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The incidence of neuroendocrine tumors (NETs) in the US is rising, with 8.3 cases per 100,000 individuals diagnosed in 2018 compared with 6.98 cases per 100,000 individuals diagnosed in 2012. 1,2 Most patients with NETs are diagnosed with metastatic disease, at which point curative surgery is no longer a treatment option. 3 Prior to 2017, available treatments for advanced NETs included somatostatin analogues (lanreotide [Somatuline] and octreotide [Sandostatin]), targeted therapy (everolimus [Afinitor] and sunitinib [Sutent]), and chemotherapy. 4-7 In 2017, the World Health Organization added a classification for well-differentiated grade 3 NETs (Ki67 > 20% and ≤ 55%). 8 Previously these tumors were placed under the umbrella of poorly differentiated neuroendocrine carcinomas. Given that well-differentiated grade 3 NETs are relatively new, standard-of-care treatment options are undefined.

Purpose: Renal and hematological toxicity are side effects and dose-limiting factors of Peptide Receptor Radionuclide Therapy (PRRT). We aimed to assess the changes in renal and hematological function and associations with survival in neuroendocrine tumor (NET) patients treated with PRRT., Methods: A retrospective cohort of 448 NET patients treated with either 177 Lu-DOTATATE or 90 Y-DOTATOC were followed for changes of renal and hematological function. Renal function was assessed by monitoring changes in serum creatinine, blood urea nitrogen and estimated glomerular filtration rate. Hematological function was determined by examining changes in white blood cell counts (WBC), platelet counts, and hemoglobin levels over time. Piecewise linear mixed effect models were applied to model the longitudinal repeated measurements of renal and hematological function. Overall survival (OS) and progression-free survival (PFS) were modelled using Cox proportional hazard regressions., Results: Of the 448 PRRT treated patients, 335 received 177 Lu-DOTATATE (74.78%) and 113 were treated with 90 Y-DOTATOC (25.22%). Comparing patients treated with 177 Lu-DOTATATE to those treated with 90 Y-DOTATOC, renal function did not differ significantly prior to, during or after PRRT. Compared with patients treated with 90 Y-DOTATOC, significantly decreased indicators of hematological function were observed in those treated with 177 Lu-DOTATATE prior to and during PRRT treatment (WBC: estimate, -0.10, 95% CI, -0.15 to -0.05; P < 0.001; platelet count: estimate, -2.53, 95% CI, -3.83 to -1.24; P < 0.001), and no significant recovery was observed in hematological function post PRRT. Individuals who received 177 Lu-DOTATATE tended to have a longer PFS (hazard ratio, 0.47, 95%CI: 0.28-0.79, P = 0.004) compared with 90 Y-DOTATOC, but there was no difference in OS., Conclusion: There was no significant renal, but minor hematological toxicity, in patients treated with 177 Lu-DOTATATE compared with 90 Y-DOTATOC. Compared to 90 Y-DOTATOC, 177 Lu-DOTATATE appears to enhance PFS, but not OS. Treatment with 177 Lu-DOTATATE may necessitate follow-up for hematological toxicity irrespective of other therapies prior to PRRT., (© 2024. The Author(s).)

Abstract: Pheochromocytomas (PHEOs) are neural crest-derived tumors originating from the chromaffin cells of the adrenal medulla and were recognized as one of the subtypes of paragangliomas by the World Health Organization in 2022. 68 Ga-labeled somatostatin analog ( 68 Ga-DOTA-NOC, 68 Ga-DOTA-TOC, and 68 Ga-DOTA-TATE) PET imaging has shown significant performance compared with 123 MIBG scintigraphy in the diagnosis of paragangliomas. It is now known that fibroblast activation protein (FAP) is overexpressed by various cancer-associated fibroblasts, including PHEOs. We would like to present the findings of 68 Ga-DOTA-FAPI-46 PET/CT and 68 Ga-DOTA-TATE PET/CT imaging performed for restaging on a 42-year-old man diagnosed with metastatic PHEO., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The role of somatostatin receptor (SSTR) PET/CT, using 68 Ga-based tracers or [ 64 Cu]Cu-DOTATATE ( 64 Cu-DOTATATE), in the management of patients with neuroendocrine neoplasm (NEN) is guided by appropriate use criteria (AUC). In this study, we performed systematic analyses of referral patterns and image findings of routine 64 Cu-DOTATATE PET/CT scans to support AUC development. Methods: We included all clinical routine 64 Cu-DOTATATE PET/CT scans performed between April 10, 2018 (start of clinical use), and May 2, 2022, at Copenhagen University Hospital-Rigshospitalet. We reviewed the referral text and image report of each scan and classified the indication according to clinical scenarios as listed in the AUC. Results: In total, 1,290 patients underwent 2,249 64 Cu-DOTATATE PET/CT scans. Monitoring of patients with NEN seen both on conventional imaging and on SSTR PET without clinical evidence of progression was the most common indication (defined as "may be appropriate" in the AUC) and accounted for 703 (31.3%) scans. Initial staging after NEN diagnosis ("appropriate" in the AUC) and restaging after curative-intent surgery ("may be appropriate" in the AUC) accounted for 221 (9.8%) and 241 (10.7%) scans, respectively. Selection of patients eligible for peptide receptor radionuclide therapy ("appropriate" in the AUC) and restaging after peptide receptor radionuclide therapy completion ("appropriate" in the AUC) accounted for 95 (4.2%) and 115 (5.1%) scans, respectively. The number of scans performed for indications not defined in the AUC was 371 (16.5%). Image result analysis revealed no disease in 669 scans (29.7%), stable disease in 582 (25.9%), and progression in 461 (20.5%). In 99 of the 461 (21.5%) scans, progression was detected on PET but not on CT. Conclusion: Our study provided real-life data that may contribute to support development of 64 Cu-DOTATATE/SSTR PET/CT guidelines including AUC. Some scenarios listed as "may be appropriate" in the current AUC were frequent in our data. Monitoring of patients with NEN without clinical evidence of progression was the most frequent indication for 64 Cu-DOTATATE PET/CT, in which disease progression was detected in more than one third, and a large proportion was visible by PET only. We therefore conclude that this scenario could potentially be classified as appropriate., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: [ 177 Lu]Lu-DOTATATE is an established somatostatin receptor (SSTR) agonist for the treatment of metastasized neuroendocrine neoplasms, while the SSTR antagonist [ 177 Lu]Lu-DOTA-LM3 has only scarcely been employed in clinics. Impressive preclinical data obtained with [ 161 Tb]Tb-DOTA-LM3 in tumor-bearing mice indicated the potential of terbium-161 as an alternative to lutetium-177. The aim of the present study was to compare the tolerability of 161 Tb- and 177 Lu-based DOTA-LM3 and DOTATATE in immunocompetent mice., Methods: Dosimetry calculations were performed based on biodistribution data of the radiopeptides in immunocompetent mice. Treatment-related effects on blood cell counts were assessed on Days 10, 28 and 56 after application of [ 161 Tb]Tb-DOTA-LM3 or [ 161 Tb]Tb-DOTATATE at 20 MBq per mouse. These radiopeptides were also applied at 100 MBq per mouse and the effects compared to those observed after application of the 177 Lu-labeled counterparts. Bone marrow smears, blood plasma parameters and organ histology were assessed at the end of the study., Results: The absorbed organ dose was commonly higher for the SSTR antagonist than for the SSTR agonist and for terbium-161 over lutetium-177. Application of a therapeutic activity level of 20 MBq [ 161 Tb]Tb-DOTA-LM3 or [ 161 Tb]Tb-DOTATATE was well tolerated without major hematological changes. The injection of 100 MBq of the 161 Tb- and 177 Lu-based somatostatin analogues affected the blood cell counts, however. The lymphocytes were 40-50% lower in treated mice compared to the untreated controls on Day 10 irrespective of the radionuclide employed. At the same timepoint, thrombocyte and erythrocyte counts were 30-50% and 6-12% lower, respectively, after administration of the SSTR antagonist (p < 0.05) while changes were less pronounced in mice injected with the SSTR agonist. All blood cell counts were in the normal range on Day 56. Histological analyses revealed minimal abnormalities in the kidneys, liver and spleen of treated mice. No correlation was observed between the organ dose and frequency of the occurrence of abnormalities., Conclusion: Hematologic changes were more pronounced in mice treated with the SSTR antagonist than in those treated with the SSTR agonist. Despite the increased absorbed dose delivered by terbium-161 over lutetium-177, [ 161 Tb]Tb-DOTA-LM3 and [ 161 Tb]Tb-DOTATATE should be safe at activity levels that are recommended for their respective 177 Lu-based analogues., (© 2024. The Author(s).)

