Follow-up Of Neuroendocrine Tumors Research Articles

Spectral Computed Tomography-Derived Iodine Content and Tumor Response in the Follow-Up of Neuroendocrine Tumors-A Single-Center Experience.

Spectral computed tomography (SCT) allows iodine content (IC) calculation for characterization of hypervascularized neoplasms and thus might help in the staging of neuroendocrine tumors (NETs). This single-center prospective study analyzed the association between SCT-derived IC and tumor response in the follow-up of metastasized NETs. Twenty-six patients with a median age of 70 years (range 51-85) with histologically proven NETs and a total of 78 lesions underwent SCT for staging. Because NETS are rare, no primary NET types were excluded. Lesions and intralesional hotspots were measured in virtual images and iodine maps. Tumor response was classified as progressive or nonprogressive at study endpoint. Generalized estimating equations served to estimate associations between IC and tumor response, additionally stratified by lesion location. Most commonly affected sites were the lymph nodes, liver, pancreas, and bones. Median time between SCT and endpoint was 64 weeks (range 5-260). Despite statistical imprecision in the estimate, patients with higher IC in lymphonodular metastases had lower odds for disease progression (adjusted OR = 0.21, 95% CI: 0.02-2.02). Opposite tendencies were observed in hepatic and pancreatic metastases in unadjusted analyses, which vanished after adjusting for therapy and primary tumor grade.

Role of Chromogranin A in the Diagnosis and Follow-up of Neuroendocrine Tumors

The aim of this study was to assess the utility of serum chromogranin A (CgA) along the clinical pathway of patients with neuroendocrine tumors (NETs). A retrospective review of medical records was conducted of patients with NET who had at least 1 measurement of CgA between January 2015 and April 2021 at a large metropolitan Australian hospital. Chromogranin A was classified as increased or decreased if there was at least a 25% change in sequential levels and was compared with disease response by anatomical or functional imaging if within 6 weeks (considered concurrent). Of 102 patients with NETs, 67 had at least 1 serum CgA level: 50 had been ordered during diagnostic workup, of which 33 were elevated (sensitivity: 66%; 95% confidence interval, 51%-79%). Of 129 CgA results concurrent with imaging, the sensitivity for detecting progressive disease was 28% (95% confidence interval, 15%-44%). Our findings support previous concerns that CgA adds little value in clinical decision-making.

Diagnostic and prognostic value of 99mTc-Tektrotyd scintigraphy and 18F-FDG PET/CT in a single-center cohort of neuroendocrine tumors.

The aim was to assess the diagnostic value of 99mTc-Tektrotyd scintigraphy (TCT) and positron emission tomography/computed tomography using F-18 fluorodeoxyglucose (18F-FDG PET/CT) in the detection and follow-up of neuroendocrine tumors (NETs), and their predictive value for disease progression. In this retrospective cohort, TCT and 18F-FDG PET/CT were performed in 90 patients (37 men, 53 women, mean age 52.7 ±15.1), with NET. Correlation of Ki67 and tumor grade versus Krenning score and SUVmax was assessed, Kaplan-Meier analysis was used for progression-free survival (PFS), and Cox regression analysis was performed to identify the association between progression-related factors and PFS. Out of 90, true positive TCT was detected in 56 (62.2%) patients, true negative in 19 (21.1%), false positive in 4 (4.4%), false negative in 11 (12.2%), while 18F-FDG PET/CT was true positive in 69 (76.7%) patients, true negative in 10 (11.1%), false positive in 5 (5.5%), false negative in 6 (6.7%). Mean 18F-FDG PET/CT SUVmax was 6.8 ±6.2. Diagnostic sensitivity of TCT was 83.6%, specificity 82.6%, accuracy 83.3% vs. 18F-FDG PET/CT sensitivity was 92.0%, specificity 66.7%, accuracy 87.8%. A significant correlation between Ki67 and SUVmax was found in positive 18F-FDG PET/CT findings, unlike the correlation between Ki67 and Krenning score. Median PFS was 25 months (95% CI: 18.2-31.8), in 18F-FDG PET/CT positive patients 23 months (95% CI: 16.3-29.7) and 18F-FDG PET/CT negative 26 months (p = 0.279). Progression-free survival predictors were SUVmax and Krenning score. In our study, TCT and 18F-FDG PET/CT have high diagnostic accuracy in detection of NET. Higher Krenning score on TCT and SUVmax in positive 18F-FDG PET/CT findings are predictors of disease progression. 99mTc-Tektrotyd scintigraphy and 18F-FDG PET/CT can be useful complementary tools in management of patients with NETs and in predicting patients' outcome.

