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Background: Modern management of cardiac arrhythmias often requires interventions in which young physicians must acquire a high level of expertise. However, concerns have been raised about the increase in side effects during procedures performed with resident involvement., Aim: This study aims to identify the effects of resident training on cardiac electrophysiological procedures within a university centre., Methods: In a single-centre study, cardiac arrhythmia procedures were reviewed retrospectively, and resident involvement was scrutinized. Univariate and multivariable models were built for the following outcomes: fluoroscopy time; operative time; length of hospitalization after procedure; and adverse events., Results: We reviewed 991 procedures, 574 without and 417 with resident involvement (650 cardiac pacemakers or defibrillators, 120 generator replacements, 188 electrophysiological studies and 153 radiofrequency ablations). Resident involvement was associated with an increase in fluoroscopy time: +1.7±0.4minutes (P<0.01) for pacemaker implantation; and +2.5±0.9minutes (P=0.01) for electrophysiological studies. Operative time was longer for electrophysiological studies (+10.8±4.9minutes; P=0.03) and pacing implantation (+8.4±2.2minutes; P<0.01). There was no significant association between resident training and adverse events (7.67 vs. 9.83%; P=0.28)., Conclusions: Cardiac electrophysiological procedures performed with resident involvement have a good safety profile. However, resident training modestly, but significantly, prolongs fluoroscopy time and operative time., (Copyright © 2024. Published by Elsevier Masson SAS.)

Targeting the prostate-specific membrane antigen (PSMA) with radiopharmaceuticals for imaging and/or therapy has demonstrated significant advancement in the management of prostate cancer patients. However, PSMA targeting remains unsuccessful in prostate cancers with low expression of PSMA, which account for 15% of cases. The neurotensin receptor-1 (NTS 1 ) has been highlighted as a suitable oncotarget for imaging and therapy of PSMA-negative prostate cancer lesions. Therefore, heterobivalent probes targeting both PSMA and NTS 1 could improve the prostate cancer management. Herein, we report the development of a branched hybrid probe ( JMV 7489 ) designed to target PSMA and/or NTS 1 bearing relevant pharmacophores and DOTA as the chelating agent. The new ligand was synthesized with a hybrid approach, which includes both syntheses in batch and in the solid phase. Saturation binding experiments were next performed on HT-29 and PC3-PIP cells to derive K d and B max values. On the PC3-PIP cells, [ 68 Ga]Ga- JMV 7489 displayed good affinity towards PSMA ( K d = 53 ± 17 nM; B max = 1393 ± 29 fmol/10 6 cells) in the same range as the corresponding reference monomer. A lower affinity value towards NTS 1 was depicted ( K d = 157 ± 71 nM; B max = 241 ± 42 fmol/10 6 cells on PC3-PIP cells; K d = 246 ± 1 nM; B max = 151 ± 44 fmol/10 6 cells on HT-29 cells) and, surprisingly, it was also the case for the corresponding monomer [ 68 Ga]Ga- JMV 7089 . These results indicate that the DOTA macrocycle and the linker are critical elements to design heterobivalent probes targeting PSMA and NTS 1 with high affinity towards NTS 1 ., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Learning to interpret electrocardiograms (ECGs) is a crucial objective in medical education. Despite its importance, errors in ECGs interpretation are common, and the optimal teaching methods have not yet been clearly established., Objectives: To evaluate students' confidence in ECGs analysis and their opinion on current teaching methods, and to assess the effectiveness of a new ECG educational approach., Methods: First, we conducted a survey on ECG learning among fourth to sixth-year medical students. Second, a 5-week multicenter comparative study was conducted with fourth-year medical students during their cardiology internship. Two different teaching methods were used, assigned by center. The first group participated in 5-minutes workshops 4 times a week using a "reversed classroom" method, supervised by a cardiologist, where students took turns selecting, presenting and discussing ECGs. The control group attended a single 2-hour face-to-face ECG course. All participants completed a 30-minute ECGs analysis test at baseline and after 5 weeks., Results: Out of 401 survey respondents, the confidence levels in ECG interpretation were 3/5 (IQR 2-3) for routine situations and 2/5 (IQR 1-3) for emergency situations. Satisfaction with ECG teaching was low (2/5, IQR 1-3) and 96.3% of respondents favored more extensive ECG training. In the comparative study, 52 students from 3 medical schools were enrolled (control group: n = 27; workshop group: n = 25). Both groups showed significant improvement in exam scores from baseline to 5-week (33/100 ± 12/100 to 44/100 ± 12/100, p < 0.0001 for the control group and 36/100 ± 13/100 to 62/100 ± 12/100, p < 0.0001 for the workshop group). The improvement was significantly greater in the workshop group compared to the control group (+ 26 ± 11 vs. + 11 ± 6, p < 0.001)., Conclusions: Among French medical students who initially reported low confidence and insufficient skills in ECG interpretation, the workshop approach using a "reversed classroom" method was found to be more effective than conventional lecture-based teaching during cardiology internship., (© 2024. The Author(s).)

