Detection Of Insulinomas Research Articles

Insulinoma detection and surgery planning: a comparative study of 5.0T MRI versus 3.0T MRI and MDCT.

To compare the ability among 5.0T MRI, 3.0T MRI and MDCT in identifying insulinomas and determining the tumor-to-duct relationship. A consecutive series of patients highly suspected of insulinomas were enrolled between October 2021 and February 2024, who underwent 5.0T MRI preoperatively, as well as 3.0T MRI or MDCT. The subjective and objective image quality, lesion-to-pancreas contrast, clarity of main pancreatic duct (MPD) and tumor-to-duct relationship at 5.0T, 3.0T MRI and MDCT were evaluated by three observers. The correlation between tumor-duct distance and clinically relevant postoperative pancreatic fistula (CR-POPF) risk was analyzed. Forty patients (14 men; mean age, 46.4 ± 16.5 years) with insulinomas were included in this study. 21 of them underwent both 5.0T and 3.0T MRI; and 38 of them underwent 5.0T MRI and MDCT. The intra- and inter-observer agreement of 5.0T MRI were good to excellent. 5.0T showed significantly higher subjective and objective image quality on T1WI and DWI compared to 3.0T (p < 0.05). Lesion-to-pancreas contrast was superior across all sequences at 5.0T compared to 3.0T(p < 0.05). A head-to-head comparison of patients who received both 5.0T and 3.0T MRI demonstrated that tumor detection was superior with 5.0T MRI (5.0T: 100%; 3.0 T: 92.0%, p < 0.05). Feasibility of tumor-to-duct relationship assessment was superior at 5.0T, compared to 3.0T and MDCT (93.2%, 64.0% and 52.3%, respectively, p < 0.05). Tumor-duct distance could predict CR-POPF after enucleation surgery (areas under the ROC curve 0.79, p = 0.01). 5.0T MRI exhibits certain superiority in detecting insulinomas and assessing tumor-to-duct relationship compared to 3.0T MRI and MDCT.

New Radiolabeled Exendin Analogues Show Reduced Renal Retention.

PET imaging of the glucagon-like peptide-1 receptor (GLP-1R) using radiolabeled exendin is a promising imaging method to detect insulinomas. However, high renal accumulation of radiolabeled exendin could hamper the detection of small insulinomas in proximity to the kidneys and limit its use as a radiotherapeutic agent. Here, we report two new exendin analogues for GLP-1R imaging and therapy, designed to reduce renal retention by incorporating a cleavable methionine-isoleucine (Met-Ile) linker. We examined the renal retention and insulinoma targeting properties of these new exendin analogues in a nude mouse model bearing subcutaneous GLP-1R-expressing insulinomas. NOTA or DOTA was conjugated via a methionine-isoleucine linker to the C-terminus of exendin-4 (NOTA-MI-exendin-4 or DOTA-MI-exendin-4). NOTA- and DOTA-exendin-4 without the linker were used as references. The affinity for GLP-1R was determined in a competitive binding assay using GLP-1R transfected cells. Biodistribution of [68Ga]Ga-NOTA-exendin-4, [68Ga]Ga-NOTA-MI-exendin-4, [177Lu]Lu-DOTA-exendin-4, and [177Lu]Lu-DOTA-MI-exendin-4 was determined in INS-1 tumor-bearing BALB/c nude mice, and PET/CT was acquired to visualize renal retention and tumor targeting. For all tracers, dosimetric calculations were performed to determine the kidney self-dose. The affinity for GLP-1R was in the low nanomolar range (<11 nM) for all peptides. In vivo biodistribution revealed a significantly lower kidney uptake of [68Ga]Ga-NOTA-MI-exendin-4 at 4 h post-injection (p.i.) (34.2 ± 4.2 %IA/g), compared with [68Ga]Ga-NOTA-exendin-4 (128 ± 10 %IA/g). Accumulation of [68Ga]Ga-NOTA-MI-exendin-4 in the tumor was 25.0 ± 8.0 %IA/g 4 h p.i., which was similar to that of [68Ga]Ga-NOTA-exendin-4 (24.9 ± 9.3 %IA/g). This resulted in an improved tumor-to-kidney ratio from 0.2 ± 0.0 to 0.8 ± 0.3. PET/CT confirmed the findings in the biodistribution studies. The kidney uptake of [177Lu]Lu-DOTA-MI-exendin-4 was 39.4 ± 6.3 %IA/g at 24 h p.i. and 13.0 ± 2.5 %IA/g at 72 h p.i., which were significantly lower than those for [177Lu]Lu-DOTA-exendin-4 (99.3 ± 9.2 %IA/g 24 h p.i. and 45.8 ± 3.9 %IA/g 72 h p.i.). The uptake in the tumor was 7.8 ± 1.5 and 11.3 ± 2.0 %IA/g 24 h p.i. for [177Lu]Lu-DOTA-MI-exendin-4 and [177Lu]Lu-DOTA-exendin-4, respectively, resulting in improved tumor-to-kidney ratios for [177Lu]Lu-DOTA-MI-exendin-4. The new exendin analogues with a Met-Ile linker showed 2-3-fold reduced renal retention and improved tumor-to-kidney ratios compared with their reference without the Met-Ile linker. Future studies should demonstrate whether [68Ga]Ga-NOTA-MI-exendin-4 results in improved detection of small insulinomas in close proximity to the kidneys with PET/CT. [177Lu]Lu-DOTA-MI-exendin-4 might open a window of opportunity for exendin-based radionuclide therapy.