Evaluation of three commercially available ELISA kits for the determination of chromogranin A

ABSTRACT Chromogranin A (CgA) is currently the most valuable tumor biomarker for diagnostic work-up, management and follow-up of neuro-endocrine tumors (NET). The aim of our study was to compare three different commercially available CgA ELISA kits and to evaluate their analytical and clinical performance. CgA was measured with three different commercial ELISA kits on leftover sera from 40 patients: Chromoa R assay (Cis), Hu chromogranin A ELISA (Dia), and Neolisa chromogranin A (Euro). Analytical and clinical performance was evaluated by measuring precision, area under the ROC curve, sensitivity, specificity, positive and negative predictive value, correlation coefficients and Passing and Bablok regression analyses. Precision (CV%) was acceptable for all evaluated ELISA’s (Cis 10.3%; Dia 9.8%; Euro 14.5%). The area under the curve (AUC) was comparable between the three assays (Cis 0.693; Dia 0.627; Euro 0.721). Sensitivity varied between 41.2% and 64.7%. Specificity ranged between 69.6% and 82.6%. Pairwise comparison revealed significant systematic and proportional differences when comparing Cis versus Dia (Cis = 25.30 + 1.94 Dia) and Euro versus Dia (Euro = 26.54 + 1.92 Dia). Analytical and clinical performance was comparable for the three ELISA’s. CgA results obtained with different ELISA’s are not interchangeable. Abbreviations CgA: Chromogranin A; ELISA: Enzyme-linked immunosorbent assay; IRMA: Immunoradiometric assay; NET: Neuroendocrine tumors; PPI: Proton-pump inhibitors; RIA: Radioimmunoassay

In Matrix Derivatization Combined with LC-MS/MS Results in Ultrasensitive Quantification of Plasma Free Metanephrines and Catecholamines.

Plasma-free metanephrines and catecholamines are essential markers in the biochemical diagnosis and follow-up of neuroendocrine tumors and inborn errors of metabolism. However, their low circulating concentrations (in the nanomolar range) and poor fragmentation characteristics hinder facile simultaneous quantification by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Here, we present a sensitive and simple matrix derivatization procedure using propionic anhydride that enables simultaneous quantification of unconjugated l-DOPA, catecholamines, and metanephrines in plasma by LC-MS/MS. Dilution of propionic anhydride 1:4 (v/v) in acetonitrile in combination with 50 μL of plasma resulted in the highest mass spectrometric response. In plasma, derivatization resulted in stable derivatives and increased sensitivity by a factor of 4–30 compared with a previous LC-MS/MS method for measuring plasma metanephrines in our laboratory. Furthermore, propionylation increased specificity, especially for 3-methoxytyramine, by preventing interference from antihypertensive medication (β-blockers). The method was validated according to international guidelines and correlated with a hydrophilic interaction LC-MS/MS method for measuring plasma metanephrines (R2 > 0.99) and high-performance liquid chromatography with an electrochemical detection method for measuring plasma catecholamines (R2 > 0.85). Reference intervals for l-DOPA, catecholamines, and metanephrines in n = 115 healthy individuals were established. Our work shows that analytes in the subnanomolar range in plasma can be derivatized in situ without any preceding sample extraction. The developed method shows improved sensitivity and selectivity over existing methods and enables simultaneous quantification of several classes of amines.

Quantitative Profiling of Platelet-Rich Plasma Indole Markers by Direct-Matrix Derivatization Combined with LC-MS/MS in Patients with Neuroendocrine Tumors.