Early use of targeted radionuclide therapy (TRT) to eradicate disseminated tumor cells (DTCs) might offer cure. Selection of appropriate radionuclides is required. This work highlights the potential of 103 Pd (T 1/2 = 16.991 d) which decays to 103m Rh (T 1/2 = 56.12 min) then to stable 103 Rh with emission of Auger and conversion electrons. Methods: The Monte Carlo track structure code CELLDOSE was used to assess absorbed doses in single cells (14-μm diameter; 10-μm nucleus) and clusters of 19 cells. The radionuclide was distributed on the cell surface, within the cytoplasm, or in the nucleus. Absorbed doses from 103 Pd, 177 Lu and 161 Tb were compared after energy normalization. The impact of non-uniform cell targeting, and the potential benefit from dual-targeting was investigated. Additional results related to 103m Rh, if used directly, are provided. Results: In the single cell, and depending on radionuclide distribution, 103 Pd delivered 7- to 10-fold higher nuclear absorbed dose and 9- to 25-fold higher membrane dose than 177 Lu. In the 19-cell clusters, 103 Pd absorbed doses also largely exceeded 177 Lu. In both situations, 161 Tb stood in-between 103 Pd and 177 Lu. Non-uniform targeting, considering four unlabeled cells within the cluster, resulted in moderate-to-severe dose heterogeneity. For example, with intranuclear 103 Pd, unlabeled cells received only 14% of the expected nuclear dose. Targeting with two 103 Pd-labeled radiopharmaceuticals minimized dose heterogeneity. Conclusion: 103 Pd, a next-generation Auger emitter, can deliver substantially higher absorbed doses than 177 Lu to single tumor cells and cell clusters. This may open new horizons for the use of TRT in adjuvant or neoadjuvant settings, or for targeting minimal residual disease., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Aims: KCNQ1 mutations cause QTc prolongation increasing life-threatening arrhythmias risks. Heterozygous mutations [type 1 long QT syndrome (LQT1)] are common. Homozygous KCNQ1 mutations cause type 1 Jervell and Lange-Nielsen syndrome (JLNS) with deafness and higher sudden cardiac death risk. KCNQ1 variants causing JLNS or LQT1 might have distinct phenotypic expressions in heterozygous patients. The aim of this study is to evaluate QTc duration and incidence of long QT syndrome-related cardiac events according to genetic presentation., Methods and Results: We enrolled LQT1 or JLNS patients with class IV/V KCNQ1 variants from our inherited arrhythmia clinic (September 1993 to January 2023). Medical history, ECG, and follow-up were collected. Additionally, we conducted a thorough literature review for JLNS variants. Survival curves were compared between groups, and multivariate Cox regression models identified genetic and clinical risk factors. Among the 789 KCNQ1 variant carriers, 3 groups were identified: 30 JLNS, 161 heterozygous carriers of JLNS variants (HTZ-JLNS), and 550 LQT1 heterozygous carriers of non-JLNS variants (HTZ-Non-JLNS). At diagnosis, mean age was 3.4 ± 4.7 years for JLNS, 26.7 ± 21 years for HTZ-JLNS, and 26 ± 21 years for HTZ-non-JLNS; 55.3% were female; and the mean QTc was 551 ± 54 ms for JLNS, 441 ± 32 ms for HTZ-JLNS, and 467 ± 36 ms for HTZ-Non-JLNS. Patients with heterozygous JLNS mutations (HTZ-JLNS) represented 22% of heterozygous KCNQ1 variant carriers and had a lower risk of cardiac events than heterozygous non-JLNS variant carriers (HTZ-Non-JLNS) [hazard ratio (HR) = 0.34 (0.22-0.54); P < 0.01]. After multivariate analysis, four genetic parameters were independently associated with events: haploinsufficiency [HR = 0.60 (0.37-0.97); P = 0.04], pore localization [HR = 1.61 (1.14-1.2.26); P < 0.01], C-terminal localization [HR = 0.67 (0.46-0.98); P = 0.04], and group [HR = 0.43 (0.27-0.69); P < 0.01]., Conclusion: Heterozygous carriers of JLNS variants have a lower risk of cardiac arrhythmic events than other LQT1 patients., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The efficacy of beta-blocker treatment in type 3 long QT syndrome (LQT3) remains debated., Objectives: The purpose of this study was to test the hypothesis that beta-blocker use is associated with cardiac events (CEs) in a French cohort of LQT3 patients., Methods: All patients with a likely pathogenic/pathogenic variant in the SCN5A gene (linked to LQT3) were included and followed-up. Documented ventricular tachycardia/ventricular fibrillation, torsades de pointes, aborted cardiac arrest, sudden death, and appropriate shocks were considered as severe cardiac events (SCEs). CEs also included syncope., Results: We included 147 patients from 54 families carrying 23 variants. Six of the patients developed symptoms before the age of 1 year and were analyzed separately. The 141 remaining patients (52.5% male; median age at diagnosis 24.0 years) were followed-up for a median of 11 years. The probabilities of a CE and an SCE from birth to the age of 40 were 20.5% and 9.9%, respectively. QTc prolongation (hazard ratio [HR] 1.12 [1.0-1.2]; P = .005]) and proband status (HR 4.07 [1.9-8.9]; P <.001) were independently associated with the occurrence of CEs. Proband status (HR 8.13 [1.7-38.8]; P = .009) was found to be independently associated with SCEs, whereas QTc prolongation (HR 1.11 [1.0-1.3]; P = .108) did not reach statistical significance. The cumulative probability of the age at first CE/SCE was not lower in patients treated with a beta-blocker., Conclusion: In agreement with the literature, proband status and lengthened QTc were associated with a higher risk of CEs. Our data do not show a protective effect of beta-blocker treatment., Competing Interests: Disclosures The authors have no conflicts to disclose., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The neuropeptide-Y (NPY) family acts through four G protein-coupled receptor subtypes in humans, namely, Y 1 , Y 2 , Y 4 , and Y 5 . A growing body of evidence suggest the involvement of the NPY system in several cancers, notably the Y 5 subtype, thus acting as a relevant target for the development of radiopharmaceuticals for imaging or targeted radionuclide therapy (TRT). Here, the [cPP(1-7),NPY(19-23),Ala 31 ,Aib 32 ,Gln 34 ]hPP scaffold, further referred to as sY 5 ago, was modified with a DOTA chelator and radiolabeled with 68 Ga and 111 In and investigated in vitro and in vivo using the MCF-7 model. For in vivo studies, MCF-7 cells were orthotopically implanted in female nude mice and imaging with small animal positron emission tomography/computed tomography (μPET/CT) was performed. At the end of imaging, the mice were sacrificed. A scrambled version of sY 5 ago, which was also modified with a DOTA chelator, served as a negative control (DOTA-[Nle]sY 5 ago&#95;scrambled). sY 5 ago and DOTA-sY 5 ago showed subnanomolar affinity toward the Y 5 (0.9 ± 0.1 and 0.8 ± 0.1 nM, respectively) and a single binding site at the Y 5 was identified. [ 68 Ga]Ga-DOTA-sY 5 ago and [ 111 In]In-DOTA-sY 5 ago were hydrophilic and showed high specific internalization (1.61 ± 0.75%/10 6 cells at 1 h) and moderate efflux (55% of total binding externalized at 45 min). On μPET/CT images, most of the signal was depicted in the kidneys and the liver. MCF-7 tumors were clearly visualized. On biodistribution studies, [ 68 Ga]Ga-DOTA-sY 5 ago was eliminated by the kidneys (∼60 %ID/g). The kidney uptake is Y 5 -mediated. A specific uptake was also noted in the liver (5.09 ± 1.15 %ID/g vs 1.13 ± 0.21 %ID/g for [ 68 Ga]Ga-DOTA-[Nle]sY 5 ago&#95;scrambled, p < 0.05), the lungs (1.03 ± 0.34 %ID/g vs 0.20 %ID/g, p < 0.05), and the spleen (0.85 ± 0.09%ID/g vs 0.16 ± 0.16%ID/g, p < 0.05). In MCF-7 tumors, [ 68 Ga]Ga-DOTA-sY 5 ago showed 12-fold higher uptake than [ 68 Ga]Ga-DOTA-[Nle]sY 5 ago&#95;scrambled (3.43 ± 2.32 vs 0.27 ± 0.15 %ID/g, respectively, p = 0.0008) at 1 h post-injection. Finally, a proof-of-principle tissular micro-imaging study on a human primary cancer sample showed weak binding of [ 111 In]In-DOTA-sY 5 ago in prostatic intra-neoplasia and high binding in the ISUP1 lesion while normal prostate was free of signal.

