Estrogen-secreting adrenocortical carcinoma.

Adrenocortical carcinoma is a rare type of endocrine malignancy with an annual incidence of approximately 1-2 cases per million. The majority of these tumors secrete cortisol, and a few secrete aldosterone or androgen. Estrogen-secreting adrenocortical carcinomas are extremely rare, irrespective of the secretion status of other adrenocortical hormones. Here, we report the case of a 53-year-old man with a cortisol and estrogen-secreting adrenocortical carcinoma. The patient presented with gynecomastia and abdominal discomfort. Radiological assessment revealed a tumor measuring 21×15.3×12 cm localized to the retroperitoneum. A hormonal evaluation revealed increased levels of estradiol, dehydroepiandrosterone sulfate, and cortisol. The patient underwent a right adrenalectomy, and the pathological examination revealed an adrenocortical carcinoma with a Weiss' score of 6. After surgery, he was treated with adjuvant radiotherapy. Twenty-one months after treatment, the patient remains alive with no evidence of recurrence.

Rosiglitazone increases endothelial cell migration and vascular permeability through Akt phosphorylation.

BACKGROUND: Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, exhibit anti-inflammatory and antioxidant properties and inhibit endothelial inflammation and dysfunction, which is anti-atherogenic. However, fluid retention, which may lead to congestive heart failure and peripheral edema, is also a concern, which may result from endothelial cell leakage. In the current study, we examined the effects of PPAR-γ agonists on vascular endothelial cell migration and permeability in order to determine its underlying mechanisms. METHODS: We used rosiglitazone and conducted cell migration assay and permeability assay using HUVEC cells and measured vascular permeability and leakage in male C57BL/6 mice. RESULTS: Rosiglitazone significantly promoted endothelial cell migration and induced permeability via activation of phosphatidylinositol-3-kinase (PI3K) - Akt or protein kinase C (PKC)ß. In addition, rosiglitazone increased vascular endothelial growth factor (VEGF) expression and suppressed expression of tight junction proteins (JAM-A and ZO-1), which might promote neovascularization and vascular leakage. These phenomena were reduced by Akt inhibition. CONCLUSIONS: Vascular endothelial cell migration and permeability change through Akt phosphorylation might be a mechanism of induced fluid retention and peripheral tissue edema by TZD.

Complete Tumor Resection for a Hepatocellular Carcinoma Secreting Parathyroid Hormone-related Peptide.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in Korea. Diverse paraneoplastic syndromes can occur in patients with HCC, but parathyroid hormone-related peptide (PTH-rP)-induced hypercalcemia is uncommon. Hypercalcemia due to PTH or particularly PTH-rP-secreting HCC is associated with poor outcomes. We report a 71-year-old man who presented with symptoms of vague abdominal discomfort, somnolence, lethargy, nausea, vomiting, and weight loss. Imaging studies revealed a large HCC without metastasis. The laboratory findings showed elevated serum calcium level, low intact parathyroid hormone (iPTH) level and elevated PTH-rP level. These results led to a diagnosis of a PTH-rP-secreting HCC and paraneoplastic hypercalcemia. After emergency management of the hypercalcemia, the patient underwent an extended right hemihepatectomy with cholecystectomy. One year after the surgery, he is alive with normal calcium, PTH-rP, and iPTH levels. This case demonstrates that the rare phenomenon of life-threatening hypercalcemia caused by HCC should not be overlooked. These symptoms offer a good opportunity to diagnose HCC early. Radical tumor resection makes it possible to cure patients with PTH-rP-secreting HCC.

Vitamin D level is not a predictor of hypocalcemia after total thyroidectomy.

