[Cardiovascular aspects of diabetes treatment : Finally a reason for cardiologists to be pleased]. / Kardiovaskuläre Aspekte der Diabetestherapie : Endlich Grund zur Freude für Kardiologen.

Cardiovascular disease significantly determines morbidity and mortality in patients with diabetes mellitus type 2. Large clinical trials in the past left controversial evidence about the effect of blood glucose-lowering treatments on cardiovascular outcomes. In 2008, the regulatory authorities defined new requirements on cardiovascular safety data for the approval of new drugs for the treatment of type 2 diabetes mellitus. Since then, numerous large safety studies have been initiated to prove cardiovascular noninferiority of new antidiabetic drugs. Preliminary data from these safety studies have become available and provided promising results. While treatment with DPP-4 inhibitors and the short acting GLP-1 receptor agonist lixisenatide were shown to be safe, treatment with the SGLT-2 inhibitor empagliflozin and the long-acting GLP-1 receptor agonist liraglutide even significantly improved cardiovascular outcomes in patients with type 2 diabetes mellitus. With the evidence of cardiovascular benefits of the new drugs, new treatment strategies for patients with diabetes mellitus type 2 are expected.

[ASCO-update 2015 - highlights of the 51. meeting of the american society of clinical oncology/ASCO 2015]. / ASCO-Update 2015 - Neuigkeiten vom 51. Meeting der American Society of Clinical Oncology/ASCO 2015.

The field of gastrointestinal oncology is rapidly developing, on the one hand through the identification of novel molecular targets and therapeutic principles, on the other hand through the establishment and improvement of multidisciplinary treatment strategies. The following manuscript summarizes the most important trial results of the ASCO Meeting 2015 for gastrointestinal cancers. Besides trials on perioperative treatment of esophageal-, pancreatic- and colon cancer, we will present impressive data on new therapeutic strategies such as immunotherapy in gastric-, liver and microsatellite instable colorectal cancer. The trials will be put into context by the authors.

Surgical Treatment of NEN of Small Bowel: A Retrospective Analysis.

BACKGROUND: Neuroendocrine Neoplasms of the small intestine have been noticed more frequently over the past 35 years. They constitute about 25% of all NENs and 29% of all tumors of the small intestine. Due to the predominantly indolent nature and overall good prognosis, the benefit of surgical treatment is still debated. METHODS: In a retrospective study, data of 83 surgically treated patients with neuroendocrine neoplasms of the small intestine, 48 males and 35 females with a median age of 62 years (range 25-86 years) were analyzed. Patient data were documented in the MaDoc database for neuroendocrine tumors of the University Medical Center of Mainz. IBM SPSS Statistics 20 was used for statistical analysis. Kaplan-Meier survival curves and Log-Rank tests, censoring patients at the time of last follow-up, were used to compare the overall survival depending on potential prognostic factors (stage, grade, surgical treatment). RESULTS: At the time of diagnoses, the most common clinical symptoms were abdominal pain (n = 31, 37.3%), bowel obstruction (n = 11, 13.3%), bowel perforation and peritonitis (n = 3, 3.6%), gastrointestinal bleeding (n = 9, 10.8%), weight loss (n = 11, 13.3%), and carcinoid syndrome (n = 27, 32.5%). 65 patients (78.3%) had lymph node metastasis and in 58 patients (69.9%) distant metastasis were present. Segmental bowel resection (44) was the most common surgical procedure, followed by right hemi-colectomy (32) and explorative laparotomy (7). In most patients (78.9%), lymphadenectomy (systematic/selective) was performed. The 5-year survival of patients who underwent a systematic or a selective lymphadenectomy differed significantly (82.2 vs. 40.0%). The overall 3-, 5-, and 10-year survival rates were 88.2, 80.3, and 71.0%, respectively. CONCLUSION: Mesenteric lymph node metastases are almost invariably present and have significant impact on patients' prognosis. Systematic lymphadenectomy prevents complications and improves the survival. Early surgical treatment should be the goal in order to prevent complications.

Surgical therapy of neuroendocrine neoplasm with hepatic metastasis: patient selection and prognosis.

