Detection Of Insulinomas Research Articles

68Ga-exendin-4 PET/CT for the localization of insulinomas

Objective To determine whether glucagon-like peptide-1 (GLP-1) receptor PET/CT with 68Ga-exendin-4 is accurate in localizing insulinomas, by comparing with conventional imaging techniques. Methods In this prospective cohort study, patients with biochemically proven endogenous hyperinsulinemic hypoglycemia from March 2014 to November 2016 were recruited consecutively. 68Ga-exendin-4 PET/CT, CT, MRI, endoscopic ultrasound (EUS), and SSTR imaging were performed before elective surgery. Surgical pathology results were considered as the gold standard. Sensitivity based on patient-analysis and positive predictive value (PPV) based on lesion-analysis were calculated and compared using χ2 test and generalized score test. Results A total of 109 patients were recruited (47 males, 62 females; average age (45.1±14.8) years), and 96 of them with insulinomas proved pathologically were included in the main assessment. Thirteen patients with positive 68Ga-exendin-4 PET/CT findings did not undergo surgical intervention. Based on patient-analysis, the sensitivities of 68Ga-exendin-4 PET/CT, CT, MRI, EUS and SSTR imaging for detecting insulinomas were 98.96%(95/96), 81.25%(78/96), 79.41%(54/68), 81.40%(35/43) and 21.84%(19/87), respectively. Based on lesion-analysis, the PPV of the above 5 methods were 100%(102/102), 97.56%(80/82), 95.16%(59/62), 83.72%(36/43) and 90.48%(19/21), respectively. 68Ga-exendin-4 PET/CT showed the highest diagnostic sensitivity than others (all P<0.01) and higher PPV than MRI, EUS and SSTR imaging (all P<0.05). Conclusion 68Ga-exendin-4 PET/CT is a highly sensitive imaging technique for detection of insulinoma. Key words: Insulinoma; Positron-emission tomography; Tomography, X-ray computed; Glucagon-like peptide 1; Gallium radioisotopes

Sporadic insulinomas on volume perfusion CT: dynamic enhancement patterns and timing of optimal tumour-parenchyma contrast.

To assess enhancement patterns of sporadic insulinomas on volume perfusion CT (VPCT), and to identify timing of optimal tumour-parenchyma contrast. Consecutive patients who underwent VPCT for clinically suspected insulinomas were retrospectively identified. Patients with insulinomas confirmed by surgery were included, and patients with familial syndromes were excluded. Two radiologists evaluated VPCT images in consensus. Tumour-parenchyma contrast at each time point was measured, and timing of optimal contrast was determined. Time duration of hyperenhancement (tumour-parenchyma contrast >20 Hounsfield units, HU) was recorded. Perfusion parameters were evaluated. Three dynamic enhancement patterns were observed in 63 tumours: persistent hyperenhancement (hyperenhancement time window ≥10s) in 39 (61.9%), transient hyperenhancement (hyperenhancement <10s) in 19 (30.2%) and non-hyperenhancement in 5 (7.9%). Timing of optimal contrast was 9s after abdominal aorta threshold (AAT) of 200 HU, with tumour-parenchyma contrast of 77.6 ± 57.2 HU. At 9s after AAT, 14 (22.2%) tumours were non-hyperenhancing, nine of which had missed transient hyperenhancement. Insulinomas with transient and persistent hyperenhancement patterns had significantly increased perfusion. Insulinomas have variable enhancement patterns. Tumour-parenchyma contrast is time-dependent. Optimal timing of enhancement is 9s after AAT. VPCT enables tumour detection even if the hyperenhancement is transient. • Enhancement patterns of insulinomas are variable and tumour-parenchyma contrast is time-dependent. • An optimized single-phase scan found 77.8% tumours to be hyperenhancing. • Hyperenhancing tumours increase to 84.1% and 87.3% with biphasic/triphasic scan. • Volume perfusion CT enables detection of insulinomas with missed transient hyperenhancement.

