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  • Author: Dagmar Fuhrer x
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Susanne Tan, Stefan Dieterle, Sonali Pechlavanis, Onno E Janssen and Dagmar Fuhrer

Objective

Autoimmune thyroid disease (AITD) has been associated with adverse pregnancy outcomes in subfertile women with spontaneous and assisted reproductive technology-induced pregnancies. The underlying pathophysiology is still elusive and an association with thyroid dysfunction or other infertility causes is discussed. However, whether thyroid autoimmunity (TAI) per se has a negative impact on female fertility has not yet been clarified. In this study, we investigated whether TAI in healthy women undergoing intracytoplasmic sperm injection (ICSI) for male infertility may affect pregnancy outcome.

Design

A retrospective, single-centre study.

Methods

The ICSI outcome data obtained from 835 euthyroid women (age: 31.4±4.3 years, BMI: 23.7±4.2 kg/m2) were correlated with pre-ICSI TAI status. The known causes of female subfertility were excluded. Outcome parameters included rates of pregnancy, birth, miscarriage and preterm delivery. Blood analysis was carried out retrospectively using blood samples drawn before ICSI. TAI was defined by elevation of anti-thyroperoxidase- or anti-thyroglobulin-antibodies >100 U/l.

Results

TAI-positive and -negative groups did not differ in age, BMI or TSH levels. TAI status did not influence any ICSI outcome parameters. In contrast, increasing maternal age was significantly correlated with lower pregnancy rate (odds ratio (OR): 0.94 (95% CI: 0.91–0.97); P=0.0003) and birth rate (OR: 0.93 (95% CI: 0.09–0.97); P<0.0001).

Conclusions

Our study suggests that TAI per se does not influence ICSI outcome. A strict definition of AITD and TAI and consideration of TAI-associated and -independent confounders are important to further elucidate the interplay between TAI and reproduction.

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Vera Tiedje, Saskia Ting, Robert Fred Walter, Thomas Herold, Karl Worm, Julia Badziong, Denise Zwanziger, Kurt Werner Schmid and Dagmar Führer

Objective

Medullary thyroid carcinoma (MTC) occurs sporadically in 75% of patients. Metastatic disease is associated with significantly poorer survival. The aim of this study was to identify prognostic markers for progressive MTC and oncogenic factors associated with response to vandetanib therapy.

Design and methods

Clinical courses of 32 patients with sporadic MTC (n=10 pN0cM0, n=8 pN1cM0, n=14 pN1cM1) were compared with genetic profiles of the patients’ primary tumour tissue. Analysis for RET proto-oncogene mutations was performed by Sanger sequencing and next-generation sequencing (NGS). The mRNA expression (mRNA count) of 33 targets was measured by nCounter NanoString analysis.

Results

Somatic RET mutations occurred in 21/32 patients. The RET918 mutation was found in 8/14 pN1cM1 patients. BRAF (P=0.019), FGFR2 (P=0.007), FGFR3 (P=0.044) and VEGFC (P=0.042) mRNA expression was significantly lower in pN1cM0/pN1cM1 compared with pN0cM0 patients, whereas PDGFRA (P=0.026) mRNA expression was significantly higher in pN1cM0/pN1cM1 when compared with pN0cM0 patients. Among the 10/32 vandetanib-treated patients, 5 showed partial response (PR), all harbouring the RET918 mutation. mRNA expression of FLT1 (P=0.039), FLT4 (P=0.025) and VEGFB (P=0.042) was significantly higher in therapy responders.

Conclusions

In this study, we identified molecular markers in primary tumour tissue of sporadic MTC associated with the development of metastasis (both lymph node and organ metastasis) as well as response to vandetanib therapy.

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Kerstin Krause, Stefan Karger, Oliver Gimm, Sien-Yi Sheu, Henning Dralle, Andrea Tannapfel, Kurt Werner Schmid, Corinne Dupuy and Dagmar Fuhrer

Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide in the human thyroid. The aim of the present study was (I) to investigate whether DEHAL1 expression is different in differentially functioning thyroid pathologies and (II) to evaluate DEHAL1 as a possible marker of thyroid cell differentiation.