BACKGROUND: Patients with neuroendocrine neoplasms (NEN) develop hepatic metastases in 50-95 %. The aims of this study were to evaluate the outcome/prognosis of patients following hepatic surgery and to identify predictive factors for the selection of patient that benefit from hepatic tumor resection. PATIENTS AND METHODS: In a retrospective single-center study (1990 to 2014), 204 patients with hepatic metastasis of NEN were included. Ninety-four were subjected to various forms of liver resection. According to the overall survival, the influence of several prognostic factors like the Ki-67 index, stage of disease, and resection status was evaluated. RESULTS: The primary tumor was located in the small intestine (n = 73), pancreas (n = 58), colon (n = 26), esophagus or stomach (n = 9) and in 38 patients the primary site was unknown. The Ki-67 index was associated with significant different overall survival. Patients with an R0 resection (n = 38) of their hepatic metastasis had a very good 10-year survival of 90.4 %. Patients in whom an R1 (n = 23) or R2 (n = 33) resection of their hepatic metastasis could be achieved had a 10-year survival of 53.4 and 51.4 %, respectively. The majority of the patients (53.9 %) could not be resected and had a poor 10-year survival rate of 19.4 %. Partial or complete control of endocrine-related symptoms was achieved in all patients with functioning tumors following surgery. The overall 5- and 10-year survival rates were 77.9 and 65.2 %, respectively. CONCLUSION: Surgical resection of hepatic NEN metastases can reduce symptoms and improve the survival in selected patients with a Ki-67 index less than 20 %. The expected outcome has to be compared to the outcome of alternative treatment strategies. An R0 situation should be the aim of hepatic surgery, but also patients with R1 or R2 resection show a good survival benefit.

Resection strategies for neuroendocrine pancreatic neoplasms.

INTRODUCTION: Due to their rarity and lack of prospective trials, the optimal treatment of pancreatic neuroendocrine neoplasms (PNENs) is still debated. Recommendations gathered by retrospective analyses of patient data should be based on the new classification of neuroendocrine neoplasms. METHODS: In a retrospective single-center study (1990 to 2012), 127 patients with PNENs were included. Tumor stage and type of resections were analyzed to evaluate successful treatment strategies. RESULTS: Seventy-nine patients (62 %) were diagnosed with stage I or II, 48 patients (38 %) with stage III or IV disease; 49.6 % of all PNENs were nonfunctional. Surgical interventions consisted of 50 enucleations, 27 distal resections, and 2 partial duodenopancreatectomies in patients with stage I or II disease. Twenty-eight patients with stage III or IV disease received a distal resection and in 13 patients, a partial duodenopancreatectomy was carried out. Exploration with debulking was performed in seven patients in stages III and IV. Stage-dependent 10-year survival rates were 93.7 (stages I and II, n = 79) and 56.0 % (stages III and IV, n = 48). CONCLUSIONS: PNENs have a good prognosis if they are well-differentiated and resected completely. Organ-preserving resection does not impair the prognosis in selected cases with stage I or II. In case of hepatic metastasis and advanced tumor stage, surgical reduction can reduce symptoms and improve the survival.

[Neuroendocrine neoplasms of the gastrointestinal tract. Classification, clinical presentation and diagnosis]. / Neuroendokrine Neoplasien des Gastrointestinaltrakts. Klassifikation, Klinik und Diagnose.

Neuroendocrine neoplasms of the digestive system represent a rare and heterogeneous group of malignancies with various clinical presentations and prognoses. The WHO classification for the year 2000 was updated in 2010 to take the histopathology and tumor biology of these tumors into account. Together with proliferation-based grading and the recently established staging system using the ENETS TNM classification, it forms the basis for the further diagnostic and therapeutic approach. Clinical presentation depends mainly on the primary site of the tumor and its functionality. Characteristic symptoms are seen only rarely, this being the reason these tumors are usually detected at an advanced stage. Approximately 30% of GEP-NEN are hormonally active and can cause a specific clinical syndrome. In addition to these specific hormones, chromogranin A is considered the most accurate general marker for the biochemical follow-up of these patients. In addition to commonly used radiological and endoscopic imaging modalities, somatostatin receptor-based functional imaging using either octreotide scintigraphy or novel PET-based techniques with specific isotopes such as Ga68-DOTA-octreotate play a crucial role in the detection of the primary tumor as well as in the evaluation of tumor extent and the selection of patients for receptor-based radionuclide therapy.

