The association between irisin and muscle metabolism in different thyroid disorders.

BACKGROUND: Irisin is a new adipo-myokine, encoded by the FNDC5 gene. Currently, there is a discussion regarding the relation between thyroid function and irisin concentration. This prospective study assesses the influence of thyrometabolic changes on serum irisin concentration in association with altered muscle metabolism. This is performed on a large cohort of patients affected by severe hypo- or hyperthyroidism, as well as by the expression of the FNDC5 gene in thyroid tissue affected by different pathologies. METHODS: The study group comprised 119 patients with newly diagnosed severe hyperthyroidism or hypothyroidism, and a control group of 45 healthy subjects. Body composition, serum irisin concentrations, and thyroid-related hormones, creatine kinase, dystrophin and titin concentrations were evaluated. FNDC5 expression was also analysed in tissue samples from 80 patients with nontoxic multinodular goitre, toxic goitre, Graves' disease and papillary thyroid cancer. RESULTS: Irisin concentration was lower in patients with prolonged hypothyroidism. There was a tendency towards lower dystrophin and titin concentrations in patients with hypothyroidism and hyperthyroidism. Restoration of euthyroidism in patients with hypothyroidism resulted in a decreased muscle mass with an increase in irisin concentrations, while the hyperthyroid group showed an increase in fat mass. Statistically significant overexpression of FNDC5 gene was found in patients with toxic goitre as compared to Graves' disease, papillary thyroid cancer and controls. CONCLUSIONS: The presented data support the theory that irisin concentration changes are associated with prolonged hypothyroidism and might primarily constitute the result of prolonged myopathy. These changes are most likely not related to the expression of the FNDC5 gene in the thyroid gland.

Incidence of pituitary autoantibodies in idiopathic diabetes insipidus.

Diabetes insipidus is a disorder resulting from insufficient action of vasopressin (ADH) characterized by excretion of highly diluted urine in large amounts. Idiopathic diabetes insipidus is associated with the presence of both autoantibodies against ADH-secreting neurons and pituitary autoantibodies. The aim of the present study was to evaluate the occurrence of autoantibodies against the pituitary microsomal fraction. The study included 33 sera of diabetes insipidus patients and 10 control sera obtained from 10 healthy persons. In all patients the secretion of pituitary hormones and thyroid autoantibodies was assessed. Human pituitaries were obtained during autopsy and homogenized in 0.01 mol/l pH 7.4 phosphate buffer. In addition, for the autoantibody evaluation, the electrophoretic method of separation in polyacrylamide gel and western blot were employed. Among the 33 subjects, in 23 patients the presence of autoantibodies against the pituitary was shown. Sera of 15 patients reacted with the pituitary microsomal fraction protein of 55 kDa. In other cases, 10 sera reacted with the pituitary antigen of 67 kDa. In addition, 5 sera reacted with the 60 kDa antigen, 5 sera with 52 kDa protein, 3 sera with 105 kDa protein, 3 sera with the 97 kDa antigen and 2 sera with pituitary antigen of 92 kDa weight. In our study, based on the immunoblotting method, we observed that pituitary autoantibodies against 55, 60 and 67 kDa antigens occurred frequently.

Nicotinamide phosphorybosiltransferase overexpression in thyroid malignancies and its correlation with tumor stage and with survivin/survivin DEx3 expression.

Nicotinamide phosphorybosiltransferase (NAMPT) plays an important role in the regulation of cellular growth, angiogenesis, and apoptosis in mammalian cells. NAMPT overexpression has been recently found in colorectal, breast, prostatic, gastric, esophageal, pancreatic cancers, and specific NAMPT inhibitors might be adjuvant therapeutic modalities. In this study, we analyzed NAMPT expression in 40 malignant and in 67 benign thyroid tissue samples using qPCR. We also investigated relationships between NAMPT expression and survivin/survivin splicing variants DEx3 and 2B expressions. NAMPT expression was significantly higher in thyroid cancers (P < 0.0001), and it was positively correlated with tumor stage (P = 0.0012; r = 0.493). NAMPT expression was significantly higher in tumors staged pT3 or pT4 (16 cases) than in tumors staged pT1 or pT2 (24 cases) (P = 0.0106). Metastases to the lymph nodes were found in 12 out of 40 cases, and NAMPT expression was higher in the metastatic group (P = 0.0258). Multifocality was not associated with higher NAMPT expression (P = 0.3451). NAMPT expression in thyroid cancers significantly correlated with survivin and with survivin splice variant DEx3 expressions (P < 0.0001; r = 0.624 and P = 0.0239; r = 0.357, respectively). There was no correlation between NAMPT and survivin 2B expressions (P = 0.3508). This is the first study demonstrating NAMPT overexpression in thyroid malignancies using quantitative RT-PCR. Moreover, it shows that NAMPT is upregulated in patients with more advanced tumor stage and metastatic disease which may prove to be clinically relevant. Further studies are needed to explain the role of NAMPT in thyroid cancer biology and the possible use of NAMPT inhibitors in thyroid cancer.

