Nutritional and Metabolic Diseases

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Epinephryl borate

Surgery to remove tumor when enrolled in the protocol.

Adrenalectomy

Observation for 6 months prior to surgery

Observation

Dhaval T Patel, M.D.

Background:

- Adrenal tumors are a common kind of tumor. Some of these secrete extra cortisol into the body, which can lead to diabetes, obesity, and other diseases. Some people with extra cortisol will show symptoms like bruising and muscle weakness. Others will show no signs. This is called subclinical hypercortisolism. Some of these adrenal tumors become malignant. Researchers want to know the best way to treat people with subclinical hypercortisolism. They want to know if removing the tumor by surgery reduces the long-term effects of the disease.

Objectives:

- To see if removing an adrenal tumor by surgery improves blood pressure, diabetes, obesity, osteoporosis, or cholesterol, and cancer detection.

Eligibility:

- Adults 18 and older with an adrenal tumor and high cortisol levels.

Design:

* Participants will be screened with medical history, blood tests, and a computed tomography (CT) scan.
* Participants will have a baseline visit. They will have blood and urine tests and 7 scans. For most scans, a substance is injected through a tube in the arm. Participants will lie still on a table in a machine that takes images.
* Participants will have surgery to remove their tumor. Some will have surgery right away. Some will have surgery 6 months later, after 2 follow-up appointments.
* Participants will have 4 follow-up visits in the first year after surgery. They will have 2 visits the second year, then yearly visits for 3 years. At each follow-up visit, they will have scans and blood tests.

Background:

* Adrenal incidentalomas are common and found in approximately 4-7% of the population.
* About 0.6 to 25% of patients with an adrenal incidentaloma are found to have subclinical hypercortisolism: 2.3% develop subclinical hypercortisolism during follow up and 0.6% develop clinical hypercortisolism during follow up.
* Subclinical hypercortisolism is defined as biochemical excess of cortisol without signs and symptoms of overt hypercortisolism but may be associated with metabolic complications or disease progression and malignancy.
* Overt signs and symptoms of hypercortisolism include facial plethora, easy bruising, violaceous striae, and proximal muscle weakness.
* Several studies suggest that subclinical hypercortisolism may lead to long term consequences such as diabetes, hypertension, hypercholesterolemia, obesity, and osteoporosis.
* Thus, patients with subclinical hypercortisolism may benefit from operative intervention to halt or reverse metabolic complications associated with the disease and the risk of malignant progression.
* The optimal management of patients with subclinical hypercortisolism and adrenal incidentalomas is controversial and no large randomized trial has been conducted.
* We hypothesize that operative treatment would reduce the risk of long term complications of subclinical hypercortisolism and malignant progression, and propose a prospective randomized trial comparing nonoperative and operative management of subclinical hypercortisolism in patients with an adrenal neoplasm.

Objectives:

Primary Endpoints:

-To determine whether unilateral adrenalectomy in patients diagnosed with subclinical hypercortisolism and adrenal neoplasm results in normalization and/or improvement of hypertension as assessed by reduction in pharmacotherapy and/or normalization of blood pressure (systolic pressure \<=140 and diastolic pressure \<=90), diabetes as assessed by reduction or elimination of pharmacotherapy and/or improvement in A1C to \<6.5%, osteoporosis by increase in bone formation markers indicative of increased bone formation, hypercholesterolemia as assessed by a reduction or elimination of pharmacotherapy and/or reduction in low density lipoprotein (LDL) levels to risk-stratified goal levels as defined by Adult Treatment Panel III (ATP III), and/or overweight or obesity as assessed by a 10 percent reduction in weight at 6 months.

Eligibility:

* An individual with an adrenal neoplasm less than 5 cm in size with biochemically confirmed evidence of hypercortisolism (2 out of 3: dexamethasone suppression test (DST) \>3 mcgl/dL, elevated urine free cortisol, and/or morning adrenocorticotrophic hormone (ACTH) \<2.2 pmol/l) without overt clinical signs and symptoms.
* Age greater than or equal to 18 years.
* Adults must be able to understand and sign the informed consent document.
* Patients must have laboratory and physical examination parameters within acceptable limits based on standard clinical practice.