Protocol for Clinical GLP-1 Receptor PET/CT Imaging with [68Ga]Ga-NODAGA-Exendin-4.

Imaging with radiolabeled exendin enables detection and characterization of glucagon-like peptide 1 receptors (GLP-1Rs) in vivo with high specificity. The novel radiotracer [68Ga]Ga-NODAGA-exendin-4 forms a stable complex after a simple and fast labeling procedure. Beta-cell mass in the islets of Langerhans can be visualized using [68Ga]Ga-NODAGA-exendin-4, which is promising for research into diabetes mellitus (DM) pathophysiology. Furthermore, this radiotracer enables very sensitive detection of insulinomas, resulting from vast overexpression of GLP-1Rs, and seems promising for the detection of focal lesions in congenital hyperinsulinism (CHI). Here, we describe the procedures involved in [68Ga]Ga-NODAGA-exendin-4 positron emission tomography (PET)/computed tomography (CT) imaging including the radiolabeling of the NODAGA-exendin conjugate with 68Ga, quality controls, and PET/CT.

Role of 68Ga-DOTATOC PET/CT in Insulinoma According to 3 Different Contexts: A Retrospective Study.

The aim of this study was to assess the performance of 68Ga-DOTATOC PET/CT in the detection and extension of insulinomas according to 3 different contexts: sporadic benign, sporadic metastatic, and multiple endocrine neoplasia type 1 (MEN1). The data of 71 adult patients who underwent 68Ga-DOTATOC PET/CT for suspected or confirmed sporadic insulinoma, suspicion of insulinoma in the context of MEN1, follow-up of metastatic insulinoma, or suspicion of recurrence of insulinoma were retrospectively analyzed. Pathological examination or strong clinical and biological findings were used as standards of truth. For the assessment of a confirmed sporadic insulinoma in 17 patients, the sensitivity of SR-PET was 75%, including 2 patients for whom metastatic lesions had been revealed by SR-PET. For 35 patients with a suspicion of insulinoma, the sensitivity was 39%. In 10 patients followed up for metastatic insulinoma, the sensitivity was 100%. For 5 patients with a history of MEN1, interpretation of SR-PET was difficult, as 3 of them presented with multiple pancreatic uptake foci. The global sensitivity of SR-PET in all insulinomas excluding those with a MEN1 story was 64% (100% for metastatic insulinomas, 62% for benign insulinomas), with a specificity of 89%. 68Ga-DOTATOC PET/CT is a useful examination tool for the assessment of insulinomas in selected contexts, with very high performance for the detection and extension workup of metastatic insulinomas and high specificity for the detection of sporadic benign insulinomas. The examination should be completed with GLP-1 receptor PET when it is negative or in a MEN1 context.

Diagnostic performance of noninvasive imaging modalities for localization of insulinoma: A meta-analysis

BackgroundInsulinoma is the most common functional neuroendocrine tumor found only in the pancreas. The early detection of insulinoma is of importance. Studies comparing the performance of noninvasive modalities were limited by sample size and heterogeneity between studies. The aim of this meta-analysis was to evaluate the diagnostic performance of PET/CT, SPECT/CT, CT and MRI for the localization of insulinoma, and to provide evidence for clinical practice. MethodsPubMed, Embase, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure were searched from inception to May 31, 2021. Pooled sensitivity, specificity, positive Likelihood Ratio (+LR) and negative Likelihood Ratio (−LR), diagnostic odds ratio (DOR), and concordance rate were calculated. ResultsA total of 19 studies including 708 patients of insulinoma reached the inclusion criteria. PET/CT imaging demonstrated a pooled sensitivity of 0.79 (95% CI: 0.54–0.92) and a pooled specificity of 0.84 (95% CI: 0.20–0.99). The pooled sensitivity and specificity of SPECT/CT were 0.77 (95% CI: 0.46–0.93) and 0.45 (95% CI: 0.22–0.70). CT showed an overall sensitivity of 0.54 (95% CI: 0.35–0.72) and specificity of 0.75 (95% CI: 0.54–0.88). The pooled sensitivity and specificity for MRI were 0.54 (95% CI: 0.31–0.75) and 0.65 (95% CI: 0.39–0.84), respectively. The concordance rates of PET, SPECT, CT, and MRI were 78% (95% CI: 66–90%), 74% (95% CI: 52–97%), 56% (95% CI: 41–72%), and 53% (95% CI: 33–73%), respectively. ConclusionResults of this study indicate that PET/CT demonstrated superior performance than SPECT/CT, CT and MRI for the localization of insulinoma. GLP-1R based PET/CT manifested better diagnostic performance in comparison with SSTR based PET/CT imaging modality.