Development of 111In-labeled exendin(9-39) derivatives for single-photon emission computed tomography imaging of insulinoma

Insulinoma is a tumor derived from pancreatic β-cells, and the resulting hyperinsulinemia leads to characteristic hypoglycemia. Recent studies have reported the frequent overexpression of glucagon-like peptide-1 receptor (GLP-1R) in human insulinomas, suggesting that the binding of a radiolabeled compound to GLP-1R is useful for the imaging of such tumors. Exendin(9-39), a fragment peptide of exendin-3 and -4, binds GLP-1R with high affinity and acts as an antagonist. Accordingly, radiolabeled exendin(9-39) derivatives have also been investigated as insulinoma imaging probes that might be less likely to induce hypoglycemia. In this study, we synthesized a novel indium-111 (111In)-benzyl-diethylenetriaminepentaacetic acid (111In-BnDTPA)-conjugated exendin(9-39), 111In-BnDTPA-exendin(9-39), and evaluated its utility as a probe for the SPECT imaging of insulinoma. natIn-BnDTPA-exendin(9-39) exhibited a high affinity for GLP-1R (IC50=2.5nM), stability in plasma, and a specific activity that improved following reactions with a solvent and solubilizer. Regarding the in vivo biodistribution of 111In-BnDTPA-exendin(9-39) in INS-1 tumor-bearing mice, high uptake levels were observed in tumors (14.6%ID/g at 15min), with corresponding high tumor-to-blood (T/B), tumor-to-muscle (T/M), and tumor-to-pancreas (T/P) ratios (T/B=2.55, T/M=22.7, T/P=2.7 at 1h). The pre-administration of excess nonradioactive exendin(9-39) significantly reduced accumulation in both the tumor and pancreas (76% and 68% inhibition, respectively) at 1h after 111In-BnDTPA-exendin(9-39) injection, indicating that the GLP-1R mediated a majority of 111In-BnDTPA-exendin(9-39) uptake in the tumor and pancreas. Finally, 111In-BnDTPA-exendin(9-39) SPECT/CT studies in mice yielded clear images of tumors at 30min post-injection. These results suggest that 111In-BnDTPA-exendin(9-39) could be a useful SPECT molecular imaging probe for the detection and exact localization of insulinomas.

Insulinoma Detection With MDCT: Is There a Role for Whole-Pancreas Perfusion?

The purpose of this study is to investigate the role of whole-pancreas perfusion in detecting insulinomas with the use of MDCT. From January 2011 to December 2011, a total of 70 consecutive patients (33 men and 37 women; mean age, 46 years; range, 17-73 years) who underwent biphasic contrast-enhanced CT and whole-pancreas CT perfusion for suspected insulinomas were identified retrospectively. Patients were monitored for at least 3 years. Two radiologists who were blinded to the clinical and surgical data independently evaluated the images, first assessing only the biphasic contrast-enhanced CT images to detect tumor and assess diagnostic confidence on a 5-point scale. Next, perfusion parametric maps were evaluated and pancreatic perfusion parameters measured, and the presence of tumor was reidentified using a combination of the biphasic CT and perfusion image sets. A ROC curve was generated to compare the diagnostic accuracy of the two image sets. The mean blood flow (BF) values of both the insulinomas and the insulinoma-harboring regions were statistically significantly higher (p < 0.01, for both) than the BF value of tumor-free pancreatic parenchyma. For the detection of insulinoma, biphasic CT had a sensitivity of 88.1%, a specificity of 85.7%, a positive predictive value of 91.1%, and a negative predictive value of 81.4%, whereas combined biphasic CT and perfusion had a sensitivity of 94.6%, a specificity of 94.7%, a positive predictive value of 96.7%, and a negative predictive value of 91.5%. The mean area under the ROC curve increased from 0.939 with biphasic CT to 0.999 with the addition of perfusion. Nine of 46 tumors (19.6%) for which findings were negative (n = 2) or indeterminate (n = 7) on biphasic CT were correctly diagnosed with the addition of perfusion. The addition of pancreatic perfusion to biphasic contrast-enhanced CT may improve the detection of insulinomas.