Design:

* Prospective randomized study comparing adrenalectomy versus observation.
* Patients assigned to the operative arm will undergo adrenalectomy and then followed postoperatively for normalization and/or improvement of metabolic complications associated with hypercortisolism and histologic examination of the resected tumor.
* Patients assigned to the non-operative arm will be monitored for possible complications associated with hypercortisolism for six months, at which point they will cross-over to the operative intervention arm.
* Patients with bilateral adrenal neoplasms will have the larger adrenal neoplasm used as the primary lesion responsible for subclinical hypercortisolism.
* Demographic, clinical, laboratory and pathologic data will be collected for each patient participant. Data will be securely stored in a computerized database.
* Patients will have biochemical testing to determine if their adrenal neoplasm is functioning or nonfunctioning.
* Projected accrual will be 15 to 20 patients per year for a total of 5 years. Thus, we anticipate accruing 62 patients on this protocol.

Study of Adrenalectomy Versus Observation for Subclinical Hypercortisolism

Randomized Control Trial of Adrenalectomy Versus Observation for Subclinical Hypercortisolism

Normalization and/or improvement of metabolic complications including hypertension, diabetes, osteoporosis, hypercholesterolemia and/or obesity after adrenalectomy is defined as 35% of patients who improve with surgery versus 5% who do not have surgery.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Patients who were tested for and found to have adrenal cancer after adrenalectomy.

Proportion of patients who were diagnosed with subclinical hypercortisolism by FDG/PET/CT scan.

An assessment of whether 1 mg dexamethasone suppression test, basal adrenocorticotropic hormone (ACTH), midnight salivary cortisol, or urinary free cortisol is the optimal test to diagnose patients with subclinical hypercortisolism.

QOL questionnaires were provided to participants to assess well being pre and post operatively. Participants take a self-administered questionnaire to assess physical and mental health according to Cushing's Quality of Life Questionnaire. The score has a minimum of 12 and maximum of 60. A higher score indicates an improved quality of life.

Proportion of patients that developed deep venous thrombosis with subclinical hypercortisolism regardless of whether the participants received adrenalectomy or not.

A skin biopsy and skin ultrasound were done to measure the dermal layer of skin to look for a decrease in the thickness of skin as compared to normal values reported in the literature as measured in millimeters of thickness. Diagnostic sensitivity and changes in skin thickness were assessed.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Clinical Center Office of the Associates Director for Radiologic&Imaging Sciences

National Cancer Institute (NCI)

Principal Investigator

No toxicities were experienced by any participants on this trial.

operative arm

Adrenalectomy: Surgery to remove tumor when enrolled in the protocol.

Operative Arm

delayed operative arm

Observation: Observation for 6 months prior to surgery

Delayed Operative Arm

Delayed Operative Arm Followed by Surgery

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Dhaval Patel

Proportion of Patients That Have Normalization and/or Improvement of Metabolic Complications After Adrenalectomy

Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)

Proportion of Patients Who Are Found to Have Adrenal Cancer After Adrenalectomy

Proportion of Patients Who Were Diagnosed With Subclinical Hypercortisolism by Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)/Computed Tomography (CT) Scan

This outcome measure was not done. Data was collected and not analyzed because we were not able to determine the optimal test since we only had four patients enrolled, and three patients on study (e.g. low accrual). Therefore, we couldn't do a head to head comparison calculating the sensitivity and specificity.

To Determine the Optimal Diagnostic Test for Subclinical Hypercortisolism

Proportion of Patients That Have Improvement in Quality of Life (QOL) After Adrenalectomy Compared to Medical Therapy

Proportion of Patients That Developed Deep Venous Thrombosis With Subclinical Hypercortisolism

Correlation Between Dermal Thickness and Patients With Subclinical Hypercortisolism

Overall Study

Adenoma

Adrenal Cortex Neoplasms

Adrenal Cortex Diseases

Oculocerebral Syndrome With Hypopigmentation

Other Dietary Supplements

Hormones

Adrenocorticotropic Hormone

Melanocyte-Stimulating Hormones

beta-Endorphin

Dehydroepiandrosterone

DHEA (Dehydroepiandrosterone)

patients diagnosed with subclinical hypercortisolism as assessed by an endocrinologist.

patients diagnosed with nonfunctional adrenal adenoma as assessed by an endocrinologist.

