Induction of Sodium/Iodide Symporter (NIS) Expression and Radioiodine Uptake in Non-Thyroid Cancer Cells

Background: This study was designed to explore the therapeutic potential of suppressing MAP kinase and PI3K/Akt pathways and histone deacetylase (HDAC) to induce the expression of sodium/iodide symporter (NIS) and radioiodine uptake in non-thyroid cancer cells. Methods: We tested the effects of the MEK inhibitor RDEA119, the Akt inhibitor perifosine, and the HDAC inhibitor SAHA on NIS expression in thirteen human cancer cell lines derived from melanoma, hepatic carcinoma, gastric carcinoma, colon carcinoma, breast carcinoma, and brain cancers. We also examined radioiodine uptake and histone acetylation at the NIS promoter in selected cells. Results: Overall, the three inhibitors could induce NIS expression, to various extents, in melanoma and all the epithelial carcinoma-derived cells but not in brain cancer-derived cells. SAHA was most effective and its effect could be significantly enhanced by RDEA119 and perifosine. The expression of NIS, at both mRNA and protein levels, was most robust in the melanoma cell M14, hepatic carcinoma cell HepG2, and the gastric carcinoma cell MKN-7 cell. Radioiodine uptake was correspondingly induced, accompanied by robust increase in histone acetylation at the NIS promoter, in these cells when treated with the three inhibitors. Conclusions: This is the first demonstration that simultaneously suppressing the MAP kinase and PI3K/Akt pathways and HDAC could induce robust NIS expression and radioiodine uptake in certain non-thyroid human cancer cells, providing novel therapeutic implications for adjunct radioiodine treatment of these cancers

Preoperative Imaging with [F-18]-Fluorocholine PET/CT in Primary Hyperparathyroidism

Primary hyperparathyroidism (pHPT) is a common endocrine disorder due to hyperfunctioning parathyroid glands. To date, the only curing therapy is surgical removal of the dysfunctional gland, making correct detection and localization crucial in order to perform a minimally invasive parathyroidectomy. F-18-Fluorocholine positron emission tomography/computed tomography (F-18-FCH PET/CT) has shown promising results for the detection of pHPT, suggesting superiority over conventional imaging with ultrasounds or scintigraphy. A total of 33 patients with pHPT who had negative or equivocal findings in conventional imaging received F-18-FCH PET/CT preoperatively and were retrospectively included. A pathological hyperfunctional parathyroid gland was diagnosed in 24 cases (positive PET, 72.7%), 4 cases showed equivocal choline uptake (equivocal PET, 12.1%), and in 5 cases, no enhanced choline uptake was evident (negative PET, 15.2%). Twelve of the twenty-four detected adenoma patients underwent surgery, and in all cases, a pathological parathyroid adenoma was resected at the site detected by PET/CT. Two of the six patients without pathological choline uptake who received a parathyroidectomy revealed no evidence of parathyroid adenoma tissue in the histopathological evaluation. This retrospective study analyzes F-18-FCH PET/CT in a challenging patient cohort with pHPT and negative or equivocal conventional imaging results and supports the use of F-18-FCH for the diagnosis of hyperfunctional parathyroid tissue, especially in this patient setting, with a 100% true positive and true negative detection rate. Our study further demonstrates the importance of F-18-FCH PET/CT for successful surgical guidance

Targeting of tumor radioiodine therapy by expression of the sodium iodide symporter under control of the survivin promoter

To test the feasibility of using the survivin promoter to induce specific expression of sodium/iodide symporter (NIS) in cancer cell lines and tumors for targeted use of radionuclide therapy, a recombinant adenovirus, Ad-SUR-NIS, that expressed the NIS gene under control of the survivin promoter was constructed. Ad-SUR-NIS mediating iodide uptake and cytotoxicity was performed in vitro. Scintigraphic, biodistribution and radioiodine therapy studies were performed in vivo. PC-3 (prostate); HepG2 (hepatoma) and A375 (melanoma) cancer cells all exhibited perchlorate-sensitive iodide uptake after infection with Ad-SUR-NIS, ∼50 times higher than that of negative control Ad-CMV-GFP-infected cells. No significant iodide uptake was observed in normal human dental pulp fibroblast (DPF) cells after infection with Ad-SUR-NIS. Clonogenic assays demonstrated that Ad-SUR-NIS-infected cancer cells were selectively killed by exposure to 131I. Ad-SUR-NIS-infected tumors show significant radioiodine accumulation (13.3±2.85% ID per g at 2 h post-injection), and the effective half-life was 3.1 h. Moreover, infection with Ad-SUR-NIS in combination with 131I suppressed tumor growth. These results indicate that expression of NIS under control of the survivin promoter can likely be used to achieve cancer-specific expression of NIS in many types of cancers. In combination with radioiodine therapy, this strategy is a possible method of cancer gene therapy

