A nuclear beacon of hope: an advanced, metastatic glucagonoma treated with [177Lu]Lu-DOTA-TATE.

Glucagonoma is a rare pancreatic neuroendocrine tumor (panNET) that can be characterized by increased secretion of glucagon and distinguishing symptoms - glucagonoma syndrome with a typical dermatosis, necrolytic migratory erythema, being its most common manifestation. While surgery and somatostatin analogs remain first-line therapeutic options in panNETs, radioligand therapy with [177Lu]Lu-DOTA-TATE is a recommended second-line palliative treatment in advanced, metastatic cases. However, its prospects and efficacy are still not vastly researched in less frequent neuroendocrine neoplasms. Here, we present an extraordinary case of a metastatic glucagonoma treated with [177Lu]Lu-DOTA-TATE used as a second-line treatment in progressive disease.

The Safety and Efficacy of Peptide Receptor Radionuclide Therapy for Gastro-Entero-Pancreatic Neuroendocrine Tumors: A Single Center Experience.

The aim of the present study was to evaluate the safety and efficacy of radionuclide therapy with [177Lu]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 [177Lu]Lu-DOTA-TATE according to the decisions of a multidisciplinary team. All patients underwent four cycles of 7-8 GBq of [177Lu]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 [177Lu]Lu-DOTA is safe and effective in controlling the burden disease of G1/G2 GEP-NETs patients.

A Rare Case of Ectopic Adrenocorticotropic Hormone Syndrome (EAS) in an Adolescent Girl With a Thymic Neuroendocrine Tumour.

In adults, Cushing's syndrome (CS) caused by tumours that produce adrenocorticotropic hormone (ACTH) outside of the pituitary gland is quite prevalent. However, it is uncommon in children and teenagers. Ectopic ACTH syndrome (EAS) is a rare occurrence in young children, accounting for less than 1% of cases. Nevertheless, when it does occur, it tends to be a severe condition due to the profound hypercortisolism that can occur independently of the tumour. Consequently, EAS should be regarded as a critical endocrine emergency, necessitating prompt action in terms of diagnostic procedures and therapeutic interventions. A 14-year-old White female from the United Kingdom (UK) presented with a two-week history of hands and feet swelling, accompanied by a non-itchy rash on the face, back, and chest for one week. Initial investigations revealed hypokalemic alkalosis, hyperglycaemia, elevated serum and 24-hour urinary cortisol, and high ACTH level. Further investigations confirmed EAS, and to find out the primary tumour location, a contrast-enhanced thoracic CT scan was done and identified a 5x3 cm mass with enhanced thymic shadow. Increased radioactivity uptake in the left upper chest along with widespread GAD-avid metastatic disease unveiled by Gallium-DOTA-TATE PET scan. An abdominal MRI, detecting multiple liver deposits, prompted a liver biopsy, revealing a malignant tumour with neuroendocrine differentiation. The patient was diagnosed with EAS with a primary neuroendocrine tumour of the thymus and metastasis. This case underscores the significance of considering EAS in patients with a diagnosis of CS, especially in young individuals with no known risk factors.

Estimation of kidney doses from [177Lu]Lu-DOTA-TATE PRRT using single time point post-treatment SPECT/CT.

BACKGROUND: Dosimetry after [177Lu]Lu-DOTA-TATE therapy can be demanding for both patients and the clinical service due to the need for imaging at several time points. In this work we compare three methods of single time point (STP) kidney dosimetry after [177Lu]Lu-DOTA-TATE therapy with a multiple time point (MTP) dosimetry method. METHOD: Method 1 (MTP): Kidney doses were calculated from 31 patients including 107 therapy cycles. Post-therapy SPECT images were acquired on day 0, 4 and 7 along with a CT scan on day 4. A mono-exponential fit was used to calculate kidney doses using cycle specific data. Method 2 (Consistent effective half-life): The effective half-life [Formula: see text] calculated in cycle 1 was assumed consistent for subsequent cycles of therapy and the activity scaled using a single day 3-5 SPECT/CT. Methods 3 and 4 (Hänscheid and Madsen approximations): The Hänscheid approximation and Madsen approximation were both evaluated using a single SPECT/CT acquired on day 0, 4 and 7. All STP methods were compared to the MTP method for accuracy. RESULTS: Using the MTP method, mean right and left kidney doses were calculated to be 2.9 ± 1.1 Gy and 2.8 ± 0.9 Gy respectively and the population [Formula: see text] was 56 ± 13 h. For the consistent [Formula: see text], Hänscheid and Madsen methods, the percentage of results within ± 20% of MTP method were 96% (n = 70), 95% (n = 80) and 94% (n = 80) respectively. CONCLUSION: All three single time point methods had > 94% of results within ± 20% of the MTP method, however the consistent [Formula: see text] method resulted in the highest alignment with the MTP method and is the only method which allows for calculation of the patient-specific [Formula: see text]. If only a single scan can be performed, day 4 is optimal for kidney dosimetry where the Hänscheid or Madsen approximation can be implemented with good accuracy.

