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Biomedical subjects

Thomas M Behr

Publications and source records attributed to Thomas M Behr.

At least 19 recordsLinked to original sources
PubMed2006

Efficacy of 99mTc pertechnetate and 131I radioisotope therapy in sodium/iodide symporter (NIS)-expressing neuroendocrine tumors in vivo.

PURPOSE: There is growing interest in the human sodium/iodide symporter (NIS) gene both as a molecular imaging reporter gene and as a therapeutic gene. Here, we show the feasibility of radioisotope therapy of neuroendocrine tumors. As a separate application of NIS gene transfer, we image NIS-expressing tumors with pinhole SPECT in living subjects. METHODS: Biodistribution studies and in vivo therapy experiments were performed in nude mice carrying stably NIS-expressing neuroendocrine tumor xenografts following i.v. injection of (131)I and (99m)Tc pertechnetate. To show the usefulness of NIS as an imaging reporter gene, (99m)Tc pertechnetate uptake was imaged in vivo using a clinical gamma camera in combination with a custom-made single pinhole collimator, followed by SPECT/small animal MRI data coregistration. RESULTS: NIS-expressing neuroendocrine tumors strongly accumulated (131)I and (99m)Tc pertechnetate, as did thyroid, stomach, and salivary gland. The volume of NIS-expressing neuroendocrine tumors decreased significantly after therapeutic administration of (131)I or (99m)Tc pertechnetate, whereas control tumors continued to grow. NIS-mediated uptake of (99m)Tc pertechnetate could be imaged in vivo at high resolution with a clinical gamma camera equipped with a custom-made single pinhole collimator. High-resolution functional and morphologic information could be combined in a single three-dimensional data set by coregistration of SPECT and small animal MRI data. Lastly, we demonstrated a therapeutic effect of (99m)Tc pertechnetate on NIS-expressing neuroendocrine tumors in cell culture and, for the first time, in vivo, thought to be due to emitted Auger and conversion electrons. CONCLUSIONS: NIS-expressing neuroendocrine tumors efficiently concentrate radioisotopes, allowing for in vivo high-resolution small animal SPECT imaging as well as rendering possible successful radioisotope therapy of neuroendocrine tumors.

Animals↗
PubMed2006

A new technique for in vivo imaging of specific GLP-1 binding sites: first results in small rodents.

EXPERIMENTAL OBJECTIVES: In vivo imaging of GLP-1 receptor-positive tissues may allow examination of physiologic and pathophysiologic processes. Based on the GLP-1 analog Exendin 4, we have developed a radiolabeled compound specifically targeting the GLP-1 receptor (DTPA-Lys40-Exendin 4). This work aims to detect GLP-1 receptor-positive tissues by biodistribution studies and in vivo small animal imaging studies. For in vivo imaging, a high-resolution multi-pinhole SPECT (single photon emission computed tomography) system was used in conjunction with an MRI (magnetic resonance imaging) system for image fusion. RESULTS: DTPA-Lys40-Exendin 4 can be labeled with 111In to high specific activity (40 GBq/micromol). The radiochemical purity reliably exceeded 95%. Using this compound for in vivo small animal imaging of rats and mice as well as for biodistribution studies, specific GLP-1 binding sites could be detected in stomach, pancreas, lung, adrenals, and pituitary. Receptor-positive tissues were visualized with a high-resolution SPECT system with a resolution of less than 1 mm. CONCLUSIONS: The new technique using DTPA-Lys40-Exendin 4 allows highly sensitive imaging of GLP-1 receptor-positive tissues in vivo. Therefore, intra-individual follow-up studies of GLP-1 receptor-positive tissue could be conducted in vivo.

Animals↗
PubMed2006

Improved tumour detection by gastrin receptor scintigraphy in patients with metastasised medullary thyroid carcinoma.