High (but Not Low) Urinary Iodine Excretion Is Predicted by Iodine Excretion Levels from Five Years Ago

Background: It has not been investigated whether there are associations between urinary iodine (UI) excretion measurements some years apart, nor whether such an association remains after adjustment for nutritional habits. The aim of the present study was to investigate the relation between iodine-creatinine ratio (ICR) at two measuring points 5 years apart. Methods: Data from 2,659 individuals from the Study of Health in Pomerania were analyzed. Analysis of covariance and Poisson regressions were used to associate baseline with follow-up ICR. Results: Baseline ICR was associated with follow-up ICR. Particularly, baseline ICR >300 mu g/g was related to an ICR >300 mu g/g at follow-up (relative risk, RR: 2.20; p < 0.001). The association was stronger in males (RR: 2.64; p < 0.001) than in females (RR: 1.64; p = 0.007). In contrast, baseline ICR <100 mu g/g was only associated with an ICR <100 mu g/g at follow-up in males when considering unadjusted ICR. Conclusions: We detected only a weak correlation with respect to low ICR. Studies assessing iodine status in a population should take into account that an individual with a low UI excretion in one measurement is not necessarily permanently iodine deficient. On the other hand, current high ICR could have been predicted by high ICR 5 years ago. Copyright (C) 2011 S. Karger AG, Base

Neuroendocrine Tumors of the Bronchopulmonary System (Typical and Atypical Carcinoid Tumors): Current Strategies in Diagnosis and Treatment. Conclusions of an Expert Meeting February 2011 in Weimar, Germany

Neuroendocrine tumors (NETs; syn. carcinoid tumors) are highly or moderately differentiated neoplasms. They comprise a large variety of rare and heterogeneous tumors with an estimated incidence of 3-5/100,000/year. They can arise in virtually every internal organ, but mainly occur in the gastroenteropancreatic and bronchopulmonary systems. Around 25% of the NETs are localized in the bronchopulmonary system. Approximately 2% of all lung tumors are NETs. According to the World Health Organization (WHO) classification of lung tumors, bronchopulmonary NETs are subdivided into typical carcinoids (TCs) and atypical carcinoids (ACs). The parameter with the highest impact on NET behavior and prognosis is the histological classification and staging according to the tumor/node/metastasis (TNM) system. The diagnosis of NETs is established by histological examination and the immunohistochemical detection of general neuroendocrine markers, such as chromogranin A (CgA) and synaptophysin. Serum markers and the use of functional imaging techniques are important additive tools to establish the diagnosis of a NET. The only curative option for lung NETs is complete surgical resection. Beyond that, the currently available interdisciplinary therapeutic options are local ablation, biotherapy (somatostatin analogues), or chemotherapy. New therapeutic options such as peptide receptor radionuclide therapy (PRRT) and molecularly targeted therapies achieve promising results and are under further evaluation. This report is a consensus summary of the interdisciplinary symposium ‘Neuroendocrine Tumors of the Lung and of the Gastroenteropancreatic System (GEP NET) - Expert Dialogue' held on February 25-26, 2011 in Weimar, Germany. At this conference, a panel of 23 German experts shared their knowledge and exchanged their thoughts about research, diagnosis, and clinical management of NETs, whereby special attention was paid to NETs of the respiratory trac

Expression of the Na(+)/l(- )symporter (NIS) is markedly decreased or absent in gastric cancer and intestinal metaplastic mucosa of Barrett esophagus

