How reliable is secondary risk stratification with stimulated thyroglobulin in patients with differentiated thyroid carcinoma? Results from a retrospective study.

OBJECTIVE: Primary risk factors in patients with differentiated thyroid carcinoma (DTC) are well established. In our institution, secondary risk stratification has been performed with stimulated Thyroglobulin (sTg; TSH > 30 mIU/l) within six months after primary therapy since 2001. In this study, we evaluated the predictive value of sTg for long-term disease-free survival (DFS). PATIENTS, METHODS: Data of 202 consecutive patients with DTC were analyzed retrospectively. Median follow-up time was 6.4 years (12 months to 16.2 years). Patients were staged according to Union International Contre le Cancer (UICC) criteria. Primary risk stratification was carried out according to European Thyroid Association criteria. Initially, 134 patients (66%) were classified as low-risk and 68 patients (34%) as high-risk. The influence of established risk factors and sTg on DFS was analyzed at three different time points, up to 36 months after initial therapy. RESULTS: In total, 169 (84%) of all patients remained in complete remission after surgery followed by radioiodine-therapy. Six patients (3%) developed tumour recurrence after initial complete remission. Primary risk factors for persistent disease were male sex, follicular or oncocytic tumour, primary tumour > 4 cm in diameter, initial lymph node involvement, initial metastatic disease and microscopic or macroscopic residual tumor. sTg ≤ 0.3 ng/ml measured within six months after initial therapy was a highly significant predictor (p ≤ 0.001) for lasting DFS, 99% of patients with sTg ≤ 0.3 ng/ml were in complete remission 36 months after initial therapy. CONCLUSIONS: A stimulated Tg ≤ 0.3 ng/ml within six months after initial therapy is a reliable predictor for long-term disease-free survival independent of primary risk stratification.

Coexpression of osteogenic and adipogenic differentiation markers in selected subpopulations of primary human mesenchymal progenitor cells.

Knowledge of the basic mechanisms controlling osteogenesis and adipogenesis might provide new insights into the prevention of osteoporosis and age-related osteopenia. With the help of magnetic cell sorting and fluorescence activated cell sorting (FACS), osteoblastic subpopulations of mesenchymal progenitor cells were characterized. Alkaline phosphatase (AP) negative cells expressed low levels of osteoblastic and adipocytic markers. AP positive cells expressed adipocytic markers more strongly than the AP negative cell populations, thus suggesting that committed osteoblasts exhibit a greater adipogenic potential. AP negative cells differentiated to the mature osteoblastic phenotype, as demonstrated by increased AP-activity and osteocalcin secretion under standard osteogenic culture conditions. Surprisingly, this was accompanied by increased expression of adipocytic gene markers such as peroxisome proliferator-activated receptor-gamma2, lipoprotein lipase and fatty acid binding protein. The induction of adipogenic markers was suppressed by transforming growth factor-beta1 (TGF-beta1) and promoted by bone morphogenetic protein 2 (BMP-2). Osteogenic culture conditions including BMP-2 induced both the formation of mineralized nodules and cytoplasmic lipid vacuoles. Upon immunogold electron microscopic analysis, osteoblastic and adipogenic marker proteins were detectable in the same cell. Our results suggest that osteogenic and adipogenic differentiation in human mesenchymal progenitor cells might not be exclusively reciprocal, but rather, a parallel event until late during osteoblast development.

[Recurrent familial cardiac myxomas and lentiginosis. Second recurrence in a 41-year-old female patient]. / Rezidivierende familiäre kardiale Myxome und Lentiginose. Zweites Myxomrezidiv bei einer 41-jährigen Patientin.

The case of a 41-year-old woman with recurrent cardiac myxomas and widespread lentiginosis is reported. The diagnosis of a Carney complex was established 7 and 25 years, respectively, after first manifestation of the cardiac myxomas in both the patient and her brother. This peculiar hereditary disease is commonly associated with multiple neoplasms and an endocrine overactivity, requiring a thorough examination of the patients and their relatives to detect additional typical manifestations.

