Diagnostic accuracy of selective arterial calcium injection test for localization of gastrinoma.

The appropriate localization of gastrinoma is still difficult. We aimed to evaluate the diagnostic accuracy of selective arterial calcium injection (SACI) for localization of gastrinomas including multiple lesions. This retrospective study included ten patients with surgically proven gastrinomas (gastrinoma group) and six patients without any findings suggesting Zollinger-Ellison syndrome (non-gastrinoma group). For SACI, calcium gluconate was injected into the arteries supplying pancreas, duodenum, and liver. Blood samples from the hepatic vein were obtained before and 30, 60, and 120 seconds after each injection. The results were considered positive when the increase in serum immunoreactive gastrin (IRG) levels within 60 seconds of calcium gluconate injection were more than 80 pg/mL and more than 20% from baseline. We evaluated the efficacy of SACI by comparing the SACI responses with definitive locations diagnosed by clinical and histopathological findings. In the gastrinoma group, false-positive responses were confirmed in seven of the ten patients. False-negative response was observed in one of the feeding arteries of one patient with gastrinomas in multiple locations. Conversely, the greatest increase in serum gastrin levels from baseline at 30 seconds indicated the true-positive responses in all patients with gastrinomas. In the non-gastrinoma group, calcium gluconate injection into gastroduodenal artery evoked positive responses in five of the six patients. In conclusion, our data suggest the strongest gastrin response evoked by SACI indicates the definitive location in patients with gastrinomas. In contrast, SACI could not accurately locate multiple gastrin-secreting lesions due to poor specificity.

A case of generalized lipodystrophy-associated progeroid syndrome treated by leptin replacement with short and long-term monitoring of the metabolic and endocrine profiles.

We herein report a case of a 28-year-old man with generalized lipodystrophy-associated progeroid syndrome treated by leptin replacement. He showed symptoms of generalized lipodystrophy around onset of puberty. His body mass index was 11.9 kg/m2, and he had a short stature, birdlike facies, dental crowding due to micrognathia, partial graying and loss of hair, and a high-pitched voice, all of which are typical features of the progeroid syndrome. Laboratory examinations and abdominal ultrasonography revealed diabetes mellitus, insulin-resistance, dyslipidemia, decreased serum leptin levels (2.2 ng/mL), elevated serum hepatobiliary enzyme levels and fatty liver. Whole exome sequencing revealed de novo heterozygous LMNA p.T10I mutation, indicating generalized lipodystrophy-associated progeroid syndrome, which is a newly identified subtype of atypical progeroid syndrome characterized by severe metabolic abnormalities. Daily injection of metreleptin [1.2 mg (0.04 mg/kg)/day] was started. Metreleptin treatment significantly improved his diabetes from HbA1c 11.0% to 5.4% in six months. It also elevated serum testosterone levels. Elevated serum testosterone levels persisted even 1 year after the initiation of metreleptin treatment. To the best of our knowledge, this is the first Japanese case report of generalized lipodystrophy-associated progeroid syndrome. Furthermore, we evaluated short and long-term effectiveness of leptin replacement on generalized lipodystrophy by monitoring metabolic and endocrine profiles.

Clinical outcomes of 20 Japanese patients with insulinoma treated with diazoxide.

Diazoxide is recognized as an effective medical treatment for insulinoma. However, due to its adverse effects, such as fluid retention, it is sometimes difficult to employ diazoxide at an effective dose in clinical practice. This study aimed to clarify the clinical factors, which may affect efficacy and safety of the diazoxide treatment. We retrospectively evaluated the medical records of 20 patients with insulinoma including 4 malignant cases. The patients were divided into two groups according to the presence or absence of favorable outcomes or adverse effects, and the clinical features of both groups were compared. Diazoxide was effective and ineffective in each 9 patients, respectively. In other 2 cases, the efficacy could not be determined. In the effective group, all patients had benign insulinoma. Additionally, the tumor size determined by imaging test was tended to smaller than the ineffective group but not statistically significant when malignant cases were excluded (p = 0.065). Fluid retention was observed more frequently in females than in males (p = 0.025). Five patients displayed unacceptable thrombocytopenia within a few weeks after the administration of diazoxide. In these patients, the diazoxide dose was significantly higher than that in the other patients [400 mg/day (250-500 mg/day) vs. 225 mg/day (50-425 mg/day), p = 0.027]. These findings may be informative in determining the indication and dose of diazoxide against insulinoma. In addition, a careful evaluation of platelet count would be required for a few weeks after the initiation of diazoxide treatment.