PURPOSE: Radiopeptide imaging is a valuable imaging method in the management of patients with neuroendocrine tumours (NET). To determine the clinical performance of gastrin receptor scintigraphy (GRS), it was compared with somatostatin receptor scintigraphy (SRS), computed tomography (CT) and (18)F-FDG positron emission tomography (PET) in patients with metastasised/recurrent medullary thyroid carcinoma (MTC). METHODS: Twenty-seven consecutive patients underwent imaging with GRS, SRS (19 patients), CT and PET (26 patients). GRS and SRS were compared with respect to tumour detection and uptake. CT, PET, magnetic resonance imaging (MRI), ultrasound (US) and follow-up were used for verification of findings. In addition, GRS, CT and PET were directly compared with each other to determine which method performs best. RESULTS: Nineteen patients underwent both GRS and SRS. Among these, GRS showed a tumour detection rate of 94.2% as compared to 40.7% for SRS [mean number of tumour sites (+/-SD) and 95% confidence intervals (CI): GRS 4.3+/-3.1/2.8-5.7, SRS 1.8+/-1.6/1.1-2.6]. In 26 patients, GRS, CT and PET were compared. Here, GRS showed a tumour detection rate of 87.3% (CT 76.1%, PET 67.2%; mean number of tumour sites and 95% CI: GRS 4.5+/-4.0/2.9-6.1, CT 3.9+/-3.5/2.5-5.3, PET 3.5+/-3.3/2.1-4.8). If GRS and CT were combined, they were able to detect 96.7% of areas of tumour involvement. CONCLUSION: GRS had a higher tumour detection rate than SRS and PET in our study. GRS in combination with CT was most effective in the detection of metastatic MTC.

Adult↗
PubMed2006

How to successfully implement E-learning for both students and teachers.

RATIONALE AND OBJECTIVES: Electronic learning (e-learning) may provide a means to enhance learning efficacy. However, introduction of e-learning often fails. We describe a strategy of how an e-learning curriculum was successfully implemented. MATERIALS AND METHODS: The curriculum was designed based on published evidence. It consists of self-directed learning, an online discussion forum, and discussion rounds. The e-content in nuclear medicine and radiotherapy was produced by the k-MED team of medical authors, web designers, and psychologists. The online courses were delivered via a dedicated learning management system. The e-content for diagnostic radiology and physics was provided as PDF/HTML script by the respective teachers who objected to participate in the k-MED project. The exam was taken online. Online evaluation of the curriculum by the students was taken at the end of the course. RESULTS: The new curriculum proved very effective. The time for the preparation for the clinical part of the radiology course could be reduced from 4 to 2 weeks. The students particularly enjoyed the self-directed learning. Although the material provided by k-MED received 90%-99% positive scores, the HTML and PDF scripts scored worse (13%-67% positive ratings). The positive results of the evaluation convinced the teachers responsible for physics and diagnostic radiology to participate in k-MED. CONCLUSIONS: As our example shows, new e-learning curricula can successfully be introduced. The strategy of implementation should be based on the existing evidence from the literature. The new curriculum helped to increase the efficacy of teaching and save time as the duration of the respective part of the course could be reduced by half.

Computer-Assisted Instruction↗
PubMed2006

Assessment of cardiac allograft vasculopathy late after heart transplantation: when is coronary angiography necessary?

BACKGROUND: Cardiac allograft vasculopathy (CAV) represents a major prognostic factor in long-term survivors of heart transplantation (HTx). Reliable diagnosis of CAV late after HTx is important but remains the domain of invasive techniques such as coronary angiography. METHODS: To test alternative approaches, 54 consecutive HTx recipients (mean time since HTx: 52 months) were studied with intravascular ultrasound (IVUS), angiography, dobutamine stress echocardiography and immunofluorescence staining against anti-thrombin III (AT-III) in endomyocardial biopsies. Univariate and multivariate predictors as well as receiver-operating-characteristic (ROC) curves of different sets of predictors were calculated. RESULTS: Using IVUS as reference standard, CAV was present in 80% of subjects. Coronary angiography identified CAV correctly in only 44% of cases. If AT-III staining alone was used as a diagnostic criterion, CAV was correctly identified in 77% of subjects. In a multivariate analysis, only AT-III, donor age and echocardiography at rest emerged as independent predictors of CAV (p < 0.05 for all), yielding an excellent discriminative power. CONCLUSIONS: With almost equal reliability when compared with IVUS, CAV can be identified using information on donor age, wall motion score at rest and AT-III staining late after HTx. Coronary angiography may be limited to patients with a high probability score and should not be used routinely for surveillance of CAV.

