[Continously increasing sensitivity in thyroid cancer aftercare in the course of three generations of thyroglobulin IMAs]. / [Kontinuierliche Sensitivitatssteigerung in der Schilddrusenkarzinom-Nachsorge im Verlauf dreier Thyreoglobulin-IMA-Generationen]

UNLABELLED: Aim of our study was to evaluate the increasing sensitivity within three generations of thyroglobulin (Tg) assays, which were available during the past decade, and its clinical impact for patients with differentiated thyroid carcinoma. METHODS: Determination of Tg using the IRMA introduced in 1989 (Dynotest Tg, Henning Berlin, Berlin; assay A) and 1994 (Selco Tg, Medipan Diagnostica, Selchow; assay B), as well as the IEMA available recently (Medizym Tg Rem, Medipan Diagnostica, Selchow; assay C). RESULTS: We found a close correlation between the measurable Tg values of assay A and B (r=0.985; p<0.001) as well as assay B and C (r=0.978; p<0.001). Assay B (lowest detection limit: 0.3 ng/ml) was more than twice as sensitive as assay A and did not show quite as many disturbances of recovery (in 0.5% versus 4% of our patients). Due to its strict calibration to the European reference preparation CRM 457, Tg values determined by assay C were in the mean 1.9-fold higher than by assay B. Thus, with its functional sensitivity of 0.03 ng/ml assay C is nearly 20-fold more sensitive than assay B. Whereas the proportion of measurable Tg values was only 22% in a selected group of patients (criterion of inclusion: Tg in assay B< or =1 ng/ml with TSH-suppressive conditions; n=317 serum samples from 103 patients), it was 68% in assay C, with good intraindividual reproducibility of these values in the course. CONCLUSION: The ultrasensitive assay C is especially suitable for the follow-up of treated thyroid cancer patients being considered as cured, and may shorten the time interval until the detection of a recurrence markedly: the gain of time calculated from the Tg courses in patients with a gradually progressive tumor relapse ranged from 5 to 15 months.

Myocardial perfusion abnormalities in patients with active acromegaly.

Cardiomyopathy is often seen in patients with a long history of acromegaly. In order to screen for perfusion abnormalities, patients with active acromegaly without evidence for coronary heart disease were examined by single photon emission computed tomography (SPECT). The study included a group of 11 strictly selected patients with active acromegaly (7 males and 4 females; age 51 +/- 12 y [mean +/- S.D.]) with elevated age-adjusted IGF-I levels (IGF-I 569 +/- 193 micro g/l; GH 31.2 +/- 56.3 micro g/l) compared to an age- and sex-matched non-acromegalic control group with comparable muscle mass index of the left ventricle (126 +/- 41 active vs. 122 +/- 33 g/m 2 control group) and body mass index (26.6 +/- 2.7 vs. 27.0 +/- 5.0 kg/m 2). To address this issue, myocardial perfusion was investigated by single photon emission computed tomography (SPECT) using a triple head gamma-camera. 70 MBq 201TlCl was injected, and post-stress (from bicycle ergometer) images were obtained. Images were interpreted quantitatively by bull's eye polary map (16 regions of the left ventricle) and were compared to the control group. In the patients with active acromegaly, the mean nuclide uptake of the 16 regions of the left ventricle after bicycle stress examination was lower than in the control group (82.99 +/- 2.85 active vs 85.48 +/- 1.29 control group, p < 0.01). Non-homogeneity of nuclide uptake was defined as the standard deviations of the 16 regions and was higher in patients with active acromegaly (11.11 +/- 2.35 active vs. 8.77 +/- 1.39 control group, p < 0.01). In conclusion, myocardial perfusion is impaired in patients with active acromegaly, thus representing an early stage of cardiac involvement in acromegaly that may be directly mediated by growth hormone excess.

[Evaluation of myocardial viability with contrast-enhanced magnetic resonance imaging--comparison of the late enhancement technique with positronemission tomography]. / Myokardiale Vitalitätsdiagnostik mit kontrastverstärkter Magnetresonanztomographie - Vergleich des "late enhancement"-Konzepts mit der Positronen-Emissions-Tomographie.