Early use of targeted radionuclide therapy to eradicate tumor cell clusters and micrometastases might offer cure. However, there is a need to select appropriate radionuclides and assess the potential impact of heterogeneous targeting. Methods: The Monte Carlo code CELLDOSE was used to assess membrane and nuclear absorbed doses from 177 Lu and 161 Tb (β - -emitter with additional conversion and Auger electrons) in a cluster of 19 cells (14-μm diameter, 10-μm nucleus). The radionuclide distributions considered were cell surface, intracytoplasmic, or intranuclear, with 1,436 MeV released per labeled cell. To model heterogeneous targeting, 4 of the 19 cells were unlabeled, their position being stochastically determined. We simulated situations of single targeting, as well as dual targeting, with the 2 radiopharmaceuticals aiming at different targets. Results: 161 Tb delivered 2- to 6-fold higher absorbed doses to cell membranes and 2- to 3-fold higher nuclear doses than 177 Lu. When all 19 cells were targeted, membrane and nuclear absorbed doses were dependent mainly on radionuclide location. With cell surface location, membrane absorbed doses were substantially higher than nuclear absorbed doses, both with 177 Lu (38-41 vs. 4.7-7.2 Gy) and with 161 Tb (237-244 vs. 9.8-15.1 Gy). However, when 4 cells were not targeted by the cell surface radiopharmaceutical, the membranes of these cells received on average only 9.6% of the 177 Lu absorbed dose and 2.9% of the 161 Tb dose, compared with a cluster with uniform cell targeting, whereas the impact on nuclear absorbed doses was moderate. With an intranuclear radionuclide location, the nuclei of unlabeled cells received only 17% of the 177 Lu absorbed dose and 10.8% of the 161 Tb dose, compared with situations with uniform targeting. With an intracytoplasmic location, nuclear and membrane absorbed doses to unlabeled cells were one half to one quarter those obtained with uniform targeting, both for 177 Lu and for 161 Tb. Dual targeting was beneficial in minimizing absorbed dose heterogeneities. Conclusion: To eradicate tumor cell clusters, 161 Tb may be a better candidate than 177 Lu. Heterogeneous cell targeting can lead to substantial heterogeneities in absorbed doses. Dual targeting was helpful in reducing dose heterogeneity and should be explored in preclinical and clinical studies., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

APJ has been extensively described in the pathophysiology of angiogenesis and cell proliferation. The prognostic value of APJ overexpression in many diseases is now established. This study aimed to design a PET radiotracer that specifically binds to APJ. Apelin-F13A-NODAGA (AP747) was synthesized and radiolabeled with gallium-68 ([ 68 Ga]Ga-AP747). Radiolabeling purity was excellent (> 95%) and stable up to 2 h. Affinity constant of [ 67 Ga]Ga-AP747 was measured on APJ-overexpressing colon adenocarcinoma cells and was in nanomolar range. Specificity of [ 68 Ga]Ga-AP747 for APJ was evaluated in vitro by autoradiography and in vivo by small animal PET/CT in both colon adenocarcinoma mouse model and Matrigel plug mouse model. Dynamic of [ 68 Ga]Ga-AP747 PET/CT biodistributions was realized on healthy mice and pigs for two hours, and quantification of signal in organs showed a suitable pharmacokinetic profile for PET imaging, largely excreted by urinary route. Matrigel mice and hindlimb ischemic mice were submitted to a 21-day longitudinal follow-up with [ 68 Ga]Ga-AP747 and [ 68 Ga]Ga-RGD 2 small animal PET/CT. [ 68 Ga]Ga-AP747 PET signal in Matrigel was significantly more intense than that of [ 68 Ga]Ga-RGD 2 . Revascularization of the ischemic hind limb was followed by LASER Doppler. In the hindlimb, [ 68 Ga]Ga-AP747 PET signal was more than twice higher than that of [ 68 Ga]Ga-RGD 2 on day 7, and significantly superior over the 21-day follow-up. A significant, positive correlation was found between the [ 68 Ga]Ga-AP747 PET signal on day 7 and late hindlimb perfusion on day 21. We developed a new PET radiotracer that specifically binds to APJ, [ 68 Ga]Ga-AP747 that showed more efficient imaging properties than the most clinically advanced tracer of angiogenesis, [ 68 Ga]Ga-RGD 2 ., (© 2023. The Author(s).)

