Evidence for Somatostatin receptor 2 in thyroid tissue.

Somatostatin receptor scintigraphy has found considerable interest for imaging thyroid tumours. Recently, also therapeutic application of Somatostatin analogues labelled with beta-emitting radionuclides has been suggested as treatment option for thyroid tumours with absent radioiodine uptake. Most of the radiolabelled analogues available show a predominant affinity for Somatostatin receptor subtype 2. This study reports on the in vitro characterisation of Somatostatin receptor subtype mRNAs in thyroid tumours and normal thyroid tissue by means of RT-PCR. Surgical samples of 21 patients were collected, and mRNA of 16 tumour and 17 control specimen was isolated. mRNA expression for Somatostatin, SSTR subtype 1-5, thyroid markers (NIS, TSH, Tg, TPO) and control markers (GAPDH, beta-actin) was determined. PCR results were correlated with immunohistochemistry staining using SSTR2 receptor specific antibodies. 94% of all samples expressed Somatostatin receptor mRNA with predominant expression of subtype 2, less predominant of subtype 5 and subtype 3. Somatostatin receptor subtype 2 mRNA expression correlated well with immunohistochemical staining pattern in 13/16 samples, SSTR2 immunohistochemistry was positive in 87% of the samples. Our results show that Somatostatin receptor 2 is predominantly expressed on thyroid tissue and is a valid target for treatment of thyroid tumours. Octreotide derivatives currently used in Nuclear medicine seem to be well suited to target receptors expressed in thyroid tumours.

Evidence for interaction between the TCO and NMTC1 loci in familial non-medullary thyroid cancer.

BACKGROUND: Familial non-medullary thyroid cancer (fNMTC) is a complex genetic disorder that is more aggressive than its sporadic counterpart. Thus far, three genetic loci have been implicated in susceptibility to fNMTC by linkage analysis. METHODS: We used linkage analysis to test the significance of two of the known susceptibility loci for fNMTC, TCO on 19p13 and NMTC1 on 2q21 in 10 fNMTC families, nine of which present with cell oxyphilia, a rare histological phenotype associated with TCO. Furthermore, we used two-locus linkage analysis to examine the possibility that the TCO and NMTC1 loci interact to increase the risk of NMTC. RESULTS: The 10 families provided evidence for linkage at both TCO and NMTC, with LOD scores of 1.56 and 2.85, respectively. Two-locus linkage analysis, using a multiplicative risk model for the development of NMTC, achieved a maximum LOD of 3.92, with an LOD of 4.51 when assuming 70% of families were linked, indicating that the segregation in these families is consistent with an interaction model. Most of this evidence came from a large Tyrolean family that singularly achieved a two-locus LOD of 3.21. CONCLUSIONS: These results provide further evidence that susceptibility genes for fNMTC exist at 19p13 and 2q21, and furthermore, raise the possibility that in a subset of fNMTC pedigrees, these loci interact resulting in significantly increased risk of NMTC for patients that carry both susceptibility loci.

In vitro and in vivo evaluation of iodine-123-Ro 16-0154: a new imaging agent for SPECT investigations of benzodiazepine receptors.

The flumazenil analogue, Ro 16-0154, a benzodiazepine partial inverse agonist, has been labeled by halogen exchange to enable SPECT investigations of central benzodiazepine receptors in the human brain. The purified 123I-Ro 16-0154 was found to be stable in rat brain preparations and to be metabolized in rat liver preparations. Its pharmacologic properties were comparable to those of flumazenil. The biodistribution in rats (1 hr postinjection) resulted in a high brain-to-blood ratio of 16. Clinical studies revealed images of the benzodiazepine receptor density in the brain. Since the receptor labeling was markedly reduced by injection of flumazenil, it was considered to be specific. Storage defects due to pathologic cerebral blood flow and changed receptor density were detected; this shows the potential usefulness of the substance for diagnostic purposes, e.g., the differential diagnosis of various forms of epilepsy.

The influence of povidone-iodine treatment on thyroid hormones in severe burns.