Dipeptidyl peptidase 4 inhibitors attenuates the decline of skeletal muscle mass in patients with type 2 diabetes.

BACKGROUND: Activation of dipeptidyl peptidase 4 has been reported to be associated with impairment of insulin signalling in skeletal muscle, presumably leading to loss of muscle function. This study was aimed to investigate whether the use of dipeptidyl peptidase 4 inhibitors (DPP4i) could attenuate the progressive loss of muscle mass in patients with type 2 diabetes. METHODS: A total 105 patients with type 2 diabetes (mean age 62 ± 12 years; 39% female) were studied in this retrospective observational study. To reduce the bias due to confounding variables, propensity-score matching analysis was performed. Change in skeletal muscle index measured by the whole body dual-energy X-ray absorptiometry at 1-year follow-up was evaluated. One-year changes in visceral and subcutaneous fat area and liver attenuation index were also determined by abdominal computed tomography. RESULTS: Overall, 37 of 105 (35.2%) patients were treated with DPP4i. The estimated change in skeletal muscle index in patients with DPP4i was significantly higher than that in patients without (0.05 ± 0.06 vs -0.10 ± 0.04 kg, P = .046). In a propensity-matched population (N = 48), the same finding was observed (0.04 ± 0.03 in DPP4i versus -0.12 ± 0.03 kg in non-DPP4i, P = .033). There were no significant differences in changes of visceral and subcutaneous fat area and liver attenuation index between patients with DPP4i and those without. CONCLUSIONS: Our data suggest the potential of DPP4i to prevent the progressive loss of muscle mass with ageing in patients with type 2 diabetes.

A case of TSH-secreting pituitary adenoma with cyclic fluctuations in serum TSH levels.

A 29-year-old man was referred to our department due to adrenal insufficiency with the inappropriate secretion of TSH (SITSH). Magnetic resonance imaging revealed a pituitary tumor. A weak TSH response in the TRH test, elevated sex hormone binding globulin (SHBG) levels, and the absence of a family medical history of SITSH or TRß gene mutations supported the diagnosis of TSH-secreting pituitary adenoma (TSHoma). However, complete TSH suppression and a blunted cholesterol response in the T3 suppression test as well as normal glycoprotein α-subunit (α-GSU) levels were not compatible with TSHoma. Since TSH, FT3, and FT4 spontaneously returned to normal ranges after admission, he was discharged. One month after his discharge, thyrotoxicosis with elevated serum TSH levels relapsed. After admission, his serum TSH levels returned to within the normal range. After his discharge from the second admission, his serum TSH levels fluctuated in accordance with serum FT3 and FT4 levels and symptoms, such as palpitations. Ten months after his discharge, he was admitted to our department again due to adrenal insufficiency and thyrotoxicosis with elevated serum TSH levels, suggesting cyclic SITSH. Although resistance to thyroid hormone (RTH) was not completely excluded, the pituitary tumor was removed by transsphenoidal surgery (TSS). A pathological diagnosis confirmed TSHoma. We herein report a case of TSHoma in which serum TSH, FT3, and FT4 levels fluctuated periodically. To the best of our knowledge, this is the first case report of "cyclic TSHoma", which needs to be considered when making a differential diagnosis of SITSH.

Luseogliflozin reduces epicardial fat accumulation in patients with type 2 diabetes: a pilot study.

