A rapidly increasing proportion of the population in the United States is taking glucagon-like peptide-1 receptor agonists (GLP-1RAs) for type 2 diabetes or weight loss. Consequently, an increasing number of patients presenting with new cases of cancer also have a current prescription for GLP-1RAs. The impact of GLP-1RAs on metabolism is quite profound, and it is entirely reasonable to assume these agents are also very impactful on the metabolism of cancer cells, in addition to the general metabolism of the patient. Although these drugs are relatively recent on the market, the study of metabolism in cancer is a well-established field and we can make predictions about how GLP-1RAs will interface with cancer treatments. In fact, some evidence points to a possible neoadjuvant effect of these drugs for patients with cancer that would justify the initiation of GLP-1RAs to support therapy in a subset of patients. At the same time, there is a very present concern that drugs that induce weight loss may also precipitate the loss of muscle mass, cachexia, in patients. Here, we will provide an overview of the existing literature around diabetes and metabolism in the context of cancer and cachexia.

Accurate preoperative localization is imperative for the treatment of insulinomas. Glucagon-like peptide-1 receptor (GLP-1R) imaging has demonstrated remarkable efficacy in localization of insulinomas. The aim of this study was to assess the diagnostic performance of GLP-1R PET/CT with 68Ga-exendin-4 in localization of insulinoma, and to provide evidence for clinical practice from a real-world study.

This is a retrospective analysis of our prospective cohort study of 68Ga-exendin-4 PET/CT in insulinoma (NCT02560376). Patients with endogenous hyperinsulinemic hypoglycemia and definite final diagnosis were enrolled. Results of contrast-enhanced CT (CECT) with pancreatic perfusion scan, MRI, endoscopic ultrasound, and 99mTc-HYNIC-TOC SPECT/CT were collected. The gold standard for diagnosis was histopathology (for insulinoma) or a definite clinical diagnosis of the etiology of hyperinsulinemic hypoglycemia after hospitalization in the endocrinology department (for non-insulinomatous hypoglycemia).

A total of 357 patients (including 296 insulinoma patients and 61 non-insulinoma patients) with were included. The overall sensitivity, specificity, accuracy, PPV, and NPV of 68Ga-exendin-4 PET/CT in localizing insulinoma were 94.93% (95%CI, 91.78%˜97.14%), 100.00% (95%CI, 94.13%˜100%), 95.79% (95%CI, 93.16%˜97.63%), 100.00% (95%CI, 98.32%˜100%), 80.26% (95%CI, 71.29%˜86.94%), respectively. The area under the ROC of 68Ga-exendin-4 PET/CT for diagnosing insulinoma was 0.975 (95%CI, 0.953 ˜ 0.988), which was superior to that of CECT (AUC = 0.873 [95%CI, 0.833 ˜ 0.906]), MRI (AUC = 0.825 [95%CI, 0.773 ˜ 0.869]), EUS (AUC = 0.746 [95%CI, 0.652 ˜ 0.825]) and 99mTc-HYNIC-TOC SPECT/CT (AUC = 0.618 [95%CI, 0.562 ˜ 0.672]). The lesion-based sensitivity of 68Ga-exendin-4 PET/CT in sporadic benign insulinoma was 95.47% (95%CI, 92.22%˜97.64%), and the PPV was 99.61% (95%CI 99.60%˜99.62%). In contrast, the diagnostic efficacy of 68Ga-exendin-4 PET/CT was found to be less effective in cases of sporadic malignant insulinoma or inherited syndromes, yielding a lesion-based detection rate of 66.43% and 68.04%, respectively.

68Ga-exendin-4 PET/CT is a preferred imaging modality in diagnosing insulinoma, particularly in sporadic benign insulinomas.

Accurate preoperative localization is particularly important for surgical treatment of insulinomas. Current imaging methods, including 18F-FDG (FDG) PET/CT, 68Ga-DOTATATE (TATE) PET/CT, CE-CT, and CE-MRI, have limitations. This prospective study provides a direct comparison of 68Ga-NOTA-Exendin-4 (Ex4) PET/CT with other imaging techniques.

47 patients with biochemically proven endogenous hyperinsulinemic hypoglycemia underwent Ex4 PET/CT and other imaging methods. Sensitivity and accuracy of all imaging procedures for localizing insulinoma were calculated at the patient level and lesion level. Both clinical (>10 years experience) and junior (< 2 years experience) nuclear medicine physician readings were used to assess the diagnostic efficacy. We compared the SUVmax and tumor-to-background ratio (TBR) of three tracers and analyzed the values with Ki-67, maximum tumor diameter, and glucose metabolism indicators.

In patient level, the sensitivity and accuracy of Ex4 PET/CT (94.11% and 95.74%) were higher than TATE PET/CT (70.59%, p = 0.026; 78.72%, p = 0.030), FDG PET/CT (50.00%, p < 0.001; 63.83%, p < 0.001), CE-CT (77.77%, p = 0.135; 72.22%, p = 0.007), and CE-MRI (63.64%, p = 0.135; 43.75%, p < 0.001), respectively. Interobserver agreement was higher for Ex4 PET/CT than TATE PET/CT and FDG PET/CT (Cohen κ, 0.839 vs. 0.707 and 0.784, respectively). SUVmax and TBR of Ex4 and TATE PET/CT were significantly higher than FDG PET/CT (p < 0.01). Negative correlations of tumor Ki-67 with TATE PET/CT were observed with SUVmax (r = -0.637, p < 0.001). SUVmax and TBR of three molecular imaging methods had positive correlations with the maximum tumor diameter (p < 0.05), except TBR of FDG PET/CT. Semi-quantitative values of the three tracers showed no correlation with the lowest blood glucose level, corresponding insulin, and C-peptide level. TBR of TATE PET/CT showed a positive correlation with C-peptide (r = 0.393, p = 0.043).

Ex4 PET/CT showed superior characteristics in localization compared to routine imaging modalities in benign insulinomas. Ex4 PET/CT demonstrates better imaging quality and interpretability than FDG PET/CT and TATE PET/CT. Combined Ex4 and TATE PET/CT could provide a comprehensive evaluation/localization of insulinoma.

The trial was retrospectively registered at ClinitalTrial.gov (NCT06690957 and NCT06725693) on November 14, 2024 and December 5, 2024.