Currently, several indole markers are measured separately to support diagnosis and follow-up of patients with neuroendocrine tumors (NETs). We have developed a sensitive mass spectrometry method that simultaneously quantifies all relevant tryptophan-related indoles (tryptophan, 5-hydroxytryptophan, serotonin, 5-hydroxyindoleacetic acid) in platelet-rich plasma. Direct-matrix derivatization was used to make the chemical properties of the indoles uniform and to improve the analytical sensitivity and specificity of the assay. In situ derivatization was performed directly in platelet-rich plasma with propionic anhydride at an ambient temperature. The derivatized indoles were extracted by online solid-phase extraction and eluted to the analytical column for separation followed by mass spectrometric detection. The method was validated according to international guidelines. Platelet-rich plasma samples from 68 healthy individuals and 40 NET patients were analyzed for tryptophan, 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid. The method reproducibly quantified relevant indoles in 8.5 min, including online sample cleanup. Intra- and interassay imprecision, evaluated at 3 different concentrations, ranged from 2.0% to 12% and 1.9% to 13%, respectively. The limit of quantification was sufficient to measure endogenous concentrations of all 4 indoles. Healthy individuals and NET patients had different concentrations of 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid, but tryptophan concentrations were the same. Direct-matrix derivatization in combination with LC-MS/MS is a powerful tool for the simultaneous quantification of all tryptophan-related indoles in platelet-rich plasma. Simultaneous profiling of relevant indoles improves the biochemical characterization and follow-up of NETs.

A serum and platelet-rich plasma serotonin assay using liquid chromatography tandem mass spectrometry for monitoring of neuroendocrine tumor patients

BackgroundSerotonin is used for the diagnosis and follow-up of neuroendocrine tumors (NET). We describe the analytical and clinical validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) based serotonin assay for serum and platelet-rich plasma (PRP). MethodsAn LC-MS/MS based method for serum and PRP serotonin was validated by determination of assay imprecision, carry-over, linearity, interference, recovery, sample stability and a matrix/method comparison of serum and PRP serotonin was made with whole blood serotonin. Furthermore, upper limits of normal were determined and serotonin concentrations of healthy individuals, 14 NET patients without evidence of disease and 51 NET patients with evidence of disease were compared. ResultsFor serum and PRP fractions, total assay imprecision was <5%. All correlation coefficients were 0.98 and the serum and platelet-rich serotonin upper limit of normal were 5.5nmol/109 platelet and 5.1nmol/109 platelet, respectively. NET patients with confirmed evidence of disease had significantly higher serum and PRP serotonin levels when compared to NET patients without evidence of disease and healthy volunteers. ConclusionsLC-MS/MS based serum and PRP serotonin assays were developed with suitable analytical characteristics. Furthermore, serum and PRP serotonin was found to be useful for monitoring NET patients.

Clinical diagnostic utility of a blood-based multi-transcriptome assay for gastroenteropancreatic disease.

4106 Background: Current blood-based biomarkers for the diagnosis and follow-up of neuroendocrine tumors (NETs) do not achieve acceptable metrics of sensitivity and specificity. We report the sensi...

PTH-093 Chromogranin-a : Can It Predict Radiological Progression In Neuroendocrine Tumours?

IntroductionChromogranin A (CgA) is considered as the best general marker for the diagnosis and follow-up of neuroendocrine tumours (NETs) and is also of prognostic value. In literature, there are no...

Sa1935 Variation and Utility Ofchromogranin a Assays for Gastric Carcinoid Type 1

Introduction: Chromogranin A (CgA) is considered as the best and most sensitive general marker for the diagnosis and follow-up of neuroendocrine tumors (NETs) and is also of prognostic value. However, there are no available studies to date, which analysed the role of CgA as a predictor of radiological disease progression in all NETs. Aim: To investigate the prognostic value of CgA as a predictor of radiological disease progression in NET patients. Methods: Patients with metastatic NETs and evidence of Radiological Progression (RP) according to Radiological Evaluation Criteria In Solid Tumors (RECIST 1.1) were identified from our NETs database. Plasma CgA were measured 6 and 12 months before RP and at the event of RP. CgA was measured with the Supra-regional-Assay-Service radioimmunoassay (Hammersmith Hospital). In our laboratory, the reference value of CgA has been established as 20%). Results: 152 patients were evaluable including 91 midgut NETs (mNETs) and 61 pancreatic NETs (PNETs). Of these, 56 were G1 NETs, 65 G2, 10 G3, 21 of unknown histology. The majority of the patients (95.4%) had liver metastases, whereas bone and lung metastases were present in a smaller proportion of patients (27.6% and 9.9%, respectively). Median CgA for all NETs, 6 months before RP,