Distinctive detection of insulinoma using [18F]FB(ePEG12)12-exendin-4 PET/CT

Specifying the exact localization of insulinoma remains challenging due to the lack of insulinoma-specific imaging methods. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging, especially positron emission tomography (PET), has emerged. Although various radiolabeled GLP-1R agonist exendin-4-based probes with chemical modifications for PET imaging have been investigated, an optimal candidate probe and its scanning protocol remain a necessity. Thus, we investigated the utility of a novel exendin-4-based probe conjugated with polyethylene glycol (PEG) for [18F]FB(ePEG12)12-exendin-4 PET imaging for insulinoma detection. We utilized [18F]FB(ePEG12)12-exendin-4 PET/CT to visualize mouse tumor models, which were generated using rat insulinoma cell xenografts. The probe demonstrated high uptake value on the tumor as 37.1 ± 0.4%ID/g, with rapid kidney clearance. Additionally, we used Pdx1-Cre;Trp53R172H;Rbf/f mice, which developed endogenous insulinoma and glucagonoma, since they enabled differential imaging evaluation of our probe in functional pancreatic neuroendocrine neoplasms. In this model, our [18F]FB(ePEG12)12-exendin-4 PET/CT yielded favorable sensitivity and specificity for insulinoma detection. Sensitivity: 30-min post-injection 66.7%, 60-min post-injection 83.3%, combined 100% and specificity: 30-min post-injection 100%, 60-min post-injection 100%, combined 100%, which was corroborated by the results of in vitro time-based analysis of internalized probe accumulation. Accordingly, [18F]FB(ePEG12)12-exendin-4 is a promising PET imaging probe for visualizing insulinoma.

Glucagon-like Peptide-1 Receptor as Emerging Target: Will It Make It to the Clinic?

The glucagon-like peptide-1 receptor (GLP-1R) is an emerging target due to its high expression in benign insulinomas as well as in islet cell hypertrophia/hyperplasia (nesidioblastosis) and pancreatic β-cells. In 2008, occult insulinomas were localized for the first time in men using the metabolically stable radiolabeled glucagon-like peptide-1 (GLP-1) agonist [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 (111In-DTPA-exendin-4). Afterward, several radiopharmaceuticals for GLP-1R PET/CT imaging were synthesized and evaluated, for example, [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4 (68Ga-DOTA-exendin-4), [Cys40(MAL-NOTA-68Ga)NH2]-exendin-4 (68Ga-NOTA-exendin-4), and [Lys40(NODAGA-68Ga)NH2]-exendin-4 (68Ga-NODAGA-exendin-4). Several prospective comparison studies provided evidence that GLP-1R PET/CT is significantly more sensitive than contrast-enhanced MRI (ceMRI), contrast-enhanced CT (ceCT), GLP-1R SPECT/CT, somatostatin receptor PET/CT, and SPECT/CT in the detection of benign insulinomas, and insulinomas in the context of multiple endocrine neoplasia type 1. As a result, the European Neuroendocrine Tumor Society guidelines recommend GLP-1R imaging or selective intraarterial calcium stimulation and venous sampling (ASVS) in patients for whom there is a clinical suspicion of having an insulinoma but who have a negative ceMRI/ceCT or negative endoscopic ultrasound. Furthermore, there is growing evidence that GLP-1R PET/CT can visualize and localize adult nesidioblastosis. This is clinically relevant as the distinction between focal and diffuse nesidioblastosis is critical in directing a therapeutic strategy in these patients. Prospective studies have proven the clinical relevance of GLP-1R imaging as it is often the only imaging modality able to localize the insulinoma or nesidioblastosis. It is therefore likely that this noninvasive imaging modality will replace the invasive localization of insulinomas using ASVS. More experimental indications for GLP-1R imaging include the diagnosis of an insulinoma/nesidioblastosis in patients with postprandial hypoglycemia after bariatric bypass surgery and monitoring β-cells in patients with brittle type 1 diabetes after islet-cell transplantation. We believe that these indications and possibly future indications will bring GLP-1R imaging to the clinic.