PURPOSE: To compare contrast-enhanced magnetic resonance imaging (MRI) and positron emission tomography (PET) in the evaluation of myocardial viability. METHODS: [ (18)F]-FDG-PET, [ (201)Tl]-TlCl-SPECT and contrast-enhanced MRI were performed in 29 patients with proven coronary artery disease and impaired left ventricular function to assess myocardial viability. MRI scans were done on a 1.5 T scanner (Magnetom Sonata, Siemens, Germany). After the steady-state free precession cine study, 0.2 mmol/kg BW of Gd-DPTA (Magnevist(R), Schering, Germany) were administered i. v. For the detection of "late enhancement" (LE) indicating scar, left ventricular long axes and contiguous short axis slices of 8 mm thickness were scanned using an inversion recovery turbo gradient echo sequence (TR 8.0 ms; TE 4.0 ms; TI 180 - 240 ms; FA 20 degrees ). The evaluation of LE and FDG uptake in PET with perfusion defect in SPECT was done using an 8 (basal, mid) and 4 (apical) segment model in all short axes to cover the entire ventricle. The transmural extent of LE was assessed using a 4-point score system. Comparison between the two modalities was performed on a segmental basis. RESULTS: A total of 1753 segments were assessed. In MRI, 40 % of the segments showed myocardial scar, whereas PET revealed impaired uptake in 25 %. MRI obtained a very low interobserver variability in detecting myocardial scar (kappa 0.92). Using PET as the standard of reference in the segmental comparison, contrast-enhanced MRI yielded a sensitivity of 84 % and a specificity of 76 % for the detection of scar. 18 % of all segments showed LE but normal FDG uptake, 83 % of them referred to subendocardial scars. CONCLUSIONS: There is close agreement between contrast-enhanced MRI and PET in detecting transmural myocardial scars. Superior spatial resolution enables MRI to detect and quantify even subendocardial scar. Therefore, larger studies using functional recovery after revascularisation as an endpoint have to prove whether MRI might replace PET as the standard of reference in the assessment of myocardial viability.

[Sinus node dysfunction with intermittent sinus arrest and AV-nodal escape rhythm as initial manifestation of pheochromocytoma]. / Sinusknotendysfunktion mit intermittierendem Sinusarrest und AV-junktionaler Ersatzrhythmus als Erstmanifestation eines Phäochromozytoms.

A 25-year-old male student complained about episodic palpitations, dizziness, nausea and headache 5 years prior to presentation. No otorhinolaryngic, neurologic or gastrointestinal causes were identified. Several ECG recordings revealed sinus node dysfunction with intermittent sinus arrest and AV-nodal escape rhythm. The patient was given a permanent DDD-pacemaker. Six months later, the clinical symptoms were unchanged. During an attack, physical examination revealed paleness, diffuse sweating and an arterial blood pressure of 250/130 mmHg, which decreased to 120/80 mmHg within a few minutes. Abdominal ultrasound and abdominal computed tomographic scan demonstrated the presence of a large (6.4 x 5.5 cm) left-sided adrenal mass. Two 24-h-urinary collections demonstrated elevated noradrenaline (mean 315 micrograms/24 h, normal < 80 micrograms/24 h) and adrenaline (mean 268 micrograms/24 h, normal < 20 mg/24 h) levels. Blood samples, which were drawn during excessive blood pressure rise, revealed elevation of plasma catecholamines (6.793 pg/ml for adrenaline (normal 50-150 pg/ml) and 10.424 pg/ml for noradrenaline (normal 200-500 pg/ml), so that the diagnosis of pheochromocytoma was considered established. The tumor was successfully removed during laparascopic surgery. After surgery, the patient remained well and normotensive. Three months later, several long-term ECG recordings showed sinus arrhythmia with no evidence of sinus arrest or AV-nodal escape rhythm, so that the DDD pacemaker was turned off. This case underlines that sinus node dysfunction with intermittent sinus arrest and AV-nodal escape rhythm is a potential early manifestation of a pheochromocytoma. These changes seem to disappear after successful removal of the tumor.

Fluorine-18 fluorodeoxyglucose positron emission tomography in medullary thyroid cancer: results of a multicentre study.