Bivalent ligands, i.e., molecules having two ligands covalently connected by a linker, have been gathering attention since the first description of their pharmacological potential in the early 80s. However, their synthesis, particularly of labeled heterobivalent ligands, can still be cumbersome and time-consuming. We herein report a straightforward procedure for the modular synthesis of labeled heterobivalent ligands (HBLs) using dual reactive 3,6-dichloro-1,2,4,5-tetrazine as a starting material and suitable partners for sequential S N Ar and inverse electron-demand Diels-Alder (IEDDA) reactions. This assembly method conducted in a stepwise or in a sequential one-pot manner provides quick access to multiple HBLs. A conjugate combining ligands toward the prostate-specific membrane antigen (PSMA) and the gastrin-releasing peptide receptor (GRPR) was radiolabeled, and its biological activity was assessed in vitro and in vivo (receptor binding affinity, biodistribution, imaging) as an illustration that the assembly methodology preserves the tumor targeting properties of the ligands., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

The imaging of Prostate-Specific Membrane Antigen (PSMA) is now widely used at the initial staging of prostate cancers in patients with a high metastatic risk. However, its ability to detect low-grade tumor lesions is not optimal., Methods: First, we prospectively performed neurotensin receptor-1 (NTS 1 ) IHC in a series of patients receiving both [ 68 Ga]Ga-PSMA-617 and [ 68 Ga]Ga-RM2 before prostatectomy. In this series, PSMA and GRP-R IHC were also available (n = 16). Next, we aimed at confirming the PSMA/GRP-R/NTS 1 expression profile by retrospective autoradiography (n = 46) using a specific radiopharmaceuticals study and also aimed to decipher the expression of less-investigated targets such as NTS 2 , SST 2 and CXCR4., Results: In the IHC study, all samples with negative PSMA staining (two patients with ISUP 2 and one with ISUP 3) were strongly positive for NTS 1 staining. No samples were negative for all three stains-for PSMA, GRP-R or NTS 1 . In the autoradiography study, binding of [ 111 In]In-PSMA-617 was high in all ISUP groups. However, some samples did not bind or bound weakly to [ 111 In]In-PSMA-617 (9%). In these cases, binding of [ 111 n]In-JMV 6659 and [ 111 In]In-JMV 7488 towards NTS 1 and NTS 2 was high., Conclusions: Targeting PSMA and NTS 1 /NTS 2 could allow for the detection of all intraprostatic lesions.