Incidence of radioiodine induced Graves' disease in patients with multinodular toxic goiter.

In this study, we assessed the incidence of Graves' disease (GD) following radioiodine therapy (RIT) in a large cohort of well characterized patients with autonomy in comparison to the clinical course of control patients with thyroidal autonomy not definitively treated with (131)I or surgery. 622 consecutive patients were treated with (131)I for autonomy (unifocal: n = 321; multifocal: n = 199; disseminated: n = 102) and followed up for at least 6 months post RIT. 108 consecutive patients with autonomy not definitively treated (unifocal: n = 49; multifocal: n = 42; disseminated: n = 11) followed up for at least 6 months served as controls. Initial evaluation and follow-up included determination of FT3, FT4, TSH, autoantibodies against the thyroid peroxidase (anti-TPO) and TSH-receptor antibodies (TRAb) by highly sensitive radio receptor-assay, quantitative thyroid scintigraphy and sonography. After 6 months, GD was newly diagnosed in 1/321 patients with unifocal autonomy, in 1/199 patients with multifocal autonomy and in 0/108 control patients. In patients with disseminated autonomy (group C), GD was diagnosed significantly more often compared to the other groups (5/102 patients; 4,1 %; p < 0.05). In conclusion, RIT may induce Graves' disease in a few cases with toxic multinodular goiter. The incidence in this population is small. Compared with patients suffering from uni- or multifocal autonomy, subjects with disseminated autonomy have a more than tenfold higher risk for the development of GD.

Expression of the sodium iodide symporter in differentiated thyroid cancer: clinical evidence.

AIM: Molecular analysis of the expression of the sodium iodide symporter (NIS) in 32 patients with differentiated thyroid cancer (DTC) and correlation with scintigraphic findings ((131)I,(123)I) in 19 (59.4%) of them. PATIENTS, METHODS: NIS expression of 27 primary tumours, 13 lymphnodes and 18 distant metastases was determined by immunostaining using a murine monoclonal anti-NIS-antibody. NIS expression and radionuclide uptake of metastases were analysed by a semiquantitative visual score. Patients were divided into two subgroups: Group 1 (n = 8 patients): indirect correlation of radioiodine uptake (RIU) of subsequent metastases with NIS expression of 7 primary tumours and 3 metastases; Group 2 (n=11 patients): direct correlation of radionuclide uptake with NIS expression of 19 metastases which were excised after imaging. RESULTS: 49 of 58 specimens (84.5%) were NIS-positive. A preserved NIS-expression was found in 12 primary tumours and 8 of 10 (80%) synchrone and 6 of 7 (85.7%) metachrone metastases. Group 1 revealed a 100% positive predictive value (PPV) of a preserved NIS expression in the primary tumour regarding radioiodine uptake in metastases while a lack of NIS expression in the primary tumor did not reliable predict a loss of the metastases' ability to concentrate radioiodine. In group 2, only 11 of 19 (57.9%) specimens showed a concordant NIS expression and RIU whereas in the remaining 8 cases without visible RIU NIS expression was still present. CONCLUSIONS: NIS expression of the primary tumour and metastases in DTC is usually well preserved. We found a positive correlation between NIS expression of the primary and metastatic tissue but could not identify such well correspondence between NIS expression and the RIU of subsequent metastases.

Evidence of downregulation of matrix extracellular phosphoglycoprotein during terminal differentiation in human osteoblasts.