Clinical impact of using [18F]AlF-NOTA-octreotide PET/CT instead of [68Ga]Ga-DOTA-SSA PET/CT: Secondary endpoint analysis of a multicenter, prospective trial.

[18F]AlF-NOTA-octreotide ([18F]AlF-OC) is a promising alternative for [68Ga]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 [18F]AlF-OC PET/CT and [68Ga]Ga-DOTA-SSA PET/CT in the work-up of neuroendocrine tumor (NET) patients. Patients who underwent both [18F]AlF-OC and [68Ga]Ga-DOTA-TATE or [68Ga]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 [68Ga]Ga-DOTA-SSA or [18F]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 [18F]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 [68Ga]Ga-DOTA-SSA, the use of [18F]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 [18F]AlF-OC. The use of [18F]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 [18F]AlF-OC PET/CT as an alternative for [68Ga]Ga-DOTA-SSA PET/CT. The trial is registered under ClinicalTrials.gov identifier NCT04552847 and EudraCT 2020-000549-15.

[68Ga]Ga-DOTA-TATE in diagnosis of MEN syndrome.

Not required for Clinical Vignette.

Lutetium [177Lu]-DOTA-TATE in gastroenteropancreatic-neuroendocrine tumours: rationale, design and baseline characteristics of the Italian prospective observational (REAL-LU) study.

PURPOSE: Gastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [177Lu]-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 [177Lu]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 [177Lu]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 [177Lu]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. [177Lu]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.

Radio theranostics in paragangliomas and pheochromocytomas.

This continuing education aims to present in a clear and easy-to-understand manner the biology of paragangliomas and pheochromocytomas (PPGLs), the functional imaging studies available for their diagnosis and therapeutic planning, the requirements necessary to administer radioligand therapy (RLT) and the characteristics of these treatments (inclusion criteria, administration protocols, adverse effects and future perspectives). In this pathology we have two RLT options: [131I]MIBG and [177Lu]Lu-DOTA-TATE. The indication for treatment is determined by the expression of its therapeutic target in functional imaging studies, allowing precision and personalized medicine. Although most of the results we have for both treatments have as origin small retrospective series, RLT is presented as a safe and well-tolerated therapeutic option in PPGLs with slow-moderate progression or with uncontrollable symptoms, obtaining high disease control rates.

Efficacy of [67Cu]Cu-EB-TATE Theranostic Against Somatostatin Receptor Subtype-2-Positive Neuroendocrine Tumors.