Purpose: This study aims to compare the calculated absorbed dose in target organs and tumors obtained using the different imaging protocols and the calculation methodologies implemented by HERMES HybridViewer dosimetry software for 177 Lu-PSMA I&T and 177 Lu-DOTATATE therapy., Methods: Multiple time-point whole-body planar images and one SPECT/CT image were acquired from 18 patients including 177 Lu-PSMA I&T (13 patients) and 177 Lu-DOTATATE treatment (5 patients) after administration of 3.80-8.58 GBq injected activity. The regions of interest were drawn in the whole body, kidneys, liver, urinary bladder, salivary glands, and tumors to determine the time-integrated activity (TIA) in source organs. Absorbed doses in target organs were calculated according to the Medical Internal Radiation Dose (MIRD) scheme using the HERMES HybridViewer dosimetry integrated with OLINDA/EXM V.2.1 that utilizes the non-uniform rational B-splines (NURBS) for computational digital phantom., Results: The planar-based dosimetry showed a higher dose per injected activity compared to the hybrid-based dosimetry, primarily due to organ overlap. The highest difference in absorbed dose between the imaging scenarios was observed in the spleen with a variation of up to 51.6%, while the difference for other target organs and tumors was less than 40%., Conclusion: The dosimetry calculation derived from the 2D planar-based method consistently demonstrates a significantly higher absorbed dose in organs and tumors compared with the hybrid-based method. However, the hybrid method outperforms the planar method in terms of tumor visualization and overlap-free organ delineation., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Objectives: Somatostatin receptor positron emission tomography/computed tomography (SSTR-PET/CT) using [ 68 Ga]-labeled tracers is a widely used imaging modality for neuroendocrine tumors (NET). Recently, [ 18 F]SiTATE, a SiFAlin tagged [Tyr3]-octreotate (TATE) PET tracer, has shown great potential due to favorable clinical characteristics. We aimed to evaluate the reproducibility of Somatostatin Receptor-Reporting and Data System 1.0 (SSTR-RADS 1.0) for structured interpretation and treatment planning of NET using [ 18 F]SiTATE., Methods: Four readers assessed [ 18 F]SiTATE-PET/CT of 95 patients according to the SSTR-RADS 1.0 criteria at two different time points. Each reader evaluated up to five target lesions per scan. The overall scan score and the decision on peptide receptor radionuclide therapy (PRRT) were considered. Inter- and intra-reader agreement was determined using the intraclass correlation coefficient (ICC)., Results: The ICC analysis on the inter-reader agreement using SSTR-RADS 1.0 for identical target lesions (ICC ≥ 85%), overall scan score (ICC ≥ 90%), and the decision to recommend PRRT (ICC ≥ 85%) showed excellent agreement. However, significant differences were observed in recommending PRRT among experienced readers (ER) (p = 0.020) and inexperienced readers (IR) (p = 0.004). Compartment-based analysis demonstrated good to excellent inter-reader agreement for most organs (ICC ≥ 74%), except for lymph nodes (ICC ≥ 53%)., Conclusion: SSTR-RADS 1.0 represents a highly reproducible and consistent framework system for stratifying SSTR-targeted PET/CT scans, even using the novel SSTR-ligand [ 18 F]SiTATE. Some inter-reader variability was observed regarding the evaluation of uptake intensity prior to PRRT as well as compartment scoring of lymph nodes, indicating that those categories require special attention during further clinical validation and might be refined in a future SSTR-RADS version 1.1., Clinical Relevance Statement: SSTR-RADS 1.0 is a consistent framework for categorizing somatostatin receptor-targeted PET/CT scans when using [ 18 F]SiTATE. The framework serves as a valuable tool for facilitating and improving the management of patients with NET., Key Points: SSTR-RADS 1.0 is a valuable tool for managing patients with NET. SSTR-RADS 1.0 categorizes patients with showing strong agreement across diverse reader expertise. As an alternative to [ 68 Ga]-labeled PET/CT in neuroendocrine tumor imaging, SSTR-RADS 1.0 reliably classifies [ 18 F]SiTATE-PET/CT., (© 2024. The Author(s).)

Purpose: Small cell lung cancer (SCLC) is a highly aggressive tumor with neuroendocrine origin. Although SCLC frequently express somatostatin receptor type 2 (SSTR2), a significant clinical benefit of SSTR2-targeted radionuclide therapies of SCLC was not observed so far. We hypothesize that combination treatment with a PARP inhibitor (PARPi) could lead to radiosensitization and increase the effectiveness of SSTR2-targeted therapy in SCLC., Methods: SSTR2-ligand uptake of the SCLC cell lines H69 and H446 was evaluated in vitro using flow cytometry, and in vivo using SPECT imaging and cut-and-count biodistribution. Single-agent (Olaparib, Rucaparib, [ 177 Lu]Lu-DOTA-TOC) and combination treatment responses were determined in vitro via cell viability, clonogenic survival and γH2AX DNA damage assays. In vivo, we treated athymic nude mice bearing H69 or H446 xenografts with Olaparib, Rucaparib, or [ 177 Lu]Lu-DOTA-TOC alone or with combination treatment regimens to assess the impact on tumor growth and survival of the treated mice., Results: H446 and H69 cells exhibited low SSTR2 expression, i.e. 60 to 90% lower uptake of SSTR2-ligands compared to AR42J cells. In vitro, combination treatment of [ 177 Lu]Lu-DOTA-TOC with PARPi resulted in 2.9- to 67-fold increased potency relative to [ 177 Lu]Lu-DOTA-TOC alone. We observed decreased clonogenic survival and higher amounts of persistent DNA damage compared to single-agent treatment for both Olaparib and Rucaparib. In vivo, tumor doubling times increased to 1.6-fold (H446) and 2.2-fold (H69) under combination treatment, and 1.0 to 1.1-fold (H446) and 1.1 to 1.7-fold (H69) in monotherapies compared to untreated animals. Concurrently, median survival was higher in the combination treatment groups in both models compared to monotherapy and untreated mice. Fractionating the PRRT dose did not lead to further improvement of therapeutic outcome., Conclusion: The addition of PARPi can markedly improve the potency of SSTR2-targeted PRRT in SCLC models in SSTR2 low-expressing tumors. Further evaluation in humans seems justified based on the results as novel treatment options for SCLC are urgently needed., (© 2024. The Author(s).)

Objective: When patients administered 177 Lu-DOTATATE are released or discharged from rooms where radiopharmaceuticals are used, the time required for release or discharge varies across patients. This study investigated whether the amount of radioactivity accumulated on 111 In-somatostatine receptor scintigraphy ( 111 In-SRS) performed prior to treatment can predict the 1 cm dose-equivalent rate at a distance of 1 m from the patient on the day after 177 Lu-DOTATATE administration., Methods: Whole-body planar 111 In-SRS images were acquired for 21 patients. Pixel values within whole-body and abdominal (35 × 25 cm) regions of interest (ROIs) were converted to radioactivity dose (MBq). The 1 cm dose-equivalent rate (µSv/h) at a distance of 1 m from the patient 18.3 ± 0.5 h after administration of 177 Lu-DOTATATE was measured using an ionization survey meter., Results: The following relationships were observed between the radioactivity on 111 In-SRS and the 1 cm dose-equivalent rate on the day after administration of 177 Lu-DOTATATE: whole-body ROI: y = 0.16x + 5.01 (r = 0.56, p = 0.009), abdominal ROI: y = 0.27x + 5.13 (r = 0.63, p = 0.002). The regression equations indicate that patients cannot be released or discharged from the radiopharmaceutical room the day after 177 Lu-DOTATATE administration if the whole-body and abdominal ROI doses are greater than 81 and 48 MBq, respectively, on 111 In-SRS., Conclusions: The amount of radioactivity accumulated on 111 In-SRS may be a predictor of release criteria for patients receiving 177 Lu-DOTATATE., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Vertebral tumors in patients with tumor-induced osteomalacia (TIO) have a low diagnostic rate and poor postoperative outcomes. The application of 68  Ga-DOTATATE-PET/CT significantly increased the detection rate. Compared with tumor curettage, segmental resection was recommended as the preferred surgical type due to its high recovery rate., Purpose: Tumor-induced osteomalacia (TIO) is an acquired hypophosphatemic osteomalacia, and surgery is the first-line therapy. Most TIO tumors are found in the bones of the appendicular skeleton, cranium, and paranasal sinuses but rarely in the vertebrae. Tumor curettage and segmental resection are the two main surgical options for vertebral TIO patients. However, research on the clinical characteristics and surgical prognosis of vertebral TIO patients is rare. In the present study, for the first time, we investigated the clinical characteristics of 16 vertebral TIO patients and compared the surgical outcomes of patients who underwent surgery via two different surgical methods., Methods: This was a retrospective cohort study. In this study, we included 16 adult TIO patients with lesions in vertebrae from Peking Union Medical College Hospital (PUMCH), all of whom underwent surgery. Baseline laboratory data were collected through medical records review. Technetium-99 m octreotide scintigraphy ( 99 Tc m -OCT) and 68 gallium-DOTA-TATE-positron emission tomography/computed tomography ( 68  Ga-DOTATATE-PET/CT) were conducted at the Department of Nuclear Medicine of PUMCH. The tumor histopathology was confirmed by a senior pathologist at our center., Results: Vertebral TIO patients had lower serum phosphorus and TmP/GFR and higher serum alkaline phosphatase (ALP), serum parathyroid hormone (PTH), and serum C-terminal cross-linked telopeptide of type I collagen (β-CTX) levels than the normal range. The sensitivity of 68  Ga‒DOTATATE PET/CT was 100%, significantly greater than that of 99 Tc m -OCT (40%). After comparing the outcomes between the two surgical methods, we found that the recovery rate after segmental resection (62.5%) was greater than that after tumor curettage (12.5%). In the thoracic and sacral vertebrae, segmental resection surgery had a good prognosis., Conclusion: 68  Ga-DOTATATE PET/CT could serve as the first diagnostic tool in patients with vertebral TIO, and segmental resection could be used as the preferred surgery. This study would raise awareness of the clinical features and management of these rare vertebral TIO patients., (© 2024. The Author(s).)