PURPOSE: As the incidence of thyroid cancer has increased, hypocalcemia, a common complication of thyroid surgery, has become a serious problem. However, no definite predictor of postoperative hypocalcemia is known. In this study, our purpose was to investigate the potential role of vitamin D as a predictor of postoperative hypocalcemia. METHODS: A prospective observational study was performed on patients who underwent total thyroidectomy for thyroid cancer performed by a single experienced surgeon between October 2013 and September 2014. MEASUREMENTS: Their serum 25-OH vitamin D levels were measured preoperatively. On the day after surgery, serum calcium and intact parathyroid hormone levels were measured, and symptoms of hypocalcemia were recorded. RESULTS: Of the 134 patients, laboratory and symptomatic hypocalcemia developed in 52 patients (39 %) and 25 patients (19 %), on the day after surgery. The preoperative vitamin D level was 16.5 ± 9.2 ng/mL, and this value did not differ according to laboratory or symptomatic hypocalcemia (p = 0.94). The incidence of laboratory or symptomatic hypocalcemia did not differ according to vitamin D deficiency. Only incidental parathyroidectomy was associated with symptomatic hypocalcemia (p = 0.03). CONCLUSIONS: Vitamin D level is not a predictor of hypocalcemia after total thyroidectomy for thyroid cancer. Thus, routine preoperative screening for vitamin D is not recommended.

Central lymph node metastasis in papillary thyroid microcarcinoma can be stratified according to the number, the size of metastatic foci, and the presence of desmoplasia.

BACKGROUND: Lymph node (LN) metastasis is common in papillary thyroid microcarcinoma (PTMC). The aim of this study was to investigate the impact of LN metastasis and its risk stratification on PTMC recurrence. METHODS: We retrospectively reviewed the data of 336 patients with PTMC who underwent surgery from 2005 to 2006 at a single institution. LN metastasis was stratified according to the number of metastatic LNs, the ratio of metastatic to removed LNs, the size of metastatic foci in LNs, and the presence of extranodal extension and desmoplasia. RESULTS: Of the 336 patients, 93 (28%) had LN metastasis. During the follow-up of 5.3 years, 16 (4.8%) experienced locoregional recurrence. Among several clinicopathologic factors, LN metastasis was the most important risk factor for recurrence (P = .02). Lateral LN metastasis was correlated with recurrence-free survival (P < .01), whereas central LN metastasis was not (P = .20). When central LN metastasis was stratified, a high number of metastatic LNs (≥3), larger metastatic foci (≥0.2 cm), and the presence of desmoplasia were associated with recurrence-free survival (P < .05). CONCLUSION: The prognostic significance of central LN metastasis can differ according to the number of metastatic LNs, the size of metastatic foci, and the presence of desmoplasia. Patients with a high number of metastatic LNs, larger metastatic foci, and presence of desmoplasia in LNs should be treated aggressively and supervised carefully for PTMC recurrence.

Preoperative localization and intraoperative parathyroid hormone assay in korean patients with primary hyperparathyroidism.

BACKGROUND: The intraoperative parathyroid hormone (IOPTH) assay is widely used in patients with primary hyperparathyroidism (PHPT). We investigated the usefulness of the IOPTH assay in Korean patients with PHPT. METHODS: We retrospectively reviewed the data of 33 patients with PHPT who underwent parathyroidectomy. Neck ultrasonography (US) and 99mTc-sestamibi scintigraphy (MIBI scan) were performed preoperatively and IOPTH assays were conducted. RESULTS: The sensitivity of neck US and MIBI scans were 91% and 94%, respectively. A 50% decrease in parathyroid hormone (PTH) levels 10 minutes after excision of the parathyroid gland was obtained in 91% (30/33) of patients and operative success was achieved in 97% (32/33) of patients. The IOPTH assay was 91% true-positive, 3% true-negative, 0% false-positive, and 6% false-negative. The overall accuracy of the IOPTH assay was 94%. In five cases with discordant neck US and MIBI scan results, a sufficient decrease in IOPTH levels helped the surgeon confirm the complete excision of the parathyroid gland with no additional neck exploration. CONCLUSION: The IOPTH assay is an accurate tool for localizing hyperfunctioning parathyroid glands and is helpful for evaluating cases with discordant neck US and MIBI scan results.

Medullary thyroid carcinoma with ectopic adrenocorticotropic hormone syndrome.

