CRCS: An automatic image processing pipeline for hormone level analysis of Cushing's disease.

Due to the abnormal secretion of adreno-cortico-tropic-hormone (ACTH) by tumors, Cushing's disease leads to hypercortisonemia, a precursor to a series of metabolic disorders and serious complications. Cushing's disease has high recurrence rate, short recurrence time and undiscovered recurrence reason after surgical resection. Qualitative or quantitative automatic image analysis of histology images can potentially in providing insights into Cushing's disease, but still no software has been available to the best of our knowledge. In this study, we propose a quantitative image analysis-based pipeline CRCS, which aims to explore the relationship between the expression level of ACTH in normal cell tissues adjacent to tumor cells and the postoperative prognosis of patients. CRCS mainly consists of image-level clustering, cluster-level multi-modal image registration, patch-level image classification and pixel-level image segmentation on the whole slide imaging (WSI). On both image registration and classification tasks, our method CRCS achieves state-of-the-art performance compared to recently published methods on our collected benchmark dataset. In addition, CRCS achieves an accuracy of 0.83 for postoperative prognosis of 12 cases. CRCS demonstrates great potential for instrumenting automatic diagnosis and treatment for Cushing's disease.

Glucocorticoid modulates oxidative and thermogenic function of rat brown adipose tissue and human brown adipocytes.

Chronic and excessive glucocorticoid (GC) exposure can cause Cushing's syndrome, resulting in fat accumulation in selected body areas. Particularly in the brown adipose tissue (BAT), GC acts negatively, resulting in whitening of the tissue. We hypothesized that dysregulation of microRNAs by GC could be an additional mechanism to explain its negative actions in BAT. Male Wistar rats were divided into two groups: (1) Control sham and (2) GC group that was administered dexamethasone 6.25 mg/200 µL via osmotic pump implantation over 28 days. After this period, the animals were euthanized and BAT tissue was properly stored. Human fat cells treated with dexamethasone were used to translate the experimental results found in animals to human biology. GC-treated rat BAT presented with large lipid droplets, severely impaired thermogenic activation, and reduced glucose uptake measured by 18F-FDG PET/CT. GC exposure induced a reduction in the mitochondrial OXPHOS system and oxygen consumption. MicroRNA profiling of BAT revealed five top-regulated microRNAs and among them miR-21-5p was the most significantly upregulated in GC-treated rats compared to the control group. Although upregulation of miR-21-5p in the tissue, differentiated primary brown adipocytes from GC-treated rats had decreased miR-21-5p levels compared to the control group. To translate these results to the clinic, human brown adipocytes were treated with dexamethasone and miR-21-5p inhibitor. In human brown cells, inhibition of miR-21-5p increased brown adipocyte differentiation and prevented GC-induced glucose uptake, resulting in a lower glycolysis rate. In conclusion, high-dose GC therapy significantly impacts brown adipose tissue function, with a notable association between glucose uptake and miR-21-5p.

Circadian and ultradian rhythms: Clinical implications.

The hypothalamic-pituitary-adrenal axis is an extremely dynamic system with a combination of both circadian and ultradian oscillations. This state of 'continuous dynamic equilibration' provides a platform that is able to anticipate events, is sensitive in its response to stressors, remains robust during perturbations of both the internal and external environments and shows plasticity to adapt to a changed environment. In this review, we describe these oscillations of glucocorticoid (GC) hormones and why they are so important for GC-dependent gene activation in the brain and liver, and their consequent effects on the regulation of synaptic and memory function as well as appetite control and metabolic regulation. Abnormalities of mood, appetite and metabolic regulation are well-known consequences of GC therapy, and we suggest that the pattern of GC treatment and hormone replacement should be a much higher priority for endocrinologists and the pharmaceutical industry. One of the major impediments to our research on the importance of these cortisol rhythms in our patients has been our inability to measure repeated levels of hormones across the day in patients in their home or work surroundings. We describe how new wearable methodologies now allow the measurement of 24-h cortisol profiles - including during sleep - and will enable us to define physiological normality and allow us both to develop better diagnostic tests and inform, at an individual patient level, how to improve replacement therapy.

