[Diseases of the thyroid gland in men and women-Status quo and new research needs]. / Schilddrüsenerkrankungen bei Frauen und Männern ­ Status quo und neuer Forschungsbedarf.

"Diseases of the thyroid gland occur more frequently in women": this statement has been used in textbooks for decades; however, is this equally true for all thyroid gland diseases and can conclusions be derived from this for a different disease relevance and prognosis in men and women? Is possibly even a sex-specific treatment needed? These questions are taken up and subsequently the epidemiological data and studies that have investigated the influence of gender on the course of thyroid gland diseases are taken into consideration. It is shown that the data situation is much more restricted than is to be expected for frequent diseases in the general population.

[Systemic treatment of metastasized thyroid cancer-approved treatments and new approaches]. / Systemtherapien bei metastasierten Schilddrüsenkarzinomen ­ zugelassene Therapien und neue Ansätze.

The treatment of radioiodine-refractory differentiated thyroid carcinoma (rrDTC) and medullary thyroid carcinoma (MTC) remains challenging. Based on phase III clinical studies, four multi-kinase inhibitors (MKI) are approved for the treatment of progressive thyroid cancer in Germany. The indications for starting systemic treatment remain a challenge as the diseases can be stable and asymptomatic over long periods of time. In contrast, MKI treatment, which slows the disease progression but is not curative, is often associated with side effects that can impair quality of life. For this reason, an aim is to develop more specific treatments with low off-target effects. In this context selective RET kinase inhibitors represent a promising new approach, which is currently tested intensively in clinical trials, e.g. for advanced symptomatic MTC.

[Pheochromocytomatosis after adrenalectomy: metastasis or cell seeding?] / Phäochromozytomatose nach Adrenalektomie: Metastasierung oder Zellverschleppung?

Pheochromocytomatosis is defined as a multifocal cell dissemination limited to the operatively opened space with no signs of distant metastasis. After primary adrenalectomy due to a pheochromocytoma this is a rare and underrecognized manifestation of a tumor recurrence. Between 2010 and 2019 a total of 5 patients with the presentation of pheochromocytomatosis were treated in this center. Clinical and survival data were compared to 12 patients with a metastasized pheochromocytoma. Patients presenting with pheochromocytomatosis showed a better but not significant overall survival (136.8 vs. 107 months). Furthermore, patients with pheochromocytomatosis presented more often with a noradrenaline secretion type. Tumor recurrence in the pheochromocytomatosis group occurred on average 69.2 months after the initial diagnosis and was therefore much later than in patients with distant metastases from a pheochromocytoma (39 months, p = 0.13). This article outlines this special manifestation of recurrence of a pheochromocytoma based on this patient collective. Besides technical operative aspects there appears to be evidence for tumor-specific factors that promote the development of pheochromocytomatosis. Importantly, it seems that all patients with a pheochromocytoma should receive lifelong aftercare and that patients should be closely monitored during the first 5 years after surgery.

Thyroxine promotes lung cancer growth in an orthotopic mouse model.

Thyroid hormones are important for physiology and homeostasis. In addition to nuclear thyroid hormone receptors, the plasma membrane protein integrin αvß3 has been recognized as a receptor for both thyroxine (T4) and triiodothyronine (T3). Here, we studied whether thyroid hormone promotes growth of murine lung cancer via αvß3 in vivo. Murine Lewis lung carcinoma cells (3LL), stably transfected with luciferase, were injected into mouse lungs. Tumor growth in untreated mice was compared to hypothyroid mice and hypothyroid mice treated with T3 or T4 with or without the αvß3 inhibitor 3,5,3',5'-tetraiodothyroacetic acid (Tetrac). Tumor progression was determined by serial in vivo imaging of bioluminescence emitted from the tumor. Tumor weight was recorded at the end of the experiment. Neoangiogenesis was determined by immunohistochemistry for CD31. Tumor growth was reduced in hypothyroidism and increased by T4 treatment. Strikingly, only T4 but not T3 treatment promoted tumor growth. This T4 effect was abrogated by the αvß3 inhibitor Tetrac. Tumor weight and neoangiogenesis were also significantly increased only in T4-treated mice. The T4 effect on tumor weight and neoangiogenesis was abolished by Tetrac. In vitro, T4 did not stimulate 3LL cell proliferation or signaling pathway activation. We conclude that T4 promotes lung cancer growth in this orthotopic mouse model. The tumor-promoting effect is mediated via the plasma membrane integrin αvß3 and increased neoangiogenesis rather than direct stimulation of 3LL cells. These data suggest that such effects of levothyroxine may need to be considered in cancer patients on T4 substitution.

