Peptide Receptor Radionuclide Therapy or Everolimus in Metastatic Neuroendocrine Tumors: The SeqEveRIV Study, a National Study from the French Group of Endocrine Tumors and Endocan-RENATEN Network.

Everolimus and peptide receptor radionuclide therapy (PRRT, 177Lu-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 mo (6.0%) and 16.1 mo (95% CI, 11.5-20.7 mo), respectively, under everolimus and 19 mo (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.

Neurologic Symptoms After 177Lu-Prostate-Specific-Membrane Antigen-617 Therapy: A Single-Center Experience.

Treatment with 177Lu-prostate-specific membrane antigen (PSMA)-617 (177Lu-vipivotide tetraxetan [Pluvicto]) prolongs both progression-free and overall survival in advanced PSMA-positive metastatic castration-resistant prostate cancer. Data examining specifically neurologic symptoms after 177Lu-PSMA-617 treatment are scarce. In this study, we aimed to review the neurologic findings in a large cohort of metastatic castration-resistant prostate cancer patients undergoing 177Lu-PSMA-617 therapy. Methods: The clinical records and imaging data of patients who received their initial dose of 177Lu-PSMA-617 between March 2022 and November 2022 were retrospectively reviewed. All patients presenting for medical evaluation, regardless of specific specialty appointments, with new or worsening neurologic symptoms were included in the study. Results: A total of 185 patients underwent 177Lu-PSMA-617 therapy. The median age was 70 y (range, 58-90 y). The mean follow-up time was 12.04 ± 2.87 mo. Fifty-five new or worsening neurologic symptoms were observed in 50 patients (27%, 50/185). Of these, 27 (11.9%, 27/185) reported altered taste. Eleven patients (6%, 11/185) experienced dizziness with no other clear etiology; 2 of these patients were admitted to the emergency department (ED). Paresthesia symptoms were reported in 6 patients (3.2%, 6/185). Five patients (2.7%, 5/185) reported headaches, 3 of these patients were admitted to the ED because of the severity of the symptoms. Two patients (1.08%, 2/185) presented with extremity weakness. Two patients (1.08%, 2/185) had an ischemic stroke and were admitted to the ED. One patient (0.05%, 1/185) exhibited gait disturbances. In total, 7 patients (3.78%, 7/185) were admitted to the ED because of neurologic symptoms. None of the patients discontinued or failed to complete the 177Lu-PSMA-617 therapy because of neurologic symptoms. Conclusion: After 177Lu-PSMA-617 treatment, the most common neurologic symptoms were dysgeusia and dizziness. In this study, our follow-up period and population size might not have been sufficient to detect delayed or uncommon neurologic symptoms. In patients without neurologic symptoms or central nervous system metastases before treatment, we found the development of severe neurologic problems to be rare and unlikely to require discontinuation of treatment.