Pre-clinical data suggest that mutations in the MEN1, DAXX, and/or ATRX genes may potentially increase radiation efficacy in cancer cells. Herein, we explore the association between response to peptide receptor radionuclide therapy (PRRT) and those mutations in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We analyzed tissue-based next generation sequencing (NGS) assay results and clinicopathologic data from 28 patients with GEP-NETs treated with PRRT. Findings were correlated with progression-free survival (PFS) and objective response rate (ORR). Patients with mutations in MEN1, DAXX, and/or ATRX (n = 13) had a longer median PFS (26.47 vs 12.13 months; P = 0.014) than wild-type (n = 15) patients when adjusted for surgery prior to PRRT, tumor grade, and presence of TP53 mutation. Alterations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended toward longer PFS compared to patients without concurrent mutations (31.53 vs 17.97 months; P = 0.09). ORR was higher in patients with a mutation in MEN1, DAXX, or ATRX (41.67% vs 15.38%). In pancreatic NET patients, these target mutations also showed a longer PFS (28.43 vs 9.83 months; P = 0.04). TP53 alterations showed a shorter PFS than wild-type cases (11.17 vs 20.47 months; P = 0.009). Mutations in MEN1/DAXX/ATRX are associated with improved PFS in patients with GEP-NETs receiving PRRT and might be used as a biomarker for treatment response.

Our objective is to explore quantitative imaging markers for early prediction of treatment response in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) undergoing [ 177 Lu]Lu-DOTATATE therapy. By doing so, we aim to enable timely switching to more effective therapies in order to prevent time-resource waste and minimize toxicities. Methods: Patients diagnosed with unresectable or metastatic, progressive, well-differentiated, receptor-positive GEP-NETs who received 4 sessions of [ 177 Lu]Lu-DOTATATE were retrospectively selected. Using SPECT/CT images taken at the end of treatment sessions, we counted all visible tumors and measured their largest diameters to calculate the tumor burden score (TBS). Up to 4 target lesions were selected and semiautomatically segmented. Target lesion peak counts and spleen peak counts were measured, and normalized peak counts were calculated. Changes in TBS (ΔTBS) and changes in normalized peak count (ΔnPC) throughout treatment sessions in relation to the first treatment session were calculated. Treatment responses were evaluated using third-month CT and were binarized as progressive disease (PD) or non-PD. Results: Twenty-seven patients were included (7 PD, 20 non-PD). Significant differences were observed in ΔTBS second-first , ΔTBS third-first , and ΔTBS fourth-first (where second-first, third-first, and fourth-first denote scan number between the second and first, third and first, and fourth and first [ 177 Lu]Lu-DOTATATE treatment cycles), respectively) between the PD and non-PD groups (median, 0.043 vs. -0.049, 0.08 vs. -0.116, and 0.109 vs. -0.123 [ P = 0.023, P = 0.002, and P < 0.001], respectively). ΔnPC second-first showed significant group differences (mean, -0.107 vs. -0.282; P = 0.033); ΔnPC third-first and ΔnPC fourth-first did not reach statistical significance (mean, -0.122 vs. -0.312 and -0.183 vs. -0.405 [ P = 0.117 and 0.067], respectively). At the optimal threshold, ΔTBS fourth-first exhibited an area under the curve (AUC) of 0.957, achieving 100% sensitivity and 80% specificity. ΔTBS second-first and ΔTBS third-first reached AUCs of 0.793 and 0.893, sensitivities of 71.4%, and specificities of 85% and 95%, respectively. ΔnPC second-first , ΔnPC third-first , and ΔnPC fourth-first showed AUCs of 0.764, 0.693, and 0.679; sensitivities of 71.4%, 71.4%, and 100%; and specificities of 75%, 70%, and 35%, respectively. Conclusion: ΔTBS and ΔnPC can predict [ 177 Lu]Lu-DOTATATE response by the second treatment session., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Advancements in somatostatin receptor (SSTR) targeted imaging and treatment of well-differentiated neuroendocrine tumors (NETs) have revolutionized the management of these tumors. This comprehensive review delves into the current practice, discussing the use of the various FDA-approved SSTR-agonist PET tracers and the predictive imaging biomarkers, and elaborating on Lu177-DOTATATE peptide receptor radionuclide therapy (PRRT) including the evolving areas of post-therapy imaging practices, PRRT retreatment, and the potential role of dosimetry in optimizing patient treatments. The future directions sections highlight ongoing research on investigational PET imaging radiotracers, future prospects in alpha particle therapy, and combination therapy strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Preclinical data have shown that 161 Tb-labeled peptides targeting the somatostatin receptor are therapeutically more effective for peptide receptor radionuclide therapy than are their 177 Lu-labeled counterparts. To further substantiate this enhanced therapeutic effect, we performed cellular dosimetry to quantify the absorbed dose to the cell nucleus and compared dose-response curves to evaluate differences in relative biological effectiveness in vitro. Methods: CA20948 cell survival was assessed after treatment with [ 161 Tb]Tb- and [ 177 Lu]Lu-DOTATATE (agonist) and with [ 161 Tb]Tb- and [ 177 Lu]Lu-DOTA-LM3 (antagonist) via a clonogenic assay. Cell binding, internalization, and dissociation assays were performed up to 7 d to acquire time-integrated activity coefficients. Separate S values for each type of particle emission (Auger/internal conversion [IC] electrons and β - particles) were computed via Monte Carlo simulations, while considering spheric cells. Once the absorbed dose to the cell nucleus was calculated, survival curves were fitted to the appropriate linear or linear-quadratic model and corresponding relative biological effectiveness was evaluated. Results: Although the radiopeptide uptake was independent of the radionuclide, [ 161 Tb]Tb-DOTATATE and [ 161 Tb]Tb-DOTA-LM3 delivered a 3.6 and 3.8 times higher dose to the nucleus, respectively, than their 177 Lu-labeled counterparts on saturated receptor binding. This increased nucleus-absorbed dose was mainly due to the additional emission of IC and not Auger electrons by 161 Tb. When activity concentrations were considered, both [ 161 Tb]Tb-DOTATATE and [ 161 Tb]Tb-DOTA-LM3 showed a lower survival fraction than did labeling with 177 Lu. When the absorbed dose to the nucleus was considered, no significant difference could be observed between the dose-response curves for [ 161 Tb]Tb- and [ 177 Lu]Lu-DOTATATE. [ 161 Tb]Tb-DOTA-LM3 showed a linear-quadratic dose response, whereas [ 161 Tb]Tb-DOTATATE showed only a linear dose response within the observed dose range, suggesting additional cell membrane damage by Auger electrons. Conclusion: The IC, rather than Auger, electrons emitted by 161 Tb resulted in a higher absorbed dose to the cell nucleus and lower clonogenic survival for [ 161 Tb]Tb-DOTATATE and [ 161 Tb]Tb-DOTA-LM3 than for the 177 Lu-labeled analogs. In contrast, [ 161 Tb]Tb-DOTATATE showed no higher dose response than [ 177 Lu]Lu-DOTATATE, whereas for [ 161 Tb]Tb-DOTA-LM3 an additional quadratic response was observed. Because of this quadratic response, potentially caused by cell membrane damage, [ 161 Tb]Tb-DOTA-LM3 is a more effective radiopeptide than [ 161 Tb]Tb-DOTATATE for labeling with 161 Tb., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Abstract: Glioblastoma multiforme (GBM) is a highly vascularized tumor with reported high prostate-specific membrane antigen (PSMA) expression. On the other hand, bevacizumab as an antiangiogenesis drug is increasingly used in the treatment of GBM recurrence. We present a case of GBM recurrence with significant reduction of 99m Tc-HYNIC-PSMA-11 uptake in her tumor 1 week after administration of 2 doses of bevacizumab with 2 weeks' interval. This case emphasizes the main mechanism of PSMA uptake in GBM secondary to angiogenesis and also implies a potential interaction of bevacizumab with PSMA uptake that should be especially considered during diagnostic and therapeutic application of PSMA radiotracers in GBM., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: A 61-year-old man underwent splenopancreasectomy for a 3-cm neuroendocrine tumor of the body of the pancreas (G2, pT1 pN0, Ki67 3%). Five months after surgery 68 Ga-DOTATOC PET/CT showed increased radiotracer uptake in a solid tissue of the splenic fossa, possibly referring to a splenosis nodule. After 19 months, a further 68 Ga-DOTATOC PET/CT showed a significant functional and dimensional increase of the previously detected tissue and the appearance of a new finding in the left lateral abdominal wall. In the suspicion of neuroendocrine tumor relapse, the patient underwent surgical excision of the documented lesions. Histology showed splenosis in both nodules., Competing Interests: Conflicts of interest and sources of funding: G.R. received speaker and consultant honoraria from AAA and Bracco Imaging, respectively. The other authors have no relevant financial or nonfinancial interests to disclose. The authors declare that no funds, grants, or other supports were received during the preparation of this manuscript., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Patients with advanced, well-differentiated neuroendocrine tumors (WD-NETs) often require both peptide receptor radionuclide therapy (PRRT) and subsequent chemotherapy. However, no mid-PRRT predictors are available to identify patients who will not benefit from subsequent PRRT to limit their radiation exposure. Our aim is to characterize patients for whom subsequent PRRT is less efficacious on the basis of mid-PRRT evaluation., Materials and Methods: A retrospective study of patients with WD-NET who underwent ≥four PRRT cycles. Data gathered included demographics, tumor grade, stage, and response (partial response [PR], stable disease [SD], and progressive disease [PD]) on the basis of RECIST 1.1 criteria and 68 Ga-dotatate positron emission tomography-computerized tomography pretreatment, after second and fourth treatment cycle, 6 months after fourth cycle, and at last follow-up., Results: Fifty-one patients (51.6% women; age at diagnosis 66.0 ± 1.65 years), with pancreatic NET (PNET; n = 24), small intestine NET (n = 13), or other NET (n = 14), received PRRT, resulting in PR (n = 21), SD (n = 23), and PD (n = 3). Of the patients reaching PR after PRRT, most reached PR after two treatments (70.4%), with only 11.8% PR occurring between subsequent cycles ( P = .001). Furthermore, patients with PR at mid-treatment had higher PR rates after PRRT completion than those with SD ( P = .007). Patients harboring PNET who achieved PR had a more pronounced reduction of tumor burden in additional cycles than patients who did not (25.6% v 1.5%; P = .03, respectively). On the multivariable model, adjusted for grade and primary site, PR at mid-treatment evaluation was associated with a 20.9 adjusted odds ratio for additional PR at PRRT completion ( P = .002)., Conclusion: Mid-PRRT assessment predicts subsequent PRRT response in patients with WD-NET, especially those with PNET, informing personalized management and consideration of reduced bone marrow radiation exposure in high-risk patients.