Carbidopa-assisted 18F-fluorodihydroxyphenylalanine PET/CT for the localization and staging of non-functioning neuroendocrine pancreatic tumors.

CD premedication was found to increase the value of 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT imaging in the detection of adult insulinoma. The aim of this study was to evaluate the performance of CD-assisted 18F-FDOPA PET/CT in the diagnosis and staging of non-functioning pNETs. Twenty consecutive patients with low-grade pNETs who underwent CD-assisted 18F-FDOPA PET/CT imaging and 111In-somatostatin receptor scintigraphy (SRS) were evaluated. Histology was considered as the gold standard. In case where no surgical resection was performed, the diagnosis of pNET was made by the confrontation of the different available imaging modalities. CD-assisted 18F-FDOPA PET/CT was positive in 18/20 cases (90%), whereas SRS was positive in 13/19 cases (68%). When considered the 19 patients underwent both nuclear medicine examinations, 18F-FDOPA PET/CT was significantly more sensitive then SRS for primary tumor detection (p=0.049). False-negative results of both 18F-FDOPA PET/CT and SRS were observed in 2 cystic pNETs. SRS failed to detect one additional cystic tumor and 3 pNETs of 10, 12 and 17mm, respectively. 18F-FDOPA PET/CT correctly identified all patients with lymphatic, visceral and bone metastases. SRS failed to detect lymphatic spread and was falsely negative in one patient with splenic metastasis. Contrary to widely held assumptions, our study further expands the application of CD-assisted 18F-FDOPA PET/CT for non-functioning pNETs when 68Ga-radiolabeled somatostatin analogs are not available.

FO-SPR based dextrose sensor using Ag/ZnO nanorods/GOx for insulinoma detection

In this piece of work, a fiber optic sensor has been fabricated and characterized using surface plasmon resonance for dextrose sensing. The concentration range used in this study is for diagnosing the cases of hypoglycaemia especially in suppression tests of insulinoma. Insulinoma is a medical case in which the person is recognized being hypoglycaemic with the blood dextrose level falling down to 2.2mM or less. Thus, the sensor has been characterized for the dextrose concentration range of 0 mM–10mM including the cases of normal blood dextrose range. Coatings of silver layer and zinc oxide nanorods have been carried out on the bare core fiber with a dual role of zinc oxide followed by immobilization of glucose oxidase. A three stage optimization procedure has been adopted for the best performance of the sensor. Absorbance spectra have been plotted and peak absorbance wavelengths have been extracted for each concentration chosen along with the sensitivities. The results have been made conclusive with control experiments. The probe has also been tested on sample having blood serum to check the reliability of the sensor. The sensor shows better selectivity and response time along with its real time applications, online monitoring, remote sensing and reusability.

Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers.

