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

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

Background: With the development of endoscopic technology, the application of upper endoscopy can quickly target the lesion site of patients with peptic ulcer complicated with upper gastrointestinal bleeding., Objective: This study aims to discuss the clinical effect of octreotide combined with upper endoscopy in treating peptic ulcer complicated with upper gastrointestinal hemorrhage., Methods: A total of 82 patients diagnosed with peptic ulcer complicated with upper gastrointestinal hemorrhage were recruited as study objects in the researchers' hospital. According to the treatment method, this retrospective study divided the patients into a control group (n=41, receiving adrenaline injection under upper endoscopy only) and a treatment group (n=41, receiving adrenaline injection under upper endoscopy and Octreotide intravenously)., Results: After treatment, the volume of blood loss, average hemostasis time, hospital stay, and time of occult blood turning negative in the treatment group were shorter than those in the control group (P < .05). After treatment, the clinical efficacy of the treatment group was better than that of the control group (P < .05). The levels of prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT) levels in the treatment group were lower than those in the control group, with significant differences (P < .05)., Conclusion and Relevance: Combining octreotide and upper endoscopy has affirmative efficacy and good hemostatic effect on treating peptic ulcer complicated with upper gastrointestinal hemorrhage with less pain and short recovery time, which is worthy of clinical application.

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

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

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

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

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

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

Gastrointestinal angiodysplasia (GIA) is a common, acquired, vascular abnormality of the digestive tract, and a frequent cause of bleeding. Refractory GIA criteria usually include recurrent bleeding, transfusions and/or repeat endoscopy. Pharmacological and interventional treatments have been the subject of recent high-quality publications. This review provides an overview of the latest updates on non-endoscopic management of refractory GIA. Aortic valve replacement has shown its efficacy in Heyde syndrome and should be considered if indicated. Anti-angiogenic drugs, such as Octreotide and Thalidomide, are efficient treatments of refractory GIA-related bleeding. Somatostatin analogs should, based on efficacy and tolerance profile, be considered first. In the future, a better understanding of the physiopathology of GIA might help develop new-targeted therapies., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

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

Background: Postoperative pancreatic fistulas lead to substantially increased morbidity, mortality, and healthcare costs after pancreatectomy. Studies have reported conflicting data on the role of prophylactic somatostatin analogs in the reduction of postoperative pancreatic fistula. Current practice patterns, surgeon beliefs, and barriers to using these drugs in the Americas is not known., Methods: An online 26-question cross-sectional survey was distributed via email to the members of the Americas Hepato-Pancreato-Biliary Association in April 2023., Results: One hundred and two surgeons responded in spring 2023. 48.0% of respondents reported using prophylactic SSAs during their surgical training, however, only 29.4% do so in their current practice, most commonly when performing Whipple procedures. Octreotide was the most frequently used SSA (34.3%), followed by octreotide LAR (12.7%) and pasireotide (11.8%). Reasons for not prescribing included a lack of high-quality data (62.7%), perception of limited efficacy (34.3%) and high cost (30.4%)., Conclusion: These results highlight key areas for future study including understanding surgeon rationale for patient and drug selection. Variable practice patterns amongst surgeons also underscore the importance of generalizability in the design of future clinical trials in order to maximize impact., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Variceal hemorrhage treatment includes endoscopy within 12 hours of admission and octreotide therapy for 2-5 days post-endoscopy. Duration of pre-endoscopy octreotide can be prolonged when intervention is delayed. Objective: This study aimed to evaluate the impact of extended pre-endoscopy octreotide on rebleeding after endoscopy when comparing short vs long durations of post-endoscopy octreotide. Methods: This was a single center, retrospective cohort evaluating adult cirrhotic patients with esophageal variceal hemorrhage admitted between July 1, 2017 and June 30, 2020. Study groups included patients receiving octreotide ≥12 hours prior to endoscopy followed by ≤ 48 (short course) or >48 hours (standard course) after endoscopy. The primary outcome was post-endoscopy rebleeding, defined as hemoglobin decrease of ≥2 g/dL from baseline or the requirement of ≥1 unit of packed red blood cells. Results: Of the 169 patients included, 88 patients received short course octreotide after endoscopy, and 81 patients received standard course octreotide after endoscopy. Twenty-nine (33%) patients in the short course group and 43 (53.1%) in the standard course group experienced the primary endpoint (OR 2.3, 95% CI 1.24 - 4.29; P = .008). Conclusion: Extended pre-endoscopy octreotide may be beneficial in preventing rebleeding when intervention is delayed. Further studies are needed to determine the necessary octreotide duration in delayed endoscopy and varying bleeding risk., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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