Role of PET/CT and Therapy Management of Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine neoplasms (panNENs) are heterogeneous neoplasms with neuroendocrine differentiation that show peculiar clinical and histomorphological features, with variable prognosis. In recent years, advances in knowledge regarding the pathophysiology and heterogeneous clinical presentation, as well as the availability of different diagnostic procedures for panNEN diagnosis and novel therapeutic options for patient clinical management, has led to the recognition of the need for an active multidisciplinary discussion for optimal patient care. Molecular imaging with positron emission tomography/computed tomography (PET/CT) has become indispensable for the management of panNENs. Several PET radiopharmaceuticals can be used to characterize either panNEN receptor expression or metabolism. The aim of this review is to offer an overview of all the currently used radiopharmaceuticals and of the new upcoming tracers for pancreatic neuroendocrine tumors (panNETs), and their clinical impact on therapy management. [68Ga]Ga-DOTA-peptide PET/CT (SSA-PET/CT) has high sensitivity, specificity, and accuracy and is recommended for the staging and restaging of any non-insulinoma well-differentiated panNEN cases to carry out detection of unknown primary tumor sites or early relapse and for evaluation of in vivo somatostatin receptors expression (SRE) to select patient candidates for peptide receptor radiometabolic treatment (PRRT) with 90Y or 177Lu and/or cold analogs. SSA-PET/CT also has a strong impact on clinical management, leading to a change in treatment in approximately a third of the cases. Its role for treatment response assessment is still under debate due to the lack of standardized criteria, even though some semiquantitative parameters seem to be able to predict response. [18F]FDG PET/CT generally shows low sensitivity in small growing and well-differentiated neuroendocrine tumors (NET; G1 and G2), while it is of utmost importance in the evaluation and management of high-grade NENs and also provides important prognostic information. When positive, [18F]FDG PET/CT impacts therapeutical management, indicating the need for a more aggressive treatment regime. Although FDG positivity does not exclude the patient from PRRT, several studies have demonstrated that it is certainly useful to predict response, even in this setting. The role of [18F]FDOPA for the study of panNET is limited by physiological uptake in the pancreas and is therefore not recommended. Moreover, it provides no information on SRE that has crucial clinical management relevance. Early acquisition of the abdomen and premedication with carbidopa may be useful to increase the accuracy, but further studies are needed to clarify its utility. GLP-1R agonists, such as exendin-4, are particularly useful for benign insulinoma detection, but their accuracy decreases in the case of malignant insulinomas. Being a whole-body imaging technique, exendin-PET/CT gives important preoperative information on tumor size and localization, which is fundamental for surgical planning as resection (enucleation of the lesion or partial pancreatic resection) is the only curative treatment. New upcoming tracers are under study, such as promising SSTR antagonists, which show a favorable biodistribution and higher tumor-to-background ratio that increases tumor detection, especially in the liver. [68Ga]pentixafor, an in vivo marker of CXCR4 expression associated with the behavior of more aggressive tumors, seems to only play a limited role in detecting well-differentiated NET since there is an inverse expression of SSTR2 and CXCR4 in G1 to G3 NETs with an elevation in CXCR4 and a decrease in SSTR2 expression with increasing grade. Other tracers, such as [68Ga]Ga-PSMA, [68Ga]Ga-DATA-TOC, [18F]SiTATE, and [18F]AlF-OC, are also under investigation.

Comparison of angio-CT versus multidetector CT in the detection and location for insulinomas

To compare the diagnostic performance of angio-computed tomography (CT) with multidetector CT (MDCT) in the detection and location for insulinomas. From April 2015 to April 2018, 60 consecutive patients who underwent MDCT and angio-CT for clinically suspected insulinomas were identified retrospectively. The CT attenuation values of tumours, normal pancreatic parenchyma, and tumour-to-pancreas contrast were measured quantitatively in the arterial phase (AP) and portal venous phase (PVP) of both methods by two radiologists with interobserver agreement. The detection sensitivity and localisation accuracy were calculated based on surgical and pathological findings, which are the reference standard, and compared between both methods using the chi-square test. Receiver operating characteristic (ROC) analysis was performed to compare diagnostic performance. Fifty-four patients with insulinoma with a mean age of 53.8 years old (range 21-69 years) were reviewed. The detection sensitivity and location accuracy were 68.5%, 58.3% for MDCT and 94.4%, 90.7% for angio-CT, respectively; the detection sensitivity and location accuracy of angio-CT were significantly higher than those obtained with MDCT (p < 0.05). The mean tumour-to-pancreas attenuations were 105.1±25 HU in the AP of MDCT and 285±48.7 HU in the AP of angio-CT. There were significant differences in the tumour-to-pancreas contrast in the AP between MDCT and angio-CT (p < 0.05). The Az values were 0.93 and 0.84 for the AP of angio-CT and MDCT, 0.62 and 0.54 for the PVP. The AP of angio-CT was significantly more accurate for insulinoma detection (p < 0.05). Angio-CT produces higher tumour conspicuity and is superior in the detection and location of insulinomas compared to MDCT.

Detection of insulinoma: one-stop pancreatic perfusion CT with calculated mean temporal images can replace the combination of bi-phasic plus perfusion scan.