6-18F-fluoro-L-dihydroxyphenylalanine positron emission tomography is superior to 123I-metaiodobenzyl-guanidine scintigraphy in the detection of extraadrenal and hereditary pheochromocytomas and paragangliomas: correlation with vesicular monoamine transporter expression.

CONTEXT: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) may be better detected by (18)F-fluorodihydroxyphenylalanine-positron emission tomography (FDOPA-PET) than (123)I-metaiodobenzyl-guanidine (123-I-MIBG) scintigraphy. OBJECTIVE: The objective of the study was to correlate functional imaging results with immunohistochemical, molecular-genetic, and biochemical findings. DESIGN AND SETTING: Thirty consecutive patients with suspected PHEO/PGL presenting at a tertiary referral centre were investigated in a prospective study. PATIENTS: Twenty-five patients had confirmed PHEO/PGL. Thirteen of 25 patients had a hereditary PHEO/PGL syndrome (two multiple endocrine neoplasia II, six succinate dehydrogenase complex, subunit D, two succinate dehydrogenase complex, subunit B, one von Hippel Lindau tumor suppressor protein, two Neurofibromatosis-1), and 12 of 25 were classified as sporadic. Five patients had hormonally inactive adrenal incidentalomas. MAIN OUTCOME MEASURES: In all patients computed tomography scan and/or magnetic resonance imaging as well as both 123-I-MIBG scintigraphy and FDOPA-PET were performed. Resected tumors were examined by immunohistochemistry for expression of the vesicular monoamine transporter (VMAT)-1 and -2 and other markers. RESULTS: A total of 64 lesions were found with both functional imaging modalities. FDOPA-PET detected 62 lesions, whereas only 34 lesions were detected by 123-I-MIBG scintigraphy. This resulted in an overall sensitivity and specificity for FDOPA-PET of 98 and 100% and for MIBG of 53 and 91%, respectively. Comparable sensitivities were found for adrenal and extraadrenal abdominal lesions (94 vs. 97%), whereas in thoracic/cervical lesions, the sensitivity for 123-I-MIBG scintigraphy (15%) was inferior to that of FDOPA-PET imaging (100%). Immunohistochemistry demonstrated a lack of VMAT-1 expression in all MIBG-negative tumors. Clinical predictors for MIBG negativity were a predominant norepinephrine/normetanephrine secretion, an age less than 45 yr, and a hereditary cause. CONCLUSION: FDOPA-PET is superior to 123-I-MIBG scintigraphy in patients with extraadrenal, predominantly noradrenaline-secreting, and hereditary types of PHEO/PGL. The lack of VMAT-1 expression predicts negativity for MIBG-scintigraphy.

In vivo molecular imaging of somatostatin receptors in pancreatic islet cells and neuroendocrine tumors by miniaturized confocal laser-scanning fluorescence microscopy.

The aim of the study was to evaluate real time in vivo molecular imaging of somatostatin receptors (sstrs) using a handheld miniaturized confocal laser scan microscope (CLM) in conjunction with fluorescein-labeled octreotate (OcF) in healthy mice and murine models of neuroendocrine tumors. For CLM a small rigid probe (diameter 7 mm) with an integrated single line laser (488 nm) was used (optical slice thickness 7 mum; lateral resolution 0.7 mum). OcF was synthesized via Fmoc solid-phase peptide synthesis and purified by HPLC showing high-affinity binding to the sstr2 (IC(50) 6.2 nmol). For in vitro evaluation, rat and human pancreatic cancer cells were used and characterized with respect to its sstr subtype expression and functional properties. For in vivo confocal imaging, healthy mouse pancreatic islet and renal tubular cells as well as immunoincompetent nude mice harboring sstr-expressing tumors were evaluated. Incubation of sstr-positive cells with OcF showed a specific time- and dose-dependent staining of sstr-positive cells. CLM showed rapid internalization and homogenous cytoplasmatic distribution. After systemic application to mice (n = 8), specific time-dependent internalization and cytoplasmatic distribution into pancreatic islet cells and tubular cells of the renal cortex was recorded. After injection in tumor-harboring nude mice (n = 8), sstr-positive cells selectively displayed a cell surface and cytoplasmatic staining. CLM-targeted biopsies detected sstr-positive tumor cells with a sensitivity of 87.5% and a specificity of 100% as correlated with ex vivo immunohistochemistry. CLM with OcF permits real-time molecular, functional, and morphological imaging of sstr-expressing cell structures, allowing the specific visualization of pancreatic islet cells and neuroendocrine tumors in vivo.

