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MaryO

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  1. Presented by

    Varun Kshettry, MD
    Director, Advanced Endoscopic & Microscopic Neurosurgery
    Cleveland Clinic Lerner College of Medicine

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    Date: Tuesday, February 18, 2020 
    Time: 10:00 AM - 11:00 AM Pacific Standard Time, 1:00 PM - 2:00 PM Eastern Standard Time

    Learning Objectives:

    Discuss patient expectations for pituitary surgery and recovery
    Discuss best practices to minimize risk of complications
    What questions to ask your medical providers

    Presenter Bio

    Dr. Varun R. Kshettry, a neurosurgeon specializing in skull base and pituitary disorders at the Cleveland Clinic. He is also the director of the Advanced Endoscopic & Microscopic Neurosurgery Laboratory. He is an assistant professor of neurosurgery at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr. Kshettry received his BA in philosophy at the University of Pennsylvania. He earned his medical degree from Northwestern University. He completed his residency training at the Cleveland Clinic, during which he performed a research fellowship in skull base & microsurgical anatomy at Ohio State University. He then performed a clinical fellowship in minimally invasive cranial base & pituitary surgery at Thomas Jefferson University under Dr. James Evans. Dr. Kshettry has authored more than 100 peer-reviewed publications and book chapters and is an editor for a book entitled Endoscopic and Keyhole Cranial Base Surgery. He serves as an editor or reviewer for multiple neurosurgical journals. He serves on the Value-Based Healthcare Committee for the North American Skull Base Society. He serves as faculty director for the Cleveland Clinic Pituitary Tumor Board and is an investigator in several multi-center pituitary clinical trials. Dr. Kshettry collaborates closely with pituitary endocrinologists, neuro-ophthalmologists, otolaryngologists, pituitary pathologists, and radiation oncologists for multi-disciplinary care for patients with pituitary diseases.

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    Published: 

    Abstract

    Background

    Primary aldosteronism (PA) plus subclinical Cushing’s syndrome (SCS), PASCS, has occasionally been reported. We aimed to clinically characterize patients with PASCS who are poorly profiled.

    Methods

    A population-based, retrospective, single-center, observational study was conducted in 71 patients (age, 58.2 ± 11.2 years; 24 males and 47 females) who developed PA (n = 45), SCS (n = 12), or PASCS (n = 14). The main outcome measures were the proportion of patients with diabetes mellitus (DM), serum potassium concentration, and maximum tumor diameter (MTD) on the computed tomography (CT) scans.

    Results

    The proportion of DM patients was significantly greater in the PASCS group than in the PA group (50.0% vs. 13.9%, p <  0.05), without a significant difference between the PASCS and SCS groups. Serum potassium concentration was significantly lower in the PASCS group than in the SCS group (3.2 ± 0.8 mEq/L vs. 4.0 ± 0.5 mEq/L; p <  0.01), without a significant difference between the PASCS and PA groups. Among the 3 study groups of patients who had a unilateral adrenal tumor, MTD was significantly greater in the PASCS group than in the PA group (2.7 ± 0.1 cm vs. 1.4 ± 0.1 cm; p <  0.001), without a significant difference between the PASCS and SCS groups.

    Conclusions

    Any reference criteria were not obtained that surely distinguish patients with PASCS from those with PA or SCS. However, clinicians should suspect the presence of concurrent SCS in patients with PA when detecting a relatively large adrenal tumor on the CT scans.

    Background

    Primary aldosteronism (PA), an adrenocortical disorder caused by an adrenal tumor that overproduces aldosterone, accounts for 5 to 15% of patients with hypertension [1]. Cushing’s syndrome (CS), an endocrinopathy resulting from the prolonged, excessive adrenocortical secretion of cortisol, falls roughly into the following 2 categories: adrenocorticotropic hormone (ACTH)-dependent CS and ACTH-independent CS; the former includes Cushing’s disease that is primarily caused by a pituitary ACTH-secreting tumor and ectopic ACTH syndrome resulting from extrapituitary ACTH-secreting tumors (eg, bronchial carcinoid) [2], while the latter is usually caused by unilateral adenomas or carcinomas that provoke the autonomous adrenal cortical secretion [3]. Subclinical Cushing’s syndrome (SCS), an ill-defined endocrine disorder leading to the ACTH-independent secretion of cortisol from an adrenal adenoma that is not fully restrained by pituitary feedback [4], is known to cause hypertension, glucose intolerance, and dyslipidemia [5].

    The concurrence of clinically overt hyperaldosteronism and subclinical hypercortisolism is rare in PA patients [6]. To date, a few number of studies have examined the clinicopathological features of patients with PA plus SCS (PASCS), the incidences of which have ranged between about 10 and 20% [78]. Lower plasma ACTH levels and a greater tumor size were found in patients with PASCS than in patients with PA alone [8]. In the clinical settings, we rarely encounter PASCS patients who show a small adrenal tumor on the computed tomography (CT) scans and/or do not have a low plasma ACTH level in blood samples collected in the early morning. To examine the clinical features of PASCS patients in the present study, we compared clinical, laboratory, and imaging characteristics among patients with PA, SCS, or PASCS.

    Methods

    Patients

    We conducted a population-based, retrospective, single-center, observational study in 187 patients (119 with PA, 54 with SCS, and 14 with PASCS) at Saitama Medical University Hospital, Saitama, Japan, between January 1999 and December 2016. Hypertensive patients with suspected PA or SCS, as well as normotensive or hypertensive patients with an adrenal incidentaloma were referred to our hospital. A total of 116 patients were excluded from the study: 31 who were diagnosed with PA or SCS only because tests required to definitely diagnose these endocrinopathies were not conducted; 61 who failed to meet the new Japanese diagnostic criteria of SCS [9]; 1 who failed to meet the new Korean diagnostic criteria of subclinical hypercortisolism [10]; and 23 who failed to meet the Japanese [11] and United States [12] diagnostic criteria of PA. Therefore, we investigated 71 patients who were definitely diagnosed with PA and/or SCS (45 with PA, 12 with SCS, and 14 with PASCS). This study was approved by the institutional review board of Saitama Medical University. Patients provided written informed consent to the use of their clinical and laboratory data in the study.

    Diagnosis of PA and SCS

    Hormones required for the diagnosis of PA and SCS were assayed according to the procedures described in the pertinent guidelines [911]. Serum cortisol and plasma ACTH levels were determined by electrochemiluminescence immunoassay, plasma aldosterone concentration (PAC) and plasma renin activity (PRA) by radioimmunoassay, and serum dehydroepiandrosterone sulfate (DHEAS) level by chemiluminescent enzyme immunoassay (SRL Inc., Tokyo, Japan). Blood samples were collected in the early morning (7 a.m. to 9 a.m.). PA was suspected when detecting elevated PAC (≥ 150 pg/mL), low PRA (≤ 1.0 ng/mL/hr), and/or the elevated aldosterone-to-renin ratio (> 200). We conducted the following 3 challenge tests in accordance with the Japanese guidelines of PA [11]: captopril challenge test, furosemide upright posture challenge test, and ACTH challenge test. PA was diagnosed when at least 1 of these 3 challenge tests afforded results compatible with the disease. Furthermore, we also referred to the American guideline of PA [12] for selecting only patients who met the diagnostic criteria for PA. Prior to the confirmatory tests, patients had not received any antihypertensive drugs for at least 2 weeks except for those with severe hypertension treated with calcium-channel blockers and/or α-blockers. Adrenal venous sampling (AVS), whose usefulness was well documented in the Japanese and United States guidelines [11,12,13], was conducted in all of patients who had PA or PASCS to make the differential diagnosis of uni- or bilateral aldosterone hypersecretion.

    The low-dose (1-mg) dexamethasone suppression test (DST) and the corticotropin-releasing hormone (CRH) challenge test were conducted, and the diurnal rhythms of cortisol were also determined—all for the diagnosis of SCS. Moreover, the high-dose (8-mg) DST was also conducted to rule out ACTH-dependent CS. Test results were assessed in accordance with the diagnostic criteria advocated by the Japan Endocrine Society [9] to make the definite diagnosis of SCS. Concretely, patients were required to meet the requisites 1–3)—1) presence of an adrenal incidentaloma; 2) lack of characteristic features of Cushing’s syndrome; and 3) normal basal serum cortisol levels, as well as to have either of the requisites 4–6)—4) the cutoff value of serum cortisol level for the diagnosis of SCS was ≥ 5 μg/dL after the 1-mg DST, 5) the cutoff value of serum cortisol level for the diagnosis of SCS was ≥ 3 μg/dL after the 1-mg DST, and at least 1 of “Low plasma levels of ACTH in the early morning,” “No diurnal changes in serum cortisol levels,” “Unilateral uptake on adrenal scintigraphy,” “Low serum levels of DHEAS,” or the presence of “Transient adrenal insufficiency or atrophy of the attached normal adrenal cortex after removal of the adrenal tumor,” or 6) the cutoff value of serum cortisol level for the diagnosis of SCS was ≥ 1.8 μg/dL after the 1-mg DST, with the presence of “Low plasma levels of ACTH in the early morning” and “No diurnal changes in serum cortisol levels,” or the presence of “Transient adrenal insufficiency or atrophy of the attached normal adrenal cortex after removal of the adrenal tumor.” In the present study, we examined only patients who met the requisites 1–3) and either 1 of the requisites 4–6) as patients with SCS. All patients underwent 128-slice CT of the adrenal glands. 131I-adosterol adrenal scintigraphy was conducted in all of patients who had SCS or PASCS to specify the laterality of the adrenal tumor. Consequently, 7 of 12 patients with SCS and 8 of 14 patients with PASCS underwent adrenalectomy. Postsurgical histopathological examination confirmed cortisol hypersecretion based on the atrophy of the normal area adjacent to the adenoma of the removed adrenal gland [9].

    Study outcome measures

    At the initial visit, all patients were checked up for their age and sex. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and the outcome measures listed in Table 1 were examined in untreated patients. At the time of admission to the hospital for making the definite diagnosis, height and body weight were measured to calculate body mass index (BMI). In the early morning of the next day of admission to the hospital, blood pressures were measured. Blood samples were collected to determine PAC, PRA, as well as plasma ACTH, serum cortisol, and serum DHEAS levels. The laterality of the adrenal tumor was confirmed based on the results from AVS and/or CT. The Hounsfield number and MTD of adrenal tumors were determined on the CT scans.

    Table 1 Clinical, laboratory, and imaging characteristics of untreated patients with PA, SCS, or PASCS
     

    The following terms were defined for PASCS: hypertension, SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg [14]; diabetes mellitus (DM), an fasting plasma glucose (FPG) level ≥ 126 mg/dL, a 2-h plasma glucose level ≥ 200 mg/dL in the 75-g oral glucose tolerance test, and/or a serum hemoglobin A1c (HbA1c) level ≥ 6.5% in national glycohemoglobin standardization program [15]; and dyslipidemia, a serum triglyceride (TG) level ≥ 150 mg/dL, a serum high-density lipoprotein cholesterol (HDL-C) level < 40 mg/dL, or a serum low-density lipoprotein cholesterol (LDL-C) level ≥ 140 mg/dL [16]. To specify the source of aldosterone hypersecretion by AVS, the following diagnostic criteria were used: 1) the laterality ratio (LR) and the contralaterality ratio (CR) calculated before and after the ACTH challenge test in reference to the Japanese guidelines of PA [11]; 2) the absolute PAC value of ≥ 14,000 pg/mL in reference to the articles of Ohmura [17] and Makita [18]; and 3) the aldosterone ratio of the right and left adrenal veins. According to the Japanese guidelines of PA [11], an LR of > 4 and a CR of < 1 after the ACTH challenge test were used as the cutoff values. Tumor laterality was determined based on a CR of < 1 and the absolute PAC value of ≥ 14,000 pg/mL when the ACTH challenge test indicated an LR of 2 to 4 or a discrepancy occurred in tumor laterality before and after the ACTH challenge test. Since serum cortisol levels considerably differed in the adrenal veins of PASCS patients, the adrenal gland secreting cortisol predominantly was determined based on the aldosterone ratio and on the right-to-left ratio of aldosterone and cortisol in the adrenal veins in reference to the article of Hiraishi et al. [8]. Moreover, tumor laterality was determined based on the results from 131I-adosterol adrenal scintigraphy and on the absolute value of PAC in reference to the articles of Funder et al. [12] and Minami et al. [13]. We did not measure plasma metanephrine concentrations, although the measurement thereof is useful for determining the need for AVS [19] in patients with the suspected concurrence of aldosterone and cortisol hypersecretion.