Bilateral inferior petrosal sinus sampling in the differential diagnosis of ACTH-dependent Cushing's syndrome: A reappraisal.

Cushing's syndrome (CS) is a rare disorder, once exogenous causes have been excluded. However, when diagnosed, the majority of cases are adrenocorticotropic hormone (ACTH)-dependent, of which a substantial minority are due to a source outside of the pituitary, ectopic ACTH syndrome (EAS). Differentiating among pituitary-dependent CS, Cushing's disease (CD) and an ectopic source can be problematic. Because non-invasive tests in the evaluation of CS patients often lack adequate sensitivity and specificity, bilateral inferior petrosal sinus sampling (BIPSS), a minimally invasive procedure performed during the investigation of ACTH-dependent CS, can be extremely helpful. BIPSS is considered to be the gold standard for differentiating CD from the EAS. Furthermore, although such differentiation may indeed be challenging, BIPSS is itself a complex investigation, especially in recent times due to the widespread withdrawal of corticotrophin-releasing hormone and its replacement by desmopressin. We review current published data on this investigation and, in the light of this and our own experience, discuss its appropriate use in diagnostic algorithms.

Disruptions to protein kinase A localization in adrenal pathology.

Cell signaling fidelity requires specificity in protein-protein interactions and precise subcellular localization of signaling molecules. In the case of protein phosphorylation, many kinases and phosphatases exhibit promiscuous substrate pairing and therefore require targeting interactions to modify the appropriate substrates and avoid cross-talk among different pathways. In the past 10 years, researchers have discovered and investigated how loss of specific interactions and subcellular targeting for the protein kinase A catalytic subunit (PKAc) lead to cortisol-producing adenomas and the debilitating stress disorder adrenal Cushing's syndrome. This article reviews classical studies regarding PKA localization in glucocorticoid-producing adrenal cells and synthesizes recent evidence of disrupted PKA localization and selective regulatory interactions in adrenal pathology.

Cosyntropin Stimulation Testing is More Selective than Postoperative Day 1 Basal Cortisol for Diagnosing Secondary Adrenal Insufficiency After Unilateral Adrenalectomy.

BACKGROUND: Secondary adrenal insufficiency (SAI) may occur in patients after unilateral adrenalectomy for adrenal-dependent hypercortisolism (HC) or primary aldosteronism (PA). This study aimed to assess whether postoperative day (POD) 1 basal cortisol was predictive of an abnormal cosyntropin stimulation test (CST) result and the need for glucocorticoid replacement (GR). METHODS: A retrospective review of consecutive patients who underwent unilateral adrenalectomy for HC, PA, or both between September 2014 and September 2022 was performed. On POD1, CST was performed for all the patients with HC, and before 2021 for all the patients with PA. The patients with an abnormal CST result were deemed at risk of SAI and discharged with GR. Receiver operating characteristic (ROC) curves were generated to evaluate the sensitivity (SN) and specificity (SP) of basal cortisol thresholds to predict an abnormal CST result. RESULTS: The patients underwent unilateral adrenalectomy for overt hypercortisolism (OH; n = 42), mild autonomous cortisol excess (MACE; n = 70), mixed PA/HC (n = 22), or PA (n = 73). On POD1, CST was performed for 152 patients (93% OH, 96% MACE,73% PA/HC, 41% PA), and 80 patients (53%) had SAI (67% OH, 55% MACE, 44% PA/HC, 33% PA). The SN and SP of a basal cortisol level of 10 µg/dL or lower to predict an abnormal CST were respectively 92% and 77% for OH, 94% and 73% for MACE, 100% and 85% for PA, and 100% and 67% for PA/HC. The optimal basal cortisol level for predicting an abnormal CST for patients with PA or PA/HC was 5 µg/dL or lower (SN/SP, 100%). CONCLUSIONS: After unilateral adrenalectomy for HC, PA, or mixed PA/HC, POD1 CST improved identification of patients at risk for SAI compared with basal cortisol levels alone. The authors recommend that POD1 CST be performed to determine the risk for SAI and the need for postoperative GR after unilateral adrenalectomy for patients with HC.

