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Key Clinical Message: Radioligand Therapy (RLT) in the form of [177Lu] Lu‐DOTA‐TATE (Lutathera®) is a promising treatment for pancreatic neuroendocrine tumors (pNETs) with cardiac metastasis. We present a patient treated with [177Lu] Lu‐DOTA‐TATE that showed shrinkage of metastasis after four treatments at 7.4 GBq every 8 weeks. [ABSTRACT FROM AUTHOR]

Background: Patients with high-risk neuroblastoma (NB) have a 5-year event-free survival of less than 50 %, and novel and improved treatment options are needed. Radiolabeled somatostatin analogs (SSTAs) could be a treatment option. The aims of this work were to compare the biodistribution and the therapeutic effects of 177Lu-octreotate and 177Lu-octreotide in mice bearing the human CLB-BAR NB cell line, and to evaluate their regulatory effects on apoptosis-related genes. Methods: The biodistribution of 177Lu-octreotide in mice bearing CLB-BAR tumors was studied at 1, 24, and 168 h after administration, and the absorbed dose was estimated to tumor and normal tissues. Further, animals were administered different amounts of 177Lu-octreotate or 177Lu-octreotide. Tumor volume was measured over time and compared to a control group given saline. RNA was extracted from tumors, and the expression of 84 selected genes involved in apoptosis was quantified with qPCR. Results: The activity concentration was generally lower in most tissues for 177Lu-octreotide compared to 177Lu-octreotate. Mean absorbed dose per administered activity to tumor after injection of 1.5 MBq and 15 MBq was 0.74 and 0.03 Gy/MBq for 177Lu-octreotide and 2.9 and 0.45 Gy/MBq for 177Lu-octreotate, respectively. 177Lu-octreotide treatment resulted in statistically significant differences compared to controls. Fractionated administration led to a higher survival fraction than after a single administration. The pro-apoptotic genes TNSFS8, TNSFS10, and TRADD were regulated after administration with 177Lu-octreotate. Treatment with 177Lu-octreotide yielded regulation of the pro-apoptotic genes CASP5 and TRADD, and of the anti-apoptotic gene IL10 as well as the apoptosis-related gene TNF. Conclusion: 177Lu-octreotide gave somewhat better anti-tumor effects than 177Lu-octreotate. The similar effect observed in the treated groups with 177Lu-octreotate suggests saturation of the somatostatin receptors. Pronounced anti-tumor effects following fractionated administration merited receptor saturation as an explanation. The gene expression analyses suggest apoptosis activation through the extrinsic pathway for both radiopharmaceuticals.

Key Clinical Message Radioligand Therapy (RLT) in the form of [177Lu] Lu‐DOTA‐TATE (Lutathera®) is a promising treatment for pancreatic neuroendocrine tumors (pNETs) with cardiac metastasis. We present a patient treated with [177Lu] Lu‐DOTA‐TATE that showed shrinkage of metastasis after four treatments at 7.4 GBq every 8 weeks.

Neuroendocrine tumor (NET) metastasis to the thyroid is rare, and its presentation as the first manifestation of primary malignancy elsewhere is even more uncommon. We present a case of a 41-year-old female who underwent biopsy of enlarging thyroid nodules with findings suspicious for medullary thyroid cancer (MTC). Subsequent thyroidectomy demonstrated NET of unknown primary in the left lower lobe. Immediate workup with 68Ga-DOTATATE-PET/CT revealed abnormal somatostatin receptor (SR) expressing lesions in the liver, right cervical nodes, thoracic paravertebral soft tissue, precoccygeal soft tissue, and right acetabulum concerning for sites of neuroendocrine malignancy. Due to disease progression while on octreotide injections, a decision was made at the multidisciplinary NET board for the patient to receive peptide receptor radionuclide therapy (PRRT) which includes 4 cycles of 77Lu-DOTATATE (Lutathera). The patient had no side effects nor toxicities during the 8 months of PRRT and achieved a partial treatment response in the early post-treatment scan at 6 weeks. This case illustrates the importance of distinguishing NET metastasis to the thyroid from MTC to ensure appropriate workup and treatment as well as predict the response of neuroendocrine malignancies to PRRT based on the visualized overexpression of SR in the SR-PET scans, despite the organ of origin.