Evaluation of survivin splice variants in pituitary tumors.

PURPOSE: Survivin is an apoptosis inhibitor, expressed in almost all types of human malignancies, but rarely in differentiated normal tissues. Recently, survivin gene splice variants with different anti-apoptotic activities have been reported. The current study was undertaken to examine the expression of survivin and its splice variants ∆Ex3 and 2ß in pituitary tumors, and to correlate the amount of particular transcripts with clinical staging in pituitary adenomas. Quantitative detection of survivin and its splice variants ∆Ex3 and 2ß transcripts in non-cancerous pituitary tissues (n = 12) and different types of pituitary tumor (n = 50). METHODS: Samples were collected from 50 pituitary tumors including 26 non-functional tumors, 21 GH-secreting tumors, 2 PRL-secreting tumors and 1 ACTH-secreting tumor. 12 normal pituitary glands received after autopsy served as a control of the study. 29 thyroid cancers tissues were used as a positive control. The RT-qPCR with TaqMan hydrolysis probes were used to determine the expression of analyzed splice variants of survivin. RESULTS: The obtained data showed that both survivin and its splice variants were expressed in different types of pituitary adenoma as well as in normal pituitary tissue. However, the level of its expression was similar in all studied cases. Patient age negatively correlated with tumor invasiveness. Moreover, our study showed a tendency for negative correlation between patient age and tumor diameter. CONCLUSIONS: No significant differences between survivin and its splice variants ∆Ex3 and 2ß expression in pituitary tumors and in normal pituitary glands as well as in invasive and in non-invasive tumors were found, suggesting that survivin does not play a significant role in pituitary tumorigenesis.

The role of antithyroglobulin, antiperoxidase and anti-TSH receptor autoantibodies in amiodarone-induced thyrotoxicosis and amiodarone-induced hypothyroidism (A two-center study).

OBJECTIVE: It has been reported that patients experiencing side effects of amiodarone (AM) therapy, such as amiodarone-induced thyrotoxocosis (AIT) or amiodarone-induced hypothyroidism (AIH), have changes in serum concentrations of anti-TSH receptor (TSHR), antithyroglobulin (Tg), and antiperoxidase (TPO) autoantibodies (Abs). The purpose of our study was to identify and analyze the changes in levels of listed antibodies in patients with several thyroid disorders. METHODS: 280 patients from two centers in Poland were included. Titers of TSHR-Abs, TPO-Abs and Tg-Abs were analyzed retrospectively in the following groups of patients: A - euthyroid patients with a history of hyperthyroidism prior to re-administration of AM; B - patients with AIT who discontinued the AM therapy; C - patients with AIT chronically treated with AM; D - hypothyroid patients. RESULTS: Serum Tg-Abs were not elevated in any of the studied groups. However, there were significant differences between A and B and also D and other groups (p<0.05). TPO-Abs titers were not elevated in most cases, there were no significant differences between groups. The serum titers of TSHR-Abs were not elevated in any group. We found statistically significant differences between B and D, C and other groups (p<0.05). CONCLUSIONS: Regardless of the statistically significant differences observed for Tg-Abs and TSHR-Abs levels, this observation have a limited clinical applicability. In almost all cases we observed normal to slightly increased titers of TPO-Abs, Tg-Abs, TSHR-Abs. Discontinuation or continuation of AM therapy had no influence on autoantibody titers. Furthermore, we found it impossible to differentiate between the type I and II of AIT based on autoantibody titers.