Analytical and preanalytical validation of a new mass spectrometric serum 5-hydroxyindoleacetic acid assay as neuroendocrine tumor marker

BackgroundSerum 5-hydroxyindoleacetic acid (5-HIAA) could replace the determination of 24-h urinary 5-HIAA for diagnosis and follow-up of neuroendocrine tumors (NETs). We developed and validated a straightforward liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for serum 5-HIAA. MethodsWe used serum samples from healthy volunteers (n=136) and patients suspected or followed for NET (n=129). Samples were spiked with 5-HIAA-D2, extracted and quantified by LC-MS/MS. We studied the effects of sample storage, sample device, a meal and diurnal variation on serum 5-HIAA. Furthermore, we established a reference range for serum 5-HIAA and compared our assay with a urinary 5-HIAA HPLC assay and a commercial plasma chromogranin A (CgA) immunoassay. ResultsOur LC-MS/MS assay is sensitive (LOQ 5nmol/L), has a wide assay range (5–10,000nmol/L) and short analysis time (7min). 5-HIAA in serum is stable for several days in various temperatures and during five freeze–thaw cycles. We found no diurnal variation (p≥0.20) and a meal had no effect on serum 5-HIAA (p=0.89). We suggest an upper reference limit of 123nmol/L for serum 5-HIAA. The area under curve (AUC) in receiver operator characteristics (ROC) analysis was 0.83 for urinary 5-HIAA, 0.81 for serum 5-HIAA and 0.76 for CgA, respectively. ConclusionsThe LC-MS/MS assay for serum 5-HIAA discriminates between healthy individuals and patients with NET and is well suited for the diagnosis and follow-up of NETs.

Evolving Role of SPECT/CT in Neuroendocrine Tumors Management

The combined use of SPECT and CT strongly supports the molecular imaging of neuroendocrine tumors (NETs) with somatostatin receptor radiopharmaceuticals or with meta-iodobenzylguanidine. SPECT/CT fusion images provide potential attenuation correction, higher specificity, and accurate localization for the staging, evaluation of treatment response, and follow-up of NETs.

Registry of Neuroendocrine Tumors (NET) in Czech Republic After Th ree Years of Data Collection

Neuroendocrine tumors are traditionally considered to be "rare" diseases. On contrary, the prevalence of neuroendocrine tumors is high. Therefore, the diagnostics, treatment and follow-up of neuroendocrine tumors are subjected to an evolving interest. There are various specifics of neuroendocrine tumors requiring an appropriate feedback of each intervention i.e. data collection and central data evaluation. The "Cooperative Group for Neuroendocrine Tumors" (KSPNN) has been conducting a nationwide neuroendocrine tumors registry since June 2009. The first data summary after three years is aimed at evaluation of feasibility and data utility. The anonymous data on diagnostics, therapy and follow up of patients with neuroendocrine tumors of any primary site are collected in the registry. The contribution is conditioned by morphologically proven diagnosis according to the current WHO 2010 classification, in earlier cases WHO 2000 classification. The registry is operated by the Institute of Biostatistics and Analyses, Masaryk University (Brno). The initial analysis includes data from June 2009 to October 2012. Data of a substantial share of neuroendocrine tumor carriers have been collected - 742 subjects with a valid record, i.e. about 14% of presumed prevalence. Moreover, the registry covers nearly one fourth of incidence in the period 2009- 2011. The morphological diagnoses with the sign of nonspecific "neuroendocrine tumors" comprise the majority of records (75%); the most frequent is "carcinoid tumor neuroendocrine tumors". This results in a clear requirement for more detailed specifications of morphology as well as separation of small cell (neuroendocrine) carcinoma possessing principal bio-logic differences to neuroendocrine tumors itself. There is an apparent polarity of recorded clinical stages. Both stage I and stage IV comprise 30% of the records. This result is presumably related to how the diagnosis is established, either early and incidentally in initial stage or late with a developed endocrine symptomatology, in advanced stage. There is an evident selection bias. The treatment data reflect current trends, dominance of surgical therapy including reasonable cytoreductive surgery, vast use of somatostatine analogues in advanced disease and persistent position of chemotherapy for high grade tumors. The distribution of treatment modalities in the records documents a certain adherence to international treatment standards (ENETS, ESMO, NCCN). The dynamics of data contributions confirm feasibility of data collection in the registry. The registry reveals a clear requirement for more detailed analyses of biopsies and more detailed disease morphology classification. In the near future, the registry is aimed to maintain the increasing volume of collected data and to cover the majority of neuroendocrine tumors incidence.