    Statistical analyses

    Continuous and categorical variables were analyzed according to the one-way analysis of variance and Fisher’s exact test, respectively. Two of the 3 study groups were analyzed according to Student’s t-test. Bonferroni’s correction was applied to the p values from Student’s t-test or Fisher’s exact test in multiple comparisons between 2 among the 3 study groups. Blood steroid profiles were compared between 2 groups according to Student’s t-test or the Mann-Whitney U-test.

    In addition, the multiple linear regression analysis adjusted for age, sex, and BMI was performed to examine differences in MTD and serum potassium concentration among the PA, SCS, and PASCS groups. MTD was not measured in 1 of 42 patients in the PA group who had a unilateral adrenal tumor. Therefore, the data from the patient were excluded as the missing data.

    A value of p <  0.05 was considered statistically significant. The JMP software version 9.0 (SAS Institute, Cary, NC, USA) was used to make all statistical analyses except multiple linear regression analysis that was performed using the STATA software version 14 (Stata Corp, College Station, TX, USA).

    Results

    Study population

    The clinical, laboratory, and imaging characteristics of 71 patients are shown in Table 1. Mean age was 58.2 ± 11.2 years, females (n = 47, 66.2%) were predominant, and mean BMI was 25.2 ± 4.5 kg/m2. No significant difference was found in age, sex, and BMI among the PA, SCS, and PASCS groups (Table 1). SBP and DBP of patients with untreated hypertension were 165.6 ± 26.1 mmHg and 96.0 ± 13.6 mmHg, respectively, in the PA group in contrast to 145.6 ± 26.9 mmHg and 80.0 ± 12.7 mmHg, respectively, in the SCS groups. DBP was significantly greater (p <  0.01) in the PA group than in the SCS group.

    Comorbidities are shown in Table 1. Hypertension occurred in 45 (100%), 9 (75.0%), and 13 (92.9%) patients in the PA, SCS, and PASCS groups, respectively. The proportion of patients with hypertension was significantly greater (p <  0.05) in the PA group than in the SCS group; however, no significant difference was found between the PASCS group and the PA group. Notably, the incidence of hypertension was 100% in patients with PA. DM occurred in 6 (14.0%), 6 (50.0%), and 7 (50.0%) patients in the PA, SCS, and PASCS groups, respectively. The proportion of DM patients was significantly greater (p <  0.05) in the PASCS group than in the PA group. Dyslipidemia occurred in 25 (56.8%), 10 (83.3%), and 9 (64.3%) patients in the PA, SCS, and PASCS groups, respectively; however, no significant difference was found among these study groups.

    Results from laboratory tests are shown in Table 1. FPG was greater not statistically but numerically in the PASCS group than in the PA group (131.6 ± 52.1 mg/dL vs. 103.8 ± 28.5 mg/dL; p = 0.09). On the other hand, FPG was statistically greater in the SCS group than in the PA group (150.0 ± 60.7 mg/dL vs. 103.8 ± 28.5 mg/dL; p <  0.01). HbA1c was greater not statistically but numerically in the PASCS group than in the PA group (6.5 ± 2.1% vs. 5.7 ± 0.9%; p = 0.21). On the other hand, HbA1c was significantly greater in the SCS group than in the PA group (7.3 ± 2.2% vs. 5.7 ± 0.9%; p <  0.01). Serum potassium concentration was significantly lower in the PA group than in the SCS group (3.3 ± 0.7 mEq/L vs. 4.0 ± 0.5 mEq/L; p <  0.01) and in the PASCS group than in the SCS group (3.2 ± 0.8 mEq/L vs. 4.0 ± 0.5 mEq/L; p <  0.01). No significant difference was found in serum potassium concentration between the PA group and the PASCS group. Serum alkaline phosphatase (ALP) level was significantly greater in the PASCS group than in the PA group (279.1 ± 105.4 U/L vs. 212.3 ± 46.3 U/L; p <  0.01). No significant difference was found in serum ALP level between the SCS group and the PASCS group.

    Subsequently, differences in CT Hounsfield units and MTD of adrenal tumors among the 3 study groups were examined with respect to 65 patients who had a unilateral adrenal tumor (Table 2). MTD on the CT scans was significantly greater in the PASCS group than in the PA group (2.7 ± 0.1 cm vs. 1.3 ± 0.1 cm; p <  0.001) and was also greater in the SCS group than in the PA group (2.7 ± 0.2 cm vs. 1.3 ± 0.1 cm; p <  0.001). No significant difference was found in MTD between the SCS group and the PASCS group. MTD was significantly smaller in the PA group than in the other 2 groups, was second smallest in the SCS group, and was largest in the PASCS group (Table 2). MTD ranged as follows: 0.3–2.2 cm, 1.8–3.5 cm, and 1.1–5.0 cm in the PA, SCS, and PASCS groups, respectively (Fig. 1).

    Table 2 Maximum tumor diameters and computed tomography Hounsfield units of adrenal tumors in patients who had a unilateral adrenal tumor
    Fig. 1
     

    figure1

    Maximum tumor diameters in patients with PA, SCS, or PASCS who had a unilateral adrenal tumor. PA, primary aldosteronism; SCS, subclinical Cushing’s syndrome, PASCS, primary aldosteronism plus subclinical Cushing’s syndrome

     

    The blood steroid profiles of patients with PA or PASCS are shown in Table 3. PAC was significantly greater in the PASCS group than in the PA group (255.0 [713.3–153.5] vs. 208.0 [273.0–159.8]; p <  0.005). No significant difference was found in PRA in the morning, while the PAC/PRA ratio was significantly greater in the PASCS group than in the PA group (1450.0 [5010.0–529.4] vs. 1258.3 [1956.3–643.1]; p <  0.005). The PAC/PRA ratio in the captopril challenge test was significantly greater in the PASCS group than in the PA group (3028.5 ± 3648.9 vs. 730.7 ± 745.7; p <  0.001) as with PAC in the captopril challenge test (348.6 ± 340.1 vs. 149.0 ± 94.2; p <  0.005). Serum cortisol level was significantly greater in the PASCS group than in the PA group (16.4 ± 6.6 μg/dL vs. 12.4 ± 4.3 μg/dL; p <  0.05). The mean serum cortisol level was 17.8 ± 5.9 μg/dL in the SCS group and was not significantly greater in the SCS group than in the PASCS group (17.8 ± 5.9 μg/dL vs. 16.4 ± 6.6 μg/dL; p = 0.49). No significant difference was found in plasma ACTH and serum DHEAS levels in the early morning; however, these variables were not significantly lower in the PASCS than in the PA group (p = 0.29 for ACTH and p = 0.40 for DHEAS). On the other hand, the peak plasma ACTH levels in the CRH challenge test were significantly lower in the PASCS group than in the PA group (18.9 ± 8.9 vs. 57.1 ± 10.8; p <  0.005) (Table 3) and were not significantly greater in the SCS group than in the PASCS group (15.3 ± 5.6 μg/dL vs. 18.9 ± 8.9 μg/dL; p = 0.64).

    Table 3 Blood steroid profiles of patients with PA or PASCS

    Multiple linear regression analysis on MTD and serum potassium concentration with respect to patients in the PA, SCS, and PASCS groups who had a unilateral adrenal tumor

    MTD was significantly greater in the PASCS and SCS groups than in the PA group with respect to patients who had a unilateral adrenal tumor (Table 2). Therefore, we conducted a multiple linear regression analysis adjusted for age, sex, and BMI to examine differences in MTD among the PA, SCS, and PASCS groups. Consequently, MTD was significantly smaller in the PA group than in the PASCS group (difference, – 1.19 cm; 95% CI, – 1.66 to – 0.72 cm). However, no significant difference was found in MTD between the SCS group and the PASCS group (Table 4). Serum potassium concentration was significantly greater in the SCS group than in the PASCS group (difference, 0.97 mEq/L; 95% CI, 0.38 to 1.54 mEq/L). However, no significant difference was found in serum potassium concentration between the PASCS group and the PA group (Table 4).

    Table 4 Multiple regression analysis on maximum tumor diameter and serum potassium concentration with respect to patients in the PA, SCS, and PASCS groups who had a unilateral adrenal tumor (n = 65)

    The cutoff value of 2.4 cm for tumor size seemed to produce the largest proportion of classified patients (91.0%). Patients with PA who had a tumor size of > 2.4 cm almost certainly had the elements of PASCS (specificity 100%). Namely, the sensitivity and specificity were calculated to be 58.0 and 100%, respectively, when the cutoff point for tumor diameter was set to 2.4 cm. The odds ratio for tumor diameter when comparing PA with PASCS was 0.06 (95% CI, 0.006–0.261).

    Discussion

    We found several clinical and laboratory differences between patients with PASCS and patients with either PA or SCS. Regarding the impact of PA and SCS on glucose metabolism, the risk of developing DM in SCS is enhanced by the overproduction of cortisol that leads to increased gluconeogenesis [20]. Moreover, the risk is also enhanced by PA through 1) a hypokalemia-induced decrease in initial pancreatic insulin release and 2) a reduction in insulin sensitivity [21,22,23]. Hypokalemia is caused by the mineralocorticoid receptor-mediated overexcretion of potassium from the kidneys in both hypercortisolism and hyperaldosteronism [122425]. Serum potassium concentration decreased significantly in the PA group than in the SCS group (p <  0.01). Similarly, the concurrence of PA and SCS significantly decreased serum potassium concentration against the SCS group (p <  0.01), but not the PA group. Of special note was the fact that the PASCS group involving both hyperaldosteronism and hypercortisolism did not show any greater decrease in serum potassium concentration as compared with the PA group. The mineralocorticoid receptors (MRs) bind both mineralocorticoids and glucocorticoids with high affinity (deoxycorticosterone = corticosterone ≥ aldosterone = cortisol) [26]. On the other hand, a cortisol-degrading enzyme—11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)—is expressed in renal epithelial cells and regulates the binding of aldosterone to the MRs by impeding cortisol binding to the MRs through the inactivation of cortisol to cortisone [2627]. Namely, this physiological event explains the MR-mediated renal excretion of potassium that is enhanced by both cortisol and aldosterone. We hypothesize that the renal potassium excretion-enhancing activity is greater for aldosterone than for cortisol due to the 11β-HSD2-induced, extensive inactivation of cortisol and that the hyperaldosteronism-enhanced renal excretion of potassium in patients with PASCS becomes more apparent, with the less effect of hypercortisolism on renal potassium excretion. Zallocchi et al. [28] described that renal 11β-HSD2 activity is regulated by glucocorticoids, is downregulated following adrenalectomy, and is restored by corticosterone replacement. These findings lead us to hypothesize that 11β-HSD2 may suppress the binding of corticosteroids to the MRs almost completely in subclinical hypercortisolism or that the expression/activity of renal 11β-HSD2 may be increased in PA. However, these hypotheses require further research for its demonstration.

    The proportion of DM patients increased significantly in the PASCS group than in the PA group (p <  0.05), which is in line with a previous study that described abnormal glucose metabolism in PA patients with cortisol hypersecretion [29]. Hyperaldosteronism found in patients with PA also induces abnormal glucose metabolism [21,22,23], although being less intense as compared with hypercortisolism found in patients with SCS. The proportions of DM patients in the PA and SCS groups increased, which resulted to nullify a statistically significant difference in the proportion of DM patients between the 2 study groups. The fact that the risk for DM is increased in PA patients with mild glucocorticoid excess has been reported [30,31,32]; the finding was also described in Japanese patients with PA and patients with PASCS [33].

    Interestingly, patients with PASCS involving hypercortisolism- and hyperaldosteronism-induced hypokalemia showed neither additive or synergic impact on abnormal glucose metabolism contrary to our prediction. The proportion of DM patients was comparable between the PASCS group and the SCS group. However, the reason for these findings is unknown, awaiting the further accumulation of clinical evidence.