Familial syndromes associated with neuroendocrine tumours.

Neuroendocrine tumours may be associated with familial syndromes. At least eight inherited syndromes predisposing to endocrine neoplasia have been identified. Two of these are considered to be major factors predisposing to benign and malignant endocrine tumours, designated multiple endocrine neoplasia type 1 and type 2 (MEN1 and MEN2). Five other autosomal dominant diseases show more heterogeneous clinical patterns, such as the Carney complex, hyperparathyroidism-jaw tumour syndrome, Von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1) and tuberous sclerosis. The molecular and cellular interactions underlying the development of most endocrine cells and related organs represent one of the more complex pathways not yet to be deciphered. Almost all endocrine cells are derived from the endoderm and neuroectoderm. It is suggested that within the first few weeks of human development there are complex interactions between, firstly, the major genes involved in the initiation of progenitor-cell differentiation, secondly, factors secreted by the surrounding mesenchyme, and thirdly, a series of genes controlling cell differentiation, proliferation and migration. Together these represent a formula for the harmonious development of endocrine glands and tissue.

The influence of radioiodine therapy on ocular changes and their relation to urine cotinine level in patients with Graves' Ophthalmopathy.

OBJECTIVES: Radioiodine therapy (RIT) is frequently used as the definitive treatment in patients with Graves' hyperthyroidism when remission is not achieved with anti-thyroid drugs (ATDs). In this observational study, we intended to examine whether the use of high doses of radioiodine (RAI) [22 mCi (814 MBq)] with prophylaxis of oral glucocorticoids (oGCS) does not exacerbate Graves ophthalmopathy (GO) in smokers and non-smokers, especially regards to the urine level cotinine and ocular changes before and after RIT. PATIENTS AND METHODS: The studied group consisted of 26 smokers, aged 28-61 years and 25 non-smoker patients, aged 21-54 years, respectively. The patients were enrolled to RAI after one-year of ineffective ATDs treatment. Criterion for inclusion in the study were patients with mild GO with hyperthyroidism at diagnosis based on the severity (NOSPECTS) and activity (CAS) scale. All the patients were subjected to RIT with oGCS prophylaxis and evaluated prospectively during a one-year follow-up. The ophthalmological examination was performed at various stages of RIT: initial pre-radioiodine administration, at the time of treatment 6, and 12 months after RAI. The present study is unique, because the urine cotinine measurement was employed to detect nicotine exposure, also in regard to smoking intensity. RESULTS: In smokers, the values of serum TPO-Abs were statistically significant in the second and six month (p<0.05) and in the second and after one year (p<0.005). The TSHR-Abs concentration was significantly higher in smokers (p<0.05), rising from 22.9±1.2 IU/L before therapy to 29.6±5.3 IU/L - 2 months, 32.6±8.6 IU/L - 6 months, and slightly decreased 28.9±10.6 IU/L - 12 months. These observed changes were statistically different between groups at baseline (p<0.05) and after one-year of follow-up (p<0.005). Mean urine cotinine were considerably higher in smokers comparing to non smokers in each point of observation [903.4±770.0 and 5.2±1.7 ng/mL at baseline (p<0.001), 412.8±277.3 and 3.0±0.6 ng/mL after 2 months (p<0.001), 452.0±245 and 6.6±3.6 after 6 months (p<0.001), 379.4±236.8 and 1.0±1.2 after one year (p<0.001)]. The CAS values in the smoking group before RIT increased statistically from 2.8±0.2 points at baseline to 4.3±0.3 after 6 months, and 4.0±0.5 (12 months), while in the non-smoking patients it was 1.4±0.2, 2.8±0.3 and 2.2±0.2, respectively. The level of urine cotinine correlated positively with CAS and TSHR-Ab in the smoking group (r=0.41; p<0.05) at baseline and during follow-up (2 months: r=0.46; p<0.001, 6 months: r=0.47, p<0.005; 12 months: r=0.46; p<0.005). In the NOSPECS classification, the symptoms changed from mild to moderate, mostly in smoking patients. CONCLUSIONS: 1) ablative RIT dose with prophylactic oral prednisone is a safe treatment in both smokers and non-smokers with mild GO; 2) The post hoc analysis showed that urinary level of cotinine can be very helpful in the assessment of exacerbation of ophthalmological clinical symptoms before and after RIT particularly in smokers.