Average iodine serum levels of 2.5 mg/100 ml were obtained in 10 patients with an average burn area of 50% and treated with povidone-iodine. Simultaneous measurements of the thyroid hormones failed to reveal any significant impairment of thyroid function apart from depressed T3 coupled with increased reverse T3. Similar findings were obtained with a control group of 10 multiply-injured patients. If renal function is unimpaired the resorbed iodine is quickly excreted. No clinical signs of iodine intoxication were observed.

The use of electronic autoradiography in radiopharmacy.

The use of Microchannel Plate Analysers (Instant Imager, Canberra Packard), the so called Electronic Autoradiography, in Radiopharmacy is described. The system can be used for quality control of radiopharmaceuticals as well as for scientific research purposes. Quantitative analysis of 2-dimensional radioactive samples of all radionuclides used in Nuclear Medicine (especially 99mTc) can be performed in a very short time with little effort. Advantages and limitations for radiopharmaceutical work are described.

Determination of Sn(II) in technetium cold kits by voltammetry at the hanging mercury drop electrode (HMDE) and relevant radiopharmaceutical applications.

A novel approach for the determination of the stannous content in cold kits for labelling with 99mTc is described. The method is based on differential pulse polarography on the hanging mercury drop electrode in a methanol/water/perchloric acid mixture and is easy to perform. Examples for the determination of tin(II) in fractionated technetium cold kits are shown. The stability of tin(II) in solution was mainly dependent on the storage temperature and the kit composition. The low stability of stannous ions under certain conditions was shown to be the main reason for low radiochemical purity. Limits and dangers of fractionating kits are discussed and related to content and instability of tin(II).

Incidence and clinical characteristics of thyroid carcinoma after iodine prophylaxis in an endemic goiter country.

Iodized salt prophylaxis has been performed in Austria since 1963. Through this approach, mean urinary iodine excretion has been normalized to 144+/-23.5 microg/g creatinine per day. Thus Tyrol is no longer an endemic goiter area. We have analyzed the impact of iodized salt prophylaxis on thyroid cancer (TC) comparing data from the early 1960s with those corresponding to the period 1986 to 1995, when iodine supply was normalized. The study included 439 patients from Tyrol and Southern Tyrol. The incidence of TC in Tyrol has risen during the past decades from 3.07 between in 1957 and 1970 to 7.8 between 1990 and 1994 (CR/100000/year). We observed a rise in the percentage of differentiated adenocarcinomas (56% to 91.5%) with a predominance of papillary TC (54.4%) along with a decrease of anaplastic TC. In addition to these histological features, a shift to less advanced TNM stages, eg, T1-3, N0-1a, M0, was obvious, increasing from 29% to 72.2%, whereas advanced tumors, ie, T4 or N1b or M1, decreased from 71% to 28%. These changes have significantly improved prognosis. The current 5-year survival rate is 90.7% as compared with a rate of 73% in the 1960s; the values for 7-year survival are 89% and 48%, respectively. The marked effects of age, tumor stages, and histology on prognosis were confirmed with the Kaplan-Meier method. We conclude that together with normalization of iodine supply in an endemic goiter region the epidemiological profile of TC has changed. Even though the incidence of TC has risen, prognosis has significantly improved due to a shift towards differentiated forms of TC that are diagnosed at earlier stages.

beta 1-Integrin expression in papillary thyroid carcinoma.

beta 1-integrins are widespread adhesion molecules which belong to a family of heterodimeric membrane glycoproteins and consist of two subunits, alpha and beta. Integrins seem to play an important role in the spreading and metastasis of malignant tumors. We investigated the expression and distribution of these adhesion molecules on papillary thyroid carcinomas by immunohistochemistry on formalin-fixed, paraffin embedded cancer tissues. We estimated the beta 1-integrin expression in cancerous areas in comparison to normal adjacent thyroid tissue. Our results revealed a highly significant difference in all investigated parameters between cancer and normal thyroid cells (p < 0.0001). Comparing our findings with the metastatic potential of the primary thyroid tumors, our results show that beta 1-integrin expression could be used as a prognostic parameter for papillary thyroid tumors.