Considering the wide range of therapeutic options for localized prostate cancer (e.g., active surveillance, radiation-beam therapy, focal therapy, and radical prostatectomy), accurate assessment of the aggressiveness and localization of primary prostate cancer lesions is essential for treatment decision making. National Comprehensive Cancer Network guidelines recognize prostate-specific membrane antigen (PSMA) PET/CT for use in initial staging of high-risk primary prostate cancer. The gastrin-releasing peptide receptor (GRP-R) is a neuropeptide receptor overexpressed by low-risk prostate cancer cells. We aimed to perform the first (to our knowledge) prospective head-to-head comparison of PSMA- and GRP-R-targeted imaging at initial staging to understand how PSMA PET and GRP-R PET can be used or combined in clinical practice. Methods: This was a prospective, single-center, diagnostic cross-sectional imaging study using anonymized, masked, and independent interpretations of paired PET/CT studies in 22 patients with 68 Ga-PSMA-617 (a radiolabeled PSMA inhibitor) and 68 Ga-RM2 ( 68 Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, a radiolabeled GRP-R antagonist). We enrolled patients with newly diagnosed, biopsy-proven prostate cancer. None had received neoadjuvant hormone therapy or chemotherapy, and all underwent extended pelvic lymph node dissection. Histologic findings served as a reference. Results: On a lesion-based analysis (including lesions < 0.1 cm 3 ), 68 Ga-PSMA-617 PET/CT detected 74.3% (26/35) of all tumor lesions and 68 Ga-RM2 PET/CT detected 78.1% (25/32; 1 patient could not be offered 68 Ga-RM2 PET/CT). Paired examinations showed positive uptake of the 2 tracers in 21 of 32 lesions (65.6%), negative uptake in 5 of 32 lesions (15.6%), and discordant uptake in 6 of 32 lesions (18.8%). Uptake of 68 Ga-PSMA-617 was higher when the International Society of Urological Pathology (ISUP) score was at least 4 versus at least 1 ( P < 0.0001) or 2 ( P  = 0.0002). There were no significant differences in uptake between ISUP scores for 68 Ga-RM2. Median 68 Ga-RM2 SUV max was significantly higher than median 68 Ga-PSMA-617 SUV max in the ISUP-2 subgroup ( P  = 0.01). Conclusion: 68 Ga-PSMA-617 PET/CT is useful to depict higher, more clinically significant ISUP score lesions, and 68 Ga-RM2 PET/CT has a higher detection rate for low-ISUP tumors. Combining PSMA PET and GRP-R PET allows for better classification of intraprostatic lesions., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Neurotensin receptor 2 (NTS 2 ) is a well-known mediator of central opioid-independent analgesia. Seminal studies have highlighted NTS 2 overexpression in a variety of tumors including prostate cancer, pancreas adenocarcinoma, and breast cancer. Herein, we describe the first radiometalated neurotensin analogue targeting NTS 2 . JMV 7488 (DOTA-(βAla) 2 -Lys-Lys-Pro-(D)Trp-Ile-TMSAla-OH) was prepared using solid-phase peptide synthesis, then purified, radiolabeled with 68 Ga and 111 In, and investigated in vitro on HT-29 cells and MCF-7 cells, respectively, and in vivo on HT-29 xenografts. [ 68 Ga]Ga-JMV 7488 and [ 111 In]In-JMV 7488 were quite hydrophilic (logD 7.4 = -3.1 ± 0.2 and -2.7 ± 0.2, respectively, p < 0.0001). Saturation binding studies showed good affinity toward NTS 2 ( K D = 38 ± 17 nM for [ 68 Ga]Ga-JMV 7488 on HT-29 and 36 ± 10 nM on MCF-7 cells; K D = 36 ± 4 nM for [ 111 In]In-JMV 7488 on HT-29 and 46 ± 1 nM on MCF-7 cells) and good selectivity (no NTS 1 binding up to 500 nM). On cell-based evaluation, [ 68 Ga]Ga-JMV 7488 and [ 111 In]In-JMV 7488 showed high and fast NTS 2 -mediated internalization of 24 ± 5 and 25 ± 11% at 1 h for [ 111 In]In-JMV 7488, respectively, along with low NTS 2 -membrane binding (<8%). Efflux was as high as 66 ± 9% at 45 min for [ 68 Ga]Ga-JMV 7488 on HT-29 and increased for [ 111 In]In-JMV 7488 up to 73 ± 16% on HT-29 and 78 ± 9% on MCF-7 cells at 2 h. Maximum intracellular calcium mobilization of JMV 7488 was 91 ± 11% to that of levocabastine, a known NTS 2 agonist on HT-29 cells demonstrating the agonist behavior of JMV 7488. In nude mice bearing HT-29 xenograft, [ 68 Ga]Ga-JMV 7488 showed a moderate but promising significant tumor uptake in biodistribution studies that competes well with other nonmetalated radiotracers targeting NTS 2 . Significant uptake was also depicted in lungs. Interestingly, mice prostate also demonstrated [ 68 Ga]Ga-JMV 7488 uptake although the mechanism was not NTS 2 -mediated., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Purpose: Neurotensin receptor-1 (NTS 1 ) is increasingly recognized as a potential target in diverse tumors including breast cancer, but factors associated with NTS 1 expression have not been fully clarified., Methods: We studied NTS 1 expression using the Tissue MicroArray (TMA) of primary breast tumors from Institut Bergonié. We also studied association between NTS 1 expression and clinical, pathological, and biological parameters, as well as patient outcomes., Results: Out of 1419 primary breast tumors, moderate to strong positivity for NTS 1 (≥ 10% of tumoral cells stained) was seen in 459 samples (32.4%). NTS 1 staining was cytoplasmic in 304 tumors and nuclear in 155 tumors, a distribution which appeared mutually exclusive. Cytoplasmic overexpression of NTS 1 was present in 21.5% of all breast tumors. In multivariate analysis, factors associated with cytoplasmic overexpression of NTS 1 in breast cancer samples were higher tumor grade, Ki67 ≥ 20%, and higher pT stage. Cytoplasmic NTS 1 was more frequent in tumors other than luminal A (30% versus 17.3%; p < 0.0001). Contrastingly, the main "correlates" of a nuclear location of NTS 1 were estrogen receptor (ER) positivity, low E&E (Elston and Ellis) grade, Ki67 < 20%, and lower pT stage. In NTS 1 -positive samples, cytoplasmic expression of NTS 1 was associated with shorter 10-year metastasis-free interval (p = 0.033) compared to NTS 1 nuclear staining. Ancillary analysis showed NTS 1 expression in 73% of invaded lymph nodes from NTS 1 -positive primaries., Conclusion: NTS 1 overexpression was found in about one-third of breast tumors from patients undergoing primary surgery with two distinct patterns of distribution, cytoplasmic distribution being more frequent in aggressive subtypes. These findings encourage the development of NTS 1 -targeting strategy, including radiopharmaceuticals for imaging and therapy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: [ 68 Ga]Ga-RM2 is a potent Gastrin-Releasing Peptide-receptor (GRP-R) antagonist for imaging prostate cancer and breast cancer, currently under clinical evaluation in several specialized centers around the world. Targeted radionuclide therapy of GRP-R-expressing tumors is also being investigated. We here report the characteristics of a kit-based formulation of RM2 that should ease the development of GRP-R imaging and make it available to more institutions and patients., Methods: Stability of the investigated kits over one year was determined using LC/MS/MS and UV-HPLC. Direct 68 Ga-radiolabeling was optimized with respect to buffer (pH), temperature, reaction time and shaking time. Conventionally prepared [ 68 Ga]Ga-RM2 using an automated synthesizer was used as a comparator. Finally, the [ 68 Ga]Ga-RM2 product was assessed with regards to hydrophilicity, affinity, internalization, membrane bound fraction, calcium mobilization assay and efflux, which is a valuable addition to the in vivo literature., Results: The kit-based formulation, kept between 2 °C and 8 °C, was stable for over one year. Using acetate buffer pH 3.0 in 2.5-5.1 mL total volume, heating at 100 °C during 10 min and cooling down for 5 min, the [ 68 Ga]Ga-RM2 produced by kit complies with the requirements of the European Pharmacopoeia. Compared with the module production route, the [ 68 Ga]Ga-RM2 produced by kit was faster, displayed higher yields, higher volumetric activity and was devoid of ethanol. In in vitro evaluations, the [ 68 Ga]Ga-RM2 displayed sub-nanomolar affinity (K d = 0.25 ± 0.19 nM), receptor specific and time dependent membrane-bound fraction of 42.0 ± 5.1% at 60 min and GRP-R mediated internalization of 24.4 ± 4.3% at 30 min. The [ nat Ga]Ga-RM2 was ineffective in stimulating intracellular calcium mobilization. Finally, the efflux of the internalized activity was 64.3 ± 6.5% at 5 min., Conclusion: The kit-based formulation of RM2 is suitable to disseminate GRP-R imaging and therapy to distant hospitals without complex radiochemistry equipment.

Background: Inflammatory vascular disease of the arteries, such as inflamed atheromatous plaques or arteritis, may cause aneurysms or ischemic strokes. In this context, using positron emission tomography (PET) to image inflammation may help select patients who would benefit from appropriate therapeutic interventions. This study sought to assess the usefulness of the 18 kDa translocator protein (TSPO) tracers [ 11 C]-PBR28 and [ 18 F]-PBR06 for imaging inflammatory vascular disease in vitro and in vivo. Immunohistochemistry for macrophage infiltration as well as autoradiography with [ 18 F]-PBR06 were performed on eight paraffin-embedded, formalin-fixed atherosclerosis plaques prospectively collected after carotid endarterectomy of eight patients affected by ischemic stroke. Six different patients, one of whom was also included in the in vitro study, underwent PET imaging. Two patients with carotid stenosis associated with ischemic stroke were imaged with [ 18 F]-PBR06 PET/CT, and four other patients (three with large vessel vasculitis and one with bilateral carotid stenosis but without stroke) were imaged with [ 11 C]-PBR28., Results: All in vitro sections showed specific binding of [ 18 F]-PBR06, which co-localized with immunohistochemistry markers for inflammation. However, in vivo TSPO imaging with either [ 11 C]-PBR28 or [ 18 F]-PBR06 was negative in all participants., Conclusion: Despite good uptake on surgical samples in vitro, [ 11 C]-PBR28 and [ 18 F]-PBR06 are not viable clinical tools for imaging inflammatory vascular disease., Trial Registration: NCT02513589, registered 31 July 2015 and NCT00547976, registered 23 October 2007. https://clinicaltrials.gov .