Enhancing [177Lu]Lu-DOTA-TATE therapeutic efficacy in vitro by combining it with metronomic chemotherapeutics.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) uses [177Lu]Lu-[DOTA0-Tyr3]octreotate ([177Lu]Lu-DOTA-TATE) to treat patients with neuroendocrine tumours (NETs) overexpressing the somatostatin receptor 2A (SSTR2A). It has shown significant short-term improvements in survival and symptom alleviation, but there remains room for improvement. Here, we investigated whether combining [177Lu]Lu-DOTA-TATE with chemotherapeutics enhanced the in vitro therapeutic efficacy of [177Lu]Lu-DOTA-TATE. RESULTS: Transfected human osteosarcoma (U2OS + SSTR2A, high SSTR2A expression) and pancreatic NET (BON1 + STTR2A, medium SSTR2A expression) cells were subjected to hydroxyurea, gemcitabine or triapine for 24 h at 37oC and 5% CO2. Cells were then recovered for 4 h prior to a 24-hour incubation with 0.7-1.03 MBq [177Lu]Lu-DOTA-TATE (25 nM) for uptake and metabolic viability studies. Incubation of U2OS + SSTR2A cells with hydroxyurea, gemcitabine, and triapine enhanced uptake of [177Lu]Lu-DOTA-TATE from 0.2 ± 0.1 in untreated cells to 0.4 ± 0.1, 1.1 ± 0.2, and 0.9 ± 0.2 Bq/cell in U2OS + SSTR2A cells, respectively. Cell viability post treatment with [177Lu]Lu-DOTA-TATE in cells pre-treated with chemotherapeutics was decreased compared to cells treated with [177Lu]Lu-DOTA-TATE monotherapy. For example, the viability of U2OS + SSTR2A cells incubated with [177Lu]Lu-DOTA-TATE decreased from 59.5 ± 22.3% to 18.8 ± 5.2% when pre-treated with hydroxyurea. Control conditions showed no reduced metabolic viability. Cells were also harvested to assess cell cycle progression, SSTR2A expression, and cell size by flow cytometry. Chemotherapeutics increased SSTR2A expression and cell size in U2OS + SSTR2A and BON1 + STTR2A cells. The S-phase sub-population of asynchronous U2OS + SSTR2A cell cultures was increased from 45.5 ± 3.3% to 84.8 ± 2.5%, 85.9 ± 1.9%, and 86.6 ± 2.2% when treated with hydroxyurea, gemcitabine, and triapine, respectively. CONCLUSIONS: Hydroxyurea, gemcitabine and triapine all increased cell size, SSTR2A expression, and [177Lu]Lu-DOTA-TATE uptake, whilst reducing cell metabolic viability in U2OS + SSTR2A cells when compared to [177Lu]Lu-DOTA-TATE monotherapy. Further investigations could transform patient care and positively increase outcomes for patients treated with [177Lu]Lu-DOTA-TATE.

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) - Current literature review of diagnostics and therapy. What has changed in the management?

<b>Introduction:</b> Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are malignancies originating from cells of the diffuse endocrine system. They are rare and localize in the upper and lower parts of the gastrointestinal tract and in the pancreas. Despite such a varied location, GEP-NENs are considered a common group of neoplasms due to the fact of their similar morphology and ability to secrete peptide hormones and biologically active amines. They are associated with clinical manifestations specific to the substances produced by a particular neoplasm. The classification of GEP-NENs is constantly systematized and updated based on their differentiation and grading. The development of available diagnostic and treatment methods for these tumors has made significant progress over the past 10 years and is still ongoing.<b>Aim:</b> In the following paper, we review the diagnostics and treatment of GEP-NENs, taking into account the latest molecular, immunological, or gene-based methods. Imaging methods using markers for receptors allow for high diagnostic sensitivity<b>Methods:</b> Medical databases were searched for the latest information. The authors also sought confirmation of the content of a particular publication in another publications, so as to present the most reliable information possible.<b>Results:</b> Research results revealed that the diagnostics and treatment of GEP-NENs have significantly advanced in recent years. Surgical interventions, especially minimally invasive techniques, have shown efficacy in treating GEP-NENs, with specific therapies such as somatostatin analogs, chemotherapy, and peptide receptor radionuclide therapy demonstrating promising outcomes. The evolution of diagnostic methods, including imaging techniques and biomarker testing, has contributed to improved patient care and prognosis.<b>Conclusions:</b> The increasing incidence of GEP-NENs is attributed to enhanced diagnostic capabilities rather than a rise in population prevalence. The study emphasizes the importance of ongoing research to identify specific markers for early detection and targeted therapies to further enhance the effectiveness of treating these rare and heterogeneous malignancies. The findings suggest a positive trajectory in the management of GEP-NENs, with future prospects focused on personalized and targeted treatment approaches.

Palladium-103 (103Pd/103mRh), a promising Auger-electron emitter for targeted radionuclide therapy of disseminated tumor cells - absorbed doses in single cells and clusters, with comparison to 177Lu and 161Tb.

