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Some resected adrenal-confined adrenocortical carcinomas metastasize and others not. The present study was designed to evaluate the expression of metallothionein protein (MT) and minichromosome maintenance protein-2 (MCM2) in adrenocortical carcinomas and adrenocortical adenomas, and to test the correlation between this and adrenocortical carcinoma aggressiveness.The study comprised 14 patients operated on for adrenocortical carcinoma, 15 operated on for adrenocortical adenoma and 2 with normal adrenals. Hematoxylin-eosin staining was used for histological evaluation under light microscopy, and sequential sections were used for MCM2 and MT staining.In normal adrenals, positive staining was weak for MT and zero for MCM2. Rates of positive staining for MT and MCM2 were significantly higher in adrenocortical carcinomas than in adrenocortical adenomas (P=0.008 and P0.001, respectively). In adrenocortical carcinomas, a significant positive correlation was found between MCM2 staining and Weiss revisited score (P=0.022) but not for Weiss score, and a significant positive correlation was found between MCM2 and mitotic rate on histology (P=0.033). MCM2 but not MT staining was also shown to correlate significantly with stage IV carcinoma (P=0.008 and P=0.165, respectively).MCM2 and MT are overexpressed in adrenocortical carcinoma, and MCM2 expression correlates significantly with metastatic disease.

BackgroundCushing’s syndrome (CS) is associated with numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole, an orally administered ketoconazole stereoisomer, is in clinical trials for the treatment of CS.MethodsSONICS, a prospective, open-label, phase 3 study in adults with confirmed CS and mean 24-h urinary free cortisol (mUFC) ≥1.5× ULN, included dose-titration, 6-month maintenance, and 6-month extension phases. This subanalysis evaluated the efficacy of levoketoconazole in patients with DM (n = 28) or without DM (n = 49) who entered the maintenance phase. Safety was evaluated in the overall population (N = 94) during the dose-titration and maintenance phases.ResultsNormalization of mUFC at the end of maintenance phase (EoM), without a dose increase during maintenance (SONICS primary endpoint) was observed in 46% of patients with DM (95% CI, 28 to 66%; P = 0.0006 vs null hypothesis of ≤20%) and 33% of patients without DM (95% CI, 20 to 48%; P = 0.0209). At EoM, mean HbA1c decreased from 6.9% at baseline to 6.2% in patients with DM and from 5.5 to 5.3% in patients without DM. Mean fasting blood glucose decreased from 6.85 mmol/L (123.4 mg/dl) to 5.82 mmol/L (104.9 mg/dl) and from 5.11 mmol/L (92.1 mg/dl) to 4.66 mmol/L (84.0 mg/dl) in patients with and without DM, respectively. Adverse events that were more common in patients with DM included nausea (58.3%), vomiting (19.4%), and urinary tract infection (16.7%); none prompted study drug withdrawal.ConclusionsTreatment with levoketoconazole led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with DM.Clinical Trial Registration(ClinicalTrials.gov), NCT01838551.

Osteoporosis in rheumatic diseases is a very well-known complication. The possible combination of age-related bone loss, sarcopenia, potential frailty, reduced physical activity, joint deformities and increased risk of falls, systemic inflammatory disease, and glucocorticoid treatment, places elderly patients with rheumatic diseases at extremely high risk for osteoporotic fracture. All elderly patients with rheumatic diseases, regardless of other fracture risks, should be considered for non-pharmacological interventions. Elderly patients with previous fragility fracture, patients with osteoporosis, and patients with ongoing treatment with supra-physiological corticosteroid dosage should be candidates for pharmacological treatment. Elderly patients with osteopenia should be evaluated for clinical fracture risk in order to decide whether they should be treated pharmacologically. Bisphosphonates are often the first-line pharmacological treatment choice for osteoporosis in most countries, and the duration of treatment is an issue that should be considered carefully. Long-standing glucocorticoid treatment may lead to hypothalamic-pituitary-adrenal suppression, making patients steroid-dependent, and glucocorticoid cessation in these patients may lead to adrenal insufficiency. Here we propose a practical and simplified regimen for steroid withdrawal.