[Management of Graves' orbitopathy: evidence-based recommendations]. / Vorgehen bei endokriner Orbitopathie. Evidenzbasierte Empfehlungen.

Patients with Graves' orbitopathy (GO) suffer from disfiguring proptosis, orbital pain and diplopia. Compression of the optic nerve may cause functional restrictions to the point of loss of vision. Since suboptimal management of GO seems to be widespread, the European Group On Graves' Orbitopathy (EUGOGO) provided a consensus statement on the management of GO. According to EUGOGO, patients with GO should be referred to multidisciplinary specialist centers. All patients should be encouraged to quit smoking. Prompt treatment of thyroid dysfunction is mandatory in order to restore and maintain euthyroidism. The first-line treatment for optic neuropathy and/or corneal ulceration are intravenous glucocorticoids. If the response is poor after 1-2 weeks, orbital decompression surgery should follow. Intravenous glucocorticoids are also recommended in patients with moderate-to-severe and active GO. If GO is inactive, surgery should be considered. Local measures and an expectant strategy are sufficient in most patients with mild GO, but if quality of life is affected significantly, specific treatment may be justified. Thus, management of GO remains challenging and is best performed within a multidisciplinary orbital center.

Short stature and decreased insulin-like growth factor I (IGF-I)/growth hormone (GH)-ratio in an adult GH-deficient patient pointing to additional partial GH insensitivity due to a R179C mutation of the growth hormone receptor.

OBJECTIVE: Genetic factors play an expanding role in understanding growth hormone (GH) disorders, therefore the German KIMS Pharmacogenetics Study was initiated with the aim of genotyping various GH-/IGF-I-axis-related genes of GH-deficient adult patients to investigate genotype:phenotype relationships and response to GH therapy. PATIENTS AND METHODS: 129 consecutively enrolled GH-deficient adult patients were genotyped for variant 1 (V1) of the alternatively spliced noncoding exons in the 5'-untranslated region and for the nine coding exons of the GH receptor (GHR) gene, which obviously play a striking role in the function of the GH-IGF-I-axis. After detection of a heterozygous, non-synonymous mutation R179C in exon 6 in one single patient with acquired GH-deficiency (GHD) in late adulthood, analysis of her clinical data followed, leading to the diagnosis of mild short stature (-1.5SD). For further endocrine evaluation, five pituitary stimulation tests (arginine) of this patient were statistically compared to stimulation tests (arginine) of ten GH-deficient control patients, retrospectively. RESULTS: The formerly in patients with Laron syndrome and idiopathic short stature reported mutation R179C leads to an amino acid change from an arginine residue (codon CGC) to a cysteine residue (codon TGC) in position 179 of the extracellular domain of the GHR. Statistical analysis revealed significant decreased IGF-I/GH(0) ratio (p=0.004) and IGF-I/GH(max) ratio (p=0.001) of the index patient compared to the control patients, implying growth hormone resistance of the index patient at the level of the GHR, according to the detected R179C mutation. CONCLUSIONS: This study reports on the unusual case of a patient with mild short stature, who acquired GHD in late adulthood due to a non-secreting pituitary adenoma and get additionally diagnosed for pre-existing growth hormone insensitivity due to a formerly in two short statured patients described, single, heterozygous, non-synonymous mutation in the GHR. Our findings support the theory that heterozygous mutations in the GHR gene can have mild phenotypical consequences.