Patients with chronic hepatitis type C and interferon-alpha-induced hyperthyroidism in two-years clinical follow-up.

OBJECTIVES: Interferon-α (IFN-α) is a gold standard in the therapy of viral chronic hepatitis type C (CHC). However, such treatment might lead to thyroid dysfunction. Patients usually present hypothyroidism, but rarely also hyperthyroidism may develop. The aim of the study is to present two-year clinical follow-up of patients with CHC and IFN-α-induced hyperthyroidism (IIH), with special regard to the methods and efficacy of the therapy. METHODS: A group of 106 patients with CHC and IIH were analyzed. Subjects were divided into two groups according to etiology: group 1, with Graves' disease (GD) and group 2, with Hashitoxicosis (HT). The diagnosis of GD and HT was based on: clinical signs of hyperthyroidism, hormonal profile (TSH, fT4, fT3), level of thyroid autoantibodies (Tg-Abs, TPO-Abs, TSHRAbs). Treatment of hyperthyroidism was monitored by repeated clinical assessment and laboratory tests. RESULST: 28 patients (26 with GD of which 5 exhibited mild orbitopathy and 2 with HT) were treated with radioiodine [the average dose of was 17 mCi [668 MBq]. In adition 78 out of 80 patients with HT mostly ß-blocker therapy was successful (transient hyperthyroidism). At the end of the observation period, in group 1 remission was achieved in 17 (65.4%) cases, 6 (23.1%) patients showed hypothyroidism and 3 (11.5%) presented recurrence of hyperthyroidism. CONCLUSIONS: Most patients with IIH present Hashitoxicosis, while a minority of them develop Graves' disease. In a majority of patients with HT spontaneous remission of disease occurs. In patients with long-term hyperthyroidism, radioiodine therapy is an effective and well-tolerated.

Assessment of real-world usage of lanreotide AUTOGEL 120 in Polish acromegalic patients - results from the prospective 12-month phase of Lanro-Study.

AIM OF THE STUDY: To assess resource utilization and costs of treatment with lanreotide AUTOGEL 120 mg (ATG120) administered as part of routine acromegaly care in Poland. MATERIAL AND METHODS: A multicentre, non-interventional, observational study on resource utilization in Polish acromegalic patients treated with ATG120 at 4 weeks or extended (> 4 weeks) dosing interval. The study recruited adult acromegalic patients treated medically for ≥ 1 year including at least 3 injections of ATG120. Data on dosing interval, aspects of administration, and resource utilization were collected prospectively during 12 months. Costs were calculated in PLN from the public health-care payer perspective for the year 2013. RESULTS: 139 patients were included in the analysis. Changes in dosing regimen were reported in 14 (9.4%) patients. Combined treatment was used in 11 (8%) patients. Seventy patients (50%) received ATG120 at an extended dosing interval; the mean number of days between injections was 35.56 (SD 8.4). ATG120 was predominantly administered in an out-patient setting (77%), by health-care professionals (94%). Mean time needed for preparation and administration was 4.33 and 1.58 min, respectively, mean product wastage - 0.13 mg. Patients were predominantly treated in an out-patient setting with 7.06 physician visits/patient/year. The most common control examinations were magnetic resonance imaging of brain and brain stem (1.36/patient/year), ultrasound of the neck (1.35/patient/year), GH (1.69/patient/year), glycaemia (1.12/patient/year), IGF-1 (0.84/patient/year), pituitary-thyroid axis hormone levels assessment (TSH-0.58/patient/year, T4-0.78/patient/year). There were 0.43 hospitalizations/patient/year. For direct medical costs estimated at PLN 50 692/patient/year the main item was the costs of ATG120 (PLN 4103.87/patient/month; 97%). The mean medical cost, excluding pharmacotherapy, was PLN 1445/patient/year (out-patient care - 49%, hospitalization - 23%, diagnostics/laboratory tests - 28%). CONCLUSIONS: These results represent the current use of ATG120 in the population of Polish acromegalic patients in a realistic clinical setting. Findings that 50% of patients could be treated with dose intervals of longer than 28 days support the potential of ATG120 to reduce the treatment burden.