[Genetics of thyroid nodules and thyroid carcinoma]. / Genetik von Schilddrüsenknoten und Schilddrüsenkarzinomen.

Thyroid nodules are heterogeneous tumors with variable genetic signatures. Thyroid cancers are monoclonal lesions with a defined histomorphology that largely depends on the underlying somatic mutation. While the mutation rate is generally low in differentiated thyroid cancers, poorly differentiated and anaplastic thyroid cancers show a high mutation load. The identification of somatic mutations in fine needle aspirates can be helpful for the differential diagnostics of thyroid nodules; however, a prognostic contribution is less certain. The molecular pathology of thyroid tumors is helpful for the development of targeted therapies and may infer novel immuno-oncological concepts for advanced aggressive thyroid cancers.

[Somatostatin receptor PET/CT (SSTR-PET/CT)]. / Somatostatinrezeptor-PET/CT.

The present guideline is focused on quality assurance of somatostatin receptor PET/CT (SSTR-PET/CT) in oncology patients. The document has been developed by a multidisciplinary board of specialists providing consensus of definitions, prerequisites, methodology, operating procedures, assessment, and standardized reporting. In particular, imaging procedures for the two most commonly used radioligands of human SSTR, i. e. 68Ga-DOTATOC and 68Ga-DOTATATE are presented. Overall, SSTR-PET/CT requires close interdisciplinary communication and cooperation of referring and executing medical disciplines, taking into account existing guidelines and recommendations of the European and German medical societies, including the European Association of Nuclear Medicine (EANM), German Society for Endocrinology (DGE), German Society for Nuclear Medicine (DGN) and German Society for Radiology (DRG).

Rapid recovery of hypogonadism in male patients with end stage renal disease after renal transplantation.

PURPOSE: End stage renal disease (ESRD) in male patients is associated with a high prevalence of hypogonadism. After renal transplantation (RTx) an improvement in gonadal function is often observed. However, the time course of changes in pituitary-gonadal axis after RTx and the influence of renal function, age and anthropometric parameters are not well characterized. We prospectively evaluated pituitary-gonadal axis in male patients with ESRD before and after RTx for up to 1 year. METHODS: Ninety-seven male patients with ESRD were consecutively investigated on day of surgery and 1, 3, 6, and 12 months after RTx. Time course of changes in sex hormones (total testosterone ((TT)), calculated free testosterone ((cfT)), estradiol (E2), LH, FSH and prolactin), and interdependence with renal function, age, anthropometric factors, cause of ERDS, time on dialysis, and transplant associated factors were analyzed. RESULTS: Hypogonadism (TT < 8 nmol/l) was present in 40% of pts prior to RTX and in only 18% at 1 year after RTX. Recovery from hypogonadism was significantly higher in pts < 50 years and occurred within 3 months. RTx resulted in a decrease in E2/T ratio starting at 1 month and suggesting a shift from estrogen to testosterone production. BMI and waist circumference had the similar impact on T levels after successful RTx compared to patients without renal disease. No specific impact on recovery of hypogonadism was found for time on dialysis prior to RTx and living or cadaver transplantation. CONCLUSIONS: Successful RTx is associated with a rapid recovery from hypogonadism within 3 months preceeded by improvement in renal function particularly in patients younger than 50 years.

[Molecular Pathogenesis of Thyroid Nodules: Relevance for Clinical Care]. / Molekulare Pathogenese von Schilddrüsenknoten ­ Bedeutung für die klinische Versorgung.

Thyroid nodules represent heterogeneous tumors with distinct molecular signatures. While benign thyroid nodules correspond to poly- or monoclonal tumors, thyroid carcinomas are monoclonal and thus "real" neoplasms. These are caused by somatic mutations that lead to the constitutive activation of specific signaling cascades and determine the corresponding histology and also partly the functional phenotype of the thyroid tumor. Dedifferentiation of thyroid carcinomas is accompanied by the occurrence of additional mutations in the tumors. The mutation load of thyroid carcinomas correlates with their biological behavior. In clinical practice, detection of somatic mutations can help in the cytological differential diagnosis. In the prognostic assessment of thyroid tumors, proof of classical oncogene mutations (BRAF, RAS) has little relevance. Other genetic alterations, especially TERT promoter mutations that occur with increasing frequency in advanced thyroid carcinomas, probably have a prognostic significance. The molecular signature, however, is of great relevance for the development and application of targeted therapies in advanced carcinomas (radioactive iodine-refractory DTC, PDTC and ATC, metastatic medullary carcinoma). For this, there is increasing evidence from clinical studies and case reports that underline the concept of "oncogene addiction" as a pathogenetically relevant mechanism of thyroid tumorigenesis and carcinogenesis.