Surgical therapy for primary hyperparathyroidism in patients with previous thyroid surgery.

BACKGROUND: In patients with primary hyperparathyroidism (HPTH) and previous thyroid operations, complications of parathyroidectomy are more frequent than in patients undergoing initial neck surgery. The aim of this study was to investigate the value of preoperative imaging with regard to its influence on the surgical strategy. METHODS: We retrospectively analyzed 17 patients with primary HPTH and previous thyroid surgery. Preoperatively 16 patients underwent sonography and/or scintigraphy. RESULTS: Sonography had an overall accuracy to correctly localize enlarged parathyroid glands of 80%, and scintiscanning had overall accuracy of 78.6%. The accuracy of localization was increased up to 84.6% if both diagnostic procedures were applied. In patients with normal thyroid residues the accuracy of sonography was 85.7%, and it was 100% if scintiscanning was used. CONCLUSIONS: Preoperative localization techniques in patients with primary HPTH and previous thyroid surgery have high accuracy. This allows for an imaging-directed operative strategy, thus preventing unnecessary bilateral neck explorations, which carry a high risk of recurrent laryngeal nerve injury.

Comparison of serum neopterin levels and urinary neopterin excretion in renal allograft recipients.

Determination of serum and urinary neopterin levels was performed daily in 30 patients undergoing kidney transplantation for treatment of end-stage renal failure. Neopterin serum levels were determined by RIA and urinary excretion by HPLC. In parallel, the same samples were tested for creatinine content. Results indicated a strong correlation between the clearance of neopterin and creatinine. This correlation was independent of the extent of functional impairment as well as of the different causes of renal insufficiency. As a consequence, a strong relationship between serum and urinary neopterin levels was only obtained when values were corrected for different renal function by dividing them by the creatinine levels. It thus appears that major attention has to be paid to the functional state of the kidney when studying neopterin serum and/or urine values. It also appears that under these prerequisites both methods of detection as well as both sample sources yield comparable results.

[Quality control of radiopharmaceuticals from the clinical aspect--a necessity?]. / Qualitätskontrolle von Radiopharmaka in der Klinik--eine Notwendigkeit?

Radiopharmaceuticals are a special group of drugs since many are eventually prepared in the hospital and the nuclear medicine department is responsible for meeting quality criteria such as sterility, radionuclide, radiochemical and chemical purity of these drugs. We tested 266 preparations of 14 different radiopharmaceuticals from commercial kits for their radiochemical purity. Only four compounds showed deficiencies in labelling (anti-granulocyte MAb, HIG, HMPAO, MAG3, altogether 18 preparations). All of them were 99mTc-pharmaceuticals with a relatively low tin content of the kit. The reasons for the poor quality of these products could be found. This study shows the importance of a good quality control system (including other tests like sterility and environmental monitoring) to guarantee the safety and efficacy of radiopharmaceuticals prepared in the hospital.

Radiochemical purity of routinely prepared 99Tcm radiopharmaceuticals: a retrospective study.

Radiochemical purity is an important quality parameter for radiopharmaceuticals. In this study, the radiochemical purity of 2090 samples out of 7000 routine preparations of 20 different 99Tcm radiopharmaceuticals was tested using standard methods over a period of more than 7 years. The mean radiochemical purity was 96.92% (standard deviation = 6.71%). Seventy-four preparations failed to meet radiochemical purity limits; that is, 3.54% of all preparations tested or 1.06% of all preparations in the observation period. The reasons for substandard preparations were mainly related to laboratory-specific conditions. The introduction of a dedicated quality control protocol allowed the elimination of many sources of labelling failures and could reduce the number of administered preparations with an insufficient radiochemical purity. We stress the need for quality control in the preparation of radiopharmaceuticals and provide original radiochemical purity values of routinely prepared 99Tcm radiopharmaceuticals.

Double-tracer SPECT in patients with AIDS encephalopathy: a comparison of 123I-IMP with 99Tcm-HMPAO.