To evaluate the feasibility of one-stop pancreatic perfusion CT with mean temporal (MT) imaging replacing the combination of a bi-phasic scan plus a perfusion scan to detect insulinoma. Forty-five patients with suspected insulinoma, who underwent both biphasic and perfusion CT, were enrolled in this retrospective study. MT datasets including images for different delineation purposes were generated by averaging 3 dynamic datasets from perfusion CT, which are MTA for arterial, MTPV for portal vein and MTO for lesions. Two readers assessed the image quality and diagnostic performance separately for biphasic and MT datasets. Radiation doses were also assessed. Paired t tests, Wilcoxon signed-rank tests and McNemar's tests were applied for comparison. Compared with bi-phasic CT images, image noise, SNR and CNR of the MTA and MTPV datasets were all non-inferior (noise and CNR of the portal vein, p = 0.565 and p = 0.227, respectively) or superior (p ≤ 0.001). The subjective image quality was better in the MTA and MTPV images (p < 0.001 to p = 0.004). The sensitivity and NPV of MT images were also better (95% vs 75% and 75% vs 37.5% for reader 1; 97.5% vs 72.5% and 85.7% vs 35.3% for reader 2). Omitting the bi-phasic scan resulted in a dose reduction of 25% ± 4%. MT imaging can allow pancreatic perfusion CT to be used alone without the need for an additional bi-phasic CT in the detection of insulinoma. • Mean temporal images reconstructed from perfusion CT with an averaging technique reproduce usual bi-phasic images (arterial and portal phases). • The image quality of mean temporal images is non-inferior or superior to native bi-phasic CT. The sensitivity and NPV for the diagnosis of insulinoma are better for mean temporal images than for traditional bi-phasic CT. • Mean temporal imaging can allow pancreatic perfusion CT to be used alone without the need for an additional bi-phasic CT in the detection of insulinoma. Radiation dose saving is important.

Prospective Comparison of Reduced Field-of-View (rFOV) and Full FOV (fFOV) Diffusion-Weighted Imaging (DWI) in the Assessment of Insulinoma: Image Quality and Lesion Detection

To prospectively compare the image quality (IQ) and lesion detection performance of reduced field-of-view (rFOV) and full FOV (fFOV) diffusion-weighted imaging (DWI) sequences in detecting insulinomas. From October 2017 to September 2018, 67 patients with suspected insulinomas were prospectively enrolled and underwent imaging with both types of DWI sequences. The slice thickness (4 mm) and slice gaps (1 mm) were the same for the two DWI sequences, and the TR/TE was 2235/56 ms for the rFOV sequence and 1892/63 ms for the fFOV sequence. Three radiologists independently assessed the imaging quality (IQ) subjectively with a 5-point scale and objectively with signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) measurements. The IQ scores, CNR, SNR, lesion detection rates, and ADC values were compared. Receiver operating characteristic curves were generated, and the area under the curve (AUC) was used to compare the diagnostic performance. Fifty patients were tumor positive, with 65 tumors (size: 1.31 ± 0.77 cm, range: 0.6-5.8 cm). The IQ score, SNR, and CNR were significantly higher for rFOV DWI than for fFOV DWI (IQ: 3.64 ± 0.487 vs 3.310 ± 0.577, SNR: 22.520 ± 8.690 vs 10.284 ± 3.321, CNR: 3.454 ± 2.642 vs 1.327 ± 2.801, and all p < 0.05). For lesions less than 1.5 cm (n = 55), the lesion detection rates of the rFOV were statistically improved compared to those of the fFOV (90.7% vs. 75.9%, p = 0.039). The sensitivity of lesion detection was significantly improved with the rFOV-DWI sequences compared to that with the fFOV-DWI sequences (0.924 vs. 0.773, p = 0.013). The ADC values of the two DWI sequences were consistent for insulinomas and normal parenchyma. Considering the improvements in overall IQ and lesion detection and the consistency of ADC measurements, we suggest that rFOV DWI is a reliable auxiliary alternative to fFOV DWI for clinical practice in the detection of pancreatic insulinomas.

Exendin-4 Derivatives with an Albumin-Binding Moiety Show Decreased Renal Retention and Improved GLP-1 Receptor Targeting.

The glucagon-like peptide-1 receptor (GLP-1R) is highly and specifically expressed on the pancreatic β-cells. It plays an important role in glucose metabolism as well as in β-cell-derived diseases like diabetes, insulinoma, or congenital and adult hyperinsulinemic hypoglycemia. Radiolabeled exendin-4, a ligand of GLP-1R, has routinely been used in clinics to image insulinomas. However, its major drawback is the high kidney accumulation. Here, we show that the addition of an albumin-binding moiety (ABM) to radiolabeled exendin-4 results in a significant reduction of kidney uptake while retaining its high affinity and specificity to GLP-1R. The four tested peptides were shown to have high affinity to the GLP-1 receptor (IC50 of 3.7 ± 0.6 to 15.1 ± 0.8 nM). The radiolabeled derivatives were taken up into cells efficiently, internalizing between 39 ± 2 and 56 ± 2% after 2 h. Thus, the derivatives with ABM outperformed the reference peptide with its IC50 of 22.5 ± 2.9 nM and internalization of 41 ± 4%. Stability in human blood plasma was slightly enhanced by the addition of the albumin binder. In biodistribution studies, the radioligands exhibited an improved target-to-kidney ratio in comparison to the reference peptide of up to seven-fold. This was confirmed qualitatively in single-photon-emission computed tomography (SPECT)/CT imaging. This study demonstrated in vitro and in vivo that the addition of an ABM to radiolabeled exendin-4 strongly decreased kidney accumulation while retaining affinity to GLP-1R. Thus, exendin-4 derivatives with an albumin-binding moiety could present a viable class of diagnostic tracers for the detection of insulinomas and other GLP-1R-positive tissue in clinical application.