Perspectives for immunotherapy in endocrine cancer.

The fight against cancer has seen major breakthroughs in recent years. More than a decade ago, tyrosine kinase inhibitors targeting constitutively activated signaling cascades within the tumor inaugurated a new era of oncological therapy. Recently, immunotherapy with immune checkpoint inhibitors has started to revolutionize the treatment of several malignancies, most notably malignant melanoma, leading to the renaissance and the long-awaited breakthrough of immunooncology. This review provides an overview of the basis of immunotherapy from its initial concepts of anti-tumor immunity and cell-based therapy to the development of immune checkpoint inhibitors and discusses published studies and the perspectives of immunooncology for the treatment of endocrine malignancies.

The Transcriptional Regulation of FOXO Genes in Thyrocytes.

FOXO transcription factors are key regulators of DNA damage repair, proliferation and apoptosis in thyrocytes. Thyroid malignancies show impaired FOXO function. In this study, we investigated the transcriptional regulation of FOXO isoforms in thyroid epithelial cells. mRNA expression of FOXO isoforms (FOXO1, 3 and 4) was determined in FRTL-5 cells stimulated with different growth factors and H2O2. Furthermore, the impact of PI3K/AKT signalling on FOXO transcription was investigated in PI3K p110α mutant FRTL-5 cells and regulatory dependence of FOXO transcription on FOXO was studied in FRTL-5 cells with hFOXO3 overexpression. Finally, mRNA expression levels of FOXO isoforms were determined in human epithelial thyroid tumours. Growth factor deprivation induced transcription of FOXO1, 3 and 4, whereas insulin stimulation decreased FOXO1 and FOXO4 transcription in FRTL-5 cells. Inhibition of the PI3K/AKT cascade amplified FOXO1 and FOXO4 expression. In contrast, H2O2 and TSH did not influence FOXO transcription in thyrocytes. Overexpression of PI3K p110α inhibited FOXO3 and induced FOXO4 transcription. In human thyroid tumours, FOXO1 and FOXO3 mRNA levels were significantly downregulated in papillary thyroid carcinoma when compared to normal tissues. In contrast, follicular thyroid carcinomas showed significant upregulation of FOXO4 mRNA.In this paper, we demonstrate an influence of PI3K signalling on FOXO transcription in thyrocytes. Moreover, we show that thyroid cancers exhibit alterations in FOXO transcription besides the previously reported alterations in posttranslational FOXO3 regulation. These findings may add to the concept of targeting the PI3K pathway in advanced thyroid cancers.

Sunitinib Efficacy in Patients with Advanced pNET in Clinical Practice.

Sunitinib treatment leads to improvement in progression-free survival in patients with advanced pancreatic neuroendocrine tumours (pNETs). However, limited data exist regarding the effectiveness, safety and tolerability in clinical practice. We present the results of the first detailed pNET cohort analysis since sunitinib was approved. Patients with advanced, differentiated pNET treated with sunitinib were retrospectively analysed. All patients had progressive disease before start of sunitinib treatment. Twenty-one patients, with a median age of 64 years (range 28-78), were included in this study. Nineteen patients could be analysed for treatment effectiveness. Twelve (57%) patients exhibited either a partial response (1 patient) or stable disease (11 patients) according to the RECIST criteria. The median progression-free survival was 7.0 months (95% CI 3.0-12.0); the probability of being event-free at 6 months was 52.6% (95% CI 28.4-72.1). Potential influencing factors as Ki-67 index, age or duration of disease did not show significant correlations with the response to sunitinib therapy. Considering the differences in patients' characteristics, sunitinib in daily practice showed effectiveness parameters similar to the phase III trial.

A 6-Base Pair in Frame Germline Deletion in Exon 7 Of RET Leads to Increased RET Phosphorylation, ERK Activation, and MEN2A.