The glucagon-like peptide-1 (GLP-1) receptors are important biomarkers for imaging pancreatic β-cell mass and detection of benign insulinomas. Using GLP-1 receptor antagonists, we aimed to eliminate the insulin-related side effects reported for all GLP-1 receptor agonists. Additionally, using a nonresidualizing tracer, (125)I-Bolton-Hunter-Exendin(9-39)NH2 ((125)I-BH-Ex(9-39)NH2), we aimed to reduce the high kidney uptake, enabling a better detection of insulinomas in the tail and head of the pancreas. The affinity and biodistribution of Ex(9-39)NH2-based antagonists, modified with DOTA or NODAGA chelators at positions Lys(27) and Lys(40) and labeled with (68)Ga and (125)I-BH-Ex(9-39)NH2, were compared with the reference GLP-1 receptor agonist [Nle(14),Lys(40)(Ahx-DOTA-(68)Ga)NH2]Ex-4. The inhibitory concentration of 50% (IC50) values were determined using autoradiography on human tissues with (125)I-GLP-1(7-36)NH2 as a radioligand. Pharmacokinetics and PET imaging were studied in nude mice bearing rat Ins-1E tumors. Conjugation of DOTA and NODAGA chelators at positions Lys(27) and Lys(40) of Ex(9-39)NH2 resulted in a distinct loss of affinity toward GLP-1 receptor in vitro. Among the studied antagonists, [Lys(40)(NODAGA-(nat)Ga)NH2]Ex(9-39) showed the lowest IC50 value (46.7 ± 16.3 nM). The reference agonist [Nle(14),Lys(40)(Ahx-DOTA)NH2]Ex-4 demonstrated the highest affinity (IC50 = 0.9 ± 0.3 nM). Biodistribution of [Nle(14),Lys(40)(Ahx-DOTA-(68)Ga)NH2]Ex-4 at 1 h after injection demonstrated 40.2 ± 8.2 percentage injected activity per gram (%IA/g) uptake in Ins-1E tumor, 12.5 ± 2.2 %IA/g in the pancreas, and 235.8 ± 17.0 %IA/g in the kidney, with tumor-to-blood and tumor-to-kidney ratios of 100.52 and 0.17, respectively. Biodistribution of [Lys(40)(NODAGA-(68)Ga)NH2]Ex(9-39) showed only 2.2 ± 0.2 %IA/g uptake in Ins-1E tumor, 1.0 ± 0.1 %IA/g in the pancreas, and 78.4 ± 8.5 %IA/g in the kidney at 1 h after injection, with tumor-to-blood and tumor-to-kidney ratios of 7.33 and 0.03, respectively. In contrast, (125)I-BH-Ex(9-39)NH2 showed tumor uptake (42.5 ± 8.1 %IA/g) comparable to the agonist and 28.8 ± 5.1 %IA/g in the pancreas at 1 h after injection. As we hypothesized, the kidney uptake of (125)I-BH-Ex(9-39)NH2 was low, only 12.1 ± 1.4 %IA/g at 1 h after injection. The tumor-to-kidney ratio of (125)I-BH-Ex(9-39)NH2 was improved 20-fold. Our results suggest that iodinated Ex(9-39)NH2 may be a promising tracer for imaging GLP-1 receptor expression in vivo. Because of the 20-fold improved tumor-to-kidney ratio (125)I-BH-Ex(9-39)NH2 may offer higher sensitivity in the detection of insulinomas and imaging of β-cell mass in diabetic patients. Further studies with (124)I-BH-Ex(9-39)NH2 are warranted.

DIAGNOSTICS OF INSULINOMA AND NESIDIOBLASTOSIS AT THE SYNDROME OF HYPERINSULINISM

Insulinoma is the most frequently seen functional pancreatic neuroendocrine tumor. Materials and Methods: We conducted a retrospective review of 42 patients with pancreatic neuroendocrine neoplasms diagnosed pathomorpgologically and treated at the A. V. Vishnevsky Institute of Surgery, between 2011 and 2015. Results: The sensitivity in the detection of insulinoma was as follows: ultrasound - 62%, CT - 82%, MRI - 87,5%, endoscopic ultrasound - 83,3%, intraoperative ultrasound - 94,8%. Conclusions: The presence of the tumor before the operation must be confirmed by at least 2 instrumental diagnostic methods. Nesidioblastosis be suspected when a negative search result insulinoma all methods, but the final verification of the disease is possible only at the morphological study.