Ectopic adrenocorticotropic hormone (ACTH) syndrome is caused most frequently by a bronchial carcinoid tumor or by small cell lung cancer. Medullary thyroid carcinoma (MTC) is a rare etiology of ectopic ACTH syndrome. We describe a case of Cushing syndrome due to ectopic ACTH production from MTC in a 48-year-old male. He was diagnosed with MTC 14 years ago and underwent total thyroidectomy, cervical lymph node dissection and a series of metastasectomies. MTC was confirmed by the pathological examination of the thyroid and metastatic mediastinal lymph node tissues. Two years after his last surgery, he developed Cushingoid features, such as moon face and central obesity, accompanied by uncontrolled hypertension and new-onset diabetes. The laboratory results were compatible with ectopic ACTH syndrome. A bilateral adrenalectomy improved the clinical and laboratory findings that were associated with Cushing syndrome. This is the first confirmed case of ectopic ACTH syndrome caused by MTC in Korea.

Predictive factors of malignancy in thyroid nodules with a cytological diagnosis of follicular neoplasm.

In cases of follicular neoplasm identified by thyroid fine-needle aspiration (FNA), surgery is required to achieve a precise diagnosis. We investigated potential clinical factors for the preoperative prediction of malignancy in thyroid nodules with a cytological diagnosis of follicular neoplasm. We retrospectively reviewed the data of 97 patients who were diagnosed with follicular neoplasm by FNA and had undergone surgery at the Korea Cancer Center Hospital between April 2010 and April 2012. Age, sex, laboratory data (such as thyroid-stimulating hormone, free T4, thyroglobulin (Tg), and Tg antibody), and ultrasonographic findings were reviewed from the electronic medical records. Of 97 patients, 50 (51.5 %) were diagnosed with benign nodules, 16 (16.5 %) with follicular thyroid carcinoma (FTC), and 31 (32.0 %) with papillary thyroid carcinoma (PTC). In comparison with the features of benign nodules, FTC presented with a large nodule size, high serum Tg level, isoechogenicity, calcifications, and peripheral halo, whereas PTC exhibited traits similar to those of benign nodules, except for high serum Tg level and the presence of calcifications on ultrasonography. Therefore, a high serum Tg level (≥75 ng/mL) and calcification were the only significant predictive factors for malignancy in case of follicular neoplasm (p < 0.01). Serum Tg levels and the presence of calcification on ultrasonography are important clinical features to predict malignancy in thyroid nodules with cytological diagnosis of follicular neoplasm.

A novel mutation in the von hippel-lindau tumor suppressor gene identified in a patient presenting with gestational diabetes mellitus.

BACKGROUND: Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited, multisystemic tumor syndrome caused by mutations in the VHL gene. To date, more than 1,000 germline and somatic mutations of the VHL gene have been reported. We present a novel mutation in the VHL tumor suppressor gene that presented with gestational diabetes mellitus. METHODS: A 30-year-old woman presented with gestational diabetes mellitus. She sequentially showed multiple pancreatic cysts, spinal cord hemangioblastoma, cerebellar hemangioblastoma, and clear cell type renal cell carcinomas. Also, her father and brother had brain hemangioblastomas. Each of the three exons of the VHL gene was individually amplified by polymerase chain reaction and direct sequencing was performed using an ABI 3730 DNA analyzer. RESULTS: DNA sequence analysis to determine the presence of VHL mutation in her family revealed del291C, a novel frameshift mutation. CONCLUSION: We found a novel mutation in the VHL tumor suppressor gene that presented with gestational diabetes mellitus.

Differential proteome profiling using iTRAQ in microalbuminuric and normoalbuminuric type 2 diabetic patients.