ß--emitting 177Lu-octreotate is an approved somatostatin receptor subtype 2 (SSTR2)-directed peptide receptor radionuclide therapy for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). However,177Lu-octreotate has fast pharmacokinetics, requiring up to 4 treatment doses. Moreover, 177Lu is less than ideal for theranostics because of the low branching ratio of its γ-emissions, which limits its SPECT imaging capability. Compared with 177Lu, 67Cu has better decay properties for use as a theranostic. Here, we report the preclinical evaluation of a long-lived somatostatin analog, [67Cu]Cu-DOTA-Evans blue-TATE (EB-TATE), against SSTR2-positive NETs. Methods: The in vitro cytotoxicity of [67Cu]Cu-EB-TATE was investigated on 2-dimensional cells and 3-dimensional spheroids. In vivo pharmacokinetics and dosimetry were studied in healthy BALB/c mice, whereas ex vivo biodistribution, micro-SPECT/CT imaging, and therapy studies were done on athymic nude mice bearing QGP1.SSTR2 and BON1.SSTR2 xenografts. Therapeutic efficacy was compared with [177Lu]Lu-EB-TATE. Results: Projected human effective doses of [67Cu]Cu-EB-TATE for male (0.066 mSv/MBq) and female (0.085 mSv/MBq) patients are tolerable. In vivo micro-SPECT/CT imaging of SSTR2-positive xenografts with [67Cu]Cu-EB-TATE showed tumor-specific uptake and prolonged accumulation. Biodistribution showed tumor accumulation, with concurrent clearance from major organs over a period of 72 h. [67Cu]Cu-EB-TATE was more effective (60%) at eliminating tumors that were smaller than 50 mm3 within the first 15 d of therapy than was [177Lu]Lu-EB-TATE (20%) after treatment with 2 doses of 15 MBq administered 10 d apart. Mean survival of [67Cu]Cu-EB-TATE-treated groups was 90 d and more than 90 d, whereas that of [177Lu]Lu-EB-TATE was more than 90 d and 89 d against vehicle control groups (26 d and 53 d), for QGP1.SSTR2 and BON1.SSTR2 xenografts, respectively. Conclusion: [67Cu]Cu-EB-TATE exhibited high SSTR2-positive NET uptake and retention, with favorable dosimetry and SPECT/CT imaging capabilities. The antitumor efficacy of [67Cu]Cu-EB-TATE is comparable to that of [177Lu]Lu-EB-TATE, with [67Cu]Cu-EB-TATE being slightly more effective than [177Lu]Lu-EB-TATE for complete remission of small tumors. [67Cu]Cu-EB-TATE therefore warrants clinical development.

Prediction of [177Lu]Lu-DOTA-TATE therapy response using the absorbed dose estimated from [177Lu]Lu-DOTA-TATE SPECT/CT in patients with metastatic neuroendocrine tumour.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-TATE has shown efficacy in patients with metastatic neuroendocrine tumours (NETs). Personalised dosimetry is crucial to optimise treatment outcomes and minimise adverse events. In this study, we investigated the correlation between the tumour-absorbed dose (TAD) estimated from [177Lu]Lu-DOTA-TATE SPECT/CT and the therapeutic response. METHOD: A retrospective analysis was conducted on patients with advanced well-differentiated NETs grades 1-3 who underwent PRRT and exhibited greater uptake than liver on pre-therapeutic [68Ga]Ga-DOTA-TOC PET/CT. Target lesions were selected based on the RECIST 1.1 and PERCIST 1.0 criteria using [177Lu]Lu-DOTA-TATE SPECT/CT and pre-therapeutic contrast-enhanced CT scans. For anatomical image analysis, the sum of the longest diameter (SLD) of the target lesions was measured using the RECIST 1.1 criteria for patient-based analysis and the longest diameter (LD) of the target lesion using the RECIST-L criteria for lesion-based analysis. Standardised uptake values (SUVs) were measured on SPECT/CT images, and TADs were calculated based on the SUVs. Dosimetry was performed using a single SPECT/CT imaging time point at day 4-5 post-therapy. Statistical analyses were conducted to investigate correlations and determine the target lesion responses. RESULTS: Twenty patients with primary tumour sites and hepatic metastases were included. Fifty-five target lesions, predominantly located in the pancreas and liver, were analysed. The cumulative TAD (lesion-based analysis: r = 0.299-0.301, p = 0.025-0.027), but not the cycle 1 SUV (lesion-based analysis: r = 0.198-0.206, p = 0.131-0.147) or cycle 1 TAD (lesion-based analysis: r = 0.209-0.217, p = 0.112-0.126), exhibited a significant correlation with the change in LD of the target lesion. Binary logistic regression analysis identified the significance of the cumulative TAD in predicting disease control according to the RECIST-L criteria (odds ratio = 1.031-1.051, p = 0.024-0.026). CONCLUSIONS: The cumulative TAD estimated from [177Lu]Lu-DOTA-TATE SPECT/CT revealed a significant correlation with change in LD, which was significantly higher for the cumulative TAD than for the cycle 1 SUV or TAD. A higher cumulative TAD was associated with disease control in the target lesion. However, considering the limitations inherent to a confined sample size, careful interpretation of these findings is required. Estimation of the cumulative TAD of [177Lu]Lu-DOTA-TATE therapy could guide the platform towards personalised therapy.

Selective Control of Phases and Electronic Structures of Monolayer TaTe2.