Preoperative localization of an insulinoma: selective arterial calcium stimulation test performance

Preoperative localization of an insulinoma is recommended to improve the cure rate, but non-invasive procedures can fail to detect the tumour. The objective of the study was to assess the performance of a selective arterial calcium stimulation test in the preoperative localization of insulinomas that were not detected by conventional imaging procedures. We conducted a monocenter retrospective case review of 13 patients who had endogenous hyperinsulinism and were treated between 1994 and 2013. Patients were selected on the basis of negative or doubtful non-invasive preoperative imaging. A selective arterial calcium stimulation test was performed by pancreatic and hepatic arteriography with selective intra-arterial calcium stimulation and hepatic venous sampling in order to obtain the plasma insulin measurement. We evaluated the efficacy of the test by comparing the results with an endoscopic ultrasound. Twelve of the 13 patients underwent surgery, and the presence of an insulinoma was proven in 11 patients by pathological analysis of the tumour. An endoscopic ultrasound was consistent with surgery in 71.4 % of cases, while selective arterial calcium stimulation was consistent with surgery in 90.9 % and allowed detection of an insulinoma in two additional patients with a negative endoscopic ultrasound. One false-negative and one false-positive arterial calcium test were observed. No adverse events were recorded except transient skin flush following calcium injection in one patient. The selective arterial calcium stimulation test is a sensitive diagnostic procedure for localizing insulinomas and may be considered when non-invasive radiological imaging does not allow the detection of an occult insulinoma.

Localization of Hidden Insulinomas with ⁶⁸Ga-DOTA-Exendin-4 PET/CT: A Pilot Study.

(111)In-DOTA-exendin-4 SPECT/CT has been shown to be highly efficient in the detection of insulinomas. We aimed at determining whether novel PET/CT imaging with [Nle(14),Lys(40)(Ahx-DOTA-(68)Ga)NH2]exendin-4 ((68)Ga-DOTA-exendin-4) is feasible and sensitive in detecting benign insulinomas. (68)Ga-DOTA-exendin-4 PET/CT and (111)In-DOTA-exendin-4 SPECT/CT were performed in a randomized cross-over order on 5 patients with endogenous hyperinsulinemic hypoglycemia. The gold standard for comparison was the histologic diagnosis after surgery. In 4 patients histologic diagnosis confirmed a benign insulinoma, whereas one patient refused surgery despite a positive (68)Ga-DOTA-exendin-4 PET/CT scan. In 4 of 5 patients, previously performed conventional imaging (CT or MR imaging) was not able to localize the insulinoma. (68)Ga-DOTA-exendin-4 PET/CT correctly identified the insulinoma in 4 of 4 patients, whereas (111)In-DOTA-exendin-4 SPECT/CT correctly identified the insulinoma in only 2 of 4 patients. These preliminary data suggest that the use of (68)Ga-DOTA-exendin-4 PET/CT in detecting hidden insulinomas is feasible.

Early-phase thin-slice CT in the diagnosis of small insulinomas.

Insulinomas, which are generally smaller than 2 cm, may be difficult to detect by routine imaging modalities including abdominal ultrasonography, computed tomography, and magnetic resonance imaging. Although preoperative detection of insulinomas is essential for operative planning, it is often challenging due to their small size. While arterial stimulation and venous sampling has been used in patients with insulinomas it has been largely supplanted by early-phase thin-slice computed tomography. We report three patients with insulinomas, which were not detected by routine computed tomography scan, but were successfully imaged using early-phase thin-slice computed tomography. Enucleation was performed in all patients based on preoperative imaging. All three patients had an unremarkable postoperative course. Early-phase thin-slice computed tomography is recommended for the preoperative identification of insulinomas. This non-invasive imaging technique should be considered before performing arterial stimulation and venous sampling.

