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Background: Peptide receptor radionuclide therapy (PRRT) has been recently approved for advanced, metastatic, or progressive neuroendocrine tumors (NETs). Objectives: This study reports the adverse events (AEs) observed with patient-tailored administered activity. Methods: Fifty-two PRRT naive patients were treated with 177Lu-DOTATATE. The administered activity ranges between 2.78 and 5.55 GBq/cycle using the patient's unique characteristics (age, symptoms, blood work, and biomarkers). Results: The protocol was well tolerated with the overwhelming majority of participants being forty- six (88%), completing all 4 induction therapy cycles. The median cumulative administered activity was 19.6 GBq (ranged 3.8-22.3 GBq). A total of 42/52 (81%) reported at least one symptom, and 43/52 (83%) had evidence of biochemical abnormality at enrollment that would meet grade 1 or 2 criteria for AEs. These symptoms only slightly increase with treatment to 50/52 (96%) and 51/52 (98%), respectively. The most common symptoms were mild fatigue (62%), shortness of breath (50%), nausea (44%), abdominal pain (38%), and musculoskeletal pain (37%). The most common biomarker abnormalities were mild anemia (81%), reduced estimated glomerular filtration rate (eGFR) (58%), increased alkaline phosphatase (ALP) (50%), and leukopenia (37%). Of critical importance, no 177Lu-DOTATATE related grade 3 or 4 AEs were observed. Conclusion: Tailoring the administered activity of 177Lu-DOTATATE to the individual patient with a variety of NETs is both safe and well-tolerated. No patient developed severe grade 3 or 4 AEs. Most patients exhibit symptoms or biochemical abnormality before treatment and this only slightly worsens following induction therapy.

Copyright © 2021 The Author(s). Aim: To evaluate the cost-effectiveness of [177Lu]Lu-DOTA-TATE versus relevant comparators for the treatment of neuroendocrine tumours located in the gastrointestinal tract (GI-NETs) and the pancreas (P-NETs). Materials and methods: A three-state partitioned survival model was developed to perform a cost-utility analysis of [177Lu]Lu-DOTA-TATE versus standard of care (high dose Octreotide LAR), everolimus and sunitinib. Effectiveness data for SoC, everolimus and sunitinib were obtained from published Kaplan–Meier survival curves. Given a lack of head-to-head effectiveness data, matching adjusted indirect comparisons (MAICs) were performed to population-adjust [177Lu]Lu-DOTA-TATE survival data based on prognostic factors and derive estimates of relative effectiveness. Health state utilities were estimated from real-world evidence. Drug acquisition costs were taken from nationally published sources (BNF, NICE), and administration costs were based on treatment protocols in [177Lu]Lu-DOTA-TATE studies, combined with nationally published unit costs (PSSRU, DoH reference costs). Incidence of adverse events were estimated using published sources. A discount rate of 3.5% was applied to both utilities and costs, and deterministic and probabilistic sensitivity analyses were performed. Costs were included from an NHS perspective and presented in 2017/18 GBP (and PPP Euros for base case). Results: In GI-NETs, the incremental cost-effectiveness ratio (ICER) of [177Lu]Lu-DOTA-TATE compared to SoC and everolimus was £26,528 (€27,672) and £24,145 (€25,186) per QALY, respectively. In P-NETs, the ICER of [177Lu]Lu-DOTA-TATE compared to SoC was £22,146 (€23,101) or £28,038 (€29,251) dependent on matched population, and £21,827 (€22,766) and £15,768 (€16,445) compared to everolimus and sunitinib, respectively. Conclusions: At a willingness to pay threshold of £30,000, [177Lu]Lu-DOTA-TATE is likely to be a cost-effective treatment option for GI-NET and P-NET patients versus relevant treatment comparators (NHS perspective). Advanced Accelerator Applications (AAA), a Novartis company.

Peptide receptor radionuclide therapy (PRRT) is used for the treatment of patients with unresectable or metastasized somatostatin receptor type 2 (SSTR2)-expressing gastroenteropancreatic neuroendocrine tumours (GEP-NETs). The radiolabelled somatostatin analogue [177Lu]Lu-DOTA-TATE delivers its radiation dose to SSTR2-overexpressing tumour cells, resulting in selective cell killing during radioactive decay. While tumour control can be achieved in many patients, complete remissions remain rare, causing the majority of patients to relapse after a certain period of time. This raises the question whether the currently fixed treatment regime (4 × 7.4 GBq) leaves room for dose escalation as a means of improving therapy efficacy. The kidneys have shown to play an important role in defining a patient's tolerability to PRRT. As a consequence of the proximal tubular reabsorption of [177Lu]Lu-DOTA-TATE, via the endocytic megalin/cubilin receptor complex, the radionuclides are retained in the renal interstitium. This results in extended retention of radioactivity in the kidneys, generating a risk for the development of radiation nephropathy. In addition, a decreased kidney function has shown to be associated with a prolonged circulation of [177Lu]Lu-DOTA-TATE, causing increased irradiation to the bone marrow. This can on its turn lead to myelosuppression and haematological toxicity, owing to the marked radio sensitivity of the rapidly proliferating cells in the bone marrow. In contrast to external beam radiotherapy (EBRT), the exact absorbed dose limits for these critical organs (kidneys and bone marrow) in PRRT with [177Lu]Lu-DOTA-TATE are still unclear. Better insights into these uncertainties, can help in optimizing PRRT to reach its maximum therapeutic potential, while avoiding severe adverse events, like nephropathy and hematologic toxicities. In this review we focus on the nephrotoxic effects of PRRT with [177Lu]Lu-DOTA-TATE for the treatment of GEP-NETs. If the absorbed dose to the kidneys can be lowered, higher activities can be administered, enlarging the therapeutic window for PRRT. Therefore, we evaluated the renal protective potential of current and promising future strategies and discuss the importance of (renal) dosimetry in PRRT. ispartof: NUCLEAR MEDICINE AND BIOLOGY vol:102 pages:1-11 ispartof: location:United States status: published