Background: Peptide receptor radionuclide therapy (PRRT) is one of the most promising therapeutic strategies in neuroendocrine neoplasms (NENs). Nevertheless, its role in certain tumor sites remains unclear. This study sought to elucidate the efficacy and safety of [177Lu]Lu-DOTATATE in NENs with different locations and evaluate the effect of the tumor origin, bearing in mind other prognostic variables. Advanced NENs overexpressing somatostatin receptors (SSTRs) on functional imaging, of any grade or location, treated at 24 centers were enrolled. The protocol consisted of four cycles of 177Lu-DOTATATE 7.4 GBq iv every 8 weeks (NCT04949282). Results: The sample comprised 522 subjects with pancreatic (35%), midgut (28%), bronchopulmonary (11%), pheochromocytoma/ paraganglioma (PPGL) (6%), other gastroenteropancreatic (GEP) (11%), and other non-gastroenteropancreatic (NGEP) (9%) NENs. The best RECIST 1.1 responses were complete response, 0.7%; partial response, 33.2%; stable disease, 52.1%; and tumor progression, 14%, with activity conditioned by the tumor subtype, but with benefit in all strata. Median progression-free survival (PFS) was 31.3 months (95% CI, 25.7–not reached [NR]) in midgut, 30.6 months (14.4-NR) in PPGL, 24.3 months (18.0-NR) in other GEP, 20.5 months (11.8-NR) in other NGEP, 19.8 months (16.8–28.1) in pancreatic, and 17.6 months (14.4–33.1) in bronchopulmonary NENs. [177Lu]Lu-DOTATATE exhibited scant severe toxicity. Conclusion: This study confirms the efficacy and safety of [177Lu]Lu-DOTATATE in a wide range of SSTR-expressing NENs, regardless of location, with clinical benefit and superimposable survival outcomes between pNENs and other GEP and NGEP tumor subtypes different from midgut NENs. [ABSTRACT FROM AUTHOR]

177Lu-DOTATATE has gained wide clinical acceptance for the treatment of advanced gastroenteropancreatic neuroendocrine tumors; however, little is known regarding its accumulation in ascites. As such, clinical staff performing paracenteses shortly after a treatment dose may be concerned about their potential radiation exposure or the risk of contamination. Methods: In this report, therapeutic paracenteses were performed on a patient with metastatic intestinal carcinoid complicated by recurrent chylous ascites at various time intervals after a standard 7.4 GBq dose of 177Lu-DOTATATE. Samples of the fluid were analyzed in a scintillation counter to estimate the concentration of radioactivity. Results: The concentration of activity in the ascitic fluid obtained 3 d after an infusion was exceptionally low (175.3 ± 25.9 Bq/mL). Conclusion: Our findings suggest that paracenteses conducted as soon as 3 d after a standard dose of 177Lu-DOTATATE pose little to no risk in terms of radiation safety to staff performing the procedure. [ABSTRACT FROM AUTHOR]