Iodine-131MIBG SPECT/CT in neuroendocrine tumours: An institutional experience

Context:Radiolabelled metaiodobenzylguanidine (MIBG) is commonly used for imaging of neuroendocrine tumors (NETs). The hybrid imaging with single photon emission computerized tomography/computerized tomography (SPECT/CT) co-registration can give that additional edge to this functional imaging modality.Aims:To study the additional value of 131I-MIBG SPECT/CT scintigraphy in evaluation of NETs.Settings and Design:We performed a retrospective study of the scintigraphic data of patients referred to our department for detection and follow-up of NETs from 2004 to 2008.Materials and Methods:Total number of studies were 370. Twenty-eight patients with equivocal findings on planar imaging had undergone additional SPECT/CT imaging. The contribution made by SPECT/CT imaging in these studies was analyzed.Results:In 27 of 28 cases, SPECT/CT provided vital additional information.Conclusions:We concluded that SPECT/CT co-registration helps in exclusion, identification, and localization of primary and metastatic NETs. It differentiates physiological from pathological tracer distribution. It helps increase the confidence in reporting, especially in equivocal findings on planar imaging.

Nuclear oncology in Cancer Imaging 2011

Nuclear oncology featured strongly in the 2011 issue of Cancer Imaging with 5 reviews, 2 original articles and 3 case reports. Many articles described diagnostic applications of novel or emerging tracers. Stomatostatin receptor scintigraphy provided the focus of 2 original articles and a case report. Jindal et al.[1] (New Delhi, India) evaluated of the role of [18F]FDG-PET/CT and [68Ga]DOTATOC-PET/CT in 20 patients with pulmonary carcinoids and concluded that the different uptake patterns of the 2 tracers and the ratio of measured uptake may be helpful in differentiating between typical and atypical carcinoids. A case report of concomitant lung and gastroenteropancreatic neuroendocrine tumours by Kaemmerer et al.[2] (Bad Berka, Germany) highlighted the utility of gallium-68 somatostatin receptor PET/CT based detection and follow-up of neuroendocrine tumours. A study by Beauregard et al.[3] (Quebec City, Canada) described the development of a quantitative 177Lu SPECT imaging method using a commercially available SPECT/CT system. The authors highlighted the potential for the technique to yield more accurate dosimetry estimates and facilitate therapeutic response assessment for therapeutic agents such [177Lu]octreotate. A case report by Holter et al.[4] (Oklahoma City, USA) illustrates the utility of [18F]fluorothymidine-PET imaging in the diagnosis of leptomeningeal involvement with diffuse large B-cell lymphoma. Tracers such as [18F]fluorthymidine that depict proliferation, as well as hypoxia markers such as 18F-labelled fluorinated imidazoles, are also highlighted by ICIS fellow Wim Oyen (Nijmegen, The Netherlands) in his review of the prospects for molecular imaging in the Special Issue in which he explores the role of PET beyond FDG for patient selection, treatment modification and adaptation and early response monitoring following radiotherapy[5]. The use of the more widely used PET tracer [18F]fluorodeoxyglucose is considered in 3 articles related to thoracic malignancies. Kaira et al.[6] (Shizuoka, Japan) systematically reviewed the role of [18F]FDG-PET in thymic epithelial tumours and concluded that [18F]FDG-PET may be useful in differentiating thymomas and thymic carcinomas. A case report by Akosman et al.[7] (Istanbul, Turkey) entitled Unicentric mixed variant Castleman disease associated with Hashimoto disease: the role of PET/CT in staging and evaluating response to the treatment proposes a potential role for [18F]FDG-PET/CT not only in staging Castleman disease but also in the assessment of treatment response. In the Special Issue, ICIS fellow Sheila Rankin (London, UK) reviews the value of [18F]FDG-PET/CT in oesophageal cancer highlighting the technique’s accepted role as an adjunct to conventional imaging for the staging of oesophageal cancer, for response assessment and identification of recurrent disease[8]. An issue that potentially affects imaging with any PET tracer is the clinical significance and management of lesion motion due to respiration during PET/CT scanning, which was reviewed by Callahan et al.[9] (Melbourne, Australia). They illustrate how accurate characterization of PET-avid disease in areas of high respiratory motion can be challenging and describe different approaches that have been used to address the issue of respiratory motion in PET/CT. The continuing development of conventional gamma imaging in oncology is shown by Dizdarevic and Peters[10] (Brighton, UK) who review the imaging of multidrug resistance in cancer with an emphasis on [99mTc]MIBI scintigraphy, illustrating the opportunities for cost-effectively guiding individualized treatment in an era of personalized medicine. These Cancer Imaging articles testify to the ongoing importance of nuclear medicine in the imaging and treatment of cancer.