Head-to-head comparisons of the efficacy of treatments for gastroenteropancreatic neuroendocrine tumours (GEP-NETs) have not yet been reported. This study used a series of matching-adjusted indirect comparisons to indirectly compare the effectiveness of [177Lu]Lu-DOTA-TATE to everolimus, sunitinib and best supportive care (BSC) for extending progression-free survival and overall survival in patients with advanced, unresectable gastrointestinal (GI)-NETs and P-NETs. The results of the main analysis suggest that after accounting for differences in key prognostic variables, the hazard of progression was 62% (hazard ratio [HR], 0.38; confidence interval [CI]95 0.25–0.58) and 65% (HR 0.35 CI95 0.21–0.59) lower in patients with GI-NETs treated with [177Lu]Lu-DOTA-TATE than in those treated with everolimus and BSC, respectively. Similarly, the hazard of progression was 64% (HR 0.36 CI95 0.18–0.70), 54% (HR 0.46 CI95 0.30–0.71) and 79–87% (HR 0.21 CI95 0.13–0.32; HR 0.13 CI95 0.08–0.22) lower in patients with P-NET treated with [177Lu]Lu-DOTA-TATE than in those treated with sunitinib, everolimus and BSC, respectively. The hazard of death was 58% (HR 0.42 CI95 0.25–0.72), 47% (HR 0.53 CI95 0.33–0.87) and 44–64% (HR 0.56 CI95 0.36–0.90; HR 0.34 CI95 0.20–0.57) lower in P-patients with NET treated with [177Lu]Lu-DOTA-TATE than in those treated with sunitinib, everolimus and BSC, respectively. While our results must be interpreted with caution given the non-randomised nature of the comparisons and the potential for residual confounding, the magnitude of the effect sizes we observe and their consistency across comparators suggest that [177Lu]Lu-DOTA-TATE may be a more effective treatment option than everolimus, sunitinib and BSC in advanced, unresectable GEP-NETs.

BACKGROUND A quantitative imaging biomarker is desirable to provide a comprehensive measure of whole-body tumor burden in patients with metastatic neuroendocrine tumors, and to standardize the evaluation of treatment-related changes. Therefore, we evaluated volumetric parameters for quantification of whole-body tumor burden from somatostatin receptor (SSR)- targeted PET/CT. METHODS 32 patients with metastastic grade1/grade 2 gastroenteropancreatic neuroendocrine tumors who underwent a 68Ga-DOTA-TATE PET/CT for staging of disease before initiation of peptide receptor radionuclide therapy were included in this retrospective cohort analysis. Volumetric parameters of tumor lesions, SSR-derived tumor volume (SSR-TV) and total lesion SSR (TL-SSR), were calculated for each patient using a computerized volumetric technique with a 40% SUVmax cut-off, and compared with serum chromogranin A (CgA) levels. Progression-free survival (PFS) was determined in relation to volumetric parameters. In a subgroup of 18 patients, the feasibility of volumetric parameters for treatment monitoring was evaluated. RESULTS Mean SSR-TV was 178±214 cm3 (range, 9-797 cm3), whereas mean TL-SSR was 4096±5191 cm3 (range, 61-19203 cm3). Baseline CgA levels were associated with whole- body tumor burden (SSR-TV, r=0.57, P=0.0008; and TL-SSR, r=0.43, P=0.01, respectively). PFS was shorter in patients with high SSR-TV and high TL-SSR (HR 5.16 (95% CI, 1.61- 29.67), P=0.009), and SSR-TV (P = 0.0067) and TL-SSR (P = 0.0215) emerged as the sole predictors of progression in regression analysis. Changes in CgA did not correctly identify treatment response (P=0.25). CONCLUSIONS SSR-derived volumetric parameters provide a quantitative imaging biomarker for whole-body tumor burden, and may hold potential as a clear-cut measure for assessment of treatment response.