Diabetic nephropathy (DN) is a long-term complication of diabetes mellitus that leads to end-stage renal disease. Microalbuminuria is used for the early detection of diabetic renal damage, but such levels do not reflect the state of incipient DN precisely in type 2 diabetic patients because microalbuminuria develops in other diseases, necessitating more accurate biomarkers that detect incipient DN. Isobaric tags for relative and absolute quantification (iTRAQ) were used to identify urinary proteins that were differentially excreted in normoalbuminuric and microalbuminuric patients with type 2 diabetes where 710 and 196 proteins were identified and quantified, respectively. Some candidates were confirmed by 2-DE analysis, or validated by Western blot and multiple reaction monitoring (MRM). Specifically, some differentially expressed proteins were verified by MRM in urine from normoalbuminuric and microalbuminuric patients with type 2 diabetes, wherein alpha-1-antitrypsin, alpha-1-acid glycoprotein 1, and prostate stem cell antigen had excellent AUC values (0.849, 0.873, and 0.825, resp.). Moreover, we performed a multiplex assay using these biomarker candidates, resulting in a merged AUC value of 0.921. Although the differentially expressed proteins in this iTRAQ study require further validation in larger and categorized sample groups, they constitute baseline data on preliminary biomarker candidates that can be used to discover novel biomarkers for incipient DN.

Carotid intimal-medial thickness is not increased in women with previous gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is known to increase the risk of cardiovascular diseases. Measuring the carotid artery intimal-medial thickness (CIMT) is a non-invasive technique used to evaluate early atherosclerosis and to predict future cardiovascular diseases. We examined the association between CIMT and cardiovascular risk factors in young Korean women with previous GDM. METHODS: One hundred one women with previous GDM and 19 women who had normal pregnancies (NP) were recruited between 1999 and 2002. At one year postpartum, CIMT was measured using high-resolution B-mode ultrasonography, and oral glucose tolerance tests were performed. Fasting glucose, glycated hemoglobin A1c (HbA1c), insulin levels and lipid profiles were also measured. CIMTs in the GDM and NP groups were compared, and the associations between CIMT and cardiovascular risk factors were analyzed in the GDM group. RESULTS: CIMT results of the GDM group were not significantly different from those of the NP group (GDM, 0.435±0.054 mm; NP, 0.460±0.046 mm; P=0.069). In the GDM group, a higher HbA1c was associated with an increase in CIMT after age adjustment (P=0.011). CIMT results in the group with HbA1c >6.0% were higher than those of the normal HbA1c (HbA1c ≤6.0%) (P=0.010). Nine of the patients who are type 2 diabetes mellitus converters within one year postpartum but showed no significant difference in CIMT results compared to NP group. CONCLUSION: Higher HbA1c is associated with an increase in CIMT in women with previous GDM. However, CIMT at one year postpartum was not increased in these women compared to that in NP women.

Effects of Sulfonylureas on Peroxisome Proliferator-Activated Receptor γ Activity and on Glucose Uptake by Thiazolidinediones.

BACKGROUND: Sulfonylurea primarily stimulates insulin secretion by binding to its receptor on the pancreatic ß-cells. Recent studies have suggested that sulfonylureas induce insulin sensitivity through peroxisome proliferator-activated receptor γ (PPARγ), one of the nuclear receptors. In this study, we investigated the effects of sulfonylurea on PPARγ transcriptional activity and on the glucose uptake via PPARγ. METHODS: Transcription reporter assays using Cos7 cells were performed to determine if specific sulfonylureas stimulate PPARγ transactivation. Glimepiride, gliquidone, and glipizide (1 to 500 µM) were used as treatment, and rosiglitazone at 1 and 10 µM was used as a control. The effects of sulfonylurea and rosiglitazone treatments on the transcriptional activity of endogenous PPARγ were observed. In addition, 3T3-L1 adipocytes were treated with rosiglitazone (10 µM), glimepiride (100 µM) or both to verify the effect of glimepiride on rosiglitazone-induced glucose uptake. RESULTS: Sulfonylureas, including glimepiride, gliquidone and glipizide, increased PPARγ transcriptional activity, gliquidone being the most potent PPARγ agonist. However, no additive effects were observed in the presence of rosiglitazone. When rosiglitazone was co-treated with glimepiride, PPARγ transcriptional activity and glucose uptake were reduced compared to those after treatment with rosiglitazone alone. This competitive effect of glimepiride was observed only at high concentrations that are not achieved with clinical doses. CONCLUSION: Sulfonylureas like glimepiride, gliquidone and glipizide increased the transcriptional activity of PPARγ. Also, glimepiride was able to reduce the effect of rosiglitazone on PPARγ agonistic activity and glucose uptake. However, the competitive effect does not seem to occur at clinically feasible concentrations.