Transition metal dichalcogenide (TMDC) films exhibit rich phases and superstructures, which can be controlled by the growth conditions as well as post-growth annealing treatment. Here, the selective growth of monolayer TaTe2 films with different phases as well as superstructures using molecular beam epitaxy (MBE) is reported. Monolayer 1H-TaTe2 and 1T-TaTe2 films can be selectively controlled by varying the growth temperature, and their different electronic structures are revealed through the combination of angle-resolved photoemission spectroscopy measurements (ARPES) and first-principles calculations. Moreover, post-growth annealing of the 1H-TaTe2 film further leads to a transition from a 19 × 19 $\sqrt {19}{\times }\sqrt {19}$ superstructure to a new 2 × 2 superstructure, where two gaps are observed in the electronic structure and persist up to room temperature. First-principles calculations reveal the role of the phonon instability in the formation of superstructures and the effect of local atomic distortions on the modified electronic structures. This work demonstrates the manipulation of the rich phases and superstructures of monolayer TaTe2 films by controlling the growth kinetics and post-growth annealing.

Case report: 177Lu DOTA-TATE: a new scheme for the treatment of prostate neuroendocrine cancer.

Background: Most instances of small cell carcinoma originate from the lungs, while the gastrointestinal tract serves as a secondary site. Only a minuscule proportion of cases manifest within the urogenital system. Prostate small cell carcinoma (SCCP) represents an exceedingly uncommon pathological subtype within the realm of prostate cancer, displaying significant rarity in clinical settings. This scarcity has resulted in a paucity of adequate foundational and clinical research for SCCP treatment. While investigations have unveiled a certain therapeutic efficacy of radiotherapy and chemotherapy for SCCP, clinical practice has revealed suboptimal treatment outcomes. We hereby present a case report detailing the utilization of 177Lu-DOTA-TATE in the treatment of SCCP, aiming to investigate the therapeutic efficacy of 177Lu-DOTA-TATE for SCCP. Case presentation: A male patient in his 80s presented with elevated prostate-specific antigen (PSA) levels and underwent a biopsy that revealed prostate adenocarcinoma. The patient received CAB (bicalutamide + goserelin) therapy. One year later, disease progression was detected, and a second biopsy confirmed the presence of prostate small cell carcinoma. Following the diagnosis of prostate small cell carcinoma, the patient underwent two cycles of 177Lu-DOTA-TATE treatment. Subsequent to the treatment, the original lesions showed shrinkage, metastatic lesions disappeared, and there was significant improvement, approaching complete remission. Conclusion: SCCP exhibits a high degree of malignancy and aggressive invasiveness, currently lacking effective therapeutic modalities. The treatment course of this patient serves as compelling evidence for the efficacy of 177Lu-DOTA-TATE in managing SCCP, thereby opening new avenues for future SCCP treatments.

Spinal phosphaturic mesenchymal tumors: a rare etiology causing tumor-induced osteomalacia-a review of experience at a UK tertiary referral center and literature review.

PURPOSE: This article aims to provide a comprehensive review of the management challenges associated with Spinal Phosphaturic Mesenchymal tumors (PMTs) and evaluates the surgical management outcomes for this rare entity linked to Tumor-induced osteolysis. The primary objective of this study is to enhance the familiarity of treating physicians with the clinical features, diagnosis, and treatment options for Spinal PMTs. METHODS: A retrospective analysis was conducted, reviewing electronic medical records of patients diagnosed with spinal PMTs at our hospital between January 2019 and December 2022. The data collected included demographic information, clinical presentation, radiological findings, surgical details, and follow-up outcomes. RESULTS: A total of three cases of Spinal PMTs causing Tumor-induced osteomalacia were identified. The diagnosis of Spinal PMTs presented challenges, with incidental detection often occurring during routine imaging. Surgical management was undertaken, resulting in successful symptom resolution and normalization of phosphate levels. The application of 68 Ga-DOTA-TATE PET/CT scans facilitated tumor localization, aiding in surgical planning. Spinal PMTs demonstrated a favorable response to surgical intervention. CONCLUSION: Spinal PMTs play a significant role in Tumor-induced osteolysis, warranting timely and accurate diagnosis. Although diagnosing Spinal PMTs presents challenges, surgical management has proven to yield favorable outcomes, effectively alleviating symptoms and restoring phosphate levels. A multidisciplinary approach and continued vigilance are essential in ensuring early diagnosis, effective treatment, and long-term monitoring for patients affected by spinal PMTs.