Purpose: This study aimed to analyze neuroendocrine neoplasm (NEN) bone metastasis (BM) and gallium-68 (68Ga)-DOTA-TATE performance and to explore their correlation with the immunohistochemical proliferation index (Ki-67). Procedures: A total of 112 patients with BMs were screened from 1082 NEN patients who underwent [68Ga]Ga-DOTA-TATE imaging. All patients had pathological results, and BMs were affirmed by clinical/imaging follow-up and/or histopathology. The maximum standard uptake value (SUVmax) ratio of BM to normal bone determined for each patient was used in the final analysis. Results: The incidence rate of BMs in NENs was 10.35%. BMs occurred in the spine (75%), pelvis (72.3%), ribs (58%), clavicles and scapulae (41.1%), limbs (37.5%), and skull (28.6%). Most cases were associated with liver metastases (70.5%) and lymph node metastases (65.2%) simultaneously. The SUVmax ratio of G3b (median ratio = 3.77, Ki-67 >55%) was significantly lower than that of G1 (11.43, Ki-67 ≤2%) and G2a (11.15, 3% ≤ Ki-67 ≤10%) separately (p < 0.05), while no differences were found for G2b (8.5, 11% ≤ Ki-67 ≤55%) and G3a (6.64, Ki-67 >55%) groups. In the total patients, there was a significant negative correlation between the SUVmax ratio of BMs to normal bone and Ki-67 (r = −0.267, p < 0.01). According to the changes in bone density on CT scans, the cases were divided into 4 groups: osteogenesis, osteolysis, no change, and a mixed group (median Ki-67: 6.5%, 15%, 12%, and 22.5%). The Ki-67 values were significantly different between the osteogenesis group and the other groups (p < 0.05). Conclusion: BM is present in 10.35% of NEN patients and most have simultaneous liver and/or lymph node metastases. The occurrence of osteogenesis indicates relatively good differentiation, and there is a negative correlation between SUVmax ratio of BMs and NEN proliferation.

Nuclear medicine uses radioactive pharmaceuticals for diagnostic or therapeutic purposes. The ionizing radiation emitted from the radiopharmaceutical is partially absorbed within the patient's body and internal dosimetry is the method to estimate the absorbed dose to a tumour or risk organ. This is of special importance in radiopharmaceutical therapy (RPT), where particle-emitting radionuclides are utilized for their therapeutic effect. A better understanding of where and to what extent the radiation energy is deposited, i.e. dosimetry, in combination with a better understanding of the irradiation-induced biological processes in tissues and tumours, i.e., radiobiology, is the foundation to establish an absorbed dose-effect relationship. This thesis comprises quantitative methods and modelling within dosimetry and radiobiology, with a special focus on quantitative methods for activity concentration, absorbed dose calculation and quantification of biological effects after nuclear medicine exposures. Nonuniformity of activity distribution and the biological effect of internal irradiation is considered in Paper I and Paper II. When a radiopharmaceutical primarily localizes within specific tissue substructures of an organ, the average absorbed dose to the whole organ may become insufficient for dosimetric analysis. Hence, the nonuniformities of the distribution of activity need to be considered and absorbed dose calculations to part of an organ, cellular, or a sub-cellular structure may be a better predictor of the therapy outcome or normal tissue toxicity. In Paper I, a small-scale anatomical dosimetry model of the liver tissue structure addressed the issue of activity nonuniformity. Monte Carlo simulations were performed to simulate the particle transport from various substructure sources within the organ model for some clinically available radionuclides. The model enabled comparison between the average absorbed dose to the entire organ and the local absorbed dose close to the source region, which for particle emitting radionuclides differed significantly. To address the resulting biological effect after internal irradiation, an ex vivo method using the γH2AX surrogate marker to visualize and quantify DNA double-strand breaks in in vivo-irradiated tissues was developed. The method was demonstrated to be useful for γH2AX-foci quantification in both the fast proliferating, radiosensitive testis tissue and the slow proliferating and more radioresistant liver tissue. Image-based activity quantification and absorbed dose estimation are considered in Paper III and Paper IV, using somatostatin receptor targeting agents for both diagnostic and therapeutic applications for neuroendocrine tumours. In Paper III, the quantitative accuracy of pre-therapeutic 111In-Octreoscan® SPECT/CT and [68Ga]Ga-DOTA-TATE PET/CT images was investigated due to the change in clinical method to use PET- instead of SPECT-imaging. Further, the quantitative relationship between the theragnostic pair of DOTA-TATE was investigated in Paper IV. The relationship between activity uptakes observed at [68Ga]Ga-DOTA-TATE PET imaging and absorbed doses at subsequent [177Lu]Lu-DOTA-TATE therapy was studied. The study demonstrated that on a group level, a higher tumour uptake measured from pretherapeutic PET images is associated with higher absorbed doses in subsequent therapy with [177Lu]Lu-DOTA-TATE. However, on the individual level, there are limitations of using the 68Ga PET as a predictor for therapy absorbed dose.

PET imaging with F-18 DOPA (FDOPA) and Ga-68 DOTATATE (TATE) shows the most promising results to detect medullary thyroid cancer (MTC) recurrence. We performed this comparative study to detect the site of recurrent or metastatic disease in MTC patients with elevated serum calcitonin (Ctn) and/or carcinoembryonic antigen (CEA) levels. We studied 46 MTC patients (25 women, 21 men) with elevated Ctn and/or CEA levels during follow-up who had both FDOPA and TATE PET/CT scans for re-staging purposes. FDOPA PET imaging yielded an overall sensitivity of 86.8%, specificity of 100%, PPV of 100%, NPV of 61.5%, and accuracy of 89.1%, while TATE PET scan had the same values as 84.2%, 87.5%, 96.9%, 53.8%, and 84.6%, respectively, and there was no statistically significant difference between the two modalities with the exception of the specificity value that was higher for FDOPA imaging. In a subgroup of patients with overt Ctn or CEA elevation, sensitivity of FDOPA increased significantly, whereas TATE sensitivity did not change. FDOPA PET imaging was significantly superior in detecting liver and regional lymph node (LN) metastases, while TATE PET scan was significantly better in the skeletal metastases. Early FDOPA demonstrated 11 invisible lesions on late FDOPA. Both FDOPA and TATE PET/CT imaging are useful to localize recurrences in MTC patients. While TATE imaging is superior to reveal skeletal disease, FDOPA seems better in liver and regional LN metastases; therefore, the two modalities appear complementary in monitoring MTC patients with elevated serum Ctn and/or CEA levels.