    MTD was significantly smaller (p <  0.001) in the PA group than in the PASCS or SCS group, and multiple regression analysis on MTD revealed that MTD was significantly larger by 1.2 cm in the PASCS group than in the PA group (p <  0.001). Previous studies [834] examined the clinical characteristics of patients with PA or PASCS and described significant differences in MTD between the 2 study groups. Their results were concordant with and support our results that indicated no significant difference in MTD between the PASCS group and the SCS group.

    Most of previous clinical studies in patients with SCS have described adrenal tumors of ≥ 2 cm in diameter [3536]. In addition, an adrenal adenoma causing the overproduction of both cortisol and aldosterone is considered to have a ≥ 2.5 cm diameter [34]. In the present study, however, the adrenal tumor was smaller in both patients with SCS and patients with PASCS. Concretely, the smallest MTD was 1.1 cm in patients with PASCS (Fig. 1). None of patients, who had PA and an adrenal tumor < 1 cm in diameter, developed SCS. Therefore, the dexamethasone suppression test may not be required for them.

    Regarding bone metabolism impairment in SCS, the risk of developing osteoporosis is enhanced by the overproduction of cortisol in SCS [3738]. On the other hand, hyperaldosteronism is also known to increase the risk for osteoporosis [39]. SCS and PA are the risk factors for a reduction in BMD and an increase in vertebral fracture [37,38,39]. In the present study, serum ALP level was significantly greater in the PASCS group than in the PA group (p <  0.01). No significant difference was found in serum ALP level between the SCS group and the PASCS group. If this ALP represents bone alkaline phosphatase (BAP), the deleterious effects of hyperaldosteronism on bone metabolism might be masked by the severe abnormalities of bone metabolism caused by hypercortisolism in patients with PASCS. However, the relevant effects are difficult to assess by means of bone metabolism markers [eg, BAP] in patients with hypercortisolism as found in SCS [37]. Unfortunately, we neither used bone metabolism markers, nor measured BMD. Therefore, we will intend to investigate these variables in the future.

    Limitations

    The present study has several limitations. First, the study was retrospective in design and had a relatively small number of patients. Therefore, selection bias and sampling bias cannot be discarded. Second, not all patients underwent AVS or had a histopathological diagnosis. Patients, to whom challenge tests for either PA or SCS were conducted, were not included in the present study. Hence, the number of patients resulted to be relatively small. Third, the lack of data in the present study impeded the analysis of BMD and bone metabolism markers. Fourth, 131I-adosterol adrenal scintigraphy is not only useful for the diagnosis of SCS, but also is a very important imaging modality to predict postsurgical hypoadrenalism [40]. However, we could not investigate the latter.

    Conclusions

    We could not obtain any reference criteria to surely distinguish patients with concurrent endocrinopathies from those with a single endocrinopathy. However, clinicians should suspect the presence of concurrent SCS in patients with PA when detecting an adrenal tumor (≥ 1 cm in diameter) on the CT scans.

    Availability of data and materials

    The datasets analyzed during the current study are available from the corresponding author on a reasonable request.

    Abbreviations

    ACTH:

    Adrenocorticotropic hormone

    ALP:

    Alkaline phosphatase

    BMI:

    Body mass index;

    CRH:

    corticotropin-releasing hormone

    CT:

    computed tomography

    DBP:

    Diastolic blood pressure

    DHEAS:

    Dehydroepiandrosterone sulfate

    FPG:

    Fasting plasma glucose

    HbA1c:

    Hemoglobin A1c

    HDL-C:

    High-density lipoprotein cholesterol

    HU:

    Hounsfield unit

    LDL-C:

    Low-density lipoprotein cholesterol

    MTD:

    Maximum tumor diameter

    NGSP:

    National glycohemoglobin standardization program

    PA:

    Primary aldosteronism

    PAC:

    Plasma aldosterone concentration

    PASCS:

    Primary aldosteronism plus subclinical Cushing’s syndrome

    PRA:

    Plasma renin activity

    SBP:

    Systolic blood pressure

    SCS:

    Subclinical Cushing’s syndrome

    TG:

    Triglyceride

    UA:

    Uric acid

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    Acknowledgments

    The authors would like to express their gratitude Kazuyuki Inoue, MD and Takujiro Iuchi, MD for their role in the data collection. The authors also thank Satoshi Sakima, MD, for valuable discussions about the manuscript.

    Funding

    No funding was obtained for this study.

    Author information

    Affiliations

    1. Department of Endocrinology and Diabetes, Saitama Medical University, Morohongo 38, Moroyama, Iruma-gun, Saitama, 350-0495, Japan
      • Shigemitsu Yasuda
      • , Yusuke Hikima
      • , Shinichiro Iida
      • , Yoichi Oikawa
      • , Masashi Isshiki
      • , Ikuo Inoue
      • , Akira Shimada
      •  & Mitsuhiko Noda
    2. Department of Home Care Medicine, Sowa Hospital, Sagamihara, Kanagawa, Japan
      • Yusuke Kabeya
    3. Department of Diabetes, Metabolism and Endocrinology, Ichikawa Hospital, International University of Health and Welfare, Chiba, Japan
      • Mitsuhiko Noda

    Contributions

    SY analyzed and interpreted the data, drafted, and finalized the manuscript. YK performed statistical analyses, YH, YK, SI, YO, MI, II, AS, and MN contributed to the discussion and critically revised the manuscript, AS and MN are taking full responsibility for the work as a whole. All authors read and approved the final manuscript.

    Corresponding author

    Correspondence to Shigemitsu Yasuda.

    Ethics declarations

    Ethics approval and consent to participate

    All participants gave written informed consent. The present study followed the recommendations of the Declaration of Helsinki and was approved by the ethics committee of Saitama Medical University (18049.01).

    Consent for publication

    This manuscript does not report personal data such as individual details, images or videos; therefore, consent for publication is not applicable.

    Competing interests

    The authors declare that they have no conflict of interest.

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    Cite this article

    Yasuda, S., Hikima, Y., Kabeya, Y. et al. Clinical characterization of patients with primary aldosteronism plus subclinical Cushing’s syndrome. BMC Endocr Disord 20, 9 (2020). https://doi.org/10.1186/s12902-020-0490-0

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    Keywords

    • Primary aldosteronism
    • Subclinical Cushing’s syndrome
    • Adrenal tumor
    • Maximum tumor diameter
    • Diabetes mellitus
    • Serum potassium
     
    • Like 1

  3. Houston Methodist neurosurgeons and neuroscientists are looking at a new way to classify pituitary tumors that could lead to more precise and accurate diagnosing for patients in the future.

    Found in up to 10% of the population, pituitary tumors, also called adenomas, are noncancerous growths on the pituitary gland and very common. Although these pituitary tumors are benign in nature, they pose a major health challenge in patients.

    The new tests being investigated at Houston Methodist not only have the potential to lead to better diagnoses for patients with pituitary adenomas, but also for many other types of brain tumors in the future. The findings, which were published Jan. 28 in Scientific Reports, an online journal from Nature Publishing Group, describe a new way being looked at to study the blood of patients with pituitary tumors to determine exactly what tumor type they have and whether they might respond to medical treatment rather than surgery.

    "Often called the 'master gland,' the pituitary gland controls the entire endocrine system and regulates various body functions by secreting hormones into the bloodstream to control such things as metabolism, growth and development, reproduction and sleep," said corresponding author Kumar Pichumani, Ph.D., a research physicist at the Houston Methodist Research Institute. "When pituitary adenomas occur, they may secrete too much of one or more hormones that could lead to a variety of issues, ranging from infertility and sexual dysfunction to vision problems and osteoporosis, among many other health problems."

    Neurosurgeon David S. Baskin, M.D., director of the Kenneth R. Peak Center for Brain and Pituitary Tumor Treatment and Research in the Department of Neurosurgery at Houston Methodist Hospital, collaborated with Pichumani on this study. He said some pituitary tumors can be treated with medication rather than surgery, but a precise diagnosis of the type of tumor someone has and what hormone it's secreting is essential for proper treatment. This is sometimes very difficult to do based on standard endocrine hormone testing.

    "To guide our decisions on diagnosis and treatment, we currently rely on a blood-based hormone panel test that measures the levels of hormones in the blood to determine which hormones are overproducing in the tumor," Baskin said. "However, some tumors secrete too much of more than one hormone, making this test ambiguous for diagnosis."

    Led by Pichumani and Baskin, a team of researchers from the Peak Brain and Pituitary Tumor Treatment and Research Center and Houston Methodist Neurological Institute studied 47 pituitary adenoma patients of different subtypes by collecting blood during surgery to remove their tumors. They confirmed that elevated blood levels of a non-hormonal compound called betahydroxybutyrate, also known as BHB, was found only in patients with the prolactinoma subtype of noncancerous pituitary gland brain tumor that overproduces the hormone prolactin. This compound is known to supply energy to the brain during starvation, which led the researchers to speculate that BHB might be providing non-hormonal energy to these prolactinoma tumors causing them to grow and spread. The discovery could be further developed into a diagnostic lab test.

    This study is part of a developing field called metabolomics in which researchers study small molecules in tumors to see what's unique about their metabolism and how they're used as nutrients to supply energy. This contributes to better diagnoses and discovering new ways to kill tumors by poisoning the specific energy they use without causing damage to normal cells.

    The researchers are now enrolling more patients in a larger study currently underway to validate the results of their pilot study. If successful, they say BHB could be used as a non-hormonal metabolic biomarker for prolactinoma pituitary tumor diagnosis and prognosis to supplement the current hormone panel tests. They're also looking for biological reasons why only prolactin-secreting tumors have elevated BHB blood levels to inform therapeutic intervention.

    From https://medicalxpress.com/news/2020-02-pituitary-tumors-potential-treatments.html

    • Like 1

  4. Adrenococortical carcinoma (ACC) is a rare cancer, occurring at the rate of one case in two million person years. Cushing syndrome or a mixed picture of excess androgen and glucocorticoid production are the most common presentations of ACC. Other uncommon presentations include abdominal pain and adrenal incidentalomas. In the present report, a 71-year-old male presented with abdominal pain and was eventually diagnosed with ACC. He was found to have pulmonary thromboembolism following an investigation for hypoxemia, with the tumor thrombus extending upto the right atrium. This interesting case represents the unique presentation of a rare tumor, which if detected late or left untreated is associated with poor outcomes, highlighting the need for a low index of suspicion for ACC when similar presentations are encountered in clinical practice.

    ACC is a rare but aggressive tumor. ACC commonly presents with rapid onset of hypercortisolism, combined hyperandrogenism and hypercortisolism, or uncommonly with compressive symptoms. Clinicians should have a low index of suspicion for ACC in patients presenting with rapid onset of symptoms related to hypercortisolism and/or hyperandrogenism. Venous thromboembolism and extension of the tumor thrombus to the right side of the heart is a very rare but serious complication of ACC that clinicans should be wary of. The increased risk of venous thromboembolism in ACC could be explained by direct tumor invasion, tumor thrombi or hypercoagulability secondary to hypercortisolism. Early diagnosis and prompt treatment can improve the long-term survival of patients with ACC.

    Endocrinology, diabetes & metabolism case reports. 2019 Nov 25 [Epub ahead of print]

    Skand Shekhar, Sriram Gubbi, Georgios Z Papadakis, Naris Nilubol, Fady Hannah-Shmouni

    Section on Endocrinology & Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA., Diabetes, Endocrinology, and Obesity Branch, National Institute of Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA., Department of Medical Imaging, Heraklion University Hospital, Medical School, University of Crete, Crete, Greece., Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    PubMed http://www.ncbi.nlm.nih.gov/pubmed/31765326

     

    From https://www.urotoday.com/recent-abstracts/urologic-oncology/adrenal-diseases/118539-adrenocortical-carcinoma-and-pulmonary-embolism-from-tumoral-extension.html

    • Like 1

  5. Seliciclib.jpg
     
    Sponsor:
    Information provided by (Responsible Party):
    Shlomo Melmed, MD, Cedars-Sinai Medical Center
     
    Brief Summary:

    This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of 4 weeks of oral seliciclib in patients with newly diagnosed, persistent, or recurrent Cushing disease.