To examine statistical correlation between mSASSS and serum levels of testosterone in males suffering from AS.Ankylosing spondylitis (AS) is a chronic progressive inflammatory rheumatic disease primarily involving sacroiliac joints and spine. Structural damage, caused by AS, manifests with development of vertebral syndesmophytes and can be calculated as units of modified Spinal Ankylosing Spondylitis Syndesmophyte Score (mSASSS). The rate of growth of spinal syndesmophytes differs among individual AS patients, while male patients develop significantly more structural damage compared to females in general.Twenty males with AS known for at least 5 years (average disease duration 12.8 years) and aged between 25 to 40 years donated 5 ml of peripheral blood for serum testosterone assay, and underwent X-ray films of cervical and lumbar spine. The mSASSS was calculated and correlation with serum testosterone levels was examined using Pearson correlation test.The mSASSS values of patients included in the final analysis ranged from 0-14 units and testosterone levels ranged from 8.4-25.5 nmol/L. No significant correlation was found between mSASSS values and testosterone levels in this cohort.This study did not find statistical correlation between mSASSS and serum levels of testosterone in males suffering from AS.

Summary Purpose In order to differentiate between Cushing's syndrome (CS) and Pseudo-Cushing's syndrome, it is customary to use a test that is conducted by cortisol suppression with low-dose dexamethasone, followed by the administration of corticotropin releasing hormone (Dex-CRH test). In children with severe obesity, Dex-CRH test has shown a specificity of 55%. The aim of current study was to evaluate the specificity of Dex-CRH test in morbid obese adults. Methods The study included a total of 19 subjects with a body mass index (BMI) equal or higher than 40kg/m 2 . In all subjects Dex-CRH test was performed, and 24h urinary free cortisol was collected prior the test and during the second day of dexamethasone administration (2nd-day-UFC). Results BMI was 45.1±4.6kg/m 2 and 45.7±3.3kg/m 2 in women and men, respectively. 14 subjects underwent bariatric surgery. No subject had surgical or perioperative complications and surgically treated subjects had mean body weight loss of 46.5±16.6kg. All except for 2 subjects had normal Dex-CRH test, as 15-min cortisol falling below 1.4μg/dl. During follow-up, no subject gained additional weight, neither developed signs of CS. 15-min-cortisol concentration of 1.4μg/dl revealed a specificity of 89% and 2nd-day-UFC of 16μg/24h showed a specificity of 100%. Conclusions Morbid obesity in adults seems not to comprise a significant confounder in Dex-CRH test, and 15-min-cortisol concentration of 1.4μg/dl had a higher specificity than previously reported in obese children.

BACKGROUND Earlier research on 1 μg low-dose test (LDT) performed using 20.3 cm plastic IV tubing on healthy volunteers, has shown that afternoon testing was associated with a sevenfold increased likelihood of failing the test. Nevertheless, it has been claimed that subnormal cortisol response using plastic tubes might have resulted from cosyntropin adherence to the tube and, thus, loss of the delivered dosage. Following from our previous study, which showed that using a short (2.5 cm) plastic tube does not alter in-vitro-cosyntropin dosage delivery or healthy-volunteers' morning cortisol responses, we predicted that, when using the same short plastic tube, LDT would show comparable morning and afternoon cortisol stimulation. The current study was designed to investigate this prediction by comparing morning and afternoon cortisol responses in healthy volunteers during LDT, using a short plastic tube. METHODS Thirteen healthy adult volunteers were recruited for the study. Each subject underwent morning and afternoon LDT via 25 mm plastic intravenous line tube. Baseline serum cortisol (SC) in addition to SC and salivary free cortisol (SFC) 30-minute responses were determined. RESULTS Mean baseline morning SC concentration was higher in the morning than in the afternoon (13.63±3.42 and 9.18±2.78 μg/dL, respectively; P

Studies on 1 μg low-dose test showed that among 1 μg cosyntropin samples pushed through long IV plastic tubing, some adrenocorticotropic hormone dosage was not recovered, and in healthy volunteers it provided subnormal cortisol responses. The aim of the current study is to assess whether there is any loss in adrenocorticotropic hormone 1-24 concentration when pushed through a short plastic tube, and to assess serum and salivary cortisol responses in low-dose test among healthy volunteers, using a similar short plastic tube vs. direct intravenous consyntropin injection.We evaluated in vitro if adrenocorticotropic hormone was absorbed in a 2.5 cm plastic tube by measuring adrenocorticotropic hormone 1-24 concentration in a 1 μg/ml adrenocorticotropic hormone aliquot solution before and after being flushed through the plastic tube. For the in vivo study, we recruited 20 healthy adult volunteers. Each subject underwent low-dose test via 2.5 cm plastic tube via plastic tube and via direct intravenous injection by a metal syringe via direct intravenous injection, and cortisol responses were determined.Mean adrenocorticotropic hormone 1-24 concentration did not differ significantly when flushed via plastic tube or measured in the aliquot solution (P = 0.25). In vivo, mean 30-min serum cortisol concentrations were 20.47 ± 2.87 and 21.62 ± 3.89 μg/dl in via plastic tube and in via direct intravenous injection tests, respectively, and did not show a significant difference (P = 0.16).In low-dose test, using a 2.5 cm plastic tube ensures completeness of the intravenous adrenocorticotropic hormone injection dosage and provides equivalent cortisol responses.