Background Gallium 68-tetraazacyclododecane-tetraacetic acid-octreotate ([68Ga]Ga-DOTA-TATE) is a selective somatostatin analogue ligand, which shows increased affinity for somatostatin receptor subtype (SSTR) 2 and has been used routinely for imaging neuroendocrine tumors with PET/CT. We investigated the utility of [68Ga]Ga-DOTA-TATE positron emission tomography/computed tomography (PET/CT) in patients with suspected pituitary pathology. We reviewed imaging for twenty consecutive patients (8 men, 12 women, mean age of 48.2, range 14–78) with suspected pituitary pathology who were referred for [68Ga]Ga-DOTA-TATE PET/CT. Results Nine patients presented with recurrent Cushing’s syndrome following surgical resection of pituitary adenomas due to recurrent Cushing’s disease (seven patients) and ectopic ACTH secreting tumor (2 patients). All seven patients with recurrent Cushing’s disease showed positive pituitary [68Ga]Ga-DOTA-TATE uptake while both cases of ectopic hormonal secretion had absented pituitary uptake. In 1 of these 2 patients, [68Ga]Ga-DOTA-TATE was able to localize the source of ectopic ACTH tumor. Six patients presented de novo with Cushing’s due to ectopic ACTH secretion; [68Ga]Ga-DOTA-TATE PET/CT was able to localize ectopic tumors in six of eight patients (3 lungs, 2 pancreases, 1 mid-gut) There was high uptake [68Ga]Ga-DOTA-TATE in 3 cases of recurrent central hyperthyroidism (SUVmax 6.6–14.3) and 2 cases of prolactinoma (SUVmax 5.5 and 11.3). Conclusion Absent [68Ga]Ga-DOTA-TATE activity in the pituitary fossa is useful in excluding pituitary disease in recurrent Cushing’s. Recurrent pituitary thyrotropinomas and prolactinomas showed moderate to high pituitary activity. In addition, in Cushing’s syndrome, [68Ga]Ga-DOTA-TATE is useful for detection of ectopic sources of ACTH production, especially where anatomic imaging is negative.

There is significant interest in the development of targeted alpha-particle therapies (TATs) for treatment of solid tumors. The metal chelator-peptide conjugate, DOTA-TATE, loaded with the β-particle emitting radionuclide 177Lu ([177Lu]Lu-DOTA-TATE) is now standard care for neuroendocrine tumors that express the somatostatin receptor 2 (SSTR2) target. A recent clinical study demonstrated efficacy of the corresponding [225Ac]Ac-DOTA-TATE in patients that were refractory to [177Lu]Lu-DOTA-TATE. Herein, we report the radiosynthesis, toxicity, biodistribution (BD), radiation dosimetry (RD), and efficacy of [225Ac]Ac-DOTA-TATE in small animal models of lung neuroendocrine neoplasms (NENs). [225Ac]Ac-DOTA-TATE was synthesized and characterized for radiochemical yield, purity and stability. Non-tumor–bearing BALB/c mice were tested for toxicity and BD. Efficacy was determined by single intravenous injection of [225Ac]Ac-DOTA-TATE into SCID mice–bearing human SSTR2 positive H727 and H69 lung NENs. RD was calculated using the BD data. [225Ac]Ac-DOTA-TATE was synthesized with 98% yield, 99.8% purity, and displayed 97% stability after 2 days incubation in human serum at 37 °C. All animals in the toxicity study appeared healthy 5 months post injection with no indications of toxicity, except that animals that received ≥111 kBq of [225Ac]Ac-DOTA-TATE had chronic progressive nephropathy. BD studies revealed that the primary route of elimination is by the renal route. RD calculations determined pharmacokinetics parameters and absorbed α-emission dosages from 225Ac and its daughters. For both tumor models, a significant tumor growth delay and time to experimental endpoint were observed following a single administration of [225Ac]Ac-DOTA-TATE relative to controls. These results suggest significant potential for the clinical translation of [225Ac]Ac-DOTA-TATE for lung NENs.