68Ga]Ga-NOTA-MAL-Cys39-exendin-4, a potential GLP-1R targeted PET tracer for the detection of insulinoma

Glucagon-like peptide-1 receptor (GLP-1R) is a kind of G protein coupled receptor which regulates the insulin secretion and serves as potential target in the diagnosis of functional pancreas neuroendocrine tumor. The aim of this study was to evaluate the feasibility of GLP-1R targeted tracer [68Ga]Ga-NOTA-MAL-Cys39-exendin-4 in the detection of insulinoma. MethodsNOTA-MAL-Cys39-exendin-4 was synthesized and then radiolabeled with gallium-68 in iQS® Ga-68 Fluidic Labeling Module. The in vitro binding affinity and cell uptake studies were evaluated in INS-1 cells. The in vivo micro-PET/CT imaging and biodistribution studies were performed on INS-1 xenograft tumor models. Results[68Ga]Ga-NOTA-MAL-Cys39-exendin-4 can be efficiently radiolabelled with a yield of about 85% (non-decay corrected) and radiochemical purity of >95% with a favorable stability. The molar activity was at least 145.5 GBq/μmol. The affinity (IC50) for [68Ga]Ga-NOTA-MAL-Cys39-exendin-4 was 12.99 ± 0.81 nM. Micro-PET/CT images showed intense tumor uptake with good contrast to background. Biodistribution study showed the predominant uptake was in the kidney, followed by pancreas, and the liver and spleen just showed mild uptake in the blood-pool phase with rapid clearance. At 1 h post- injection, the tumor to blood, muscle and pancreas ratios were 30.64, 40.21 and 6.46, respectively. Blocking studies showed significantly decreased tumor uptake, which further confirmed binding affinity of [68Ga]Ga-NOTA-MAL-Cys39-exendin-4 to GLP-1R. Conclusion[68Ga]Ga-NOTA-MAL-Cys39-exendin-4 was easily synthesized with high yield, favorable biodistribution and high affinity to islet tumor cell, making the tracer may have great potential in the detection of GLP-1R positive tumor such as an insulinoma.

Molecular Imaging to the Surgeons Rescue: Gallium-68 DOTA-Exendin-4 Positron Emission Tomography-Computed Tomography in Pre-operative Localization of Insulinomas.

Background:Insulinoma is an islet-cell neoplasm that secretes insulin. It is usually localized to the pancreas and is often the most common cause of endogenous hyperinsulinemic hypoglycaemia in non-diabetic adult patients. Surgical excision with a curative intent is the standard modality of treatment, and it requires precise localization of tumor tissue. Ga-68 DOTA-exendin-4 PET/CT scan is a clinically reasonable and sensitive scan for the identification of insulinoma. The aim of this prospective cohort study was to determine the overall accuracy of Ga-68 DOTA-exendin-4 PET/CT scan in the detection of insulinoma.Materials and Methods:Eight patients with fasting hyperinsulinemic hypoglycaemia with neuroglycopenic symptoms were enrolled in this study which was conducted during October 2016 to October 2017. Whole body PET/CT scan was performed on a Philips time of flight PET/CT scanner, 60 minutes after injection of Ga-68 DOTA-exendin-4 (and also Ga-68 DOTANOC). The imaging findings were compared to the histopathological diagnosis in six out of eight patients and to subsequent follow up in the remaining two patients who did not undergo surgery.Results:The sensitivity of Ga-68 DOTA-Exendin-4 PET/CT scan in insulinoma detection was found to be 75%.Conclusion:Ga-68 DOTA-Exendin-4 PET/CT scan is highly sensitive for identification and exact localization of insulinoma which can guide better surgical exploration. However, randomised controlled trials are needed to assess the accuracy of Ga-68 DOTA-Exendin PET/CT scan in localization of insulinoma.

(68)Ga-exendin-4 PET-CT for the localization of occult insulinomas: a prospective cohort study

Objective: To explore the accuracy in localizing occult insulinomas with Glucagon-like peptide-1 receptor(GLP-1R) PET-CT with (68)Ga-exendin-4. Methods: In this prospective cohort study, patients with biochemically proven endogenous hyperinsulinemic hypoglycemia and negative contrast-enhanced CT with pancreatic perfusion scans were enrolled consecutively at Department of Nuclear Medicine, Peking Union Medical College Hospital from February 2014 to June 2018.There were 37 males and 32 females, with age of (43.2±17.9)years. (68)Ga-exendin-4 PET-CT, MRI and endoscopic ultrasound(EUS) were done before elective surgery. Sensitivity, specificity, accuracy, positive predictive value(PPV) and negative predictive value(NPV) of the above imaging modalities were calculated. Results: A total of 69 patients were recruited. Thirty-two patients were diagnosed with insulinomas at histology. Four patients with positive (68)Ga-exendin-4 PET-CT findings did not undergo surgery so far. Twenty-eight patients were proven to be noninsulinoma induced hyperinsulinemic hypoglycemia. Five patients were unknown of etiology of hypoglycemia. The sensitivity, specificity, accuracy, PPV and NPV of (68)Ga-exendin-4 in localizing occult insulinomas were 96.9%(31/32), 100%(30/30), 98.3%(59/60), 100%(29/29), 96.8%(30/31), respectively.The sensitivity, specificity, accuracy, PPV and NPV of MRI were 74.1%(20/27), 9/11, 76.3%(29/38), 90.9%(20/22), 9/16, respectively. The sensitivity, specificity, accuracy, PPV and NPV of EUS were 75.0% (15/20), 2/2, 77.3%(17/22), 15/15, and 2/7. Conclusion: (68)Ga-exendin-4 PET-CT has a high sensitivity, specificity and accuracy for detection of occult insulinoma, which shows superiority to MRI and EUS.