Adult↗
PubMed2006

Added value of gastrin receptor scintigraphy in comparison to somatostatin receptor scintigraphy in patients with carcinoids and other neuroendocrine tumours.

Gastrin receptor scintigraphy (GRS) is a new imaging method primarily developed for the detection of metastases of medullary thyroid carcinoma (MTC). As gastrin-binding CCK(2) receptors are also expressed on a variety of other neuroendocrine tumours (NET), we compared GRS to somatostatin receptor scintigraphy (SRS) in patients with NET. SRS and GRS were performed within 21 days in a series of 60 consecutive patients with NET. GRS was directly compared with SRS. If lesions were visible on GRS but not detectable by SRS, other imaging modalities (MRI, CT) and follow-up were used for verification. Of the 60 evaluable patients, 51 had carcinoid tumours, 3 gastrinomas, 2 glucagonomas, 1 insulinoma and 3 paragangliomas. The overall tumour-detection rate was 73.7% for GRS and 82.1% for SRS. In the 11 patients with negative SRS, GRS was positive in 6 (54.5%). Based on the number of tumour sites detected and the degree of uptake, GRS performed better than SRS in 13 patients (21.7%), equivalent images were obtained in 18 cases (30.0%) and SRS performed better in 24 (40.0%) cases. In six of the SRS positive patients, 18 additional sites of tumour involvement could be detected. Overall, GRS detected additional tumour sites in 20% of the patients. Localisation of the primary tumours or their functional status had no influence on the outcome of imaging. GRS should be performed in selected patients as it may provide additional information in patients with NET with equivocal or absent somatostatin uptake.

Adult↗
PubMed2005

Phase II trial of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after salvage resection of colorectal metastases in the liver: five-year safety and efficacy results.

PURPOSE: Although complete resection (R0) of liver metastases (LM) remains the treatment of choice for colorectal cancer (CRC) patients amenable to curative therapy, only approximately one third survive for 5 years. The objective of this phase II study was to evaluate the safety and efficacy of radioimmunotherapy (RAIT) after salvage resection of LM. PATIENTS AND METHODS: Twenty-three patients who underwent surgery for LM of CRC received a dose of 40 to 60 mCi/m2 of 131I-labetuzumab, which is a humanized monoclonal antibody against carcinoembryonic antigen. Safety (n = 23), disease-free survival (DFS; n = 19), and overall survival (OS; n = 19) were determined. RESULTS: With a median follow-up of 64 months, the median OS time from the first liver resection for RAIT patients was 68.0 months (95% CI, 46.0 months to infinity), and the median DFS time was 18.0 months (95% CI, 11.0 to 31.0 months). The 5-year survival rate was 51.3%. RAIT benefited patients independently of bilobar involvement, size and number of LM, and resection margins. The major adverse effect was transient myelosuppression, resulting mostly in grade < or = 3 neutropenia and/or thrombocytopenia. CONCLUSION: Because both the median OS and 5-year survival rates seem to be improved with adjuvant RAIT after complete LM resection in CRC, compared with historical and contemporaneous controls not receiving RAIT, these results justify further evaluation of this modality in a multicenter, randomized trial.

Adenocarcinoma↗
PubMed2005

Use of polyglutamic acids to reduce uptake of radiometal-labeled minigastrin in the kidneys.