Currently, radiolabeled DOTA-[Tyr3]-octreotate (DOTA-TATE) is most commonly used in the clinic to image and treat neuroendocrine tumors. To further improve tumor uptake, and thus treatment, the amount of radiotracer that can accumulate in the tumor might be increased by prolonging the blood circulation time of the radiotracer. To achieve this, we designed Albutate-1, with both DOTA and an albumin-binding domain coupled to TATE via a suitable linker. The aim of this study was to determine the characteristics of the novel radiotracer Albutate-1. A competition binding assay was performed using [111In]In-DOTA-TATE on fresh-frozen SSTR2+ tumor sections. In vitro cell-uptake and internalization of [111In]In-Albutate-1 and [111In]In-DOTA-TATE were determined. The stability of [177Lu]Lu-Albutate-1 was tested. A biodistribution study was performed to provide tumor and organ uptake of [177Lu]Lu-Albutate-1. The biodistribution data was used to determine time-activity curves and the radiation dose for each organ and the tumor. The in vitro IC50 value of Albutate-1 was 1.2 nM. A higher amount of the tracer was found in the intracellular fraction than in the membrane fraction ([111In]In-Albutate-1 14.0 vs 1.9% of the added amount; [111In]In-DOTA-TATE 11.0 vs 1.5% of the added amount). After radiolabeling [111In] In-Albutate-1 was stable up to 3 days (93.1-88.9%) in labeling solution and very stable in mouse serum (90-94%) for at least 24 h. In vivo, [177Lu]Lu-Albutate-1 was cleared slowly from the circulation (1 h p.i. 58%ID/g, 168h p.i. 2%ID/g). The addition of an albumin-binding domain to DOTA-TATE extended the blood circulation to T1/2= 27.5h. The tumor absorbed dose was raised to 1455 mGy/MBq. Bone marrow, the dose-limiting organ in the mouse spine, unfortunately, received 765 mGy/MBq. All other organs also received a high radiation dose, reducing the therapeutic index.

A [18F]AlF-labeled somatostatin receptor (SSTR) antagonist was developed for imaging of neuroendocrine neoplasms (NENs), evaluated and compared with [68Ga]Ga-DOTA-TATE. [18F]AlF-NOTA-JR11 was synthesized manually and qualified with high-performance liquid chromatography (HPLC) and liquid chromatography–mass spectrometry (LC-MS). The cellular uptake, internalization, and saturation binding were performed with HEK293-SSTR2 cells. Biodistribution and micro-PET imaging were carried out with HEK293-SSTR2 tumor-bearing mice. [18F]AlF-NOTA-JR11 PET/MR imaging and [68Ga]Ga-DOTA-TATE PET/CT were performed with ten patients of NEN at 50~60 min post-injection (p.i.). Normal organ biodistribution and tumor detectability were evaluated. [18F]AlF-NOTA-JR11(24~36 GBq/μmol) was prepared within 30 min and 51.35 ± 3.30% (n > 10)of radiochemical yield. The radiochemical purity was 98.74 ± 1.24% (n > 10). Two stereoisomers were found and confirmed by LC-MS. The cellular uptake of [18F]AlF-NOTA-JR11 and [68Ga]Ga-DOTA-TATE were 4.50 ± 0.31 and 4.50 ± 0.13 %AD/105 cells at 30 min, and the internalization at 37 °C of [18F]AlF-NOTA-JR11 (5.47 ± 0.32% at 60 min) was significantly lower than [68Ga]Ga-DOTA-TATE (66.89 ± 1.62% at 60 min). The affinity of [18F]AlF-NOTA-JR11 (Kd = 11.59 ± 1.31 nM) was slightly lower than [68Ga]Ga-DOTA-TATE (Kd = 7.36 ± 1.02 nM); [18F]AlF-NOTA-JR11 showed high uptake in tumor (9.02 ± 0.92 %ID/g at 60 min p.i.) which can be blocked by 50 μg of NOTA-JR11 (3.40 ± 1.64 %ID/g at 60 min p.i.); the result was coincident with micro-PET imaging. Imaging study of NEN patients showed that more lesions were found only by [18F]AlF-NOTA-JR11 (n = 67 vs. 1 only by [68Ga]Ga-DOTA-TATE), and the uptakes of [18F]AlF-NOTA-JR11 in majority normal organs were significantly lower than [68Ga]Ga-DOTA-TATE. The target to nontarget of maximum of standard uptake value (SUVmax) of [18F]AlF-NOTA-JR11 in liver lesions were significantly higher than those of [68Ga]Ga-DOTA-TATE. Qualitied [18F]AlF-NOTA-JR11 is prepared conveniently with reasonable yield, and it can bind SSTR2 specifically with high affinity. Excellent imaging capability of [18F]AlF-NOTA-JR11 for NENs is superior to [68Ga]Ga-DOTA-TATE, especially in digestive system. It has a great potential for imaging of NENs.

Objectives Somatostatin is an endocrine peptide hormone that regulates neurotransmission and cell proliferation by interacting with G protein-coupled somatostatin receptors (SSTRs). SSTRs are specific molecular targets of several radiotracers for neuroendocrine tumor (NET) imaging. Gallium-68 (68Ga)-DOTA-TATE is widely used for positron emission tomography/computed tomography (PET/CT) imaging of SSTRs and has shown a higher affinity for SSTR2, the most common SSTR subtype found in NETs. We aimed to analyze the distribution pattern of 68Ga-DOTA-TATE in normal subjects. Methods A total of 617 consecutive 68Ga-DOTA-TATE PET/CT whole-body scans performed in our department from May 2015 through April 2020 with known or suspected neuroendocrine malignancies, mostly to evaluate adrenal adenomas, were retrospectively analyzed by 2 nuclear medicine physicians. One hundred eighteen subjects without a diagnosis of NET, with no tracer avid lesion of NET on 68Ga-DOTA-TATE PET/CT, and followed up for at least 6 months (average 2-3 years) without any biochemical, clinical, or imaging findings suggestive of NET were included in this study. Results The highest uptake of 68Ga-DOTA-TATE was noted in the spleen followed by the kidneys, adrenal glands, liver, stomach, small intestine, prostate gland, pancreas head, pancreas body, thyroid gland, and uterus, in descending order. Minimal to mild uptake was detected in the submandibular glands, parotid glands, thymus, muscles, bones, breast, lungs, and mediastinum. Conclusion Our study shows the biodistribution pattern of 68Ga-DOTA-TATE in normal subjects and the ranges of the maximum standard uptake value (SUVmax) and SUVmean values of 68Ga-DOTA-TATE obtained in several tissues for reliably identifying malignancy in 68Ga-DOTA-TATE PET/CT studies.