DHEAS.24h-UFC,ACTH and cortisol are measured in the experimental group

experimental group

Dalong Zhu, MD,PhD

Ping Li, MD,PhD

The purpose of this study is to evaluate the serum dehydroepiandrosterone sulfate in subclinical hypercortisolism

In the past few years, with the widespread use of chest and abdominal imaging, the prevalence of adrenal incidentaloma (AIs) has been increasing and now approaches the 8.7% incidence reported in autopsy series. subclinical hypercortisolism (SH) is noted in up to 30% of patients with adrenal incidentalomas. Several groups have reported adverse clinical sequelae in individuals with SH, with recent studies highlighting an increase in cardiovascular morbidity and mortality compared to the general population. Accurate exclusion or confirmation of a diagnosis of SH is therefore a key step in the investigation and management of patients with AIs. Suppressed adrenocorticotropic hormone (ACTH) and low dehydroepiandrosterone sulfate (DHEAS) levels are frequently found in SH patients. Present study added new evidence for the limitations of ACTH and confirmed the usefulness of DHEAS for the detection of SH especially with unsuppressed ACTH in AI patients. On one hand, in the cross-sectional study, biometric measurements and sex hormones (including DHEAS, 24h-UFC, ACTH and cortisol) are analysed to explore the differences among SH patients, and nonfunctional adrenal adenoma patients. One the other hand, in the longitudinal study, changes in DHEAS, ACTH and cortisol in SH with surgical management and SH with conservative management both at baseline and different follow-up months after their different treatment management are collected to explore the changes of DHEAS and ACTH of SH patients.

Evaluation of New Diagnostic Indicator of Subclinical Hypercortisolism

The Cross-sectional Study and Longitudinal Study of the Diagnostic Efficiency of Serum Dehydroepiandrosterone Sulfate in Subclinical Hypercortisolism

age in years and sex (female or male) of patients

BMI(body mess index) in kg/m\^2= (weight in kg) /(height in m)\^2

plasma ACTH in pmol/L at 8:00 am, 16:00 pm and 24:00 midnight

serum cortisol in nmol/L at 8:00 am, 16:00 pm and 24:00 midnight measured on the same day as plasma ACTH

Dexamethasone 1mg (0.75mg/ tablet, 1.5 tablets) was taken orally at 24:00 midnight, and plasma ACTH in pmol/L and serum cortisol in cortisol levels were measured by blood sample at 8:00 the next day

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Chief Physician

Immune System Diseases

Hypersensitivity

Glucocorticoids

adrenalectomy

Iacopo Chiodini, Professor

Subclinical hypercortisolism (SH) is a status of asymptomatic hypercortisolism, frequently found in patients with adrenal adenomas (estimated prevalence: 0.8-2% after 60 years of age). Although SH may lead to diabetes, hypertension and osteoporosis, the diagnostic SH criteria and those suggesting the need of adrenalectomy are debated. Indeed, beside the cortisol secretion, the individual cortisol sensitivity may play a role in determining the SH consequences.

Subjects with possible SH due to adrenal adenoma will be randomized to surgery/conservative follow up. The effects of surgery on the cardiovascular, bone, metabolic complications of SH and on neuropsychological aspects and quality of life (QoL) and the possibility to predict them by using cortisol sensitivity and secretion markers will be studied. The study may clarify how to individuate patients who can benefit from surgery. These results will help reducing the costs of both useless surgical operations and SH consequences.

Subclinical hypercortisolism (SH) is a status of asymptomatic hypercortisolism, which is present in up to the 30% of patients with incidentally discovered adrenal adenomas (adrenal incidentalomas, AI). Since AI are present in 7-10% of individuals after 60 years of age, the estimated SH prevalence in this population is 0.8-2%. In patients with SH due to an adrenal adenoma the risk of diabetes, hypertension, cardiovascular events, osteoporosis and mortality seems to be increased, and monolateral adrenalectomy beneficial. However, no randomized studies evaluated the effects of surgery on SH consequences and established the criteria indicating the need of surgery itself. Thus, in many patients the SH diagnosis is uncertain and the best approach (surgical or conservative) unknown. These uncertainties are also due to the influence of the individual glucocorticoid (GC) sensitivity. Indeed, in the single individual the various polymorphisms of GC receptor (GR) and the different 11ß-hydroxysteroid-dehydrogenase type 2 enzyme (11HSD2) activity, regulating the tissue exposure to the active GC, may differently predispose to the consequences of GC excess. Therefore, in AI patients, beside the evaluation of the degree of the cortisol hypersecretion, the assessment of the cortisol sensitivity may be useful in establishing the individual risk of SH consequences and the possible usefulness of a surgical approach.

Specific Aim:

In AI subjects with uncertain SH the combined evaluation of the clinical features together with the parameters of cortisol secretion and sensitivity will consent to decide which patient has the greatest probability to ameliorate after surgery.