Several independent studies have demonstrated the overexpression of NTS 1 in various malignancies, which make this receptor of interest for imaging and therapy. To date, radiolabeled neurotensin analogues suffer from low plasmatic stability and thus insufficient availability for high uptake in tumors. We report the development of 68 Ga-radiolabeled neurotensin analogues with improved radiopharmaceutical properties through the introduction of the silicon-containing amino acid trimethylsilylalanine (TMSAla). Among the series of novel radiolabeled neurotensin analogues, [ 68 Ga] Ga- JMV6659 exhibits high hydrophilicity (log D 7.4 = -3.41 ± 0.14), affinity in the low nanomolar range toward NTS 1 ( K d = 6.29 ± 1.37 nM), good selectivity ( K d NTS 1 / K d NTS 2 = 35.9), and high NTS 1 -mediated internalization. It has lower efflux and prolonged plasmatic half-life in human plasma as compared to the reference compound ([ 68 Ga]Ga-JMV6661 bearing the minimum active fragment of neurotensin and the same linker and chelate as other analogues). In nude mice bearing HT-29 xenograft, [ 68 Ga]Ga-JMV6659 uptake reached 7.8 ± 0.54 %ID/g 2 h post injection. Uptake was decreased to 1.38 ± 0.71 %ID/g with injection of excess of non-radioactive neurotensin. Radiation dose as extrapolated to human was estimated as 2.35 ± 0.6 mSv for a standard injected activity of 100MBq. [ 68 Ga]Ga-JMV6659 was identified as a promising lead compound suitable for PET imaging of NTS 1 -expressing tumors.

Background: Targeted radionuclide therapy (TRT) is gaining importance. For TRT to be also used as adjuvant therapy or for treating minimal residual disease, there is a need to increase the radiation dose to small tumours. The aim of this in silico study was to compare the performances of 161 Tb (a medium-energy β - emitter with additional Auger and conversion electron emissions) and 177 Lu for irradiating single tumour cells and micrometastases, with various distributions of the radionuclide., Methods: We used the Monte Carlo track-structure (MCTS) code CELLDOSE to compute the radiation doses delivered by 161 Tb and 177 Lu to single cells (14 μm cell diameter with 10 μm nucleus diameter) and to a tumour cluster consisting of a central cell surrounded by two layers of cells (18 neighbours). We focused the analysis on the absorbed dose to the nucleus of the single tumoral cell and to the nuclei of the cells in the cluster. For both radionuclides, the simulations were run assuming that 1 MeV was released per μm 3 (1436 MeV/cell). We considered various distributions of the radionuclides: either at the cell surface, intracytoplasmic or intranuclear., Results: For the single cell, the dose to the nucleus was substantially higher with 161 Tb compared to 177 Lu, regardless of the radionuclide distribution: 5.0 Gy vs. 1.9 Gy in the case of cell surface distribution; 8.3 Gy vs. 3.0 Gy for intracytoplasmic distribution; and 38.6 Gy vs. 10.7 Gy for intranuclear location. With the addition of the neighbouring cells, the radiation doses increased, but remained consistently higher for 161 Tb compared to 177 Lu. For example, the dose to the nucleus of the central cell of the cluster was 15.1 Gy for 161 Tb and 7.2 Gy for 177 Lu in the case of cell surface distribution of the radionuclide, 17.9 Gy for 161 Tb and 8.3 Gy for 177 Lu for intracytoplasmic distribution and 47.8 Gy for 161 Tb and 15.7 Gy for 177 Lu in the case of intranuclear location., Conclusion: 161 Tb should be a better candidate than 177 Lu for irradiating single tumour cells and micrometastases, regardless of the radionuclide distribution.

Background: Targeting G protein-coupled receptors on the surface of cancer cells with peptide ligands is a promising concept for the selective tumor delivery of therapeutically active cargos, including radiometals for targeted radionuclide therapy (TRT). Recently, the radiolanthanide terbium-161 ( 161 Tb) gained significant interest for TRT application, since it decays with medium-energy β-radiation but also emits a significant amount of conversion and Auger electrons with short tissue penetration range. The therapeutic efficiency of radiometals emitting Auger electrons, like 161 Tb, can therefore be highly boosted by an additional subcellular delivery into the nucleus, in order to facilitate maximum dose deposition to the DNA. In this study, we describe the design of a multifunctional, radiolabeled neuropeptide-Y (NPY) conjugate, to address radiolanthanides to the nucleus of cells naturally overexpressing the human Y 1 receptor (hY 1 R). By using solid-phase peptide synthesis, the hY 1 R-preferring [F 7 ,P 34 ]-NPY was modified with a fatty acid, a cathepsin B-cleavable linker, followed by a nuclear localization sequence (NLS), and a DOTA chelator (compound pb12). In this proof-of-concept study, labeling was performed with either native terbium-159 ( nat Tb), as surrogate for 161 Tb, or with indium-111 ( 111 In)., Results: [ nat Tb]Tb-pb12 showed a preserved high binding affinity to endogenous hY 1 R on MCF-7 cells and was able to induce receptor activation and internalization similar to the hY 1 R-preferring [F 7 ,P 34 ]-NPY. Specific internalization of the 111 In-labeled conjugate into MCF-7 cells was observed, and importantly, time-dependent nuclear uptake of 111 In was demonstrated. Study of metabolic stability showed that the peptide is insufficiently stable in human plasma. This was confirmed by injection of [ 111 In]In-pb12 in nude mice bearing MCF-7 xenograft which showed specific uptake only at very early time point., Conclusion: The multifunctional NPY conjugate with a releasable DOTA-NLS unit represents a promising concept for enhanced TRT with Auger electron-emitting radiolanthanides. Our research is now focusing on improving the reported concept with respect to the poor plasmatic stability of this promising radiopeptide.

Ga-labeled prostate-specific membrane antigen inhibitors and Ga-labeled gastrin-releasing peptide receptor antagonists showed interesting results for staging biochemically recurrent prostate cancer. In this case, Ga-prostate-specific membrane antigen-617 PET/CT, Ga-RM2 PET/CT, and F-choline PET/CT were performed in a patient (66-year-old man, prostate-specific antigen = 6.7 ng/mL) with biopsy-proven Gleason 9 (5 + 4) prostate cancer, candidate for radical prostatectomy and lymph node dissection.