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 103Pd (T1/2 = 16.991 d) which decays to 103mRh (T1/2 = 56.12 min) then to stable 103Rh 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 103Pd, 177Lu and 161Tb 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 103mRh, if used directly, are provided. Results: In the single cell, and depending on radionuclide distribution, 103Pd delivered 7- to 10-fold higher nuclear absorbed dose and 9- to 25-fold higher membrane dose than 177Lu. In the 19-cell clusters, 103Pd absorbed doses also largely exceeded 177Lu. In both situations, 161Tb stood in-between 103Pd and 177Lu. Non-uniform targeting, considering four unlabeled cells within the cluster, resulted in moderate-to-severe dose heterogeneity. For example, with intranuclear 103Pd, unlabeled cells received only 14% of the expected nuclear dose. Targeting with two 103Pd-labeled radiopharmaceuticals minimized dose heterogeneity. Conclusion: 103Pd, a next-generation Auger emitter, can deliver substantially higher absorbed doses than 177Lu 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.

Preclinical evaluation of [225Ac]Ac-crown-TATE - An alpha-emitting radiopharmaceutical for neuroendocrine tumors.

BACKGROUND: Targeted alpha therapy (TAT) of somatostatin receptor-2 (SSTR2) positive neuroendocrine tumors (NETs) involving Ac-225 ([225Ac]Ac-DOTA-TATE) has previously demonstrated improved therapeutic efficacy over conventional beta particle-emitting peptide receptor radionuclide therapy agents. DOTA-TATE requires harsh radiolabeling conditions for chelation of [225Ac]Ac3+, which can limit the achievable molar activities and thus therapeutic efficacy of such TAT treatments. Macropa-TATE was recently highlighted as a potential alternative to DOTA-TATE, owing to the mild radiolabeling conditions and high affinity toward [225Ac]Ac3+; however, elevated liver and kidney uptake were noted as a major limitation and a suitable imaging radionuclide is yet to be reported, which will be required for patient dosimetry studies and assessment of therapeutic benefit. Previously, [155Tb]Tb-crown-TATE has shown highly effective imaging of NETs in preclinical SPECT/CT studies, with high tumor uptake and low non-target accumulation; these favourable properties and the versatile coordination behavior of the crown chelator may therefore show promise for combination with Ac-225 for TAT. METHODS: Crown-TATE was labeled with Ac-225, and radiochemical yield was analyzed as the function of crown-TATE concentration. LogD7.4 was measured as the indication of hydrophilicity. Free [225Ac]Ac3+ release from [225Ac]Ac-crown-TATE in human serum was studied. Biodistribution studies of [225Ac]Ac-crown-TATE in mice bearing AR42J tumors was evaluated at 1, 4, 24, 48, and 120 h, and the absorbed dose to major organs calculated. Therapy-monitoring studies with AR42J tumor bearing mice were undertaken using 30 kBq and 55 kBq doses of [225Ac]Ac-crown-TATE and compared to controls treated with PBS or crown-TATE. RESULTS: [225Ac]Ac-crown-TATE was successfully prepared with high molar activity (640 kBq/nmol), and characterized as a moderately hydrophilic radioligand (LogD7.4 = -1.355 ± 0.135). No release of bound Ac-225 was observed over 9 days in human serum. Biodistribution studies of [225Ac]Ac-crown-TATE showed good initial tumor uptake (11.1 ± 1.7% IA/g at 4 h) which was sustained up to 120 h p.i. (6.92 ± 2.03% IA/g). Dosimetry calculations showed the highest absorbed dose was delivered to the tumors. Therapy monitoring studies demonstrated significant (log-rank test, P < 0.005) improved survival in both treatment groups compared to controls. CONCLUSIONS: This preclinical study demonstrated the therapeutic efficacy of [225Ac]Ac-crown-TATE for treatment of NETs, and highlights the potential of using crown chelator for stable chelation of Ac-225 under mild conditions.

Development of [177Lu]Lu-LNC1010 for peptide receptor radionuclide therapy of nasopharyngeal carcinoma.