In-vivo confocal real-time mini-microscopy in animal models of human inflammatory and neoplastic diseases.

BACKGROUND AND STUDY AIMS: Although various improvements in tissue imaging modalities have recently been achieved, in-vivo molecular and subsurface imaging in the field of gastroenterology remains a technical challenge. In this study we evaluated a newly developed, handheld, miniaturized confocal laser microscopy probe for real-time in-vivo molecular and subsurface imaging in rodent models of human disease. MATERIALS AND METHODS: The minimicroscope uses a 488-nm, single line laser for fluorophore excitation. The optical slice thickness is 7 microm, the lateral resolution 0.7 microm. The range of the z-axis is 0-250 microm below the tissue surface. Imaging was performed using different fluorescent staining protocols; 5-carboxyfluorescein-labeled octreotate was synthesized for targeted molecular imaging. RESULTS: Cellular and subcellular details of the gastrointestinal tract could be visualized in vivo at high resolution. Confocal real-time microscopy allowed in-vivo identification of tumor vessels and liver metastases, as well as diagnosis of focal hepatic inflammation, necrosis, and associated perfusion anomalies. Somatostatin-receptor targeting permitted in-vivo molecular staining of AR42-J-induced carcinoma and pancreatic islet cells. CONCLUSIONS: Confocal mini-microscopy allows rapid in-vivo molecular and subsurface imaging of normal and pathological tissue in the gastrointestinal tract at high resolution. Because this technology is applicable to humans, it might impact on future in-vivo microsocpic and molecular diagnosis of diseases such as cancer and inflammation.

Role of the insulin-like growth factor system in adrenocortical growth control and carcinogenesis.

Clinically silent adrenocortical adenomas are the most frequent abnormalities in the adrenal gland. In contrast, adrenocortical carcinoma is a rare tumor with an extremely poor prognosis. The factors responsible for the frequent occurrence of benign adrenocortical tumors on one hand and the rare malignant transformation on the other are not known. Several genetic alterations such as loss of imprinting or loss of heterozygosity of the 11p15 gene locus causing a strong IGF-II overexpression have been demonstrated in the majority of adrenocortical carcinomas. In addition to IGF-II overexpression, increased levels of the IGF-I-receptor and IGFBP-2 have been found in advanced human adrenocortical carcinomas, suggesting an important role for the IGF-system in adrenocortical carcinogenesis. IGFs are potent mitogens regulating growth and apoptosis through interaction with the IGF-I-receptor, and overexpression of the human IGF-I-receptor promotes ligand-dependent neoplastic transformation in a variety of different cell systems. It is evident, therefore, that high levels of IGF-II in combination with overexpression of the IGF-I-receptor can provide a significant growth advantage for adrenocortical carcinoma cells and thus contribute to the highly malignant phenotype of this rare type of cancer. Additionally, it has been shown that overexpression of IGFBP-2 can promote malignant transformation of Y1 mouse adrenocortical tumor cells through unknown IGF-independent mechanisms. As one possible mechanism, we have recently found altered expression of catalase in IGFBP-2-overexpressing tumor cells, thus implicating IGFBP-2 in influencing intracellular peroxide levels. However, since transgenic mice with IGF-II or IGFBP-2 overexpression in the adrenal gland do not show an increased frequency of adrenal tumors, IGF-II or IGFBP-2 may act as progression factors but not as initiation factors in adrenocortical tumorigenesis.

Increased activity of catalase in tumor cells overexpressing IGFBP-2.