BACKGROUND: Accumulation of epicardial fat (EF) is associated with increased cardio-metabolic risks and coronary events, independently of traditional cardiovascular risk factors. Therefore, the reduction of EF volume (EFV) may be associated with reduced cardio-metabolic risks and future cardiovascular events. Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce body fat including visceral fat and cardiovascular events in patients with type 2 diabetes. However, it has still been unknown whether SGLT2 inhibitors can reduce EFV. METHODS: Type 2 diabetic patients with HbA1c 6.5-9.0% and body mass index (BMI, kg/m2) ≥25.0 were enrolled in this single arm pilot study. Participants were administered luseogliflozin 2.5 mg daily and the dosage was tolerated to be increased up to 5.0 mg daily. EFV [median (interquartile range), cm3] was measured by magnetic resonance imaging. Primary endpoint was the decrease in EFV at 12 weeks. Visceral fat area (VFA, cm2) and liver attenuation index (LAI) measured by the abdominal computed tomography, and skeletal muscle index (SMI) and body fat (%) measured by the whole body dual-energy X-ray absorptiometry were also determined at baseline and at 12 weeks. RESULTS: Nineteen patients (mean age: 55 ± 12 years; 26% female) completed this study. Luseogliflozin treatment significantly reduced EFV at 12 weeks [117 (96-136) to 111 (88-134), p = 0.048]. The body weight, BMI, systolic and diastolic blood pressure, HbA1c, fasting plasma glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), triglycerides, SMI, and body fat were significantly reduced by luseogliflozin at 12 weeks. The reduction of EFV was significantly correlated with the reduction of C-reactive protein (r = 0.493, p = 0.019). Neither VFA nor LAI were significantly reduced by the luseogliflozin treatment. No severe adverse events were observed. CONCLUSIONS: Our data suggest that luseogliflozin could reduce the EFV in parallel with the improvement of systemic micro-inflammation and the reduction of body weight in Japanese patients with type 2 diabetes. The reduction of muscle mass after the administration of SGLT2 inhibitors may require a particular attention. Trial registration umin.ac.jp, UMIN000019072.

Insulin Treatment Attenuates Decline of Muscle Mass in Japanese Patients with Type 2 Diabetes.

Sarcopenia is defined as an age-related loss of skeletal muscle mass and strength, and is a major cause of disability and mobility limitations. Recent studies have demonstrated that type 2 diabetes and insulin signaling deficiencies contribute to the progression of sarcopenia, suggesting that a sufficient supply of insulin to the skeletal muscles may be important for the maintenance of muscle function; however, little has been reported regarding whether insulin treatment can protect against sarcopenia. We conducted a retrospective observational study to examine the impact of insulin treatment on the muscle mass of patients with type 2 diabetes. A total of 312 patients (mean age: 64 ± 11 years; 40.8% female; 27.6% treated with insulin) were studied in this retrospective observational study. Skeletal muscle index (SMI) and grip strength (kg) were used to assess sarcopenia. The prevalence of sarcopenia was 18.0%. Insulin treatment was shown to be protective against the annual decline of SMI (standardized ß 0.195; p = 0.025) even after adjusting for covariates, including age, gender, duration of diabetes, and body mass index. In a cohort matched by propensity scores, insulin treatment significantly increased the 1-year change in SMI (mean ± SE) compared with non-insulin-treated group (2.40 ± 0.98% vs. -0.43 ± 0.98%; p = 0.050). Our data suggest that insulin treatment could attenuate the progression of sarcopenia in patients with type 2 diabetes.

Assessment of vascular autonomic function using peripheral arterial tonometry.

Peripheral autonomic function is impaired in diabetic polyneuropathy. However, it is difficult to evaluate it due to the lack of non-invasive quantitative assessment. We aimed to establish a novel index to evaluate vascular autonomic function using reactive hyperemia peripheral arterial tonometry (RH-PAT), a widely performed endothelial function test. Sixty-five subjects were enrolled, including healthy subjects, cases with sympathetic nerve blockers, and diabetic patients. RH-PAT was performed with 5-min blood flow occlusion in unilateral arm. We calculated the reduction ratio of the post-occlusion pulse amplitude to the baseline in the non-occluded arm (RPN), with 1-min sliding window. In healthy subjects, RPN gradually increased with time-dependent manner. However, this phenomenon was eliminated in cases with sympathetic nerve blockers. Plasma concentration of norepinephrine was measured before and after the blood flow occlusion, which showed a significant increase. We then compared RPNs with the change in heart rate variability (HRV) parameters. RPN calculated at 5 min after the reperfusion had the highest correlation with the change in sympathetic HRV parameter, and thus, we named sympathetic hypoemia index (SHI). Finally, we studied the relationship between SHI and diabetes. SHI was significantly lower in diabetic patients than matched controls. SHI, a novel index derived from RH-PAT, represented the peripheral sympathetic activity. SHI may be useful for assessing the vascular autonomic activity in diabetic patients.

Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: a randomized control trial.