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

Abstract Background Neuroblastoma (NB) is one of the most frequently diagnosed tumors in infants. NB is a neuroendocrine tumor type with various characteristics and features, and with diverse outcome. The most malignant NBs have a 5-year survival rate of only 40–50%, indicating the need for novel and improved treatment options. 177Lu-octreotate is routinely administered for treatment of neuroendocrine tumors overexpressing somatostatin receptors (SSTR). The aim of this study was to examine the biodistribution of 177Lu-octreotate in mice bearing aggressive human NB cell lines, in order to evaluate the potential usefulness of 177Lu-octreotate for treatment of NB. Methods BALB/c nude mice bearing CLB-BAR, CLB-GE or IMR-32 tumor xenografts (n = 5–7/group) were i.v. injected with 0.15 MBq, 1.5 MBq or 15 MBq 177Lu-octreotate and sacrificed 1 h, 24 h, 48 h and 168 h after administration. The radioactivity concentration was determined for collected tissue samples, tumor-to-normal-tissue activity concentration ratios (T/N) and mean absorbed dose for each tissue were calculated. Immunohistochemical (IHC) staining for SSTR1–5, and Ki67 were carried out for tumor xenografts from the three cell lines. Results High 177Lu concentration levels and T/N values were observed in all NB tumors, with the highest for CLB-GE tumor xenografts (72%IA/g 24 h p.i.; 1.5 MBq 177Lu-octreotate). The mean absorbed dose to the tumor was 6.8 Gy, 54 Gy and 29 Gy for CLB-BAR, CLB-GE and IMR-32, respectively, p.i. of 15 MBq 177Lu-octreotate. Receptor saturation was clearly observed in CLB-BAR, resulting in higher concentration levels in the tumor when lower activity levels where administered. IHC staining demonstrated highest expression of SSTR2 in CLB-GE, followed by CLB-BAR and IMR-32. Conclusion T/N values for all three human NB tumor xenograft types investigated were high relative to previously investigated neuroendocrine tumor types. The results indicate a clear potential of 177Lu-octreotate as a therapeutic alternative for metastatic NB.

Recently, the treatment landscape for metastatic pheochromocytomas and paragangliomas (MPPGL) has seen both progress and setbacks. We provide an up-to-date review of the multimodality management of MPPGL and discuss novel opportunities and current challenges in the treatment landscape. Given the unique clinical presentation of MPPGL, we discuss the management of hormone-related clinical sequelae and traditional modalities of therapy. Advances in the understanding of the molecular biology of these diverse tumors have enabled novel strategies such as augmenting DNA damage by targeted delivery of radionuclides such as 131I and 177Lu, abrogating tumor angiogenesis, hypoxia resistance, and DNA damage repair. Despite progress, we address the significant challenges still faced by patients and researchers engaged in efforts to improve outcomes in these rare cancers. [ABSTRACT FROM AUTHOR]

Purpose: Given the recent and rapid development of peptide receptor radionuclide therapy (PRRT), increasing emphasis should be placed on the early identification and quantification of therapeutic radiopharmaceutical (thRPM) extravasation during intravenous administration. Herein, we provide an analytical model of 177Lu-DOTA0-Tyr3-octreotate (Lutathera®) infusion for real-time detection and characterization of thRPM extravasation. Methods: For 33 Lutathera®-based PRRT procedures using the gravity infusion method, equivalent dose rates (EDRs) were monitored at the patient's arm. Models of flow dynamics for nonextravasated and extravasated infusions were elaborated and compared to experimental data through an equivalent dose rate calibration. Nonextravasated infusion was modeled by assuming constant volume dilution of 177Lu activity concentration in the vial and Poiseuille-like laminar flow through the tubing and patient vein. Extravasated infusions were modeled according to their onset times by considering elliptically shaped extravasation region with different aspect ratios. Results: Over the 33 procedures, the peak of the median EDR was reached 14 min after the start of the infusion with a value of 450 µSv h−1. On the basis of experimental measurements, 1 mSv h−1 was considered the empirical threshold for Lutathera® extravasation requiring cessation of the infusion and start again with a new route of injection. According to our model, the concentration of extravascular activity was directly related to the time of extravasation onset and its duration, a finding inherent in the gravity infusion method. This result should be considered when planning therapeutic strategy in the case of RPM extravasation because the local absorbed dose for β-emitters is closely linked to activity concentration. For selected EDR values, charts of extravasated activity, volume, and activity concentration were computed for extravasation characterization. Conclusion: We proposed an analytical model of Lutathera® infusion and extravasation (gravity method) based on EDR monitoring. This approach could be useful for the early detection of thRPM extravasation and for the real-time assessment of activity concentration and volume accumulation in the extravascular medium. [ABSTRACT FROM AUTHOR]