Elevated levels of IGFBP-2 are found in serum and tissues under various stressful conditions and in many malignancies. In previous studies, we have shown that overexpression of IGFBP-2 results in increased tumorigenic potential in Y-1 mouse adrenocortical tumor cells, and that these effects are presumably mediated through IGF-independent mechanisms. Here, we show that highly proliferative IGFBP-2-overexpressing Y-1 cells, but not control Y-1 cells, grow to very high cell densities. In order to evaluate whether the increased cell densities in IGFBP-2-transfected Y-1 cells were accompanied by alterations in the oxidative stress system, we analyzed the effect of IGFBP-2 overexpression on the activity of various antioxidative enzymes in two malignant cell lines. Among the tested antioxidative enzymes (catalase, superoxide-dismutase, glutathione peroxidase, glutathione S-transferase), only catalase enzyme activity was significantly higher in IGFBP-2-transfected Y-1 mouse adrenocortical tumor cells and in IGFBP-2-transfected human colon tumor cells (Caco-2) compared to control-transfected Y-1 and Caco-2 cells and non-tumor 293 human epithelial cells. However, overexpression of catalase in malignant cells did not result in increased resistance to oxidative stress as measured by cell viability and protein oxidation after treatment of the cells with hydrogen peroxide. This might be due to an upregulation of the GST enzyme activity after treatment with H (2)O (2) that we observed selectively in the control-transfected Y-1 cells and which might compensate for the higher catalase activity in the IGFBP-2 overexpressing cells. In summary, we found a strong and selective upregulation of the catalase activity in IGFBP-2 overexpressing malignant Y-1 and Caco-2 cell lines that might contribute to the highly malignant phenotype of IGFBP-2 overexpressing tumors through as yet unknown mechanisms.

Alterations of the insulin-like growth factor system in patients with polycythemia vera.

The molecular etiology of Polycythemia vera (PV) is still undetermined. Recently, enhanced tyrosine phosphorylation of the insulin-like growth factor-I receptor (IGF-IR) has been shown in PV bone marrow progenitors and peripheral blood mononuclear cells (PBMNC), and elevated levels of IGF binding protein-1 (IGFBP-1) in the serum of PV patients have been reported. To identify further alterations of circulating IGFBPs, the IGFBP profile in the serum of 12 PV patients was compared with age- and sex-matched controls by Western ligand blot (WLB), two-dimensional WLB, IGFBP-3 immunoblot and specific RIA for IGFBP-1, -2, -3 and IGFBP-4. To elucidate a role for the IGF-IR in the pathogenesis of PV, basal and IGF-I stimulated tyrosine phosphorylation of the IGF-IR beta-subunit in PBMNC of PV patients or controls was determined by WLB. Furthermore, exons 2, 3 and 15-21 of the IGF-IR were screened for mutations by PCR-single strand conformation polymorphism analysis (PCR-SSCP). We found alterations of the IGFBP profile in the serum of eight out of 12 examined patients including elevated levels of IGFBP-1, -2 and -4, decreased levels of IGFBP-3 and an increase in IGFBP-3 fragment. However, no differences in tyrosine phosphorylation of the IGF-IR in PV patients, neither basal nor IGF-I induced, were detected. Furthermore, no mutations within the screened exons of the IGF-IR could be identified by PCR-SSCP. We conclude that there is no direct impairment of IGF-IR structure or function, but an altered IGFBP profile in a significant portion of PV patients which might contribute to the pathogenesis of PV in these patients.

Surgical management of unstable angina and symptomatic coronary artery disease.

The treatment of coronary artery disease and, in particular, acute coronary syndromes has evolved from watchful waiting to an early aggressive intervention strategy. Patients are currently receiving either percutaneous or surgical revascularization. Several major clinical trials have identified those patients mostly likely to benefit from surgical intervention. These patients typically include those with left-main coronary artery disease, triple vessel disease with decreased left ventricular function, and other clinical risk factors. As a result of these studies, unique needs and outcomes of special populations have been identified. This article will present an overview of surgical treatment of coronary artery disease with emphasis on patient selection with particular attention to women, older persons, diabetic patients, and innovations in surgical techniques that may improve patient outcomes.

Overexpression of insulin-like growth factor-binding protein-2 results in increased tumorigenic potential in Y-1 adrenocortical tumor cells.