Liraglutide, an analogue of human glucagon-like peptide 1, reduces cardiovascular events in patients with type 2 diabetes; however, it has still been unknown by which mechanisms liraglutide could reduce cardiovascular events. Type 2 diabetic patients with insulin treatment were enrolled in this randomized, open-label, comparative study. Participants were randomly assigned to liraglutide plus insulin (liraglutide group) and insulin treatment (control group) at 1:1 allocation. Primary endpoint was the change in viscera fat are (VFA, cm2) at 24 weeks. Liver attenuation index (LAI) measured by abdominal computed tomography, urinary albumin-to-creatinine ratio (ACR, mg/g), and C-reactive protein (CRP) levels, skeletal muscle index (SMI), and quality of life (QOL) related to diabetes treatment were also determined. Seventeen patients (8; liraglutide group, 9; control group, mean age 59 ± 13 years; 53% female) completed this study. Liraglutide treatment significantly reduced VFA at 24 weeks; whereas, SFA was unchanged. ACR, LAI, and CRP levels were significantly reduced by liraglutide at 24 weeks and there was no difference in SMI between the two groups. Changes in VFA from baseline to 24 weeks were significantly associated with those in LAI, albuminuria, and HbA1c. Liraglutide treatment significantly improved QOL scores associated with anxiety and dissatisfaction with treatment and satisfaction with treatment. No severe adverse events were observed in both groups. Our data suggest that liraglutide could reduce visceral adiposity in parallel with attenuation of hepatic fat accumulation, albuminuria and micro-inflammation and improve QOL related to diabetes care in insulin-treated patients with type 2 diabetes.

Clinical relevance of dual-energy X-ray absorptiometry (DXA) as a simultaneous evaluation of fatty liver disease and atherosclerosis in patients with type 2 diabetes.

BACKGROUND: Whole body dual-energy X-ray absorptiometry (DXA) can simultaneously measure both regional fat and non-fat mass. Android-to-gynoid (A/G) ratio measured by DXA has been reported to be associated with cardiovascular risks and visceral adiposity; however, little is known regarding its relationship with fatty liver disease and atherosclerosis among patients with diabetes. This study was designed to investigate the association of android and gynoid fat mass measured by DXA with fatty liver disease and atherosclerosis in patients with type 2 diabetes. METHODS: This is a cross-sectional study of 259 patients with type 2 diabetes (mean age 64 ± 13 years; 40.2 % female). Android and gynoid fat mass (kg) were measured by DXA. Skeletal muscle index (SMI) was calculated as appendicular non-fat mass (kg) divided by height (m(2)). Visceral fat area (VFA, cm(2)), subcutaneous fat area (SFA, cm(2)), and liver attenuation index (LAI) were assessed by abdominal computed tomography. Intima media thickness (IMT, mm) in common carotid arteries was determined by carotid ultrasonography. RESULTS: A/G ratio was significantly correlated with VFA (r = 0.72, p < 0.001), SFA (r = 0.32, p < 0.001) and LAI (r = -0.26, p < 0.001). A/G ratio (standardized ß -0.223, p = 0.002) as well as VFA (standardized ß -0.226, p = 0.001) were significantly associated with LAI in the univariate model. A/G ratio remained to be significantly associated with LAI (standardized ß -0.224, p = 0.005) after adjusting for covariates including body mass index and transaminases. Among patients with low SMI (SMI < 7.0 in male and < 5.4 in female), A/G ratio was significantly associated with carotid IMT in the multivariate model (standardized ß 0.408, p = 0.014). CONCLUSIONS: DXA can be used to simultaneously estimate the risks for both fatty liver disease and atherosclerosis in patients with type 2 diabetes.

Is visceral adiposity a modifier for the impact of blood pressure on arterial stiffness and albuminuria in patients with type 2 diabetes?