A 62-year-old woman with a history of abdominal pain presented with multiple hepatic lesions and dilatation of portal, splenic and superior mesenteric veins on the magnetic resonance imaging referred for a 99mTc-octreotide scan. Accordingly, similar octreotide-avid lesions were found as well as an uptake in the epigastric region conforming to the anatomy of the portocaval venous system, compatible with a tumor thrombosis. Then, the patient underwent two cycles of therapy with 177Lu-DOTA-TATE, on that the same appearance was observed. The uptake in the tumor thrombus remained somewhat unchanged, but clinically, a significant improvement of the intractable ascites was achieved.

Tumor dosimetry was performed for 177Lu-DOTA-TATE with the aims of better understanding i) the range and variation of the tumor absorbed doses (ADs), ii) how different dosimetric quantities evolve over the treatment cycles, and iii) whether this evolution differs depending on the tumor grade. Such information is important for radiobiological interpretation and may inform the design of alternative administration schemes. Methods: Data come from 41 patients with neuroendocrine tumors (NETs) of grade 1 (n = 23) or 2 (n = 18), that had received between 2 and 9 treatment cycles. Dosimetry was performed for 182 individual lesions, giving in total 880 individual AD assessments across all cycles. Hybrid planar-SPECT/CT imaging was used, including quantitative SPECT reconstruction, voxel-based absorbed-dose-rate calculation, semi-automatic image segmentation, and partial-volume correction. Linear mixed-effect models were used to analyze changes over cycles in tumor ADs, absorbed-dose rates and activity concentrations at day-1, effective half-times, and tumor volumes. Tumors smaller than 8 ml were excluded from analyses. Results: Tumor ADs ranged between 2 and 77 Gy per cycle. On average the AD decreased over the cycles, with significantly different rates (P < 0.05) for grade 1 and 2 NETs of 6% and 14% per cycle, respectively. The absorbed-dose rates and activity concentrations at day-1 decreased by similar amounts. The effective half-times were less variable but shorter for grade 2 than grade 1 (P < 0.001). For grade 2 NETS the tumor volumes decreased, with a similar tendency in grade 1. Conclusion: The tumor AD, absorbed-dose rate and activity uptake decrease, in parallel with tumor volumes, between 177Lu-DOTA-TATE treatment cycles, particularly for grade 2 NETs. The effective half-times vary less but are lower for grade 2 than grade 1 NETs. These results may indicate the development of radiation-induced fibrosis and could have implications for the design of future treatment and dosimetry protocols.

Background Tumor-induced osteomalacia (TIO) is often misdiagnosed as hypophosphatemia that is not valued. The aim of this study was to analyze the diagnostic value of 68Ga-DOTA-TATE PET/CT imaging for TIO. Methods Clinical data was retrospectively collected for 56 patients with suspected TIO at the Affiliated Hospital of Southwest Medical University between January 2016 and December 2019, where patients were examined by 68Ga-DOTA-TATE PET/CT and 99mTc-HYNIC-TOC SPECT. Based on the results of the patient's surgery, the diagnostic efficacy of the two imaging techniques on TIO were analyzed. Results Of the 56 patients, 41 were diagnosed with TIO, with phosphorus levels ranging from 0.25 to 0.75 mmol/L. The remaining 15 patients were non-TIO. Results of 99mTc-HYNIC-TOC SPECT showed 33 cases were positive, with a diagnostic sensitivity, specificity, and accuracy of 58.54%, 86.67%, and 66.07%, respectively. Results of 68Ga-DOTA-TATE PET/CT imaging showed 46 cases were positive, with a diagnostic sensitivity, specificity, and accuracy of 95.13%, 60.00%, 71.43%, respectively. The average tumor size with 68Ga-DOTA-TATE PET/CT imaging was 2.58±1.71 cm. The lesions of 41 patients involved bone and soft tissue, while 18 patients showed osteolytic bone destruction. Distribution was mainly under the skin, followed by intermuscular space, and cortex of bone. Compared with muscle density, the lesions showed uniformly or slightly lower density nodules. Using 99mTc-HYNIC-TOC SPECT, the planar imaging of 30 patients showed that radioactive uptake increased at the early stage, and it can be accurately positioned on the SPECT imaging. Conclusions The 68Ga-DOTA-TATE PET/CT imaging demonstrated high accuracy in the diagnosis of TIO and detected small lesions, which could provide more comprehensive information for clinicians, and provide a reference value for the treatment and prognosis of patients.