Purpose: Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRP-R) are expressed in prostate cancer and can be targeted with radiolabeled inhibitors and antagonists. Their performances for the initial characterization of prostatic tumors have been barely evaluated but never compared. We aimed to gather comparative preclinical data of the role of PSMA and GRP-R targeting in prostate cancer., Procedures: We retrospectively studied 20 frozen prostatectomy samples with various metastatic risks of the D'Amico classification. Tissue samples were investigated by tissular microimaging using the radiolabeled PSMA inhibitor 111 In-PSMA-617 and the radiolabeled GRP-R antagonist 111 In-RM2. Bindings of the two radiopharmaceuticals were compared to histology and clinico-biological data (Gleason score, PSA values, metastatic risks)., Results: Binding of 111 In-PSMA-617 was high whatever the metastatic risk (p = 0.665), Gleason score (p = 0.555), or PSA value (p = 0.404) while 111 In-RM2 exhibited a significantly higher binding in the low metastatic risk group (p = 0.046), in the low PSA value group (p = 0.001), and in samples with Gleason 6 score (p = 0.006)., Conclusion: PSMA and GRP-R based imaging might have complementary performances for the initial characterization of prostatic tumors. Prospective clinical studies comparing the two tracers in this setting are needed.

Neurotensin and its high-affinity receptor, NTR₁, are involved in the growth of various tumors. Few data are available regarding NTR₁ expression in normal and tumoral human prostate tissue samples. NTR₁ expression was assessed using immunohistochemistry in 12 normal prostate tissues, 11 benign prostatic hyperplasia (BPH), 44 prostate cancers, and 15 related metastatic lymph nodes (one per patient, when available). NTR₁-staining was negative in normal prostate and BPH samples. NTR₁ was overexpressed in four out of 44 (9.1%) primary tumors. There was no clear association between NTR₁ overexpression and age, PSA-values, Gleason score, pT-status, nodal-status, or margin. NTR₁ was expressed at a high level of five out of 15 (33.3%) metastatic lymph nodes. NTR₁ overexpression was thus more frequent in metastatic lymph nodes than in primary tumors ( p = 0.038). In this limited series of samples, NTR₁ overexpression was observed in few primary prostate cancers. Upregulation was more frequent in related lymph nodes. The presence of this target in metastatic lymph nodes may open new perspectives for imaging and radionuclide therapy of prostate cancer. Factors driving NTR₁ expression in primary prostate cancer and in nodal and distant metastases still need to be characterized.

The Gastrin-Releasing Peptide Receptor (GRPR) is over-expressed in estrogen receptor (ER) positive breast tumors and related metastatic lymph nodes offering the opportunity of imaging and therapy of luminal tumors. 68Ga-RM2 binding and 18F-FDG binding in tumoral zones were measured and compared using tissue micro-imaging with a beta imager on 14 breast cancer samples (10 primaries and 4 associated metastatic lymph nodes). Results were then assessed against ER expression, progesterone receptor (PR) expression, HER2 over-expression or not and Ki-67 expression. GRPR immunohistochemistry (IHC) was also performed on all samples. We also retrospectively compared 68Ga-RM2 and 18F-FDG bindings to 18F-FDG SUVmax on the pre-therapeutic PET/CT examination, if available. 68Ga-RM2 binding was significantly higher in tumors expressing GRPR on IHC than in GRPR-negative tumors (P = 0.022). In ER+ tumors, binding of 68Ga-RM2 was significantly higher than 18F-FDG (P = 0.015). In tumors with low Ki-67, 68Ga-RM2 binding was also significantly increased compared to 18F-FDG (P = 0.029). Overall, the binding of 68Ga-RM2 and 18F-FDG displayed an opposite pattern in tumor samples and 68Ga-RM2 binding was significantly higher in tumors that had low 18F-FDG binding (P = 0.021). This inverse correlation was also documented in the few patients in whom a 18F-FDG PET/CT examination before surgery was available. Findings from this in vitro study suggest that GRPR targeting can be an alternative to 18F-FDG imaging in ER+ breast tumors. Moreover, because GRPR antagonists can also be labeled with lutetium-177 this opens new avenues for targeted radionuclide therapy in the subset of patients with progressive metastatic disease following conventional treatments., Competing Interests: The authors have declared that no competing interests exist.