PURPOSE: Somatostatin Receptor 2 (SSTR2)-targeted radiopharmaceutical [68Ga]Ga-DOTATATE has potential advantages in the diagnosis of nasopharyngeal carcinoma (NPC). This study introduces a novel long-lasting SSTR2 analogue, LNC1010, based on DOTATATE, a truncated Evans blue-binding moiety, and a polyethylene-glycol linker. We hypothesised that peptide receptor radionuclide therapy (PRRT) is more effective with [177Lu]Lu-LNC1010 than with [177Lu]Lu-DOTATATE in treating metastatic NPC. METHODS: We assessed binding characteristics of LNC1010 in vitro using C666-1 NPC cells and in-vivo pharmacokinetics of [68Ga]Ga/[177Lu]Lu-LNC1010 in C666-1 NPC xenografts via PET and SPECT imaging, biodistribution studies, and PRRT, and compared them with [68Ga]Ga/[177Lu] Lu-labelled DOTATATE. Furthermore, a proof-of-concept approach for imaging and therapy was conducted in a patient with metastatic NPC. RESULTS: LNC1010 exhibited strong uptake and specific affinity for SSTR2 in C666-1 NPC cells. PET and SPECT imaging demonstrated higher uptake and longer tumour retention of [68Ga]Ga/[177Lu]Lu-LNC1010 than [68Ga]Ga/[177Lu]Lu-DOTATATE in C666-1 NPC xenografts, indicating its suitability for PRRT applications in NPCs. Biodistribution studies confirmed the higher uptake and prolonged retention of [177Lu]Lu-LNC1010 than [177Lu]Lu-DOTATATE. In preclinical PRRT studies, [177Lu]Lu-LNC1010 showed greater inhibition of tumour growth in C666-1 NPC xenografts than [177Lu]Lu-DOTATATE. In a subsequent pilot clinical study, PRRT with [177Lu]Lu-LNC1010 achieved favourable therapeutic and negligible side effects in a patient with metastatic NPC. CONCLUSION: [177Lu]Lu-LNC1010 demonstrated increased tumour uptake and prolonged retention in SSTR2-positive NPCs, with superior anti-tumour efficacy to that of [177Lu]Lu-DOTATATE in preclinical studies. These findings suggest that PRRT with [177Lu]Lu-LNC1010 is a promising treatment for advanced NPC, extending the clinical scope of PRRT beyond neuroendocrine tumours.

Tolerability and outcomes of neuroendocrine tumors treated with PRRT and SBRT.

There is interest in optimizing peptide receptor radionuclide therapy (PRRT) for the management of metastatic neuroendocrine neoplasms (NEN). The addition of stereotactic body radiation therapy (SBRT) may provide synergistic benefits by targeting specific sites of disease that may represent areas of tumor heterogeneity. Little is known about the efficacy or potential toxicity of this approach; understanding the outcomes of patients treated with these two modalities in a sequential fashion will provide insights into the appropriateness of embarking on a combined therapy strategy. An institutional retrospective review of 21 patients with NEN treated with sequential PRRT and SBRT (64 targets) was performed. Median overall survival and progression-free survival were 19.6 months and 12.8 months, respectively. Median time to local recurrence at the SBRT site was not reached, with rates at 12 and 24 months of 1.8% and 5.9%, respectively. The toxicity profile remains favorable. Given the safety and efficacy of sequential SBRT and PRRT, further trials evaluating a concurrent treatment approach may be warranted.

Excellent Response to 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy in a Patient with Treatment-Related Neuroendocrine Prostate Cancer with Urinary Retention and Rectal Obstruction: A Case Report.

Treatment-related neuroendocrine prostate cancer (tNEPC) occurs after androgen deprivation therapy and has a poor prognosis; however, there are few effective treatments for tNEPC. Therefore, tNEPC management is often challenging. This is a case of a 65-year-old Asian male patient with prostate adenocarcinoma who had metastases at initial presentation. After prostate biopsy revealed neuroendocrine prostate cancer (NEPC), he was treated with platinum-based systemic chemotherapy followed by pembrolizumab treatment. The primary tumor regions temporarily regressed, but progression of the primary tumor resulted in urinary retention and rectal obstruction; therefore, a transverse colostomy was performed, and a urethral catheter was inserted. Following somatostatin receptor scintigraphy (SRS), it was determined that the primary tumor expressed somatostatin receptors. Based on these results, treatment with 177Lu-DODATATE peptide receptor radionuclide therapy was prescribed. Subsequently, the primary tumor regressed remarkably, and the urethral catheter was removed. 177Lu-DOTATATE peptide receptor radionuclide therapy may be an effective option for tNEPC, which has few effective treatment options.