Clinical features, diagnosis and treatment outcomes of Cushing's disease in children: A multicenter study.

OBJECTIVE: Since Cushing's disease (CD) is less common in the paediatric age group than in adults, data on this subject are relatively limited in children. Herein, we aim to share the clinical, diagnostic and therapeutic features of paediatric CD cases. DESIGN: National, multicenter and retrospective study. PATIENTS: All centres were asked to complete a form including questions regarding initial complaints, physical examination findings, diagnostic tests, treatment modalities and follow-up data of the children with CD between December 2015 and March 2017. MEASUREMENTS: Diagnostic tests of CD and tumour size. RESULTS: Thirty-four patients (M:F = 16:18) from 15 tertiary centres were enroled. The most frequent complaint and physical examination finding were rapid weight gain, and round face with plethora, respectively. Late-night serum cortisol level was the most sensitive test for the diagnosis of hypercortisolism and morning adrenocorticotropic hormone (ACTH) level to demonstrate the pituitary origin (100% and 96.8%, respectively). Adenoma was detected on magnetic resonance imaging (MRI) in 70.5% of the patients. Transsphenoidal adenomectomy (TSA) was the most preferred treatment (78.1%). At follow-up, 6 (24%) of the patients who underwent TSA were reoperated due to recurrence or surgical failure. CONCLUSIONS: Herein, national data of the clinical experience on paediatric CD have been presented. Our findings highlight that presenting complaints may be subtle in children, the sensitivities of the diagnostic tests are very variable and require a careful interpretation, and MRI fails to detect adenoma in approximately one-third of cases. Finally, clinicians should be aware of the recurrence of the disease during the follow-up after surgery.

A long-term prognosis study of human USP8-mutated ACTH-secreting pituitary neuroendocrine tumours.

OBJECTIVE: Somatic variants in the ubiquitin-specific protease 8 (USP8) gene are the most common genetic cause of Cushing disease. We aimed to explore the relationship between clinical outcomes and USP8 status in a single centre. DESIGN, PATIENTS AND MEASUREMENTS: We investigated the USP8 status in 48 patients with pituitary corticotroph tumours. A median of 62 months of follow-up was conducted after surgery from November 2013 to January 2015. The clinical, biochemical and imaging features were collected and analysed. RESULTS: Seven USP8 variants (p.Ser718Pro, p.Ser719del, p.Pro720Arg, p.Pro720Gln, p.Ser718del, p.Ser718Phe, p.Lys713Arg) were identified in 24 patients (50%). USP8 variants showed a female predominance (100% vs. 75% in wild type [WT], p = .022). Patients with p.Ser719del showed an older age at surgery compared to patients with the p.Pro720Arg variant (47- vs. 24-year-olds, p = .033). Patients with p.Pro720Arg showed a higher rate of macroadenoma compared to patients harbouring the p.Ser718Pro variant (60% vs. 0%, p = .037). No significant differences were observed in serum and urinary cortisol and adrenocorticotropin hormone (ACTH) levels. Immediate surgical remission (79% vs. 75%) and long-term hormone remission (79% vs. 67%) were not significantly different between the two groups. The recurrence rate was 21% (4/19) in patients harbouring USP8 variants and 13% (2/16) in WT patients. Recurrence-free survival presented a tendency to be shorter in USP8-mutated individuals (76.7 vs. 109.2 months, p = .068). CONCLUSIONS: Somatic USP8 variants accounted for 50% of the genetic causes in this cohort with a significant female frequency. A long-term follow-up revealed a tendency toward shorter recurrence-free survival in USP8-mutant patients.

Diagnostic and management challenges in paediatric Cushing's syndrome.