1. To assess the variation of blood pressure control, lipids and glucose metabolism, vascular damage, bone mineral density (BMD), clinical and morphometric vertebral fractures, body composition, coagulation parameters, neuropsychological aspects and quality of life (QoL) in AI patients with uncertain SH after the surgical removal of the adrenal mass or after a conservative treatment.
2. To assess in AI patients and uncertain hypercortisolism the effect of the surgical and conservative approach on cardiovascular, metabolic and bone manifestations, neuropsychological aspects and quality of life (QoL), in relation to the degree of cortisol secretion and sensitivity.
3. To establish the best clinical-biochemical criteria for diagnosing SH, on the basis of the changes of the outcomes after the surgical or conservative approach, and therefore, for addressing the treatment of choice in the individual patient with AI.

Methods. During the enrollment period (24 months), all patients between 40 and 75 years of age referred for unilateral AI larger than 1 cm will be evaluated.

In all subjects, adrenocorticotroph hormone (ACTH), urinary free cortisol (UFC), cortisol after 1-mg overnight dexamethasone suppression test (1mgDST) and the GR polymorphisms of N363S, BclI and ER22/23EK will be assessed. Patients with 1mgDST \>1.8 mcg/dL will undergo a low dose (2 mg for 2 days) dexamethasone suppression test (LDDST). Patients with 1mgDST and LDDST \>5 mcg/dL and suppressed (\<5 pg/mL) ACTH levels will be excluded as affected by biochemically overt hypercortisolism, that requires surgery. AI patients with 1mgDST or LDDST \<1.8 mcg/dL will be excluded as certainly not affected with SH. AI patients with AI \>5 cm will leave the study as in this case surgery is mandatory.

Eventually, after the enrollment period, 54 AI patients with uncertain SH will be included and randomized to surgery (Group1) or conservative treatment (Group 2). The follow-up period will last 24 months (after withdrawal of GC substitution therapy, if needed, for Group 1). Group 1 patients will undergo laparoscopic or laparotomic adrenalectomy, depending on the AI size and their clinical characteristics.

Evaluations at baseline, 6, 12 and 24 months: blood pressure (BP), body weight (BW), body mass index (BMI), waist circumference, glucose, lipid and coagulation parameters, body composition and adenoma size by CT (Group 2 patients).

Group 2 patients with a \>1 cm adenoma increase or appearance of overt SH will leave the study. At baseline and after 24 months, bone mineral density (BMD) and quality (by trabecular bone score, TBS), vertebral fractures (VFx), carotid atherosclerosis, neuropsychological aspects and QoL, will be assessed.

The patients will be defined: i) obese, in the presence of BMI \>30 kg/m2; ii) hypertensive in the presence of systolic BP \>130 mmHg and/or diastolic BP \>85 mmHg and/or any antihypertensive treatment; iii) diabetic, in the presence of the World Health Organization criteria, and/or any hypoglycemic drug, iv) dyslipidemic, in the presence of triglyceride levels \>150 mg/dl or high-density lipoprotein (HDL) cholesterol levels \<40 or 50 mg/dl in males and females, respectively.

The improvement/worsening during follow-up will be defined as follows: for obesity in the presence of a \>5% BW decrease/increase, for hypertension if the non-hypertensive patients passed from a pre-hypertension category to another or the hypertensive patients from a hypertension grade to another; for diabetes and dyslipidemia if fasting glucose and cholesterol levels pass from a category to another, respectively, following the Adult Treatment Panel III criteria.

The efficacy of the surgical and conservative approach on the basis of the changes of BP, BW, glucose and lipid control, BMD, VFx incidence (primary outcomes) will be compared. The effect of surgery on the coagulation parameters, carotid atherosclerosis, body composition, neuropsychological aspects and QoL (secondary outcomes) will be also evaluated.

At baseline, and at 6, 12 and 24 months, beside ACTH, 1mgDST and UFC, the midnight salivary cortisol (MSalC) and urinary free cortisone (UFCo) levels and the UFC/UFCo ratio (index of 11HSD2 activity) will be assessed In Group 1 and Group 2 patients the association between the changes of the primary and secondary outcomes with the cortisol secretion parameters and the presence/absence of GC sensitizing GR polymorphisms and the degree of 11HSD2 activity, will be evaluated.

An algorithm for predicting the effect of the surgical or conservative approach on the primary outcomes in the individual AI patient with uncertain SH. The algorithm, based on the combination of the SH complications at baseline (hypertension, osteoporotic fractures, diabetes) with the presence/absence of GC sensitizing GR polymorphisms, degree of 11HSD2 activity and parameters of cortisol secretion, will be retrospectively tested on the study population, will be elaborated. This would consent to evaluate positive and negative predictive value of the algorithm for predicting the response to surgery in the individual patient with AI.