Novel Detection of Pleomorphic Adenomas via Analysis of 68Ga-DOTATOC PET/CT Imaging.

INTRODUCTION: Currently, the diagnosis of salivary gland tumors using imaging techniques is unreliable. METHODS: In this monocentric retrospective study, we examined patients who received a 68Ga-DOTATOC PET/CT and subsequently underwent a salivary gland tumor resection between 1 January 2010 and 31 December 2021. PET/CT image assessment was compared with somatostatin receptor (SSTR) expression and histology. RESULTS: Thirteen patients (five pleomorphic adenoma (PA) and eight other parotid lesions (OPL)) received a 68Ga-DOTATOC PET/CT. Imaging displayed strong focal tracer uptake in all PA except for one with strong tumor to background discrimination. PA revealed higher SUVmax, SUVmean, liver and blood pool quotients than those of Warthin tumors (WT) and of OPL. In comparison to the contralateral parotid, SUVmax (p = 0.02), SUVmean (p = 0.02), liver quotient (p = 0.03) and blood pool quotient (p = 0.03) were all significantly higher. In contrast, WT and OPL showed in relation to the contralateral parotid no significant differences of SUVmax (WT p = 0.79; OPL p = 0.11), SUVmean (WT p = 1.0; OPL p = 0.08), liver quotient (WT p = 0.5; OPL p = 0.08) and blood pool quotient (WT p = 0.8; OPL p = 0.19). Two PA and one granuloma were not available for examination. In the immunohistochemal analysis, all PA demonstrated the highest intensity of SSTR2 expression (grade 3). Furthermore, PA had a high percentage of cells expressing SSTR2 (20%, 80% and 55%). CONCLUSIONS: A strong tracer uptake in PA was shown in 68Ga-DOTATOC PET/CT. This may allow physicians to utilize radioligated somatostatin analogue PET CT/MR imaging to accurately diagnose PA. Additionally, it may be possible in the future to treat the PA with a noninvasive peptide receptor radionuclide therapy or with somatostatin analogues.

Safety and Efficacy of Peptide Receptor Radionuclide Therapy (PRRT) Following Bland Embolization for Metastatic Neuroendocrine Tumors.

Rationale: Evaluating the long-term safety and efficacy of peptide receptor radionuclide therapy (PRRT) in patients with metastatic neuroendocrine tumors (mNETs) who have undergone prior bland hepatic transarterial embolization (TAE). Methods: Retrospective review of mNET patients who received PRRT with 177Lu-DOTATATE between 4/2018 and 02/2022 with and without prior TAE. The most recent clinical, imaging, and laboratory findings, including hepatic Common Terminology Criteria for Adverse Events v5.0, were compared to pre-PRRT. Results: 171 patients (95 M, 76 F, median age = 66) with mNET of different primary sites (9 foregut, 100 midgut, 9 hindgut, 44 pancreas, 9 unknown) received at least 1 cycle of PRRT with at least 6 months of follow-up, 110 of whom were embolization-naïve and 61 who had prior TAE. The median follow up was 22 months (range: 6-43). Patients with prior TAE had higher liver tumor burden on average than patients without prior TAE; however, the difference was not statistically significant (p = 0.06). There was no significant difference in the rates of G3 or G4 hepatotoxicity (p = 0.548 and p = 0.999, respectively) in patients who underwent prior TAE and those who were TAE-naïve. The hepatic progression-free survival was 22.9 months in TAE-naïve patients and 25.7, 20.2, and 12.8 months in patients with 1, 2, and 3 prior TAE treatments, respectively. Conclusion: Peptide receptor radionuclide therapy following transarterial bland embolization for mNET is safe and effective.