Matrix extracellular phosphoglycoprotein (MEPE) is an extracellular matrix protein that was first detected in tumor-induced osteomalacia (TIO). Investigations in mice revealed that MEPE is expressed in bone and teeth in a maturation-dependent manner, reaching its maximum during mineralization. However, from knockout experiments, although it has become clear that MEPE might function as a mineralization inhibitor, the exact mechanism of action is still unclear. Even less is known about the regulation of MEPE in men. Therefore, we have studied the time- and maturation-dependent expression of MEPE in two human osteoblast culture systems, the osteosarcoma cell line HOS 58 and primary trabecular osteoblasts. Cells were cultured for up to 29 days, and the influence of beta-glycerophosphate (bGP), ascorbate, transforming growth factor beta (TGF-beta), BMP-2, and dexamethasone was studied. HOS 58 cells showed no significant effect on MEPE gene expression up to 5.0 mM, but a significant inhibition was revealed at 10 and 20 mM, when osteocalcin (OC) expression was maximal. Under the same conditions, primary human osteoblasts showed no effect on MEPE gene expression. However, when cultured in the presence of 5 mM beta-glycerophosphate, ascorbate, and dexamethasone for 29 days, which are similar conditions to those described by Owen in his differentiation model in rat osteoblasts, a progressive inhibition of MEPE gene expression to 20% of the maximum was observed. Increasing osteocalcin expression indicated advancing differentiation. In conclusion, in contrast to the results in mice, when MEPE was maximally expressed during mineralization, in the human system, this factor seems to be maximally active in the proliferation and early matrix maturation phase. It was, however, strongly suppressed, associated with the mineralization phase.

Calcitonin measurement to detect medullary thyroid carcinoma in nodular goiter: German evidence-based consensus recommendation.

Serum calcitonin (CT) has become a very specific and sensitive marker for human medullary thyroid carcinoma (MTC), a neuroendocrine tumor affecting about 1 % of patients with nodular thyroid disease. MTC is characterized by early micrometastasis and a lack of curative non-surgical treatment, so that early diagnosis is desirable. Based on a systematic review of scientific evidence, we propose multidisciplinary consensus recommendations for the clinical use of CT in patients with nodular goiter. To exclude MTC, serum CT should be determined in patients with nodular thyroid disease, using a two-site CT immunoassay. If basal serum CT exceeds 10 pg/ml, CT should be analysed by pentagastrin stimulation testing, after renal insufficiency and proton pump inhibitor medication have been ruled out. As the risk for MTC is higher than 50 % in patients with stimulated CT values > 100 pg/ml, thyroidectomy is advised in these individuals. If stimulated CT exceeds 200 pg/ml, thyroidectomy and lymphadenectomy is strongly recommended. Pentagastrin-stimulated CT values < 100 pg/ml are associated with a low risk of MTC, or very rarely, non-metastasizing micro-MTC (size < 10 mm). Therefore, regular clinical and biochemical follow-up is the preferred treatment in such patients, unless thyroid malignancy is suspected otherwise.

[Clinical evaluation of a new thyroglobulin immunoradiometric assay in the follow-up of differentiated thyroid carcinoma]. / Klinischer Stellenwert eines neuen Thyreoglobulin-immunoradiometrischen Assays in der Nachsorge des differenzierten Schilddrüsenkarzinoms.

AIM: Formal and clinical comparison of a new 3 (rd) -generation-Tg-IRMA (3-G-IRMA; Dynotest Tg-plus) with a conventional Tg-IRMA (3-G-IRMA; SELco Tg-assay) for patients with differentiated thyroid carcinoma. In addition we evaluated, if thyroglobulin (Tg) levels above a specific threshold concentration indicate the need for further investigations for residual disease. PATIENTS, METHODS: Tg concentration of 105 sera of 93 consecutive patients with a differentiated thyroid cancer was determined with both assays and compared at different cut-off values (Dynotest Tg-plus: 0.2, 1, 2 ng/ml; SELco Tg-assay: 0.5, 1, 2 ng/ml) with the clinical results in respect to the corresponding TSH concentration. RESULTS: Tg concentration did not show any significant difference (SELco Tg-assay 0.5 ng/ml, Dynotest Tg-plus 0.2 ng/ml). The Tg-values of both assays correlated with 97%. However, correlation of recovery in both assays was small (40%). The sensitivities and specificities of both assays at different cut-offs and TSH values did not reveal significant differences. In patients with TSH concentration > 30 micro U/ml the functional assay sensitivity was superior to arbitrary cut-offs in the decision to start further evaluations. CONCLUSIONS: In our study neither formal nor clinical significant differences between two Tg-assays were found. In a hypothyroid patient (TSH > 30 micro U/ml, Tg concentration exceeding the functional assay sensitivity) further investigations for residual disease are warranted. Higher thresholds are of limited value, due to an unacceptably high rate of false negative results.