The effects of resistance training on muscle and body fat mass and muscle strength in type 2 diabetic women.

BACKGROUND: Our goal was to investigate the effects of low intensity resistance training on body fat, muscle mass and strength, cardiovascular fitness, and insulin sensitivity in type 2 diabetes. METHODS: Twenty-eight overweight women with type 2 diabetes were randomly assigned to a resistance training group (RG, n = 13) or a control group (CG, n = 15). RG performed resistance training using elastic bands, of which strength was equal to 40 to 50% of one repetition maximum (1RM), for three days per week. Each exercise consisted of three sets for 60 minutes. We assessed abdominal fat using computed tomography, muscle mass using dual-energy X-ray absorptiometry, and muscle strength using Keiser's chest and leg press. Insulin sensitivity was measured using the insulin tolerance test, and aerobic capacity was expressed as oxygen uptake at the anaerobic threshold (AT-VO(2)) before and after the 12-week exercise program. RESULTS: The age of participants was 56.4 +/- 7.1 years, duration of diabetes was 5.9 +/- 5.5 years, and BMI was 27.4 +/- 2.5 kg/m(2), without significant differences between two groups. During intervention, a greater increase in muscle mass and greater decreases in both total fat mass and abdominal fat were observed in RG compared to those of CG (P = 0.015, P = 0.011, P = 0.010, respectively). Increase in 1RM of upper and lower extremities was observed in the RG (P = 0.004, P = 0.040, respectively), without changes in AT-VO(2) and insulin resistance in either group. CONCLUSION: In conclusion, the low intensity resistance training was effective in increasing muscle mass and strength and reducing total fat mass without change of insulin sensitivity in type 2 diabetic patients.

A relationship between Alzheimer's disease and type 2 diabetes mellitus through the measurement of serum amyloid-beta autoantibodies.

Increasing evidence suggests that type 2 diabetes mellitus (T2DM) is strongly correlated with Alzheimer's disease (AD). To examine the relationship between T2DM and AD, autoantibodies against amyloid-Abeta were measured in the serum of T2DM patients and age-matched controls. Levels of Abeta autoantibody were measured by ELISA in serum samples of T2DM patients (n=92) and age-matched control group (n=106). Abeta autoantibody levels were increased in T2DM compared with age-matched controls by 45.4 +/- 8.1% (p< 0.001). Females had higher Abeta autoantibody levels than males in both T2DM and control group. Abeta autoantibody levels in the T2DM group were positively correlated with the levels of cholesterol (p=0.011), low density lipoprotein cholesterol (p=0.020), and triglycerides (p=0.039). In conclusion, the level of Abeta autoantibody is dramatically elevated in patient serum of T2DM, and, as such, might be used as a possible biomarker for T2DM.

Regulatory effect of common promoter polymorphisms on the expression of the 11beta-hydroxysteroid dehydrogenase type 1 gene.