OBJECTIVE: Cushing syndrome (CS) is the result of chronic exposure to glucocorticoid excess. CS in children is most often caused by the administration of exogenous steroids. Endogenous CS is rare in the paediatric population and is caused mainly by tumours of the pituitary and adrenal glands, with ectopic sources being extraordinarily rare before the age of 18 years. In addition, children and young adults with CS present with different epidemiology, management issues, prognosis and outcomes than older adult patients. This complex disorder needs early diagnosis and management to avoid the significant morbidity and even mortality that can result from chronic untreated CS. METHODS: In this review, we present the complex case of a 7-year-old boy with CS that highlights the diagnostic and management challenges of paediatric CS patients, including the considerations for genetic predisposition and life-long consequences of CS in children and young adults. RESULTS: The diagnostic protocols for the evaluation of CS have been devised for adults and tested predominantly on adults. In this review, we discuss necessary modifications so that the testing can be adjusted for use in children. Additionally, pituitary adenomas in children are generally smaller and thus more difficult to recognize on pituitary imaging. CONCLUSIONS: The management of the case and its complexities underline the need for children with CS to be managed in a centre with experienced paediatric endocrinologists and skilled neurosurgeons both for their initial diagnosis and treatment as well as for their long-term follow-up and management.

Beyond symptomatology: A comparative analysis of unilateral and bilateral macronodular mild autonomous cortisol secretion.

OBJECTIVE: To investigate the clinical, laboratory findings and signal intensity index (SII) on magnetic resonance imaging (MRI) of patients with bilateral and unilateral macronodular mild autonomous cortisol secretion (MACS). PATIENTS AND MEASUREMENTS: Clinical and laboratory findings of 81 patients with MACS were examined from retrospective records. SII of adenomas and internodular areas were evaluated by MRI. The unilateral group included patients with an adrenal macronodule (≥1 cm) in a single adrenal gland, while the bilateral group included patients with at least one macronodule in both adrenal glands. RESULTS: In total, 46 patients were in the unilateral (57%), while 35 (43%) patients were in the bilateral groups. The dehydroepiandrosterone sulphate (DHEA-S) level was lower in the unilateral than in the bilateral group (p < .001). The presence of type 2 diabetes mellitus (T2DM), glycosylated haemoglobin (HbA1c) and low-density lipoprotein (LDL) concentrations were higher in the bilateral group (p < .05). However, no significant difference was detected in terms of adrenocorticotropic hormone (ACTH) and overnight 1 mg dexamethasone suppression test (DST) between the two groups (p > .05). There was no difference in SII between adenomas within the same patient, as well as between the unilateral and bilateral groups (p > .05). Logistic regression analysis based on the differentiation between unilateral and bilateral macronodular MACS demonstrated that DHEA-S, HbA1c and LDL concentrations were associated factors. CONCLUSION: DHEA-S levels may not be as suppressed in patients with bilateral macronodular MACS as compared to those with unilateral adenoma. T2DM and hypercholesterolaemia have a higher frequency in bilateral patients. However, ACTH, overnight 1 mg DST and SII may not provide additional information for differentiation of bilaterality and unilaterality.

Assessment of plasma dexamethasone levels after 1-mg dexamethasone suppression test in adults with obesity.

BACKGROUND: The 1-mg overnight dexamethasone suppression test is the most frequently used screening test for Cushing's syndrome. It has been proposed that people with obesity may have insufficient plasma dexamethasone levels for the test which may result in false positives. We sought to compare the plasma dexamethasone levels after 1-mg dexamethasone suppression test in healthy obese participants and in optimal-weight participants. METHODS: A total of 30 optimal-weight participants (BMI ≤ 25 kg/m2 ) and 62 obese participants (BMI > 25 kg/m2 ) were enroled in the study. Obese participants were further divided into class 1 (25-29.9 kg/m2 ) and class 2 (>30 kg/m2 ). After a standard overnight 1-mg dexamethasone suppression test, blood samples were obtained for serum cortisol and plasma dexamethasone levels. Plasma dexamethasone levels were quantified using liquid chromatography - mass spectrometry (LC-MS/MS). RESULTS: No significant difference in plasma dexamethasone levels were found between obese and optimal-weight participants (3.31 ± 1.35 vs. 2.82 ± 1.11 nmol/L, mean ± SD; p = .09 respectively). There were also no correlations found between sex, BMI, body surface area and plasma dexamethasone levels. There was also no significant difference in the proportion of participants who achieved a plasma dexamethasone level >3.3 nmol/L in comparison between obesity class 1, obesity class 2, and optimal-weight groups. CONCLUSION: Our results suggest that obesity does not affect plasma dexamethasone levels. However, dexamethasone measurement may still be helpful in patients who are being investigated for Cushing's syndrome and suspected to have a false-positive DST.