Radiation exposure assessment of nuclear medicine staff administering [177Lu]Lu-DOTA-TATE with active and passive dosimetry.

BACKGROUND: The use of lutetium-177 (177Lu)-based radiopharmaceuticals in peptide receptor nuclear therapy is increasing, but so is the number of nuclear medicine workers exposed to higher levels of radiation. In recent years, [177Lu]Lu-DOTA-TATE has begun to be widely used for the treatment of neuroendocrine tumours. However, there are few studies evaluating the occupational radiation exposure during its administration, and there are still some challenges that can result in higher doses to the staff, such as a lack of trained personnel or fully standardised procedures. In response, this study aims to provide a comprehensive analysis of occupational doses to the staff involved in the administration of [177Lu]Lu-DOTA-TATE. RESULTS: A total of 32 administrations of [177Lu]Lu-DOTA-TATE (7.4 GBq/session) carried out by a physician and a nurse, were studied. In total, two physicians and four nurses were independently monitored with cumulative (passive) and/or real-time (active) dosemeters. Extremity, eye lens and whole-body doses were evaluated in terms of the dosimetric quantities Hp(0.07), Hp(3) and Hp(10), respectively. It was obtained that lead aprons reduced dose rates and whole-body doses by 71% and 69% for the physicians, respectively, and by 56% and 68% for the nurses. On average, normalised Hp(10) values of 0.65 ± 0.18 µSv/GBq were obtained with active dosimetry, which is generally consistent with passive dosemeters. For physicians, the median of the maximum normalised Hp(0.07) values was 41.5 µSv/GBq on the non-dominant hand and 45.2 µSv/GBq on the dominant hand. For nurses 15.4 µSv/GBq on the non-dominant and 13.9 µSv/GBq on the dominant hand. The ratio or correction factor between the maximum dose measured on the hand and the dose measured on the base of the middle/ring finger of the non-dominant hand resulted in a factor of 5/6 for the physicians and 3/4 for the nurses. Finally, maximum normalised Hp(3) doses resulted in 2.02 µSv/GBq for physicians and 1.76 µSv/GBq for nurses. CONCLUSIONS: If appropriate safety measures are taken, the administration of [177Lu]Lu-DOTA-TATE is a safe procedure for workers. However, regular monitoring is recommended to ensure that the annual dose limits are not exceeded.

Replacing Lu-177 with Tb-161 in DOTA-TATE and PSMA-617 therapy: potential dosimetric implications for activity selection.

AIM: To explore the dosimetric effect of substituting Lu-177 with Tb-161 in targeted radionuclide therapy (TRT) using the registered tracers DOTA-TATE and PSMA-617. METHODS: Using established kinetic data for [177Lu]Lu-DOTA-TATE and [177Lu]Lu-PSMA-617, radiation absorbed doses to typical tumour lesion as well as non-target tissues ([177Lu]Lu-DOTA-TATE: kidneys, spleen and liver, [177Lu]Lu-PSMA-617: kidneys, liver and salivary glands) were calculated for Lu-177 and Tb-161. RESULTS: For both DOTA-TATE and PSMA-617, the substitution of Lu-177 with Tb-161 results in an increase in the delivered dose per unit of activity to tumour tissue by 40%. If an equivalent non-target delivered dose is strived for in order not to increase toxicity, based on kidney absorbed dose, 7400 MBq Lu-177 per cycle should be substituted with 5400 MBq Tb-161 for DOTA-TATE and 5300 MBq of Tb-161 for PSMA-617. CONCLUSION: When substituting Lu-177 with Tb-161, activity conversion is necessary in order not to exceed non-target dose limits.