Neuroendocrine tumors (NET) are frequently associated with glycemic disorders, such as prediabetes or diabetes, which may result from either surgical or medical treatments or hormonal hypersecretion by the tumor itself. Moreover, pre-existing diabetes is a known risk factor for NET development, with metabolic control and antidiabetic therapies potentially influencing tumor progression. The complex interplay between diabetes and NET, which share several molecular pathways, has spurred interest in the anti-cancer effects of antidiabetic medications. This is particularly relevant as new antidiabetic drugs continue to emerge, including sodium-glucose cotransporter-2 (SGLT2) inhibitors and incretin-based therapies, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists and dual GIP/GLP- 1 R agonists. This review explores the impact of these novel pharmacological options on NET development and progression through a comprehensive analysis of pre-clinical and clinical studies, with the purpose to evaluate safety and feasibility of introducing these drugs in the treatment of NETs patients. We conducted a comprehensive search of online databases, including PubMed, ISI Web of Science, and Scopus, for studies assessing the therapeutic effects and potential mechanisms of action of incretins and SGLT2 inhibitors in patients with NET. These novel antidiabetic drugs exhibit promising anticancer properties, potentially inhibiting tumor cell proliferation and inducing apoptosis, though concerns about certain cancer risks remain. Based on current evidence, the benefits of incretin-based therapies outweigh any potential cancer risks, leading to the proposal of tailored management algorithms for diabetes in NET patients, factoring in the diabetes aetiology, comorbidities, and life expectancy.

The complementary role of multi-tracer PET in deciphering 2 different pathologies in multiple endocrine neoplasia 1 (MEN-1) is illustrated in this report. A 22-year-old man, with a history of altered behavior over the past 1 year and suspected to have hyperinsulinemic hypoglycemia based on a positive 72-hour fasting test and CT abdomen revealing a lesion in the pancreas, was referred for 68Ga-Exendin-4 PET/CT. The 68Ga-Exendin PET/CT revealed focal uptake in the pancreatic lesion, and 68Ga-DOTATATE PET/CT did not show any avidity in the pancreatic lesion; however, it demonstrated somatostatin receptor (SSTR) expression in a soft tissue mass, just posterior to the thyroid. Parathyroid adenoma and hyperparathyroidism were finally proven, and genetic testing was done, which came positive for the diagnosis of MEN-1 syndrome.

Semaglutide is a glucagon-like peptide 1 (GLP-1) analog that binds to GLP-1 receptors (GLP-1R) on beta-cells and neuronal cells and is used for treating type 2 diabetes and obesity. Insulin-secreting pancreatic neuroendocrine neoplasms have been reported to express high levels of GLP-1R protein, raising the possibility that GLP-1 receptor agonists could promote tumor growth. Our goal was to quantify GLP-1R expression levels in 6 neuroendocrine neoplasm cellular models and determine their proliferative response to semaglutide treatment.

Gene expression of GLP-1R in neuroendocrine neoplasm cells (BON, GOT1, NT-3, NEC913, NEC1452, and NEC1583) was measured by quantitative polymerase chain reaction. Protein expression was determined by immunofluorescent staining and Western blotting. Neuroendocrine neoplasm cells were incubated with semaglutide, and cell growth was measured using a cell viability assay. Mice harboring GOT1 xenografts were treated with semaglutide, and tumor volumes were measured.

BON, NEC1452, and NEC1583 cells expressed significantly lower levels of GLP-1R transcript and protein than GOT1, NT-3, and NEC913 cells. GOT1 and NT-3 showed the highest response to semaglutide treatment, with a 19% and 22% increase in growth. Semaglutide promotes tumor growth in mice with GOT1 xenografts by 72%.

The impact of the GLP-1 receptor agonist semaglutide on neuroendocrine cancer growth is understudied. Our data revealed that 50% of neuroendocrine neoplasm cell lines tested expressed GLP-1R, and semaglutide treatment promoted their growth. These results indicate a potential risk in the use of semaglutide in patients with neuroendocrine neoplasms expressing GLP-1R. Investigations into a larger set of neuroendocrine neoplasms would be important because they are highly heterogeneous.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for both oncological and hormone control and is a widely accepted standard of care treatment for patients with neuroendocrine neoplasms (NEN). Its use is anticipated to increase significantly, and this demands accurate tools and paradigms to assess treatment response post PRRT. This article outlines the current role and future developments of anatomical, molecular imaging and biomarkers for response assessment to PRRT, highlighting the challenges and provides perspectives for the need to focus on a multimodality, multidisciplinary and individualised approach for patients with this complex heterogeneous disease.

Glucagon-like peptide-1 receptor (GLP-1R) is an emerging critical target for the diagnosis and treatment of various diseases. Radiolabeled exendin-4 (Ex-4), a GLP-1R agonist, has been widely used as an imaging probe. However, its potential to induce hypoglycemia, especially in patients with insulinoma, limits its applicability. This study evaluated whether Ex-D3, a Glu3Asp substitution of Ex-4 with a higher internalization rate, could enhance the imaging efficacy of Ex-4 while reducing its hypoglycemic effects. We synthesized derivatives with an additional C-terminal Cys (Ex-D3-C40) for site-specific 125I labeling. Surface plasmon resonance analysis revealed that C-terminus modification did not significantly alter the binding affinity of Ex-D3-C40 to GLP-1R. In vivo studies in mice demonstrated that Ex-D3-C40 induced weaker hypoglycemic effects than Ex-4-C40. Biodistribution studies showed that 125I-labeled Ex-D3 ([125I]I-Ex-D3) achieved significantly higher pancreatic accumulation and higher pancreas-to-blood and pancreas-to-muscle ratios than [125I]I-Ex-4. Ex vivo autoradiography confirmed the binding specificity of [125I]I-Ex-D3 to GLP-1R-expressing pancreatic β-cells. These findings indicate that Ex-D3 is a promising parent peptide for the development of superior GLP-1R imaging probes with reduced hypoglycemic risk, highlighting the importance of considering pharmacological effects in designing molecular imaging probes.

Gastrin releasing peptide receptor (GRPR)-directed radiopharmaceuticals for targeted radionuclide therapy may be a very promising addition in prostate and breast cancer patient management. Aiming to provide a GRPR-targeting theranostic pair, we have utilized the Tc-99m/Re-188 radiometal pair, in combination with two bombesin based antagonists, maSSS-PEG2-RM26 and maSES-PEG2-RM26. The two main aims of the current study were (i) to elucidate the influence of the radiometal-exchange on the biodistribution profile of the two peptides and (ii) to evaluate the feasibility of using the [99mTc]Tc labeled counterparts for the dosimetry estimation for the [188Re]Re-labeled conjugates.