Reversibility of Impaired Large-Scale Functional Brain Networks in Cushing's Disease after Surgery Treatment: A Longitudinal Study.

INTRODUCTION: Chronic exposure to excessive endogenous cortisol leads to brain changes in Cushing's disease (CD). However, it remains unclear how CD affects large-scale functional networks (FNs) and whether these effects are reversible after treatment. This study aimed to investigate functional network changes of CD patients and their reversibility in a longitudinal cohort. METHODS: Active CD patients (N = 37) were treated by transsphenoidal pituitary surgery and reexamined 3 months later. FNs were computed from resting-state fMRI data of the CD patients and matched normal controls (NCs, N = 37). A pattern classifier was built on the FNs to distinguish active CD patients from controls and applied to FNs of the CD patients at the 3-month follow-up. Two subgroups of endocrine-remitted CD patients were identified according to their classification scores, referred to as image-based phenotypically (IBP) recovered and unrecovered CD patients, respectively. The informative FNs identified by the classification model were compared between NCs, active CD patients, and endocrine-remitted patients as well as between IBP recovered and unrecovered CD patients to explore their functional network reversibility. RESULTS: All 37 CD patients reached endocrine remission after treatment. The classification model identified three informative FNs, including cerebellar network (CerebN), fronto-parietal network (FPN), and default mode network. Among them, CerebN and FPN partially recovered toward normal at 3 months after treatment. Moreover, the informative FNs were correlated with 24-h urinary-free cortisol and emotion scales in CD patients. CONCLUSION: These findings suggest that CD patients have aberrant FNs that are partially reversible toward normal after treatment.

Pediatric Macrocorticotropinoma: Do They Differ from Microcorticotropinoma?

INTRODUCTION: Cushing's disease (CD) due to macrocorticotropinoma (MC) in children and adolescents is a rare entity with limited information regarding its characteristics. The objective of the study is to describe the clinical, biochemical, imaging, management, outcome, and genetic characteristics of children and adolescents with CD due to MC and compare them with those of microcorticotropinoma (mc). METHODS: This retrospective study was conducted at a single tertiary care center. Thirty-two patients with CD and MC (maximum tumor dimension ≥10 mm on imaging) and 65 patients with mc (<10 mm on imaging) aged ≤20 years at presentation were enrolled. RESULTS: Nineteen girls and 13 boys with MC presented at a median (IQR) age of 14.5 (12.0-17.9) years. Patients with MC had higher body mass index-standard deviation score (BMI-SDS) (3.70 ± 2.60 vs. 2.59 ± 2.01, p = 0.04), more frequent neuro-ophthalmic symptoms (25% vs. 9% p = 0.04) and short stature (59% vs. 34%, p = 0.049) but less frequent livid striae (53% vs. 77%, p = 0.01), hypokalemia (12% vs. 36%, p = 0.04), and lower cortisol (nmol/L) to corticotropin (pmol/L) ratio (41.20 vs. 55.74, p = 0.04) than those with mc. The remission (59% vs. 64%, p = 1.0) and relapse (53% vs. 37%, p = 0.26) rates after first-line surgery and remission rate after radiotherapy (RT) were comparable between the two cohorts, whereas time to remission after RT (27 vs. 13 months, p = 0.05) was longer in the MC group. A patient with MC had a pathogenic germline variant in CDH23. CONCLUSION: In this large monocentric series of pediatric CD, frequent mass effect symptoms and short stature, higher BMI-SDS, less frequent livid striae, and hypokalemia with lower effective cortisol secretion characterize the MC cohort. The outcomes of surgery and RT were similar between the groups except for a longer time to remission after RT in the MC cohort. Germline variants are rare (4%) in pediatric MC.