Efficacy, Toxicity, and Prognostic Factors of Re-treatment With [177Lu]Lu-DOTA-TATE in Patients With Progressing Neuroendocrine Tumors: The Experience of a Single Center.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) is an effective and safe treatment of unresectable or metastatic, progressive neuroendocrine tumours (NETs). However, if progression occurs after the initial PRRT, treatment options remain limited. Our aim was to evaluate the efficacy and safety of a repeat 177Lutetium-[DOTA°,Tyr3]octreotate ([177Lu]Lu-DOTA-TATE) PRRT course in patients with progressive NET after the first [177Lu]Lu-DOTA-TATE PRRT (peptide receptor radionuclide therapy first treatment (PRRT1)). METHODS: This is a nine-year retrospective observational study of 20 patients who were re-treated with PRRT (peptide receptor radionuclide therapy retreatment (PRRTR)) after PRRT1. RESULTS: The median progression-free survival (PFS) following PRRT1 was 32 months (interquartile range (IQR): 16.5-44.5). After PRRT1, all 20 patients progressed. Of the 20 patients included, two were lost during follow-up. The median PFS after PRRTR was 17.5 months (IQR: 7-39). At the time of analysis, 15/18 patients progressed, and 3/18 had stable disease after PRRTR. Among those patients who progressed, the median time to progression was nine months (IQR: 0-17). The median overall survival from the time of the first cycle of PRRT1 was 66 months (IQR: 65-90). No significant renal or liver toxicity was reported, nor was there a drop in haemoglobin. The decrease in platelet count after PRRTR was statistically significant (p=0.03). Two cycles at PRRTR (vs. 1) were associated with a longer PFS (p=0.014) and the presence of metastases pre-PRRTR was associated with a shorter time to progression following PRRTR (p=0.04).  Conclusion: Patients who progressed after PRRT1 can achieve good PFS and minor toxicity. Our study reinforces the efficacy and safety of PRRTR and provides an analysis of factors associated with better outcomes, which can aid clinicians in clinical decision-making.

[Mechanism of Proliferation and Apoptosis of Acute Promyelocytic Leukemia Cell Line NB4 Induced by TPA].

OBJECTIVE: To investigate the effect of phorbol-12-myristate-13-ace-tate (TPA) on the proliferation and apoptosis of acute promyelocytic leukemia cell line NB4 and its molecular mechanism. METHODS: The effect of different concentrations of TPA on the proliferation of NB4 cells at different time points was detected by CCK-8 assay. The morphological changes of NB4 cells were observed by Wright-Giemsa staining. The cell cycle and apoptosis of NB4 cells after TPA treatment were detected by flow cytometry. The mRNA expressions of NB4 cells after TPA treatment were analyzed by high-throughput microarray analysis and real-time quantitative PCR. Western blot was used to detect the protein expression of CDKN1A, CDKN1B, CCND1, MYC, Bax, Bcl-2, c-Caspase 3, c-Caspase 9, PIK3R6, AKT and p-AKT. RESULTS: Compared with the control group, TPA could inhibit the proliferation of NB4 cells, induce the cells to become mature granulocyte-monocyte differentiation, and also induce cell G1 phase arrest and apoptosis. Differentially expressed mRNAs were significantly enriched in PI3K/AKT pathway. TPA treatment could increase the mRNA levels of CCND1, CCNA1, and CDKN1A, while decrease the mRNA level of MYC. It could also up-regulate the protein levels of CDKN1A, CDKN1B, CCND1, Bax, c-Caspase 3, c-Caspase 9, and PIK3R6, while down-regulate MYC, Bcl-2, and p-AKT in NB4 cells. CONCLUSION: TPA induces NB4 cell cycle arrest in G1 phase and promotes its apoptosis by regulating PIK3/AKT signaling pathway.

Individualisation of radiation protection recommendations for patients treated with [177Lu]Lu-DOTA-TATE.

BACKGROUND: As for any other nuclear medicine treatment, patients treated with [177Lu]Lu-DOTA-TATE should be given some radiation protection recommendations after being discharged to limit the dose received by family members and public. The restriction periods will depend on the remaining activity at the time of discharge, the washout rate and patients' personal conditions. The activity in patients' whole-body follows a bi-exponential behaviour. At the time of discharge only the first part of the time-activity curve is known. However, the second phase of the bi-exponential curve should be known to individualize the time of restrictions. The main purpose of this prospective study was to establish a simple method for calculating the restriction periods based on measurements taken before discharge. METHODS: The whole-body time-activity curve was calculated for 20 patients from dose-rate measurements performed during the first week post-administration. An effective decay time [Formula: see text] was calculated from a mono-exponential fit performed with the 6 h and 24 h measurements and compared with the effective decay time [Formula: see text] obtained from the mono-exponential fit performed with the 24 h, 48 h and 168 h measurements. The differences between them were calculated and the 95th percentile of these differences was used as a correction factor for [Formula: see text]. A modified effective decay [Formula: see text] was obtained by adding the correction factor to [Formula: see text] and the restriction periods for each patient was calculated. The whole body activity washout between the first and the fourth treatment cycles of 16 patients was also compared. RESULTS: The comparison of the whole-body activity curves between the first and the fourth cycle of the treatment for 16 patients would indicate that the recommendations on radiation protection determined from the first cycle could reasonably be used for the remaining cycles in most patients. The values of [Formula: see text] and [Formula: see text] obtained for the 20 patients were significantly different. The 95th percentile of the differences between [Formula: see text] and [Formula: see text] was 46 h, which is thus the time to be added to [Formula: see text] so as to determine the restriction periods. CONCLUSIONS: The proposed method makes it possible to calculate the restriction periods for patients treated with [177Lu]Lu-DOTA-TATE before they leave the hospital in a conservative and individualized way.