UNLABELLED: Uptake of radiolabeled peptides in the kidneys may obscure abdominal tumors in radiopeptide scintigraphy. This problem is much more pronounced in peptide receptor radionuclide therapy (i.e., radiopeptide therapy), possibly leading to renal damage or even failure. Cationic peptide uptake in the kidneys can be reduced by the application of cationic amino acids, such as lysine or arginine. The aim of this study was to develop a suitable method to reduce anionic peptide uptake in the kidneys. (111)In-Diethylenetriaminepentaacetic acid dGlu(1)-minigastrin ((111)In-DTPA-dGlu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH(2)) was chosen as a model compound with a sequence of 6 negatively charged glutamic acids in a chain and an additional aspartic acid. METHODS: TT (human medullary carcinoma cells)-bearing nu/nu mice of the Institute of Cancer Research genotype received intraperitoneal injections of different chain lengths and weights of glutamic acids, aspartic acids, and derivatives of glutamic acids. Uptake in tumors and organs was determined and compared with the values for untreated control mice. RESULTS: Accretion of (111)In-DTPA-dGlu(1)-minigastrin in the kidneys could be reduced by up to 90%. The uptake values for all other organs and the tumors were not affected. These results were obtained with a chain of 5 or more glutamic acids, whereas uptake in kidneys was affected not at all or only slightly with poly-d-glutamic or polyaspartic acids and with Glu(x) (x = 1-4). CONCLUSION: These studies indicated a specific blocking of uptake by Glu(5) sequences in the kidneys. Application of polyglutamic acids is a new, successful method of reducing uptake of negatively charged peptides in the kidneys during radiopeptide therapy.

Animals↗
PubMed2005

CCK-2/gastrin receptor-targeted tumor imaging with (99m)Tc-labeled minigastrin analogs.

UNLABELLED: The aim of this study was to evaluate 3 new (99m)Tc-labeled minigastrin analogs modified with open chain tetraamines at the N-terminus for their suitability in the CCK-2/gastrin-R-targeted imaging of tumors (CCK-2/gastrin-R = cholecystokinin subtype 2/gastrin receptor). METHODS: The [(D)Glu(1)]minigastrin sequence was assembled on the solid support and the respective tetraamine precursors coupled at the N-terminus. Purified peptide conjugates were labeled with (99m)Tc under alkaline conditions. Saturation binding experiments were performed for (radio)metallated peptides [(99m)Tc/(99g)Tc]Demogastrin 1-3 in rat acinar pancreatic AR4-2J cell membranes. Internalization was studied in AR4-2J cells at 37 degrees C. Radiopeptide stability was tested in murine plasma, urine, and kidney homogenates. Tissue distribution of the peptides was compared in healthy mice and athymic mice bearing AR4-2J tumors. RESULTS: Peptide conjugates were obtained in 10%-30% overall yields by solid-phase techniques. Radiolabeling afforded >98% pure [(99m)Tc]Demogastrin 1-3 species in specific activities of approximately 37 GBq/mumol. Radiopeptides retained a high affinity for the CCK-2/gastrin-R in vitro (50% inhibitory concentration values of approximately 1 nmol/L) and internalized rapidly in CCK-2/gastrin-R-positive cells. After injection in mice they displayed rapid, high, and specific localization in the CCK-2/gastrin-R-expressing tissues (stomach and AR4-2J tumor) and were excreted from the body via the kidneys in the form of hydrophilic metabolites. CONCLUSION: The promising characteristics of [(99m)Tc]Demogastrin 1-3 both in vitro and in animal models illustrate their suitability for CCK-2/gastrin-R-targeted tumor imaging. These qualities could be confirmed for [(99m)Tc]Demogastrin 2, which provided excellent delineation of tumor deposits in a first patient with metastatic medullary thyroid cancer.