BACKGROUND: The sodium/iodide symporter (NIS) is a plasma membrane glycoprotein that mediates iodide (I(-)) transport in the thyroid, lactating breast, salivary glands, and stomach. Whereas NIS expression and regulation have been extensively investigated in healthy and neoplastic thyroid and breast tissues, little is known about NIS expression and function along the healthy and diseased gastrointestinal tract. METHODS: Thus, we investigated NIS expression by immunohistochemical analysis in 155 gastrointestinal tissue samples and by immunoblot analysis in 17 gastric tumors from 83 patients. RESULTS: Regarding the healthy Gl tract, we observed NIS expression exclusively in the basolateral region of the gastric mucin-producing epithelial cells. In gastritis, positive NIS staining was observed in these cells both in the presence and absence of Helicobacter pylori. Significantly, NIS expression was absent in gastric cancer, independently of its histological type. Only focal faint NIS expression was detected in the direct vicinity of gastric tumors, i.e., in the histologically intact mucosa, the expression becoming gradually stronger and linear farther away from the tumor. Barrett mucosa with junctional and fundic-type columnar metaplasia displayed positive NIS staining, whereas Barrett mucosa with intestinal metaplasia was negative. NIS staining was also absent in intestinalized gastric polyps. CONCLUSION: That NIS expression is markedly decreased or absent in case of intestinalization or malignant transformation of the gastric mucosa suggests that NIS may prove to be a significant tumor marker in the diagnosis and prognosis of gastric malignancies and also precancerous lesions such as Barrett mucosa, thus extending the medical significance of NIS beyond thyroid disease

Enhanced anti-tumor effects of combined MDR1 RNA interference and human sodium/iodide symporter (NIS) radioiodine gene therapy using an adenoviral system in a colon cancer model

Using an adenoviral system as a delivery mediator of therapeutic gene, we investigated the therapeutic effects of the use of combined MDR1 shRNA and human NIS (hNIS) radioiodine gene therapy in a mouse colon xenograft model. In vitro uptake of Tc-99m sestamibi was increased approximately two-fold in cells infected with an adenovirus vector that expressed MDR1 shRNA (Ad-shMDR1) and I-125 uptake was 25-fold higher in cells infected with an adenovirus vector that expressed human NIS (Ad-hNIS) as compared with control cells. As compared with doxorubicin or I-131 treatment alone, the combination of doxorubicin and I-131 resulted in enhanced cytotoxicity for both Ad-shMDR1- and Ad-hNIS-infected cells, but not for control cells. In vivo uptake of Tc-99m sestamibi and Tc-99m pertechnetate was twofold and 10-fold higher for Ad-shMDR1 and Ad-hNIS-infected tumors as compared with tumors infected with a control adenovirus construct that expressed β-galactrosidase (Ad-LacZ), respectively. In mice treated with either doxorubicin or I-131 alone, there was a slight delay in tumor growth as compared to mice treated with Ad-LacZ. However, combination therapy with doxorubicin and I-131 induced further significant inhibition of tumor growth as compared with mice treated with Ad-LacZ. We have shown successful therapeutic efficacy of combined MDR shRNA and hNIS radioiodine gene therapy using an adenoviral vector system in a mouse colon cancer model. Adenovirus-mediated cancer gene therapy using MDR1 shRNA and hNIS would be a useful tool for the treatment of cancer cells expressing multi-drug resistant genes

Treatment with Octreotide in Patients with Well-Differentiated Neuroendocrine Tumors of the Ileum: Prognostic Stratification with Ga-68-DOTA-TATE Positron Emission Tomography

We investigated the use of Ga-68-DOTA-Tyr(3)-octreotate (Ga-68-DOTA-TATE) positron emission tomography (PET) and standardized uptake values (SUVs) to predict the effectiveness of treatment with the somatostatin analogue octreotide acetate (Sandostatin LAR) in patients with neuroendocrine tumors (NETs). Thirty patients with well-differentiated NETs of the ileum (grades G1 and G2) were studied with Ga-68-DOTA-TATE. The average SUV of a 50% isocontour volume of interest covering the lesion with maximum uptake (SUVmean) and the maximum SUV (SUVmax) were determined. Patients were followed up, and the time to progression was recorded. Twenty-one patients showed progressive disease at the end of the study;nine patients had stable disease. The median progression-free survival (PFS) was 51.0 weeks (95% confidence interval [CI] 26.4-75.6). A cutoff for the SUVmax of 29.4 and for the SUVmean of 20.3 could separate between patients with a long PFS (69.0 weeks; 95% CI 9.8-128.2) and a short PFS (26.0 weeks; 95% CI 8.7-43.3) response to octreotide acetate therapy. Patients with high radiotracer uptake had significantly higher PFS with a 2.9-fold higher chance for stable disease after 45 weeks;however, the prognostic performance of SUVmax on an individual basis was poor, with a sensitivity of 75% and a specificity of 64%. SUVmax and SUVmean of NET tumor lesions in Ga-68-DOTA-TATE PET are important prognostic indices for predicting the response to therapy with octreotide acetate