[Macroadenoma of the pituitary gland with moderate hyperprolactinaemia]. / Makroadenom der Hypophyse mit mässiger Hyperprolaktinämie.

HISTORY AND CLINICAL FINDINGS: A 46-year-old woman was referred to the neurosurgery department for treatment of a macroadenoma of the pituitary. She had complained of recurrent galactorrhoea for 7 years; a hysterectomy was performed 4 years ago. The clinical investigation was unremarkable, except for a slight galactorrheoa on both sides. INVESTIGATIONS: The endocrinological work-up revealed a moderately elevated prolactin level of 3133 mU/l (147 ng/ml) with intact pituitary functions. She had no visual impairment and the MRI depicted a pituitary tumor with a maximal diameter of 1.9 cm and both intra- and suprasellar extension. DIAGNOSIS, TREATMENT AND CLINICAL COURSE: The diagnosis of a nonfunctioning macrodenoma with functional hyperprolactinemia was made and a selective transsphenoidal adenomectomy was performed. The primary histology showed a chromophobe adenoma. However, additional immunohistological investigations revealed distinct staining for prolactin. In the meantime, because of persistent galactorrhea and elevated prolactin levels, treatment with cabergolin 0.5 mg/week was started. This stopped galactorrhea and normalized the prolactin levels. A follow-up MRI after 3 months of treatment showed a significant shrinkage of the residual tumor. CONCLUSION: This case demonstrates that the differential diagnosis of macroprolactinoma with low secretory activity and functional hyperprolactinemia is very difficult preoperatively in individual cases. This is relevant because macroprolactinomas with low secretory activity can also be treated successfully with dopamine agonists. We therefore suggest a drug treatment trial with dopamine agonists in all macroadenoms with hyperprolactinemia, particularly in those with prolactin levels above 2000 mU/l (100 ng/ml).

[Thyroid hormones in the treatment of iodine deficiency goiter. Superfluous like goiter?]. / Schilddrüsenhormone in der Therapie der Jodmangelstruma Uberflüssig wie ein Kropf?

In recent years, the widespread use of iodized salt in households and industrially produced foods has considerably improved the shortage of iodine in the German diet. Recent epidemiologic studies have shown that we are now at the threshold of adequacy. Over the last decade, views on the pathogenesis of iodine deficiency goiter have changed: while TSH was previously assumed to be the major factor underlying this form of goiter, experimental data now finger the activation of local growth factors, in particular IGF1. Iodinated organic compounds, in particular iodolacton produced by iodination of unsaturated fatty acids in the thyrocyte, are the key regulators of IGF1 activity by inhibitory action, and iodine is now the therapeutic agent of first choice for iodine deficiency goiter; long-term thyroxine treatment in TSH suppressive doses has been abandoned. The recommended daily dose of iodine is 200 micrograms; higher doses may induce or aggravate autoimmune thyroiditis, and should not be used for a length of time. In pregnant women, an adequate supply of iodine is of critical importance for optimal neurophysiological development, and the general use of iodine supplementation in pregnancy therefore remains mandatory in Germany.

Increase of serum estradiol in cirrhotic men treated by transjugular intrahepatic portosystemic stent shunt.

BACKGROUND/AIMS: Liver cirrhosis is frequently associated with sexual dysfunction and hormonal abnormalities. To evaluate the effect of portosystemic shunting on sex steroid serum concentrations, a prospective study was performed in cirrhotic patients treated consecutively and electively by transjugular intrahepatic portosystemic stent shunt (TIPS). METHODS: In 27 patients with liver cirrhosis we measured serum levels of testosterone (T), sexual hormone binding globulin (SHBG), luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone sulfate, androstenedione (A), estradiol (E2), 17-OH-progesterone and the T/SHBG ratio before and 3 months after TIPS. RESULTS: In men (n = 17) 3 months after TIPS, A and E2 significantly increased, with mean serum levels rising from 4.4 +/- 2.5 to 5.6 +/- 2.9 ng/ml (P = 0.04) and from 27 +/- 9 to 40 +/- 19 pg/ml (P = 0.003), respectively. In contrast to A the increase of E2 persisted at 9 and 15 months after TIPS. Erectile dysfunction increased from 30% before TIPS to 70% after TIPS. In women (n = 10) A and E2 levels did not change significantly after TIPS. CONCLUSIONS: TIPS aggravated hormonal dysbalance of sex steroids in favor of estrogens (hyperestrogenism) in men.