The aim of this study was to evaluate the clinical use of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in medullary thyroid cancer (MTC) on the basis of comparison with findings obtained using indium-111 pentetreotide (SMS), pentavalent technetium-99m dimercaptosuccinic acid (DMSA), technetium-99m sestamibi (MIBI), computed tomography (CT) and magnetic resonance imaging (MRI). One hundred FDG-PET examinations in 85 patients (40 males, 45 females) with elevated tumour marker levels and/or pathological findings on other imaging methods were evaluated retrospectively. Eighty-two patients were examined after total thyroidectomy, and the remaining three patients prior to surgery. Overall, 181 lesions could be identified with at least one of the imaging techniques. Fifty-five lesions were confirmed histologically. FDG-PET detected 123 of 181 sites, which is a lesion detection probability of 68%. In the 55 cases with histological confirmation, we found 32 true positive, 3 false positive, 11 true negative and 9 false negative lesions using FDG-PET, resulting in a sensitivity of 78% and a specificity of 79%. Sensitivity and specificity were, respectively, 25% and 92% for SMS, 33% and 78% for DMSA, 25% and 100% for MIBI, 50% and 20% for CT and 82% and 67% for MRI. Compared with morphological techniques and functional imaging methods with single-photon emitters, FDG-PET showed the highest lesion detection probability for MTC tissue, with a high sensitivity and specificity. It is concluded that FDG-PET is a useful method in the staging and follow-up of MTC.

Parametric oesophageal multiple swallow scintigraphy for validation of dysphageal symptoms during external beam irradiation of mediastinal tumours.

The aim of the study was to evaluate dysphageal symptoms and to measure the effect of local analgesic treatment using parametric oesophageal multiple swallow scintigraphy (PES) during external beam irradiation of the mediastinal region. Fifteen patients (most with lung cancer) with dysphagia grade II underwent PES during external beam radiotherapy of the mediastinum before and after application of local analgesics. Dynamic parametric condensed images were recorded. The intensity of clinical symptoms was correlated with the emptying rate at 10 s (ER-10 s) and the mean transit time (MTT). Visual analysis of the images was performed and the results were correlated with the fields of irradiation portals. Of the 15 patients, 12 showed a correlation between irradiation portals and the region of oesophageal motility disorder. Concordant results of clinical symptoms and PES data were found. In nine patients with a decrease in dysphagia following local analgesia, an increase in mean ER-10 s and a decrease in MTT were observed. In three patients with deterioration in clinical symptoms after analgesic treatment, a similar decrease in mean ER-10 s was found, though MTT remained constant. In three patients with normal values, motility disorders were detected in the dynamic study. In conclusion, PES was found to be a sensitive tool for the validation of dysphageal symptoms in patients during external beam irradiation of mediastinal tumours and for the evaluation and quantification of the efficacy of local analgesic treatment. Additional visual analysis of the dynamic study is helpful in diagnosing minimal disorders.

Auxiliary rat liver transplantation with portal vein arterialization in acute hepatic failure.

BACKGROUND: The aim of our work was to study the effect of the portal vein arterialization of an auxiliary liver graft on survival, liver function, and regeneration of the native liver suffering from surgically induced acute liver failure (ALF). METHODS: In Lewis rats (control group: n=10), ALF was induced by resection of about 85% of liver tissue. The auxiliary liver graft (reduced size of 30%) was transplanted into the right upper quadrant of the abdomen (trial group: n=12). The portal vein was arterialized via the renal artery. The infrahepatic vena cava was anastomosed end-to-side, and the bile duct was implanted into the duodenum. RESULTS: Survival rate over a 3-month period was 10/12 in the trial group vs. 2/10 in the controls. In the trial group, the prothrombin time rose up to 38+/-2 sec on day 1 after surgery (control group: 66+/-6 sec); on day 5 after surgery, it returned to values of 30+/-1 sec. On day 1 after surgery, serum albumin fell to 25+/-1 g/L (preoperative value: 32+/-1 g/L). Within 3 weeks, it returned to normal. The hepatobiliary scan on day 7 after surgery showed normal uptake in the liver graft, whereas the uptake of the native liver was distinctly reduced. After 3 months, the transplanted liver had atrophied (0.6% of body weight), the native liver hypertrophied (2.5% of body weight), with a normal total weight for both livers of 3.1% of body weight. CONCLUSIONS: Thus, auxiliary liver transplantation with arterialized portal vein allows maintenance of liver function at the time of ALF and regeneration of the native liver.