Both peptides were successfully labeled with Re-188 and evaluated both in vitro and in vivo. In GRPR expressing PC-3 cells, both [188Re]Re-labeled peptides displayed high cellular uptake (8.5 ± 0.1% and 5 ± 0.3% of added activity, respectively), heavily GRPR-driven, while retaining the radioantagonistic profile with slow internalization rates. Both agents demonstrated high receptor affinity when loaded with natRe (7.5 nM and 8 nM, respectively). When tested in vivo in GRPR expressing PC-3 xenografts, both radioantagonists demonstrated high tumor accumulation (6.3 ± 0.5%IA/g and 5 ± 1%IA/g at 1 h pi, respectively), with good retention over time (4 ± 2%IA/g and 3.1 ± 0.1%IA/g at 4 h pi, respectively). In addition, their biodistribution profiles were closely mimicking their [99mTc]Tc-labeled counterparts. Statistically significant lower tumor uptake was found for both conjugates labeled with Tc-99m, which may result in underestimation of the dose delivered to the tumor.

All the results indicate that Tc-99 m could be used for dosimetry evaluation for the two [188Re]Re-labeled radioligands, with minimal alterations in their biodistribution pattern and tumor targeting capabilities.

Precise anatomic localization of insulinomas is crucial for surgical treatment. Current routine noninvasive imaging techniques, including CT, MRI, and 68Ga-DOTA-somatostatin analog (DOTA-SSA) PET/CT, have limited sensitivity. Endoscopic ultrasound is highly sensitive but invasive. In this prospective multicenter study, we compared the diagnostic accuracy of 68Ga-NODAGA-exendin-4 (exendin) PET/CT with all routine imaging procedures for the localization of insulinomas. Methods: Sixty-nine adults with biochemically proven adult endogenous hyperinsulinemic hypoglycemia underwent exendin PET/CT and current routine imaging. Images were evaluated in a clinical reading and in an expert reading. Image quality was determined by quantitative analysis. Results: Based on clinical readings, the accuracy of exendin PET/CT (94.4%; 95% CI, 84.6%-98.8%) was greater than that of DOTA-SSA PET/CT (64.8%; 95% CI, 50.6%-77.3%), contrast-enhanced CT/contrast-enhanced diffusion-weighted imaging-MRI (83.3%; 95% CI, 70.7%-92.1%), and endoscopic ultrasound (82.8%; 95% CI, 64.1%-94.1%). In 13% of patients, a correct diagnosis was only reached after exendin PET/CT. Interobserver agreement between readings was higher for exendin PET/CT than for DOTA-SSA PET/CT and contrast-enhanced CT/contrast-enhanced diffusion-weighted imaging-MRI (Cohen κ, 1.0 vs. 0.5 and 0.55). Exendin PET/CT provided a higher insulinoma-to-background ratio (15.3 ± 6.7 vs. 5.2 ± 3.0) and contrast-to-noise ratio (22.6 ± 11.1 vs. 5.1 ± 3.7) than did DOTA-SSA PET/CT. Conclusion: This study demonstrates the superiority of exendin PET/CT in a unique prospective comparison to all current routine imaging modalities for preoperative localization of benign insulinomas, providing the level of evidence needed for clinical implementation.

Aberrant G-protein coupled receptor (GPCR) expression is highly prevalent in cortisol-secreting primary bilateral macronodular adrenal hyperplasia (PBMAH) and unilateral adenomas. The aberrant expression of diverse GPCRs and their ligands play an important role in the over-function of various endocrine tumours. Examples include aberrant expression of MC2R, 5-HT4R, AVPR1A, LHCGR, and GnRHR in primary aldosteronism; GCGR, LHCGR, and 5-HT4R in phaeochromocytomas and paragangliomas; TRHR, GnRHR, GIPR, and GRP101 in pituitary somatotroph tumours; AVPR2, D2DR, and SSTR5 in pituitary corticotroph tumours; GLP1R, GIPR, and somatostatin receptors in medullary thyroid carcinoma; and SSTRs, GLP1R, and GIPR in other neuroendocrine tumours. The genetic mechanisms causing the ectopic expression of GIPR in cortisol-secreting PBMAHs and unilateral adenomas have been identified, but distinct mechanisms are implicated in other endocrine tumours. Development of functional imaging targeting aberrant GPCRs should be useful for identification and for specific therapies of this wide spectrum of tumours. The aim of this review is to show that the regulation of endocrine tumours by aberrant GPCR is not restricted to cortisol-secreting adrenal lesions, but also occurs in tumours of several other organs.

We report a case of a 35-year-old woman with recurrent episodes of hypoglycemia. Biochemical investigation was suggestive of hyperinsulinemic hypoglycemia, and hence a provisional diagnosis of insulinoma was made. Despite extensive investigation using magnetic resonance imaging, endoscopic ultrasound, and 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) scanning, the tumor could not be localized. Long-distance travel allowed her to undergo a 68Ga-Exendin-4 PET/CT scan that identified a lesion in the uncinate process of the pancreas, subsequently confirmed by intraoperative ultrasound. Enucleation of the 1.5-cm lesion was performed, and histopathology confirmed a well-differentiated pancreatic neuroendocrine tumor. Postoperatively, the patient has remained free of hypoglycemic episodes and has shown normalization of glucose levels. This case underscores the efficacy of 68Ga-Exendin-4 PET/CT in the localization of an occult insulinoma, facilitating timely and curative surgical intervention, and the importance of patients having access to such a facility when not locally available.

Insulinomas are rare insulin-secreting neuroendocrine neoplasms of the pancreas. First-line treatment is the surgical removal of the tumor, however, the localization with standard imaging techniques is often challenging. With the help of selective intraarterial calcium stimulation the insulinoma's localization can be narrowed down to one third of the pancreas which the selected artery supplies.

We aimed to prove the usefulness of the calcium stimulation test in case of 9 patients treated between 2006 and 2021 diagnosed with endogenous hyperinsulinemic hypoglycemia confirmed by fasting test, where conventional imaging methods, like transabdominal ultrasound, CT or MRI failed to detect the source of hyperinsulinemia.

We performed selective intraarterial calcium stimulation with angiography with calcium gluconate injected to the main supporting arteries of the pancreas (splenic, superior mesenteric and gastroduodenal arteries); blood samples were obtained from the right hepatic vein before, and 30, 60 and 120 seconds after calcium administration.