Peptide Receptor Radionuclide Therapy in Advanced Refractory Meningiomas: Efficacy and Toxicity in a Long Follow-up.

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 68Ga-DOTA-octreotide and peptide receptor radionuclide therapy (PRRT) with 90Y/177Lu-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 90Y-DOTATOC (dosage of 1.1 or 5.5 GBq) or with 177Lu-DOTATATE (dosage of 3.7 or 5.5 GBq) in a mean of 4 cycles. All patients showed intense uptake at diagnostic 68Ga-DOTATOC PET/CT or in an 111In-octreotide scan. Results: Of 42 patients treated, 5 patients received 90Y-DOTATOC with a cumulative activity of 11.1 GBq and 37 patients received 177Lu-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 177Lu-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.

New Drugs for Targeted Radionuclide Therapy in Metastatic Prostate Cancer.

Metastatic prostate cancer is a frequent and fatal disease. Targeted radionuclide therapy (TRT) has become a readily available therapeutic option since the approval of [177Lu]Lu-PSMA-617. Various molecules are currently being studied for TRT in prostate cancer. We review various combinations of isotopes and vectors being used to target prostate cancer cells and optimize pharmacokinetics. Promising innovations include chemical modifications to improve biodistribution, identification of new targets, and the use of novel radioisotopes such as α emitters. PATIENT SUMMARY: Our mini review summarizes research on targeted radioactive drugs for treatment of metastatic prostate cancer. Several promising radioactive pharmaceuticals are being evaluated in clinical trials, but more studies are necessary before these can be used in routine clinical practice.

Lead-212/Bismuth-212 In Vivo Generator Based on Ultrasmall Silver Telluride Nanoparticles.

Radionuclide therapy employing alpha emitters holds great potential for personalized cancer treatment. However, certain challenges remain when designing alpha radiopharmaceuticals, including the lack of stability of used radioconjugates due to nuclear decay events. In this work, ultrasmall silver telluride nanoparticles with a core diameter of 2.1 nm were prepared and radiolabeled with lead-212 using a chelator-free method with a radiolabeling efficiency of 75%. The results from the in vitro radiochemical stability assay indicated a very high retention of bismuth-212 despite the internal conversion effects originating from the decay of 212Pb. To further evaluate the potential of the nanoparticles, they were radiolabeled with indium-111, and their cell uptake and subcellular distribution were determined in 2D U87 cells, showing accumulation in the nucleus. Although not intentional, it was observed that the indium-111-radiolabeled nanoparticles induced efficient tumor cell killing, which was attributed to the Auger electrons emitted by indium-111. Combining the results obtained in this work with other favorable properties such as fast renal clearance and the possibility to attach targeting vectors on the surface of the nanoparticles, all well-known from the literature, these ultra-small silver telluride nanoparticles provide exciting opportunities for the design of theragnostic radiopharmaceuticals.

Intra-arterial PRRT with Lu-177 DOTATATE in Liver-dominant Metastatic Neuroendocrine Tumors: Early Assessment of Efficacy and Toxicity.