The value of fluorine-18 fluorodeoxyglucose PET in patients with medullary thyroid cancer.

The early detection of metastases from medullary thyroid cancer (MTC) is important because the only curative therapy consists in surgical removal of all tumour tissue. There is no single sensitive diagnostic imaging modality for the localization of all metastases in patients with MTC. Therefore, in many cases several imaging modalities (e.g. ultrasonography, magnetic resonance imaging, computerized tomography and scintigraphy using pentavalent technetium-99m dimercaptosuccinic acid, thallium-201 chloride, indium-111 pentetreotide, anti-CEA antibodies or metaiodobenzylguanidine) must be performed consecutively in patients with elevated calcitonin levels until the tumour is localized. In this prospective study, we investigated the value of fluorine-18 fluorodeoxyglucose positron emission tomography ([18F]FDG PET) in the follow-up of patients with MTC. [18F]FDG PET examinations of the neck and the chest were performed in 20 patients with elevated calcitonin levels or sonographic abnormalities in the neck. Positive [18F]FDG findings were validated by histology, computerized tomography or selective venous catheterization. [18F]FDG PET detected tumour in 13/17 patients (nine cases were validated by histology, four by computerized tomography). Five patients showed completely negative PET scans (of these cases, one was true-negative and four false-negative). One patient with [18F]FDG accumulation in pulmonary lesions from silicosis and one patient with a neck lesion that was not subjected to histological validation had to be excluded. Considering all validated localizations, [18F]FDG PET detected 12/14 tumour manifestations in the neck, 6/7 mediastinal metastases, 2/2 pulmonary metastases and 2/2 bone metastases. In two patients with elevated calcitonin levels, no diagnostic modality was able to localize a tumour. The sensitivity of [18F]FDG PET in the follow-up of MTC was 76% (95% confidence interval 53%-94%); this is encouraging. [18F]FDG PET promises to be a valuable diagnostic method, especially for the detection of lymph node metastases, surgical resection of which can result in complete remission.

[Relationship between thyroglobulin and reliability of thallium 201 scintigraphy in differentiated thyroid cancer]. / Beziehung zwischen Thyreoglobulin und der Treffsicherheit der Thallium-201-Szintigraphie differenzierter Schilddrüsenkarzinome.

AIM: Tumor scintigraphy with 201-TlCl is an established diagnostic method in the follow-up of differentiated thyroid cancer. We investigated the relationship between thyroglobulin (Tg) level and tumor detectability. SUBJECT AND METHODS: We analyzed the scans of 122 patients (66 patients with proven tumor). The patient population was divided into groups with Tg above (N = 33) and below (N = 33) 5 ng/ml under TSH suppression or above (N = 33) and below (N = 33) 50 ng/ml under TSH stimulation. Tumor detectability was compared by ROC-analysis (True-Positive-Fraction test, specificity 90%). RESULTS: There was no significant difference (sensitivity 75% versus 64%; p = 0.55) for patients above and below 5 ng/ml under TSH suppression and a just significant difference (sensitivity 80% versus 58%; p = 0.04) for patients above and below 50 ng/ml under TSH stimulation. In 18 patients from our sample with tumor, Tg under TSH suppression was negative, but 201-TlCl-scan was able to detect tumor in 12 patients. CONCLUSION: Our results demonstrate only a moderate dependence of tumor detectability on Tg level, probably without significant clinical relevance. Even in patients with slight Tg elevation 201-TlCl scintigraphy is justified.

[Somatostatin receptor status in non-medullary thyroid carcinoma]. / Untersuchungen zum Somatostatinrezeptor-Status bei nicht-medullären Schilddrüsenkarzinomen.