Recommended 177Lu-DOTATATE treatment regimens involve prophylaxis with antiemetics to counteract the emetogenic properties of the nephroprotective amino acid solution infusion. We describe a 58-y-old woman treated with 177Lu-DOTATATE for metastatic small-bowel carcinoid, who was allergic to many classes of antiemetics. Therefore, she was treated with 177Lu-DOTATATE without antiemetic prophylaxis. She tolerated the compounded amino acid infusion of lysine and arginine, followed by 177Lu-DOTATATE, without significant nausea or any vomiting. We hypothesize that aggressive antiemetic prophylaxis may not be necessary if a 177Lu-DOTATATE patient receives compounded lysine/arginine amino acid solutions. The omission would decrease overall health-care costs and limit possible medication side effects. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NB) is one of the most frequently diagnosed tumors in infants. NB is a neuroendocrine tumor type with various characteristics and features, and with diverse outcome. The most malignant NBs have a 5-year survival rate of only 40-50%, indicating the need for novel and improved treatment options. 177Lu-octreotate is routinely administered for treatment of neuroendocrine tumors overexpressing somatostatin receptors (SSTR). The aim of this study was to examine the biodistribution of 177Lu-octreotate in mice bearing aggressive human NB cell lines, in order to evaluate the potential usefulness of 177Lu-octreotate for treatment of NB.Methods: BALB/c nude mice bearing CLB-BAR, CLB-GE or IMR-32 tumor xenografts (n = 5-7/group) were i.v. injected with 0.15 MBq, 1.5 MBq or 15 MBq 177Lu-octreotate and sacrificed 1 h, 24 h, 48 h and 168 h after administration. The radioactivity concentration was determined for collected tissue samples, tumor-to-normal-tissue activity concentration ratios (T/N) and mean absorbed dose for each tissue were calculated. Immunohistochemical (IHC) staining for SSTR1-5, and Ki67 were carried out for tumor xenografts from the three cell lines.Results: High 177Lu concentration levels and T/N values were observed in all NB tumors, with the highest for CLB-GE tumor xenografts (72%IA/g 24 h p.i.; 1.5 MBq 177Lu-octreotate). The mean absorbed dose to the tumor was 6.8 Gy, 54 Gy and 29 Gy for CLB-BAR, CLB-GE and IMR-32, respectively, p.i. of 15 MBq 177Lu-octreotate. Receptor saturation was clearly observed in CLB-BAR, resulting in higher concentration levels in the tumor when lower activity levels where administered. IHC staining demonstrated highest expression of SSTR2 in CLB-GE, followed by CLB-BAR and IMR-32.Conclusion: T/N values for all three human NB tumor xenograft types investigated were high relative to previously investigated neuroendocrine tumor types. The results indicate a clear potential of 177Lu-octreotate as a therapeutic alternative for metastatic NB. [ABSTRACT FROM AUTHOR]

Introduction: The efficacy of 177Lu-Dotatate was shown in the NETTER-1 trial, an international, open-label, multicentre phase III clinical trial that evaluated the safety and efficacy of 177Lu-Dotatate in patients with well-differentiated, advanced midgut neuroendocrine tumours (NETs) with evidence of disease progression. Recently, retreatment with peptide receptor radionuclide therapy (PRRT) has been proposed as a valid therapeutic option in patients without other effective options who had responded to initial PRRT; however, data on this therapeutic option are still inadequate. Case Report: In this report, we present the case of a patient who achieved a delayed complete radiological response after initial 177Lu-Dotatate treatment and who had a complete tumour response with PRRT retreatment 5 years later. Conclusions: This case report shows that, although rare, a complete, prolonged tumour response may occur in patients with advanced small-bowel NETs receiving PRRT. Retreatment with PRRT may be a valid option in cases of subsequent disease recurrence. [ABSTRACT FROM AUTHOR]

