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Supplementary Table Legend from Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma

High MET expression in ACC patients (S1); High MET mRNA expression levels in ACC (S2); cMET signaling is activated in ACC (S3); Increased HGF/cMET signaling is associated with enhanced proliferation and reduced apoptosis in tumors from ACC patients (S4); HGF stimulates NCI-H295R ACC cell proliferation (S5); HGF/cMET signaling is important for ACC cell energy metabolism (S6).

Basic patients characteristics of the cohort used for serum HGF measurements ; Patients characteristics of second TMA ; Genes with significantly (P {less than or equal to} 0.05, absolute value of log ratio > 0.1) changed expression in tumors from ACC patients (dataset GSE10927) relative to expression in normal adrenocortical tissues ; Biological processes Significantly (P 0.1) changed in tumors from ACC patients with high MET expression compared to those with low MET expression (dataset GSE10927) ; Gene set enrichment analysis of ACC patients' cohort for genes related to cell proliferation (dataset GSE10927) ; Gene set enrichment analysis of ACC patients' cohort for genes related to the negative regulation of cell apoptosis (dataset GSE10927) ; Gene set enrichment analysis of ACC patients' cohort for genes related to cell proliferation (dataset GSEA49278) ; Gene set enrichment analysis of ACC patients' cohort for genes related to the negative regulation of cell apoptosis (dataset GSEA49278) ; Drug metabolism-related genes with significantly (P {less than or equal to} 0.05, absolute value of log ratio > 0.1) changed expression in tumors from ACC patients (dataset GSE10927) with high MET expression relative to those with low MET expression ; Gene set enrichment analysis detail of ACC patients' cohort for genes associated with resistance and metabolism of cisplatin, etoposide and doxorubicin (dataset GSEA10927) ; Gene set enrichment analysis detail of ACC patients' cohort for genes associated with resistance and metabolism of cisplatin, etoposide and doxorubicin (dataset GSEA49278) .

Thyroid-stimulating hormone (TSH) suppression treatment can induce signs and symptoms of hyperthyroidism and hypothyroidism due to inappropriate treatment or poor compliance to the treatment. The current study aimed to investigate TSH levels, frequency of being on target TSH, adherence to levothyroxine (LT4) suppression treatment in differentiated thyroid cancer (DTC) patients after surgery in a multicentric setting.This multicentric cross-sectional study was conducted at 21 medical centres from 12 cities in Turkey. DTC patients followed at least one year in the same center included in the study. Clinical data, serum TSH, free thyroxine (FT4), thyroglobulin (Tg) and anti-Tg levels were recorded during the most recent visit. Body mass index, systolic and diastolic blood pressures, pulse rate were measured. LT4 doses were recorded and doses per kilogram of bodyweight were calculated. Pill ingestion habits recorded and adherence to the therapy were evaluated using the Morisky Medication Adherence Scale and categorized as good, moderate or poor compliant based on their scores. Risk stratification forpredicting the disease persistance and/or reccurence was assessed using the American Joint Committee on Cancer-7th edition thyroid cancer staging calculator. TSH serum concentrations were classified as severe suppression (TSH lt; 0.01 mU/L), moderate suppression (TSH: 0.01-0.1 mU/L), mild suppression (TSHL 0.1-0.5 mU/L), euthyroid (TSH: 0.5-4 mU/L) and hypothyroid (TSH gt; 4 mU/L). TSH levels can also be classified as on being on target, under the target, or beyond over the target, according to the American Thyroid Association recommendations.A group of 1125 patients (F/M: 941/184, 50.7 ± 11.7 years) were included in the study. The mean LT4 daily dosage was 132.4 ± 39.6 mcg/day. TSH levels showed severe suppression in 99 (%8.8) patients, moderate suppression in 277 (%24.6) patients and mild suppression in 315 (%28) patients and euthyroid range in 332 (%29.5) patients and hypothyroid range in 97 (8.6%). TSH levels were in target in 29.2% of the patients 20.4% of the patients were undertreated, 50.4% overtreated. The daily LT4 dose and LT4 dose/kg were significantly higher in the severe suppression group (p lt; .001, p lt; .001). According to the Morisky scale, 564 patients (50.1%) were good compliant, 368 patients (32.7%) were moderate compliant, and 193 patients (17.1%) were noncompliant. Patients with poor compliance need a higher dose of LT4 compared to the good compliance group (p lt; .001). TSH levels of patients with good compliance were 0.67 ± 1.96 mU/L and TSH with poor compliance was 2.74 ± 7.47 mU/L (p lt; .001). TSH levels were similar in patients on fixed and alternating dosages.In 29.2% of the DTC patients, serum TSH levels were at target levels. Remaining of the study group have TSH levels under or over treatment range, exposing the patient to medication side effects. Majorty of the study group 82.8% have good or moderate adherence to LT4 therapy. Reaching TSH targets requires simplified and applicable guidelines and following the guideline recommendations.