Purpose: We proposed to administer Lu-177-DOTATATE in intra-arterial (IA) mode for higher first-pass localization to somatostatin receptors, higher residence time in liver metastases, and more radiation to tumor. This study aimed at assessing early hematological, renal and hepatotoxicity; and objective response to IA peptide receptor radionuclide therapy (PRRT). Materials and Methods: Fourteen patients (4 females and 10 males) were prospectively assessed. 5/14 patients underwent 2 cycles, whereas 3/14 underwent 3 cycles, and 6/14 received 1 cycle of IA PRRT. 200 mCi of Lu-177-DOTATATE was administered in 15-20 min by IA route under angiographic guidance. Patients were asked to follow-up at 4 and 8 weeks with hematological, liver, and renal functional parameters, and Ga-68 DOTATATE positron emission tomography/computed tomography (PET/CT) after 8 weeks. Response was assessed using RECIST 1.1 and EORTC PET criteria. Results: Safety: 2/14 patients had high total and direct bilirubin, which reverted to normal after IA PRRT. Three patients had low albumin, which improved after 1 cycle. Nine patients showed no worsening of liver function. Two patients showed Grade 1 hematotoxicity which reverted to normal. Five patients showed high creatinine, but preserved glomerular filtration rate and EC clearance. On follow-up at 8 weeks, serum creatinine reverted to normal. Efficacy: In five patients who underwent 2 cycles of IA PRRT, 3 showed partial response (PR) on RECIST 1.1 and partial metabolic response (PMR) on EORTC criteria, whereas 2 showed stable disease (SD). In patients who underwent 3 cycles, 1 showed SD, whereas other patient showed PMR on DOTANOC PET/CT, with PR in size. Among the remaining seven patients, 5 showed PMR, whereas the other 2 showed SD. Thus 9/14 patients showed PR, whereas 5 showed SD on metabolic and size criteria. Conclusions: IA PRRT is a safe and efficacious approach for the treatment of liver dominant metastatic neuroendocrine tumors.

Comparative post-therapeutic dosimetry between 2D planar-based and hybrid-based methods for personalized Lu-177 treatment.

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 177Lu-PSMA I&T and 177Lu-DOTATATE therapy. METHODS: Multiple time-point whole-body planar images and one SPECT/CT image were acquired from 18 patients including 177Lu-PSMA I&T (13 patients) and 177Lu-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.

Treatment of an Aggressive Gonadotroph Pituitary Neuroendocrine Tumor With 177Lutetium DOTATATE Radionuclide Therapy.

Aggressive pituitary neuroendocrine tumors (PitNETs) present significant morbidity, and multimodal therapies including surgery, radiotherapy, and medications are frequently required. Chemotherapy, particularly temozolomide, is often pursued for tumors that progress despite these treatments. Although peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogs is approved for the treatment of well-differentiated gastrointestinal neuroendocrine tumors, its use in aggressive PitNETs is limited. We describe the case of a 65-year-old man who presented with vision changes and hypopituitarism at age 33 secondary to a nonfunctioning gonadotroph PitNET. His initial treatment included a craniotomy followed by radiation therapy. With tumor regrowth, he required transsphenoidal surgeries at age 44 and age 52. At age 56, further tumor regrowth and a positive octreotide scan prompted treatment with long-acting octreotide for 1 year. Given absent tumor response, 12 cycles (4 treatment cycles and 8 maintenance cycles) of PRRT with 177Lutetium-DOTATATE were pursued. This resulted in partial response with significant tumor shrinkage. Notably, there was no tumor regrowth 40 months after treatment discontinuation. This is only the second report on the effectiveness of PRRT in patients with aggressive gonadotroph PitNETs. We also provide an overview of PRRT for PitNETs and describe clinical outcomes previously reported in the literature.

Surgical management of pancreatic neuroendocrine tumors - An EYSAC and E-AHPBA international survey of current practice.

INTRODUCTION: Pancreatic neuroendocrine tumors (pNET) exhibit a wide spectrum of clinical behavior, which makes their assessment and management quite challenging. The purpose of this study was to comprehensively assess the existing treatment landscape for patients with pNET. MATERIALS AND METHODS: The study was conducted with the support of the ESSO-EYSAC Research Academy in collaboration with the E-AHPBA. An online survey was distributed via email and social media to surgical networks across Europe and beyond (September 1-30, 2023). RESULTS: Overall, 155 complete responses were obtained. A specialized NET tumor board was present at the institutions of 94 (61 %) of the study participants. The most frequently applied guidelines were from ENETS (n = 97; 63 %), NCCN (n = 74; 48 %), and ESMO (n = 53; 34 %). For resectability, similar criteria as in pancreatic ductal adenocarcinoma were used by 111 (72 %) participants, even though 116 (75 %) participants believed that pNET/pNEC should have their own resectability criteria. Most respondents used somatostatin analogues (n = 126; 81 %) and chemotherapy (n = 85; 55 %) as neoadjuvant treatments, followed by molecularly targeted agents (n = 45; 29 %) and PRRT (n = 37; 24 %). Only 17 (11 %) participants agreed/strongly agreed that the management of pNET/pNEC is sufficiently addressed in surgical education programs. CONCLUSION: This international survey highlighted areas for improvement in the care of pNET, namely the lack of pNET-specific resectability criteria and educational programs addressing pNET management.