18F-FDOPA PET/CT imaging of insulinoma revisited

(18)F-FDOPA PET imaging is increasingly used in the work-up of patients with neuroendocrine tumours. It has been shown to be of limited value in localizing pancreatic insulin-secreting tumours in adults with hyperinsulinaemic hypoglycaemia (HH) mainly due to (18)F-FDOPA uptake by the whole pancreatic gland. The objective of this study was to review our experience with (18)F-FDOPA PET/CT imaging with carbidopa (CD) premedication in patients with HH in comparison with PET/CT studies performed without CD premedication in an independent population. A retrospective study including 16 HH patients who were investigated between January 2011 and December 2013 using (18)F-FDOPA PET/CT (17 examinations) in two academic endocrine tumour centres was conducted. All PET/CT examinations were performed under CD premedication (200mg orally, 1-2h prior to tracer injection). The PET/CT acquisition protocol included an early acquisition (5min after (18)F-FDOPA injection) centred over the upper abdomen and a delayed whole-body acquisition starting 20-30min later. An independent series of eight consecutive patients with HH and investigated before 2011 were considered for comparison. All patients had a reference whole-body PET/CT scan performed about 1h after (18)F-FDOPA injection. In all cases, PET/CT was performed without CD premedication. In the study group, (18)F-FDOPA PET/CT with CD premedication was positive in 8 out of 11 patients with histologically proven insulinoma (73%). All (18)F-FDOPA PET/CT-avid insulinomas were detected on early images and 5 of 11 (45%) on delayed ones. The tumour/normal pancreas uptake ratio was not significantly different between early and delayed acquisitions. Considering all patients with HH, including those without imaging evidence of disease, the detection rate of the primary lesions using CD-assisted (18)F-FDOPA PET/CT was 53%, showing 9 insulinomas in 17 studies performed. In the control group (without CD premedication, eight patients), the final diagnosis was benign insulinoma in four, nesidioblastosis in one, and no definitive diagnosis in the remainder. (18)F-FDOPA PET/CT failed to detect any tumour in these patients. According to our experience, CD administration before (18)F-FDOPA injection leads to low residual pancreatic (18)F-FDOPA activity preserving tumoral uptake with consequent insulinoma detection in more than half of adult patients with HH and more than 70% of patients with a final diagnosis of insulinoma. If (18)F-FDOPA PET/CT is indicated, we strongly recommend combining CD premedication with early acquisition centred over the pancreas.

99mTc-GLP-1 scintigraphy, an efficient method for the detection of insulinoma: results of 3 years' experience

99mTc-GLP-1 scintigraphy, an efficient method for the detection of insulinoma: results of 3 years' experience

Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study

Small benign insulinomas are hard to localise, leading to difficulties in planning of surgical interventions. We aimed to prospectively assess the insulinoma detection rate of single-photon emission CT in combination with CT (SPECT/CT) with a glucagon-like peptide-1 receptor avid radiotracer, and compare detection rates with conventional CT/MRI techniques. In our prospective imaging study, we enrolled adults aged 25-81 years at centres in Germany, Switzerland, and the UK. Eligible patients had proven clinical and biochemical endogenous hyperinsulinaemic hypoglycaemia and no evidence for metastatic disease on conventional imaging. CT/MRI imaging was done at referring centres according to standard protocols. At three tertiary nuclear medicine centres, we used whole body planar images and SPECT/CT of the abdomen up to 168 h after injection of (111)In-[Lys40(Ahx-DTPA-(111)In)NH2]-exendin-4 ((111)In-DTPA-exendin-4) to identify insulinomas. Consenting patients underwent surgery and imaging findings were confirmed histologically. Between Oct 1, 2008, and Dec 31, 2011, we recruited 30 patients. All patients underwent (111)In-DTPA-exendin-4 imaging, 25 patients underwent surgery (with histological analysis), and 27 patients were assessed with CT/MRI. (111)In-DTPA-exendin-4 SPECT/CT correctly detected 19 insulinomas and four additional positive lesions (two islet-cell hyperplasia and two uncharacterised lesions) resulting in a positive predictive value of 83% (95% CI 62-94). One true negative (islet-cell hyperplasia) and one false negative (malignant insulinoma) result was identified in separate patients by (111)In-DTPA-exendin-4 SPECT/CT. Seven patients (23%) were referred to surgery on the basis of (111)In-DTPA-exendin-4 imaging alone. For 23 assessable patients, (111)In-DTPA-exendin-4 SPECT/CT had a higher sensitivity (95% [95% CI 74-100]) than did CT/MRI (47% [27-68]; p=0.011). (111)In-DTPA-exendin-4 SPECT/CT could provide a good second-line imaging strategy for patients with negative results on initial imaging with CT/MRI. Oncosuisse, the Swiss National Science Foundation, and UK Department of Health.