Identification and characterization of myocardial metastases in neuroendocrine tumor patients using 68Ga-DOTATATE PET-CT

Background: Focal 68Ga-DOTATATE PET lesions within the myocardium of neuroendocrine tumor (NET) patients are observed in clinical practice. We determined the frequency and characteristics of lesions that are consistent with cardiac metastasis and assessed the lesion detection rate of conventional imaging. Methods: 629 patients who underwent 68Ga-DOTATATE PET-CT at a supraregional comprehensive cancer center on NET were included from a consecutive registry. Inclusion criteria were: (1) focal 68Ga-DOTATATE tracer uptake within the myocardium in more than two sequential PET exams, and (2) contrast-enhanced CT. To determine the diagnostic accuracy of conventional CT imaging, a case-control cohort with a ratio of 1:3 was used. PET and CT were independently analyzed by two blinded readers. Cohen's K was assessed for interreader agreement Descriptive statistics were applied for frequencies and characteristics and group comparisons were analyzed using the Fisher's exact test. Results: The prevalence of myocardial metastases related to the registry was 2.4% (15 of 629 NET patients fulfilling the inclusion criteria), for a total of 21 myocardial 68Ga-DOTATATE foci detected. Myocardial lesions were most frequently located in the left ventricle (43%) and the septum (43%). No patient demonstrated a pericardial effusion. Patients with myocardial metastases did not differ in demographics, tumor grading, disease stage or circulating tumor markers compared to the overall registry (all p > 0.05). Higher Ki67-Indices were observed (p = 0.049) for patients with myocardial metastases. Interreader agreement for PET assessment was excellent (Cohen's K = 1.0). CT reading showed a sensitivity of 19% (95% confidence interval: 6-43%) at a specificity of 100% (95% confidence interval: 90-100%). Conclusions: 68Ga-DOTATATE PET enables detection of myocardial metastatic lesions in NET patients. In contrast, standard morphologic CT imaging provides very limited sensitivity

Dosimetry and optimal scan time of 18FSiTATE-PET/CT in patients with neuroendocrine tumours

PURPOSE Radiolabelled somatostatin analogues targeting somatostatin receptors (SSR) are well established for combined positron emission tomography/computer tomography (PET/CT) imaging of neuroendocrine tumours (NET). 18FSiTATE has recently been introduced showing high image quality, promising clinical performance and improved logistics compared to the clinical reference standard 68Ga-DOTA-TOC. Here we present the first dosimetry and optimal scan time analysis. METHODS Eight NET patients received a 18FSiTATE-PET/CT (250 ± 66~MBq) with repeated emission scans (10, 30, 60, 120, 180~min after injection). Biodistribution in normal organs and SSR-positive tumour uptake were assessed. Dosimetry estimates for risk organs were determined using a combined linear-monoexponential model, and by applying 18F S-values and reference target masses for the ICRP89 adult male or female (OLINDA 2.0). Tumour-to-background ratios were compared quantitatively and visually between different scan times. RESULTS After 1 h, normal organs showed similar tracer uptake with only negligible changes until 3 h post-injection. In contrast, tracer uptake by tumours increased progressively for almost all types of metastases, thus increasing tumour-to-background ratios over time. Dosimetry resulted in a total effective dose of 0.015 ± 0.004~mSv/MBq. Visual evaluation revealed no clinically relevant discrepancies between later scan times, but image quality was rated highest in 60 and 120~min images. CONCLUSION 18FSiTATE-PET/CT in NET shows overall high tumour-to-background ratios from 60 to 180~min after injection and an effective dose comparable to 68Ga-labelled alternatives. For clinical use of 18FSiTATE, the best compromise between image quality and tumour-to-background contrast is reached at 120~min, followed by 60~min after injection