    Funding Source - FDA Office of Orphan Products Development (OOPD)

     
    Condition or disease  Intervention/treatment  Phase 
    Cushing Disease Drug: Seliciclib Phase 2
     
    Detailed Description:
    This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of two of three potential doses/schedules of oral seliciclib in patients with newly diagnosed, persistent, or recurrent Cushing disease. Up to 29 subjects will be treated with up to 800 mg/day oral seliciclib for 4 days each week for 4 weeks and enrolled in sequential cohorts based on efficacy outcomes. The study will also evaluate effects of seliciclib on quality of life and clinical signs and symptoms of Cushing disease.
     
     
    Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
    Sexes Eligible for Study:   All
    Accepts Healthy Volunteers:   No
     
    Criteria

    Inclusion criteria:

    • Male and female patients at least 18 years old
    • Patients with confirmed pituitary origin of excess adrenocorticotropic hormone (ACTH) production:

      • Persistent hypercortisolemia established by two consecutive 24 h UFC levels at least 1.5x the upper limit of normal
      • Normal or elevated ACTH levels
      • Pituitary macroadenoma (>1 cm) on MRI or inferior petrosal sinus sampling (IPSS) central to peripheral ACTH gradient >2 at baseline and >3 after corticotropin-releasing hormone (CRH) stimulation
      • Recurrent or persistent Cushing disease defined as pathologically confirmed resected pituitary ACTH-secreting tumor or IPSS central to peripheral ACTH gradient >2 at baseline and >3 after CRH stimulation, and 24 hour UFC above the upper limit of normal reference range beyond post-surgical week 6
      • Patients on medical treatment for Cushing disease. The following washout periods must be completed before screening assessments are performed:

        • Inhibitors of steroidogenesis (metyrapone, ketoconazole): 2 weeks
        • Somatostatin receptor ligand pasireotide: short-acting, 2 weeks; long-acting, 4 weeks
        • Progesterone receptor antagonist (mifepristone): 2 weeks
        • Dopamine agonists (cabergoline): 4 weeks
        • CYP3A4 strong inducers or inhibitors: varies between drugs; minimum 5-6 times the half-life of drug

    Exclusion criteria:

    • Patients with compromised visual fields, and not stable for at least 6 months
    • Patients with abutment or compression of the optic chiasm on MRI and normal visual fields
    • Patients with Cushing's syndrome due to non-pituitary ACTH secretion
    • Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia
    • Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e., Carney Complex, McCune-Albright syndrome, Multiple endocrine neoplasia (MEN) 1
    • Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)
    • Patients with cyclic Cushing's syndrome defined by any measurement of UFC over the previous 1 months within normal range
    • Patients with pseudo-Cushing's syndrome, i.e., non-autonomous hypercortisolism due to overactivation of the hypothalamic-pituitary-adrenal (HPA) axis in uncontrolled depression, anxiety, obsessive compulsive disorder, morbid obesity, alcoholism, and uncontrolled diabetes mellitus
    • Patients who have undergone major surgery within 1 month prior to screening
    • Patients with serum K+< 3.5 while on replacement treatment
    • Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8%
    • Patients who have clinically significant impairment in cardiovascular function or are at risk thereof, as evidenced by congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, high grade atrioventricular (AV) block, history of acute MI less than one year prior to study entry
    • Patients with liver disease or history of liver disease such as cirrhosis, chronic active hepatitis B and C, or chronic persistent hepatitis, or patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 1.5 x ULN, serum total bilirubin more than ULN, serum albumin less than 0.67 x lower limit of normal (LLN) at screening
    • Serum creatinine > 2 x ULN
    • Patients not biochemically euthyroid
    • Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results, such as

      • History of immunocompromise, including a positive HIV test result (ELISA and Western blot). An HIV test will not be required, however, previous medical history will be reviewed
      • Presence of active or suspected acute or chronic uncontrolled infection
      • History of, or current alcohol misuse/abuse in the 12 month period prior to screening
    • Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. If a woman is participating in the trial then one form of contraception is sufficient (pill or diaphragm) and the partner should use a condom. If oral contraception is used in addition to condoms, the patient must have been practicing this method for at least two months prior to screening and must agree to continue the oral contraceptive throughout the course of the study and for 3 months after the study has ended. Male patients who are sexually active are required to use condoms during the study and for three month afterwards as a precautionary measure (available data do not suggest any increased reproductive risk with the study drugs)
    • Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to screening or patients who have previously been treated with seliciclib
    • Patients with any ongoing or likely to require additional concomitant medical treatment to seliciclib for the tumor
    • Patients with concomitant treatment of strong CYP3A4 inducers or inhibitors.
    • Patients who were receiving mitotane and/or long-acting somatostatin receptor ligands octreotide long-acting release (LAR) or lanreotide
    • Patients who have received pituitary irradiation within the last 5 years prior to the baseline visit
    • Patients who have been treated with radionuclide at any time prior to study entry
    • Patients with known hypersensitivity to seliciclib
    • Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study
    • Patients with presence of Hepatitis B surface antigen (HbsAg)
    • Patients with presence of Hepatitis C antibody test (anti-HCV)
     
     
     
    • Like 1

  6. Lacroix A, et al. Pituitary. 2019;doi:10.1007/s11102-019-01021-2.

    January 7, 2020
    lacroix_andre_2020_web.jpg
    Andre Lacroix

    Most adults with persistent or recurrent Cushing’s disease treated with the somatostatin analogue pasireotide experienced a measurable decrease in MRI-detectable pituitary tumor volume at 12 months, according to findings from a post hoc analysis of a randomized controlled trial.

    “Pasireotide injected twice daily during up to 12 months to control cortisol excess in patients with residual or persistent Cushing's disease was found to reduce the size of pituitary tumors in a high proportion of the 53 patients in which residual tumor was still visible at initiation of this medical therapy,” Andre Lacroix, MD, FCAHS, professor of medicine at the University of Montreal Teaching Hospital in Montreal, Canada, told Healio. “Pituitary tumors causing Cushing's syndrome which cannot be removed completely by surgery have the capacity to grow in time, and a medical therapy that can reduce tumor growth in addition to control excess cortisol production should be advantageous for the patients.”

     

    Lacroix and colleagues analyzed data from 53 adults with persistent or recurrent Cushing’s disease, or those with newly diagnosed Cushing’s disease who were not surgical candidates, who had measurable tumor volume data (78% women). Researchers randomly assigned participants to 600 g or 900 g subcutaneous pasireotide (Signifor LAR, Novartis) twice daily. Tumor volume was assessed independently at 6 and 12 months by two masked radiologists and compared with baseline value and urinary free cortisol response.

    Pituitary gland 2019 
    Most adults with persistent or recurrent Cushing’s disease treated with the somatostatin analogue pasireotide experienced a measurable decrease in MRI-detectable pituitary tumor volume at 12 months.
    Source: Shutterstock

    Researchers found that reductions in tumor volume were both dose and time dependent. Tumor volume reduction was more frequently observed at month 6 in the 900 g group (75%) than in the 600 g group (44%). Similarly, at month 12 (n = 32), tumor volume reduction was observed more frequently in the 900 g group (89%) than in the 600 g group (50%). Results were independent of urinary free cortisol levels.

    The researchers did not observe a relationship between baseline tumor size and change in tumor size.

    “Taken together, the results of the current analysis demonstrate that treatment with pasireotide, a pituitary-directed medical therapy that targets somatostatin receptors, can frequently lead to radiologically measurable reductions in pituitary tumor volume in patients with Cushing’s disease,” the researchers wrote. “Tumor volume reduction is especially relevant in patients with larger microadenomas, suggesting that pasireotide is an attractive option for these patients, especially in cases in which patients cannot undergo transsphenoidal surgery or do not respond to surgical management of disease.” – by Regina Schaffer

    For more information:

    Andre Lacroix, MD, FCAHS, can be reached at the University of Montreal Teaching Hospital, Endocrine Division, 3840 Saint-Urbain, Montreal, H2W 1T8, Canada; email: andre.lacroix@umontrael.ca.

    Disclosures: Novartis supported this study and provided writing support. Lacroix reports he has received funding from Novartis Pharmaceuticals to conduct clinical studies with pasireotide and osilodrostat in Cushing’s disease and served as a consultant, advisory board member or speaker for EMD Serono, Ipsen and Novartis. Please see the study for all other authors’ relevant financial disclosures.

    From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B8e4d31fb-d61a-4cf8-b4c4-7d0bdf012fbd%7D/pasireotide-reduces-pituitary-tumor-volume-in-cushings-disease

    • Like 1

  7. Sethi A, et al. Clin Endocrinol. 2019;doi:10.1111/CEN.14146.

    January 5, 2020

    Obesity is common at diagnosis of pituitary adenoma in childhood and may persist despite successful treatment, according to findings published in Clinical Endocrinology.

    “The importance of childhood and adolescent obesity on noncommunicable disease in adult life is well recognized, and in this new cohort of patients, we report that obesity is common at presentation of pituitary adenoma in childhood and that successful treatment is not necessarily associated with weight loss,” Aashish Sethi, MD, MBBS, a pediatric endocrinologist in the department of endocrinology at Alder Hey Children’s Hospital in Liverpool, United Kingdom, and colleagues wrote. “We have reported obesity, and obesity-related morbidity in a mixed cohort of children and young adults previously, but [to] our knowledge, this is the first time this observation has been reported in a purely pediatric cohort.”

     

    In a retrospective study, Sethi and colleagues analyzed clinical and radiological data from 24 white children from Alder Hey Children’s Hospital followed for a median of 3.3 years between 2000 and 2019 (17 girls; mean age at diagnosis, 15 years). Researchers assessed treatment modality (medical, surgical or radiation therapy), pituitary hormone deficiencies and BMI, as well as results of any genetic testing.

    Within the cohort, 13 girls had prolactinomas (mean age, 15 years), including 10 macroadenomas between 11 mm and 35 mm in size. Children presented with menstrual disorders (91%), headache (46%), galactorrhea (46%) and obesity (38%). Nine children were treated with cabergoline alone, three also required surgery, and two were treated with the dopamine agonist cabergoline, surgery and radiotherapy.

    Five children had Cushing’s disease (mean age, 14 years; two girls), including one macroadenoma. Those with Cushing’s disease presented with obesity (100%), short stature (60%) and headache (40%). Transsphenoidal resection resulted in biochemical cure; however, two patients experienced relapse 3 and 6 years after surgery, respectively, requiring radiotherapy. One patient also required bilateral adrenalectomy.

    Six children had a nonfunctioning pituitary adenoma (mean age, 16 years; two girls), including two macroadenomas. These children presented with obesity (67%), visual field defects (50%) and headache (50%). Four required surgical resections, with two experiencing disease recurrence after surgery and requiring radiotherapy.

    During the most recent follow-up exam, 13 children (54.1%) had obesity, including 11 who had obesity at diagnosis.

    “The persistence of obesity following successful treatment, in patients with normal pituitary function, suggests that mechanisms other than pituitary hormone excess or deficiency may be important,” the researchers wrote. “It further signifies that obesity should be a part of active management in cases of pituitary adenoma from diagnosis.” – by Regina Schaffer

    Disclosures: The authors report no relevant financial disclosures.

    From https://www.healio.com/endocrinology/adrenal/news/online/%7Bde3fd83b-e8e0-4bea-a6c2-99eb896356ab%7D/long-term-obesity-persists-despite-pituitary-adenoma-treatment-in-childhood

    • Like 1

  8. A diagnostic technique called bilateral inferior petrosal sinus sampling (BIPSS), which measures the levels of the adrenocorticotropic hormone (ACTH) produced by the pituitary gland, should only be used to diagnose cyclic Cushing’s syndrome patients during periods of cortisol excess, a case report shows.

    When it is used during a spontaneous remission period of cycling Cushing’s syndrome, this kind of sampling can lead to false results, the researchers found.

    The study, “A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing’s syndrome,” was published in BMC Endocrine Disorders.

    Cushing’s syndrome is caused by abnormally high levels of the hormone cortisol. This is most often the result of a tumor on the pituitary gland that produces too much ACTH, which tells the adrenal glands to increase cortisol secretion.