Purpose: Well-differentiated neuroendocrine neoplasms (NETs) overexpress the somatostatin receptor, which is the target for the peptide receptor radionuclide therapy (PRRT). NETs have a slow growth rate and can metastasize to liver, bone, and lungs. In NETs patients, liver metastasis is an important prognostic marker because liver failure is one of the most common causes of death in this population. In this regard, we aimed to describe the changes in laboratorial parameters in patients submitted to PRRT with 177 Lu-DOTATATE, focusing on hepatic parameters., Patients and Methods: One hundred ten patients treated with 1 to 4 cycles of 7.4 GBq (200 mCi) of 177 Lu-DOTATATE from January 2011 to December 2021 were analyzed in this retrospective observational single-center study. Patients were submitted to blood tests before and after each cycle of PRRT. Laboratory measurements were collected to assess liver function, cholestasis, kidney, and bone marrow function., Results: In the general population (n = 110), ALP ( P = 0.013) and GGT ( P < 0.001) showed a statistically significant reduction. Patients with high liver disease volume showed a statistically significant reduction in ALT ( P = 0.016), whereas patients with low liver disease volume showed a statistically significant reduction in GGT ( P = 0.013). All parameters for bone marrow function showed a statistically significant decrease in all population subsets., Conclusions: Patients treated with 177 Lu-DOTATATE showed a significant improvement in liver function and cholestasis parameters, and a consistent decrease in bone marrow function, even in the presence of advanced liver disease., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The aim of the present study was to evaluate the safety and efficacy of radionuclide therapy with [ 177 Lu]Lu-DOTA-TATE according to our single center experience at the University of Naples Federico II. For the present analysis, we considered 21 patients with progressive, advanced, well-differentiated G1 and G2 in patients with gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs) treated with [ 177 Lu]Lu-DOTA-TATE according to the decisions of a multidisciplinary team. All patients underwent four cycles of 7-8 GBq of [ 177 Lu]Lu-DOTA-TATE every 8 weeks. A whole-body scan (WBS) was performed 4, 48, and 168 h after each treatment. The dosimetry towards the organ at risk and target lesions was calculated. For each patient, renal and bone marrow parameters were evaluated before, during, and 3 months after the end of the treatment. Follow-up data were obtained and RECIST criteria were considered as the endpoint. Among 21 patients enrolled (mean age 65 ± 9 years); 17 (81%) were men and the small intestine was the most frequent location of disease (n = 12). A mild albeit significant variation ( p < 0.05) in both platelets and white blood cell counts among all time points was observed, despite it disappearing 3 months after the end of the therapy. According to the RECIST criteria, 11 (55%) patients had a partial response to therapy and 8 (40%) had stable disease. Only one (5%) patient had disease progression 4 months after treatment. Our data confirm that [ 177 Lu]Lu-DOTA is safe and effective in controlling the burden disease of G1/G2 GEP-NETs patients.

Proper collimator selection is critical to obtaining high-quality, interpretable nuclear medicine images. Collimators help eliminate scatter, which leads to poor spatial resolution and blurry images. We present the case of a posttherapy 177 Lu-DOTATATE (Lutathera) patient who was initially imaged with a low-energy, high-resolution collimator routinely used in 99m Tc imaging. On image review, the patient was reimaged with the appropriate medium-energy, high-resolution collimator, which resulted in improved image quality. When reviewing the quality of images, it is important to understand modifications to the imaging that can significantly improve image quality and interpretation., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

177 Lu-DOTATATE is an effective second-line treatment for metastatic or nonresectable neuroendocrine tumors. This treatment can result in hematologic severe adverse reactions (SARs). Preemptive identification of patients at risk of SARs could mitigate this risk and improve treatment safety and outcomes. Methods: Demographic and oncologic history, pretreatment laboratory values, and SAR frequency were obtained for 126 sequential patients treated with 177 Lu-DOTATATE. Univariable and multivariable logistic regression models identified factors correlating with SARs. Results: Relative pretreatment anemia, leukopenia, thrombocytopenia, and elevated mean corpuscular volume (MCV) were significantly correlated with SARs, with an odds ratio of 16 (95% CI, 5-65) in patients with an MCV greater than 95 fL. Conclusion: Pretreatment bone marrow dyscrasias, including an MCV greater than 95 fL, may predict patients at risk for SARs when treated with 177 Lu-DOTATATE. Further study is needed to determine whether the risks of SARs outweigh the benefit in these patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Everolimus and peptide receptor radionuclide therapy (PRRT, 177 Lu-DOTATATE) are 2 treatments recommended in guidelines for gastroenteropancreatic metastatic neuroendocrine tumors. However, the best treatment sequence remains unknown. Methods: We designed a retrospective multicenter study that included patients from the national prospective database of the Groupe d'Étude des Tumeurs Endocrines who had been treated using everolimus and PRRT between April 2004 and October 2022. The primary aim was to compare the 2 treatments (everolimus and PRRT) in terms of efficacy and safety, and the secondary aim was to evaluate the sequences (PRRT followed by everolimus or everolimus followed by PRRT) based on overall progression-free survival (PFS) (PFS during first treatment + PFS during second treatment) in patients with metastatic neuroendocrine tumors. Results: Both treatments were used for 84 patients. The objective response rate and median PFS were 5 (6.0%) and 16.1 mo (95% CI, 11.5-20.7 mo), respectively, under everolimus and 19 (22.6%) and 24.5 mo (95% CI, 17.7-31.3 mo), respectively, for PRRT. The safety profile was also better for PRRT. Median overall PFS was 43.2 mo (95% CI, 33.7-52.7 mo) for the everolimus-PRRT sequence and 30.6 mo (95% CI, 17.8-43.4 mo) for the PRRT-everolimus sequence (hazard ratio, 0.69; 95% CI, 0.39-1.24; P = 0.22). Conclusion: PRRT was more effective and less toxic than everolimus. Overall PFS was similar between the 2 sequences, suggesting case-by-case discussion if the patient is eligible for both treatments, but PRRT should be used first when an objective response is needed or in frail populations., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Recurrence of meningiomas after surgery and radiotherapy deserves specific attention because of the lack of active third-line therapies. Somatostatin receptors are usually overexpressed on the cell membrane of meningiomas, and this has led the way to a radionuclide theranostic approach. Diagnoses with 68 Ga-DOTA-octreotide and peptide receptor radionuclide therapy (PRRT) with 90 Y/ 177 Lu-DOTA-octreotide are currently possible options within experimental protocols or as compassionate use in small patient groups. Methods: From October 2009 to October 2021, 42 meningioma patients with radiologic recurrence after standard therapies were treated with 90 Y-DOTATOC (dosage of 1.1 or 5.5 GBq) or with 177 Lu-DOTATATE (dosage of 3.7 or 5.5 GBq) in a mean of 4 cycles. All patients showed intense uptake at diagnostic 68 Ga-DOTATOC PET/CT or in an 111 In-octreotide scan. Results: Of 42 patients treated, 5 patients received 90 Y-DOTATOC with a cumulative activity of 11.1 GBq and 37 patients received 177 Lu-DOTATATE with a cumulative activity of 22 GBq. The disease control rate was 57%. With a median follow-up of 63 mo, median progression-free survival was 16 mo, and median overall survival was 36 mo. Retreatment 177 Lu-PRRT was performed in 6 patients with an administered median activity of 13 GBq in a mean of 5 cycles. With a 75.8-mo follow-up, median progression-free survival and overall survival were 6.5 and 17 mo, respectively. Only 1 patient discontinued the treatment because of grade 3 platelet toxicity. A rapidly transient grade 2 neutropenia was recorded in 1 retreated patient. Conclusion: PRRT in patients with advanced meningiomas overexpressing somatostatin receptor 2 was active and well tolerated, showing a 57% disease control rate. Furthermore, PRRT could represent a potential retreatment option. Further studies, also in combination with other treatments, are warranted., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Somatostatin receptor (SSTR) imaging features are predictive of treatment outcome for neuroendocrine tumor (NET) patients receiving peptide receptor radionuclide therapy (PRRT). However, comprehensive (all metastatic lesions), longitudinal (temporal variation), and lesion-level measured features have never been explored. Such features allow for capturing the heterogeneity in disease response to treatment. Furthermore, models combining these features are lacking. In this work we evaluated the predictive power of comprehensive, longitudinal, lesion-level 68 GA-SSTR-PET features combined with a multivariate linear regression (MLR) model., Methods: This retrospective study enrolled NET patients treated with [ 177 Lu]Lu-DOTA-TATE and imaged with [ 68 Ga]Ga-DOTA-TATE at baseline and post-therapy. All lesions were segmented, anatomically labeled, and longitudinally matched. Lesion-level uptake and variation in uptake were measured. Patient-level features were engineered and selected for modeling of progression-free survival (PFS). The model was validated via concordance index, patient classification (ROC analysis), and survival analysis (Kaplan-Meier and Cox proportional hazards). The MLR was benchmarked against single feature predictions., Results: Thirty-six NET patients were enrolled and stratified into poor and good responders (PFS ≥ 25 months). Four patient-level features were selected, the MLR concordance index was 0.826, and the AUC was 0.88 (0.85 specificity, 0.81 sensitivity). Survival analysis led to significant patient stratification (p<.001) and hazard ratio (3⨯10 -5 ). Lastly, in a benchmark study, the MLR modeling approach outperformed all the single feature predictors., Conclusion: Comprehensive, lesion-level, longitudinal 68 GA-SSTR-PET analysis, combined with MLR modeling, leads to excellent predictions of PRRT outcome in NET patients, outperforming non-comprehensive, patient-level, and single time-point feature predictions., Message: Neuroendocrine tumor, peptide receptor radionuclide therapy, Somatostatin Receptor Imaging, Outcome Prediction, Treatment Response Assessment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study aimed to develop a user-friendly prediction formula for dose rate adjustment after initial 177 Lu-Dotatate therapy from a prospective observational study of patients., Materials and Methods: This study included consenting patients in a prospective observational study who underwent their first treatment in four cycles of 177 Lu-Dotatate treatment at our hospital between January 2022 and February 2024. All patients received 7.4 GBq of 177 Lu-Dotatate. The prediction formula was derived from the regression analysis of tumor-related factors and renal function. Creatinine clearance was estimated using the Cockcroft-Gault equation in this study for renal function., Results: Among the 13 patients (seven males, six females, median age: 59 years), logarithmically transformed total tumor volume (cc) and maximum tumor diameter (mm) of primary tumors or metastases showed strong correlations (p < 0.001, R 2  = 0.897). As such, the maximum tumor diameter was used as the tumor parameter in the prediction formula. Additionally, maximum tumor diameter and creatinine clearance showed strong (p < 0.001, R 2  = 0.768) and moderate (p = 0.013, R 2  = 445) correlations, respectively, with the ratio of the dose rate 5.5-h post-administration to the dose rate immediately post-administration (%) at 1 m from the body surface. The resulting formula, 51.4 + 0.360 × maximum tumor diameter (mm) - 0.212 × creatinine clearance (ml/min), demonstrated an extremely strong correlation (p < 0.001, R 2  = 0.937)., Conclusion: The present study showed that the maximum tumor diameter and renal function affected the declining the dose rate of patients surface after 177 Lu-Dotatate, which can inform post-administration dose rate management and potentially facilitate outpatient treatment in Japan., (© 2024. The Author(s).)