Animals↗
PubMed2004

Eprosartan improves cardiac performance, reduces cardiac hypertrophy and mortality and downregulates myocardial monocyte chemoattractant protein-1 and inflammation in hypertensive heart disease.

OBJECTIVE: The purpose of this investigation was to determine whether angiotensin II receptor (AII1R) antagonism interferes with cardiac monocyte chemoattractant protein-1 (MCP-1) expression in hypertrophic cardiomyopathy and failure. DESIGN: We studied the effects of the AII1R antagonist eprosartan on MCP-1 expression, and on the recruitment of macrophages into the myocardium in a model of cardiac hypertrophy and morbidity/mortality. METHODS: Stroke-prone spontaneously hypertensive rats fed a high-salt, high-fat diet (SFD) developed heart failure characterized by left ventricular (LV) hypertrophy/pathology and hypocontractility. These rats received either normal diet, SFD, or SFD with the daily administration of 30 mg/kg eprosartan for 28 weeks. LV function and wall thickness was assessed by echocardiography, MCP-1 expression was measured by TaqMan real-time polymerase chain reaction, enzyme-linked immunosorbent assay and immunohistochemistry, and macrophage infiltration into the LV was determined by microscopy. RESULTS: Eprosartan reduced the rate of morbidity/mortality (P = 0.001), LV MCP-1 mRNA (P < 0.05) and protein expression (P < 0.01), and LV macrophage infiltration (P < 0.01), while preserving ventricular function (P < 0.05). Eprosartan also produced a moderate (16%; P < 0.05) decrease in blood pressure. CONCLUSIONS: These data demonstrate that AII1R antagonism in an animal model of hypertensive heart disease reduces MCP-1 expression in the myocardium that results in reduced macrophage recruitment. These effects parallel the preservation of LV systolic function and the reduction in cardiac remodeling/disease progression and reduced morbidity/mortality. Suppression of MCP-1 expression might explain in part the beneficial effects of AII1R antagonism in this model.

Acrylates↗
PubMed2004

18F-FDG PET, somatostatin receptor scintigraphy, and CT in metastatic medullary thyroid carcinoma: a clinical study and an analysis of the literature.

AIM: To determine the clinical potential of 2-[F]fluoro-2-deoxy-D-glucose positron emission tomography (F-FDG PET) in patients with medullary thyroid carcinoma (MTC), we compared it to computed tomography (CT), and somatostatin receptor scintigraphy (SRS). PATIENTS AND METHODS: Blinded evaluation of PET, CT and SRS images obtained from 26 patients with histologically proven metastatic MTC was done by nuclear medicine and radiology specialists. Sites of tumour involvement were classified as "sure" or "suspicious". The data were analysed in comparison to two different standards. Either those sites classified as "sure" by at least one of the methods were defined as the standard or those sites of involvement which were classified as "sure" by at least two methods. RESULTS: Dependent on the type of data analysis performed, PET was able to demonstrate 56.8%/80.6% of the tumour sites, CT showed 64.5%/79.6%, and SRS showed 47.5%/69.9% of the tumour sites. CONCLUSION: Overall, CT is similar or better than PET in our patients (dependent on the standard) while SRS is inferior to both other techniques. Our data are in agreement with publications that consider CT superior to PET in the diagnosis of metastatic MTC while other studies show superiority of PET. However, a combination of CT and PET seems to be the most appropriate non-invasive diagnostic approach in patients with MTC.

Adolescent↗
PubMed2003

Clinical value of parathyroid scintigraphy with technetium-99m methoxyisobutylisonitrile: discrepancies in clinical data and a systematic metaanalysis of the literature.