BackgroundLutetium 177 (177Lu) - DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) utilized in the treatment of neuroendocrine tumors. Data on 177Lu-DOTATATE-induced thyroid dysfunction is limited.Case DescriptionA 29-year-old male with SDHB positive metastatic paraganglioma enrolled under the 177Lu-DOTATATE trial (NCT03206060) underwent thyroid function test (TFT) evaluation comprised of thyroid stimulating hormone (TSH) and free thyroxine (FT4) immunoassay measurements per protocol prior to 177Lu-DOTATATE therapy. The TSH was suppressed [1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87–169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to 177Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient’s symptoms resolved.SummaryWe report, for the first time, a patient with asymptomatic primary hyperthyroidism who rapidly developed symptomatic primary hypothyroidism 1 month after 177Lu-DOTATATE therapy, accompanied by marked changes in TFTs and thyroid auto-antibody titers, with functional imaging evidence of diffuse uptake of 177Lu-DOTATATE in the thyroid gland.ConclusionsThyroid dysfunction can be associated with PRRT. Thyroid uptake patterns on pre-treatment diagnostic somatostatin analog scans might predict individual susceptibility to PRRT-associated TFT disruption. Therefore, periodic evaluation of TFTs should be considered in patients receiving PRRT.

Background: Lutetium 177 (177Lu) - DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) utilized in the treatment of neuroendocrine tumors. Data on 177Lu-DOTATATE-induced thyroid dysfunction is limited. Case Description: A 29-year-old male with SDHB positive metastatic paraganglioma enrolled under the 177Lu-DOTATATE trial (NCT03206060) underwent thyroid function test (TFT) evaluation comprised of thyroid stimulating hormone (TSH) and free thyroxine (FT4) immunoassay measurements per protocol prior to 177Lu-DOTATATE therapy. The TSH was suppressed [<0.01 µIU/ml (0.27–4.2 µIU/ml)], and FT4 was normal [1.3 ng/dl (0.9–1.7 ng/dl)]. The TSH receptor antibody and thyroid stimulating immunoglobulin index were undetectable [<1 IU/L (≤1.75 IU/L), and <1 (≤1.3) respectively], while the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were elevated [605 IU/ml (0.0–34.9 IU/ml), and 178 IU/ml (0.0-40.0 IU/ml) respectively]. Mass spectrometry on a stored (-80°C) plasma sample obtained one-month pre-PRRT revealed elevated total triiodothyronine (TT3) [235 ng/dl (65–193 ng/dl)] and FT4 [3.9 ng/dl (1.2–2.9 ng/dl)] levels. The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi 177Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 µIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87–169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to 177Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved. Summary: We report, for the first time, a patient with asymptomatic primary hyperthyroidism who rapidly developed symptomatic primary hypothyroidism 1 month after 177Lu-DOTATATE therapy, accompanied by marked changes in TFTs and thyroid auto-antibody titers, with functional imaging evidence of diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Conclusions: Thyroid dysfunction can be associated with PRRT. Thyroid uptake patterns on pre-treatment diagnostic somatostatin analog scans might predict individual susceptibility to PRRT-associated TFT disruption. Therefore, periodic evaluation of TFTs should be considered in patients receiving PRRT. [ABSTRACT FROM AUTHOR]