The use of octreotide scans in the diagnosis and follow-up of neuroendocrine tumors (NETs).

e14631 Background: NETs are usually diagnosed and followed via a variety of imaging modalities, including MRI, CT scans and somatostatin scintigraphy (OctreoScan, SRS). SRS works by detecting somatostatin receptors found on NETs. There is ongoing debate as to which imaging modality should routinely be used to diagnose and follow patients affected with NETs. This project aims to determine if the information gathered from SRS corresponds or adds to results obtained from modern CT or MRI. Methods: We conducted a retrospective chart review by identifying all patients diagnosed with a NET who were seen at TOHCC between 2003-01-01 and 2009-03-31. We then identified all patients who underwent an SRS within 30 days of a CT or MRI. Results of the SRS were then compared against those of the latter imaging modalities. Results: 70 patients with a diagnosis of NET were identified. Of these, 28 had an SRS within 30 days of a CT or MRI. 5 patients had serial SRS plus either a CT or MRI within the defined time window. In total, 33 SRS results were allowed in the study. When compared to the results of the CT or MRI, 13 (39.4%) were true negatives (TN) SRS, 9 (33.3%) were true positives (TP), and 8 (24.3%) were false negatives (FN) in the setting of metastatic disease. The liver was the most common site missed. One patient had a false positive (FP) SRS (3.0%) with the location of the supposed lesion thought to be in the small bowel. Conclusions: The sensitivity of CT scans and MRIs is superior to that of SRS when investigating NET. There were no cases were an SRS identified lesions that were truly present but not seen on CT or MRI. The most common site missed by the SRS was the liver. This data suggest that SRS does not provide additional information and does not appear to be useful in the diagnosis and follow up of patients with NET, however, further research is needed.

Concomitant lung and gastroenteropancreatic neuroendocrine tumors and the value of gallium-68 PET/CT

Well-differentiated neuroendocrine tumors (NETs) of the lung occur as typical and atypical carcinoids. Little is known about the biology of these tumors in respect of their ability to metastasize or the probability of development of concomitant neuroendocrine tumors. Here we report a patient diagnosed with a second neuroendocrine tumor of the ileum 4 years after curative resection of a typical carcinoid of the left lung. The intestinal neuroendocrine tumor was successfully detected by gallium-68 based somatostatin receptor positron emission tomography (PET)/computed tomography (CT) and surgically removed using gamma probe detection based on the same labeling. This case report underlines the utility of somatostatin receptor PET/CT based detection and follow-up of NETs.