CONTEXT: Multiple endocrine neoplasia type 2 (MEN2) is usually caused by missense mutations in the proto-oncogene, RET. OBJECTIVE: This study aimed to determine the mutation underlying MEN2A in a female patient diagnosed with bilateral pheochromocytoma at age 31 years and with medullary thyroid carcinoma (MTC) 6 years later. METHODS: Leukocyte DNA was used for exome and Sanger sequencing. Wild-type (WT) RET and mutants were expressed in HEK293 cells. Activation of MAPK/ERK and PI3K/AKT was analyzed by Western blotting and luciferase assay. The effect of RET mutants on cell proliferation was tested in a colony forming assay. RESULTS: Exome sequencing revealed a 6-nucleotide/2-amino acid in-frame deletion in exon 7 of RET (c.1512_1517delGGAGGG, p.505_506del). In vitro expression showed that phosphorylation of the crucial tyrosine 905 was much stronger in the p.505_506del RET mutant compared with WT RET, indicating ligand-independent autophosphorylation. Furthermore, the p.505_506del RET mutant induced a strong activation of the MAPK/ERK pathway and the PI3K/AKT pathway. Consequently, the p.505_506del RET mutant cells increased HEK293 colony formation 4-fold compared with WT RET. CONCLUSION: The finding of bilateral pheochromocytoma and MTC in our patient was highly suspicious of a RET mutation. Exome sequencing revealed a 6-base-pair deletion in exon 7 of RET, an exon not yet associated with MEN2. Increased ligand-independent phosphorylation of the p.505_506del RET mutant, increased activation of downstream pathways, and stimulation of cell proliferation demonstrated the pathogenic nature of the mutation. We therefore recommend screening the whole sequence of RET in MTC and pheochromocytoma patients with red flags for a genetic cause.

[Clinical importance of thyroid gland cytology]. / Klinische Bedeutung der Schilddrüsenzytologie.

The cytological evaluation of fine needle biopsies (FNB) of the thyroid gland crucially depends on a close cooperation between clinicians and cytopathologists. Scintigraphy, sonography as well as clinical data and patient history are necessary for a correct interpretation of the indications for FNB; moreover, these data are of outstanding importance for cytopathologists for the correct interpretation of the cytomorphological findings. This overview describes the present standards in the acquisition, technical workup and cytopathological interpretation of thyroid gland tissue obtained by FNB, particularly focusing on the rapidly growing relevance of additional molecular pathological investigations to increase the diagnostic accuracy of thyroid FNB.

[Medullary thyroid carcinoma]. / Das medulläre Schilddrüsenkarzinom.

Medullary thyroid carcinoma (MTC) is a very rare malignancy, which arises from parafollicular C cells and accounts for 3-5% of all thyroid cancers. MTC represents a neuroendocrine tumor with a biology that differs considerably from differentiated thyroid cancer. Presence of a RET proto-oncogene germline mutation indicates hereditary C cell disease in the context of multiple endocrine neoplasia type 2 and hence a special treatment algorithm is required. Cure of MTC is only possible through surgery. Calcitonin screening is advocated for early MTC diagnosis and preoperative MTC management stratification. In case of surgically incurable persistent MTC, estimation of calcitonin and CEA doubling time is crucial to assess tumor biology and is complemented by multimodal imaging to assess tumor burden. Treatment decisions in incurable MTC must be carefully balanced with treatment-related morbidity, since MTC may take an indolent course over years.

[Peptide receptor radionuclide therapy for patients with somatostatin receptor expressing tumours. German Guideline (S1)]. / Peptidrezeptor-Radionuklidtherapie Somatostatinrezeptor-exprimierender Tumore. DGN-Leitlinie (S1).

This document describes the guideline for peptide receptor radionuclide therapy (PRRT) published by the German Society of Nuclear Medicine (DGN) and accepted by the Association of the Scientific Medical Societies in Germany (AWMF) to be included in the official AWMF Guideline Registry. These recommendations are a prerequisite for the quality management in the treatment of patients with somatostatin receptor expressing tumours using PRRT. They are aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRT and to deliver the treatment in a safe and effective manner. The recommendations are based on an interdisciplinary consensus. The document contains background information and definitions and covers the rationale, indications and contraindications for PRRT. Essential topics are the requirements for institutions performing the therapy, e. g. presence of an expert for medical physics, intense cooperation with all colleagues involved in the treatment of a patient, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how treatment has to be carried out technically. Here, quality control and documentation of labelling are of great importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with the involved medical disciplines. Generally, the decision for PRRT should be undertaken within the framework of a multi-disciplinary tumour board.