Molecular imaging of β-cells: diabetes and beyond.

Since diabetes is becoming a global epidemic, there is a great need to develop early β-cell specific diagnostic techniques for this disorder. There are two types of diabetes (i.e., type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)). In T1DM, the destruction of pancreatic β-cells leads to reduced insulin production or even absolute insulin deficiency, which consequently results in hyperglycemia. Actually, a central issue in the pathophysiology of all types of diabetes is the relative reduction of β-cell mass (BCM) and/or impairment of the function of individual β-cells. In the past two decades, scientists have been trying to develop imaging techniques for noninvasive measurement of the viability and mass of pancreatic β-cells. Despite intense scientific efforts, only two tracers for positron emission tomography (PET) and one contrast agent for magnetic resonance (MR) imaging are currently under clinical evaluation. β-cell specific imaging probes may also allow us to precisely and specifically visualize transplanted β-cells and to improve transplantation outcomes, as transplantation of pancreatic islets has shown promise in treating T1DM. In addition, some of these probes can be applied to the preoperative detection of hidden insulinomas as well. In the present review, we primarily summarize potential tracers under development for imaging β-cells with a focus on tracers for PET, SPECT, MRI, and optical imaging. We will discuss the advantages and limitations of the various imaging probes and extend an outlook on future developments in the field.

Automated radiolabeling and in vivo evaluation of 18F-FDOPA

Objective To synthesize 18F-fluoro-L-3, 4-dihydroxyphenylalanine (18F-FDOPA) and evaluate its biodistribution and kinetics in mice, in order to explore its feasibility for insulinoma detection. Methods 18F-FDOPA was synthesized by a three-step nucleophilic reaction. Radiolabeling yield, radiochemical purity and stability in vitro were analyzed. Normal mice were scarified at 2, 5, 15, 30, 60 and 120 min postinjection to measure radioactive counts in main organs. Biodistribution and kinetics were evaluated by dynamic microPET in normal mice. The insulinoma tumor (INS-1) model was established and dynamic microPET was performed immediately after intravenous injection and stopped at 60 min. Region of interest (ROI) was drawn to access time-activity curve (TAC) in main organs and insulinoma. Results 18F-FDOPA was prepared with radiochemical yield of (11.0±0.4)%, radiochemical purity of (99.3±0.2)%. The radiochemical purity was still >99% after being stored for 120 min at room temperature. Predominant uptake of 18F-FDOPA was in the kidneys, and was cleared rapidly in blood. Pancreas showed stable uptake from 20 to 50 min, which was (5.98±0.71) percentage activity of injection dose per gram of tissue (%ID/g) at 20 min and (4.62±0.47) %ID/g at 50 min postinjection, respectively. 18F-FDOPA showed high affinity to tumor tissue of insulinoma ((11.42±0.70) %ID/g) at 2 min. Conclusions 18F-FDOPA could be easily synthesized in short total reaction time with high radiochemical purity and stability. Early phase imaging of 18F-FDOPA may be helpful for insulinoma detection. Key words: Levodopa; Isotope labeling; Fluorine radioisotopes; Insulinoma; Positron-emission tomography; Mice

The Value of Hybrid Angio-CT in Preoperative Detection and Localization of Insulinomas: A Single-Center Retrospective Study.

To investigate the performance of hybrid angio-CT in preoperative detection and localization for insulinomas. Fifty-four postoperative pathology-confirmed patients from April 2015 to March 2017 were retrospectively reviewed; all patients underwent angio-CT with administration of contrast media in SMA, GDA and SA due to negative, inconclusive or controversial findings by several preoperative diagnostic methods including TAUS, CEUS, EUS, ECT, EMRI and DSA. Surgery was used as gold standard for localization of insulinomas; detection sensitivity and localization accuracy of angio-CT were assessed and compared with other preoperative image options. Fifty-six benign insulinomas (mean diameter, 15.8mm) in 54 patients (18 men and 36 women) were found according to surgical results; the overall detection sensitivity of TAUS, CEUS, EUS, ECT, EMRI and DSA was 21.4, 78.4, 79.2, 70.0, 79.2 and 72.2%, respectively. The overall localization accuracy was 14.3, 58.8, 68.8, 60.0, 75.0 and 44.4%, respectively. A total of 53 tumors were detected by angio-CT, 51 tumors were accurately located, and the overall detection sensitivity and localization accuracy of angio-CT was 94.4 and 90.7%, which was significantly higher than that of all other preoperative diagnostic methods (p<0.05). No any serious complications occurred during angio-CT. Our study indicates the great potential value of angio-CT in the preoperative detection and localization of insulinomas; angio-CT can be used as a preferred invasive diagnostic method.