BACKGROUND: We aimed to investigate whether visceral adiposity could modify the impact of blood pressure on arterial stiffness and albuminuria in patients with type 2 diabetes. METHODS: This cross-sectional study examines the interaction of visceral adiposity with increased blood pressure on arterial stiffness and albuminuria. 638 patients with type 2 diabetes (mean age 64 ± 12 years; 40 % female) were enrolled. Visceral fat area (VFA, cm(2)) was assessed by a dual-impedance analyzer, whereby patients were divided into those with VFA < 100 (N = 341) and those with VFA ≥ 100 (N = 297). Albuminuria was measured in a single 24-h urine collection (UAE, mg/day) and brachial-ankle pulse wave velocity (ba-PWV, cm/s) was used for the assessment of arterial stiffening. Linear regression analyses were used to investigate the association of systolic blood pressure (SBP) and VFA with UAE and baPWV. RESULTS: Patients with VFA ≥ 100 were significantly younger, had higher SBP, HbA1c, triglycerides, UAE, alanine aminotransferase, C-reactive protein and lower high-density lipoprotein and shorter duration of diabetes than those with VFA < 100. SBP was significantly and almost equivalently associated with ba-PWV both in VFA < 100 (standardized ß 0.224, p = 0.001) and VFA ≥ 100 (standardized ß 0.196, p = 0.004) patients in the multivariate regression analysis adjusting for covariates including age, gender, HbA1c, diabetic complications and the use of insulin and anti-hypertensive agents. By contrast, the association of SBP with UAE was stronger in patients with VFA ≥ 100 (standardized ß 0.263, p = 0.001) than that in patients with VFA < 100 (standardized ß 0.140, p = 0.080) in the multivariate regression model. In the whole cohort, the significant interaction between SBP and VFA on UAE (standardized ß 0.172, p = 0.040) but not on ba-PWV (standardized ß -0.008, p = 0.916) was observed. CONCLUSIONS: The effect of increased blood pressure on arterial stiffness is almost similar in type 2 diabetic patients with both low and high visceral adiposity, while its association with albuminuria is stronger in the latter.

High visceral fat with low subcutaneous fat accumulation as a determinant of atherosclerosis in patients with type 2 diabetes.

BACKGROUND: Abdominal visceral obesity has been reported to be associated with cardiovascular risks than body mass index, waist circumference, and abdominal subcutaneous fat. On the other hand, there is evidence that subcutaneous fat has a beneficial role against cardio-metabolic risks such as diabetes or dyslipidemia. However, little is known regarding the association between high visceral fat with low subcutaneous fat accumulation and the risk for atherosclerosis. METHODS: This study was designed to elucidate whether high visceral fat with low subcutaneous fat accumulation enhances the risk for atherosclerosis in patients with type 2 diabetes. This is a cross-sectional study of 148 patients with type 2 diabetes (mean age 65 ± 12 years; 44.5% female). Visceral fat area (VFA, cm(2)) and subcutaneous fat area (SFA, cm(2)) were assessed by abdominal computed tomography. Carotid intima media thickness (CIMT, mm) measured by ultrasonography was used for the assessment of atherosclerosis. Patients were divided into four groups: SFA < 100 cm(2) and VFA < 100 cm(2) [S(-)V(-)], SFA ≥ 100 cm(2) and VFA < 100 cm(2) [S(+)V(-)], SFA < 100 cm(2) and VFA ≥ 100 cm(2) [S(-)V(+)], and SFA ≥ 100 cm(2) and VFA ≥ 100 cm(2) [S(+)V(+)]. Linear regression analysis with a stepwise procedure was used for the statistical analyses. RESULTS: Among the patients examined, 16.3% were S(-)V(+). Mean (95 % confidence interval) of CIMT adjusting for age and gender were 0.80 (0.69-0.91), 0.86 (0.72-1.01), 1.28 (1.11-1.44) and 0.83 (0.77-0.88) in patients with S(-)V(-), S(+)V(-), S(-)V(+) and S(+)V(+), respectively (p < 0.001). The S(-)V(+) patients exhibited significantly older than S(-)V(-) patients and those with S(+)V(+) and had a highest VFA-SFA ratio (V/S ratio) among the four groups. S(-)V(+) patients were male predominant (100% male), and S(+)V(-) patients showed female predominance (82% female). In multivariate linear regression analysis (Adjusted R(2) = 0.549), S(-)V(+) was significantly associated with CIMT (Standardized ß 0.423, p < 0.001). Notably, S(+)V(+) was inversely associated with CIMT in the multivariate model. CONCLUSIONS: This study provides evidence that high visceral fat with low subcutaneous fat accumulation is an important determinant of carotid atherosclerosis and high subcutaneous fat could be protective against atherosclerosis in patients with type 2 diabetes.

Differential gene expression profiles of POMC-related enzymes, transcription factors and receptors between non-pituitary and pituitary ACTH-secreting tumors.