Purpose: Gastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [ 177 Lu]-DOTA-TATE was approved for the treatment of GEP-NETs after the phase III NETTER 1trial demonstrated improved progression free survival, objective response rates and health-related quality of life (HRQoL) compared to high-dose somatostatin analogues. No real-world data exist on prescribing habits and clinically significant endpoints for [ 177 Lu]Lu-DOTA-TATE treatment in Italy. REAL-LU is a multicentre, long-term observational study in patients with unresectable/metastatic GEP-NETs progressing on standard therapies in Italian clinical practice. A pre-specified interim analysis was performed at the end of the enrolment period, data from which are described herein., Methods: Overall duration of REAL-LU will be approximately 48 months, with 12- and 36-month recruitment and follow-up periods, respectively. The primary objective is to evaluate [ 177 Lu]Lu-DOTA-TATE effectiveness in terms of progression-free survival. Secondary objectives include safety, impact on HRQoL, and identification of prognostic factors. This pre-specified interim analysis describes patient profiles, at the end of enrollment, of those prescribed [ 177 Lu]Lu-DOTA-TATE for GEP-NETs in Italy., Results: Among 161 evaluable patients, mean age was 64.7 ± 10.3 years at study entry, 83.8% presented with no clinical signs of disease at physical examination, and most had minor disease symptoms. All patients had metastatic disease, most commonly in the liver (83.9%) with a median of two metastatic sites. In 90.7% of patients, the disease was stage IV, and 68.3% had ≥ 1 target lesion. [ 177 Lu]Lu-DOTA-TATE was prescribed mainly as second-line therapy (61.6%) and following surgery (58.4%). HRQoL assessments revealed high levels of functioning and low levels of symptoms at baseline; 50.0% of patients were symptom-free at study entry., Conclusion: The characteristics of patients who received [177Lu]Lu-DOTA-TATE in Italy are similar to those of the GEP-NET population of NETTER 1 with trial but with a higher proportion of patients with a grade 2 (71%). With regard to the tumor grade profile, our study cohort appears to be closer to that of NETTER-2 study population which included patients with G2 or G3 advanced GEP-NETs (i.e. Ki-67 ≥ 10% and ≤ 55%). Further analysis of effectiveness and safety can be anticipated as REAL-LU data mature., Study Registration: ClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1., (© 2024. The Author(s).)

Abstract: A 76-year-old woman with liver and bone metastasis of a duodenal neuroendocrine tumor received peptide receptor radionuclide therapy with 177 Lu-DOTATATE. Scintigraphy with SPECT/CT performed 4 days after the treatment demonstrated 177 Lu-DOTATATE uptake as multifocal ground glass opacities in the bilateral lungs. This uptake was considered to be due to COVID-19 pneumonia because the patient was infected with the virus 7 days prior to the treatment. The lung opacities became smaller, showing a decreased uptake, 2 months later, after the second treatment. 177 Lu-DOTATATE may be taken up during the active phase of COVID-19 pneumonia., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The aim of this study was to assess the association among toxicity, dosimetry of organs-at-risk, and disease progression in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with 177 Lu-DOTATATE., Patients and Methods: Thirty-seven patients with GEP-NETs underwent 177 Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in a single-arm, prospective, phase 2 study, where patients were followed up with blood tests, isotopic glomerular filtration rate (iGFR), and imaging examinations (CT/MRI and PET) every 6 months until disease progression. Adverse events (AEs) graded per CTCAEv4.03 and occurring during treatment were collected and followed up until resolution. Dosimetry, including biologically effective doses (BEDs) to kidneys, BED to bone marrow, and absorbed dose (AD) to spleen, was performed after each PRRT cycle. Statistical analyses explored associations among dosimetry, toxicity, and patient progression free-survival., Results: The most common AEs were anemia and lymphopenia (65%), followed by thrombocytopenia and fatigue (each 51%), alopecia (46%), and nausea (41%). The most common grade ≥3 AE was lymphopenia (43%). There was no grade ≥3 nephrotoxicity. The median iGFR % decrease was 11% ( P < 0.001), at a median follow-up of 23 months. iGFR %decrease and renal BED did not correlate (Spearman ρ = -0.09). Similarly, no significant association was found between bone marrow BED or spleen AD and the grades of hematological toxicities. We observed no association between progression free-survival and either the decline of renal function or the occurrence of hematological toxicities during PRRT., Conclusions: This study confirms the safety profile of 177 Lu-DOTATATE PRRT in patients with GEP-NETs irrespective of the dosimetry of organs at risk. Kidney, bone marrow, and spleen dosimetry measures were not associated with renal or hematological toxicity., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: In a prior, retrospective study, 76% of patients with advanced neuroendocrine tumors undergoing 177 Lu-DOTATOC molecular radiotherapy (MRT) showed their best response within 8 months from the first MRT cycle. In 24% of patients, latency was much greater up to >22 months after the first cycle, and long after near-complete decay of 177 Lu from the last cycle. An immune response induced by MRT seems a likely explanation. As a crude measure of immunocompetence, the authors investigated whether blood cell counts (BCCs) may have predictive value for MRT outcome with 177 Lu-DOTATOC. Methods: 56 Patients with neuroendocrine tumors (NET) were administered 177 Lu-DOTATOC (mean 2.1 cycles; range 1-4) with median radioactivity of 7.0 GBq/cycle at 3-month intervals. Patients' BCCs were evaluated for four responder categories: CR, PR, SD, and PD (RECIST 1.1). Furthermore, baseline BCCs were correlated with progression-free survival (PFS). Finally, BCCs of patients with (PMT + ) and without prior medical therapy (PMT - ) were compared. Results: Significant differences between responder categories were found for baseline hemoglobin (Hb), erythrocytes, neutrophils, lymphocytes, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and LEHN-score, integrating lymphocyte, erythrocyte, and neutrophil counts, and Hb level, but not for leukocytes and platelets. LEHN-score yielded an almost complete separation between CR and PD groups. In analogy, PFS times showed significant correlations with baseline Hb, erythrocytes, neutrophils, lymphocytes, NLR, PLR, and LEHN-score, the LEHN-score showing the strongest correlation, but not with leukocytes and platelets. For PMT - patients, median PFS was 34.5 months, compared with 20.8 months in PMT + patients, with corresponding baseline lymphocyte (32.1 ± 9.6% vs. 24.5 ± 11.6%, p = 0.028) and neutrophil (54.9 ± 11.6% vs. 63.5 ± 13.7%, p = 0.039) counts. Conclusion: These findings emphasize the significance of an immune response to MRT for obtaining optimal therapy efficacy and support concepts to enhance the immune response of less immunocompetent patients before MRT. It seems advisable to avoid prior or concomitant immunosuppressant medical therapy.