A growing body of evidence suggests that gastrin-releasing peptide receptor (GRPR) might be a valuable target in breast cancer. To understand which patients can be potential candidates for GRPR-based imaging or targeted therapy, we screened invasive breast cancers by immunohistochemistry for the presence and intensity of GRPR expression. Methods: We explored a tissue microarray of 1,432 primary breast tumors from patients who underwent surgery between 2000 and 2005 at Institut Bergonié, without prior neoadjuvant treatment. We studied associations between GRPR expression and clinical, pathologic, and biologic parameters. The association between GRPR expression and distant metastasis-free interval was also examined. Results: GRPR overexpression was found in 75.8% of the 1,432 tumors and was most strongly associated with estrogen receptor (ER) positivity (GRPR was high in 83.2% of ER-positive and 12% of ER-negative tumors; P < 0.00001). When molecular subtypes of breast cancer were considered, GRPR was overexpressed in 86.2% of luminal A-like tumors, 70.5% of luminal B-like human epidermal growth factor receptor 2 (HER2)-negative tumors, 82.8% of luminal B-like HER2-positive tumors, 21.3% of HER2-enriched tumors, and 7.8% of triple-negative tumors. Importantly, when breast tumors overexpressed GRPR, high GRPR expression was also found in metastatic lymph nodes in 94.6% of cases. Primary tumors with high GRPR expression were associated with lower risk of distant metastases at follow-up in univariate analysis (Log-rank P = 0.0084) but not in multivariate analysis. Hence, the prognostic impact of GRPR was lost when examined within specific molecular subtypes. Conclusion: Because GRPR is overexpressed in a high percentage of ER-positive tumors, GRPR targeting offers wide perspectives for imaging and treatment in patients with ER-positive breast cancer, using recently developed radiolabeled GRPR ligands., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Context: Somatostatin receptor scintigraphy with (111)In-pentetreotide (SRS) is used to detect duodenopancreatic neuroendocrine tumors (dpNETs) in multiple endocrine neoplasia type 1 (MEN1). However, SRS has limited sensitivity for this purpose. Positron emission tomography/computed tomography (PET/CT) with (68)Ga-DOTA-TOC has a higher rate of sporadic dpNETs detection than SRS but there is little data for dpNETs detection in MEN1., Purpose: To compare the performances of (68)Ga-DOTA-TOC PET/CT, SRS and contrast-enhanced computed tomography (CE-CT) to diagnose dpNETs in MEN1., Design and Setting: Single-institution prospective comparative study, Patients and Methods: Nineteen consecutive MEN1 patients (aged 47 ± 13 years) underwent (68)Ga-DOTA-TOC PET/CT, SRS, and CE-CT within 2 months in random order. Blinded readings of images were performed separately by experienced physicians. Unblinded analysis of CE-CT, combined with additional magnetic resonance imaging, endoscopic-ultrasound, (18)F-2-fluoro-deoxy-D-glucose ((18)F-FDG) PET/CT or histopathology results served as reference standard for dpNETs diagnosis., Results: The sensitivity of (68)Ga-DOTA-TOC PET/CT, SRS, and CE-CT was 76, 20, and 60 %, respectively (p < 0.0001). All the true-positive lesions detected by SRS were also depicted on (68)Ga-DOTA-TOC PET/CT. (68)Ga-DOTA-TOC PET/CT detected lesions of smaller size than SRS (10.7 ± 7.6 and 15.2 ± 5.9 mm, respectively, p < 0.03). False negatives of (68)Ga-DOTA-TOC PET/CT included small dpNETs (<10 mm) and (18)F-FDG PET/CT positive aggressive dpNETs. No false positives were recorded. In addition, whole-body mapping with (68)Ga-DOTA-TOC PET/CT identified extra-abdominal MEN1-related tumors including one neuroendocrine thymic carcinoma identified by the three imaging procedures, one bronchial carcinoid undetected by CE-CT and three meningiomas undetected by SRS., Conclusions: Owing to higher diagnostic performance, (68)Ga-DOTA-TOC PET/CT (or alternative (68)Ga-labeled somatostatin analogues) should replace (111)In-pentetreotide in the investigation of MEN1 patients.

Purpose: Radionuclide therapy is increasingly seen as a promising option to target minimal residual disease. Copper-67, scandium-47 and terbium-161 have a medium-energy β(-) emission which is similar to that of lutetium-177, but offer the advantage of having diagnostic partner isotopes suitable for pretreatment imaging. The aim of this study was to compare the efficacy of (67)Cu, (47)Sc and (161)Tb to irradiate small tumors., Methods: The absorbed dose deriving from a homogeneous distribution of (67)Cu, (47)Sc or (161)Tb in water-density spheres was calculated with the Monte Carlo code CELLDOSE. The diameters of the spheres ranged from 5 mm to 10 µm, thus simulating micrometastases or single tumor cells. All electron emissions, including β(-) spectra, Auger and conversion electrons were taken into account. Because these radionuclides differ in electron energy per decay, the simulations were run assuming that 1 MeV was released per µm(3), which would result in a dose of 160 Gy if totally absorbed., Results: The absorbed dose was similar for the three radionuclides in the 5-mm sphere (146-149 Gy), but decreased differently in smaller spheres. In particular, (161)Tb delivered higher doses compared to the other radionuclides. For instance, in the 100-µm sphere, the absorbed dose was 24.1 Gy with (67)Cu, 14.8 Gy with (47)Sc and 44.5 Gy with (161)Tb. Auger and conversion electrons accounted for 71% of (161)Tb dose. The largest dose differences were found in cell-sized spheres. In the 10-µm sphere, the dose delivered by (161)Tb was 4.1 times higher than that from (67)Cu and 8.1 times that from (47)Sc., Conclusion: (161)Tb can effectively irradiate small tumors thanks to its decay spectrum that combines medium-energy β(-) emission and low-energy conversion and Auger electrons. Therefore (161)Tb might be a better candidate than (67)Cu and (47)Sc for treating minimal residual disease in a clinical setting.

Unlabelled: Radiopharmaceutical therapy, traditionally limited to refractory metastatic cancer, is being increasingly used at earlier stages, such as for treating minimal residual disease. The aim of this study was to compare the effectiveness of (90)Y, (177)Lu, (111)In, and (161)Tb at irradiating micrometastases. (90)Y and (177)Lu are widely used β(-)-emitting radionuclides. (161)Tb is a medium-energy β(-) radionuclide that is similar to (177)Lu but emits a higher percentage of conversion and Auger electrons. (111)In emits γ-photons and conversion and Auger electrons., Methods: We used the Monte Carlo code CELLDOSE to assess electron doses from a uniform distribution of (90)Y, (177)Lu, (111)In, or (161)Tb in spheres with diameters ranging from 10 mm to 10 μm. Because these isotopes differ in electron energy per decay, the doses were compared assuming that 1 MeV was released per μm(3), which would result in 160 Gy if totally absorbed., Results: In a 10-mm sphere, the doses delivered by (90)Y, (177)Lu, (111)In, and (161)Tb were 96.5, 152, 153, and 152 Gy, respectively. The doses decreased along with the decrease in sphere size, and more abruptly so for (90)Y. In a 100-μm metastasis, the dose delivered by (90)Y was only 1.36 Gy, compared with 24.5 Gy for (177)Lu, 38.9 Gy for (111)In, and 44.5 Gy for (161)Tb. In cell-sized spheres, the dose delivered by (111)In and (161)Tb was higher than that of (177)Lu. For instance, in a 10-μm cell, (177)Lu delivered 3.92 Gy, compared with 22.8 Gy for (111)In and 14.1 Gy for (161)Tb., Conclusion: (177)Lu, (111)In, and (161)Tb might be more appropriate than (90)Y for treating minimal residual disease. (161)Tb is a promising radionuclide because it combines the advantages of a medium-energy β(-) emission with those of Auger electrons and emits fewer photons than (111)In., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)