The differential gene expression of proopiomelanocortin (POMC)-related processing enzymes, transcription factors, and receptors responsible for ACTH secretion between non-pituitary and pituitary ACTH-secreting tumors remains obscure. This study was attempted to determine the gene expression profiles of transcription factors (Tpit, NeuroD1 and IKZF1), proprotein convertase (PC) 1/3 and PC2, and several key receptors linked to ACTH secretion, including corticotrophin releasing hormone receptor (CRHR1), vasopressin receptor 1b (V1bR), somatostatin receptor (SSTR) subtype-2, -5 and dopamine receptor type 2 (D2R) in non-pituitary and pituitary ACTH-secreting tumors. Surgical tissue specimens from carcinoid tumors causing ectopic ACTH syndrome (EAS: n=4) and pituitary tumors causing Cushing's disease (CD: n=13), were subjected to real-time RT-PCR for measurements of each mRNA levels. POMC and CRHR1 mRNA levels in CD were far greater than those in EAS, whereas IKZF1, PC2, SSTR-2 and -5 mRNA levels in EAS were significantly greater than those in CD. NeuroD1, Tpit, PC1/3, V1bR and D2R mRNA levels were comparable between EAS and CD. In conclusion, differential gene expression profiles revealed more abundant mRNA expression in EAS than in CD of 1) IKZF1 with its potential implication of cell differentiation and hormone secretion, 2) PC2 with its possible enhanced processing activity of mature ACTH, and 3) SSTR-2 and -5 with their potential therapeutic application of more selective agonists in EAS patients.

Clinicopathological features of primary aldosteronism associated with subclinical Cushing's syndrome.

Primary aldosteronism (PA), an autonomous aldosterone hypersecretion from adrenal adenoma and/or hyperplasia, and subclinical Cushing syndrome (SCS), a mild but autonomous cortisol hypersecretion from adrenal adenoma without signs or symptoms of Cuhing's syndrome, are now well-recognized clinical entities of adrenal incidentaloma. However, the clinicopathological features of PA associated with SCS (PA/SCS) remain unknown. The present study was undertaken to study the prevalence of PA/SCS among PA patients diagnosed at our institute, and characterize their clinicopathlogical features. The prevalence of PA/SCS was 8 of 38 PA patients (21%) studied. These 8 PA/SCS patients were significantly older and had larger tumor, higher serum potassium levels, lower basal plasma levels of aldosterone, ACTH and DHEA-S as well as lower response of aldosterone after ACTH stimulation than those in 12 patients with aldosterone-producing adenoma without hypercortisolism. All 8 PA/SCS patients showed unilateral uptake by adrenal scintigraphy at the ipsilateral side, whereas the laterality of aldosterone hypersecretion as determined by adrenal venous sampling varied from ipsilateral (3), contralateral (2), and bilateral side (2). 6 PA/SCS patinets who underwent adrenalectomy required hydrocortisone replacement postoperatively. Histopathological analysis of the resected adrenal tumors from 5 PA/SCS patients revealed a single adenoma in 3, and double adenomas in 2, with varying degrees of positive immunoreactivities for steroidgenic enzymes (3ß-HSD, P450(C17)) by immunohistochemical study as well as CYP11B2 mRNA expression as measured by real-time RT-PCR. In conclusion, PA/SCS consists of a variety of adrenal pathologies so that therapeutic approach differs depending on the disease subtype.

Clinicopathological features, biochemical and molecular markers in 5 patients with adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a very rare malignant tumor with poor prognosis. To gain insight into the pathogenic significance of ACC, we studied clinicopathological features and gene expression profile in ACC. We analyzed five ACC cases (two men and three women) with the median age of 45-year-old who underwent adrenalectomy at our institute. Endocrine studies revealed that two cases had subclinical Cushing's syndrome (SCS) and one with concomitant estrogen-secreting tumor, while the rest of three cases had non-functioning tumors. Analysis of urinary steroids profile by gas chromatography/mass spectrometry showed increased metabolites of corticosteroid precursors, such as 17-OH pregnenolone, 17-OH progesterone, dehydroepiandorosterone (DHEA), and 11-deoxycortisol in all five cases. The pathological diagnosis of ACC was based on Weiss's criteria with its score ≥ 3. The mean size of the resected tumors was 87 mm and Ki67/MIB1 labeling index, a proliferative marker, was 3-27%. Immunohistochemical analysis revealed a disorganized expression of several steroidogenic enzymes, such as 3ß-hydroxysteroid dehydrogenase, 17α-hydroxylase, and DHEA-sulfotransferase. Among several genes determined by RT-PCR, insulin-like growth factor (IGF)-II mRNA was consistently and abundantly expressed in all 5 tumor tissues. Postoperatively, two cases with SCS developed local recurrence and liver metastasis. The present study suggests that the disorganized expression of steroidogenic enzymes and the overexpression of IGF-II by the tumor are hallmarks of ACC, which could be used as biochemical and molecular markers for ACC.