Proteins differentially expressed in human beta-cells-enriched pancreatic islet cultures and human insulinomas

In view of the great demand for human beta-cells for physiological and medical studies, we generated cell lines derived from human insulinomas which secrete insulin, C-peptide and express neuroendocrine and islet markers. In this study, we set out to characterize their proteomes, comparing them to those of primary beta-cells using DIGE followed by MS. The results were validated by Western blotting. An average of 1800 spots was detected with less than 1% exhibiting differential abundance. Proteins more abundant in human islets, such as Caldesmon, are involved in the regulation of cell contractility, adhesion dependent signaling, and cytoskeletal organization. In contrast, almost all proteins more abundant in insulinoma cells, such as MAGE2, were first described here and could be related to cell survival and resistance to chemotherapy. Our proteomic data provides, for the first time, a molecular snapshot of the orchestrated changes in expression of proteins involved in key processes which could be correlated with the altered phenotype of human beta-cells. Collectively our observations prompt research towards the establishment of bioengineered human beta-cells providing a new and needed source of cultured human beta-cells for beta-cell research, along with the development of new therapeutic strategies for detection, characterization and treatment of insulinomas.

Disorders of glucose metabolism–post mortem analyses in forensic cases: part I

In developed countries, diabetes is one of the ten most common causes of death. Post mortem diagnosis of glucose metabolism disorders can be difficult and vague because of the lack of characteristic morphological findings. Reviews of the literature are presented concerning biochemical problems in cases of unclear hyper- or hypoglycemia. After repetition of causes, frequency, and mortality of diabetic metabolism disorders, we give hints for the detection of diabetic ketoacidosis, hyperosmolar coma, insulinoma, and insulin- or oral diabetic-induced hypoglycemia. The first part discusses the analytes glucose and lactate, glycated proteins and oral antidiabetics, with special regard to their matrices post mortem, to reference concentrations, stability data and to analytic procedures that should be used in clinical or toxicological laboratories to detect diabetic metabolism disorders after death.

68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET

PurposeInsulinomas are neuroendocrine tumours derived from pancreatic β-cells. The glucagon-like peptide 1 receptor (GLP-1R) is expressed with a high incidence (>90%) and high density in insulinomas. Glucagon-like peptide 1 (GLP-1), the natural ligand of GLP-1R, is rapidly degraded in vivo. A more stable agonist of GLP-1R is exendin-3. We investigated imaging of insulinomas with DOTA-conjugated exendin-3 labelled with 68Ga.MethodsTargeting of insulinomas with [Lys40(DOTA)]exendin-3 labelled with either 111In or 68Ga was investigated in vitro using insulinoma tumour cells (INS-1). [Lys40(111In-DTPA)]Exendin-3 was used as a reference in this study. In vivo targeting was investigated in BALB/c nude mice with subcutaneous INS-1 tumours. PET imaging was performed using a preclinical PET/CT scanner.ResultsIn vitro exendin-3 specifically bound and was internalized by GLP-1R-positive cells. In BALB/c nude mice with subcutaneous INS-1 tumours a high uptake of [Lys40(111In-DTPA)]exendin-3 in the tumour was observed (33.5 ± 11.6%ID/g at 4 h after injection). Uptake was specific, as determined by coinjection of an excess of unlabelled [Lys40]exendin-3 (1.8 ± 0.1%ID/g). The pancreas also exhibited high and specific uptake (11.3 ± 1.0%ID/g). High uptake was also found in the kidneys (144 ± 24%ID/g) and this uptake was not receptor-mediated. In this murine tumour model optimal targeting of the GLP-1R expressing tumour was obtained at exendin doses ≤0.1 µg. Remarkably, tumour uptake of 68Ga-labelled [Lys40(DOTA)]exendin-3 was lower (8.9 ± 3.1%ID/g) than tumour uptake of 111In-labelled [Lys40(DTPA)]exendin-3 (25.4 ± 7.2%ID/g). The subcutaneous tumours were clearly visualized by small-animal PET imaging after injection of 3 MBq of [Lys40(68Ga-DOTA)]exendin-3.Conclusion[Lys40(68Ga-DOTA)]Exendin-3 specifically accumulates in insulinomas, although the uptake is lower than that of [Lys40(111In-DTPA)]exendin-3. Therefore, [Lys40(68Ga-DOTA)]exendin-3 is a promising tracer to visualize insulinomas with PET.