A rare case of Interferon-alpha-Induced Hyperthyroidism in patients with a chronic hepatitis C with granulocytopenia and transaminasemia treated successfully with radioiodine.

BACKGROUND: Conventional management of Interferon-α-Induced Hyperthyroidism (IIH) with radioactive iodine (RAI) may be used when treatment with beta blockers or antithyroid drugs (ATD), proves ineffective or is contraindicated. CASE PRESENTATION: We present a 38-year-old woman who has been treated with combined pegylated interferon alpha (INF-α) and Ribavirin for chronic hepatitis C. Destructive thyrotoxicosis appeared after four months of continuous IFN-α therapy and a beta blocker was prescribed. Initially, the patient presented normal TSH 2.4 µIU/mL, however during therapy with INF-α, TSH diminished to 0.05 and thyroid hormones were elevated: fT4 23.1 pmol/L, fT3 7.2 pmol/L. Ultrasound examination showed completely irregular and greatly decreased echogenicity of the thyroid gland. The radioiodine uptake (RAIU) was deeply decreased to 2 and 3% at 5 h and 24 h, respectively. The thyroid scintiscan showed lack of isotope accumulation. Hypothyroidism developed and L-thyroxine was prescribed. The following year, hyperthyroidism reoccurred with TSH 0.08 µIU/mL, fT4 26.4 pmol/L, fT3 8.2 pmol/L, positive TSHR-Abs 6.2 (normal <2 IU/L) and mild Graves' Ophthalmopathy (GO). RAIU values were 23% at 5 h and 46% at 24 h. Thyroid scintiscan showed diffuse goiter. At this point beta blocker was introduced and ATD was started. After three months of therapy an increased level of aminotransferases and granulocytopaenia were observed. Hence, the patient received RAI and glucocorticosteroid, while INF-α therapy was continued. After approximately 4 months, hypothyroidism reappeared with insignificantly raised TSH level. One year later the patient was euthyroid and required no further treatment. CONCLUSIONS: Our report suggests that: 1. Radioiodine therapy might be an effective and safe method of treatment in cases of IIH with mild GO. 2. IFN-α therapy need not be discontinued in patients with IIH.

Survivin--prognostic tumor biomarker in human neoplasms--review.

Accurate diagnosis and proper monitoring of cancer patients remain important obstacles for successful cancer treatment. The search for cancer biomarkers is carried out in order to quickly identify tumor cells and predict treatment response, ultimately leading to a favorable therapeutic outcome. One such prognostic marker seems to be survivin. Many studies have shown that survivin is strongly expressed in a vast majority of cancers. Its overexpression was demonstrated in breast and lung cancer prostate, gastric, colon, bladder and esophageal carcinomas, osteosarcomas, and lymphomas. In many of those tumors, high activity of the surviving gene was associated with a poor prognosis and worse survival rates. Moreover survivin expression was correlated with resistance to chemotherapy and radiotherapy-induced apoptosis. Since survivin may be identified as an independent prognostic factor and inhibitor of apoptosis, it may prove to be a useful therapeutic target in cancer therapy

Fatal course of cyclic Cushing's disease - lessons from a case.

We present a 56-year-old patient with cyclic Cushing's disease (CCD) observed for 28 months, who presented clinically and biochemically with alternating episodes of hyper-, normo- and hypocortisolemia. The course of the disease was fatal, the patient died due to severe hypokalemia.

Coexpression of survivin and PCNA in pituitary tumors and normal pituitary.