Clinical features and management of ectopic ACTH syndrome at a single institute in Japan.

Ectopic ACTH syndrome (EAS) is a diagnostic challenge because it is often indistinguishable from Cushing's disease. We describe our series of EAS patients referred to us during 1992-2009. Among 16 cases (9 females / 7 males), with mean age of 58.4 ± 19.0yr, the ectopic source was identified in ten (proven EAS), whereas unidentified in six (occult/unknown EAS). Their salient clinical manifestations included Cushingoid feature (88%), skin pigmentation (88%), profound hypokalemia (88%), hypertension (75%), diabetes/impaired glucose tolerance (75%), hyperlipidemia (69%), and severe infection (44%). Dynamic endocrine tests revealed markedly elevated plasma ACTH levels (211 ± 116pg/mL) and cortisol levels (60.9 ± 30.1µg/dL) which showed resistance to overnight high-dose (8mg) dexamethasone suppression test in 15 (94%) and unresponsiveness to CRH stimulation in 12 (75%). No ACTH gradient during inferior petrosal sampling was noted in 13 of 15 (87%). Imaging tests by CT/MRI identified the tumors in 8 of 16 (50%), in 4 of 11 (36%) and 4 of 6 (66.7%) octreotide-responders by somatostatin receptor scintigraphy, but in only one of 9 (11.1%) by FDG-PET scan. Six cases deceased, including small cell carcinoma (2) and adenocarcinoma (1) of lung, neuroendocrine carcinoma of pancreas (1) and stomach (1), and olfactory neuroblastoma (1), whereas 4 cases survived after removal of the tumors, including bronchial carcinoid tumor (3) and thymic hyperplasia (1). Six occult/unknown EAS patients survived for 67.5 months after medical treatment with metyrapone to control hypercortisolism. Thus, various endocrine tests combined with imaging studies are required to correctly localize the tumors. Control of hypercortisolemia by metyrapone, even if tumor is unrecognized, is critical for better prognosis, and the long-term follow-up by repeated endocrine and imaging tests is mandatory.

Ectopic ACTH syndrome caused by bronchial carcinoid tumor indistinguishable from Cushing's disease.

A 75-year-old woman was admitted to our hospital because of a poor glycemic control. She was found to have Cushingoid feature and dynamic endocrine tests showed elevated plasma ACTH and cortisol levels, lack of their circadian rhythm, non-suppressibility to high-dose dexamethasone, responsiveness to CRH, but not to DDAVP, and suppression to octreotide. Pituitary MRI showed an equivocal small lesion. CT scan of the chest showed two nodular lesions in the right lung (S5, S7), while a mild uptake was noted only in S5 lesion by FDG-PET, but positive uptake was only in S7 lesion by somatostatin receptor scintigraphy (SRS). Inferior petrosal sinus sampling revealed a gradient of plasma ACTH after CRH stimulation, consistent with the diagnosis of Cushing' s disease. She underwent middle and inferior lobectomy of the right lung. The resected tumor in S7 was consistent with the diagnosis of a bronchial carcinoid tumor with positive ACTH immunoreactivity, while that of S5 was cryptococcal granuloma. RT-PCR revealed abundant expressions of POMC and SSTR (-1, -2, -5), but not of CRHR and V1bR. Postoperatively, abnormal endocrine data were normalized along with improvement of hypertension and diabetes. This was a diagnostic challenging case with ectopic ACTH syndrome indistinguishable from Cushing' s disease by various endocrine and imaging tests, among which SRS successfully localized the tumor responsible for ectopic ACTH secretion.

Successful localization of ectopic ACTH-secreting bronchial carcinoid by selective pulmonary arterial sampling.

