Radiolabeled somatostatin analogs represent valuable tools for both in vivo diagnosis and therapy of neuroendocrine tumors (NETs) because of the frequent tumoral overexpression of somatostatin receptors (sst). The 2 compounds most often used in functional imaging with PET are 68 Ga-DOTATATE and 68 Ga-DOTATOC. Both ligands share a quite similar sst binding profile. However, the in vitro affinity of 68 Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately 10-fold higher than that of 68 Ga-DOTATOC. This difference may affect their efficiency in the detection of NET lesions because it is the sst2 that is predominantly overexpressed in NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ( 68 Ga-DOTATATE and 68 Ga-DOTATOC) in the same NET patients. Methods: Forty patients with metastatic NETs underwent 68 Ga-DOTATOC and 68 Ga-DOTATATE PET/CT as part of the work-up before prospective peptide receptor radionuclide therapy. The performance of both imaging methods was analyzed and compared for the detection of individual lesions per patient and for 8 defined body regions. A region was regarded positive if at least 1 lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUVmax) was compared for concordant lesions and renal parenchyma. Results: Seventy-eight regions were found positive with 68 Ga-DOTATATE versus 79 regions with 68 Ga-DOTATOC (not significant). Overall, however, significantly fewer lesions were detected with 68 Ga-DOTATATE than with 68 Ga-DOTATOC (254 vs. 262, P , 0.05). Mean 68 Ga-DOTATATE SUVmax across all lesions was significantly lower than 68 P , 0.01). Mean SUVmax for renal parenchyma was not significantly different between 68 Ga-DOTATATE and 68 Ga-DOTATOC (12.7 6 3.0 vs. 13.2 6 3.3). Conclusion: 68 Ga-DOTATOC and 68 Ga-DOTATATE possess a comparable diagnostic accuracy for the detection of NET lesions, with 68 Ga-DOTATOC having a potential advantage. The approximately 10-fold higher affinity for the sst2 of 68 Ga-DOTATATE does not prove to be clinically relevant. Quite unexpectedly, SUVmax of 68 Ga-DOTATOC scans tended to be higher than their 68 Ga-DOTATATE counterparts.

Purpose: Six pheochromocytoma susceptibility genes causing distinct syndromes have been identified; approximately one of three of all pheochromocytoma patients carry a predisposing germline mutation. When four major genes (VHL, RET, SDHB, SDHD) are analyzed in a clinical laboratory, costs are ∼$3,400 per patient. The aim of the study is to systematically obtain a robust algorithm to identify who should be genetically tested, and to determine the order in which genes should be tested. Experimental Design: DNA from 989 apparently nonsyndromic patients were scanned for germline mutations in the genes VHL, RET, SDHB, SDHC, and SDHD. Clinical parameters were analyzed as potential predictors for finding mutations by multiple logistic regression, validated by bootstrapping. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Results: Of 989 apparently nonsyndromic pheochromocytoma cases, 187 (19%) harbored germline mutations. Predictors for presence of mutation are age <45 years, multiple pheochromocytoma, extra-adrenal location, and previous head and neck paraganglioma. If we used the presence of any one predictor as indicative of proceeding with gene testing, then 342 (34.6%) patients would be excluded, and only 8 carriers (4.3%) would be missed. We were also able to statistically model the priority of genes to be tested given certain clinical features. E.g., for patients with prior head and neck paraganglioma, the priority would be SDHD>SDHB>RET>VHL. Using the clinical predictor algorithm to prioritize gene testing and order, a 44.7% cost reduction in diagnostic process can be achieved. Conclusions: Clinical parameters can predict for mutation carriers and help prioritize gene testing to reduce costs in nonsyndromic pheochromocytoma presentations. (Clin Cancer Res 2009;15(20):6378-85)

Differentiated thyroid cancer (DTC) is the most common endocrine cancer and its incidence has increased in recent decades. Initial treatment usually consists of total thyroidectomy followed by ablation of thyroid remnants by iodine-131. As thyroid cells are assumed to be the only source of thyroglobulin (Tg) in the human body, circulating Tg serves as a biochemical marker of persistent or recurrent disease in DTC follow-up. Currently, standard follow-up for DTC comprises Tg measurement and neck ultrasound combined, when indicated, with an additional radioiodine scan. Measurement of Tg after stimulation by endogenous or exogenous TSH is recommended by current clinical guidelines to detect occult disease with a maximum sensitivity due to the suboptimal sensitivity of older Tg assays. However, the development of new highly sensitive Tg assays with improved analytical sensitivity and precision at low concentrations now allows detection of very low Tg concentrations reflecting minimal amounts of thyroid tissue without the need for TSH stimulation. Use of these highly sensitive Tg assays has not yet been incorporated into clinical guidelines but they will, we believe, be used by physicians caring for patients with DTC. The aim of this clinical position paper is, therefore, to offer advice on the various aspects and implications of using these highly sensitive Tg assays in the clinical care of patients with DTC.