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

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

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

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

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

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

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

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

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

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

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

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

Neuroendocrine tumors (NETs) are a group of well-differentiated heterogeneous neoplasms characterized by slow progression and distinct clinical and biological behavior. In the majority of patients with NET, first-line treatment is represented by somatostatin analogs (SSAs) that, despite being drugs with high tolerability (even at high doses) and providing to carcinoid symptoms control and anti-proliferative effects, may present some side effects, with potential impact on quality of life and nutritional status. The most frequent side effects are represented by gastrointestinal events in particular alterations in bowel habits (diarrhea and constipation), abdominal pain, exocrine pancreatic insufficiency, and cholelithiasis. Considering the relative rarity of NETs, literature about frequency and standard clinical management of adverse events SSA-related is still lacking and heterogeneous. The aim of this review is to arm gastroenterologists and other physicians treating NET patients with essential knowledge on the side effects of SSAs. By identifying and managing these adverse events early, healthcare professionals can offer optimal care, avert foreseeable complications, and ensure the best outcomes for patients. Without such early recognition, there is a risk of diminishing the patient's quality of life and their ability to sustain treatment over time., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

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

Growth hormone (GH) is a crucial regulator of growth, cell reproduction, and regeneration; and it is controlled by growth hormone-releasing hormone (GHRH) and somatostatin. Lipopolysaccharides (LPS) can compromise endothelial function, leading to increased inflammation and vascular leak. Octreotide (OCT) is an FDA-approved synthetic somatostatin analog (SSA) used to treat acromegaly and neuroendocrine tumors. The present study investigates the effects of OCT on LPS-induced injury in bovine and human lung endothelial cells, as well as in mouse lungs. Our in vitro observations suggest that OCT effectively counteracts LPS-induced endothelial leak, inflammation, and reactive oxygen species (ROS) generation. Furthermore, OCT reduces bronchoalveolar lavage fluid (BALF) protein concentration in an experimental model of Acute Lung Injury (ALI). Our study suggests that OCT mitigates LPS-induced endothelial cell and lung injury, suggesting that it may represent an exciting therapeutic possibility in diseases related to barrier dysfunction., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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

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

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

Aims: This study aimed to evaluate the effectiveness of somatostatin analogues (SA) for cystoid maculopathy (CM) in retinitis pigmentosa (RP) patients., Materials and Methods: In this retrospective case series, clinical and imaging characteristics of 28 RP patients with CM, unresponsive to carbonic anhydrase inhibitors, were collected from medical charts. All patients received SA treatment as an alternative (octreotide long-acting release at 20 mg/month or 30 mg/month, or lanreotide at 90 mg/month or 120 mg/month). Outcome measures were mean reduction in foveal thickness (FT) and foveal volume (FV) and mean increase in best-corrected visual acuity at 3, 6 and 12 months of treatment initiation. Linear mixed models were used to calculate the effectiveness over time., Results: 52 eyes of 28 RP patients were included; 39% were male. The median age at the start of treatment was 39 years (IQR 30-53). Median follow-up was 12 months (range 6-12). From baseline to 12 months, the mean FT decreased from 409±136 µm to 334±119 µm and the mean FV decreased from 0.31±0.10 mm 3 to 0.25±0.04 mm 3 . Linear mixed model analyses showed a significant decrease in log FT and log FV at 3, 6 and 12 months after the start of treatment compared with baseline measurements (p<0.001, p<0.001, p<0.001). Mean best-corrected visual acuity did not increase significantly (0.46±0.35 logMAR to 0.45±0.38 logMAR after 12 months)., Discussion: SA may be an effective alternative treatment to reduce CM in RP patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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

