLP). RESULTS: After one cycle of RLT, biochemical partial response (PR) was seen in 8/40 (20.0%), stable disease (SD) in 22/40 (55.0%), and progressive disease (PD) in 10/40 (25%) patients. In PSMA PET, very early molecular PR was observed in 12 (30.0%), SD in 19 (47.5%), and PD in 9 (22.5%) subjects. The PSA and TLP nadir were achieved after a median of 1 (1-5) and 2 (1-6) cycles, respectively. Nineteen (47.5%) patients showed overall biochemical PR, 11 (27.5%) had SD, and 10 (25%) experienced PD. In PSMA-directed PET, 4 patients experienced molecular complete response (CR), 24 (60.0%) had PR, 4 (10.0%) SD, and 8 (20.0%) PD. Early biochemical or radiographic response was not associated with longer overall survival (OS). Overall biochemical responders had a nearly significantly longer median OS (22.7 months) than non-responders (14.4 months, p = 0.08). Early PSA progression was associated with shorter OS (12.2 months), compared to biochemical SD/PR (18.7 months, p = 0.09). CONCLUSION: In this retrospective cohort, there was no association between early PSMA PET radiographic response and overall survival; hence, treatment should not be prematurely discontinued. In contrast, early PSA progression after one cycle of [177Lu]Lu-PSMA I&T RLT was an indicator of overall progression and poor clinical outcome.

Lymphoma-Sink Effect in Marginal Zone Lymphoma Based on CXCR4-Targeted Molecular Imaging.

PURPOSE: Recent studies investigating a tumor-sink effect in solid tumors reported on decreasing uptake in normal organs in patients with higher tumor burden. This phenomenon, however, has not been evaluated yet for theranostic radiotracers applied to hematological neoplasms. As such, we aimed to determine a potential "lymphoma-sink effect" in patients with marginal zone lymphoma (MZL) imaged with C-X-C motif chemokine receptor (CXCR) 4-directed PET/CTs. PROCEDURES: We retrospectively analyzed 73 patients with MZL who underwent CXCR4-directed [68Ga]Ga-PentixaFor PET/CT. Normal unaffected organ uptake (heart, liver, spleen, bone marrow, kidneys) was quantified using volumes of interests (VOIs) and mean standardized uptake values (SUVmean) were derived. MZL manifestations were also segmented to determine the maximum and peak standardized uptake values SUV (SUVmax/peak) and volumetric parameters, including lymphoma volume (LV), and fractional lymphoma activity (FLA, defined as LV*SUVmean of lymphoma burden). This approach resulted in 666 VOIs to capture the entire MZL manifestation load. We used Spearman's rank correlations to determine associations between organ uptake and CXCR4-expressing lymphoma lesions. RESULTS: We recorded the following median SUVmean in normal organs: heart, 1.82 (range, 0.78-4.11); liver, 1.35 (range, 0.72-2.99); bone marrow, 2.36 (range, 1.12-4.83); kidneys, 3.04 (range, 2.01-6.37); spleen, 5.79 (range, 2.07-10.5). No relevant associations between organ radiotracer uptake and MZL manifestation were observed, neither for SUVmax (ρ ≤ 0.21, P ≥ 0.07), SUVpeak (ρ ≤ 0.20, P ≥ 0.09), LV (ρ ≤ 0.13, P ≥ 0.27), nor FLA (ρ ≤ 0.15, P ≥ 0.33). CONCLUSIONS: Investigating a lymphoma-sink effect in patients with hematological neoplasms, we observed no relevant associations between lymphoma burden and uptake in normal organs. Those observations may have therapeutic implications, e.g., for "cold" SDF1-pathway disrupting or "hot," CXCR4-directed radiolabeled drugs, as with higher lymphoma load, normal organ uptake seems to remain stable.

Elevated Body Mass Index Is Associated with Improved Overall Survival in Castration-Resistant Prostate Cancer Patients Undergoing Prostate-Specific Membrane Antigen-Directed Radioligand Therapy.