Heterophilic antibodies are well described, but poorly appreciated interferents and is often not a recognized problem affecting most immunoassays. We report a patient presented with ectopic Cushing’s syndrome (CS), but repeated plasma adrenocorticotropic hormone (ACTH) concentrations conducted by immunoassay were inappropriately within the reference range and not elevated, most probably as a result of antibody interference. A 36-year-old woman, presented with large gastric neuroendocrine carcinoma and severe ectopic CS, while repeated plasma ACTH concentrations conducted by immunoassay were inappropriately within the reference range. As we expected ACTH concentration to be higher, we performed several tests to evaluate whether there was any assay interference causing falsely lower than expected ACTH results. We measured ACTH using a different immunoassay, assayed the sample in dilution, assayed the sample after being incubated in heterophilic antibody blocking agent tube and performed recovery studies. Tests indicated the presence of interfering compounds, most probably heterophilic antibodies. When clinicians find ACTH concentrations to be lower than expected, we recommend the laboratory investigate antibody interference.

OBJECTIVE: Cushing’s disease during pregnancy is associated with an increased risk for maternal and fetal complications. In recurrent Cushing’s disease following transsphenoidal surgery, and when re-operation is not feasible, medical treatment is usually considered. Cabergoline was found to be effective in reducing hypercortisolism in Cushing’s disease. Evolving data concerning the safety of cabergoline use during pregnancy show no significant increase in the rate of complications during pregnancy or the postnatal period. METHODS: We report a 29-year-old woman, gravida 0, para 0, with recurrent Cushing’s disease, three years after transsphenoidal resection of pituitary ACTH-secreting macroadenoma. Repeated MRI revealed an empty sella with a small gadolinium-enhancing lesion, suspected to be an adenoma remnant on the medial wall of the right cavernous sinus. As the patient was not willing to undergo repeat surgical intervention, treatment with cabergoline was initiated, with a gradual dose titration up to 3.5 mg/week. Clinical improvement ensued, and 4 months later, she conceived spontaneously. After discussing treatment options with the patient, cabergoline treatment at a dose of 2 mg/week was continued throughout pregnancy. RESULTS: The patient showed complete clinical remission during pregnancy. Consecutive tests of 24-h urinary free Cortisol concentration were not found to be elevated. Pregnancy and delivery were uneventful except for mild hypothyroidism observed during the second trimester. At full term the patient delivered a healthy female infant, by an elective cesarean section. CONCLUSION: This case report demonstrates that cabergoline may be an effective and safe therapeutic option for the treatment of Cushing’s disease during pregnancy.

Cushing's syndrome results from prolonged and excessive exposure to medically prescribed corticosteroids, or from excess endogenous cortisol secretion. When endogenous cortisol secretion is suspected, several screening tests are conducted in order to confirm or to rule out the diagnosis. In recent years, as the cut-off point of cortisol concentration on the 1 mg overnight dexamethasone suppression test was lowered, the prevalence of Cushing's syndrome has increased, and more cases of mild syndromes, with negative results on one or more screening tests, have increasingly been reported. In this paper, we will describe the various screening tests used for Cushing's syndrome, and will discuss their degree of sensitivity in the diagnosis of mild cases. We conclude that, in cases of mild syndromes, the sensitivity of some tests appears to be notably lower than has been reported. Until recently, the major challenge has been to distinguish between pseudo-Cushing's states and Cushing's syndrome. Today, however, the challenge has become to avoid misdiagnosis of mild cases, presenting with normal results on some screening tests. The sensitivity of urinary free cortisol seems to be lower than previously reported. Therefore, we recommend not to rely solely on this test in ruling out Cushing's syndrome.