With selective angiography we found a significant elevation of insulin levels taken from the right hepatic vein in five of the nine cases. On histopathology, the lesions were between 1-2 cm, in one case malignancy was also confirmed. In four patients we found a significant rise of insulin levels obtained from all catheterized sites, which confirmed the diagnosis of nesidioblastosis. In three cases no surgery was performed, and the symptoms relieved with medical treatment.

Selective intraarterial calcium stimulation remains an important tool in localization of the source of insulin excess, especially in cases where other diagnostic modalities fail.

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.

Background: The concept of radiotheranostics relies on the overexpression of a biomolecular target on malignant cells to direct diagnostic/therapeutic radionuclide-carriers specifically to cancer lesions. The concomitant expression of more than one target in pathological lesions may be elegantly exploited to improve diagnostic sensitivity and therapeutic efficacy. Toward this goal, we explored a first example of a combined application of [99mTc]Tc-DT11 (DT11, N4-Lys(MPBA-PEG4)-Arg-Arg-Pro-Tyr-Ile-Leu-OH; NTS1R-specific) and [99mTc]Tc-DB7(DB7, N4-PEG2-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt; GRPR-specific) in prostate cancer models. Methods: Accordingly, the behavior of [99mTc]Tc-DT11 was compared with that of the [99mTc]Tc-DT11+[99mTc]Tc-DB7 mixture in prostate adenocarcinoma PC-3 cells and xenografts in mice. The impact of stabilizing both radiotracers by Entresto®, as a source of the potent neprilysin inhibitor sacubitrilat, was also investigated. Results: The PC-3 cell binding of the [99mTc]Tc-DT11+[99mTc]Tc-DB7 mixture surpassed that of [99mTc]Tc-DT11. Likewise, the PC-3 tumor uptake of the [99mTc]Tc-DT11+[99mTc]Tc-DB7 mixture at 4 h post-injection was superior (7.70 ± 0.89%IA/g) compared with [99mTc]Tc-DT11 (4.23 ± 0.58%IA/g; p < 0.0001). Treatment with Entresto® led to further enhancement of the tumor uptake (to 11.57 ± 1.92%IA/g; p < 0.0001). Conclusions: In conclusion, this first preclinical study on prostate cancer models revealed clear advantages of dual NTS1R/GRPR targeting, justifying further assessment of this promising concept in other cancer models.

Insulinomas are the most common functional pancreatic neuroendocrine neoplasm; when treatment is delayed, they induce hyperinsulinemic hypoglycemia, which is life-threatening. As surgical resection is the only curative treatment for insulinoma, preoperative localization is crucial; however, localization based on conventional imaging modalities such as computed tomography (CT) and magnetic resonance imaging is often inconclusive. Somatostatin receptor-targeted imaging is another option for detecting pancreatic neuroendocrine neoplasms but has low sensitivity and is not specific for insulinoma. The clinical application of other localizing approaches such as selective arterial calcium stimulation and endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) is limited by their being invasive and/or technically complex. Moreover, an EUS-FNA specimen of an insulinoma may be negative on insulin immunostaining. Thus, a noninvasive and clinically practical insulinoma-specific diagnostic tool to discriminate insulinomas with high accuracy is anticipated. Glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged in the effort to fulfill this need. We recently developed the novel fluorine-18-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4) for positron emission tomography (PET) imaging and reported its clinical benefit in a case of insulinoma in the pancreatic tail. We report here a case of insulinoma in the pancreatic head in which an EUS-FNA specimen was negative on insulin immunostaining while precise preoperative localization and conclusive evidence for curative enucleation was provided by 18F-exendin-4 PET/CT (Japan Registry of Clinical Trials; jRCTs051200156).

Lung carcinoid tumours are neuroendocrine neoplasms originating from the bronchopulmonary tract's neuroendocrine cells, accounting for only 1%-3% of all lung cancers but 30% of all neuroendocrine tumours. The incidence of lung carcinoids, both typical and atypical, has been increasing over the years due to improved diagnostic methods and increased awareness among clinicians and pathologists. The most recent WHO classification includes a subgroup of lung carcinoids with atypical morphology and higher mitotic count and/or Ki67 labelling index. Despite appropriate surgery, the 5-year survival rate for atypical carcinoids barely exceeds 50%-70%. The role of adjuvant therapy in lung carcinoids is not well-defined, and clinical decisions are generally based on the presence of high-risk features. Long-term follow-up is essential to monitor for recurrence, although the optimal follow-up protocol remains unclear. To address the lack of consensus in clinical management decisions, the European Neuroendocrine Tumor Society (ENETS) initiated a survey among 20 expert centres. The survey identified varied opinions on approaches to imaging, surgery, use of adjuvant therapy, and follow-up protocols. Notably, the absence of dedicated multidisciplinary lung neuroendocrine tumour boards in some centres was evident. Experts agreed on the need for a prospective adjuvant trial in high-risk patients, emphasizing the feasibility of such a study. In conclusion, the study highlights the need for a more uniform adoption of existing guidelines in the management of lung carcinoid tumours and emphasizes the importance of international collaboration to advance research and patient care. Close collaboration between healthcare providers and patients is vital for effective long-term surveillance and management of these rare tumours.

Typical Pulmonary Carcinoid (TPC) is defined by its slow growth, frequently necessitating surgical intervention. Despite this, the long-term outcomes following tumor resection are not well understood. This study examined the factors impacting Overall Survival (OS) in patients with TPC, leveraging data from the Surveillance, Epidemiology, and End Results database spanning from 2000 to 2018. We employed Lasso-Cox analysis to identify prognostic features and developed various models using Random Forest, XGBoost, and Cox regression algorithms. Subsequently, we assessed model performance using metrics such as Area Under the Curve (AUC), calibration plot, Brier score, and Decision Curve Analysis (DCA). Among the 2687 patients, we identified five clinical features significantly affecting OS. Notably, the Random Forest model exhibited strong performance, achieving 5- and 7-year AUC values of 0.744/0.757 in the training set and 0.715/0.740 in the validation set, respectively, outperforming other models. Additionally, we developed a web-based platform aimed at facilitating easy access to the model. This study presents a machine learning model and a web-based support system for healthcare professionals, assisting in personalized treatment decisions for patients with TPC post-tumor resection.

