Intraindividual comparison of [177Lu]Lu-DOTA-EB-TATE and [177Lu]Lu-DOTA-TOC

PURPOSE: The radiolabelled somatostatin analogue [(177)Lu]Lu-DOTA-EB-TATE binds to albumin via Evans blue, thereby increasing the residence time in the blood and potentially allowing more therapeutic agent to be absorbed into the target tissue during peptide receptor radionuclide therapy. It was tested in selected patients whether the substance is superior to [(177)Lu]Lu-DOTA-TOC. METHODS: Activity kinetics in organs and tumours after [(177)Lu]Lu-DOTA-EB-TATE and [(177)Lu]Lu-DOTA-TOC were compared intraindividually in five patients with progressive somatostatin receptor-positive disease scheduled for radionuclide therapy. RESULTS: In comparison to [(177)Lu]Lu-DOTA-TOC, tumour doses per administered activity were higher for [(177)Lu]Lu-DOTA-EB-TATE in 4 of 5 patients (median ratio: 1.7; range: 0.9 to 3.9), kidney doses (median ratio: 3.2; range: 1.6 to 9.8) as well as spleen doses (median ratio: 4.7; range 1.2 to 6.2) in all patients, and liver doses in 3 of 4 evaluable patients (median ratio: 4.0; range: 0.7 to 4.9). The tumour to critical organs absorbed dose ratios were higher after [(177)Lu]Lu-DOTA-TOC in 4 of 5 patients. CONCLUSIONS: Prior to a treatment with [(177)Lu]Lu-DOTA-EB-TATE, it should be assessed individually whether the compound is superior to established substances

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

Any decline in prostate‐specific antigen levels identifies survivors scheduled for prostate‐specific membrane antigen‐directed radioligand therapy

Background Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is increasingly incorporated in the therapeutic algorithm of patients with metastatic castration-resistant prostate cancer (mCRPC). We aimed to elucidate the predictive performance of early biochemical response for overall survival (OS). Materials and Methods In this bicentric analysis, we included 184 mCRPC patients treated with $^{177}$Lu-PSMA RLT. Response to treatment was defined as decrease in prostate-specific antigen (PSA) levels 8 weeks after the first cycle of RLT (any decline or >50% according to Prostate Cancer Working Group 3). OS of responders and nonresponders was then compared using Kaplan–Meier curves and log-rank comparison. Results A total of 114/184 patients (62.0%) showed any PSA decline (PSA response >50%, 55/184 [29.9%]). For individuals exhibiting a PSA decline >50%, OS of 19 months was significantly longer relative to nonresponders (13 months; hazard ratio of death [HR] = 0.64, 95% confidence interval [95% CI] = 0.44–0.93; p = 0.02). However, the difference was even more pronounced for any PSA decline, with an OS of 19 months in responders, but only 8 months in nonresponders (HR = 0.39, 95% CI = 0.25–0.60; p < 0.001). Conclusions In mCRPC patients scheduled for RLT, early biochemical response was tightly linked to prolonged survival, irrespective of the magnitude of PSA decline. As such, even in patients with PSA decrease of less than 50%, RLT should be continued

Impact of tumor burden on normal organ distribution in patients imaged with CXCR4-targeted [68Ga]Ga-PentixaFor PET/CT

BACKGROUND: CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs. METHODS: Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [(68)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV(mean)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV(max)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV(mean) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden. RESULTS: Median SUV(mean) in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUV(max) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found. CONCLUSIONS: In patients with solid tumors imaged with [(68)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged

Predicting microenvironment in CXCR4- and FAP-positive solid tumors - a pan-cancer machine learning workflow for theranostic target structures

Simple Summary Imaging based on positron emission tomography (PET) is a crucial part of up-to-date cancer care. For this purpose, PET employs and marks target structures at the cellular surface. Recently, C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) emerged as clinically relevant PET targets. However, it is unclear whether high levels of CXCR4 and FAP represent distinct cancer states—especially in solid tumors. Therefore, we established a machine learning model based on 9242 samples from 29 different cancer entities. Our analysis revealed that—in most solid tumors—high levels of CXCR4 were associated with immune cells infiltrating these tumors. Instead, FAP-positive tumors were characterized by high amounts of tumor vessels. Our machine learning approach potentially can identify the Achilles’ heel of tumors in a non-invasive manner—by performing PET without having to obtain tumor tissue beforehand. Abstract (1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database—representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets

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&TRLT 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 signifcantly 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 onecycle of [177Lu]Lu-PSMA I&T RLT was an indicator of overall progression and poor clinical outcome

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

High SUVs have more robust repeatability in patients with metastatic prostate cancer: results from a prospective test-retest cohort imaged with 18F-DCFPyL

OBJECTIVES: In patients with prostate cancer (PC) receiving prostate-specific membrane antigen- (PSMA-) targeted radioligand therapy (RLT), higher baseline standardized uptake values (SUVs) are linked to improved outcome. Thus, readers deciding on RLT must have certainty on the repeatability of PSMA uptake metrics. As such, we aimed to evaluate the test-retest repeatability of lesion uptake in a large cohort of patients imaged with (18)F-DCFPyL. METHODS: In this prospective, IRB-approved trial (NCT03793543), 21 patients with history of histologically proven PC underwent two (18)F-DCFPyL PET/CTs within 7 days (mean 3.7, range 1 to 7 days). Lesions in the bone, lymph nodes (LN), and other organs were manually segmented on both scans, and uptake parameters were assessed (maximum (SUV(max)) and mean (SUV(mean)) SUVs), PSMA-tumor volume (PSMA-TV), and total lesion PSMA (TL-PSMA, defined as PSMA − TV × SUV(mean))). Repeatability was determined using Pearson's correlations, within-subject coefficient of variation (wCOV), and Bland-Altman analysis. RESULTS: In total, 230 pairs of lesions (177 bone, 38 LN, and 15 other) were delineated, demonstrating a wide range of SUV(max) (1.5–80.5) and SUV(mean) (1.4–24.8). Including all sites of suspected disease, SUVs had a strong interscan correlation (R(2) ≥ 0.99), with high repeatability for SUV(mean) and SUV(max) (wCOV, 7.3% and 12.1%, respectively). High SUVs showed significantly improved wCOV relative to lower SUVs (P < 0.0001), indicating that high SUVs are more repeatable, relative to the magnitude of the underlying SUV. Repeatability for PSMA-TV and TL-PSMA, however, was low (wCOV ≥ 23.5%). Across all metrics for LN and bone lesions, interscan correlation was again strong (R(2) ≥ 0.98). Moreover, LN-based SUV(mean) also achieved the best wCOV (3.8%), which was significantly reduced when compared to osseous lesions (7.8%, P < 0.0001). This was also noted for SUV(max) (wCOV, LN 8.8% vs. bone 12.0%, P < 0.03). On a compartment-based level, wCOVs for volumetric features were ≥22.8%, demonstrating no significant differences between LN and bone lesions (PSMA-TV, P =0.63; TL-PSMA, P =0.9). Findings on an entire tumor burden level were also corroborated in a hottest lesion analysis investigating the SUV(max) of the most intense lesion per patient (R(2), 0.99; wCOV, 11.2%). CONCLUSION: In this prospective test-retest setting, SUV parameters demonstrated high repeatability, in particular in LNs, while volumetric parameters demonstrated low repeatability. Further, the large number of lesions and wide distribution of SUVs included in this analysis allowed for the demonstration of a dependence of repeatability on SUV, with higher SUVs having more robust repeatability

Optical control of L-Type Ca2+ channels using a diltiazem photoswitch

L-type Ca2+ channels (LTCCs) play a crucial role in excitation-contraction coupling and release of hormones from secretory cells. They are targets of antihypertensive and antiarrhythmic drugs such as diltiazem. Here, we present a photoswitchable diltiazem, FHU-779, which can be used to reversibly block endogenous LTCCs by light. FHU-779 is as potent as diltiazem and can be used to place pancreatic β-cell function and cardiac activity under optical control