There is a considerable discrepancy in the literature concerning the sensitivity of parathyroid scintigraphy (PS) with 99mTc-MIBI. We therefore analyzed our own data and compared them to the literature in a metaanalysis. All patients who received 99mTc -MIBI scintigraphy and subsequent surgery in our department for the detection of enlarged parathyroid glands in primary (pHPT) or secondary (sHPT) hyperparathyroidism between 1991 and 1999 were included in our retrospective analysis. The results of surgery served as the gold standard. For a true positive result, the scintigraphy had to predict the exact location of parathyroid adenoma (PA) or parathyroid hyperplasia (PH). We then compared these data to the results of a nonstatistical systematic metaanalysis of the literature. Patients (178) underwent PS between 1991 and 1999; 139 were operated on and included in this study. Of these, 109 had pHPT and 30 had sHPT. The sensitivity and specificity of the PS were found to be 45%/94% for pHPT and 39%/40% for sHPT. Fifty-two studies concerning PS were included in the metaanalysis. Sensitivities reported varied from 39% to >90%. Consideration of the different possible techniques used for PS could not explain these discrepancies. Our data show that the sensitivity of PS in clinical routine may be lower than expected from the literature. Our data are consistent with other studies and with partially unpublished clinical observations from other university hospitals. We believe that a well-designed and properly conducted prospective study is necessary to evaluate the reasons for the differences observed.

Follow-Up Studies↗
PubMed2003

Influence of somatostatin receptor scintigraphy and CT/MRI on the clinical management of patients with gastrointestinal neuroendocrine tumors: an analysis in 188 patients.

AIM: Many studies describe the sensitivities and specificities of computed tomography (CT), magnetic resonance imaging (MRI), and somatostatin receptor scintigraphy (SRS) in patients with gastrointestinal neuroendocrine tumors (GNT). We performed a study to evaluate the influence of these techniques on the therapeutic management of patients with advanced stages of GNT. PATIENTS AND METHODS: The results of either CT/MRI scans or SRS were reviewed by two independent observers who decided on the therapy of a patient. They then had to determine whether the results of the complementary imaging modality would change the decision. The study design was a matched cross-over study with two groups matching in respect to tumor type, imaging modality known first to the observer, and number of patients. For further analysis, patients were divided into three subgroups dependent on tumor stage (group 1, without metastases, group 2, liver metastases, group 3, recurrent disease/extrahepatic metastases). RESULTS: 188 patients were included into the study. If SRS was known to the observers first, CT/MRI changed the therapeutic management in 16.2, 13.9 and 11.4% of the patients (subgroups 1-3). SRS changed the therapeutic management in 13.5, 12.5 and 10.3%. Overall, CT/MRI would have changed the management in 13.3% and SRS in 11.7% of the patients. CONCLUSION: Though the patients studied mainly suffered from already advanced stages of the disease, all imaging techniques change the therapeutic management to a comparable extent. Our results support the importance of combined imaging in the management of patients with GNT.

Cross-Over Studies↗
PubMed2003

Negative correlation between therapeutic success in radioiodine therapy and TcTUs: are TcTUs-adapted dose concepts the only possible answer?