Design and methods: Real-time PCR for DEHAL1 and its isoform DEHAL1B was performed in a series of 105 thyroid specimens, including toxic thyroid nodules (TTN), Graves’ disease (GD) thyroids, benign cold thyroid nodules (CTN), normal thyroid tissues and thyroid cancers (follicular thyroid carcinomas (FTC), papillary thyroid carcinomas (PTC), partially differentiated thyroid cancers (PDTC) and anaplastic thyroid carcinomas (ATC)). In addition, DEHAL1 protein expression was studied by immunohistochemistry in 163 benign and malignant thyroid pathologies and normal thyroids.

Results: (I) The highest DEHAL1 mRNA levels were found in GD thyroids, while downregulation of DEHAL1 and DEHAL1B mRNA occurred in PTC and ATC (P<0.001 and <0.05 respectively); (II) DEHAL1 protein was overexpressed in TTNs and GD thyroids with predominant apical staining in all samples; (III) a weaker and patchy staining pattern was found in CTNs and normal thyroids; (IV) in differentiated thyroid cancers (FTC and PTC), a diffuse cytoplasmic DEHAL1 expression was found; and (V) in PDTC and ATC, DEHAL1 expression was faint or absent.

Conclusion: Upregulation of DEHAL1 protein expression and sublocalisation of DEHAL1 at the apical cell pole in TTNs and GD thyroids is consistent with increased thyroid hormone turnover during thyrotoxicosis. Diffuse cytoplasmatic localisation or downregulation of DEHAL1 expression in thyroid cancers suggests alteration or loss of DEHAL1 function during thyroid cell dedifferentiation.

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Julia Wendler, Matthias Kroiss, Katja Gast, Michael C Kreissl, Stephanie Allelein, Urs Lichtenauer, Rainer Blaser, Christine Spitzweg, Martin Fassnacht, Matthias Schott, Dagmar Führer and Vera Tiedje

Context

Anaplastic thyroid carcinoma (ATC) is an orphan disease and confers a dismal prognosis. Standard treatment is not established.

Objective

The aim of this study is to describe clinical characteristics, current treatment regimens and outcome of ATC and to identify clinical prognostic markers and treatment factors associated with improved prognosis.

Design

Retrospective cohort study at five German tertiary care centers.

Patients and methods

Totally 100 ATC patients diagnosed between 2000 and 2015 were included in the analysis. Disease-specific overall survival (OS) was compared with the Kaplan–Meier method and log-rank test; Cox proportional hazard model was used to identify risk factors.

Results

The 6-month, 1-year and 5-year disease-specific OS rates were 37, 28 and 5%, respectively. Stage-dependent OS at 6 months was 78, 54 and 18% for stage IVA, B and C, respectively. 29% patients survived >1 year. Multivariate analysis of OS identified age ≥70 years, incomplete local resection status and the presence of distant metastasis as significant risk factors associated with shorter survival. Radical surgery (hazard ratio [HR] 2.20, 95% confidence interval (CI) 1.19–4.09, P = 0.012), external beam radiation therapy (EBRT) ≥40 Gy (HR = 0.34, 0.15–0.76, P = 0.008) and any kind of chemotherapy (CTX) (HR = 11.64, 2.42–60.39, P = 0.003) were associated with longer survival in multivariate analyses adjusted for age and tumor stage. A multimodal treatment regimen was significantly associated with a survival benefit (HR = 1.04, 1.01–1.08, P < 0.0001) only in IVC patients.

Conclusion

Disease-specific OS is still poor in ATC. Treatment factors associated with improved OS provide a rationale to devise treatment pathways for routine care. Collaborative research structures should be aimed to advance treatment of ATC.