    However, the disease may also occur due to adrenal tumors or tumors elsewhere in the body that also produce excess ACTH — referred to as ectopic Cushing’s syndrome.

    Because treatment strategies differ, doctors need to determine the root cause of the condition before deciding which treatment to choose.

    BIPSS can be useful in this regard. It is considered a gold standard diagnostic tool to determine whether ACTH is being produced and released by the pituitary gland or by an ectopic tumor.

    However, in people with cycling Cushing’s syndrome, this technique might not be foolproof.

    Researchers reported the case of a 43-year-old woman who had rapidly cycling Cushing’s syndrome, meaning she had periods of excess cortisol with Cushing’s syndrome symptoms — low potassium, high blood pressure, and weight gain — followed by normal cortisol levels where symptoms resolved spontaneously.

    In general, the length of each period can vary anywhere from a few hours to several months; in the case of this woman, they alternated relatively rapidly — over the course of weeks.

    After conducting a series of blood tests and physical exams, researchers suspected of Cushing’s syndrome caused by an ACTH-producing tumor.

    The patient eventually was diagnosed with ectopic Cushing’s disease, but a BIPSS sampling performed during a spontaneous remission period led to an initial false diagnosis of pituitary Cushing’s. As a result, the woman underwent an unnecessary exploratory pituitary surgery that revealed no tumor on the pituitary.

    Additional imaging studies then identified a few metastatic lesions, some of which were removed surgically, as the likely source of ACTH. However, the primary tumor still hasn’t been definitively identified. At the time of publication, the patient was still being treated for Cushing’s-related symptoms and receiving chemotherapy.

    There is still a question of why the initial BIPSS result was a false positive. The researchers think that the likely explanation is that BIPSS was performed during an “off phase,” when cortisol levels were comparatively low. In fact, a later BIPSS performed during a period of high cortisol levels showed no evidence of ACTH excess in the pituitary.

    This case “demonstrates the importance of performing diagnostic tests only during the phases of active cortisol secretion, as soon as first symptoms appear,” the researchers concluded.

    From https://cushingsdiseasenews.com/2020/01/02/cushings-syndrome-case-study-shows-drawback-in-bipss-method/

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  9. Wed, Jan 8, 2020, from 4:00 PM - 5:00 PM EST

    Presented by Paul Gardner, MD Associate Professor of Neurological Surgery Neurosurgical Director, Center for Cranial Base Surgery Executive Vice Chairman for Surgical Services University Pittsburgh Medical Center (UPMC)

    Learning Objectives: Upon completion of this webinar, participants should be able to: Recognize the role for surgery in treating recurrent adenomas Understand the risk and role of radiosurgery for treatment of recurrent Identify treatment indications for recurrent adenomas.

    Presenter Bio Paul A. Gardner, MD, is an Associate Professor in the Department of Neurological Surgery at the University of Pittsburgh School of Medicine and Neurosurgical Director of the Center for Cranial Base Surgery as well as Executive Vice Chairman for Surgical Services for the Department of Neurological Surgery at the University of Pittsburgh Medical Center (UPMC).

    Dr. Gardner joined the faculty of the Department of Neurological Surgery at the University of Pittsburgh School of Medicine in 2008 after completing his residency and fellowship training at the University of Pittsburgh. He completed his undergraduate studies at Florida State University, majoring in biochemistry, and received his Medical Degree from the University of Pittsburgh School of Medicine.

    Dr. Gardner completed a two-year fellowship in endoscopic endonasal pituitary and endoscopic and open skull base surgery at the University of Pittsburgh Medical Center. His research has focused on evaluating patient outcomes following these surgeries and more recently on molecular phenotyping of rare tumors. He is recognized internationally as a leader in the field of endoscopic endonasal surgery, a minimally invasive surgical approach to the skull base. His other surgical interests include pituitary tumors, open cranial base surgery, and vascular surgery.

    Register here

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  10. newsletters.jpg

    Approximately 20% of a cohort of adults with Cushing’s syndrome experienced at least one thrombotic event after undergoing pituitary or adrenal surgery, with the highest risk observed for those undergoing bilateral adrenalectomy, according to findings from a retrospective analysis published in the Journal of the Endocrine Society.

    “We have previously showed in a recent meta-analysis that Cushing’s syndrome is associated with significantly increased venous thromboembolic events odds vs. the general population, though the risk is lower than in patients undergoing major orthopedic surgery,” Maria Fleseriu, MD, FACE, professor of neurological surgery and professor of medicine in the division of endocrinology, diabetes and clinical nutrition in the School of Medicine at Oregon Health & Science University and director of the OHSU Northwest Pituitary Center, told Healio. “However, patients undergoing many types of orthopedic surgeries have scheduled thromboprophylaxis, especially postsurgery, which is not the standard of care in patients with Cushing’s syndrome. In this study, we wanted to look in more detail at the rates of all thrombotic events, both arterial and venous, in patients at our specialized pituitary center over more than a decade.”

    In a retrospective, longitudinal study, Fleseriu and colleagues analyzed data from 208 individuals with Cushing’s syndrome undergoing surgical (pituitary, unilateral and bilateral adrenalectomy) and medical treatment at a single center (79.3% women; mean age at presentation, 45 years; mean BMI, 33.9 kg/m²; 41.8% with diabetes). Individuals with severe illness and immediate mortality were excluded. Thromboembolic events (myocardial infarction, deep venous thrombosis [DVT], and pulmonary embolism or stroke) were recorded at any point up until last patient follow-up. Researchers assessed all patients who received anticoagulation in the immediate postoperative period and up to 3 months after surgery, recording doses and complications for anticoagulation.

    Within the cohort, 39 patients (18.2%) experienced at least one thromboembolic event (56 total events; 52% venous), such as extremity DVT (32%), cerebrovascular accident (27%), MI (21%), and pulmonary embolism (14%). Of those who experienced a thromboembolic event, 40.5% occurred within 60 days of surgery.

    Researchers found that 14 of 36 patients who underwent bilateral adrenalectomy experienced a thromboembolic event, for an OR of 3.74 (95% CI, 1.69-8.27). Baseline 24-hour urinary free cortisol levels did not differ for patients with or without thromboembolic event after bilateral adrenalectomy.

    “Despite following these patients over time, results almost surprised us,” said Fleseriu, also an Endocrine Today Editorial Board Member. “The risk of thromboembolic events in patients with Cushing’s syndrome was higher than we expected, approximately 20%. Many patients had more than one event, with higher risk at 30 to 60 days postoperatively. Use of a peripherally inserted central catheter line clearly increased risk of upper extremity DVT.”

    Among 197 patients who underwent surgery, 50 (25.38%) received anticoagulation after surgery with 2% experiencing bleeding complications.

    “We clearly need to understand more about what happens in patients with Cushing’s syndrome for all comorbidities, but especially thrombosis, and find the factors that predict higher risk and use anticoagulation in those patients,” Fleseriu said. “We have shown that among patients who had anticoagulation, risks were minimal. We also have to think more about timelines for these thromboembolic events and the duration of anticoagulation, and probably to expand it up to 30 to 60 days postoperatively if there are no contraindications, especially for patients undergoing bilateral adrenalectomy.”

    Fleseriu cautioned that the findings do not necessarily suggest that every individual with Cushing’s syndrome needs anticoagulation therapy, as the study was retrospective. Additionally, sex, age, BMI, smoking status, estrogen or testosterone supplementation, diabetes and hypertension — all known factors for increased thrombosis risk among the general population — were not found to significantly increase the risk for developing a thromboembolic event, Fleseriu said.

    “As significantly more patients have exogenous Cushing’s syndrome than endogenous Cushing’s syndrome and many of these patients undergo surgeries, we hope that our study increased awareness regarding thromboembolic risks and the need to balance advantages of thromboprophylaxis with risk of bleeding,” Fleseriu said. – by Regina Schaffer

    For more information:

    Maria Fleseriu, MD, FACE, can be reached at fleseriu@ohsu.edu.

    Disclosure: Fleseriu reports she has received research funding paid to her institution from Novartis and Strongbridge and has received consultant fees from Novartis and Strongbridge.

     

    From  https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7Bce267e5a-0d32-4171-abc8-34369b455fcf%7D/risk-for-thrombotic-events-high-after-cushings-syndrome-surgery

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  11. Written by Kathleen Doheny with Maria Fleseriu, MD, FACE, and Vivien Herman-Bonert, MD

    Cushing's disease, an uncommon but hard to treat endocrine disorder, occurs when a tumor on the pituitary gland, called an adenoma—that is almost always benign—leads to an overproduction of ACTH (adrenocorticotropic hormone), which is responsible for stimulating the release of cortisol, also known as the stress hormone.

    Until now, surgery to remove the non-cancerous but problematic tumor has been the only effective treatment. Still, many patients will require medication to help control their serum cortisol levels, and others cannot have surgery or would prefer to avoid it.

    Finally, a drug proves effective as added on or alternative to surgery in managing Cushing's disease. Photo; 123rf

    New Drug Offers Alternative to Surgery for Cushing's Disease

    Now, there is good news about long-term positive results achieved with pasireotide (Signifor)—the first medication to demonstrate effectiveness in both normalizing serum cortisol levels and either shrinking or slowing growth of tumors over the long term.1,2  These findings appear in the journal, Clinical Endocrinology, showing that patients followed for 36 months as part of an ongoing study had improved patient outcomes for Cushing’s disease.2

    "What we knew before this extension study was—the drug will work in approximately half of the patients with mild Cushing's disease," says study author Maria Fleseriu, MD, FACE, director of the Northwest Pituitary Center and professor of neurological surgery and medicine in the division of endocrinology, diabetes and clinical nutrition at the Oregon Health and Sciences University School of Medicine.

    “Pasireotide also offers good clinical benefits," says Dr. Fleseriu who is also the president of the Pituitary Society, “which includes improvements in blood pressure, other signs and symptoms of Cushing’s symptom], and quality of life.”2

    What Symptoms Are Helped by Drug for Cushing's Disease?  

    Among the signs and symptoms of Cushing’s disease that are lessened with treatment are:3

    • Changes in physical appearance such as wide, purple stretch marks on the skin (eg, chest, armpits, abdomen, thighs)
    • Rapid and unexplained weight gain
    • A more full, rounder face
    • Protruding abdomen from fat deposits
    • Increased fat deposits around the neck area

    The accumulation of adipose tissue raises the risk of heart disease, which adds to the urgency of effective treatment. In addition, many individuals who have Cushing’s disease also complain of quality of life issues such as fatigue, depression, mood and behavioral problems, as well as poor memory.2

    As good as the results appear following the longer term use of pasireotide,2 Dr. Fleseriu admits that in  any extension study in which patients are asked to continue on, there are some built-in limitations, which may influence the findings. For example, patients who agree to stay on do so because they are good responders, meaning they feel better, so they’re happy to stick with the study.

    “Fortunately, for the patients who have responded to pasireotide initially, this is a drug that can be  continued as there are no new safety signals with longer use," Dr. Fleseriu tells EndocrineWeb, "and when the response at the start is good, very few patients will lose control of their urinary free cortisol over time. That's a frequent marker used to monitor patient's status. For those patients with large tumors, almost half of them had a significant shrinkage, and all the others had a stable tumor size."

    What Are the Reasons to Consider Drug Treatment to Manage Cushing’s Symptoms

    The extension study ''was important because we didn't have any long-term data regarding patient response to this once-a-month treatment to manage Cushing's disease," she says.

    While selective surgical removal of the tumor is the preferred treatment choice, the success rate in patients varies, and Cushing's symptoms persist in up to 35% of patients after surgery. In addition, recurrent rates (ie, return of disease) range from 13% to 66% after individuals experience different durations remaining in remission.1

    Therefore, the availability of an effective, long-lasting drug will change the course of therapy for many patients with Cushing’s disease going forward. Not only will pasireotide benefit patients who have persistent and recurrent disease after undergoing surgery, but also this medication will be beneficial for those who are not candidates for surgery or just wish to avoid having this procedure, he said.