Background: Patients with high-risk neuroblastoma (NB) have a 5-year event-free survival of less than 50 %, and novel and improved treatment options are needed. Radiolabeled somatostatin analogs (SSTAs) could be a treatment option. The aims of this work were to compare the biodistribution and the therapeutic effects of 177 Lu-octreotate and 177 Lu-octreotide in mice bearing the human CLB-BAR NB cell line, and to evaluate their regulatory effects on apoptosis-related genes., Methods: The biodistribution of 177 Lu-octreotide in mice bearing CLB-BAR tumors was studied at 1, 24, and 168 h after administration, and the absorbed dose was estimated to tumor and normal tissues. Further, animals were administered different amounts of 177 Lu-octreotate or 177 Lu-octreotide. Tumor volume was measured over time and compared to a control group given saline. RNA was extracted from tumors, and the expression of 84 selected genes involved in apoptosis was quantified with qPCR., Results: The activity concentration was generally lower in most tissues for 177 Lu-octreotide compared to 177 Lu-octreotate. Mean absorbed dose per administered activity to tumor after injection of 1.5 MBq and 15 MBq was 0.74 and 0.03 Gy/MBq for 177 Lu-octreotide and 2.9 and 0.45 Gy/MBq for 177 Lu-octreotate, respectively. 177 Lu-octreotide treatment resulted in statistically significant differences compared to controls. Fractionated administration led to a higher survival fraction than after a single administration. The pro-apoptotic genes TNSFS8 , TNSFS10 , and TRADD were regulated after administration with 177 Lu-octreotate. Treatment with 177 Lu-octreotide yielded regulation of the pro-apoptotic genes CASP5 and TRADD , and of the anti-apoptotic gene IL10 as well as the apoptosis-related gene TNF ., Conclusion: 177 Lu-octreotide gave somewhat better anti-tumor effects than 177 Lu-octreotate. The similar effect observed in the treated groups with 177 Lu-octreotate suggests saturation of the somatostatin receptors. Pronounced anti-tumor effects following fractionated administration merited receptor saturation as an explanation. The gene expression analyses suggest apoptosis activation through the extrinsic pathway for both radiopharmaceuticals., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Purpose of Review: Our understanding of the genetic and epigenetic alterations in meningioma and the underlying tumor biology of meningioma has significantly changed over the past decade and resulted in revision of prognostically relevant meningioma subclasses within and beyond the WHO classification of CNS tumors. Recent Findings: The 2016 WHO classification of CNS tumors recognizes WHO grade I, II, and III based on histopathological features. Recent work has identified genetic alterations with prognostic implications, including mutations of the TERT promoter, loss of function of the DMD gene, and inactivation of the tumor suppressor BAP-1. Studies of DNA methylation patterns in meningiomas have resulted in a novel and prognostically relevant meningioma subclassification schema. Summary: There have been major advances in our understanding of prognostically relevant genetic and epigenetic changes in meningioma which will hopefully allow for improvement in clinical trial design and the development of more effective therapies for meningioma. [ABSTRACT FROM AUTHOR]

At Banner M.D. Anderson Cancer Center in Arizona, we have gained valuable knowledge of the different infusion methods for 177Lu-DOTATATE peptide receptor radionuclide therapy. Methods: Our nuclear medicine department has used 2 different methods of administration: the gravity infusion method and the infusion pump protocol. Results: Our experience with the gravity infusion method allowed us to identify problematic aspects and led us to search for and implement the infusion pump protocol. Conclusion: The pump protocol ensures that the infusion of 177Lu-DOTATATE is safe and delivers a consistent dose to every patient. [ABSTRACT FROM AUTHOR]

Abstract Lutathera®, the trademark for lutetium 177Lu-DOTATATE registered to Advanced Accelerator Applications SA, is a peptide receptor radionuclide therapy used to treat gastroenteropancreatic neuroendocrine tumors positive for hormone receptor somatostatin. Lutathera specifically targets known tumor receptors and has been shown to decrease both tumor growth and spread. While available in Europe for many years, the Federal Drug Administration approved the use of 177Lu-DOTATATE in the United States in January 2018. 177Lu (lutetium) is a radioactive isotope with special precautions and considerations for safe administration of this treatment. When nuclear medicine, radiation safety, nursing, and the physicians work together as a team, the safe administration of Lutathera provides patients with another treatment option to battle cancer. Highlights • A team approach is essential for the safe administration of Lutathera®. • Patients express renewed hope with FDA approval of Lutathera®. • Radiation safety is a key element to patient care in Lutathera® treatment. [ABSTRACT FROM AUTHOR]