Introduction: The available data for the safety and efficacy of repeat peptide receptor radionuclide therapy (PRRT) are almost exclusively from European centers. We present an updated experience with repeat PRRT in a cohort of US patients with neuroendocrine tumors (NETs) at our NET center of excellence., Methods: We used our single-center longitudinal NET registry to identify patients who had been previously treated with at least one dose of PRRT (PRRT 1, either 177 Lu DOTATATE or 90 Y DOTATOC) and following radiographic disease progression were re-treated with a second course of PRRT (PRRT 2). We reviewed patient, tumor and treatment characteristics, objective response rates, and toxicities after PRRT 1 and PRRT 2., Results: A total of 11 patients were included in the analysis. 45.5% (5/11) of patients received 177 Lu DOTATATE PRRT only, both for PRRT1 and PRRT 2, while 54.5% (6/11) of patients received 90 Y DOTATOC PRRT for PRRT1. At first restaging scan after PRRT2 (3-6 months), 18.2% (2/11), 36.4% (4/11), and 27.3% (3/11) of patients had PR, SD, and PD, respectively; 2/11 patients (18.2%) died before the first restaging scan. Therefore, 5/11 (45.5%) patients were noted to have disease progression. Median PFS for PRRT1 was 25.4 months and median PFS for PRRT2 was 13.1 months (p = 0.0001). We did not find a statistically significant difference between the occurrence of short and long-term hematological toxicities as well as renal toxicity after PRRT1 and PRRT2., Conclusion: We show that repeat PRRT may benefit select patients and have an acceptable safety profile. In our cohort, PFS was significantly lower after PRRT2 as compared to PRRT1., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

[ 75 Se]tauroselcholic acid (SeHCAT) retention measurement provides a noninvasive test for bile acid diarrhea (BAD); however, it is sensitive to the presence of other radionuclides. Two SeHCAT patients at the Royal Free Hospital (RFH) had significant discrepancies between the lower photopeak (111-159 keV) and central photopeak (242-296 keV) windows, indicating contamination with a radionuclide other than 75 Selenium. These patients had received lutetium-177 oxodotreotide ( 177 Lu-DOTATATE) therapy 98 and 151 days before their SeHCAT tests. Traces of 177 Lu may be retained longer than typically modeled, along with the contaminant 177m Lu. This work includes a retrospective audit to examine the prevalence of SeHCAT tests being affected by 177 Lu and phantom measurements to investigate the potential impact. Of 579 patients who received 177 Lu-DOTATATE therapy at our center, 11 subsequently attended for a SeHCAT test. The two previously identified patients may have had compromised SeHCAT results; however, the other patients had longer intervals between their therapy and test, and their tests are believed to be valid. Spectra were acquired from a phantom containing either a SeHCAT capsule or a mixture of 177 Lu/ 177m Lu representative of a patient >90 days after their treatment. The SeHCAT spectrum was scaled to produce simulated day-7 spectra, and the SeHCAT retention that would have been calculated if 177 Lu/ 177m Lu were present was determined. All SeHCAT measurement windows are affected by the 177 Lu/ 177m Lu, producing clinically significant errors. Patients requiring SeHCAT testing should be asked whether they have ever received 177 Lu-DOTATATE. Patient-specific background measurements may be useful for checking for significant levels of other radionuclides., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Positivity of follicular dendritic cell tumor in somatostatin receptor imaging is rare. A 68-year-old woman underwent ultrasound in health examination. The results showed abnormal echoes in the pancreatic head region, suggestive of a neuroendocrine tumor of the pancreatic head. 18 F-AlF-NOTA-octreotide PET/CT was performed for staging. 18 F-AlF-NOTA-octreotide PET/CT revealed an irregular mass between the caudate lobe of the liver and the pancreatic head with heterogeneously increased uptake, which was later confirmed as follicular dendritic cell tumor by pathological examination., Competing Interests: Conflicts of interest and sources of funding: The authors declare that they have no conflicts of interest. This work was supported in part by the Beijing Hope Run Special Fund of Cancer Foundation of China (no. LC2022B11, LC2020A04)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Resection of non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) is curative in most patients. The potential benefits of neoadjuvant treatments have, however, never been explored. The primary aim of this study was to evaluate the safety of neoadjuvant 177Lu-labelled DOTA0-octreotate (177Lu-DOTATATE) followed by surgery in patients with NF-PanNETs., Methods: NEOLUPANET was a multicentre, single-arm, phase II trial of patients with sporadic, resectable or potentially resectable NF-PanNETs at high-risk of recurrence; those with positive 68Ga-labelled DOTA PET were eligible. All patients were candidates for neoadjuvant 177Lu-DOTATATE followed by surgery. A sample size of 30 patients was calculated to test postoperative complication rates against predefined cut-offs. The primary endpoint was safety, reflected by postoperative morbidity and mortality within 90 days. Secondary endpoints included rate of objective radiological response and quality of life., Results: From March 2020 to February 2023, 31 patients were enrolled, of whom 26 completed 4 cycles of 177Lu-DOTATATE. A partial radiological response was observed in 18 of 31 patients, and 13 patients had stable disease. Disease progression was not observed. Twenty-four R0 resections and 4 R1 resections were performed in 29 patients who underwent surgery. One tumour was unresectable owing to vascular involvement. There was no postoperative death. Postoperative complications occurred in 21 of 29 patients. Severe complications were observed in seven patients. Quality of life remained stable after 177Lu-DOTATATE and decreased after surgery., Conclusion: Neoadjuvant treatment with 177Lu-DOTATATE is safe and effective for patients with NF-PanNETs., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Paragangliomas can metastasize, posing potential challenges both in symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and 177Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma-targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. Perspectives in radiotherapies of paraganglioma patients are outlined since they hold promising approaches in the near future that can improve patient outcomes., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)

[ 18 F]AlF-NOTA-octreotide ([ 18 F]AlF-OC) is a promising alternative for [ 68 Ga]Ga-DOTA-somatostatin analogs (SSAs) in positron emission tomography (PET) imaging of the somatostatin receptor (SSTR). Our aim is to assess changes in TNM staging and differences in patient management between [ 18 F]AlF-OC PET/CT and [ 68 Ga]Ga-DOTA-SSA PET/CT in the work-up of neuroendocrine tumor (NET) patients. Patients who underwent both [ 18 F]AlF-OC and [ 68 Ga]Ga-DOTA-TATE or [ 68 Ga]Ga-DOTA-NOC PET/CT in our multicenter study (Pauwels et al., J Nucl Med.2023;63:632-638) with a NET were included for analysis. TNM staging was determined and compared for both tracers. For each patient, the blinded [ 68 Ga]Ga-DOTA-SSA or [ 18 F]AlF-OC PET/CT images were presented in random order at a multidisciplinary team board. The images were presented together with clinical information and compared with previous SSTR and [ 18 F]FDG PET/CT imaging. After a consensus decision for patient management was recorded, the board was presented with the PET/CT images from the other SSTR tracer and a decision was made for the second tracer. Differences in management were classified as major if it entailed an intermodality change and minor if it led to an intramodality change. Compared with [ 68 Ga]Ga-DOTA-SSA, the use of [ 18 F]AlF-OC led to a change in 16/75 patients: TNM staging changes in 10/75 patients (13.3%; downstaging in 3/10, upstaging in 7/10) and differences in clinical management were seen in 10/75 patients (13.3%), leading to a major difference in 7/10 cases and a minor change in 3/10 cases. All 10 cases with a difference in patient management between both PET tracers were caused by additional lesion detection by [ 18 F]AlF-OC. The use of [ 18 F]AlF-OC did not impact TNM staging or clinical management in the large majority of the patients (86.7%), further validating the potential for routine clinical use of [ 18 F]AlF-OC PET/CT as an alternative for [ 68 Ga]Ga-DOTA-SSA PET/CT. The trial is registered under ClinicalTrials.gov identifier NCT04552847 and EudraCT 2020-000549-15., (© 2024 British Society for Neuroendocrinology.)