In patients with prostate cancer scheduled for systemic treatment, being overweight is linked to prolonged overall survival (OS), whereas sarcopenia is associated with shorter OS. We investigated fat-related and body composition parameters in patients undergoing prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) to assess their predictive value for OS. Methods: Body mass index (BMI, in kg/m2) and CT-derived body composition parameters (total, subcutaneous, visceral fat area, and psoas muscle area at the L3-L4 level) were determined for 171 patients scheduled for PSMA-directed RLT. After normalization for stature, the psoas muscle index was used to define sarcopenia. Outcome analysis was performed using Kaplan-Meier curves and Cox regression including fat-related and other clinical parameters (Gleason score, C-reactive protein [CRP], lactate dehydrogenase [LDH], hemoglobin, and prostate-specific antigen levels). The Harrell C-index was used for goodness-of-fit analysis. Results: Sixty-five patients (38%) had sarcopenia, and 98 patients (57.3%) had increased BMI. Relative to the 8-mo OS in normal-weight men (BMI < 25), overweight men (25 ≥ BMI > 30) and obese men (BMI ≥ 30) achieved a longer OS of 14 mo (hazard ratio [HR], 0.63; 95% CI, 0.40-0.99; P = 0.03) and 13 mo (HR, 0.47; 95% CI, 0.29-0.77; P = 0.004), respectively. Sarcopenia showed no impact on OS (11 vs. 12 mo; HR, 1.4; 95% CI, 0.91-2.1; P = 0.09). Most of the body composition parameters were tightly linked to OS on univariable analyses, with the highest C-index for BMI. In multivariable analysis, a higher BMI (HR, 0.91; 95% CI, 0.86-0.97; P = 0.006), lower CRP (HR, 1.09; 95% CI, 1.03-1.14; P < 0.001), lower LDH (HR, 1.08; 95% CI, 1.03-1.14; P < 0.001), and longer interval between initial diagnosis and RLT (HR, 0.95; 95% CI, 0.91-0.99; P = 0.02) were significant predictors of OS. Conclusion: Increased fat reserves assessed by BMI, CRP, LDH, and interval between initial diagnosis and RLT, but not CT-derived body composition parameters, were relevant predictors for OS. As BMI can be altered, future research should investigate whether a high-calorie diet before or during PSMA RLT may improve OS.

SUVmean on baseline [18F]PSMA-1007 PET and clinical parameters are associated with survival in prostate cancer patients scheduled for [177Lu]Lu-PSMA I&T.

BACKGROUND: Quantification of [68 Ga]-labeled PSMA PET predicts response in patients with prostate cancer (PC) who undergo PSMA-targeted radioligand therapy (RLT). Given the increasing use [18F]-labeled radiotracers, we aimed to determine whether the uptake derived from [18F]PSMA-1007 PET can also identify responders and to assess its prognostic value relative to established clinical parameters. METHODS: We retrospectively analyzed 103 patients with metastatic, castration-resistant PC who were treated with [177Lu]Lu-PSMA I&T. We calculated SUVmean, SUVmax, PSMA-avid tumor volume (TV), and total lesion PSMA (defined as PSMA-TV*SUVmean) on pre-therapeutic [18F]PSMA-1007 PET. Laboratory values for hemoglobin, C-reactive protein (CRP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alkaline phosphatase (AP) were also collected prior to RLT. We performed univariable Cox regression followed by multivariable and Kaplan-Meier analyses with overall survival (OS) serving as endpoint. Last, we also computed a risk factor (RF) model including all items reaching significance on multivariable analysis to determine whether an increasing number of RFs can improve risk stratification. RESULTS: A total of 48 patients died and median OS was 16 months. On univariable Cox regression, SUVmean, CRP, LDH, hemoglobin, and the presence of liver metastases were significantly associated with OS. On multivariable Cox regression, the following significant prognostic factors for OS were identified: SUVmean (per unit, HR, 0.91; P = 0.04), the presence of liver metastases (HR, 2.37; P = 0.03), CRP (per mg/dl, HR, 1.13; P = 0.003), and hemoglobin (per g/dl, HR, 0.76; P < 0.01). Kaplan-Meier analysis showed significant separation between patients with a SUVmean below or above a median SUVmean of 9.4 (9 vs 19 months, HR 0.57; P = 0.03). Of note, patients with only one RF (median OS not reached) showed longest survival compared to patients with two (11 months; HR 2.43 95% CI 1.07-5.49, P = 0.02) or more than two RFs (7 months; HR 3.37 95% CI 1.62-7.03, P < 0.001). CONCLUSION: A lower SUVmean derived from [18F]PSMA-1007, higher CRP, lower hemoglobin, and the presence of liver metastases are associated with reduced OS in patients undergoing RLT. An early RF model also demonstrated that an increasing number of those factors is linked to worse outcome, thereby emphasizing the importance of clinical and imaging parameters for adequate risk stratification.

CXCR4-Directed Imaging and Endoradiotherapy in Desmoplastic Small Round Cell Tumors.

Desmoplastic small round cell tumor (DSRCT) is a rare, radiosensitive, yet difficult-to-treat sarcoma subtype affecting predominantly male adolescents. Extensive intraperitoneal seeding is common and requires multimodal management. With no standard therapy established, the prognosis remains poor, and new treatment options are needed. We demonstrate the clinical potential of C-X-C motif chemokine receptor 4 (CXCR4)-directed imaging and endoradiotherapy in DSRCT. Methods: Eight male patients underwent dual-tracer imaging with [18F]FDG and CXCR4-directed [68Ga]pentixafor PET/CT. A visual comparison of both tracers, along with uptake quantification in active DSRCT lesions, was performed. [68Ga]pentixafor uptake was correlated with immunohistochemical CXCR4 expression on tumor cells. Four patients with end-stage progressive disease underwent CXCR4-based endoradiotherapy. We report the safety, response by RECIST 1.1, and survival after endoradiotherapy. Results: Uptake of [68Ga]pentixafor in tumor lesions was demonstrated in all patients with DSRCT, providing diagnostic power comparable to [18F]FDG PET. Corresponding CXCR4 expression was confirmed by immunohistochemistry in all DSRCT biopsies. Finally, 4 patients were treated with CXCR4-directed [90Y]endoradiotherapy, 3 in a myeloablative dose range with subsequent autologous stem cell transplantation. All 3 required transfusions, and febrile neutropenia occurred in 2 patients (resulting in 1 death). Notably, severe nonhematologic adverse events were absent. We observed signs of response in all 3 patients, translating into disease stabilization in 2 patients for 143 and 176 d, respectively. In the third patient, postmortem autopsy confirmed a partial pathologic response. Conclusion: We validated CXCR4 as a diagnostic biomarker and a promising target for endoradiotherapy in DSRCT, demonstrated its feasibility, and provided the first evidence of its clinical efficacy.

