Joachim Feldkamp

Incidentally discovered pituitary lesions : high frequency of macroadenomas and hormone-secreting adenomas : results of a prospective study

With increasing use of computed tomography and magnetic resonance imaging, pituitary adenomas are being discovered incidentally with increasing frequency. However, limited data are available concerning the clinical importance and natural history of such ‘incicentalomas’. We have undertaken a prospective study to investigate changes in adenoma size and endocrine and visual function in patients with incidentally discovered intrasellar masses.

Comparative screening for thyroid disorders in old age in areas of iodine deficiency, long‐term iodine prophylaxis and abundant iodine intake

To investigate the effect of varying amounts of iodine intake on the prevalence of thyroid dysfunction, autoimmunity and goitre in old age.

Calcitonin-specific antitumor immunity in medullary thyroid carcinoma following dendritic cell vaccination.

Abstract. In this study, we investigated the immune response following immunotherapy with calcitonin-pulsed dendritic cells (DC) in 7 patients with metastasized medullary thyroid carcinoma. After immunization with 1–5×106 autologous DC, significant calcitonin-specific T cell proliferation was detectable in 3 patients. Measurement of cytokine release from T lymphocytes demonstrated high post-treatment interferon-γ (IFN-γ) secretion after stimulation with calcitonin in 5 patients, one of whom experienced significant tumor regression. In contrast, antigen-specific interleukin-4 (IL-4) production was only slightly increased in 4 patients. All 7 patients developed a strong delayed-type hypersensitivity (DTH) skin reaction, which was confirmed to be mediated by infiltrating CD4+ T-helper cells and CD8+ cytotoxic T cells in all 3 patients who underwent skin biopsy. This is the first study to show that a polypeptide hormone can be used to develop a DC vaccination strategy for the immunotherapy of highly malignant endocrine cancers.

Response of human monocyte-derived dendritic cells to immunostimulatory DNA.

Activated dendritic cells (DC) are of key importance for the initiation of primary immune responses and represent promising tools for immunotherapies in humans. Since DNA containing CpG motifs have been described as potent immunostimulatory (IS) adjuvants for murine DC, we here studied maturation and stimulation of functional activity in human monocyte‐derived DC (MODC) in response to several immunostimulatory oligodeoxynucleotides (IS‐ODN) and plasmid DNA (IS‐PL). We show that exposure of MODC to IS‐PL, but not IS‐ODN, induced a dose‐dependent strong up‐regulation of HLA class II and co‐stimulatory molecules (CD80, CD86), similar to that observed after treatment with TNF‐α. Functional activity was assessed by the detection of increased secretions of IL‐6 and IL‐12(p75) following treatment with IS‐PL. In addition, IS‐PL‐stimulated MODC acquired a high T cell‐stimulatory capacity. T cells stimulated by tetanus toxoid‐pulsed, IS‐PL‐matured MODC were significantly more frequently IFN‐γ positive (25.2±2.7%) as compared to TNF‐α‐treated MODC (15.4±1.4 %), indicating a strong activation of Th1 lymphocytes. In conclusion, we demonstrate that human MODC are activated by IS‐PL but not IS‐ODN previously used as adjuvants in animal models. The Th1‐like immune response observed after stimulation with IS‐PL‐treated DC suggests that preincubation of human MODC with IS‐PL or coimmunization with IS‐PL may represent an useful approach to generate strongly activated human MODC for several therapeutic applications such as DC‐based tumor immunotherapy.

Dendritic cell immunotherapy in a neuroendocrine pancreas carcinoma

OBJECTIVE Metastatic neuroendocrine carcinomas of the pancreas frequently fail to respond to conventional therapies, including radiation and chemotherapy. We therefore tested a dendritic cell‐based immunotherapy in an attempt to eradicate residual tumour masses in a patient suffering from a metastatic insulin‐producing pancreatic carcinoma.