Single photon emission computed tomography (SPECT) using N-isopropyl-p-(123I)iodoamphetamine (123I-IMP) and 99Tcm-hexamethylpropyleneamine oxime (99Tcm-HMPAO) was performed in 25 patients with different clinical stages of AIDS encephalopathy. The average interval between the two examinations was 7 days. In 15 of the 25 cases (60%) 99Tcm-HMPAO scans were different from 123I-IMP scans. Uptake defects of different extent were observed in 8 of 25 cases (32%), of different extent and different location in 3 of 25 cases (12%) and of identical extent but of different location in 4 of 25 cases (16%). Differences in the uptake patterns of 123I-IMP and 99Tcm-HMPAO with regard to extent and/or location were more commonly shown in patients with early acquired immunodeficiency syndrome (AIDS) encephalopathy (P = 0.0372). In this group, 99Tcm-HMPAO showed uptake defects of greater extent more frequently than did 123I-IMP (P = 0.0156). Our data indicate different brain uptake mechanisms of 123I-IMP and 99Tcm-HMPAO in early and advanced AIDS encephalopathy.

Whole-body scintigraphy with 99Tcm-MIBI, 18F-FDG and 131I in patients with metastatic thyroid carcinoma.

We assessed the relative usefulness of whole-body planar scintigraphy with 99Tcm-methoxyisobutyl isonitrile (99Tcm-MIBI), 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG-RS) rectilinear scanning and with diagnostic and therapeutic doses of 131I, for the detection of local recurrences and metastatic lesions in 12 patients with thyroid carcinoma and elevated thyroglobulin serum levels. All images were evaluated independently by three experienced observers to define the number and location of metastatic lesions. 18F-FDG-RS and 99Tcm-MIBI scintigraphy provided similar results, but the tracer that allowed the detection of the highest number of metastases was 99Tcm-MIBI. Both 99Tcm-MIBI scintigraphy and 18F-FDG-RS appear to be more sensitive than 131I scintigraphy for the detection of metastases of thyroid carcinoma. Tomographic acquisitions were also performed on a limited field of view in each subject and, as expected, 18F-FDG-PET was more sensitive than 18F-FDG-RS. 99Tcm-MIBI scintigraphy, a widely available and relatively non-expensive technique, therefore sems suitable for the assessment and follow-up of patients with metastatic thyroid carcinoma and does not require the withdrawal of hormone therapy for lesion imaging.

One year's clinical experience of 18F-FDG PET with a modified SPET camera using molecular coincidence detection.

High-quality positron emission tomographic (PET) cameras are expensive and, therefore, not available in many centres. To allow access to clinical 18F-fluorodeoxyglucose (18F-FDG) PET, we began working with an ADAC Vertex camera equipped with a molecular coincidence detection (MCD) module in February 1997. Here we give a preliminary assessment of the clinical utility of our approach. To date, 109 studies have been performed in MCD-mode using standardized protocols (99 oncology cases, 10 neurology cases). Twenty-eight cardiological and 15 other studies were performed using 511 keV collimators without attenuation correction. The average dose of 18F-FDG for MCD studies was 150 MBq, thus avoiding overloading the detectors; cardiac studies required 370 MBq. The results obtained were carefully compared with computed tomography, magnetic resonance imaging, myocardial perfusion scans, coronary angiography and conventional radiology. The results were compared on a patient basis, including histology, surgical notes, autopsy reports and follow-up data. Oncological studies were performed to assess malignancy in a particular lesion (n = 22), staging of cancer (n = 57) or to evaluate whether therapy had been successful or not (n = 20). Indications for conducting studies were categorized as appropriate (Ia) or adequate (Ib). For Ia category cases, the results were: true-positive = 31, true-negative = 12 and false-positive = 2. For Ib category cases, the corresponding figures were: true-positive = 18, true-negative = 10, false-positive = 3 and false-negative = 1. False-positive studies were a result of inflammatory disease or artefacts. Six cases with temporal lobe epilepsy were correctly identified. In cardiac studies, we also found a good correlation with clinical parameters (i.e. hibernating myocardium or scarred tissue). Altogether, this cost-effective set-up allows nuclear medicine institutions to obtain valuable data in clinical practice with a system used both for single photon emission tomography and PET.