    Examining the Safety and Tolerability of Pasireotide  

    This long-acting therapy, pasireotide, which is given by injection, was approved in the US after reviewing results of a 12-month Phase 3 trial.1  In the initial study, participants had a confirmed pituitary cause of the Cushing's disease. After that, the researchers added the optional 12-month open-label, extension study, and now patients can continue on in a separate long-term safety study.

    Those eligible for the 12-month extension had to have mean urinary free cortisol not exceeding the upper limit of normal (166.5 nanomoles per 24 hour) and/or be considered by the investigator to be getting substantial clinical benefit from treatment with long-action pasireotide, and to demonstrate tolerability of pasireotide during the core study.1

    Of the 150 in the initial trial, 81 participants, or 54% of the patients, entered the extension study. Of those, 39 completed the next phase, and most also enrolled in another long-term safety study—these results not yet available).2

    During the core study, 1 participants were randomly assigned to 10 or 30 mg of the drug every 28 days, with doses based on effectiveness and tolerability. When they entered the extension, patients were given the same dose they received at month.1,2

    Study Outcomes Offer Advantages in Cushing’s Disease

    Of those who received 36 months of treatment with pasireotide, nearly three in four (72.2%) had controlled levels of urinary free cortisol at this time point.2 Equally good news for this drug was that tumors either shrank or did not grow. Of those individuals who started the trial with a measurable tumor (adenoma) as well as those with an adenoma at the two year mark (35 people), 85.7% of them experienced a reduction of 20% or more or less than a 20% change in tumor volume. No  macroadenomas present at the start of the study showed a change of more than 20% at either month 24 or 36.2

    Improvements in blood pressure, body mass index (BMI) and waist circumference continued throughout the extension study.1  Those factors influence CVD risk, the leading cause of death in those with Cushing's.4

    As for adverse events, most of the study participants, 91.4%, did report one or more complaint during the extension study—most commonly, it was high blood sugar, which was reported by nearly 40% of participants.2. This is not surprising when you consider that most (81.5%) of the individuals participating in the extension trial entered with a diagnosis of diabetes or use of antidiabetic medication, and even more of them (88.9%) had diabetes at the last evaluation.1  

    This complication indicates the need for people with Cushing’s disease to check their blood glucose, as appropriate.

    Do You Have Cushing’s Disese? Here's What You Need to Know 

    Women typically develop Cushing’s disease more often than men.

    What else should you be aware of if you and your doctor decide this medication will help you? Monitoring is crucial, says Dr. Fleseriu, as you will need to have your cortisol levels checked, and you should be on alert for any diabetes signals, which will require close monitoring and regular follow-up for disease management.

    Another understanding gained from the results of this drug study: "This medication works on the tumor level," she says. "If the patient has a macroadenoma (large tumor), this would be the preferred treatment." However, it should be used with caution in those with diabetes given the increased risk of experiencing high blood sugar.

    The researchers conclude that "the long-term safety profile of pasireotide was very favorable and consistent with that reported during the first 12 months of treatment. These data support the use of long-acting pasireotide as an effective long-term treatment option for some patients with Cushing's Disease."1

    Understanding Benefits of New Drug to Treat Cushing's Diseease

    Vivien S. Herman-Bonert, MD, an endocrinologist and clinical director of the Pituitary Center at Cedars-Sinai Medical Center in Los Angeles, agreed to discuss the study findings, after agreeing to review the research for EndocrineWeb.

    As to who might benefit most from monthly pasireotide injections? Dr. Herman-Bonert says, "any patient with Cushing's disease that requires long-term medical therapy, which includes patients with persistent or recurrent disease after surgery." Certainly, anyone who has had poor response to any other medical therapies for Cushing's disease either because they didn't work well enough or because the side effects were too much, will likely benefit a well, she adds.

    Among the pluses that came out of the study, she says, is that nearly half of the patients had controlled average urinary free cortisol levels after two full years, and 72% of the participants who continued on with the drug for 36 months were able to remain in good urinary cortisol control .1

    As the authors stated, tumor shrinkage was another clear benefit of taking long-term pasireotide. That makes the drug a potentially good choice for those even with large tumors or with progressive tumor growth, she says. It’s always good for anyone with Cushing’s disease to have an alterative to surgery, or a back-up option when surgery isn’t quite enough, says Dr. Herman-Bonert.

    The best news for patients is that quality of life scores improved,she adds.

    Dr Herman-Bonert did add a note of caution: Although the treatment in this study is described as ''long-term, patients will need to be on this for far longer than 2 to 3 years," she says. So, the data reported in this study may or may not persist, and we don’t yet know what the impact will be 10 or 25 years out.

    Also, the issue of hyperglycemia-related adverse events raises a concern, given the vast majority (81%) of patients who have both Cushing’s disease and diabetes. Most of those taking this drug had a dual diagnosis—having diabetes, a history of diabetes, or taking antidiabetic medicine.

    If you are under care for diabetes and you require treatment for Cushing’s disease, you must be ver mindful that taking pasireotide will likely lead to high blood sugar spikes, so you should plan to address this with your healthcare provider.

     

    Dr. Fleseriu reports research support paid to Oregon Health & Science University from Novartis and other 0companies and consultancy fees from Novartis and Strongbridge Biopharma. Dr. Herman-Bonert has no relevant disclosures.

    The study was underwritten by Novartis Pharma AG, the drug maker. 

    From https://www.endocrineweb.com/news/pituitary-disorders/62449-cushings-disease-monthly-injection-good-alternative-surgery

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  12. In patients with Cushing’s disease, removing the pituitary tumor via an endoscopic transsphenoidal surgery (TSS) leads to better remission rates than microscopic TSS, according to new research.

    But regardless of surgical approach, plasma cortisol levels one day after surgery are predictive of remission, researchers found.

    The study, “Management of Cushing’s disease: Changing trend from microscopic to endoscopic surgery,” was published in the journal World Neurosurgery.

    Because it improves visualization and accessibility, endoscopic TSS has been gaining popularity over microscopic TSS to remove pituitary tumors in Cushing’s disease patients. Yet, although this surgery has been associated with high remission rates, whether it outperforms microscopic surgery and determining the factors affecting long-term outcomes may further ease disease recurrence after TSS.

    A team with the All India Institute of Medical Sciences addressed this topic in 104 patients who underwent surgery from January 2009 to June 2017. Among these patients, 47 underwent microscopic surgery and 55 endoscopic surgery. At presentation, their ages ranged from 9 to 55 (mean age of 28). Also, patients had been experiencing Cushing’s symptoms over a mean duration of 24 months.

    Eighty-seven patients showed weight gain. Hypertension (high blood pressure) and diabetes mellitus were among the most common co-morbidities, found in 76 and 33 patients, respectively. Nineteen patients had osteoporosis and 12 osteopenia, which refers to lower-than-normal bone mineral density.

    As assessed with magnetic resonance imaging, 68 patients had a microadenoma (a tumor diameter smaller than one centimeter) and 27 had a macroadenoma (a tumor one centimeter or larger). Only two patients had an invasive pituitary adenoma.

    Two patients with larger tumors were operated on transcranially (through the skull). The surgery resulted in total tumor removal in 90 cases (86.5%). A blood loss greater than 100 milliliter was more common with endoscopic than with microscopic TSS.

    Ten patients developed transient diabetes inspidus, two experienced seizures after surgery, and six of nine patients with macroadenoma and visual deterioration experienced vision improvements after TSS.

    The incidence of intraoperative leak of cerebrospinal fluid — the liquid surrounding the brain and spinal cord — was 23.2%, while that of post-operative leak was 7.7% and was more common in microadenoma than macroadenoma surgery (9.8% vs. 5.0%).

    Seventeen patients were lost to follow-up and two died due to metabolic complications and infections. The average follow-up was shorter for endoscopic than with microscopic surgery (18 months vs. 35 months).

    Among the remaining 85 cases, 65 (76.5%) experienced remission, as defined by a morning cortisol level under 5.0 μg/dL, restored circadian rhythm (the body’s internal clock, typically impaired in Cushing’s patients), and suppression of serum cortisol to below 2 μg/dl after overnight dexamethasone suppression test.

    The remission rate was 54.5% in pediatric patients and was higher with endoscopic than with microscopic TSS (88.2% vs. 56.6%). Also, patients with microadenoma showed a trend toward more frequent remission than those with macroadenoma (73.2% vs. 64.3%).

    Ten of the remaining 20 patients experienced disease recurrence up to 28 months after surgery. Sixteen cases revealed signs of hypopituitarism, or pituitary insufficiency, which were managed with replacement therapy.

    A subsequent analysis found that morning cortisol level on day one after surgery was the only significant predictor of remission. Specifically, a one-unit increase in cortisol lowered the likelihood of remission by 7%. A cortisol level lower than 10.7 μgm/dl was calculated as predicting remission.

    Overall, the study showed that “postoperative plasma cortisol level is a strong independent predictor of remission,” the researchers wrote, and that “remission provided by endoscopy is significantly better than microscopic approach.”

    From https://cushingsdiseasenews.com/2019/09/24/cortisol-levels-predict-remission-cushings-patients-undergoing-transsphenoidal-surgery/

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  13. Presented by

    Andrew Lin, MD
    Neuro-Oncologist & Neurologist
    Memorial Sloak Kettering Cancer Center
     

    register_now_150.jpg


    After registering you will receive a confirmation email with details about joining the webinar.

    Contact us at webinar@pituitary.org with any questions or suggestions.
     

    Date: September 18, 2019 
    Time: 10:00 AM - 11:00 AM. Pacific Daylight Time, 1:00 PM - 2:00 PM Eastern Daylight Time

    Learning Objectives:

    During the conversation I will be:
    1) Defining aggressive pituitary tumors.
    2) Reviewing the current treatment options for aggressive pituitary tumors.
    3) Discussing experimental treatment options including a phase II trial investigating the activity of the immunotherapies nivolumab and ipilimumab.

    Presenter Biography:

    • I am a neuro-oncologist at Memorial Sloan Kettering Cancer Center (MSK) and a member of the Multidisciplinary Pituitary & Skull Base Tumor Center. In collaboration with my colleagues in endocrine, neurosurgery, and radiation oncology, I treat patients with aggressive pituitary tumors, who are resistant to conventional treatments (i.e. surgery and radiation), with chemotherapy. With my colleagues at MSK, I have published several research articles on pituitary tumors and opened several clinical trials.
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  14. For patients with persistent or recurring Cushing’s disease, monthly pasireotide therapy was safe and effective, leading to normal urinary free cortisol levels in 47% of patients after 2 years, according to findings published in Clinical Endocrinology.

    Maria Fleseriu headshot 2019
    Maria Fleseriu

    “The management of Cushing’s syndrome, and particularly Cushing’s disease, remains challenging,” Maria Fleseriu, MD, FACE, professor of neurological surgery and professor of medicine in the division of endocrinology, diabetes and clinical nutrition in the School of Medicine at Oregon Health & Science University and director of the OHSU Northwest Pituitary Center, told Endocrine Today. “Long-acting pasireotide provided sustained biochemical improvements and clinical benefit in a significant proportion of patients with Cushing’s disease who elected to continue in this extension study. There were many adverse events reported overall, but no new safety signals emerging over long-term treatment.”

     

    In the last decade, medical treatment for Cushing’s disease has progressed from a few steroidogenesis inhibitors to three novel drug groups: new inhibitors for steroidogenic enzymes with possibly fewer adverse effects, pituitary-directed drugs that aim to inhibit the pathophysiological pathways of Cushing’s disease, and glucocorticoid receptor antagonists that block cortisol’s action, Fleseriu, who is also an Endocrine Today Editorial Board member, said.

    In an open-label extension study, Fleseriu and colleagues analyzed data from 81 adults with confirmed Cushing’s disease with mean urinary free cortisol not exceeding the upper limit of normal, who transitioned from a 12-month, randomized controlled trial where they were assigned 10 mg or 30 mg once-monthly intramuscular pasireotide (Signifor LAR, Novartis). During the main study, researchers recruited participants with mean urinary free cortisol level concentration 1.5 to five times the upper limit of normal, normal or greater than normal plasma and confirmed pituitary source of Cushing’s disease. Participants who elected to continue in the extension were considered biochemical responders or benefited from the study drug per the clinical investigator, Fleseriu said.