Non-somatostatin receptor expressing hypovascular insulinomas can be challenging to prove through imaging. This case highlights the utility of a structured approach to molecular imaging in patients with confirmed endogenous hyperinsulinemia. A 54-year-old woman was admitted because of a sudden loss of consciousness. Her relative reported that she complained of dizziness, intense sweating, blurry vision, and upper extremity tingling before becoming unresponsive for 20 min, after which the patient had little recollection of the event. She experienced similar episodes of shorter duration, trouble recalling everyday events, and unintentional weight gain of over 10 kg during the previous two years. Abdominal magnetic resonance imaging (MRI) and multidetector computerized tomography (MDCT) were unremarkable. Selective arterial calcium stimulation significantly increased hepatic venous insulin concentrations when the superior mesenteric and gastroduodenal arteries were stimulated. Technetium-99m (99mTc) octreotide single-photon emission computed tomography (SPECT) did not localize the lesion. Gallium-68 DOTA-Exendin-4 PET/CT acquisition was performed. A single intense 2 cm hyperperfused pancreatic lesion was located anteriorly in the head of the pancreas. Earlier targeted PET/CT imaging and recognition of significant neuropsychiatric symptoms attributable to the patient's hypoglycemic state might have accelerated the resolution of her condition and obviated the need for unnecessary testing.

Neuroendocrine neoplasms (NENs), arising from various sites, present therapeutic challenges. Radioligand therapy (RLT) is effective for unresectable/metastatic NENs with increased somatostatin receptor uptake. While evidence supports RLT's efficacy in midgut NETs, its role in lung NETs remains underexplored. Clinical guidelines place RLT as a third or fourth-line option in this setting. However, in the last years several studies investigated mainly retrospectively effectiveness and safety of RLT in lung NET. The aim of this review is to assess the efficacy and safety of RLT in patients with lung NETs. Following PRISMA guidelines, a systematic review of MEDLINE and EMBASE databases retrieved English articles until March 31, 2023. Inclusion criteria encompassed studies involving RLT in lung NETs with efficacy and safety assessments. Twenty-seven studies met the criteria, totaling 786 patients. The pooled analysis revealed a 25.6% objective response rate and 75.6% disease control rate. Median progression-free survival averaged 20 months, while overall survival averaged 45 months. Factors affecting response included tumor burden, prior treatments, 18F-FDG PET scan uptake, and histological variants. RLT exhibited manageable grade 1/2 adverse effects, predominantly hematological, with Lu177 demonstrating a more favorable profile than Y90. The findings support RLT's effectiveness in lung NETs, offering hope for advanced SSTR-positive patients. Although identifying predictive factors for response remains challenging, RLT retained efficacy even after prior therapies and typical carcinoids displayed a slightly better response than atypical ones. Prospective trials are imperative to establish RLT's definitive efficacy and its place in the therapeutic landscape for lung NETs.

Pancreatic cancer (PC) is a dangerous digestive tract tumor that is becoming increasingly common and fatal. The most common form of PC is pancreatic ductal adenocarcinoma (PDAC). Bile acids (BAs) are closely linked to the growth and progression of PC. They can change the intestinal flora, increasing intestinal permeability and allowing gut microbes to enter the bloodstream, leading to chronic inflammation. High dietary lipids can increase BA secretion into the duodenum and fecal BA levels. BAs can cause genetic mutations, mitochondrial dysfunction, abnormal activation of intracellular trypsin, cytoskeletal damage, activation of NF-κB, acute pancreatitis, cell injury, and cell necrosis. They can act on different types of pancreatic cells and receptors, altering Ca2+ and iron levels, and related signals. Elevated levels of Ca2+ and iron are associated with cell necrosis and ferroptosis. Bile reflux into the pancreatic ducts can speed up the kinetics of epithelial cells, promoting the development of pancreatic intraductal papillary carcinoma. BAs can cause the enormous secretion of Glucagon-like peptide-1 (GLP-1), leading to the proliferation of pancreatic β-cells. Using Glucagon-like peptide-1 receptor agonist (GLP-1RA) increases the risk of pancreatitis and PC. Therefore, our objective was to explore various studies and thoroughly examine the role of BAs in PC.

Somatostatin receptor antagonists have shown promising performance for imaging neuroendocrine neoplasms. However, there is a lack of studies exploring the diagnostic performance of SSTR antagonists or comparing them with agonists in a large cohort of patients with NENs. This study aimed to retrospectively review all SSTR antagonist PET/CT scans conducted at Peking Union Medical College Hospital since November 2018 in patients with confirmed or suspected NENs.

Four types of SSTR antagonists were utilized, including [68Ga]Ga-NODAGA-LM3, [68Ga]Ga-DOTA-LM3, [68Ga]Ga-NODAGA-JR11, and [68Ga]Ga-DOTA-JR11. The reference standard was based on a combination of histopathology, clinical evaluation, imaging results, and follow-up. Patient-based sensitivity, specificity, and accuracy were evaluated. The SUVmax and tumor-to-liver ratio (TLR) of the hottest lesions was recorded and compared between antagonists and [68Ga]Ga-DOTATATE.

A total of 622 antagonist scans from 549 patients were included in the analysis. The patient-level sensitivity, specificity, and accuracy of antagonist imaging (all tracers combined) were 91.0% (443/487), 91.9% (57/62), and 91.1% (500/549), respectively. In 181 patients with a comparative [68Ga]Ga-DOTATATE PET/CT scan, the patient-level sensitivity, specificity, and accuracy were 87.5% (147/168), 76.9% (10/13), and 86.7% (157/181), respectively. For the hottest lesions, SSTR antagonists all tracers combined demonstrated an overall comparable SUVmax to [68Ga]Ga-DOTATATE (40.1 ± 32.5 vs. 39.4 ± 23.8, p = 0.772). While [68Ga]Ga-NODAGA-LM3 showed significantly higher uptake than [68Ga]Ga-DOTATATE (57.4 ± 38.5 vs. 40.0 ± 22.8, p<0.001), [68Ga]Ga-NODAGA-JR11 (39.7 ± 26.5 vs. 34.3 ± 23.9, p = 0.108) and [68Ga]Ga-DOTA-LM3 (38.9 ± 32.1 vs. 37.2 ± 22.1, p = 0.858) showed comparable uptake to [68Ga]Ga-DOTATATE, and [68Ga]Ga-DOTA-JR11 showed lower uptake (28.9 ± 26.1 vs. 44.0 ± 25.7, p = 0.001). All antagonists exhibited significantly higher TLR than [68Ga]Ga-DOTATATE (12.1 ± 10.8 vs. 5.2 ± 4.5, p<0.001).

Gallium-68 labeled SSTR antagonists could serve as alternatives to SSTR agonists for imaging of NENs. Among various antagonists, [68Ga]Ga-NODAGA-LM3 seems to have the best imaging profile.