AIM: Recent in-vitro and in-vivo studies demonstrated a somatostatin receptor expression in some non-medullary thyroid carcinomas. In this study we investigated the somatostatin receptor status for this particular tumor entity in a larger patient group. SUBJECT AND METHODS: We compared 131-iodine with 111-In-pentetreotide scans in 24 patients with metastasizing, non-medullary thyroid cancer. The findings were correlated with other imaging modalities. Additionally, we performed receptor autoradiography in one patient, octreotide therapy in another patient and administration of 90-Y- and 111-In-DOTATOC in 2 consecutive patients. RESULTS: In the 15 patients with papillary or follicular carcinoma, 111-In-pentetreotide was inferior to 131-I in 8/15, equal in 1/15, and superior in 6/15 patients. In 8/9 of the patients with Hürthle cell carcinoma, metastases showed a 111-In-pentetreotide accumulation of various intensity, while 131-iodine scans were negative except for one patient. 111-In-pentetreotide was equal or superior compared to 201-Tl or 99m-Tc-sestamibi, but for the most part inferior in comparison with 18-F-FDG-PET. The findings of 111-In-pentetreotide scintigraphy correlated well with the receptor autoradiography and the accumulation of DOTATOC, but not with the therapeutic effect of "cold" octreotide on the thyroid cancer metastases. CONCLUSIONS: Several metastases of papillary and follicular carcinoma, and the majority of Hürthle cell cancer metastases can express somatostatin receptors. 111-In-pentetreotide scintigraphy is a promising tool for localization of metastases especially in Hürthle cell cancer or if PET is not available, and may be useful for selection of possible candidates, if therapeutic effective beta-emitting somatostatin analogues will be available for routine application.

Fluorine-18 fluorodeoxyglucose positron emission tomography in thyroid cancer: results of a multicentre study.

The aim of this multicentre study was to evaluate the clinical significance of fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in differentiated thyroid carcinoma and to compare the results with both iodine-131 whole-body scintigraphy (WBS) and technetium-99m 2-methoxyisobutylisonitrile (MIBI) or thallium-201 chloride (Tl) scintigraphy. Whole-body PET imaging using FDG was performed in 222 patients: 134 with papillary tumours, 80 with follicular tumours and 8 with mixed-cell type tumours. Finally, for each case an overall clinical evaluation was done including histology, cytology, thyroglobulin level, ultrasonography, computed tomography and subsequent clinical course, to allow a comparison with functional imaging results. Sensitivity of FDG-PET was 75% and 85% for the whole patient group (n = 222) and the group with negative radioiodine scan (n = 166), respectively. Specificity was 90% in the whole patient group. Sensitivity and specificity of WBS were 50% and 99%, respectively. When the results of FDG-PET and WBS were considered in combination, tumour tissue was missed in only 7%. Sensitivity and specificity of MIBI/Tl were 53% and 92%, respectively (n = 117). We conclude that FDG-PET is a sensitive method in the follow-up of thyroid cancer which should be considered in all patients suffering from differentiated thyroid cancer with suspected recurrence and/or metastases, and particularly in those with elevated thyroglobulin values and negative WBS.

Technetium-99m-furifosmin in the follow-up of differentiated thyroid carcinoma.

UNLABELLED: Tumor scintigraphy with flow tracers, such as 201TI-chloride, has an established role in the follow-up of differentiated thyroid cancer. We investigated a new tracer, 99mTc-furifosmin (Technescan Q12, Mallinckrodt Diagnostika, Hennef, Germany), in patients with elevated thyroglobulin levels or sonographic suspicion of lymph node metastases or recurrent disease. METHODS: In a prospective study, we examined 20 patients with 99mTc-furifosmin. All patients underwent a 18F-fluorodeoxyglucose (FDG) PET scan of the neck and chest. Positive 99mTc-furifosmin findings were validated by biopsy, (131)I scan, CT or 18F-FDG PET examinations. RESULTS: In three patients with cervical lymph node metastases detected on a planar 99mTc-furifosmin scan, we found a rapid tracer accumulation in the tumor (maximum < 2 min) and a significant washout in 2 of 3 patients after 4 hr. The visual contrast and the tumor-to-nontumor ratio was rather poor (average 1.2:1). In 3 additional patients, 3 pulmonary and 2 mediastinal lymph node metastases were detected by the 99mTc-furifosmin SPECT scan. Two patients were true-negative, and in 13 of 18 patients, the tumor could be localized by 18F-FDG PET (10 cervical, 6 mediastinal, 4 pulmonary metastases, 1 bone metastasis); 5 patients were false-negative. In 3 of these false-negative cases we could not localize the tumor with other diagnostic methods. Two patients had a true-negative PET examination. CONCLUSION: The statistical analysis of our data on 99mTc-furifosmin reveals that the sensitivity and 95% confidence interval of 33% (11%-56%) on a patient-by-patient basis and of 34% (17%-57%) for the lesion-by-lesion analysis is significantly lower than the sensitivity and 95% confidence interval of 72% (50%-89%) on a patient-by-patient basis and of 91% (78%-100%) on lesion-by-lesion basis for 18F-FDG. The sensitivity of 99mTc-furifosmin appears to be poor, even for cervical and mediastinal tumor manifestations where the value of 201TI-chloride is established.