BACKGROUND/AIMS: Glucocorticoids play an important role in the pathogenesis of obesity and insulin resistance. 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1), which converts inactive cortisone to active cortisol, has become an emerging therapeutic target for type 2 diabetes mellitus and obesity. In this study, we examined the association between HSD11B1 polymorphisms and type 2 diabetes and metabolic phenotypes in Koreans. METHODS: We sequenced all exons including exon-intron boundaries and the promoter region of the HSD11B1 gene. Of 8 polymorphisms identified, we selected 4 common single-nucleotide polymorphisms (g.-19835G>A, g.-19609A>G, g.+27447G>C and g.+27810C>T) based on location, linkage disequilibrium and frequency and which were genotyped in 757 subjects with type 2 diabetes and 644 nondiabetic subjects. RESULTS: There was no association between the 4 common polymorphisms of HSD11B1 and type 2 diabetes. g.-19835G>A and g.-19609A>G showed modest associations with fasting plasma glucose and body mass index but the significance of these associations was lost after adjustment for multiple comparison. With regard to promoter polymorphisms in the HSD11B1 gene, a haplotype construct carrying both g.-19835A and g.-19609G showed significantly decreased promoter activity compared to other common haplotype constructs. CONCLUSION: The variations in HSD11B1 were not associated with susceptibility to type 2 diabetes or metabolic phenotypes in Koreans. However, the common promoter variants of the gene might exert a polymorphic regulatory effect on HSD11B1 expression.

Comprehensive evaluation of coronary arteries by multidetector-row cardiac computed tomography according to the glucose level of asymptomatic individuals.

BACKGROUND: Early detection of atherosclerosis in individuals with diabetes is important because of high cardiovascular mortality in this population. We performed multidetector-row computed tomography (MDCT) in asymptomatic individuals to investigate the status of coronary artery stenosis and plaque characteristics depending on the glucose level. METHODS AND RESULTS: The plaque burden (number of diseased coronary segments), severity of stenosis, plaques characteristics, and coronary artery calcium score (CACS) were assessed by MDCT in 1043 asymptomatic individuals. Anthropometric parameters and metabolic profiles were also acquired. Twenty-one percents of subjects had plaques and 5% had significant stenosis. Mean (+/-S.D.) CACS of study population was 17+/-81. Subjects with impaired fasting glucose (IFG, n=215, 21%) or diabetes (n=112, 11%) had a greater plaque burden, more coronary stenosis (>50% of diameter stenosis) and higher CACS than normal subjects (all, p<0.01). Noncalcified and mixed plaques were observed more in subjects with diabetes (19%) and IFG (11%) than normal (7%). After adjustment for confounding factors, higher fasting glucose was strongly associated with significant coronary stenosis and a greater plaque burden. CONCLUSIONS: More significant coronary stenosis and multivessel involvement, higher CACS, and greater plaque burden were observed in subjects with IFG or diabetes by MDCT, even they are asymptomatic. Proactive screening, irrespective of the imaging modalities used, in asymptomatic subjects with prediabetes and diabetes is helpful to identify those who have a higher cardiovascular morbidity and mortality. Further studies will guide us with respect to which imaging modality is more appropriate.

Derivation of a new equation for estimating creatinine clearance by using fat-free mass and serum creatinine concentration in Korean patients with type 2 diabetes mellitus.

AIMS: Equations to predict creatinine clearance (Ccr) or glomerular filtration rate have limitations in applying to a wide range of ethnicities with different fat-free mass (FFM). We aimed to determine the serum creatinine (Scr) concentrations that indicate renal insufficiency and formulate a new equation to estimate Ccr by a function of FFM in Korean type 2 diabetic patients. METHODS: Ccr was measured in 283 type 2 diabetic patients by 24-h urine collection. Receiver operating characteristic (ROC) curve was used to determine the Scr concentration corresponding to a Ccr of 60 mL min(-1) x 1.73 m(-2). A new equation to predict Ccr was derived by using Scr and FFM. RESULTS: The Scr concentration corresponding to a Ccr of 60 mL min(-1) x 1.73 m(-2) was 1.15 mg/dL in men and 0.95 mg/dL in women. The regression equation estimating the Ccr was expressed as (1.72 x FFM-0.23 x age)/Scr, and it showed a good correlation with the measured Ccr (r=0.718, P<0.001). CONCLUSIONS: Scr concentrations indicating renal insufficiency in the Korean patients were considerably lower than those in Caucasians. The equation derived in this study would be more useful in Korean or other Asian type 2 diabetic patients.