Presentation of a kindred with familial medullary thyroid carcinoma and Cys611Phe mutation of the RET proto-oncogene demonstrating low grade malignancy.

OBJECTIVE: Both multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are caused by germline mutations of the RET proto-oncogene. A broad spectrum of malignancy within and between families has been described with no clear genotype-phenotype correlation due to a scarcity of available data of large kindreds. DESIGN: Here we present the only known family with a germline mutation of codon 611 TGC to TTC (exon 10) in the RET proto-oncogene leading to a replacement of cysteine by phenylalanine (Cys611Phe or C611F). RESULTS: Twenty family members of this large kindred are gene carriers (GCs) and seven (5-13 years old) are potential carriers but have yet to be analysed. The clinical course of medullary thyroid carcinoma (MTC) in this family is characterized by a very slow evolution and progression of the tumour with no MTC-related death to date. Of 11 patients (30-69 years old) having undergone thyroidectomy six were classified as pT1, four as pT2 and one as C-cell hyperplasia according to the TNM system of the International Union Against Cancer. Due to cervical and mediastinal lymph node metastasis one patient (44 years old) had to be operated on a second time. The seven non-operated GCs of the fourth and fifth generation (17-26 years old) are yearly monitored with pentagastrin stimulation tests; one non-operated GC (43 years old) has refused any further investigations. Screening for primary hyperparathyroidism and phaeochromocytoma was negative in all cases. CONCLUSION: We suggest from these experiences that the general advice for thyroidectomy in early childhood should be modified in certain families, depending on genotype.

Persistent hypocalcemia with elevated parathyroid hormone levels after long-term primary hyperparathyroidism: report of a case.

We report herein the case of a 48-year-old man with long-term persistent primary hyperparathyroidism (pHPT) despite undergoing a parathyroidectomy in 1976, followed by a reoperation in 1978, for whom resection of a parathyroid adenoma in the upper mediastinum was eventually performed. His postoperative course was complicated by recurrent hypocalcemia refractory to oral calcium substitution and significantly elevated levels of parathyroid hormone (PTH). The radiological findings are presented, and we discuss the possible reasons for the coincidence of severe hypocalcemia with increased PTH levels in association with pHPT.

[Clinical implications of a new TSH receptor antibody assay (DYNOtest TRAKhuman) in autoimmune thyroid diseases]. / Klinische Implikationen eines neuen TSH-Rezeptor-Antikörper-Assays (DYNOtest TRAKhuman) bei autoimmunen Schilddrüsenerkrankungen.

AIM: Conventional radioreceptor-antibody-assays (RAAs) fail in the detection of TSH-receptor antibodies (TRAKs) in 10-30% of patients with Graves' disease (GD). The aim of this study was the evaluation of the diagnostic and clinical impact of a new RRA (DYNOtest TRAKhuman) which uses the human recombinant TSH-Receptor in the diagnosis of autoimmune thyroid disease. METHODS: Sera from 142 consecutive patients (GD: n = 50, autoimmune thyroiditis/AIT: n = 92) and from 55 controls (31 patients without any thyroid disease and 14 with euthyroid goiter) were evaluated both with the DYNOtest TRAKhuman-assay and a conventional RRA (TRAK-Assay). Thyroid in vitro parameters and thyroid sonography were performed in all patients. RESULTS: The DYNOtest TRAK-assay was significantly superior to the conventional RRA in the diagnosis of GD (p < 0.00012), especially in those who were treated by thionamides (p < 0.003) and in the diagnosis of TRAK-positive patients with AIT (p < 0.003). The majority of TRAK-positive AIT-patients suffered from hypothyroidism. One false positive result in patients with euthyroid goiter was found in the TRAK-Assay as well as in the DYNOtest TRAKhuman-Assay. Therefore the specificity of the DYNOtest TRAKhuman was not inferior compared with the conventional assay. CONCLUSION: The DYNOtest TRAK-assay is superior in the diagnostic work up of Graves' disease compared with a conventional TRAK-assay and offers an equal specificity.