Analysis of mitochondrial DNA indicates that domestic sheep are derived from two different ancestral maternal sources: no evidence for contributions from urial and argali sheep.

To investigate the origins and phylogenetic relationships of domestic sheep, mitochondrial DNA (mtDNA) from 243 sheep of five European, one African, and four Asian breeds and several mouflon (Ovis musimon), urial (O. vignei bochariensis), and argali (O. ammon nigrimontana, O. a. collium) were assayed for restriction fragment length polymorphisms (RFLP). Twenty haplotypes were identified which occurred in three major phlogenetic groups: urial/argali, mouflon/domestic, and domestic sheep. From the branches that contain mouflon and domestic sheep, two major domestic sheep lineages are apparent. One lineage, termed European lineage, contains the majority of haplotypes detected among European domestic sheep. These mtDNAs resemble mouflon haplotypes. The other lineage, termed Asian lineage, consists of haplotypes found in central Asian and some European domestic sheep. The mean sequence difference between these two lineages (0.72%) is of similar magnitude as that between two argali subspecies. To accurately estimate sequence differences between the European and Asian mtDNA types, the mitochondrial control region of one animal from each lineage and of one mouflon and urial were completely sequenced. Sequence comparisons show that Asian and European domestic sheep lineages differ by 4.43%. The mouflon sequences diverges from the Asian type by 4.52%, but by only 1.36% from the European type. Our data supports the hypothesis that some modern domestic sheep and European mouflon derive from a common ancestor and provide evidence of an additional wild ancestor, other than the urial and argali groups, which has yet to be identified.

Redifferentiation therapy with retinoids: therapeutic option for advanced follicular and papillary thyroid carcinoma.

During the course of tumor progression the differentiated morphologic and functional characteristics of differentiated thyroid carcinomas (DTC) disappear. This corresponds to more aggressive growth, metastatic spread, and loss of iodine uptake. Experimental data give strong evidence that differentiated functions of iodine metabolism can be reinduced by retinoic acids. Results of a study performed in patients with advanced DTC are presented. Twenty patients with DTC (eight follicular, seven papillary, five oxyphilic) were selected for treatment with retinoic acid 1.5 mg/kg body weight/day over 5 weeks. All patients had advanced tumor stages with prior operative and radioiodine treatment. Extensive tumor invasion, distant metastatic spread, or insufficient or no radioiodine uptake precluded any conventional therapeutic option. The aim was to assess the changes under retinoid treatment. Iodine uptake increased in eight patients (three follicular, three papillary, two oxyphilic). Thyroglobulin (TG) as parameter for tumor mass and differentiation increased in 12 (63%) patients, decreased in 6 (32%), and did not change in 1 (5%). Retinoids do have an effect on differentiation status of DTC, reinducing iodine uptake in 50% of patients. TG levels do not always parallel a response in iodine uptake.

Redifferentiation therapy of differentiated thyroid carcinoma with retinoic acid: basics and first clinical results.

Retinoic acids (RA) regulate growth and differentiation of normal epithelial tissue. They have been employed in anticancer treatment and showed positive effects in hematopoetic and various epithelial tumors. Experimental data with follicular thyroid tumor cells showed strong evidence of induction of differentiated cell function and antiproliferative effects. Based on these data a consecutive series of 10 patients with advanced thyroid carcinoma were treated with 13-cis-retinoic acid (Roaccutan) 1.5 mg/kg body weight for six weeks. Follow-up demonstrated renewed uptake of radioiodine in 4 of 10 patients allowing performance of further radioiodine therapy. Reduction in tumor size due to antiproliferative effects of RA could not yet be verified.