Calculation of iodine-131 activities for radioiodine treatment (RIT) in patients with disseminated thyroid autonomy may be difficult because of uncertainties in the determination of the autonomous volume (vol(aut)). The algorithm established by Emrich is used for calculation of the vol(aut) based on the TcTUs (technetium thyroid uptake under TSH suppression) (vol(aut)= 5xTcTUs+0.6). Clinical experience using this approach has shown that there is a negative correlation between increasing TcTUs and the results of RIT. Our aim was to identify the reasons for this observation as well as to assess the relation between TcTUs and sonographic vol(aut). Furthermore, we intended to find an alternative algorithm for the TcTUs-based calculation of the vol(aut). Data from 100 patients with unifocal autonomy who met strict inclusion criteria were used to evaluate the correlation between TcTUs and sonographic vol(aut). Using Marinelli's algorithm, we calculated the therapeutic activities for a standardised patient at a target dose of 300 Gy. The vol(aut) was determined based on the TcTUs using the four published algorithms [Emrich 1993 (vol(aut)= 5xTcTUs+0.6), Kreisig 1992 (vol(aut)=10xTcTUs-9.3), Joseph 1977 (vol(aut)=8.33xTcTUs-6.67) and 1994 (vol(aut)=2.88xTcTUs+0.09)]. We then compared the results of the calculation of therapeutic activities obtained using Emrich's algorithm (with known success rates) with those obtained by the other algorithms in order to determine which algorithm would lead to better results in RIT. Only a weak correlation was found between the TcTUs and the sonographic vol(aut) ( r(2)=0.39). The calculated therapeutic activities of (131)I were similar for all algorithms at a TcTUs of around 2% but Joseph's (1977) and Kreisig's (1992) algorithms resulted in clearly higher activities than Emrich's algorithm at a TcTUs above 2%. The need for target doses to increase with TcTUs in RIT may be overcome by the use of adequate algorithms for determination of the vol(aut). The algorithm published by Joseph and co-workers in 1977 probably offers the most reliable approach to the TcTUs-based calculation of vol(aut) in RIT. In contrast to the other algorithms, it is based on autoradiographic planimetric data. Thus, it takes into account the polyclonal origin of thyroid nodules as well as the presence of regressive or cystic changes. The well-established algorithm of Emrich underestimates the true vol(aut), which explains the decreasing success of RIT with increasing TcTUs.

Algorithms↗
PubMed2003

Improved kinetic stability of DTPA- dGlu as compared with conventional monofunctional DTPA in chelating indium and yttrium: preclinical and initial clinical evaluation of radiometal labelled minigastrin derivatives.

The development of monofunctional DTPA derivatives has been a major breakthrough in the labelling of proteins or peptides with a variety of radiometals. Although this methodology is simple and useful for indium-111 labelling, the stability of these conjugates is too low for most therapeutic nuclides. Cyclic chelators, such as DOTA, have shown excellent kinetic stability with a variety of radiometals, but the labelling procedure is more difficult, requiring ultra-pure reagents and a heating step that sometimes endangers the biomolecule's integrity. The aim of this work was twofold: (a) to develop a novel, open chain chelator which can be easily labelled with various radiometals, displaying higher kinetic stability than monofunctional DTPA, and (b) to evaluate this chelator in vitro and in vivo when conjugated to a CCK-B receptor ligand as a detection modality for receptor-(over-)expressing tumours. DTPA derivatives of Leu(1)- and dGlu(1)-minigastrin were synthesised. All conjugates could be labelled with (111)In or (88/90)Y at high specific activities (8.5-44.4 GBq/micro mol) and with high radiochemical purity. Serum stability testing was performed, and the labelled conjugates were compared concerning their stability against DTPA challenge. The biodistribution of the radiolabelled Leu(1)- and dGlu(1)-minigastrin derivatives was studied in tumour-bearing nude mice, in one healthy human volunteer and in three patients with metastatic medullary thyroid carcinoma. The transchelation of all tested radiometals to serum proteins was significantly slower with the DTPA-Glu conjugates as compared with their Leu analogues (e.g. transchelation t(1/2) of DTPA- dGlu(1)-minigastrin vs its Leu(1) analogue at 37 degrees C in human serum for (111)In: 239 h vs 91 h; for (90)Y: 130 h vs 53 h). In animals, all labelled CCK-B receptor ligands showed fast and specific uptake in CCK-B-receptor-positive tissues, such as the stomach and tumour, as well as a fast renal clearance pattern. However, DTPA-Leu(1)-minigastrin showed higher background activity in the whole body and those organs known to accumulate the respective free radiometal (e.g. (88)Y-DTPA-Leu(1)-minigastrin had bone uptake of 22%ID/g as compared to only 1.2%ID/g with its dGlu(1) analogue). In humans, fast tumour and stomach uptake was observed for both (111)In-labelled compounds, but DTPA- dGlu(1)-minigastrin lacked the liver, spleen and bone marrow uptake observed with its Leu(1) analogue. In conclusion, anionic amino acid derivatives of DTPA may display improved metabolic stability as compared with monofunctional DTPA conjugates. DTPA- dGlu(1)-minigastrin is preferred to "monofunctional" DTPA-Leu(1)-minigastrin for diagnostic application with (111)In for the in vivo detection of CCK-B receptor-expressing tissues.