In 2018, the United States Food and Drug Administration (FDA) approved a total of 59 new drugs, three of them (5%) are TIDES (or also, -tides), two oligonucleotides and one peptide. Herein, the three TIDES approved are analyzed in terms of medical target, mode of action, chemical structure, and economics.

177 Lu-DOTATATE has gained wide clinical acceptance for the treatment of advanced gastroenteropancreatic neuroendocrine tumors; however, little is known regarding its accumulation in ascites. As such, clinical staff performing paracenteses shortly after a treatment dose may be concerned about their potential radiation exposure or the risk of contamination. Methods: In this report, therapeutic paracenteses were performed on a patient with metastatic intestinal carcinoid complicated by recurrent chylous ascites at various time intervals after a standard 7.4 GBq dose of 177 Lu-DOTATATE. Samples of the fluid were analyzed in a scintillation counter to estimate the concentration of radioactivity. Results: The concentration of activity in the ascitic fluid obtained 3 d after an infusion was exceptionally low (175.3 ± 25.9 Bq/mL). Conclusion: Our findings suggest that paracenteses conducted as soon as 3 d after a standard dose of 177 Lu-DOTATATE pose little to no risk in terms of radiation safety to staff performing the procedure., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Simple Summary: Neuroendocrine tumors are slow growing and initially associated with vague symptoms and, therefore, often spread in the patient's body at diagnosis, leading to a poor prognosis without means of curation through surgery. Although tumor-targeting treatments exist and are used in clinics, they are not fully optimized. The aim of this study was to test different dosages and time intervals of the radioactive pharmaceutical 177Lu-octreotate. We found that dividing a dosage into several portions and administering it at short time intervals resulted in a stronger tumor reduction and/or prolonged time for regrowth in mice than if given as a single dose. The biggest differences were seen in the lower dosage levels of the study. The findings indicate that there is clear room for improvements in the treatment of neuroendocrine tumors with 177Lu-octreotate. Radionuclide treatment of patients with neuroendocrine tumors has advanced in the last decades with favorable results using 177Lu-octreotate. However, the gap between the high cure rate in animal studies vs. patient studies indicates a potential to increase the curation of patients. The aim of this study was to investigate the tumor response for different fractionation schemes with 177Lu-octreotate. BALB/c mice bearing a human small-intestine neuroendocrine GOT1 tumor were either mock treated with saline or injected intravenously with a total of 30–120 MBq of 177Lu-octreotate: 1 × 30, 2 × 15, 1 × 60, 2 × 30, 1 × 120, 2 × 60, or 3 × 40 MBq. The tumor volume was measured twice per week until the end of the experiment. The mean tumor volume for mice that received 2 × 15 = 30 and 1 × 30 MBq 177Lu-octreotate was reduced by 61% and 52%, respectively. The mean tumor volume was reduced by 91% and 44% for mice that received 2 × 30 = 60 and 1 × 60 MBq 177Lu-octreotate, respectively. After 120 MBq 177Lu-octreotate, given as 1–3 fractions, the mean tumor volume was reduced by 91–97%. Multiple fractions resulted in delayed regrowth and prolonged overall survival by 20–25% for the 120 MBq groups and by 45% for lower total activities, relative to one fraction. The results indicate that fractionation and hyperfractionation of 177Lu-octreotate are beneficial for tumor reduction and prolongs the time to regrowth. [ABSTRACT FROM AUTHOR]