Molecular imaging of arterial fibroblast activation protein: association with calcified plaque burden and cardiovascular risk factors.

PURPOSE: We aimed to assess prevalence, distribution, and intensity of in-vivo arterial wall fibroblast activation protein (FAP) uptake, and its association with calcified plaque burden, cardiovascular risk factors (CVRFs), and FAP-avid tumor burden. METHODS: We analyzed 69 oncologic patients who underwent [68 Ga]Ga-FAPI-04 PET/CT. Arterial wall FAP inhibitor (FAPI) uptake in major vessel segments was evaluated. We then investigated the associations of arterial wall uptake with calcified plaque burden (including number of plaques, plaque thickness, and calcification circumference), CVRFs, FAP-positive total tumor burden, and image noise (coefficient of variation, from normal liver parenchyma). RESULTS: High focal arterial FAPI uptake (FAPI +) was recorded in 64/69 (92.8%) scans in 800 sites, of which 377 (47.1%) exhibited concordant vessel wall calcification. The number of FAPI + sites per patient and (FAPI +)-derived target-to-background ratio (TBR) correlated significantly with the number of calcified plaques (FAPI + number: r = 0.45, P < 0.01; TBR: r = - 0.26, P = 0.04), calcified plaque thickness (FAPI + number: r = 0.33, P < 0.01; TBR: r = - 0.29, P = 0.02), and calcification circumference (FAPI + number: r = 0.34, P < 0.01; TBR: r = - 0.26, P = 0.04). In univariate analysis, only body mass index was significantly associated with the number of FAPI + sites (OR 1.06; 95% CI, 1.02 - 1.12, P < 0.01). The numbers of FAPI + sites and FAPI + TBR, however, were not associated with other investigated CVRFs in univariate and multivariate regression analyses. Image noise, however, showed significant correlations with FAPI + TBR (r = 0.30) and the number of FAPI + sites (r = 0.28; P = 0.02, respectively). In addition, there was no significant interaction between FAP-positive tumor burden and arterial wall FAPI uptake (P ≥ 0.13). CONCLUSION: [68 Ga]Ga-FAPI-04 PET identifies arterial wall lesions and is linked to marked calcification and overall calcified plaque burden, but is not consistently associated with cardiovascular risk. Apparent wall uptake may be partially explained by image noise.

Impact of CXCR4-Directed PET/CT on Staging and Proposed Oncologic Management in Patients With Digestive System Tumors.

PURPOSE: To elucidate the influence of CXC motif chemokine receptor 4 (CXCR4)-directed imaging on staging and proposed oncologic management in patients with digestive system tumors compared with guideline-appropriate imaging (GAI). METHODS: From our PET/CT database, we retrospectively identified 37 patients with advanced digestive system tumors, which had been scheduled for CXCR4-targeted [ 68 Ga]Ga-pentixafor PET/CT for potential theranostic considerations. In all subjects, concurrent GAI was also available. Patients were afflicted with gastroenteropancreatic neuroendocrine neoplasms (21/37 [56.8%]), pancreatic duct adenocarcinoma (6/37 [16.2%]), cholangiocarcinoma (5/37 [13.5%]), hepatocellular carcinoma (4/37 [10.8%]), and colorectal carcinoma (1/37 [2.7%]). Staging results and impact on proposed oncologic management by a board-certified gastroenterologist were compared between GAI and [ 68 Ga]Ga-pentixafor PET/CT. RESULTS: Relative to GAI, CXCR4-directed PET/CT resulted in staging changes in 14 of 37 patients (37.8%). Upstaging was seen in 1 of 14 patients (7.1%), whereas downstaging was recorded in the remaining 13 of 14 patients (92.9%). Among those, staging changes would not have triggered any changes in oncological management in 4 of 14 (28.6%). For the remaining 10 of 14 patients (71.4%), however, findings on [ 68 Ga]Ga-pentixafor PET/CT would have impacted subsequent clinical algorithm, including the necessity for further diagnostic steps or failure to initiate antitumor therapy. CONCLUSION: [ 68 Ga]Ga-pentixafor PET/CT missed tumor lesions in 13 patients with digestive system tumors, which would have led to inappropriate downstaging and clinical treatment of 10 patients. As such, our results do not support a more widespread use of [ 68 Ga]Ga-pentixafor PET/CT for clinical staging in those tumor entities.