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Julia Badziong, Saskia Ting, Sarah Synoracki, Vera Tiedje, Klaudia Brix, Georg Brabant, Lars Christian Moeller, Kurt Werner Schmid, Dagmar Fuhrer and Denise Zwanziger

Objective

Thyroid hormone (TH) transporters are expressed in thyrocytes and most play a role in TH release. We asked whether expression of the monocarboxylate transporter 8 (MCT8) and the L-type amino acid transporters LAT2 and LAT4 is changed with thyrocyte dedifferentiation and in hyperfunctioning thyroid tissues.

Design and methods

Protein expression and localization of transporters was determined by immunohistochemistry in human thyroid specimen including normal thyroid tissue (NT, n = 19), follicular adenoma (FA, n = 44), follicular thyroid carcinoma (FTC, n = 45), papillary thyroid carcinoma (PTC, n = 40), anaplastic thyroid carcinoma (ATC, n = 40) and Graves’ disease (GD, n = 50) by calculating the ‘hybrid’ (H) score. Regulation of transporter expression was investigated in the rat follicular thyroid cell line PCCL3 under basal and thyroid stimulating hormone (TSH) conditions.

Results

MCT8 and LAT4 were localized at the plasma membrane, while LAT2 transporter showed cytoplasmic localization. MCT8 expression was downregulated in benign and malignant thyroid tumours as compared to NT. In contrast, significant upregulation of MCT8, LAT2 and LAT4 was found in GD. Furthermore, a stronger expression of MCT8 was demonstrated in PCCL3 cells after TSH stimulation.

Conclusions

Downregulation of MCT8 in thyroid cancers qualifies MCT8 as a marker of thyroid differentiation. The more variable expression of LATs in distinct thyroid malignancies may be linked with other transporter properties relevant to altered metabolism in cancer cells, i.e. amino acid transport. Consistent upregulation of MCT8 in GD is in line with increased TH release in hyperthyroidism, an assumption supported by our in vitro results showing TSH-dependent upregulation of MCT8.

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Ilonka Kreitschmann-Andermahr, Tsambika Psaras, Maria Tsiogka, Daniel Starz, Bernadette Kleist, Sonja Siegel, Monika Milian, Johannes Kohlmann, Christa Menzel, Dagmar Führer-Sakel, Jürgen Honegger, Ulrich Sure, Oliver Müller and Michael Buchfelder

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Ilonka Kreitschmann-Andermahr, Tsambika Psaras, Maria Tsiogka, Daniel Starz, Bernadette Kleist, Sonja Siegel, Monika Milian, Johannes Kohlmann, Christa Menzel, Dagmar Führer-Sakel, Jürgen Honegger, Ulrich Sure, Oliver Müller and Michael Buchfelder

Objective

To obtain structured information on the diagnostic delay in patients with Cushing's disease (CD) from the patients perspective to provide leverage points for earlier diagnosis.

Design

The study includes 176 patients with ACTH-dependent CD who had received pituitary surgery completed a self-developed questionnaire on their symptomatology before the illness was diagnosed, the course and length of the diagnostic process, and the role of the involved health care professionals.

Methods

Data were analyzed statistically. Answers in free text options were categorized and counted.

Results

The overall diagnostic process took 3.8±4.8 years (median 2 years), during which 4.6±3.8 (1–30) physicians were consulted, most frequently the family physician (FP; 83.0%). The presented symptoms were various and often vague, e.g. ‘poor general condition’ (at FPs), or very common in the field of the visited specialist (i.e. ‘skin changes’ at dermatologists). Women recognized the first CD symptoms themselves significantly more frequently than men, whereas physicians recognized CD symptoms significantly more frequently in males.

Conclusion

A clear difficulty of diagnosing CD seems that patients describe isolated symptoms to the FP or the respective specialists according to their fields of specialization. As FPs are contacted most frequently, they should be trained to recognize the broad spectrum of CD symptoms, especially in female patients with weight gain, and initiate endocrinological referral.