    “As in all extension studies, the bias is inherent that patients deemed responders tend to continue, but for any type of treatment for pituitary tumors, and particularly Cushing’s disease, long-term, robust data on efficacy and safety parameters is essential,” Fleseriu said.

    Median overall exposure to pasireotide at the end of the extension study was 23.9 months, with nearly half of patients receiving at least 1 year of treatment during the extension phase. Researchers found that improvements in clinical signs of hypercortisolism were sustained throughout the study and median urinary free cortisol remained within normal range. Overall, 38 participants (47%) had controlled urinary free cortisol at month 24 (after 12 months of treatment during the extension phase), with researchers noting that the proportion of participants with controlled or partially controlled urinary free cortisol was stable throughout the extension phase.

    “Interestingly, the median salivary cortisol level decreased but remained above normal (1.3 times upper limit of normal) at 3 years,” Fleseriu said.

    As seen in other pasireotide studies, and expected based on the mechanism of action, researchers observed hyperglycemia-related adverse events in 39.5% of participants, with diabetes medications initiated or escalated in some patients, Fleseriu said. However, mean fasting glucose and HbA1c were stable during the extension phase, after increasing in the main study. Within the cohort, 81.5% had type 2 diabetes at baseline (entering extension phase) and 88.9% patients had type 2 diabetes at last assessment.

    “Pasireotide acts at the tumor level, and tumor shrinkage is seen in many patients,” Fleseriu said. “In this study, 42% and 32.1% had a measurable microadenoma or macroadenoma, respectively, on MRI at the start of pasireotide treatment; an adenoma was not visible in almost a quarter of patients at 2 years.”

    Among patients with a measurable adenoma at baseline and at month 24 (n = 35), 85.7% experienced a reduction of at least 20% or a 20% change in tumor volume between the two time points. Improvements in median systolic and diastolic blood pressure, BMI and waist circumference were sustained during the extension, Fleseriu said.

    “The long-term safety profile of pasireotide was favorable and consistent with that reported during the first 12 months of treatment,” the researchers wrote. “These data support the use of long-acting pasireotide as an effective long-term treatment option for some patients with [Cushing’s disease].”

    Fleseriu said individualized treatment selecting patients who will derive benefit from therapy will be crucial, balancing both efficacy and the potential risks and costs. – by Regina Schaffer

    Disclosures: Fleseriu reports she has received consultant fees and her institution has received research support from Novo Nordisk and Pfizer. Please see the study for all other authors’ relevant financial disclosures.

    From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B5da4611f-34b2-4306-80b8-46babd2aad4a%7D/long-acting-pasireotide-provides-sustained-biochemical-improvements-in-cushings-disease?page=2

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  15. Abstract

    OBJECTIVE:

    To report our management of bilateral adrenalectomy with autologous adrenal gland transplantation for persistent Cushing's disease, and to discuss the feasibility of autologous adrenal transplantation for the treatment of refractory Cushing's disease.

    MATERIAL AND METHODS:

    A retrospective analysis was performed in 4 patients (3 females, aged 14-36 years) who underwent autologous adrenal transplantation for persistent Cushing's disease after endonasal transsphenoidal resection of a pituitary tumor. The procedure was performed by implanting a vascularized adrenal graft into the left iliac fossa with direct and indirect anastomoses. Postoperative follow-up was performed in 1, 1.5, 8, and 10 years, and an over 8-year long-term follow-up was reached in 2 out of the 4 cases. Hormone replacement dosage was guided by clinical symptoms and endocrine results including serum cortisol (F), 24 h urine-free cortisol, and adrenocorticotrophic hormone levels.

    RESULTS:

    All 4 patients with symptomatic Cushing's disease experienced resolution of symptoms after autotransplantation without Nelson Syndrome. Functional autografts were confirmed through clinical evaluation and endocrine results. One year after transplantation, adrenal function and hormone replacement dosage remained stable without adrenal hyperplasia. After long-term follow-up, dosages of hormone replacement were reduced in all patients.

    CONCLUSIONS:

    In this series of 4 patients, we demonstrate the long-term efficacy of bilateral adrenalectomy with autologous adrenal transplantation and propose this procedure as a viable treatment option for refractory Cushing's disease.

    © 2019 S. Karger AG, Basel.

    KEYWORDS:

    Cortisol; Adrenalectomy; Autologous adrenal gland transplantation ; Cushing’s disease; Nelson syndrome

     

    PubMed http://www.ncbi.nlm.nih.gov/pubmed/31434089

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  16. MENLO PARK, Calif., Aug. 28, 2019 (GLOBE NEWSWIRE) -- Corcept Therapeutics Incorporated (NASDAQ: CORT) announced today that the United States Patent and Trademark Office has issued a Notice of Allowance for a patent covering the administration of Korlym® with food.  The patent will expire in November 2032.

    “This patent covers an important finding of our research – that for optimal effect, Korlym must be taken with food,” said Joseph K. Belanoff, MD, Corcept’s Chief Executive Officer. “Korlym’s label instructs doctors that ‘Korlym must always be taken with a meal.’”

    Upon issuance, Corcept plans to list the patent, entitled “Optimizing Mifepristone Absorption” (U.S. Pat. App. 13/677,465), in the U.S. Food and Drug Administration’s Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”).  Korlym is currently protected by ten patents listed in the Orange Book.

    Hypercortisolism

    Hypercortisolism, often referred to as Cushing’s syndrome, is caused by excessive activity of the hormone cortisol. Endogenous Cushing’s syndrome is an orphan disease that most often affects adults aged 20-50. In the United States, an estimated 20,000 patients have Cushing’s syndrome, with about 3,000 new patients diagnosed each year. Symptoms vary, but most people with Cushing’s syndrome experience one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper-body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Hypercortisolism can affect every organ system in the body and can be lethal if not treated effectively.

    About Corcept Therapeutics Incorporated

    Corcept is a commercial-stage company engaged in the discovery and development of drugs that treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of the stress hormone cortisol.  Korlym® (mifepristone) was the first treatment approved by the U.S. Food and Drug Administration for patients with Cushing’s syndrome.  Corcept has discovered a large portfolio of proprietary compounds, including relacorilant, exicorilant and miricorilant, that selectively modulate the effects of cortisol but not progesterone. Corcept owns extensive United States and foreign intellectual property covering the composition of its selective cortisol modulators and the use of cortisol modulators, including mifepristone, to treat a variety of serious disorders.

    Forward-Looking Statements

    Statements in this press release, other than statements of historical fact, are forward-looking statements, which are based on Corcept’s current plans and expectations and are subject to risks and uncertainties that might cause actual results to differ materially from those such statements express or imply. These risks and uncertainties include, but are not limited to, Corcept’s ability to generate sufficient revenue to fund its commercial operations and development programs; the availability of competing treatments, including generic versions of Korlym; Corcept’s ability to obtain acceptable prices or adequate insurance coverage and reimbursement for Korlym; and risks related to the development of Corcept’s product candidates, including regulatory approvals, mandates, oversight and other requirements. These and other risks are set forth in Corcept’s SEC filings, which are available at Corcept’s website and the SEC’s website. In this press release, forward-looking statements include those concerning Corcept’s plans to list the patent “Optimizing Mifepristone Absorption” in the Orange Book; Korlym’s current protection by ten patents listed in the Orange Book; and the scope and protective power of Corcept’s intellectual property. Corcept disclaims any intention or duty to update forward-looking statements made in this press release.      

    CONTACT:
    Christopher S. James, MD
    Director, Investor Relations
    Corcept Therapeutics
    650-684-8725
    cjames@corcept.com
    www.corcept.com

    • Like 2

  17. Levels of adrenocorticotropic hormone (ACTH) in circulation after pituitary surgery may help predict which Cushing’s disease patients will achieve early remission and which will eventually see the disease return, a study shows.

    Also, the earlier that patients reached their lowest peak of ACTH levels, the better their long-term outcomes.

    The study, “Prognostic usefulness of ACTH in the postoperative period of Cushing’s disease,” was published in the journal Endocrine Connections.

    Removing the pituitary tumor through a minimally invasive surgery called transsphenoidal surgery is still the treatment of choice for Cushing’s disease patients. But not all patients enter remission, and even among those who do, a small proportion will experience disease recurrence.

    While cortisol levels have been suggested as a main predictor of remission and recurrence, there is no consensus as to which cutoff point should be used after surgery, or the best time for measuring this hormone.

    Because Cushing’s disease is caused by an ACTH-producing tumor in the pituitary gland, and ACTH has a short half-life (approximately 10 minutes), it is expected that ACTH levels drop markedly within a few hours after surgery.

    Thus, a group of researchers in Spain aimed to determine whether blood levels of ACTH could be useful for predicting remission of Cushing’s disease both immediately after surgery (defined as less than 72 hours) and in the long term.

    Researchers analyzed 65 patients with Cushing’s disease who had undergone transsphenoidal surgery (seven required a second intervention) between 2005 and 2016. Remission within three months was seen in 56 of 65 cases; late disease recurrence was seen in 18 of 58 cases.

    Investigators measured the ACTH nadir concentration (defined as the lowest concentration) and the time taken to reach nadir levels after surgery, as well as the plasma ACTH concentration before hospital discharge.

    While ACTH levels had no predictive value, the team found that people who went into remission had significantly lower ACTH nadir levels and ACTH levels at discharge. On the other hand, levels of ACHT nadir and at discharge were significantly higher for people who experienced a relapse, compared to those who remained in remission.

    Using artificial intelligence algorithms, the researchers further found that ACTH nadir, ACTH at discharge, and cortisol nadir values were all of great relevance to predict remission within three months.

    Analysis indicated that using a cutoff point of 3.3 pmol/L of ACTH after surgery and before discharge gave the best sensitivity and specificity for predicting a patient’s prognosis.

    Researchers further found that the time patients took to reach their ACTH nadir, regardless of nadir levels, also influenced their outcomes. In fact, patients reaching this nadir in less than than 46 hours more likely achieved early remission.

    And taking longer than 39 hours to reach the ACTH nadir was significantly more frequent in patients who experienced recurrence. This indicates that the time to ACTH nadir is an important measure for prognosis.

    “In the immediate postoperative period of patients with [Cushing’s disease], the ACTH concentration is of prognostic utility in relation to late disease remission,” the researchers said.

    Overall, “we propose an ACTH value <3.3 pmol/L as a good long-term prognostic marker in the postoperative period of CD. Reaching the ACTH nadir in less time is associated to a lesser recurrence rate,” the study concluded.

     
    Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
     
    • Like 1

  18. Authors Ježková J, Ďurovcová V, Wenchich LHansíková H, Zeman J, Hána V, Marek J, Lacinová Z, Haluzík M, Kršek M

    Received 18 March 2019

    Accepted for publication 13 June 2019

    Published 19 August 2019 Volume 2019:12 Pages 1459—1471

    DOI https://doi.org/10.2147/DMSO.S209095

    Checked for plagiarism Yes

    Review by Single-blind

    Peer reviewers approved by Dr Melinda Thomas

    Peer reviewer comments 3

    Editor who approved publication: Dr Antonio Brunetti

     

    Jana Ježková,1 Viktória Ďurovcová,1 Laszlo Wenchich,2,3 Hana Hansíková,3 Jiří Zeman,3Václav Hána,1 Josef Marek,1 Zdeňka Lacinová,4,5 Martin Haluzík,4,5 Michal Kršek1

    1Third Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 2Institute of Rheumatology, Prague, Czech Republic; 3Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 4Institute of Medical Biochemistry and Laboratory Diagnostic, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 5Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

    Correspondence: Jana Ježková
    Third Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 1128 02 Praha 2, Prague, Czech Republic
    Tel +420 60 641 2613
    Fax +420 22 491 9780
    Email fjjezek@cmail.cz

    Purpose: Cushing’s syndrome is characterized by metabolic disturbances including insulin resistance. Mitochondrial dysfunction is one pathogenic factor in the development of insulin resistance in patients with obesity. We explored whether mitochondrial dysfunction correlates with insulin resistance and other metabolic complications.