Pancreatic neuroendocrine tumors (PanNETs) and lung NETs (LNETs) represent a rare but clinically significant subgroup of neoplasms. While the majority is sporadic, approximately 17% of PanNETs and a subset of LNETs develop in the context of monogenic familial tumor syndromes, especially multiple endocrine neoplasia type 1 (MEN1) syndrome. Other inherited syndromes associated with PanNETs include MEN4, von Hippel-Lindau (VHL) syndrome, neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). These syndromes are highly penetrant and their clinical manifestations may vary even among members of the same family. They are attributed to genetic mutations involving key molecular pathways regulating cell growth, differentiation, and angiogenesis. Pancreatic NETs in hereditary syndromes are often multiple, develop at a younger age compared to sporadic tumors, and are associated with endocrine and nonendocrine tumors derived from multiple organs. Lung NETs are not as common as PanNETs and are mostly encountered in MEN1 syndrome and include typical and atypical lung carcinoids. Early detection of PanNETs and LNETs related to inherited syndromes is crucial, and specific follow-up protocols need to be employed to optimize diagnosis and management. Genetic screening is recommended in childhood, and diagnostic screening starts often in adolescence, even in asymptomatic mutation carriers. Optimal management and therapeutic decisions should be made in the context of a multidisciplinary team in specialized centers, whereas specific biomarkers aiming to identify patients denoted to follow a more aggressive course need to be developed.

Diabetes mellitus (DM) is one of the major diseases in the world. Nuclear medicine imaging may be able to detect functional status of pancreatic β cells in vivo, which might elucidate the pathological mechanisms of diabetes and develop individualized treatment plans. In this study, we evaluated the ability of [125I]ADAM, a serotonin transporter (SERT) imaging agent, as a probe for detecting pancreatic β-cell mass (BCM).

In vitro cell studies were evaluated in INS-1 cells (rat islet β cell line). Biodistribution studies were performed in male normal Sprague-Dawley rats and alloxan-induced type 1 diabetes mellitus (T1DM) rats. Distribution and expression of SERT protein in pancreas of rats were also measured by immunofluorescence staining and Western blot.

In vitro cell studies showed that the concentration of [125I]ADAM associated with the INS-1 cells was increased gradually with incubation time, and the SERT specific inhibitor, escitalopram, exhibited the inhibitory effect on this interaction. Biodistribution studies also showed that the uptake of [125I]ADAM in the pancreas of normal rats was decreased in the presence of escitalopram. However, in the T1DM rat model with a significant β cells reduction, the uptake of pancreas was increased when compared with the control. Through immunofluorescence staining and Western blot, it was found that both the endocrine and exocrine cells of the normal pancreas expressed SERT protein, and the level of SERT protein in the exocrine cells was higher than islets. In the diabetic state, the expression of SERT in the exocrine cells was further increased.

The SERT imaging agent, [125I]ADAM, at the present form will not be suitable for imaging β cells, specifically because there were extraordinarily high non-specific signals contributing from the exocrine cells of pancreas. In addition, we noticed that the level of SERT expression was abnormally elevated in the diabetic state, which might provide an unexpected target for studying the pathological mechanisms of diabetes.

The overexpression of one or more somatostatin receptors (SST1-5R) in human tumors has provided an opportunity for diagnosis and therapy with somatostatin-like radionuclide carriers. The application of "pansomatostatin" analogs is expected to broaden the clinical indications and upgrade the diagnostic/therapeutic efficacy of currently applied SST2R-prefering radioligands. In pursuit of this goal, we now introduce two bicyclic somatostatin-14 (SS14) analogs, AT5S (DOTA-Ala1-Gly2-c[Cys3-Lys4-Asn5-c[Cys6-Phe7-DTrp8-Lys9-Thr10-Cys11]-Thr12-Ser13-Cys14]) and AT6S (DOTA-Ala1-Gly2-c[Cys3-Lys4-c[Cys5-Phe6-Phe7-DTrp8-Lys9-Thr10-Phe11-Cys12]-Ser13-Cys14]), suitable for labeling with trivalent radiometals and designed to sustain in vivo degradation. Both AT5S and AT6S and the respective [111In]In-AT5S and [111In]In-AT6S were evaluated in a series of in vitro assays, while radioligand stability and biodistribution were studied in mice. The 8/12-mer bicyclic AT6S showed expanded affinity for all SST1-5R and agonistic properties at the SST2R, whereas AT5S lost all affinity to SST1-5R. Both [111In]In-AT5S and [111In]In-AT6S remained stable in the peripheral blood of mice, while [111In]In-AT6S displayed low, but specific uptake in AR4-2J tumors and higher uptake in HEK293-SST3R tumors in mice. In summary, high radioligand stability was acquired by the two disulfide bridges introduced into the SS14 motif, but only the 8/12-mer ring AT6S retained a pansomatostatin profile. In consequence, [111In]In-AT6S targeted SST2R-/SST3R-positive xenografts in mice. These results call for further research on pansomatostatin-like radioligands for cancer theranostics.

Somatostatin receptor (SST) PET/CT is the gold standard for well-differentiated neuroendocrine tumours (NET) imaging. Higher grades of neuroendocrine neoplasms (NEN) show preferential [18F]FDG (FDG) uptake, and even low-grade NET may de-differentiate over time. FDG PET/CT's prognostic role is widely accepted; however, its impact on clinical decision-making remains controversial and its use varies widely. A questionnaire-based survey on FDG PET/CT use and perceived decision-making utility in NEN was submitted to the ENETS Advisory Board Meeting attendees (November 2022, response rate = 70%). In 3/15 statements, agreement was higher than 75%: (i) FDG was considered useful in NET, irrespective of grade, in case of mis-matched lesions (detectable on diagnostic CT but negative/faintly positive on SST PET/CT), especially if PRRT is contemplated (80%); (ii) in NET G3 if curative surgery is considered (82%); and (iii) in NEC prior to surgery with curative intent (98%). FDG use in NET G3, even in the presence of matched lesions, as a baseline for response assessment was favoured by 74%. Four statements obtained more than 60% consensus: (i) FDG use in NET G3 if locoregional therapy is considered (65%); (ii) in neuroendocrine carcinoma before initiating active therapy as a baseline for response assessment (61%); (iii) biopsy to re-assess tumour grade prior to a change in therapeutic management (68%) upon detection of FDG-positivity on the background of a prior G1-2 NET; (iv) 67% were in favour to reconsider PRRT to treat residual SST-positive lesions after achieving complete remission on FDG of the SST-negative disease component. Multidisciplinary opinion broadly supports the use of FDG PET/CT for characterisation of disease biology and to guide treatment selection across a range of indications, despite the lack of full consensus in many situations. This may reflect existing clinical access due to lack of reimbursement or experience with this investigation, which should be addressed by further research.