Background: Chyle leakage/ascites after surgical resection of neuroblastic tumors may delay the start of chemotherapy and worsen prognosis. Previous studies have reported a highly variable incidence and risk factors remain largely unknown. This study aims to analyze the true incidence of chyle leaks and ascites and seeks to identify risk factors and optimal treatment strategies., Methods: Medline/Embase databases were searched according to PRISMA guidelines. Literature reviews, case reports, and non-English papers were excluded. Data were extracted independently following paper selection by 2 authors., Results: The final analysis yielded 15 studies with N = 1468 patients. Chylous ascites was recorded postoperatively in 171 patients (12%). Most patients experiencing chyle leaks were successfully treated conservatively with drainage, bowel rest, parenteral nutrition and octreotide with variable combinations of these treatment options. 7/171 (4%) patients required operative exploration to control troublesome persistent chyle leaks. In risk factor analysis, higher tumor stage was significantly associated with the risk of chyle leak (P < 0.0001) whereas no correlation was observed with adrenal vs non-adrenal tumor location, INRG risk groups and tumor laterality., Conclusion: Chyle leakage after surgery for neuroblastic tumors is a common morbid complication occurring in some 12% of patients. Higher INSS tumor stage portends greater risk(s). Conservative therapy strategies appear successful in the majority of cases. To avert this complication meticulous mesenteric lymphatic ligation is recommended especially for those patients with higher tumor stage(s) requiring extensive radical surgery including retroperitoneal lymph node resection., Level of Evidence: III., Type of Study: Systematic review., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Pharmacological prevention of postoperative pancreatic fistula (POPF) after pancreatectomy is open to debate. The present study compares clinically significant POPF rates in patients randomized between somatostatin versus octreotide as prophylactic treatment., Methods: Multicentric randomized controlled open study in patient's candidate for pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) comparing somatostatin continuous intravenous infusion for 7 days versus octreotid 100 μg, every 8 hours subcutaneous injection for 7 days, stratified by procedure (PD vs DP) and size of the main pancreatic duct (>4 mm) on grade B/C POPF rates at 90 days based on an intention-to-treat analysis., Results: Of 763 eligible patients, 651 were randomized: 327 in the octreotide arm and 324 in the somatostatin arm, with comparable the stratification criteria - type of surgery and main pancreatic duct dilatation. Most patients had PD (n=480; 73.8%), on soft/normal pancreas (n=367; 63.2%) with a nondilated main pancreatic duct (n=472; 72.5%), most often for pancreatic adenocarcinoma (n=311; 47.8%). Almost all patients had abdominal drainage (n=621; 96.1%) and 121 (19.5%) left the hospital with the drain in place (median length of stay=16 days). A total of 153 patients (23.5%) developed a grade B/C POPF with no difference between both groups: 24.1%: somatostatin arm and 22.9%: octreotide arm (χ 2 test, P =0.73, ITT analysis). Absence of statistically significant difference persisted after adjustment for stratification variables and in per-protocol analysis., Conclusion: Continuous intravenous somatostatin is not statistically different from subcutaneous octreotide in the prevention of grade B/C POPF after pancreatectomy., Findings: In the PREFIPS Randomized Clinical Trial including 651 patients, a total of 153 patients (23.5%) developed a grade B/C POPF with no significant difference between both groups: 24.1%: somatostatin arm and 22.9%: octreotide arm (χ 2 test, P =0.73, ITT analysis). Absence of statistically significant difference persisted after adjustment for stratification variables and in per-protocol analysis., Competing Interests: S.G. reported grants, personal fees, and nonfinancial support fomr IPSEN, Mylan, Mayoli, Novartis. The remaining authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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

Competing Interests: The authors report no conflicts of interest.

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

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

Although predictors of response to first-generation somatostatin receptor ligands (fg-SRLs), and to a lesser extent to pasireotide, have been studied in acromegaly for many years, their use is still not recommended in clinical guidelines. Is there insufficient evidence to use them? Numerous biomarkers including various clinical, functional, radiological and molecular markers have been identified. The first ones are applicable pre-surgery, while the molecular predictors are utilized for patients not cured after surgery. In this regard, factors predicting a good response to fg-SRLs are specifically: low basal GH, a low GH nadir in the acute octreotide test, T2 MRI hypointensity, a densely granulated pattern, high immunohistochemistry staining for somatostatin receptor 2 (SSTR2), and E-cadherin. However, there is still a lack of consensus regarding which of these biomarkers is more useful or how to integrate them into clinical practice. With classical statistical methods, it is complex to define reliable and generalizable cut-off values for a single biomarker. The potential solution to the limitations of traditional methods involves combining systems biology with artificial intelligence, which is currently providing answers to such long-standing questions that may eventually be finally included into the clinical guidelines and make personalized medicine a reality. The aim of this review is to describe the current knowledge of the main fg-SRLs and pasireotide response predictors, discuss their current usefulness, and point to future directions in the research of this field., Competing Interests: Declaration of Competing Interest MM and MPD have received funding for advisory boards or for being a speaker from Pfizer, Novartis, Ipsen and Recordati. MAC has received funding for being a speaker from Recordati. The REMAH (Registro Español Molecular de Adenomas Hipofisarios) initiative was supported by Novartis. All authors declare that they have received financial support for attending educational programs not directly related to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Acromegaly is a rare endocrine disorder usually caused by a benign growth hormone‒secreting pituitary adenoma. Surgical adenoma resection is typically the first line of treatment, and medical therapy is used for patients with persistent disease following surgery, for adenoma recurrence, or for patients ineligible for, or declining, surgery. Approved somatostatin receptor ligands (SRLs) have been limited to injectable options, until recently. Oral octreotide capsules (OOC) are the first approved oral SRL for patients with acromegaly., Areas Covered: We review published reports and provide case study examples demonstrating practical considerations on the use of OOC. Using two hypothetical case scenarios, we discuss current treatment patterns, breakthrough symptoms and quality of life (QoL), efficacy of SRLs, OOC dose titration, evaluation of OOC treatment response, and incidence and management of adverse events., Expert Opinion: OOC are an option for patients with acromegaly including those who experience breakthrough symptoms, who have preference for oral therapies, or other reasons for declining injectable SRLs. OOC have been associated with improved patient-reported QoL measures compared with those reported for lanreotide and octreotide. Continued real-world experience will determine whether OOC, alone or in combination with other therapies, provides further advantages over current injectable acromegaly treatments.

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

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