Among patient with ACTH-dependent Cushing's syndrome, about 10-20% of those with ectopic ACTH syndromes (EAS) have occult or unknown tumors. Despite the intensive search for the culprit tumors by dynamic endocrine tests and imaging tests, it is often difficult to localize and confirm the source of occult ectopic ACTH secretion. We report a patient with EAS caused by a small bronchial carcinoid tumor, which was successfully localized by a selective pulmonary arterial sampling for the first time. A 69-year-old woman presented with typical Cushingoid features and elevated plasma ACTH and cortisol levels, which showed lack of circadian rhythm, no suppression by high-dose dexamethasone, and no response to CRH stimulation. No mass lesion was detected by pituitary MRI, and inferior petrosal sinus sampling showed no central to peripheral ACTH gradient. Although CT scan of the chest revealed a very small nodule in the right lung, it could not be confirmed by either somatostatin receptor scintigraphy or fluorodeoxyglucose positron emission tomography. Selective pulmonary arterial sampling of the wedged blood from a pulmonary artery branch affecting the nodule showed a marked ACTH gradient, and the lobectomy of the right middle lung resulted in dramatic decreases in plasma ACTH and cortisol levels. The resected tumor was diagnosed as a bronchial carcinoid tumor with positive immunostaining for ACTH. Thus, selective pulmonary arterial sampling, because of its more site-selective measurement of hormonal secretion, could be one of the useful tools to localize and confirm the ectopic ACTH production by a small pulmonary tumor.

Defective expression of prohormone convertase 4 and enhanced expression of insulin-like growth factor II by pleural solitary fibrous tumor causing hypoglycemia.

A 75-year-old man was admitted to our hospital because of unconsciousness. His plasma glucose was very low, but his serum levels of insulin and IGF-I were also low. He was found to have a giant solitary pleural tumor, which was completely resected, after which his hypoglycemia ameliorated postoperatively. Histologically, the tumor was consistent with the pathological diagnosis of a solitary fibrous tumor derived from the pleura. Immunohistochemical study revealed positive immunostaining for IGF-II in tumor cells. The presence of high molecular weight (HMW) form of IGF-II in the tumor tissue and patient's serum was confirmed by Western blot analysis. Steady-state mRNA levels of IGF-II and prohormone convertases (PC) 4, a potential protease responsible for IGF-II processing, as determined by RT-PCR were about 14-fold greater and 5-fold less in the tumor tissue than those in normal placental tissue, respectively. Therefore, it is suggested that biologically active, unprocessed HMW form of IGF-II generated from the impaired processing of IGF-II precursor by the defective PC4 expression in the tumor was responsible for the non-islet cell tumor hypoglycemia (NICTH) in the present case.

Diagnostic accuracy of adrenal venous sampling in comparison with other parameters in primary aldosteronism.

This retrospective study was aimed 1) to compare the difference of the findings between adrenal CT scan and adrenal venous sampling (AVS) in 35 cases with definite primary aldosteronism (PA) for assessment of the diagnostic efficacy of PA subgroup (unilateral and bilateral adrenal hypersecretion: UAH and BAH), and 2) to determine the clinical and biochemical parameters as potential predictors for PA subgroup. There were significant discordant results based on AVS and CT scan in subgrouping PA; 9 of 17 BAH patients (53%) had unilateral lesion on CT scan, while 4 of 18 UAH patients (22%) had no apparent or bilateral lesions on CT scan. Among three diagnostic criteria, absolute values of plasma aldosterone concentration (PAC) in both adrenal veins, lateralized and contralateral ratios of aldosterone/cortisol after ACTH stimulation during AVS to determine the laterality, none of them showed 100% diagnostic accuracy if applied alone. Among several clinical and biochemical parameters, hypokalemia (<3.4 mEq/l), younger age (<52 y) and poor response of PAC (<1.45) after furosemide-upright posture, proved to be significant predictors for UAH, with higher specificities (100%, 88%, 94%, respectively). Therefore, despite AVS as a gold standard method to determine the laterality of aldosterone hypersecretion in PA, our study shows that no single criterion could provide definite diagnostic value for its laterality by AVS. It is also suggested that most PA patients, if not all, with a distinct unilateral adrenal lesion on CT accompanied by hypokalemia, younger age and poor aldosterone response to renin stimulation, could undergo adrenalectomy without prior AVS.