Disseminated thyroid autonomy or Graves' disease: reevaluation by a second generation TSH receptor antibody assay.

The clinical diagnosis of disseminated autonomy (DISA) can only be established by exclusion of Graves' disease (GD). Both hyperthyroid conditions share the same scintigraphic appearance and can only be distinguished from each other clinically either by the presence or absence of endocrine ophthalmopathy (EO) or thyrotropin (TSH) binding inhibiting immunoglobulins (TBIIs). The purpose of this study was the reevaluation of thyroid autonomies originally classified as DISAs by a second-generation radioreceptor antibody assay (RAA) (DYNOtest TRAKhuman) (B.R.A.H.M.S. Diagnostika, Berlin, Germany). The analysis included 32 patients (female: n = 25, male: n = 7; mean age: 46 +/- 18 years) who were initially diagnosed with DISA. All patients were TSH receptor (TSHR) antibody (TRAb) negative by a conventional radioimmunoassay (RIA) (TSH-REZAK RIA) (Medipan Diagnostica, Selchow, Germany) during their first evaluation. The presence of EO was excluded by clinical signs in all patients. Surgery had been performed prior to our evaluation in 5 patients and after our survey in 1 patient. Four patients had been treated previously with 131I. Ten patients were treated with thionamides during our evaluation, and 13 had not been treated before. One hundred three patients who had either healthy thyroids, nontoxic goiters, or focal autonomies served as controls and were evaluated both by the TSH-REZAK assay and the DYNOtest TRAKhuman assay. Seven of thirty-two (22%) patients originally classified as DISA were TRAb positive in the second-generation assay. In this group, 5 of 7 patients had a total thyroid volume (TTV) <30 mL (positive predictive value [PPW] for TRAb positivity 71%), and 5 of 7 patients had a diffuse goiter (PPW for TRAb-positivity 71%). Six of seven patients were anti-thyroperoxidase (TPO) positive (PPW for TRAb positivity 85%). A hypoechoid pattern on ultrasound was present by visual analysis in 3 of 7 patients (PPW for TRAb positivity 43%). A 100% PPW for TRAb positivity could be obtained if a goiter <30 ml was combined with anti-TPO positivity, but this combination was present in only 4 of 7 (57%) patients. With the second-generation assay, one false positive test result was observed in the control group. Surgery was performed in 6 patients who were TRAb negative in both assays. In all these cases, the histologic findings were compatible with autonomous transformation of the thyroid. Our study demonstrates that a significant number (22%) of patients formerly classified as DISA may actually have GD. However, DISA still exists as a clinical entity, and its pathophysiological link to multifocal and unifocal autonomy should be further investigated.

Psychoendocrine sequelae of chronic testosterone deficiency.

The precise role of testosterone in regulating mood, especially in alleviating depression, remains unclear although converging evidence indicates that androgens may exert antidepressant action. A model that may potentially assist in the clarification of androgen-mediated effects on mood is the study of cryptorchid men who may grow up with varying degrees of testosterone deficiency depending on the time in their life when cryptorchism is corrected. In this report, we describe a rare case of bilateral cryptorchism that did not come to the attention of the physician to implement effective substitution with testosterone until much later in adult life. The patient developed severe and suicidal depression which responded solely to testosterone. In addition, the patient experienced a delayed but accelerated puberty without any adverse events. These observations, although based on a single case, provide strong evidence that testosterone may exert powerful antidepressant action in the absence of concomitant antidepressant agents.