Differentiated thyroid cancer is a malignant tumour that has a fairly good prognosis, with patients surviving for many years. Multimodal therapy with surgery, radioiodine therapy and TSH suppressive medication is of proven efficacy. However, loss of differentiation is observed in up to one-third of patients with differentiated thyroid cancer, paralleled by an increase in tumour grading and loss of thyroid-specific functions (thyrotropin receptor, iodine accumulation). Such tumours may no longer be amenable to standard treatment protocols, including TSH suppression and radioiodide therapy. Retinoic acids have been shown to exert re-differentiating effects on thyrocytes in various experimental studies and case reports, and it was on this basis that this pilot study was initiated. Patients with advanced thyroid cancer and without the therapeutic options of operation or radioiodide therapy were treated with 13- cis-retinoic acid at a dosage of 1.5 mg/kg body weight daily over 5 weeks. Parameters for assessment of the therapeutic effect were serum thyroglobulin (TG) levels, radioiodine uptake, and tumour size prior to and after retinoid treatment. Fifty patients were evaluated for response, classified as reduction in tumour size and TG levels, stable disease or disease progression. Thirteen patients showed a clear increase in radioiodine uptake, and eight a mild increase. TG levels were unchanged or decreased in 20 patients. Tumour size was assessable in 37 patients; tumour regression was observed in six, and there was no change in 22. In total, a response was seen in 19 patients (38%). Response to retinoid therapy did not always correlate with increased radioiodine uptake, so other direct antiproliferative effects have to be assumed. The encouraging results of the study and the low rate of side-effects with good tolerability of retinoids warrant further studies with altered inclusion criteria and employment of other redifferentiating drugs or combinations of agents.

Early diagnosis of medullary thyroid carcinoma (MTC) can improve long-term prognosis. MTC can be detected at an early stage by calcitonin screening in all patients with thyroid nodules. This approach, however, is controversial due to high costs and a limited specificity of calcitonin. It was the aim of the present study to investigate whether ultrasonography may contribute to the diagnosis of MTC in patients with thyroid nodules. The study included 19 patients with newly diagnosed MTC. Ten patients had sporadic MTC, 7 had multiple endocrine neoplasia (MEN) type 2A, and 2 patients had MEN 2B. In all subjects conventional ultrasound, and in 14 patients color Doppler sonography were performed before primary surgery. For comparison, ultrasound appearance of 139 benign thyroid nodules was evaluated. In conventional ultrasound, MTC in 17/19 (89%) patients were hypoechoic, contained intranodular calcifications, and had no "halo sign". The combination of these criteria were found in only 8/139 (6%) of benign thyroid nodules. Intranodular blood flow was found in 11/14 patients with MTC (79%), perinodular blood flow in 7/14 MTC (50%). In conclusion, conventional ultrasound reveals a combination of hypoechogenicity, intranodular calcifications, and absence of "halo sign" in the vast majority of MTC. Since this sonographic pattern only rarely occurs in benign thyroid nodules, the results indicate that thyroid ultrasound can contribute to the diagnosis of MTC. In addition, the findings may have implications for calcitonin screening in nodular thyroid disease.

Twenty-two patients (mean age 61) with metastasizing, progressive, nonradioiodine-accumulating thyroid carcinoma of the follicular epithelium were treated with doxorubicin between 2000 and 2005. Tumors were histologically classified as follicular in 15 patients (68%) and papillary in 7 patients (32%). In addition, nine patients (mean age 51 years) with medullary thyroid carcinoma were treated with doxorubicin between 1997 and 2005. Treatment consisted of doxorubicin: either 8 cycles of 15 mg/m2 weekly or 3 cycles of 60 mg/m2 every 3 weeks, repeated once, depending on response and side effects. The effect of therapy was evaluated by radiographic imaging, [18F] FDG-PET, and bone scans. In patients with papillary or follicular thyroid carcinoma, 5% had a partial regression over 6 months, 42% had stable disease for a median of 7 months (range: 1-22), and 53% had continuous progression established over 5 months (range: 1-11). Three patients died before completing chemotherapy. In patients with medullary thyroid carcinoma, 11% had a partial regression over 6 months followed by stable disease for 3 months, 11% had stable disease over 7 months, and 79% demonstrated progressive disease established over 5 months (range: 2-12). Doxorubicin can be a valid chemotherapy option, especially for advanced or metastatic thyroid carcinoma of the follicular epithelium.