Insulinomas are rare functional pancreatic neuroendocrine tumours, which metastasize in 10% of cases. As predicting the prognosis can be challenging, there is a need for the determination of clinicopathological factors associated with metastatic potential. The aim of this study is to evaluate the glucagon-like peptide-1 receptor (GLP-1R) expression in insulinomas and to analyse its association with clinicopathological features and patient outcome. This retrospective study involves pancreatic tumour tissue samples from fifty-two insulinoma patients. After histological re-evaluation, formalin-fixed paraffin-embedded tissue samples were processed into tissue microarrays and stained immunohistochemically with a monoclonal GLP-1R antibody. Forty-eight of the forty-nine (98%) non-metastatic tumours expressed GLP-1R, while one non-metastatic, multiple endocrine neoplasia type 1 (MEN1)-related tumour and all three of the metastatic tumours lacked GLP-1R expression. The lack of GLP-1R expression was associated with impaired overall survival, larger tumour diameter, higher Ki-67 PI and weaker insulin staining. Somatostatin receptor 1-5 expression did not differ between GLP-1R-positive and GLP-1R-negative insulinomas. In conclusion, the lack of GLP-1R expression is associated with metastatic disease and impaired survival in insulinoma patients. Thus, GLP-1R expression could be a useful biomarker in estimating the metastatic potential of the tumour and the prognosis of surgically treated patients.

Radioligand therapy (RLT) with [177Lu]Lu-DOTA-TATE is a standard of care for adult patients with somatostatin-receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Taking advantage of this precision nuclear medicine approach requires diligent monitoring and surveillance, from the use of diagnostic SSTR-targeted radioligand imaging for the selection of patients through treatment and assessments of response. Published evidence-based guidelines assist the multidisciplinary healthcare team by providing acceptable approaches to care; however, the sheer heterogeneity of GEP-NETs can make these frameworks difficult to apply in individual clinical circumstances. There are also contradictions in the literature regarding the utility of novel approaches in monitoring and surveilling patients with GEP-NETs receiving RLT. This article discusses the emerging evidence on imaging, clinical biochemistry, and tumor assessment criteria in the management of patients receiving RLT for GEP-NETs; additionally, it documents our own best practices. This allows us to offer practical guidance on how to effectively implement monitoring and surveillance measures to aid patient-tailored clinical decision-making.

Theranostic in nuclear medicine combines diagnostic imaging and internal irradiation therapy using different therapeutic nuclear probes for visual diagnosis and precise treatment. GLP-1R is a popular receptor target in endocrine diseases, non-alcoholic steatohepatitis, tumors, and other areas. Likewise, it has also made breakthroughs in the development of molecular imaging. It was recognized that GLP-1R imaging originated from the study of insulinoma and afterwards was expanded in application including islet transplantation, pancreatic β-cell mass measurement, and ATP-dependent potassium channel-related endocrine diseases. Fortunately, GLP-1R molecular imaging has been involved in ischemic cardiomyocytes and neurodegenerative diseases. These signs illustrate the power of GLP-1R molecular imaging in the development of medicine. However, it is still limited to imaging diagnosis research in the current molecular imaging environment. The lack of molecular-targeted therapeutics related report hinders its radiology theranostic. In this article, the current research status, challenges, and emerging opportunities for GLP-1R molecular imaging are discussed in order to open a new path for theranostics and to promote the evolution of molecular medicine.

Since angiogenesis/neoangiogenesis has a major role in tumor development, progression and metastatic spread, the establishment of angiogenesis-targeting imaging and therapeutic vectors is of utmost significance. Aminopeptidase N (APN/CD13) is a pivotal biomarker of angiogenic processes abundantly expressed on the cell surface of active vascular endothelial and various neoplastic cells, constituting a valuable target for cancer diagnostics and therapy. Since the asparagine-glycine-arginine (NGR) sequence has been shown to colocalize with APN/CD13, the research interest in NGR-peptide-mediated vascular targeting is steadily growing. Earlier preclinical experiments have already demonstrated the imaging and therapeutic feasibility of NGR-based probes labeled with different positron emission tomography (PET) and single-photon emission computed tomography (SPECT) radionuclides, including Gallium-68 (68Ga), Copper-64 (64Cu), Technetium-99m (99mTc), Lutetium-177 (177Lu), Rhenium-188 (188Re) or Bismuth-213 (213Bi). To improve the tumor binding affinity and the retention time of single-receptor targeting peptides, NGR motifs containing heterodimers have been introduced to identify multi-receptor overexpressing malignancies. Preclinical studies with various tumor-bearing experimental animals provide useful tools for the investigation of the in vivo imaging behavior of NGR-based heterobivalent ligands. Herein, we review the reported preclinical achievements on NGR heterodimers that could be highly relevant for the development of further target-specific multivalent compounds in diagnostic and therapeutic settings.

PET/CT imaging of glucagon-like peptide receptor 1 has recently filled a gap in reliably diagnosing insulinoma through non-invasive means. 68Ga-labelled derivatives of exendin-4 show high sensitivity as well as sufficient serum stability to enable routine clinical application. Here, we provide data for automated production of [68Ga][Nle14,Lys40(Ahx-DOTA-Ga)NH2]exendin-4 ([68Ga]Ga-DOTA-exendin-4) on a cassette based synthesis module (Modular-Lab PharmTracer, Eckert & Ziegler) using commercially available cassettes in combination with an approved 68Ge/68Ga generator (GalliaPharm, Eckert & Ziegler). This setup ensured high reproducibility as well as low radiation burden for the production team. Quality control including determination of radiochemical purity was performed by RP-HPLC using a water/0.1 % TFA/acetonitrile gradient on a C18 column. A modified TLC system with ammonium acetate & methanol as mobile phase and a novel limit test for determination of polysorbate 80 content in the final formulation are also described in this study.

Reliable yields as well as high molar activity for patient use were only achieved using a fractionated elution approach. Batch data showed radiochemical purity of >93 % as determined by RP-HPLC and TLC as well as good stability over 2 h post production. Testing for polysorbate 80 confirmed a concentration <1 mg/mL in the final product solution. Specifications for routine production were established based on existing Pharmacopeia monographs for other radiopharmaceuticals and were validated with 5 master batches.