Animals↗
PubMed2003

Radioiodide treatment after sodium iodide symporter gene transfer is a highly effective therapy in neuroendocrine tumor cells.

This study evaluates the possibility of treating Bon1 and QGP pancreatic neuroendocrine tumor cells with radioactive iodide ((131)I) after stable transfection with the thyroid sodium iodide symporter (NIS). NIS expression was driven either by the strong viral cytomegalovirus promoter or by the tissue-specific chromogranin A promoter. Using either approach, NIS expression was confirmed by reverse transcription-PCR and Western blotting. Uptake of radioactive iodide was increased approximately 20-fold by chromogranin A promoter-driven NIS expression and approximately 50-fold by cytomegalovirus promoter-driven NIS expression. Maximal uptake was reached within 15 min in QGP cells and 30 min in Bon1 cells. Effective half-life was 5 min in QGP and 30 min in Bon1 cells. No evidence of organification was detected by high-performance liquid chromatography and gel filtration chromatography. (131)I was a highly effective treatment in NIS-expressing QGP and Bon1 cells, reducing clone formation by 99.83 and 98.75%, respectively, in the in vitro clonogenic assay. In contrast, clone formation was not reduced in QGP and Bon1 cells without NIS expression after incubation with the same activity concentration of (131)I as compared with mock treated cells. Absorbed doses to QGP and Bon1 cells are up to 150 and 30 Gy, respectively. In addition, a direct cytotoxic effect of radioiodide was demonstrated in NIS-expressing Bon1 cells after (131)I incubation. In conclusion, radioiodide treatment after NIS gene transfer appears to be a promising novel approach in the therapy of neuroendocrine tumors if its highly encouraging in vitro effectiveness can be transferred to the in vivo situation.

Carcinoid Tumor↗
PubMed2003

Sustained activation of nuclear factor kappa B and activator protein 1 in chronic heart failure.

OBJECTIVE: Innate immune response proteins such as inflammatory cytokines, inducible nitric oxide synthase, and toll like receptors are implicated in myocardial depression and left ventricular (LV) remodeling after myocardial infarction (MI). Although all these innate immunity proteins share the downstream activation of the transcription factor NF-kappaB (nuclear factor kappa B) and activator protein 1 (AP-1), the involvement of NF-kappaB and AP-1 in LV remodeling has not been demonstrated so far. METHODS AND RESULTS: Nuclear translocation of NF-kappaB and AP-1 was studied by electrophoretic mobility shift assays and ELISA 10 weeks after large experimental MI in rats, the chronic phase of LV remodeling. In the non-infarcted myocardium of MI rats, NF-kappaB and AP-1 were significantly activated (2.5-fold) as compared to sham-operated animals. Immunohistochemistry demonstrated NF-kappaB activation mainly in cardiac myocytes. Treatment with the ACE (angiotensin converting enzyme) inhibitor trandolapril led to a further 2-fold increase in the activation of NF-kappaB and AP-1 when compared to placebo-treated animals with the same MI size (P<0.001). Human failing hearts explanted at the time of heart transplantation exhibited marked nuclear translocation of NF-kappaB in cardiac myocytes when compared to control hearts. NF-kappaB as well as AP-1 were both significantly activated in congestive heart failure due to ischemic or dilated cardiomyopathy. CONCLUSION: In experimental and human heart failure, both NF-kappaB and AP-1 are chronically activated in cardiac myocytes. These findings suggest an important involvement of NF-kappaB and AP-1 in the cardiac remodeling process.

Adult↗