Peptides have been widely adopted as biological targeting vectors for applications in molecular imaging and peptide-receptor radionuclide therapy (PRRT). Somatostatin (SST) analogues such as octreotate (TATE) are exogenous ligands for somatostatin receptors (SSTRs), which are highly expressed on neuroendocrine tumors (NETs). Recently, both [68Ga]Ga-DOTA-TATE (NETSPOT) and [177Lu]Lu-DOTA-TATE (LUTATHERA) received U.S. Food and Drug Administration approval for positron emission tomography (PET) imaging and PRRT of NETs, respectively. However, to the best of our knowledge a well-described synthesis of DOTA-TATE has not been reported in the literature. Herein, we report a fully reoptimized DOTA-TATE synthesis, including the application of a simple ultrasonic bath to greatly improve yields, reduce coupling times, and decrease the amount of reagents required for each coupling step by a half. The most prevalently used cyclizing agents such as iodine, thallium(III) trifluoroacetate, hydrogen peroxide, and dimethyl sulfoxide were compared. On-resin cyclizations using mechanical agitation showed higher yields (23% and 25% using I2 and Tl(III), respectively) than off-resin (1.3% and 11% using DMSO and H2O2, respectively), and the total synthesis time of DOTA-TATE was ∼540 min excluding the cyclization step, with a total synthesis yield of ∼23%. The same manual SPPS methods/reagents were reoptimized with ultrasonic (US) agitation, resulting in an immense reduction in the total synthesis time by ∼8-fold to ∼70 min for DOTA-TATE with a higher yield (∼29% yield), and ∼13-fold to 105 min for DOTA-PEG4-TATE (∼29% yield). Also, the use of US agitation reduces the need for excess molar equivalents of the reagents to a half, which is particularly important when coupling expensive or custom-synthesized groups such as bifunctional chelators and linkers. Finally, the synthesized DOTA-TATE was successfully radiolabeled with [68Ga]Ga3+ (t1/2 = 68 min) with high radiochemical yields (30 min, 95 °C). We believe this work opens the door to the facile and low-cost synthesis of many new chelator-linker-peptide conjugates that were previously cumbersome or cost-prohibitive to produce with manual SPPS.

PURPOSE In our study, tumor heterogeneity was evaluated using the parameters skewness and kurtosis on pretreatment Ga-68 DOTA-TATE PET/CT to assess therapy responses of lesions in patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs) treated with peptide receptor radionuclide therapy (PRRT). METHOD We retrospectively studied the texture analysis with relatively simple first-order parameters skewness and kurtosis on pretreatment Ga-68 DOTA-TATE PET/CT from 22 patients (eight females, 14 males; with a mean age: 54 ± 11 years) with GEP NETs who were treated with 2-6 therapy cycles of Lu-177 DOTA-TATE. A total of 326 lesions of 22 patients were evaluated in terms of treatment response by Ga-68 DOTA-TATE PET/CT examination performed before and after treatment. Receiver-operating characteristic (ROC) curves were generated to assess skewness and kurtosis to discriminate between responder and nonresponder lesions. RESULT A total of 326 lesions of 22 patients were evaluated and 137 lesions responded partially or completely to the treatment, 189 lesions did not respond to treatment, remained stable or progressed. The skewness and kurtosis values of the lesions which did not respond to the PRRT were significantly higher than those with response to PRRT treatment (P < 0.001 and P = 0.004, respectively). However, ROC curves provided a moderate area under the curve value for skewness and a relatively low value for kurtosis (0.619 and 0.518, respectively). CONCLUSION Texture analysis using skewness and kurtosis of the lesions on pretreatment Ga-68 DOTA-TATE PET/CT was able to predict their responsiveness to PRRT.

Background Dosimetry for diagnostic agents is performed to assess the risk of radiation detriment (e.g., cancer) associated with the imaging agent and the risk is assessed by computing the effective dose coefficient, e. Stylized phantoms created by the MIRD Committee and updated by work performed by Cristy-Eckerman (CE) have been the standard in diagnostic dosimetry. Recently, the ICRP developed voxelized phantoms, which are described in ICRP Publication 110. These voxelized phantoms are more realistic and detailed in describing human anatomy compared with the CE stylized phantoms. Ideally, all tissues should be represented and their pharmacokinetics collected for an as accurate a dosimetric calculation as possible. As the number of source tissues included increases, the calculated e becomes more accurate. There is, however, a trade-off between the number of source tissues considered, and the time and effort required to measure the time-activity curve for each tissue needed for the calculations. In this study, we used a previously published 68Ga-DOTA-TATE data set to examine how the number of source tissues included for both the ICRP voxelized and CE stylized phantoms affected e. Results Depending upon the number of source tissues included e varied between 14.0–23.5 μSv/MBq for the ICRP voxelized and 12.4–27.7 μSv/MBq for the CE stylized phantoms. Furthermore, stability in e, defined as a < 10% difference between e obtained using all source tissues compared to one using fewer source tissues, was obtained after including 5 (36%) of the 14 source tissues for the ICRP voxelized, and after including 3 (25%) of the 12 source tissues for the CE stylized phantoms. In addition, a 2-fold increase in e was obtained when all source tissues where included in the calculation compared to when the TIAC distribution was lumped into a single reminder-of-body source term. Conclusions This study shows the importance of including the larger tissues like the muscles and remainder-of-body in the dosimetric calculations. The range of e based on the included tissues were less for the ICRP voxelized phantoms using tissue weighting factors from ICRP Publication 103 compared to CE stylized phantoms using tissue weighting factors from ICRP Publication 60.