OBJECTIVES: The survivin is the protein involved in regulation of basic and cycle-specific functions of cells both in normal and cancer tissue. Recent studies present survivin as a factor having the leading role in the regulation of apoptosis and mitosis as well as a target of anticancer therapy. The employing of survivin in this therapy is based on its high expression level in most human cancers, as well as its association with the disease's progression. The aim of our study was to evaluate the expression and localization of survivin's gene product on the protein level in different types of pituitary tumors and normal pituitary. The coexpression of survivin and proliferating cell nuclear antigen - PCNA in pituitary was also examined. DESIGN AND METHODS: The study was conducted on the postoperative pituitary tumors tissue taken during standard neurosurgical removal of tumor from 43 patients. The group of patients consists of 23 women and 20 men, aged from 27 to 71 years. As a control of the study three normal pituitary tissues obtained at the autopsy were used. Evaluation of survivin and PCNA expression was performed using immunohistochemical staining. RESULTS: The study demonstrated the presence of survivin in all analyzed by us pituitary tumors. Survivin was present also in normal pituitary tissue. The protein was localized mainly in cell's nuclei, however the less intense immunostaining was observed also in the cytoplasm of pituitary tumors cells. Furthermore survivin was found in normal pituitary, but the positive immunostaining was limited to a single cells. The analysis of pituitary tumor cells proliferation index based on PCNA reactivity showed that survivin is coexpressed with PCNA, especially in invasive tumors. CONCLUSIONS: The study documented the presence of survivin in different types of pituitary tumors as well as in normal pituitary. Additionally the coexpression of survivin and PCNA in tumor cells was shown. The expression of survivin in both normal and cancer pituitary cells suggests that it may play an important role in regulation of the gland's proliferation.

Survivin products in pituitary tumors.

OBJECTIVES: Survivin is a member of the inhibitor of apoptosis protein family, which was recently showed to be expressed by different benign and malignant human tumors. Still very little is known about survivin expression in pituitary tumors. In spite of the fact that pituitary tumors in histological examination are usually benign, in the clinical process a certain number of pituitary adenomas is capable of aggressive growth, recurrence and invasion of the surrounding structures. The aim of the present study was to assess the presence of survivin transcripts and protein in different types of pituitary tumors and to evaluate survivin expression levels in invasive and non-invasive pituitary tumors. DESIGN AND METHODS: The analyzed material consisted of tumor tissue samples obtained during standard neurosurgical removal of the tumor from 23 patients in whom acromegaly (n=14), non-functioning pituitary tumor (n=6), prolactinoma (n=2) and corticotropinoma (n=1) were diagnosed. As a control of the study normal pituitary tissue obtained at autopsy was used. Amplification of survivin gene using sequence specific primers and qRT-PCR method and immunohistochemical staining with primary polyclonal antibodies against human survivin were performed. RESULTS: Our study demonstrated the presence of survivin mRNA in all 23 analyzed pituitary tumors. Survivin expression was also observed in normal pituitary, but the level of its expression was 6-fold lower than in tumors tissue when studied by real time RT-PCR. The difference between the levels of survivin expression in invasive and non-invasive tumors was not statistically significant. Immunohistochemical analyses revealed the presence of the protein in both normal and tumor tissue of pituitary. Immunostaining of tumor tissue was not uniform. Survivin was observed mainly in the nuclei of cells collected in clusters. The presence of the protein in normal pituitary was restricted to small population of cells. CONCLUSIONS: The present study showed that overexpression of survivin is characteristic for pituitary tumors. Further analysis of this protein expression profile should demonstrate whether survivin might be use as a prognostic marker in diagnosis and therapy of pituitary adenomas.

Changes of Nicotinamide Phosphoribosyltransferase Expressions in Thyroid Glands of Patients with Different Thyroid Pathologies.

PURPOSE: Our aim was to analyze NAMPT expression in thyroid tissue derived from patients with Graves' disease with (GD) and without (GO) orbitopathy, patients with toxic nodular goiters (TNG) and thyroid cancers (TC), and healthy controls. METHODS: 153 thyroid tissue samples of consecutive patients who underwent thyroidectomy were collected. Previous therapy with steroids was an exclusion criterion. We collected clinicopathological data of all subjects and we assessed NAMPT expression using qPCR. RESULTS: We found the highest NAMPT expression in the thyroids of patients with GO (n = 20) and cancers (n = 40). Also, there was statistically significant NAMPT overexpression in patients with TNG (n = 30). Relatively low NAMPT expression was found in GD patients (n = 21) and in the control group (n = 39). In one-way ANCOVA, we confirmed that NAMPT expression differs between subgroups and that it is not influenced by age, BMI, or sex of patients. CONCLUSIONS: Reported alteration of NAMPT expression might suggest its involvement in thyroid pathologies. Observed NAMPT overexpression in patients with GO and its relatively low levels in thyroids of patients with GD without eye changes do not confirm causal relationship between NAMPT level and orbitopathy, but this needs further investigation.