    Patients and methods: We investigated the changes of mRNA expression of genes encoding selected subunits of oxidative phosphorylation system (OXPHOS), pyruvate dehydrogenase (PDH) and citrate synthase (CS) in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) and mitochondrial enzyme activity in platelets of 24 patients with active Cushing’s syndrome and in 9 of them after successful treatment and 22 healthy control subjects.

    Results: Patients with active Cushing’s syndrome had significantly increased body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) and serum lipids relative to the control group. The expression of all investigated genes for selected mitochondrial proteins was decreased in SCAT in patients with active Cushing’s syndrome and remained decreased after successful treatment. The expression of most tested genes in SCAT correlated inversely with BMI and HOMA-IR. The expression of genes encoding selected OXPHOS subunits and CS was increased in PM in patients with active Cushing’s syndrome with a tendency to decrease toward normal levels after cure. Patients with active Cushing’s syndrome showed increased enzyme activity of complex I (NQR) in platelets.

    Conclusion: Mitochondrial function in SCAT in patients with Cushing’s syndrome is impaired and only slightly affected by its treatment which may reflect ongoing metabolic disturbances even after successful treatment of Cushing’s syndrome.

    Keywords: Cushing’s syndrome, insulin resistance, mitochondrial enzyme activity, gene expression

    Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

    Download Article [PDF]  View Full Text 

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  19. Presented by

    Nathan T Zwagerman MD
    Director of Pituitary and Skull base surgery
    Department of Neurosurgery
    Medical College of Wisconsin
     

    register_now_150.jpg


    After registering you will receive a confirmation email with details about joining the webinar. 

    Date: Wednesday, August 21, 2019

    Time: 10:00 AM - 11:00 AM Pacific Daylight Time 1:00 PM - 2:00 PM Eastern Daylight Time


    Webinar Description:

    Learning Objectives:

    1. Describe the signs and symptoms of Cushing's Disease
    2. Describe the work up for patients with Cushing's Disease
    3. Understand the goals, risks, and expected outcomes for treatment
    4. Describe alternative treatments when surgery is not curative.

    Presenter Bio:

    Dr. Zwagerman is a Professor of Neurosurgery at the Medical College of Wisconsin. He did his undergraduate work in psychology at Calvin College in Grand Rapids, Michigan. He earned his medical degree at Wayne State University in Detroit. He did his fellowship in endoscopic and open cranial base surgery, and then his residency in neurological surgery at the University of Pittsburgh Medical Center.

    • Like 1

  20. Recovery of the hypothalamus-pituitary-adrenal (HPA) axis can occur as late as 12 months after transsphenoidal adenomectomy (TSA), according to study results published in The Journal of Clinical Endocrinology & Metabolism. These findings emphasize the need to periodically assess these patients to avoid unnecessary hydrocortisone replacement.

    The primary treatment for most pituitary lesions is TSA. After pituitary surgery, the recovery of pituitary hormone deficits may be delayed; limited data are available regarding the postsurgical recovery of hormonal axes or predictors of recovery. The goal of this study was to assess HPA axis dysfunction and predictive markers of recovery following TSA, as well as time to recovery, to identify subgroups of patients who may be more likely to recover.

    This single-center observational retrospective study enrolled 109 patients in the United Kingdom (71 men; mean age, 56 years; range, 17 to 82 years) who underwent TSA between February 2015 and September 2018 and had ≥1 reevaluation of the HPA axis with the short Synacthen (cosyntropin) test. The primary outcome was recovery of HPA axis function 6 weeks, 3 months, 6 months, and 9 to 12 months after TSA.

    In 23 patients (21.1%), there was no evidence of pituitary hormone deficit before TSA. In 44 patients (40.4%), there was 1 hormone deficiency and in 25 patients (22.9%), preoperative evaluation showed >1 hormone deficiency.

    Of the 23 patients with abnormal HPA function before surgery, 8 patients (34.8%) had recovered 6 weeks after the surgery. Patients who recovered were younger (mean age, 50±14 vs 70±9 years; P =.008) compared with patients who did not respond. Of the 15 remaining patients, 2 (13.3%) recovered at 3 months and 3 (20%) recovered at 9 to 12 months.

    With regard to HPA function in the entire cohort 6 weeks after surgery, 32 patients (29.4%) did not pass the short Synacthen test. Of this group, 5 patients (15.6%) recovered at 3 months, 4 (12.5%) at 6 months, and 2 (6.2%) recovered 9 to 12 months after the surgery.

    Predictors of future adrenal recovery at 6 weeks included having preoperative 30-minute cortisol >430 nmol/L (P <.001) and a day 8 postoperative cortisol >160 nmol/L (P =.001). With these cutoffs, 80% of patients with preoperative 30-minute cortisol >430 nmol/L (odds ratio [OR], 7.556; 95% CI, 2.847-20.055) and 80% of patients with day 8 postoperative cortisol >160 nmol/L (OR, 9.00; 95% CI, 2.455-32.989) passed the short Synacthen test at 6 weeks postsurgery. In addition, a 6-week baseline short Synacthen test cortisol level above or below 180 nmol/L (P <.001) predicted adrenal recovery at that time point.

    None of the patients with all 3 variables below the aforementioned cutoffs recovered HPA axis within 1 year. On the other hand, 91.8% of patients with all 3 variables above those cutoffs had normal adrenal function at 6 weeks (OR, 12.200; 95% CI, 5.268-28.255).

    In addition to the retrospective design, the study had other limitations, including the potential for selection bias, a heterogeneous patient cohort, and no data beyond 12 months after the surgery.

    “[T]hese data offer the opportunity for patients who may have been given life-long replacement, to safely come off therapy and therefore avoid unnecessary glucocorticoid exposure,” wrote the researchers.

    Reference

    Pofi R, Gunatilake S, Macgregor V, et al. Recovery of the hypothalamo-pituitary-adrenal axis following transsphenoidal adenomectomy for non-ACTH secreting macroadenomas [published online June 21, 2019]. J Clin Endocrinol Metab. doi:10.1210/jc.2019-00406

    From https://www.endocrinologyadvisor.com/home/topics/adrenal/recovery-of-hpa-axis-can-occur-late-after-transsphenoidal-adenomectomy/

    • Like 1

  21. Dr. Theodore Friedman hosts Gautam Mehta, MD for a fascinating webinar on Approaches for Pituitary Surgery


    Dr. Mehta is a neurosurgeon specializing in pituitary surgery at the House Clinic in Los Angeles. He was trained by Ian McCutcheon, MD and Ed Oldfield, MD
     
    Topics to be discussed include:
    • How does Dr. Friedman diagnose Cushing’s Disease
    • How does Dr. Friedman determine who goes to surgery?
    • What type of patients need surgery besides those with Cushing’s Disease?
    • How do the neurosurgeon and the Endocrinologist work together?
    • How does the neurosurgeon read pituitary MRIs?
    • What types of surgical approaches are used for pituitary surgery?
    • How long does surgery take and how long will a patient be in the hospital? 
    • What are the risks of pituitary surgery and how can they be minimized?
     
    Sunday • August 4 • 6 PM PDT


    Click here to start your meeting.

    or
    https://axisconciergemeetings.webex.com/axisconciergemeetings/j.php?MTID=ma1d8d5ef99605e305980e2f7cdfdb7bd
    OR
    Join by phone: (855) 797-9485
    Meeting Number (Access Code): 807 028 597 Your phone/computer will be muted on entry. 
    Slides will be available on the day of the talk at slides 
    There will be plenty of time for questions using the chat button. Meeting Password: hormones
    For more information, email us at mail@goodhormonehealth.com
     

    c6372630-a961-47e1-9409-f2b513fda463.jpgd1de84b3-37b4-4de2-baf4-79bcd913d67e.jpg

    • Like 1

  22. Cases of adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome are often caused by unilateral tumors in the adrenal glands, but Indian researchers have now reported a rare case where the condition was caused by tumors in both adrenal glands.

    Fewer than 40 cases of bilateral tumors have been reported so far, but an accurate diagnosis is critical for adequate and prompt treatment. Sampling the veins draining the adrenal glands may be a good way to diagnose the condition, researchers said.

    The study, “Bilateral adrenocortical adenomas causing adrenocorticotropic hormone-independent Cushing’s syndrome: A case report and review of the literature,” was published in the World Journal of Clinical Cases.

    Cushing’s syndrome, a condition characterized by excess cortisol in circulation, can be divided into two main forms, depending on ACTH status. Some patients have tumors that increase the amount of ACTH in the body, and this hormone will act on the adrenal glands to produce cortisol in excess. Others have tumors in the adrenal glands, which produce excess cortisol by themselves, without requiring ACTH activation. This is known as ACTH-independent Cushing’s syndrome.

    Among the latter, the disease is mostly caused by unilateral tumors — in one adrenal gland only —  with cases of bilateral tumors being extremely rare in this population.

    Now, researchers reported the case of a 31-year-old Indian woman who developed ACTH-independent Cushing’s syndrome because of tumors in both adrenal glands.

    The patient complained of weight gain, red face, moon face, bruising, and menstrual irregularity for the past two years. She recently had been diagnosed with high blood pressure and had started treatment the month prior to the presentation.

    A physical examination confirmed obesity in her torso, moon face, buffalo hump, thin skin, excessive hair growth, acne, swollen legs and feet, and skin striae on her abdomen, arms, and legs.

    Laboratory examinations showed that the woman had an impaired tolerance to glucose, excess insulin, and elevated cortisol in both the blood and urine. Consistent with features of Cushing’s syndrome, cortisol levels had no circadian rhythm and were non-responsive to a dexamethasone test, which in normal circumstances lowers cortisol production.

    Because ACTH levels were within normal levels, researchers suspected an adrenal tumor, which led them to conduct imaging scans.

    An abdominal computed tomography (CT) scan showed adrenal adenomas in both adrenal glands (right: 3.1 cm × 2.0 cm × 1.9 cm; left: 2.2 cm × 1.9 cm × 2.1 cm). A magnetic resonance imaging (MRI) scan showed that the pituitary gland (which normally produces ACTH) was normal.

    To determine whether both adrenal tumors were producing cortisol, researchers sampled the adrenal veins and compared their cortisol levels to those of peripheral veins. They found that the left adrenal gland was producing higher amounts of cortisol, thought the right adrenal gland was also producing cortisol in excess.

    “Our case indicates that adrenal vein [blood] sampling might be useful for obtaining differential diagnoses” in cases of Cushing’s syndrome, researchers stated. Also, they may help design a surgical plan that makes much more sense.”

    The tumors were surgically removed — first the left, and three months later the right — which alleviated many of her symptoms. She also started prednisolone treatment, which helped resolve many disease symptoms.

    “Bilateral cortisol-secreting tumors are a rare cause of Cushing’s syndrome,” researchers said. So when patients present bilateral adrenal lesions, “it is crucial to make a definitive diagnosis before operation since various treatments are prescribed for different causes,” they said.

    The team recommends that in such cases the two tumors should not be removed at the same time, as this approach may cause adrenal insufficiency and the need for glucocorticoid replacement therapy.

    From https://cushingsdiseasenews.com/2019/06/27/rare-case-of-cs-due-to-bilateral-tumors-in-the-adrenal-glands/

    • Like 1

  23. Are adrenal incidentalomas, which are found by chance on imaging, really harmless? In this paper, the authors looked at 32 studies, including 4121 patients with benign non-functioning adrenal tumours (NFATs) or adenomas that cause mild autonomous cortisol excess (MACE).

    Only 2.5% of the tumours grew to a clinically significant extent over a mean follow-up period of 50 months, and no one developed adrenal cancer. Of those patients with NFAT or MACE, 99.9% didn’t develop clinically significant hormone (cortisol) excess.

    This was a group (especially those with MACE) with a high prevalence of hypertension, diabetes, and obesity. This could be because adrenal adenomas promote cardiometabolic problems, or vice versa, or maybe this group with multimorbidities is more likely be investigated. Adrenal incidentalomas are already found in around 1 in 20 abdominal CT scans, and this rate is likely to increase as imaging improves.

    So it’s good news that this study supports existing recommendations, which say that follow-up imaging in the 90% of incidentalomas that are smaller than 4 cm diameter is unnecessary.  

    From https://blogs.bmj.com/bmj/2019/07/03/ann-robinsons-journal-review-3-july-2019/

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