Effect of Surgical or Conservative Approach in Patients With Adrenal Incidentalomas

Effect of Surgical or Conservative Approach in Patients With Adrenal Incidentalomas on Cardiovascular, Metabolic, Neuropsychological and Bone Manifestations: Respective Roles of Cortisol Secretion and Glucocorticoid Sensitivity

To assess the variation of blood pressure ambulatory systolic and diastolic blood pressure (BP, mmHg), and antihypertensive treatment at baseline and follow-up will be assessed; BP will be considered improved or worsened if the non-hypertensive patients passed from a pre-hypertension category to another or the hypertensive patients from a hypertension grade to another in accordance to giudelines, of if if antihypertensive treatment was reduced by 50%

To assess the variation of glucose levels, fasting glucose levels and glucose levels after oral glucose tolerance test will be evaluated at baseline and follow-up. Glucose levels will be considered improved or worsened if fasting glucose levels pass from a category to another, following the Adult Treatment Panel III criteria or if antidiabetic treatment was reduced by 50%

At baseline and follow up triglyceride levels; total cholesterol levels, HDL and LDL levels (mg/dl) will be evaluated. Dyslipidemia will be diagnosed in the presence of triglyceride levels \>150 mg/dl or high-density lipoprotein (HDL) cholesterol levels \<40 or 50 mg/dl in males and females. dyslipidemia will be defined improved or worsened if cholesterol levels pass from a category to another, following the Adult Treatment Panel III criteria

At baseline and follow up body weight (kilograms) will be evaluated. the improvement/worsening during follow-up will be defined in the presence of a \>5% BW decrease/increase

To assess the variation of bone mineral density at baseline and follow-up a Dual-energy X-ray absorptiometry (DXA) scan will be performed

A dorso-lumbar spine x-ray to evaluate the presence of morphometric fractures (presence/absence) will be performed

To assess the variation of vascular damage a supra-aortic trunk echo-Doppler to evaluate at baseline and follow-up variations of intimal medial thickness will be performed

the variation of Relative wall thickness (RWT) will be evaluated by an echocardiography. It will be calculated from Left ventricular end diastolic dimension (LVEDD) (mm); Interventricular septal end diastole (IV Sd, mm) and Posterior wall thickness at end-diastole (PWd) parameters (mm)

Sheehan Disability Scale will be evaluated to assess perceived stress (SDS-stress scale ranges 1-10, a higher score means higher levels of stress)

BACS evaluate verbal memory score (normal if \>33); working memory (normal if \>14.9); verbal fluency (normal if \>31.6), symbol coding (normal if \>40.5), tower of london (\>12.4)

To correlate the effect of the surgical and conservative approach in relation to the degree of cortisol secretion and sensitivity we will evaluate the GR polymorphisms of N363S, BclI and ER22/23EK ,midnight salivary cortisol (MSalC) and urinary free cortisone (UFCo) levels and the UFC/UFCo ratio (index of 11HSD2 activity)

irisine, Tumor Necrosing Factor (TNF)- alpha, interleukin (IL)-6, adiponectin, resistin, sclerostin, Dickkopf-related protein (DKK) 1, N-terminal propeptide of type 1 collagen (P1NP) , monocytechemoattractant protein 1 (CCL2/MCP-1) levels will be assessed (pg/ml). Paired samples T-test will be used to compare baseline and follow-up levels.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Adrenalectomy Versus Observation for Subclinical Hypercortisolism	NCT02001051	Subclinical Hyp... Cushing Syndrom... Adrenal Neoplas...	Adrenalectomy Observation	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
Evaluation of New Diagnostic Indicator of Subclinical Hypercortisolism	NCT04833192	Adrenal Inciden... Subclinical Hyp...	experimental gr...	18 Years - 75 Years	The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Effect of Surgical or Conservative Approach in Patients With Adrenal Incidentalomas	NCT04860180	Adrenal Inciden... Subclinical Hyp...	adrenalectomy	18 Years - 75 Years	Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Effect of Surgical or Conservative Approach in Patients With Adrenal Incidentalomas	NCT04860180	Adrenal Inciden... Subclinical Hyp...	adrenalectomy	18 Years - 75 Years	Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Evaluation of New Diagnostic Indicator of Subclinical Hypercortisolism	NCT04833192	Adrenal Inciden... Subclinical Hyp...	experimental gr...	18 Years - 75 Years	The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

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