Background and aims: Retrospective, observational study to compare clinical symptoms and TSH-receptor antibodies (TRAb) in Graves ophthalmopathy (GO) in euthyroid and primarily hypothyroid patients to those in hyperthyroid patients. Methods: Clinical symptoms (NOSPECS (severity) and CAS (activity) score), prevalence and levels of thyroid specific antibodies and the course of the disease were evaluated in 143 primarily hyperthyroid, 28 primarily euthyroid and 11 primarily hypothyroid patients with GO. Results: Patients with euthyroid/hypothyroid GO developed significantly less severe GO symptoms (NOSPECS score 4.4 vs 5.7; p = 0.03), less active GO (CAS score 3.9 vs 5.2; p = 0.002) and more asymmetrical disease (proptosis side difference: 1.9 mm vs 1.0 mm (p = 0.01); side difference of >3 mm: 23% vs 4.8%) than hyperthyroid patients. TRAb levels 6 months after GO onset were significantly lower (2.2 IU/l, p = 0.02) in euthyroid/hypothyroid than in hyperthyroid patients (8.6 IU/l), as was the prevalence of both TRAb and thyroid peroxidase antibodies (75% vs 94.6%, p = 0.0008). Conclusions:The knowledge about the phenotype of GO in primarily euthyroid and hypothyroid patients is helpful for differential diagnosis and patient consultation. TRAb titres are very low in these patients, and the availability of a sensitive assay technique is therefore an important diagnostic tool in euthyroid and hypothyroid patients.

The antitumor effect of IFN-α is mediated by the activation of CTLs, NK cells, and the generation of highly potent Ag-presenting dendritic cells (IFN-DCs). In this study, we show that IFN-DCs generated in vitro from monocytes express CD56 on their surface, a marker which has been thought to be specific for NK cells. FACS analyses of CD56+ and CD56− IFN-DCs showed a nearly identical pattern for most of the classical DC markers. Importantly, however, only CD56+ IFN-DCs exhibited cytolytic activity up to 24% that could almost completely be blocked (−81%) after coincubation with anti-TRAIL. Intracytoplasmatic cytokine staining revealed that the majority of IFN-DCs independently of their CD56 expression were IFN-γ positive as well. In contrast, CD56+ IFN-DCs showed stronger capacity in stimulating allogenic T cells compared with CD56− IFN-DC. Based on these results, five patients with metastasized medullary thyroid carcinoma were treated for the first time with monocyte-derived tumor Ag-pulsed IFN-DCs. After a long term follow-up (in mean 37 mo) all patients are alive. Immunohistochemical analyses of delayed-type hypersensitivity skin reaction showed a strong infiltration with CD8+ cells. In two patients no substantial change in tumor morphology was detected. Importantly, by analyzing PBMCs, these patients also showed an increase of Ag-specific IFN-γ-secreting T cells. In summary, we here describe for the first time that cytotoxic activity of IFN-DCs is mainly mediated by an IFN-DC subset showing partial phenotypic and functional characteristics of NK cells. These cells represent another mechanism of the antitumor effect induced by IFN-α.

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This third interim report demonstrates the feasibility of the registry with excellent data quality and completeness from 20 study centers. The results must be interpreted with caution, since the numbers are still small; however the disease severity is remarkably high and suggests that adsorber treatment might be used as an ultimate treatment in life-threatening situations. There were no device-associated side effects.

Aims/hypothesis Adipocytes secrete signalling molecules that elicit responses from target cells, including pancreatic beta cells. Wnt signalling molecules have recently been identified as novel adipocyte-derived factors. They also regulate insulin secretion in pancreatic beta cells and the cell cycle. The aim of this study was to investigate the effect of adipocyte-derived Wnt signalling molecules on insulin secretion and beta cell proliferation. Methods Human adipocytes were isolated to generate fat cell-conditioned medium (FCCM). Ins-1 cells were stimulated with FCCM and transiently transfected with reporter genes. Proliferation assays using [ 3 H]thymidine incorporation were carried out in Ins-1 cells and primary islet cells. Insulin secretion from primary islets was assessed by radioimmunoassay. Gene expression in primary islets was assessed by Taqman PCR. Results Treatment with human FCCM increased the transcription of a T cell-specific transcription factor reporter gene (TOPFLASH) in Ins-1 cells (241%, p<0.05). FCCM induced the proliferation of Ins-1 cells (1.8 fold, p<0.05) and primary mouse islet cells (1.6 fold, p<0.05). Antagonizing Wnt signalling with secreted Frizzled-related protein 1 (FRP-1) inhibited the proliferative effect induced by Wnt3a and FCCM on Ins-1 cells by 49 and 41%, respectively. In addition, FCCM led to a twofold (p<0.05) induction of cyclin D1 promoter activity in Ins-1 cells. Furthermore, FCCM stimulated insulin secretion (204% of controls, p>0.05) in primary mouse islets, and this stimulation was inhibited by sFRP-1. At a molecular level, canonical Wnt signalling induced glucokinase gene transcription in a peroxisome proliferator-activated receptor γ-dependent fashion, thereby defining the glucokinase gene as a novel Wnt target gene. Conclusions/interpretation Taken together, these data show that adipocyte-derived Wnt signalling molecules induce beta cell proliferation and insulin secretion in vitro, suggesting a novel mechanism linking obesity to hyperinsulinaemia.