Recommended 177 Lu-DOTATATE treatment regimens involve prophylaxis with antiemetics to counteract the emetogenic properties of the nephroprotective amino acid solution infusion. We describe a 58-y-old woman treated with 177 Lu-DOTATATE for metastatic small-bowel carcinoid, who was allergic to many classes of antiemetics. Therefore, she was treated with 177 Lu-DOTATATE without antiemetic prophylaxis. She tolerated the compounded amino acid infusion of lysine and arginine, followed by 177 Lu-DOTATATE, without significant nausea or any vomiting. We hypothesize that aggressive antiemetic prophylaxis may not be necessary if a 177 Lu-DOTATATE patient receives compounded lysine/arginine amino acid solutions. The omission would decrease overall health-care costs and limit possible medication side effects., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

The success of Lutathera™ ([177Lu]Lu-DOTA-TATE) in the NETTER-1 clinical trial as a peptide receptor radionuclide therapy (PRRT) for somatostatin receptor expressing (SSTR) neuroendocrine tumours (NET) is likely to increase the demand for patient stratification by positron emission tomography (PET). The current gold standard of gallium-68 radiolabelled somatostatin analogues (e.g., [68Ga]Ga-DOTA-TATE) works effectively, but access is constrained by the limited availability and scalability of gallium-68 radiopharmaceutical production. The aim of this review is three-fold: firstly, we discuss the peptide library design, biological evaluation and clinical translation of [18F]fluoroethyltriazole-βAG-TOCA ([18F]FET-βAG-TOCA), our fluorine-18 radiolabelled octreotide; secondly, to exemplify the potential of the 2-[18F]fluoroethylazide prosthetic group and copper-catalysed azide-alkyne cycloaddition (CuAAC) chemistry in accessing good manufacturing practice (GMP) compatible radiopharmaceuticals; thirdly, we aim to illustrate a framework for the translation of similarly radiolabelled peptides, in which in vivo pharmacokinetics drives candidate selection, supported by robust radiochemistry methodology and a route to GMP production. It is hoped that this review will continue to inspire the development and translation of fluorine-18 radiolabelled peptides into clinical studies for the benefit of patients. [ABSTRACT FROM AUTHOR]

Peptide receptor radiotherapy using 177 Lu-labeled somatostatin ligand analogs is a well-established treatment for neuroendocrine tumors, with 177 Lu-DOTATATE having acquired marketing authorization in Europe and the United States. The investigation of the pharmacokinetics of these radiopharmaceuticals in vivo in humans is crucial for personalized treatment management and understanding of treatment effects. Such an investigation requires input data on the in vivo stability of the radiopharmaceuticals in blood and plasma. The work presented here is devoted to the investigation of the in vivo stability of 177 Lu-DOTATATE in humans affected by neuroendocrine tumors. Methods: Blood samples of 6 patients undergoing 177 Lu-DOTATATE were taken at 0.5, 4, 24, and 96 h after injection. Analysis of metabolic stability was performed using high-performance liquid chromatography. Results: A fast metabolism of the radiopharmaceutical was observed, with the fraction of intact 177 Lu-DOTATATE in plasma decreasing rapidly to 23% ± 5% (mean ± SD) at 24 h and 1.7% ±0. 9% at 96 h after injection. Conclusion: The in vivo stability of 177 Lu-DOTATATE is much lower than previously assumed, with the major part of radioactivity in plasma consisting of 177 Lu-labeled metabolites already at 24 h after injection., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Peptide receptor radionuclide therapy (PRRT) is an effective form of treatment of patients with metastatic neuroendocrine tumors, delivering modest objective tumor response rates but notable survival and symptomatic benefits. The first PRRT approved by the US Food and Drug Administration was lutetium 177-DOTATATE and is for use in adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. The treatment paradigm typically leads to significant improvement in symptomology coupled with an extended period of progression-free survival. Side effects are limited, with a small fraction of individuals experiencing clinically significant long-term renal or hematologic toxicity., (Published by Elsevier Inc.)