Introduction: Well-differentiated, Neuroendocrine Tumors (NET) are highly heterogenic and slow-growing pathologies, characterized by unspecific symptomatology and elevated expression of somatostatin receptors (SSTR). Despite the high incidence of NETs, several patients are diagnosed in advance stages of the disease when surgery is insufficient to treat the pathology. Peptide receptor radionuclide therapy (PRRT) has emerged as a new state-of-the-art treatment for NET-patients in advanced stages. Results: In this retrospective study, between 2004 and 2018 a total of 66 patients with advanced-stage-NETs, refractory to other therapies, were treated with [177Lu]Lu DOTA TATE. At the end of the study, 56.1% of the patients were alive and the median overall survival for all patients in the study was 86.3 months. Patients that received doses ≥ 22.2 GBq showed increased overall survival (OS) in comparison with patients that received doses < 22.2 GBq (HR, 0.168; 95%CI 0.12- 0.99; p

Introduction The demand for Gallium-68 (68Ga) for labelling PET radiopharmaceuticals has increased over the past few years. 68Ga is obtained through the decayed parent radionuclide 68Ge using commercial 68Ge/68Ga generators. The principal limitation of commercial 68Ge/68Ga generators is that only a limited and finite quantity of 68Ga ( Methods Enriched ZnCl2 was electrodeposited on a platinum backing using a NH4Cl (pH 2–4) buffer. The Zn target was irradiated with GE PETtrace 880 at 35 μA and 14.5 and 12.0 MeV beam energy. The irradiated Zn target was purified using octanol resin on an automated system. Results Following the described procedure, 68Ga was obtained in 6.30 ± 0.42 GBq after 8.5 min bombardment and with low radionuclidic impurities (66Ga ( 70%. Conclusions A straightforward procedure for producing 68Ga on a low energy medical cyclotron was described. Current efforts are focus on high activity production and radiolabelling using solid target produced 68Ga.

Introduction The widespread clinical utilization of 90Y for preparation of target specific radiopharmaceuticals demands development of a facile, efficient and cost-effective method for radiochemical separation of 90Y from 90Sr via 90Sr/90Y generator. In this article, we describe an efficient and facile method for radiochemical separation of 90Y from 90Sr for preparation of radiopharmaceuticals by exploiting the large difference in the solubility product constants (Ksp) of Y(OH)3 and Sr(OH)2. Methods A two-step radiochemical separation procedure based on selective precipitation of 90Y under alkaline conditions from 90Sr/90Y equilibrium mixture was developed. The 90Y(OH)3 colloid formed at pH ~ 10 was selectively trapped in 0.22 μm sterile filter and was subsequently retrieved by dissolution in HCl solution. Detailed quality control analyses of obtained 90Y were carried out and its utility towards preparation of different radiopharmaceuticals was assessed. Results Using the same feed solution of 90Sr (3.7 GBq), consistent and repeated separation of 90Y could be achieved in different batches with >85% yield and >99.999% radionuclidic purity. Yttrium-90 obtained from this process was found suitable for preparation of therapeutically relevant doses of three different radiopharmaceutical formulations, namely, 90Y-DOTA-TATE, 90Y-PSMA-617 and 90Y-CHX-A″-DTPA-Cetuximab with >95% radiochemical purity. Conclusions The promising results obtained in this study would facilitate implementation of the developed technique for obtaining 90Y in adequate quantity and of required purity from a centralized radiopharmacy setup.

Neuroendocrine tumors (NETs) are relatively rare neoplasms arising from the hormone-producing neuroendocrine system that can occur in various organs such as pancreas, small bowel, stomach and lung. As the majority of these tumors express somatostatin receptors (SSR) on their cell membrane, utilization of SSR analogs in nuclear medicine is a promising, but relatively costly approach for detection and localization. The aim of this study was to analyze the cost-effectiveness of 68Ga-DOTA-TATE PET/CT (Gallium-68 DOTA-TATE Positron emission tomography/computed tomography) compared to 111In-pentetreotide SPECT/CT (Indium-111 pentetreotide Single Photon emission computed tomography/computed tomography) and to CT (computed tomography) alone in detection of NETs. A decision model on the basis of Markov simulations evaluated lifetime costs and quality-adjusted life years (QALYs) related to either a CT, SPECT/CT or PET/CT. Model input parameters were obtained from publicized research projects. The analysis is grounded on the US healthcare system. Deterministic sensitivity analysis of diagnostic parameters and probabilistic sensitivity analysis predicated on a Monte Carlo simulation with 30,000 reiterations was executed. The willingness-to-pay (WTP) was determined to be $ 100,000/QALY. In the base-case investigation, PET/CT ended up with total costs of $88,003.07 with an efficacy of 4.179, whereas CT ended up with total costs of $88,894.71 with an efficacy of 4.165. SPECT/CT ended up with total costs of $89,973.34 with an efficacy of 4.158. Therefore, the strategies CT and SPECT/CT were dominated by PET/CT in the base-case scenario. In the sensitivity analyses, PET/CT remained a cost-effective strategy. This result was due to reduced therapy costs of timely detection. The additional costs of 68Ga-DOTA-TATE PET/CT when compared to CT alone are justified in the light of potential savings in therapy costs and better outcomes.