The described synthesis method enables reproducible, automated in-house production of [68Ga]Ga-DOTA-exendin-4 for routine clinical application.

Neuroendocrine neoplasms represent an uncommon disease with an increasing incidence. Thanks to improvements in diagnostic and therapeutic methods, metastases previously considered uncommon, such as bone metastases, or even very rare, such as brain, orbital and cardiac metastases, are more frequently found in daily practice. Due to the great heterogeneity of these neoplasms, there is a lack of high-quality evidence on the management of patients with these types of metastases. The aim of this review is to provide the current state of the art, reviewing neuroendocrine neoplasm specific studies and useful information from other tumor types and to propose a treatment recommendation with algorithms to consider in daily clinical practice.

Insulinomas are the most common functioning pancreatic neuroendocrine neoplasms, and these tumors induce hypoglycemia due to hyperinsulinemia. Hypoglycemia caused by insulinomas can cause seizures, coma or death due to the delayed diagnosis. The only curative treatment is surgical resection. To perform curative surgical resection of insulinomas, preoperative localization is crucial. However, localization of insulinomas is often challenging using conventional imaging methods such as computed tomography (CT) and magnetic resonance imaging. Although endoscopic ultrasound (EUS) fine-needle aspiration and selective arterial calcium stimulation test, which can reflect the endocrine character of the tumor, are performed in such cases, these modalities are invasive and require operator-dependent techniques. Additionally, somatostatin receptor (SSTR)-targeted imaging has a relatively low sensitivity for detecting insulinomas due to its low SSTR type 2 expression. Thus, there is an urgent need for developing a noninvasive diagnostic technique which is specific for detecting insulinomas. Consequently, glucagon-like peptide-1 receptor-targeted imaging has recently emerged and gained a wide interest. Recently, we have developed a novel 18F-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4), for positron emission tomography (PET) imaging. Here we report a case of insulinoma in which 18F-exendin-4 PET/CT noninvasively provided critical information for localization.

This is a case of a 58-year-old male with symptomatic hypoglycemia for 10 years; however, a preoperative diagnosis of insulinoma was not established due to the difficulty in differentiating it from an accessory spleen using conventional imaging. Moreover, the patient requested to avoid invasive diagnostic procedures including EUS. 18F-exendin-4 PET/CT revealed significant uptakes in the pancreatic tail whereas no apparent uptakes were observed in the spleen; thus, curative laparoscopic enucleation of the pancreatic tail was performed. The diagnosis of insulinoma was confirmed via histopathological examination. This is the first case report of insulinoma diagnosed using 18F-exendin-4 PET/CT.

In this case, PET information led to curative resection through enucleation of the pancreas. 18F-exendin-4 PET/CT may serve as a useful noninvasive clinical tool for insulinoma localization.

This ENETS guidance paper aims to provide practical advice to clinicians for the diagnosis, treatment and follow-up of functioning syndromes in pancreatic neuroendocrine tumours (NET). A NET-associated functioning syndrome is defined by the presence of a clinical syndrome combined with biochemical evidence of inappropriately elevated hormonal levels. Different hormonal syndromes can be encountered in pancreatic NET patients, including insulinoma, gastrinoma as well as the rare glucagonoma, VIPoma, ACTHoma, PTHrPoma, carcinoid syndrome, calcitoninoma, GHRHoma and somatostatinoma. The recommendations provided in this paper focus on the biochemical, genetic and imaging work-up as well as therapeutic management of the individual hormonal syndromes in well-differentiated, grade 1-3, functioning NET with the primary tumour originating in the pancreas, and for specific subtypes also in the duodenum.

This cross-sectional study compared the value of molecular imaging (Exendin-4 positron emission tomography/computed tomography [PET/CT], ⁶⁸Ga-DOTATATE PET/CT, ¹⁸F- fluorodeoxyglucose [FDG] PET/CT) in insulinoma localization by stratified tumor size and grading, and explored the correlation of the related the maximum standardized uptake value (SUVmax) with insulinoma grading, Ki-67, maximum tumor diameter, and glucose metabolism.

In 28 insulinoma patients, the sensitivity of three types of PET/CT for localizing insulinoma was calculated according to tumor size and grade. We compared the SUVmax for different insulinoma grades and analyzed the correlation of SUVmax with Ki-67, maximum tumor diameter, and glucose metabolism indicators.

The study included 12 grade (G) 1 and 16 G2 cases, with maximum tumor diameters ranging from 9 to 40 mm. Without differentiation by size and grade, the sensitivity of Exendin-4 PET/CT to localize insulinoma was 100%, which significantly exceeded that of ⁶⁸Ga-DOTATATE PET/CT and ¹⁸F-FDG PET/CT (75% and 57%, respectively). In tumors with a maximum diameter ≤ 20 mm and ≤ 15 mm, the sensitivity of Exendin-4 (both 100%) significantly exceeded that of ⁶⁸Ga-DOTATATE PET/CT (74% and 64%, respectively) and ¹⁸F-FDG PET/CT (54% and 50%, respectively). In G1 tumors, the sensitivity of Exendin-4 PET/CT was significantly higher than that of ¹⁸F-FDG PET/CT, but not that of ⁶⁸Ga-DOTATATE PET/CT, while in G2 tumors, the sensitivity of Exendin-4 PET/CT was significantly higher than that of both other types. However, all three PET/CT types missed a metastatic lymph node in one patient. The ¹⁸F-FDG PET/CT SUVmax was significantly lower than that of the other PET/CT types and that of ⁶⁸Ga-DOTATATE PET/CT was significantly lower in G2 than in G1. ⁶⁸Ga-DOTATATE PET/CT SUVmax correlated negatively with Ki-67. A receiver operating characteristic (ROC) curve suggested that ⁶⁸Ga-DOTATATE PET/CT SUVmax > 19.9 could predict G1 tumors.

Exendin-4 PET/CT was superior to ⁶⁸Ga-DOTATATE PET/CT and ¹⁸F-FDG PET/CT for insulinoma localization, particularly small and G2 tumors, but its diagnostic value in small metastatic lymph nodes requires further exploration. ⁶⁸Ga-DOTATATE PET/CT SUVmax could be used as an adjunct to pathology, and a value > 19.9 could predict G1 tumors. No PET/CT SUVmax could predict tumor maximum diameter and glucose metabolism.