Does conventional abdominal preoperative ultrasonography have a role in the detection of pancreatic insulinoma? A case report

Combinations of strategies as MRI, endoscopic sonography, selective arteriography, were the first choice for the detection of pancreatic insu-linoma. In these proposal, therefore, abdominal was not in- cluded at all. Case presentation: a 78-year-old no diabetic women was referred to us because fasting hypoglycemic symptoms. The clinical and laboratory findings suggested an insulinoma. Abdominal ultrasound showed a small solid mass in the head-istmus pancreatic tract. Conclusion: the solid mass was confirmed with a contrast-enhanced- computed tomogra-phy of the abdomen. A surgical enucleation of the tumor was achieved by laparoscopy and histological examination of the specimen estab-lished a diagnosis of insulinoma. This case re-inforced the value of the conventional trans- abdomen ultrasound in addition to accuracy of anamneses and biochemical tests as the first step in the hospital clinical setting for man-agement of pancreatic insulinoma, reserving as the second step more expensive and invasive-ness techniques.

Multiple pancreatic insulinomas: multislice CT

Imaging techniques are in permanent evolution and so are their respective sensitivities. We present a case of a patient who had three abdominal CT scans over 10 years for the detection of pancreatic insulinomas. The first was made on an incremental CT and showed no lesion, the second on a single-slice helical CT which revealed a single centimetric tumor of the head of the pancreas, and the third on 64-slice CT which revealed 5 infracentimetric tumors. We do not know if all were present at the first scan but it is possible that these small tumors could have been missed on thick CT scan slices with overlap. The ideal imaging technique for the detection of endocrine pancreatic tumor is not known yet. The detection rates in the latest publications are 80% for CT scans and 70% for MRI, but there is a slight preference for CT scan because of its larger availability and higher resolution.

The value of multidetector-row CT in the preoperative detection of pancreatic insulinomas

The authors sought to quantitatively analyse enhancement characteristics of pancreatic insulinomas in different phases and determine the value of multidetector-row computed tomography (CT) for detecting insulinomas. Forty-six patients with surgically proven insulinomas diagnosed between 2002 and 2007 were retrospectively reviewed. These patients underwent single-phase (group 1) or dual-phase (group 2) helical CT scanning. Sensitivity for detecting insulinomas in group 2 was superior to that in group 1 (p<0.05).The sensitivity for insulinoma detection in the arterial phase was superior to that in the portal-venous phase (p<0.05). The mean attenuation values of the insulinomas and normal pancreas during the unenhanced arterial and portal-venous phases were, respectively, 40.5+/-8.75 HU (Hounsfield units), 114.48+/-27.30 HU, 112.19+/-19.52 HU and 44.56+/-6.48 HU, 81.16+/-15.22 HU, 90.54+/-13.80 HU, and there was statistical difference between them (p=0.000). The contrast enhancement of insulinomas in the arterial and portal-venous phases was 74.03+/-29.51 HU and 70.90+/-21.93 HU, respectively, and there was no statistical difference between them (p=0.499). The tumour to normal-pancreas attenuation differences in the arterial and portal-venous phases were respectively 33.32+/-20.96 HU and 20.58+/-16.32 HU, respectively, and there was statistical difference between them (p=0.011). Dual-phase CT has a promising sensitivity in detecting pancreatic insulinomas. The acquisition of images in the arterial phase is more helpful for detecting insulinomas.