Objective: We investigated metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on pre-treatment FDG-PET as prognostic markers for survival in patients with metastatic neuroendocrine neoplasms (NENs) receiving peptide receptor radionuclide therapy (PRRT)., Methods: A retrospective review of patients with metastatic NENs receiving PRRT was undertaken. Pre-treatment FDG-PET images were analyzed and variables collected included MTV and TLG (dichotomized by median into high vs low). Main Outcomes were overall survival (OS) and progression-free survival (PFS) by MTV and TLG (high vs low)., Results: One hundred five patients were included. Median age was 64 years (50% male). Main primary NEN sites were small bowel (43.8%) and pancreas (40.0%). Median MTV was 3.8 mL and median TLG was 19.9. Dichotomization formed identical cohorts regardless of whether MTV or TLG were used. Median OS was 72 months; OS did not differ based on MTV/TLG high versus low (47.4 months vs not reached; hazard ratio, 0.43; 95% confidence interval [CI], 0.18-1.04; P = 0.0594). Median PFS was 30.4 months; PFS differed based on MTV/TLG high versus low (21.6 months vs 45.7 months; hazard ratio, 0.35; 95% CI, 0.19-0.64; P = 0.007)., Conclusions: Low MTV/TLG on pre-treatment FDG-PET was associated with longer PFS in metastatic NEN patients receiving PRRT., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Myocardial somatostatin PET uptake is observed not only in most patients with acute myocarditis (AM) but also in some oncology patients referred for routine somatostatin PET. This raises concerns about the specificity of somatostatin PET for detecting myocarditis. The current study aims to identify factors associated with the detection of myocardial uptake on somatostatin PET scans recorded for oncology indications and differential PET criteria that characterize myocardial uptake in AM patients. Methods: We analyzed factors associated with the detection of myocardial [ 68 Ga]Ga-DOTATOC uptake in 508 [ 68 Ga]Ga-DOTATOC PET scans from 178 patients, performed for confirmed or suspected oncologic disease (Onc-PET) and PET criteria that could differentiate myocardial [ 68 Ga]Ga-DOTATOC uptake in 31 patients with MRI-ascertained AM (AM-PET) from that in the Onc-PET group. Results: Significant myocardial uptake was detected in 137 (26.9%) Onc-PET scans and was independently associated with somatostatin analog treatment (exp(β), 0.805; 95% CI, 0.728-0.890; P < 0.001) and age (exp(β), 1.005; 95% CI, 1.001-1.009; P = 0.012). A comparable model was selected for predicting the myocardial-to-blood SUV max ratio using somatostatin analog treatment ( P < 0.001) and history of coronary artery disease ( P = 0.022). Myocardial uptake was detected in 12.9% (25/193) of Onc-PET scans from patients treated with somatostatin analogs but in 43.4% (59/136) of untreated patients over the median age of 64 y. Myocardial uptake was apparent in all 31 AM-PET scans, with volume and intensity of uptake dramatically higher than in the 137 Onc-PET scans showing myocardial uptake. A myocardial-to-blood SUV max ratio threshold of 2.20 provided a sensitivity of 87% (27/31) and a specificity of 88% (44/50) for differentiating myocardial uptake between the AM-PET group and an Onc-PET group restricted to patients with clinical characteristics comparable to those of patients in the AM-PET group (≤64 y of age, no coronary artery disease history, and no somatostatin agonists). A myocardial uptake volume threshold of 18 cm 3 provided comparable diagnostic accuracy (sensitivity, 84% [26/31]; specificity, 94% [47/50]). Conclusion: Myocardial uptake was detected in 26.9% of somatostatin PET scans recorded for oncology indications. This rate was decreased by somatostatin analog treatments and increased in older individuals. However, somatostatin PET scans, analyzed with the quantitative criterion of uptake intensity or volume, are able to identify AM and to differentiate it from myocardial uptake of other origins., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Single time point measurement approach and hybrid dosimetry were proposed to simplify the dosimetry process. It is anticipated that utilizing patient-specific S-value would enable more accurate dosimetry assessment based on imaging compared to using the conventional MIRD S-values., Purpose: We performed planar image-based dosimetry scaled with a single SPECT image for the entire treatment cycle using patient-specific S-values (PSS dosimetry) of organs. PSS dosimetry could further simplify the dosimetry procedure compared with a conventional 2D planar/3D SPECT hybrid dosimetry, as PSS dosimetry requires only one SPECT/CT image for the treatment of the entire cycle, whereas the conventional hybrid dosimetry requires a SPECT/CT image for each treatment cycle., Methods: 177Lu-DOTATATE SPECT/CT and planar image datasets acquired from Seoul National University Hospital (SNUH, Seoul, Republic of Korea) were utilized for the evaluation. Images were acquired 4, 24, 48, and 120 h after patients' intravenous injection of 177Lu-DOTATATE. Dose estimations based on a Monte Carlo (MC) simulation using the Geant4 Application for Emission Tomography (GATE) (v.8.2) were considered as the reference. Planar image-based dosimetry scaled with a single SPECT image was performed using the patient-specific S-value (PSS). Briefly, the CT image was considered as the patient's anatomical reference and PSSs were quantified using the multiple voxel S-value (VSV) method. Then, PSS dosimetry was performed by obtaining activity information from sequential planar images and a scaling factor derived from a single SPECT/planar image pair. Hybrid dosimetry using sequential planar images and a single SPECT image was performed for comparison. The absorbed doses of the kidneys, bone marrow (BM) in the lumbar spine, liver, and spleen calculated using the PSS and hybrid dosimetries were compared with the reference MC results., Results: The mean differences (MDs) of the self-absorption S-values between S-value of OLINDA/EXM and PSS for the kidneys, liver, and spleen were -0.04%, -2.39%, and -2.62%, respectively. However, the differences in the self-absorption S-values were significantly higher for the BM (84.99%) and the remainder of the body (ROB) (280.84%). The absorbed doses estimated by the PSS and hybrid dosimetries showed relatively high errors compared with MC simulation result, regardless of the organ. In contrast, the PSS and hybrid dosimetries produced similar dose estimates. For the entire cycles of the treatment, the MDs of absorbed doses between PSS and hybrid dosimetries were -3.31%, -6.04%, 3.37%, and -2.17% for the kidneys, BM, liver, and spleen, respectively. Through a correlation analysis and the Wilcoxon signed-rank test, we concluded that there was no significant difference between the results obtained by the two dosimetry methods., Conclusions: As the PSS was derived using CT images with actual anatomical information and organ-specific volume of interest (VOI), PSS dosimetry provided reliable results. PSS dosimetry was robust in estimating the absorbed dose for the later treatment cycles. Therefore, PSS dosimetry outperformed hybrid dosimetry in terms of dose estimation for a greater number of treatment cycles., (© 2024 American Association of Physicists in Medicine.)

Abstract: We report the case of a 25-year-old man who was undergoing follow-up for neurofibromatosis type 1. The man underwent 68 Ga-DOTATOC PET/CT for a suspected well-differentiated duodenal neuroendocrine tumor. This examination did not reveal any significant uptake, whereas complementary 18 F-FDG PET/CT showed moderate 18 F-FDG uptake in the primary tumor as well as the adenopathy. Histology, a well-differentiated duodenal neuroendocrine tumor was confirmed, consistent with the diagnosis of somatostatinoma. Although rare, this well-differentiated neuroendocrine tumor should be kept in mind as a possible source of false-negative somatostatin receptor PET/CT findings., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

177 Lu-DOTATATE therapy is an effective treatment for advanced neuroendocrine tumors, despite its dose-limiting hematotoxicity. Herein, the significance of off-target splenic irradiation is unknown. Our study aims to identify predictive markers of peptide receptor radionuclide therapy-induced leukopenia. Methods: We retrospectively analyzed blood counts and imaging data of 88 patients with histologically confirmed, unresectable metastatic neuroendocrine tumors who received 177 Lu-DOTATATE treatment at our institution from February 2009 to July 2021. Inclusion criterium was a tumor uptake equivalent to or greater than that in the liver on baseline receptor imaging. We excluded patients with less than 24 mo of follow-up and those patients who received fewer than 4 treatment cycles, additional therapies, or blood transfusions during follow-up. Results: Our study revealed absolute and relative white blood cell counts and relative spleen volume reduction as independent predictors of radiation-induced leukopenia at 24 mo. However, a 30% decline in spleen volume 12 mo after treatment most accurately predicted patients proceeding to leukopenia at 24 mo (receiver operating characteristic area under the curve of 0.91, sensitivity of 0.93, and specificity of 0.90), outperforming all other parameters by far. Conclusion: Automated splenic volume assessments demonstrated superior predictive capabilities for the development of leukopenia in patients undergoing 177 Lu-DOTATATE treatment compared with conventional laboratory parameters. The reduction in spleen size proves to be a valuable, routinely available, and quantitative imaging-based biomarker for predicting radiation-induced leukopenia. This suggests potential clinical applications for risk assessment and management., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Recombinant α 1 -microglobulin (A1M) is proposed as a protector during 177 Lu-octreotate treatment of neuroendocrine tumors, which is currently limited by bone marrow and renal toxicity. Co-administration of 177 Lu-octreotate and A1M could result in a more effective treatment by protecting healthy tissue, but the radioprotective action of A1M is not fully understood. The aim of this study was to examine the proteomic response of kidneys and bone marrow early after 177 Lu-octreotate and/or A1M administration. Mice were injected with 177 Lu-octreotate and/or A1M, while control mice received saline or A1M vehicle solution. Bone marrow, kidney medulla, and kidney cortex were sampled after 24 h or 7 d. The differential protein expression was analyzed with tandem mass spectrometry. The dosimetric estimation was based on 177 Lu activity in the kidney. PHLDA3 was the most prominent radiation-responsive protein in kidney tissue. In general, no statistically significant difference in the expression of radiation-related proteins was observed between the irradiated groups. Most canonical pathways were identified in bone marrow from the 177 Lu-octreotate+A1M group. Altogether, a tissue-dependent proteomic response followed exposure to 177 Lu-octreotate alone or together with A1M. Combining 177 Lu-octreotate with A1M did not inhibit the radiation-induced protein expression early after exposure, and late effects should be further studied.

Pituitary carcinoma is a rare entity comprising 0.1-0.2% of all pituitary tumors and presents significant diagnostic and therapeutic challenges. Intraspinal drop metastasis in these tumors is even rarer. We report a case of a prolactin secreting pituitary carcinoma with intracranial metastasis and multiple intraspinal drop metastasis. This is the first case where 68Gallium labelled [1,4,7,10 - tetraazacyclododecane - 1,4,7,10 - tetraacetic acid] -1- NaI3 - octreotide (68Ga-DOTANOC) whole-body positron emission tomography-computed tomography (PET-CT) has been used in a case of malignant prolactinoma, in an attempt to ascertain the somatostatin receptor (SSTR) expression on tumor cells. Through this paper, we suggest that SSTR targeted radionuclide therapy could have a potential role in aggressive pituitary tumors and pituitary carcinomas similar to the promising role of lutetium-labelled peptides in inoperable or metastasized gastroentero-pancreatic neuroendocrine tumors (GEP-NETs)., (Copyright © 2024 Copyright: © 2024 Neurology India, Neurological Society of India.)