Detection of myocardial involvement in systemic lupus erythematosus: mismatch between normal perfusion scans with 201Thallium and pathological 18FDG uptake.

BACKGROUND: Systemic lupus erythematosus (SLE) patients can frequently present cardiac symptoms, however its etiology is not well known. EXPERIMENTAL DESIGN: prospective study. SETTINGS: specialized out-patient unit for SLE patients at an university hospital. PATIENTS: 15 SLE patients (13 females, 2 males; age range 18-64 years). INTERVENTIONS: metabolic studies of the heart were done using 18F-deoxy-glucose (18FDG, 296-333 MBq on a 2-head hybrid system) as well as heart perfusion studies (111MBq 201Tl). Additional studies: resting ECG, echocardiography, stress ECG, immunological activity parameters, antibody analyses (ANA, ENA, anti-cardiolipin antibodies), CPK, troponin-T, and lipid profiles. MEASURES: degree of correlation between conventional diagnostics and the imaging techniques. RESULTS: Abnormal ECG in 10 cases, pericardial involvement in 11 cases, elevated CPK in 1 case. ANTIBODY PROFILES: anti-cardiolipin in 10/15, ENA in 9/15, ANA in 14/15. None of these changes were associated with parameters of immune activation. In the majority of cases (10/15) the 18FDG scan showed a speckled, inhomogeneous pattern of distribution, which contrasted sharply with a normal 201Tl scan. A similar pattern was observed in the patients with ocular mitochondrial myopathy, the anti-phospholipid syndrome as well as in dermatomyositis. CONCLUSIONS: Our preliminary results suggest that SLE patients with cardiac symptoms may have an abnormal glucose metabolism of the myocardium as shown by a pathological 18FDG scan, whereas perfusion appears to be normal (reversed mismatch). The lack of correlation with acute elevation of cardiac enzymes or with ECG changes suggest a chronic process.

[Tumor markers in endocrinology (without gynecology and urology)]. / Tumormarker in der Endokrinologie (ohne Gynäkologie und Urologie).

In tumours of the endocrine system there are very few real "tumour markers" (e.g. CEA); all other relevant tests measure by radioassay several endocrine materials which are produced in similar ways by tumours and normal glands. Therefore, tumour marker assays in endocrinology are usually performed in follow-up studies after more or less radical therapy of tumours of the pituitary gland, thyroid gland, parathyroid glands, endocrine pancreas and the adrenal glands. On the basis of approximately 3000 assays of HGH, prolactin, thyroglobulin, calcitonin, CEA, insulin, gastrin, cortisol and aldosterone (in part with suppression and/or stimulation techniques), it is shown that these mostly indirect tumour marker assays are very important in follow-up programmes after therapy of neoplasms of the endocrine system. Their sensitivity amounts to 80%, their specificity is of the same degree.

[Advances in the diagnosis of renal function with radionuclides (author's transl)]. / Fortschritte der nuklearmedizinischen Funktionsdiagnostik der Nieren.

Nuclear medicine offers the possibility of quantitative (clearance techniques) and semiquantitative (sequential gamma-camera studies) renal function studies, which can be done with minimal discomfort to the patient at a low radiation exposure. Scintillation cameras with data-storing and computer systems are used after administration of labelled chelates (99mTc-DTPA, 111In-DTPA, 51Cr-EDTA) and labelled contrast media excreted by glomerular filtration (131I-Iothalamate, 131I-Hypaque) and after injection of 131I-ortho-iodo-hippuric acid (131I-Hippuran). The use of 99mTc gives further information on regional renal perfusion, which can be supplemented by exact data after injection of 133Xe into the renal artery. The described methods have proved to be valuable in the diagnosis of renal artery stenoses, in the follow-up of inflammatory kidney disease, in the assessment of hypertensive patients, in the differentiation of renal lesions with destruction of parenchyma, in the follow-up of urinary tract obstruction and in the follow-up of patients with transplanted kidneys over many years. The correlation of nuclear medicine data with chemical and clinical parameters is excellent. Studies of renal function by radionuclides have, thus, acquired an important role in the evaluation and follow-up of nephrological and urological patients.