We studied plasma cortisol levels at 00:00 h and 08:00 h in 103 patients with Cushing's syndrome and 144 patients in whom this diagnosis had been excluded. These patients were hospitalized in our department from 1975 to 1996. Additionally, we measured these parameters in 20 healthy volunteers and in 5 patients with nonendocrine disease. Corresponding data of urinary free cortisol and low-dose dexamethasone suppression testing were included in the evaluation. Values (mean+/-SD) from patients with Cushing's syndrome: 510+/-232 nmol/l (range 165-1488) for plasma cortisol 00:00 h, 574+/-242 nmol/l (range 236-1612) for plasma cortisol 08:00 h, 991+/-885 nmol/24 h (range 154-4866) for urinary free cortisol and 479+/-304 nmol/l (range 34 - 1,393) for plasma cortisol after 1.5 mg dexamethasone. Values from the patients excluded from Cushing's syndrome: 99+/-76 nmol/l (range 5-371) for plasma cortisol 00:00 h, 393+/-136 nmol/l (range 119-812) for plasma cortisol 08:00 h, 126+/-84 nmol/24 h (range 30-485) for urinary free cortisol, and 64+/-82 nmol/l (range 5-395) for plasma cortisol after 1.5 mg dexamethasone. Values of the healthy volunteers respectively patients with non-endocrine disease: 59+/-30 nmol/l (range 25-130) respectively 127+/-80 nmol/l (range 62-265) for plasma cortisol 00:00 h and 388+/-144 nmol/l (range 157-651) respectively 498+/-113 nmol/l (range 302-581) for plasma cortisol 08:00 h. None of the Cushing patients exhibited a 00:00 h plasma cortisol below 140 nmol/l and only one had a urinary free cortisol below 200 nmol/24 h, whereas 4 were complete dexamethasone suppressors. The diagnostic value of these parameters was examined based on various cutoffs. We recommend determination of midnight plasma cortisol as an efficient and simple additional procedure for the diagnosis of Cushing's syndrome. The sensitivity and specificity of this procedure is similar to urinary free cortisol and slightly above the low-dose dexamethasone suppression testing in our hospitalized patients.

MIP in connection with ultrasonography, sestamibi scintigraphy and intraoperative PTH measurement offers a promising treatment for patients with pHPT.

Carriers of the C allele of the common C825T polymorphism in the GNB3 gene of the G protein have been associated with the development of follicular thyroid adenomas. Since the C allele of this polymorphism is related to a lower signalling capacity, it was speculated whether the C825T polymorphism may play a particular role in oncocytic thyroid tumours, which are recognized for their reduced ability to synthesize thyroid-specific proteins and hormones, although they possess an intact thyroid-stimulating hormone receptor-adenylyl cyclase system. Using pyrosequencing, both the genotype distribution and the allele frequency of the C825T polymorphism were investigated in a series of 104 patients with oncocytic thyroid tumours of follicular cell origin [58 adenomas, 41 follicular thyroid carcinomas (FTCs), and five papillary thyroid carcinomas (PTCs)]; the results were compared with those obtained from 321 age and gender-matched healthy blood donors and a series of 327 non-oncocytic thyroid tumours of follicular cell origin (119 adenomas, 80 FTCs, and 186 PTCs). Analysis of the genotype distribution (comparing oncocytic with non-oncocytic tumours of the present series) revealed a significantly increased odds ratio (OR) for CC versus TT (OR = 4.22; p = 0.011) and CC versus CT (OR = 1.62; p = 0.049) carriers to develop an oncocytic thyroid tumour; ORs to develop an oncocytic thyroid tumour were also increased comparing the genotype distribution between the group of oncocytic tumours and healthy controls for CC versus TT (OR = 3.73; p = 0.017) and CC versus all T carriers (OR = 1.56; p = 0.034). Oncocytic thyroid tumours as a group showed a statistically significant increase of the C-allele frequency when compared with all non-oncocytic tumours (p = 0.0039) as well as healthy blood donors (p = 0.017). The results strongly suggest that the C allele of the GNB3 C825T polymorphism of the G protein beta3-subunit is associated with an increased risk for the development of oncocytic thyroid tumours. This polymorphism may thus be considered a (co)factor favouring the development of oncocytic thyroid tumours, although the biological mechanism(s) underlying this association remain obscure.

The thyrotropin receptor-cAMP pathway is central in growth regulation of thyroid cells and thyroid tumorigenesis, and it regulates expression of thyroid specific genes. Recently, 2 new protein kinase A-independent cAMP effectors named EPAC1 and 2 were described that activate additional intracellular pathways. The aim of our study was to investigate the role of EPAC proteins in growth regulation of thyroid cells and thyroid carcinomas. EPAC1 expression was investigated immunohistochemically in tissues of various thyroid tumors. Utilizing MTT assay, the effect of EPAC stimulation on proliferation in thyroid carcinoma cells and in non-transformed rat FRTL5 cells was investigated. The activation of intracellular signaling pathways was examined by RAP pull-down assay and Western blots. EPAC1 expression was strong in non-oxyphilic follicular thyroid adenomas and carcinomas and in follicular papillary thyroid carcinomas. It was moderate in oxyphilic follicular tumors and classical and tall cell papillary carcinomas. In contrast, EPAC1 expression was low in poorly differentiated carcinomas and very low in anaplastic carcinomas. Thyroid carcinoma cell lines showed no or very weak EPAC1 expression and exhibited no growth-promoting effect after EPAC stimulation. Non-transformed rat FRTL5 cells were growth-stimulated by an EPAC-specific cAMP-analogue and showed EPAC-dependent activation of RAP, ERK, and p70S6 kinase. EPAC1 expression and cellular response to EPAC activation in rat FRTL5 cells reflect cellular responses to cAMP and TSH stimulation in non-transformed thyroid cells. In undifferentiated thyroid carcinomas, loss of EPAC1 expression may be in accordance with the loss of thyroid-specific functions and the loss of responsiveness of the TSHR-cAMP pathway.

We describe the successful endoscopic removal of six extra-adrenal pheochromocytomas in three patients. One neoplasia was located retrocavally, two between the aorta and vena cava, two by the para-aortal, and one by the parailiacal. The tumors were removed by the posterior retroperitoneoscopic or by the anterior laparoscopic approach, respectively. The intraoperative and postoperative courses were uneventful.