MicroRNAs miR-146a1, miR-155_2, and miR-200a1 Are Regulated in Autoimmune Thyroid Diseases

Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are the most common autoimmune thyroid diseases (AITDs). The exact etiology of the immune response in both is still unknown. MicroRNAs (miRNAs) constitute a recently discovered family of small RNAs that control gene expression. Accumulating data suggest that miRNAs crucially control innate and adaptive immune responses, and implicate some miRNAs as having an important role in the pathophysiology of immunity and autoimmunity (1). To the best of our knowledge, there are currently no data on the involvement of miRNA in AITDs. We have determined the levels of some key immunoregulatory miRNAs in the thyroid glands of AITD patients and healthy controls. We investigated the thyroid gland fine-needle aspiration biopsies of patients with HT and GD. There were 28 unrelated Caucasians who were included in this study. The control groups comprised 9 Caucasians without AITDs; there were 9 patients with GD in the GD, and there were 10 patients with HT in the HT group. Ultrasound-guided fine-needle aspiration biopsies were performed using a 20-gauge needle. Total RNA, including miRNA, was extracted from thyroid tissue samples and reverse transcribed with an miRNeasy Mini Kit (Qiagen GmbH). Semiquantitative TaqMan PCR was performed in an ABI PRISM 7700 Sequence Detector (PE Applied Biosystems) using the miScript SYBR Green PCR Kit (Qiagen GmbH). The specific miScript Primer Assays (Qiagen GmbH) were used for the amplification of 13 miRNAs: miR-34a, miR-143_1, miR-143_1*, miR-146a_1, miR-155*_1, miR-155_2, miR-181a*_1, miR-181a2*, miR-181b1, miR-200a1, miR-200a*2, miR-200a1, and miR-1238. All data were analyzed using the nonparametric Kruskal–Wallis test. Results with p < 0.05 were considered statistically significant. Bonferroni-corrected Mann– Whitney U-tests were used as post hoc tests (see Supplementary Data, available online at www.liebertpub.com/thy). In the thyroid tissue of the GD group, miR-146a1 was significantly decreased in comparison to the control group (mean relative expression 5.17 vs. 8.37, respectively, p = 0.019). In the HT group, miR-155_2 was significantly decreased in comparison to the control group (8.30 vs. 11.20, respectively, p = 0.001), and miR-200a1 was significantly increased (12.02 vs. 8.01, p = 0.016). There were no significant differences between the HT and GD groups (see Supplementary Data) or for the other miRNAs tested. Our pilot study was undertaken to evaluate the influence of candidate miRNAs in AITDs that have been suspected of being involved in immunoregulation based on previously published observations (1–4). We found a significant decrease of miR-146a1 in the thyroid tissue of a patient with GD. miR-146a has been reported to be differentially regulated in other autoimmune diseases. Nakasa et al. demonstrated that miR-146a was highly expressed in rheumatoid arthritis (RA) synovial tissue compared to normal synovial tissue (2). This is in contrast to the decrease of miR-146a in our study, and is consistent with the perception that RA is characterized by a predominance of Th1-cytokines, while GD is characterized by the production of Th2-cytokines in thyroid tissue-emigrating mononuclear cells. Furthermore, we report here that miR200a1 is increased in the thyroid tissue of HT patients, but not in that of patients with GD. This further substantiates the findings by Glinsky, who found in an SNP-guided miRNA map that miR-200, miR-34a, miR-143, and miR-1238 were associated with AITDs in general and GD in particular (4). To date, the potential role of miR-200a1 is not understood and warrants further research. This is the first report that there is a significant decrease of miR-155_2 in the thyroid tissue of patients with HT. This miRNA was previously shown to possess important functions in the mammalian immune system by Thai et al. (3). The other miRNA candidates tested did not significantly differ between AITDs, even though evidence exists for their involvement in immunoregulation. We assume that the reported miRNA variations in thyroid tissue are caused by infiltrating activated lymphocytes, because—according to additionally performed microscopy of fine-needle aspirations—these cells are dominant.

Mortality rate of chronically ill geriatric patients with subnormal serum thyrotropin concentration: a 2-yr follow-up study.

We investigated the natural course of subclinical thyroid dysfunctions in geriatric patients, especially regarding their association with mortality rate. Ninety-three randomly selected chronically ill geriatric patients 64–87 (median: 77) yr of age participated in the screening study with a 2-yr follow-up. Serum thyrotropin (thyroid-stimulating hormone [TSH]), free thyroxine, triiodothyronine, and antibodies against thyroid peroxidase were measured. During the follow-up, patients with suppressed TSH levels who were otherwise euthyroid (untreated) had a higher mortality rate than patients with normal TSH (5/8 vs 18/64; p<0.05). The initial clinical state of these two subgroups did not differ significantly. Two-thirds of patients with treated hyperthyroidism died. The mortality rate of patients with initially subnormal but not suppressed TSH level was average and did not differ statistically from either the euthyroid or the hyperthyroid groups. Only 1 of 13 euthyroid patients with positive thyroid antibody titers developed a subsequent subclinical hypothyroidism. Subclinical hyperthyroidism was found to be associated with a higher mortality rate in chronically ill geriatric patients, which justifies screening for thyroid dysfunction and treatment of subclinical hyperthyroidism. In addition, a subnormal but measurable TSH was not indicative regarding the future development of hyperthyroidism. Finally, during the 2-yr follow-up, antibody positivity in the euthyroid cases did not prove to be predictive for the subsequent development of hypothyroidism.