The 250 microg adrenocorticotropin test (high-dose test) is the most commonly used adrenal stimulation test, though the use of physiologic doses (1.0 microg or 0.5 microg/1.73 m) (low-dose test) has recently gained wider acceptance. These variants and the use of adrenocorticotropin test in the ICU, however, remain controversial. The validity of the low-dose test and the parameters for evaluation of high- and low-dose tests in different situations need reevaluation.In the last few years, numerous studies have used the low-dose test as a single test following previous findings that it is more sensitive and accurate than the high-dose test. It is used mainly in secondary adrenal insufficiency and after treatment with therapeutic glucocorticosteroids to define hypothalamo-pituitary-adrenal suppression. Unless there is a very recent onset of disease, the results are interpreted by most researchers as diagnostic. The treatment of relative adrenal insufficiency, based on delta cortisol, has not yielded proof of correlation between this diagnosis and better prognosis with glucocorticoid treatment.For interpretation of an adrenocorticotropin test, only peak - and not delta - cortisol should be used. The use of 240-300 mg of hydrocortisone daily in ICU patients, including septic shock, should be considered as pharmacologic, rather than as a replacement dose. Using the low-dose test for this purpose will lead to further misdiagnosis.

A 54-year-old woman presented with a stalk mass that was discovered incidentally with mild visual fields defect. The mass was operated surgically by the fronto-temporal approach, and histology met the diagnosis of neurohypophesial granular cell tumor (GCT). After surgery, the patient suffered from an irreversible severe bi-temporal visual deficit and an irreversible hypopituitarism. We review the literature and discuss the clinical nature of GCTs, treatment options and outcome. In an effort to avoid the severe complications that may result from surgical removal of neurohypophesial GCT, we discuss also the possibility of choosing the conservative approach with close follow-up. The tumor's firm consistency, tendency to hemorrhage, involving the pituitary stalk and lack of dissection plane from basal brain structure render surgery difficult, and maximal resection often requires sacrificing the stalk. Moreover, small asymptomatic neurohypophysial GCTs are common findings, most probably benign tumors with slow growing nature. Hence, for a neurohypophesial tumor which is suspected to be a GCT, we offer to consider the alternative approach, with close clinical, visual field and radiological study follow up.

AIM: To describe disease characteristics and treatment modalities in a group of rare patients with metastatic gastric carcinoid type 1 (GCA1). METHODS: Information on clinical, biochemical, radiological, histopathological findings, the extent of the disease, as well as the use of different therapeutic modalities and the long-term outcome were recorded. Patients’ data were assessed at presentation, and thereafter at 6 to 12 monthly intervals both clinically and biochemically, but also endoscopically and histopathologically. Patients were evaluated for the presence of specific symptoms; the presence of autoimmune disorders and the presence of other gastrointestinal malignancies in other family members were also recorded. The evaluation of response to treatment was defined using established WHO criteria. RESULTS: We studied twenty consecutive patients with a mean age of 55.1 years. The mean follow-up period was 83 mo. Twelve patients had regional lymph node metastases and 8 patients had liver metastases. The primary tumor mean diameter was 20.13 ± 10.83 mm (mean ± SD). The mean Ki-67 index was 6.8% ± 11.2%. All but one patient underwent endoscopic or surgical excision of the tumor. The disease was stable in all but 3 patients who had progressive liver disease. All patients remained alive during the follow-up period. CONCLUSION: Metastatic GCA1 carries a good overall prognosis, being related to a tumor size of ≥ 1 cm, an elevated Ki-67 index and high serum gastrin levels.

We present a case of adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome diagnosed in a patient in the third trimester of her pregnancy, with an adrenal mass observed on imaging studies. Laparoscopic adrenalectomy was performed successfully at 32 weeks. To the best of our knowledge, this is the latest gestational age at which laparoscopic adrenalectomy has been reported. We present the various considerations for determining the surgical approach and the optimal timing for surgery. Adrenalectomy during pregnancy for the treatment of Cushing's syndrome caused by adrenocortical adenoma has been reported in 23 patients in the English-language medical literature to date and seems safe and beneficial. According to the data, surgical treatment has led to a reduction in perinatal mortality and maternal morbidity rates, but has not affected the occurrence of preterm birth and intrauterine growth restriction. The best outcome can be achieved by a multidisciplinary approach, with a team comprising a maternal–fetal medicine specialist, an endocrinologist and a surgeon. The timing of surgery and the surgical approach need to be determined according to the surgeon's expertise, the severity of the condition, the patient's preferences, and gestational age. Laparoscopy may prove to be the preferred surgical approach. The small number of cases precludes providing evidence-based recommendations.