Objectives: Vitamin D deficiency is a controversial issue in pregnant women. The 1,25 dihydroxyvitamin D3 level is higher in pregnant than non-pregnant women. This study aimed to investigate the 1,25 di-hydroxyvitamin D3 status in vitamin D deficient pregnant women at the first trimester. Materials and Methods: This study was conducted during December 2011 and April 2012 in 2 hospitals of Istanbul, Turkey. Pregnant women who attended for the regular examination on the 12th gestational week were randomly assigned. They were divided into 2 groups including vitamin D deficient (vitamin D

Objective Our aim is to compare the serum SIRT1 levels between patients with hypogonadotropic hypogonadism and healthy subjects. Material and method Twenty-five male patients diagnosed with isolated hypogonadotropic hypogonadism (IHH) and thirty healthy male as a control group were included in the study. Serum SIRT1, hormone levels and biochemical parameters, age, body mass index and insulin resistance were compared in both groups. Results Mean serum SIRT1 levels in patient and control group were 20.1 ± 11.7 ng/ml and 12.8 ± 7.1 ng/ml, respectively. Difference between both groups was statistically significant ( p = 0.02). The difference of Homeostasis Model Assessment-Insulin Resistance index (HOMA-IR) between two groups was also statistically significant. Patient group had more insulin resistance than the control group and it was statistically significant (mean HOMA-IR 2.66 ± 1.57 vs. 1.38 ± 0.43; p = 0.002). Conclusions This is the first human study that investigates SIRT1 levels and its relation with metabolic and hormonal parameters. We demonstrated that serum SIRT1 levels in patients with IHH were significantly higher than controls, and there is a negative correlation between testosterone and SIRT1 levels. The reason for elevated SIRT1 levels may be a compensation mechanism against both hypogonadotropic hypogonadism and insulin resistance. To understand the relation between SIRT1 and androgen deficiency, further large-scale randomized control studies are needed.

Tutuncu, Neslihan Bascil/0000-0002-1816-3903; Gonen, Mustafa Sait/0000-0002-1089-623X; CORAPCIOGLU, DEMET/0000-0003-0940-9147; Satman, Ilhan/0000-0001-8613-1797; nuhoglu, irfan/0000-0003-0650-3242; Sahin, Ibrahim/0000-0002-6231-0034; Demirci, Ibrahim/0000-0003-0498-3115; Altuntas, Seher Cetinkaya/0000-0002-9733-9443; Yildiz, Bulent O./0000-0003-1797-7662; BALCI, Mustafa Kemal/0000-0002-6494-3249; Araz, Mustafa/0000-0001-6741-7474; Saydam, Basak Ozgen/0000-0001-9457-8919; Bozkus, Yusuf/0000-0002-6976-6659; Sabuncu, Tevfik/0000-0001-6504-5355; SELEK, ALEV/0000-0002-0646-8697; Ozturk, Feyza Yener/0000-0001-5584-4954; Salman, Serpil/0000-0003-4867-3725; AKBAS, EMIN MURAT/0000-0002-3033-0073; KIRIK, Ali Murat/0000-0002-5771-4843; Sonmez, Alper/0000-0002-9309-7715; Cesur, Fazil Mustafa/0000-0002-1029-2604, WOS:000452704800016, PubMed: 30244051, Aims: Turkey has the highest prevalence of diabetes in Europe. It is therefore essential to know the overall cardiovascular risk and reveal the predictors of metabolic control in Turkish adults with diabetes mellitus. Methods: A nationwide, multicenter survey consecutively enrolled patients who were under follow up for at least a year. Optimal control was defined as HbA1c, Turkish Society of Endocrinology and Metabolism, The TEMD study has been funded by the Turkish Society of Endocrinology and Metabolism. Automated blood pressure monitors were provided by Sanovel A/S. The funding agencies had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; or the preparation, review or approval of the manuscript.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy that is usually large (>5 cm) at time of diagnosis. Delayed diagnosis significantly worsens survival. We describe adrenal gland morphology prior to ACC diagnosis and discern potential causes of delayed diagnosis. ACC patients seen at The University of Texas MD Anderson Cancer Center between 1998 and 2014 who had cross-sectional body imaging ≥3 months prior to their diagnosis. We conducted a detailed review of clinical and radiological features in these patients prior to ACC diagnosis. Of 439 patients with ACC, 25 had imaging preceding ACC diagnosis (5 with normal adrenal glands and 20 with preexisting masses). On the first available images, the median mass size was 2.8 cm (range 0-9) with median precontrast density of 36 Hounsfield units (range 17-43) and became 9 cm (range 1-18) at the time of ACC diagnosis. The median interval between first available image and ACC diagnosis was 20 months (range 3-89). In the 5 patients whose initial images showed normal adrenal glands, the time between the last normal scan and ACC diagnosis ranged from 5 to 36 months. The most common reason for delayed ACC diagnosis was the presumed benign status of the preexisting mass (n = 13, 65 %). Radiologically suspicious adrenal masses can precede ACC diagnosis and have variable growth patterns. ACC can also develop de novo within a few months in a radiologically documented normal adrenal gland. The presumed benignancy of preexisting masses based on size is the main reason for delayed ACC diagnosis.

Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA–mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer. Cancer Res; 75(19); 4131–42. ©2015 AACR.

Thyroid cancer is the most common endocrine malignancy, and its incidence is increasing. Standard therapy for most patients with localized differentiated thyroid cancer (DTC) includes surgery, radioactive iodine, and thyroid hormone replacement. A minority of thyroid cancer patients requires systemic therapy for metastatic disease. Patients with metastatic DTC do not usually benefit from traditional cytotoxic chemotherapy. In this review, we describe newly developed small-molecule tyrosine kinase inhibitors (TKIs) that are being actively tested and used in the management of advanced thyroid cancer. The use of TKIs as a form of molecular targeted therapy is evolving based on understanding of the pathways involved in DTC. Disrupting tumor vascular supply by targeting vascular endothelial growth factor receptor signaling is the most commonly used approach to treat advanced/metastatic DTC. Other mechanisms include targeting BRAF, MAPK/ERK kinase, or mammalian target of rapamycin signaling. Although TKIs appear to have superior efficacy compared to cytotoxic chemotherapy, they can cause substantial adverse effects; symptomatic management of adverse effects, dose adjustment, or cessation of therapy may be required.