[Differentiated thyroid cancer]. / Differenzierte Schilddrüsenkarzinome.

Thyroid carcinoma is a rare and heterogeneous disease. Initial therapy and follow-up has to be adjusted to the individual risk for an excellent vs. poor prognosis. Differentiated thyroid cancer has a very high cure rate and is treated by surgery, usually followed by radioiodine ablation. Depending on the response to initial therapy the risk for persisting or recurrent disease should be re-evaluated. Continued TSH suppressive levothyroxine therapy is only recommended in high-risk patients. In contrast, metastatic radioiodine-refractory thyroid cancers have a poor prognosis and may benefit from multidisciplinary treatment concepts including tyrosine kinase inhibitors. Due to its complexity, management of thyroid cancer patients should be performed in close collaboration with a specialized thyroid cancer team.

Expression of the cAMP binding protein EPAC1 in thyroid tumors and growth regulation of thyroid cells and thyroid carcinoma cells by EPAC proteins.

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.

[Thyroid dysfunction in pregnancy]. / Schilddrüsenfunktionsstörungen in der Schwangerschaft.

Thyroid dysfunction may impair fertility, course of pregnancy and fetal development. Physiological alterations of thyroid function parameters, that occur during pregnancy need to be distinguished from pathophysiological states of hypo- and hyperthyroidism. We performed a literature search (PubMed 1990-2013) and review relevant publications as well as consensus and practice guidelines of international thyroid/endocrine societies. Interpretation of thyroid function values in pregnancy must be based on trimester-specific TSH and T4 ranges. Alterations in thyroid function are present in up to 15% of pregnancies (0.4% overt hypothyroidism, 0.1-0.4% hyperthyroidism) and may lead to preventable complications in the pregnant woman and the fetus. Hypothyroidism is associated with an increased risk for abortion, premature delivery and stillbirth, besides impairment of neurocognitive development. The latter has also been shown in situations of grave iodine deficiency. In addition to new-born screening directed at early recognition of congenital hypothyroidism (incidence 0.03%), universal screening of all pregnant women should be implemented in health care guidelines. Newly diagnosed overt hypothyroidism in a pregnant woman requires immediate levothyroxine substitution at adequate doses. In subclinical hypothyroidism thyroid hormone replacement should be considered. Iodine supplementation is strongly recommended in all pregnant and breast-feeding women. Pregnancy causes a number of, that need to be of thyroid dysfunction. Both hypothyroidism and thyrotoxicosis may impair the course of pregnancy and may negatively affect the fetus. In particular, maternal hypothyroidism may lead to irreparable and detrimental deficits in the neurocognitive development of the fetus. Autoimmune thyroid disease is the most common cause of thyroid dysfunction in pregnancy. Hashimoto's thyroiditis is associated with impaired fertility and miscarriage, and may first manifest in pregnancy due to the increased thyroid hormone requirement. Graves' disease often shows a characteristic course in pregnancy with amelioration of thyrotoxicosis in the second half of pregnancy and exacerbation after delivery. In addition transplacental passage of maternal TSH receptor antibodies may lead to thyrotoxicosis in the fetus and/or newborn.

[Thyroid hormone action beyond classical concepts. The priority programme "Thyroid Trans Act" (SPP 1629) of the German Research Foundation]. / Schilddrüsenhormonwirkung--jenseits klassischer Konzepte. Das Schwerpunktprogramm "Thyroid Trans Act" (SPP 1629) der Deutschen Forschungsgemeinschaft.

Thyroid hormones are of crucial importance for the function of nearly all organ systems. In case of dysfunction of thyroid hormone production and function many organ systems may be affected. The estimation of normal thyroid function is based on determination of TSH and the thyroid hormones T3 and T4. However, international conventions about the normal TSH range are still lacking which bears consequences for patient`s treatment. Hence not unexpected, many patients complain although their thyroid hormone status is in the normal range by clinical estimation. Here, more precise parameters are needed for a better definition of the healthy thyroid status of an individual. Recently, new key players in the system of thyroid hormone action were detected, like specific transporters for uptake of thyroid hormones and thyroid hormone derivatives. DFG, the German Research Foundation supports the priority program Thyroid Trans Act to find answers to the main question: what defines the healthy thyroid status of an individual. The overall aim of this interdisciplinary research consortium is to specify physiological and pathophysiological functions of thyroid hormone transporters and thyroid hormone derivative as new players in thyroid regulation in order to better evaluate, treat, and prevent thyroid-related disease.