Tubarial salivary glands show a low relative contribution to functional salivary gland tissue mass.

BACKGROUND: In 2021, the tubarial salivary glands (TSGs) were newly identified on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) as macroscopic glands in the nasopharyngeal wall. However, the relative contribution of the TSGs to the total salivary gland function, and consequently on the development of xerostomia after external beam radiotherapy (EBRT) or PSMA-targeted radionuclide therapy (RNT) is not known. Therefore, we aimed to determine the presence of the TSGs and to quantify uptake in the TSGs on PSMA PET. METHODS: Qualitative and quantitative analyses were performed on 68Ga-PSMA-11 PET/CT scans of 100 patients with prostate cancer. The mean and maximum standardized uptake value (SUVmean and SUVmax) in the TSGs were measured and compared to the parotid, submandibular and sublingual salivary glands (PSGs, SMSGs and SLSGs, respectively). Furthermore, proportional function of the TSGs was compared to the PSGs, SMSGs and SLSGs based on the total organ PSMA (TO-PSMA). RESULTS: The TSGs were visible on 95% of the 68Ga-PSMA-11 PET/CT scans. The normalized median SUVmean and SUVmax was significantly higher for the PSGs (p < 0.001) and SMSGs (p < 0.001) compared to the TSGs, but not for the SLSGs (p = 0.242 and p = 0.300, respectively). The normalized median TO-PSMA was significantly higher for the PSGs (p < 0.001) and SMSGs (p < 0.001), and significant lower for the SLSGs (p < 0.001) compared the TSGs. CONCLUSIONS: The SUVmean, SUVmax and TO-PSMA of the TSGs were most comparable to the SLSGs. However, the measured PSMA uptake may be disproportional towards the saliva production. Therefore, future studies should focus on the relation between PSMA uptake and salivary function before and after PSMA therapy.

Feasibility and therapeutic potential of [177Lu]Lu-FAPI-2286 in patients with advanced metastatic sarcoma.

INTRODUCTION: The unique expression pattern of fibroblast activation protein (FAP) in stromal and tumor cells, particularly in sarcomas, and its absence in normal tissues, have positioned it as a promising theragnostic approach for the detection and treatment of various cancer types. The objective of this prospective study is to assess the feasibility, safety, biodistribution, and therapeutic efficacy of [177Lu]Lu-FAPI-2286 in patients with advanced metastatic sarcoma. PATIENTS AND METHODS: Eight patients with advanced metastatic sarcoma, who were unresectable or had experienced disease recurrence following conventional treatments, underwent PTRT (peptide-targeted radionuclide therapy) using [177Lu]Lu-FAPI-2286. Prior to the treatment, confirmation of tumor uptake was obtained through [68Ga]Ga-FAPI-2286 PET/CT. RESULTS: After four cycles of PTRT with [177Lu]Lu-FAPI-2286 (6660-7400 MBq), with a 6-8-week interval between each cycle, no grade 3 or 4 side effects were observed in the patients, and the treatment was well tolerated by all participants. The results demonstrated a 52.37% reduction in the average volume of the primary tumor, accompanied by a significant decrease in SUVmax and TBR of the metastatic lesions (29.67% and 43.66% respectively), especially in cases of lung metastasis. Furthermore, besides the improvement in physical capacity, there was a noticeable reduction in pain, an increase in overall survival, and enhanced satisfaction with the treatment reported by the patients. CONCLUSION: [177Lu]Lu-FAPI-2286 PTRT, utilized for diverse cancer types, exhibited favorable tolerability in sarcoma patients, with minimal side effects, long-lasting retention of the radiopeptide within the tumor, and promising therapeutic effects. Preliminary findings of this prospective study need to be confirmed through further clinical trials.