Decreased expression of survivin 2B in human pituitary adenomas. A preliminary study.

INTRODUCTION: We aimed to investigate survivin and its splice variants DEx3 and 2B expressions in pituitary adenomas and normal pituitary glands using immunohistochemistry. MATERIAL AND METHODS: The study group consisted of eight pituitary adenomas: five of non-functional tumors, two of GH-secreting tumors, and one PRL-secreting tumor. Eight healthy pituitary tissue samples obtained after autopsy served as controls. RESULTS: Survivin expression was found in 87.5% of the study group and 100% of the controls. A positive staining of survivin 2B was found in 62.5% of pituitary adenomas and 100% of controls. Survivin DEx3 was recognized in 25% of pituitary adenomas and 12.5% of normal pituitary glands. There was significantly lower immunoreactivity of survivin 2B in pituitary adenomas when compared with normal pituitary glands (p = 0.0498). CONCLUSIONS: Survivin and its splice variants might be involved to some extent in benign tumor growth of pituitary adenomas. However, survivin cannot be regarded as a candidate for targeted therapy or molecular biomarker of pituitary adenomas.

Survivin DEx3 as a biomarker of thyroid cancers: A study at the mRNA and protein level.

Survivin and its splice variants DEx3 and 2B are involved in pathogenesis of numerous types of cancer. Proliferating cell nuclear antigen (PCNA) level correlates with cellular proliferation. The present study aimed to analyze the potential utility of survivin and its splice variants DEx3 and 2B as biomarkers for thyroid cancer. PCNA, survivin and its splice variants DEx3 and 2B expressions were analyzed in 22 tissue samples (15 thyroid cancers and 7 benign lesions) by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry (IHC). There was significantly higher staining for survivin (P=0.019), survivin DEx3 (P=0.001), survivin 2B (P=0.0149) and PCNA (P=0.0237) in thyroid malignant tumors when compared with benign lesions. The receiver operating characteristics curve analysis has shown that the cut-off points of survivin IHC expression >2 [sensitivity 46.7%; specificity 100%; area under curve (AUC) 0.810; P=0.0005] and survivin DEx3 IHC expression >0 (sensitivity 86.7%; specificity 100%; AUC 0.933; P<0.0001) were the best predictors of thyroid malignancy. Additionally, PCNA staining >1 (sensitivity 93.3%; specificity 71.4%; AUC 0.790; P=0.0243) and survivin 2B >2 (sensitivity 46.7%; specificity 100%; AUC 0.824; P=0.0002) were the best predictors of thyroid cancer. In conclusion, the present study exhibited that survivin DEx3 expression has high specificity and sensitivity for discrimination between benign thyroid lesions and cancers. Survivin DEx3 may be considered a biological marker of thyroid malignancy and therefore applied in clinical practice.

Management of the hormonal syndrome of neuroendocrine tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP/NET) are unusual and rare neoplasms that present many clinical challenges. They characteristically synthesize store and secrete a variety of peptides and neuroamines which can lead to the development of distinct clinical syndrome, however many are clinically silent until late presentation with mass effects. Management strategies include surgery cure and cytoreduction with the use of somatostatin analogues. Somatostatin have a broad range of biological actions that include inhibition of exocrine and endocrine secretions, gut motility, cell proliferation, cell survival and angiogenesis. Five somatostatin receptors (SSTR1-SSTR5) have been cloned and characterized. Somatostatin analogues include octreotide and lanreotide are effective medical tools in the treatment and present selectivity for SSTR2 and SSTR5. During treatment is seen disapperance of flushing, normalization of bowel movements and reduction of serotonin and 5-hydroxyindole acetic acid (5-HIAA) secretion. Telotristat represents a novel approach by specifically inhibiting serotonin synthesis and as such, is a promising potential new treatment for patients with carcinoid syndrome. To pancreatic functionig neuroendocrine tumors belongs insulinoma, gastrinoma, glucagonoma and VIP-oma. Medical management in patients with insulinoma include diazoxide which suppresses insulin release. Also mTOR inhibitors may inhibit insulin secretion. Treatment of gastrinoma include both proton pump inhibitors (PPIs) and histamine H2 - receptor antagonists. In patients with glucagonomas hyperglycaemia can be controlled using insulin and oral blood glucose lowering drugs. In malignant glucagonomas smatostatin analogues are effective in controlling necrolytic migratory erythemia. Severe cases of the VIP-oma syndrome require supplementation of fluid losses. Octreotide reduce tumoral VIP secretion and control secretory diarrhoea.