[Absorption and pharmacokinetics of large doses of 1-thyroxine in man (author's transl)]. / Resorption und Pharmakokinetik grosser Dosen von 1-Thyroxin beim Menschen

In recent years suppression tests with a single dose of 3 mg 1-thyroxine (T4) and weekly doses of 1 mg T 4 in the treatment of hypothyroidism have been put to clinical trial and the lack of side-effects of such high doses (5 to 15 X daily requirements) was stressed. Hence, it was decided to study the absorption of 1-T-4 from the gastrointestinal tract and its metabolism in euthyroid patients. Doses from 250 to 2500 mug T 4, mixed with 250 muCi 131I-thyroxine were given to 10 patients. After the thyroid had been blocked with perchlorate, the excretion was followed in faeces and urine for 4 to 5 days, the thyroid uptake of 131I was checked and serial blood samples were drawn to follow plasma activity curves. Quantitative analyses of T 4, triiodothyronine (T 3), ETR and TSH were also performed on the plasma samples, whilst paper chromatography of urine samples allowed a further separation of iodide and organic iodine compounds. The results showed a definite rise in plasma T 4 levels after administration of large T 4 doses, with a simultaneous increase in T 3 values. Doses of 2500 mug T 4 temporarily produce abnormally elevated plasma T 4 and ETR values, whilst T 3 increases to the upper limit of the normal range. The relatively moderate reaction of the mentioned parameters following the administration of large T 4 doses can be partly explained by the considerably lower faecal excretion of T 4 with doses of 250 mug T 4 than with high T 4 doses. There is also an intensive binding of T 4 to TBG up to single doses of 1000 mug T 4, which provides an adequate metabolic "buffer" and declines only after saturation of the TBG binding capacity at higher dosage. Moreover, larger doses of T 4 are metabolized quicker than smaller ones. The above-mentioned results allow the following conclusions: 1. Very large single doses of T 4 (2500 to 3000 mug) are less easily absorbed from the gastrointestinal tract than "physiological" doses. 2. The degradation of T 4 at high dosage is quicker than at lower dosage. 3. The intensive binding of T 4 to TBG explains the lack of side effects with large doses of orally-administered T 4. 4. On the basis of the present data single doses of 500 to 1000 mug T 4 can be recommended for therapeutic purposes.

[Thyroid proteins in endemic goitre and their relationship to the intrathyroidal thyroid hormone concentration]. / Schilddrüsenproteine in endemischen Strumen und ihre Beziehung zur intrathyreoidalen Schilddrüsenhormonkonzentration.

According to several reports we suspected that the pathogenesis of endemic goitre cannot be explained by iodine deficiency only, but that other--partially endogenous--goitrogenic factors must be present. We therefore studied 16 cases of "euthyroid" endemic goitre from the endemic goitre area of the province of Bolzano in Italy. After fractionation of tissue homogenates, T 4 and T 3 were measured by RIA and the I concentration was also termined. Thyroglobulin and its fractions were measured by ultracentrifuge procedures after assessment of the total protein concentration. Evaluation of the present results suggests that an insufficient synthesis of thyroglobulin in the examined goitres induces an inadequate adaptation of the organism to iodine deficiency, which, in turn, decreases the thyroid hormone concentration in thyroid tissue and enhances goitrogenesis. Considering the normal iodine content of the examined tissues, there obviously seems to be two intrathyroidal iodine pools, one of which supplies the body with thyroid hormones under pituitary stimulation even though its thyroglobulin pool is reduced, while a significant amount of the thyroidal iodine pool is bound in metabolically inert protein molecules and therefore increases the goitrogenic effect of iodine deficiency.