Abstract: In adults, 68 Ga-FAP inhibitor ( 68 Ga-FAPI) PET/CT outperforms 68 Ga-radiolabeled somatostatin analog peptides ( 68 Ga PET/CT) and 18 F-FDG PET/CT in detecting thyroid lesions. This is the case of a 13-year-old boy newly diagnosed with medullary thyroid cancer with high calcitonin level. 68 Ga PET/CT revealed the presence of only a primary thyroid lesion. Proven to be superior in detecting metastasis, 68 Ga-FAPI PET/CT was performed. The results came out negative for primary and potential metastatic lesions. This case sheds shed light on false-negatives reported in 68 Ga-FAPI PET/CT scans in pediatric patients, emphasizing the need for alternate radiotracers when a negative study is met., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: We report the cases of 4 patients treated for recurrent meningiomas of various grades. Pretreatment 68 Ga-DOTATOC PET/CT was performed prior to screening for vectorized internal radiotherapy with 177 Lu-DOTATATE or prior external radiotherapy to aid contouring. None of these patients had sufficient uptake to be eligible for 177 Lu-DOTATATE or reliable contouring. Most recurrences were grades II and III, suggesting a loss of physiological somatostatin receptor overexpression in these tumors. Therefore, the benefit of treatment with 177 Lu-DOTATATE in the current indication is questionable. In the absence of a validated systemic treatment, and considering a few case reports, treatment with 177 Lu-PSMA could be investigated as an additional vectorized internal radiotherapy option., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Radio-guided surgery (RGS) holds promise for improving surgical outcomes in neuroendocrine tumors (NETs). Previous studies showed low specificity (SP) using γ-probes to detect radiation emitted by radio-labeled somatostatin analogs., Objective: We aimed to assess the sensitivity (SE) and SP of the intraoperative RGS approach using a β-probe with a per-lesion analysis, while assessing safety and feasibility as secondary objectives., Methods: This prospective, single-arm, single-center, phase II trial (NCT05448157) enrolled 20 patients diagnosed with small intestine NETs (SI-NETs) with positive lesions detected at 68 Ga-DOTA-TOC positron emission tomography/computed tomography (PET/CT). Patients received an intravenous injection of 1.1 MBq/Kg of 68Ga-DOTA-TOC 10 min prior to surgery. In vivo measurements were conducted using a β-probe. Receiver operating characteristic (ROC) analysis was performed, with the tumor-to-background ratio (TBR) as the independent variable and pathology result (cancer vs. non-cancer) as the dependent variable. The area under the curve (AUC), optimal TBR, and absorbed dose for the surgery staff were reported., Results: The intraoperative RGS approach was feasible in all cases without adverse effects. Of 134 specimens, the AUC was 0.928, with a TBR cut-off of 1.35 yielding 89.3% SE and 86.4% SP. The median absorbed dose for the surgery staff was 30 µSv (range 12-41 µSv)., Conclusion: This study reports optimal accuracy in detecting lesions of SI-NETs using the intraoperative RGS approach with a novel β-probe. The method was found to be safe, feasible, and easily reproducible in daily clinical practice, with minimal radiation exposure for the staff. RGS might potentially improve radical resection rates in SI-NETs., Clinical Trials Registration: 68 Ga-DOTATOC Radio-Guided Surgery with β-Probe in GEP-NET (RGS GEP-NET) [NCT0544815; https://classic., Clinicaltrials: gov/ct2/show/NCT05448157 ]., (© 2024. Society of Surgical Oncology.)

Background Somatostatin receptors, and specifically somatostatin receptor type 2 (SSTR2), have primarily been associated with neuroendocrine tumors and have revolutionized the imaging and therapy of patients with these tumors. SSTR2 is expressed on other tumors at lower prevalence. Purpose To evaluate the potential of SSTR2-targeted imaging and therapy in patients with breast cancer. Materials and Methods In a preclinical experiment, SSTR2 expression was assessed in tissue microarrays of breast cancer samples using H-score analysis. H-scores higher than 50 (0-300 scale) were considered positive. Then, a prospective phase 2 clinical trial of SSTR2-targeted tetraazacyclododecane tetraacetic acid octreotate (Dotatate) PET/CT was performed in participants with biopsy-proven estrogen receptor (ER)-positive breast cancer from January to August 2023. A positive Dotatate PET/CT scan was defined as tumors with a Krenning score of 3 (avidity greater than liver) or 4 (avidity greater than spleen). The proportion of positive scans and the 95% CI were calculated. One participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET/CT result underwent treatment with SSTR2-targeted actinium 225 ( 225 Ac) Dotatate. Results Preclinical microarrays demonstrated that 63 of 123 ER-positive breast cancer tissue samples (51% [95% CI: 42, 60]) but only 22 of 121 ER-negative breast cancer tissue samples (18% [95% CI: 12, 26]) were enriched for SSTR2 ( P < .001). Thirty female participants (mean age, 66 years ± 15) with metastatic ER-positive breast cancer were accrued to the phase 2 SSTR2-targeted imaging trial and underwent Dotatate PET/CT. Dotatate PET/CT demonstrated that nine of 30 participants (30% [95% CI: 15, 49]) had tumors with Krenning scores of 3 or 4, indicating strong SSTR2 expression. SSTR2-targeted therapy with alpha-emitting 225 Ac-Dotatate resulted in a near complete response in a heavily pretreated participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET result. Conclusion Molecular imaging targeting SSTR2 and radioligand therapy with SSTR2-targeted 225 Ac-Dotatate enables a new therapeutic option for patients with metastatic breast cancer. Clinical trial registration no. NCT05880394 © RSNA, 2024 See also the editorial by Lin and Choyke in this issue.

Peptide receptor radionuclide therapy presents the possibility of tracing and quantifying the uptake of the drug in the body and performing dosimetry, potentially allowing individualization of treatment schemes. However, the details of how neuroendocrine tumors (NETs) respond to different absorbed doses are insufficiently known. Here, we investigated the relationship between tumor-absorbed dose and tumor response in a cohort of patients with NETs treated with [ 177 Lu]Lu-DOTATATE. Methods: This was a retrospective study based on 69 tumors in 32 patients treated within a clinical trial. Dosimetry was performed at each cycle of [ 177 Lu]Lu-DOTATATE, rendering 366 individual absorbed dose assessments. Hybrid planar-SPECT/CT imaging using [ 177 Lu]Lu-DOTATATE was used, including quantitative SPECT reconstruction, voxel-based absorbed dose rate calculation, semiautomatic image segmentation, and partial-volume correction. Changes in tumor volume were used to determine tumor response. The volume for each tumor was manually delineated on consecutive CT scans, giving a total of 712 individual tumor volume assessments. Tumors were stratified according to grade. The relationship between absorbed dose and response was investigated using mixed-effects models and logistic regression. Tumors smaller than 4 cm 3 were excluded. Results: In grade 2 NETs, a clear relationship between absorbed dose and volume reduction was observed. Our observations suggest a 90% probability of partial tumor response for an accumulated tumor-absorbed dose of at least 135 Gy. Conclusion: Our findings are in accordance with previous observations regarding the relationship between tumor shrinkage and absorbed dose. Moreover, our data suggest an absorbed dose threshold for partial response in grade 2 NETs. These observations provide valuable insights for the design of dosimetry-guided peptide receptor radionuclide therapy schemes., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Accurate identification of lymph node (LN) metastases is pivotal for surgical planning of pancreatic neuroendocrine tumours (PanNETs); however, current imaging techniques have sub-optimal diagnostic sensitivity. Aim of this study is to investigate whether [ 68 Ga]Ga-DOTATOC PET radiomics might improve the identification of LN metastases in patients with non-functioning PanNET (NF-PanNET) referred to surgical intervention., Methods: Seventy-two patients who performed preoperative [ 68 Ga]Ga-DOTATOC PET between December 2017 and March 2022 for NF-PanNET. [ 68 Ga]Ga-DOTATOC PET qualitative assessment of LN metastases was measured using diagnostic balanced accuracy (bACC), sensitivity (SN), specificity (SP), positive and negative predictive values (PPV, NPV). SUVmax, SUVmean, Somatostatin receptor density (SRD), total lesion SRD (TLSRD) and IBSI-compliant radiomic features (RFs) were obtained from the primary tumours. To predict LN involvement, these parameters were engineered, selected and used to train different machine learning models. Models were validated using tenfold repeated cross-validation and control models were developed. Models' bACC, SN, SP, PPV and NPV were collected and compared (Kruskal-Wallis, Mann-Whitney)., Results: LN metastases were detected in 29/72 patients at histology. [ 68 Ga]Ga-DOTATOC PET qualitative examination of LN involvement provided bACC = 60%, SN = 24%, SP = 95%, PPV = 78% and NPV = 65%. The best-performing radiomic model provided a bACC = 70%, SN = 77%, SP = 61%, PPV = 60% and NPV = 83% (outperforming the control model, p < 0.05*)., Conclusion: In this study, [ 68 Ga]Ga-DOTATOC PET radiomics allowed to increase diagnostic sensitivity in detecting LN metastases from 24 to 77% in NF-PanNET patients candidate to surgery. Especially in case of micrometastatic involvement, this approach might assist clinicians in a better patients' stratification., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)