Helpful diagnostic markers of steroidogenesis for defining hyperandrogenemia in hirsute women

HYPOTHESIS Androgen excess carries varied clinical manifestations in women. Although testosterone and dehydroepiandrostendionesulfate (DHEAS) determination is considered useful in diagnostic workup, there is no laboratory definition that sufficiently describes androgen excess. DESIGN We studied 464 hirsute women with a Ferriman and Gallwey score of at least 8 between 2000 and 2005. Our examination included clinical data, total testosterone (T), sex hormone-binding globulin (SHBG), the free androgen index (FAI), and DHEAS. Additionally, androstendione, 17alpha-hydroxyprogesterone (17OHP), dehydroepiandrostendione (DHEA), and 11-deoxycortisol were determined at baseline and 60min after corticotropin challenge (250microg synacthen). RESULTS Of 464 women, 77.6% fulfilled the clinical criteria for hyperandrogenemia. Of these 360 women, 78.1% had hyperandrogenic hirsutism. Of these 281 women, 43.4% showed increased stimulation of 17OHP to 250microg of synacthen. Another 37.4% showed adrenal steroid biosynthesis defects other than 21alpha-hydroxylase deficiency, such as defective 11beta-hydroxylation or 3beta-hydroxysteroid dehydrogenase malfunction. The diagnosis of polycystic ovary syndrome was applicable to 12.4%. In addition, our results show that 72% of 281 patients with secondary hirsutism had normal T concentrations, and 55% had a normal FAI. Only 5% of hirsute patients with a normal FAI had elevated DHEAS values. However, 40% showed elevated DHEA levels, while 26% of the women with normal FAI showed androstendione values over the maximal levels in the 79 controls. CONCLUSIONS Our data suggest that in addition to testosterone and FAI, androstendione and DHEA are significantly helpful parameters in diagnosing hyperandrogenemia in hirsute women. DHEAS was not found to be helpful.

Fine Needle Aspiration in the Investigation of Thyroid Nodules: Indications, Procedures and Interpretation

BACKGROUND Thyroid nodules are a common finding in Germany. Most are benign; thyroid cancer is very rare. The challenge for the physician is to diagnose malignant tumors early. Fine needle aspiration is an important tool for this purpose. METHODS This review is based on pertinent articles (1980-2014) retrieved by a selective search in PubMed and on the current recommendations of guidelines issued by the specialty societies in Germany and abroad. RESULTS Clinical, ultrasonographic, and scintigraphic criteria are used to identify high-risk nodules, which are then further studied by fine needle aspiration. Important ultrasonographic criteria for malignancy are low echodensity (positive predictive value [PPV]: 1.85), microcalcifications (PPV: 3.65), irregular borders (PPV: 3.76), and intense vascularization. Fine needle aspiration of the thyroid gland is an inexpensive and technically straight - forward diagnostic procedure that causes little discomfort for the patient. It helps prevent unnecessary thyroid surgery and is used to determine the proper surgical strategy if malignancy is suspected. The cytological study of fine needle aspirates enables highly precise diagnosis of many tumor entities, but follicular neoplasia can only be diagnosed histologically. In the near future, molecular genetic methods will probably extend the diagnostic range of fine needle aspiration beyond what is currently achievable with classic cytology. CONCLUSION Fine needle aspiration biopsy of the thyroid gland in experienced hands is an easily performed diagnostic procedure with very little associated risk. It should be performed on ultrasonographically suspect nodules for treatment stratification and before any operation for an unclear nodular change in the thyroid gland.

A Case of Catecholamine and Glucocorticoid Excess Syndrome Due to a Corticotropin-Secreting Paraganglioma

Abstract:  We present a case of a 61‐year‐old female patient with ectopic corticotropin (ACTH) syndrome, hypopituitarism, and catecholamine excess due to a paraganglioma at the inferior pole of the left kidney. In this article we discuss the hormonal findings in the patient and its consequences, the pitfalls of the endocrine workup, and the results of our immunohistological and molecular studies in more detail.