Simultaneous Imaging of Ga-DOTA-TATE and Lu-DOTA-TATE in Murine Models of Neuroblastoma.

68Ga-DOTA-TATE and 177Lu-DOTA-TATE are radiolabeled somatostatin analogs used to detect or treat neuroendocrine tumors. They are administered separately for either diagnostic or therapeutic purposes but little experimental data for their biokinetics are measured simultaneously in the same biological model. By co-administering 68Ga-DOTA-TATE and 177Lu-DOTA-TATE in three laboratory mice bearing two IMR32 tumor xenografts expressing different levels of somatostatin receptors (SSTRs) on their shoulders and imaging both 68Ga and 177Lu simultaneously, we investigated the relationship between the uptake of 68Ga-DOTA-TATE and 177Lu-DOTA-TATE in organs and tumors. In addition, using the percent of injected activity (%IA) values of 68Ga-DOTA-TATE at 0 hr and 4 hr, we investigated the correlation between 68Ga-DOTA-TATE %IA and the time-integrated activity coefficients (TIACs) of 177Lu-DOTA-TATE to estimate the organ-based and tumor-based doses of 177Lu-DOTA-TATE. The results showed that the extrapolated clearance time of 68Ga-DOTA-TATE linearly correlated with the TIACs of 177Lu-DOTA-TATE in the IMR32-SSTR2 tumor, kidneys, brain, heart, liver, stomach and remainder body. The extrapolated %IA value at 0 hr of 68Ga-DOTA-TATE linearly correlated with the TIACs of 177Lu-DOTA-TATE in the IMR32 tumor and lungs. In our murine study, both kidneys and lungs were organs that showed high absorbed doses of 177Lu-DOTA-TATE.

AI-based quantification of whole-body tumour burden on somatostatin receptor PET/CT.

BACKGROUND: Segmenting the whole-body somatostatin receptor-expressing tumour volume (SRETVwb) on positron emission tomography/computed tomography (PET/CT) images is highly time-consuming but has shown value as an independent prognostic factor for survival. An automatic method to measure SRETVwb could improve disease status assessment and provide a tool for prognostication. This study aimed to develop an artificial intelligence (AI)-based method to detect and quantify SRETVwb and total lesion somatostatin receptor expression (TLSREwb) from [68Ga]Ga-DOTA-TOC/TATE PET/CT images. METHODS: A UNet3D convolutional neural network (CNN) was used to train an AI model with [68Ga]Ga-DOTA-TOC/TATE PET/CT images, where all tumours were manually segmented with a semi-automatic method. The training set consisted of 148 patients, of which 108 had PET-positive tumours. The test group consisted of 30 patients, of which 25 had PET-positive tumours. Two physicians segmented tumours in the test group for comparison with the AI model. RESULTS: There were good correlations between the segmented SRETVwb and TLSREwb by the AI model and the physicians, with Spearman rank correlation coefficients of r = 0.78 and r = 0.73, respectively, for SRETVwb and r = 0.83 and r = 0.81, respectively, for TLSREwb. The sensitivity on a lesion detection level was 80% and 79%, and the positive predictive value was 83% and 84% when comparing the AI model with the two physicians. CONCLUSION: It was possible to develop an AI model to segment SRETVwb and TLSREwb with high performance. A fully automated method makes quantification of tumour burden achievable and has the potential to be more widely used when assessing PET/CT images.