O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) uptake in insulinoma: first results from a xenograft mouse model and from human

IntroductionHerein we have evaluated the uptake of O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) in insulinoma in comparison with those of 6-18F-fluoro-3,4-dihydroxy-l-phenylalanine (18F-FDOPA) providing first data from both murine xenograft model and one patient with proved endogenous hyperinsulinemic hypoglycemia. MethodsDynamic 18F-FET and carbidopa-assisted 18F-FDOPA PET were performed on tumor-bearing nude mice after subcutaneous injection of RIN-m5F murine beta cells and on a 30-year-old man with type-1 multiple endocrine neoplasia and hyperinsulinemic hypoglycemia defined by a positive fasting test. ResultsSeven and three nude mice bearing a RIN-m5F insulinoma xenograft were respectively studied by 18F-FET and 18F-FDOPA μPET. Insulinoma xenograft was detected in all the imaged animals. Xenograft was characterized by an early but moderate increase of 18F-FET uptake followed by a slight decline of uptake intensity during the 20 min dynamic acquisition. Tumoral radiotracer peak intensity and the highest tumor-to-background contrast were reached about 5 minutes after 18F-FET iv. injection (mean SUV: 1.21 ± 0.10). The biodistribution of 18F-FET and 18F-FDOPA and their dynamic tumoral uptake profile and intensity were similar. In the examined patient, 18F-FDOPA and 18F-FET PET/CT showed one concordant focal area of well-defined increased uptake in the pancreatic tail corresponding to 11 mm histologically proved insulinoma. The SUVmax tumor to liver ratio was 1.5, 1.1 for 18F-FDOPA, 1.1, 1 for 18F-FET at early (0-5 min post injection) and delayed (5-20 min post injection) PET/CT acquisition, respectively. Despite the relatively low tumoral uptake intensity, insulinoma was clearly identified due to the low background in the pancreas. At the contrary, no 18F-FDOPA or 18F-FET tumoral uptake was revealed on whole-body PET/CT images performed about 30 min after radiotracer administration. Note of worth, the dynamic uptake pattern of 18F-FET and 18F-FDOPA were similar between human insulinoma and mice xenograft tumor. Conclusion18F-FET PET compared equally to 18F-FDOPA PET in a preclinical RIN-m5F murine model of insulinoma and in one patient with insulinoma-related hypoglycemia. However, in both cases, the tumoral uptake intensity was moderate and the tumor was only visible until 20 min after radiotracer injection. Hence, caution should be taken before asserting the translational relevance of our results in the clinical practices. However, the structural analogies between 18F-FET and 18F-FDOPA as well as the limited pancreatic uptake of 18F-FET in human, encourage evaluating 18F-FET as diagnostic radiotracer for insulinoma detection in further prospective studies involving large cohorts of patients.

Prospective comparison of biphasic contrast‐enhanced CT, volume perfusion CT, and 3 Tesla MRI with diffusion‐weighted imaging for insulinoma detection

To evaluate the diagnostic performance of biphasic contrast-enhanced CT (CECT), volume perfusion CT (VPCT) and 3 Tesla MRI with diffusion-weighted imaging (DWI), in patients with clinically suspected insulinomas. This prospective study was approved by the institutional review board. Sixty-four patients with clinically suspected insulinomas underwent biphasic CECT, VPCT, and 3T MR with DWI. Two radiologists independently determined the presence/absence of tumor using a 5-scale confidence level. Conspicuity of the lesion and clarity of tumor-to-pancreatic duct distance were graded. Receiver operating characteristic analysis was performed to compare diagnostic performance. Forty-seven patients were tumor positive, with 51 tumors. The differences between the areas under the curve values for tumor detection were as follows: 0.715 (CECT), 0.903 (VPCT), 0.832 (MRI without DWI) and 0.955 (MRI with DWI) for reader 1, and 0.738 (CECT), 0.895 (VPCT), 0.841 (MRI without DWI), and 0.956 (MRI with DWI) for reader 2. MRI with DWI and VPCT were significantly more accurate than CECT for insulinoma detection (P = 0.01 and 0.02 for reader 1, and P = 0.01 and 0.03 for reader 2). Lesion conspicuity was better on MRI compared with VPCT (P = 0.01), and both were better than CECT (both P < 0.01). Tumor-to-pancreatic duct distance was better appreciated on MRI, compared with CECT and VPCT (both P < 0.01). The weighted k values indicate good to excellent agreement between observers for determining tumor presence/absence (k = 0.64-0.84). The 3T MRI with DWI and VPCT are significantly more accurate than CECT for insulinoma detection. MRI demonstrates higher tumor conspicuity and is superior in depicting the tumor-to-duct distance. 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1648-1655.