Increased concentrations of insulin-like growth factor-binding protein-2 (IGFBP-2) have been observed in human malignancies including adrenocortical carcinomas. To elucidate the functional consequences of IGFBP-2 overexpression, we have stably transfected the cDNA of murine IGFBP-2 in mouse adrenocortical tumor cells (Y-1). Long-term overexpression of IGFBP-2 was associated with significant morphological alterations, enhanced cell proliferation, and increased cloning efficiency as compared with mock transfected control cells. The enhanced proliferation of IGFBP-2 secreting clones was independent of exogenous insulin-like growth factors (IGFs). These data suggest that elevated levels of IGFBP-2 may contribute to the highly malignant phenotype of adrenocortical cancer by a thus far unknown, presumably IGF-independent, mechanism.

Interleukin-3 and interleukin-6 stimulate bovine adrenal cortisol secretion through different pathways.

Several interleukins have been reported to play a major role in the regulation of steroid secretion at all three levels of the hypothalamic-pituitary-adrenal axis. The objective of this study was to investigate the effect of interleukin-3 (IL-3) and interleukin-6 (IL-6) on cortisol secretion of bovine adrenocortical cells in primary culture under serum-free conditions. Both IL-3 and IL-6 stimulated basal cortisol secretion dose-dependently to a similar extent at a similar time course. After incubation with IL-3 or IL-6 at concentrations of 100 microg/l, a maximum 4.1-fold increase of the cortisol secretion was reached after 12 h (P<0.01). Coincubation of IL-3 and IL-6 (100 microg/l) revealed no significant synergism. To elucidate a possible involvement of arachidonic acid metabolites in the signal transduction, we coincubated IL-3 or IL-6 together with the cyclo-oxygenase inhibitor indometacin or the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA). Coincubation with indometacin completely abolished the stimulatory effect of IL-6 but had no effect on IL-3 stimulated cortisol secretion. In contrast, specific inhibition of the lipoxygenase system by nordihydroguaiaretic acid blocked IL-3 stimulated steroidogenesis while the effect of IL-6 was not affected. Neither IL-3 nor IL-6 altered cAMP levels significantly, whereas ACTH significantly induced cAMP levels in parallel to its steroidogenic effect. In conclusion, our data indicate that IL-3 and IL-6 stimulate the steroid secretion of bovine adrenocortical cells to a similar extent and with a similar time course. However, the effects of IL-3 and IL-6 are mediated through different, cAMP-independent pathways. While the stimulatory effect of IL-3 seems to be dependent on the lipoxygenase pathway, the effect of IL-6 on adrenocortical cortisol secretion is mediated through the cyclo-oxygenase pathway.

The role of the insulin-like growth factor system in adrenocortical tumourigenesis.

BACKGROUND: The insulin-like growth factor (IGF) system plays a central role in the mechanism of transformation and tumourigenesis. Elevated levels of IGF-II and IGF-I have been found in adrenocortical carcinomas. MATERIAL AND METHODS: We examined binding characteristics and concentrations of both IGF-receptors in normal adult human adrenocortical glands, and compared them with the IGF-I receptor binding in adrenocortical rumours of various origins. The human IGF-I receptor was overexpressed in the mouse adrenocortical tumour cell line Y1, and growth studied in response to IGF stimulation. The influence of IGF-II on adrenal morphology and function was assessed in transgenic mice that postnatally overexpress IGF-II. RESULTS: While the abundance of the IGF-I receptor in adrenocortical hyperplasias and adenomas was similar to normal tissue, a strong overexpression of the intact IGF-I receptor was found in three out of four adrenocortical carcinomas. Y1 cells overexpressing the human IGF-I receptor respond to IGF-I with an increase in thymidine incorporation by 140%. Furthermore, the antiproliferative effect of ACTH is blunted. In transgenic mice postnatally overexpressing IGF-II, adrenal weight is increased, mainly due to a 50% increase in the number of zona fasciculata cells. Plasma corticosterone levels in these mice are twofold higher than in controls, in contrast to similar plasma ACTH levels, thus indicating a direct effect of IGF-II on adrenal cell hyperplasia and function. CONCLUSION: There is substantial evidence that the IGF-system is involved in adrenal growth and tumourigenesis. High local levels of IGF-II in combination with elevated IGF-I receptor concentrations would represent a significant growth advantage of the adrenocortical carcinoma cell and could contribute to a highly malignant phenotype. IGF-II overexpression alone seems not to be sufficient for malignant transformation.