Hindgut neuroendocrine neoplasms - characteristics and prognosis.

INTRODUCTION: The aim of the study was to analyze the clinicopathologic characteristics and prognostic factors of hindgut-rectal neuroendocrine neoplasms. MATERIAL AND METHODS: The study included 38 patients with rectal neuroendocrine tumors who were treated at the Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland from February 2010 to December 2015. The clinicopathological data were retrospectively reviewed, extracted, analyzed, and patients were followed up to determine their survival status. Follow-up data were available for all 38 patients. Uni- and multivariate Cox regression analyses were performed to determine the prognostic factors significantly associated with overall survival. RESULTS: The tumors occurred mostly in the middle and lower rectum, and the most typical symptoms experienced by patients were hematochezia and diarrhea. The median distance between the tumors and the anal edges was 4.7 ±1.3 cm, and the median diameter of the tumors was 0.9 ±1.2 cm. The major pathological types were neuroendocrine neoplasm G1 in 31 patients, and neuroendocrine neoplasm G2 in 7 patients. Tumor-node-metastasis (TNM) stages I, II, III and IV tumors accounted for 76.3% (29/38), 5.3% (2/38), 7.9% (3/38) and 10.5% (4/38) of patients, respectively. The main treatment method was transanal extended excision or endoscopic resection. The 1-, 3- and 5-year survival rates of the whole group of patients were 100%, 83.7%, and 75.3%, respectively. CONCLUSIONS: Univariate analysis showed that age (p = 0.022), tumor diameter (p < 0.001), histological type (p < 0.001), and TNM stage (p < 0.001) were all prognostic factors.

Ghrelin concentrations in acromegalic patients in relation to the administered therapy.

OBJECTIVES: Very little is still known about ghrelin in cases of GH hypersecretion. We decided to evaluate whether ghrelin concentrations in acromegalic patients differ according to the administered therapy (surgical and/or with long acting octreotide). We wanted to assess the correlation between serum ghrelin levels and 1) the treatment applied in the past or being applied at the time of our study 2) GH, IGF-1 and insulin concentrations. MATERIAL: Serum ghrelin, GH, IGF-1 and insulin were measured in 42 acromegalic patients who had received surgical and/or long acting octreotide therapy or who hadn't receive any treatment at all. According to the applied treatment, we divided the patients into groups, as follows: 1) LAO/+/, surgery /-/, 2) LAO /+/, surgery /+/, 3) LAO /-/, surgery /-/, 4) LAO /-/, surgery /+/. Ghrelin was also evaluated in 18 control healthy subjects. RESULTS: The difference between mean ghrelin level in the healthy subjects and acromegalic patients was not statistically significant (p=0.08). LAO /-/, surgery /-/ patients showed fasting ghrelin levels indistinguishable from those seen in healthy subjects (p=0.1). There wasn't any statistically significant difference between LAO /-/, surgery /-/ patients and LAO /-/, surgery /+/ group (p=0.14). Serum ghrelin levels in LAO /+/, surgery /+/ group were significantly lower from those observed in LAO /-/, surgery /+/ patients (p=0.006). A similar reduction in ghrelin levels was also found in patients LAO /+/ (both after and without surgery) compared to LAO /-/ patients (both after or without surgery) (p=0.001). Serum ghrelin levels showed a significant negative correlation with IGF-1 concentration and a tendency to a statistically significant correlation with GH in LAO /-/ group (p<0,05). CONCLUSIONS: Ghrelin concentrations were significantly lower in acromegalic patients who had been receiving long acting somatostatin analogue treatment; there was no significant difference in serum ghrelin levels between patients who had and who had not undergone surgery. A significant negative correlation between ghrelin and IGF-1 and a tendency to such correlation between ghrelin and GH was observed in LAO /-/ group of patients.