Molecular imaging of neuroendocrine tumors

Molecular imaging represents tissue-specific imaging and quantification of physiologically functional and molecular events in tumors, utilizing new noninvasive imaging modalities. It combines anatomic, physiologic and metabolic information in a single imaging session. Neuroendocrine tumors (NETs) present unique features to use specific nuclear imaging, such as somatostatin receptor scintigraphy (SRS), metaiodobenzylguanidine scans and PET scanning. NETs express somatostatin receptors on tumor cells and can, thus, be visualized by 111In–gadolinium-diethylenetriame pentaacetic acid–octreotide (OctreoScan®), which is currently the most common scanning technique for NETs. Every patient with a NET should be subjected to SRS. Technetium-labeled somatostatin analogs are currently growing in importance. Metaiodobenzylguanidine scanning was previously the only method for detection and follow-up of NETs, but is nowadays more or less replaced by octreotide scanning. During the last decade, PET scanning has been developed for detection and follow-up of patients with NETs. It has clearly demonstrated the highest sensitivity and specificity in the range of 85–95%. It detects smaller tumors down to 3 mm, compared with SRS, which has a size limit of approximately 1 cm. 68Ga–DOTA–octreotide will, in the future, replace SRS owing to its higher sensitivity and specificity, and also reduce the time for investigation. It will also offer the possibility to evaluate the number of somatostatin receptors in a specific tumor. In the future, PET scanning will be more readily available and less expensive, and it will be possible to study tumor biology, vascularization and gene expression in NETs with the development of new tracers.

Elevated Cocaine- and Amphetamine-Regulated Transcript Immunoreactivity in the Circulation of Patients with Neuroendocrine Malignancy

Cocaine- and amphetamine-regulated transcript (CART) codes for a peptide widely distributed in nervous and endocrine tissues. CART immunoreactivity (CART-LI) has been detected in human insulinomas. The objective of the study was to investigate the measurement of plasma CART-LI as a tumor marker of neuroendocrine malignancy. Plasma CART-LI levels were measured in 401 patients with a range of diagnoses: neuroendocrine malignancy (n = 131), after removal of neuroendocrine malignancy (n = 27), without any form of tumor or renal impairment (n = 192), with renal impairment (n = 17) and with nonneuroendocrine tumors (n = 34). Chromatography methods were used to investigate CART-LI circulating in human plasma. The upper limit of normal calculated for CART-LI was 150 pmol/liter. Mean circulating plasma CART-LI among neuroendocrine tumor patients was 440 pmol/liter, 56% of subjects having levels greater than 150 pmol/liter. Measuring CART-LI in addition to chromogranin (Cg)-A improved the sensitivity for neuroendocrine malignancy from 85 to 91%, whereas combined use of CgA and CgB had a joint sensitivity of 89%. Of 38 patients with pancreatic neuroendocrine tumors, 71% had plasma CART-LI levels greater than 150 pmol/liter, increasing to 95% in those classified with progressive disease (n = 20, mean CART-LI 625 pmol/liter), compared with 80% for CgA. Chromatographic analysis suggests that circulating CART-LI is present as one major form, which may correspond to CART (62-102) or another unknown form. We demonstrate CART-LI as a specific tumor marker in patients with a range of neuroendocrine tumors. Used in combination with CgA, CART-LI measurement has the potential to improve sensitivity in diagnosis and follow-up of neuroendocrine tumors, in particular progressive pancreatic neuroendocrine tumors.

18F]fluoro-2-deoxy-d-glucose ([18F]FDG) positron emission tomography imaging of thymic carcinoid tumor presenting with recurrent Cushing’s syndrome

We report a case of a young woman with Cushing's syndrome (CS), in whom although endocrine investigations and negative pituitary imaging were suggestive of ectopic ACTH secretion, the results of inferior petrosal sinus (IPS) sampling after coricotropin-releasing hormone (CRH) stimulation were suggestive of pituitary ACTH hypersecretion. (111)In-labelled octreotide and high-resolution computer tomography (CT) revealed a lesion possibly responsible for the ACTH source in the thymus. Thymectomy confirmed concomitant ectopic CRH and probable ACTH production by a thymic neuroendocrine carcinoma. After an 8-year remission period the patient developed a clinical and biochemical relapse. A high-resolution computed tomography (CT) scan of the thorax showed a 2-cm nodule in the thymic bed, which was positive on a [(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) positron emission tomography (PET) scan. However, a repeated thymectomy did not result in remission. A repeat [(18)F]FDG PET study showed persistent disease in the thymic bed and also uptake in the adrenals. The patient underwent bilateral adrenalectomy, which resulted in clinical remission. A further [(18)F]FDG PET scan 8 months later showed no progression of the thymic tumor and confirmed complete excision of the adrenals. This is a rare case of concomitant CRH and ACTH secretion from a thymic carcinoid tumor; the case illustrates the usefulness of functional imaging with [(18)F]FDG PET in the diagnosis, management and follow-up of neuroendocrine tumors.