Cushing's Disease May Have Higher Incidence than Previously Thought: A Nationwide Study in Iceland 2010-2019.

INTRODUCTION: In 2011, we reported the overall incidence of Cushing's disease (CD) in Iceland from 1955 through 2009 to be 1.5 cases per million per year with highest incidence in the last decade of the study, a higher incidence then earlier reported. We now present a follow-up study reporting the epidemiology of the disease in Iceland during the 10-year period from 2010 to 2019. METHODS: In this nationwide retrospective study, clinical information on patients diagnosed with CD was obtained from electronic medical records, reviewed by consulting endocrinologists. RESULTS: Seventeen patients were diagnosed with CD, 12 women (71%) and 5 men (29%) giving an overall incidence of 5.2 cases per million per year. The mean age at diagnosis was 46 years (range 13-85 years). Biochemical analysis was recorded for all patients and 12 patients (71%) had visible pituitary adenoma on imaging studies. Sixteen patients (94%) were treated with transsphenoidal surgery of which 4 patients (24%) had gamma knife radiosurgery and three (18%) bilateral adrenalectomy after pituitary surgery. Two patients died during the study period. CONCLUSION: The overall incidence of CD of 5.2 cases per million per year is higher than previously reported, indicating the importance of awareness of CD. As all patients with CD are diagnosed and/or treated at the only University Hospital in Iceland, housing the only department of endocrinology as well as neurosurgery, we are confident that all cases diagnosed during the study period were included in the study.

Cushing's syndrome developing myasthenia gravis with takotsubo cardiomyopathy after adrenalectomy: a case report.

BACKGROUND: Several cases of autoimmune disease onset after treatment for Cushing's syndrome have been reported. CASE PRESENTATION: Herein, we report a case of myasthenia gravis crisis in a 51-year-old woman 2 months after adrenalectomy for adrenal Cushing's syndrome accompanied by takotsubo cardiomyopathy. The resolution of excessive endogenous cortisol after adrenalectomy may have triggered the onset of previously latent myasthenia gravis. CONCLUSIONS: Observing the similarities in symptoms between myasthenia gravis and adrenal crisis, which can sometimes be challenging to differentiate, is essential. Moreover, the presence of takotsubo cardiomyopathy as a non-motor manifestation of myasthenic crisis must be noted.

Thyroid function spectrum in Cushing's syndrome.

PURPOSE: Thyroid disorders have been reported in hypercortisolism patients. Endogenous Cushing's syndrome (CS) potentially complicates its metabolic sequelae. We investigated thyroid function in CS patients to determine this relationship. METHODS: In this cross-sectional study, we screened CS patients from 2016 to 2019 at our hospital. Patient demographic, medical history, and laboratory data were collected. Additionally, we performed a meta-analysis to demonstrate the prevalence of thyroid dysfunction in patients with CS. RESULTS: Among 129 CS patients, 48.6% had triiodothyronine (TT3), 27.9% had thyroxine (TT4), 24.6% had free T3 (FT3), 27.7% had free T4 (FT4), and 6.2% had thyroid-stimulating hormone (TSH) levels below the reference values. Those with clinical CS showed more pronounced thyroid suppression than did those with subclinical CS. Cortisol levels were markedly greater in patients with pituitary hypothyroidism (P < 0.001). Serum cortisol levels throughout the day and post low-dose dexamethasone-suppression test (LDDST) results correlated with thyroid hormone levels, particularly in ACTH-independent CS. Correlations varied by thyroid status; FT3 and TSH were linked to cortisol in euthyroid individuals but not in those with low T3 or central hypothyroidism. TSH levels notably halved from the lowest to highest cortisol tertile post-LDDST. Finally, meta-analysis showed 22.7% (95% CI 12.6%-32.9%) central hypothyroidism in 528 CS patients of nine studies. CONCLUSION: Thyroid hormone levels are significantly correlated with cortisol levels and are impaired in patients with CS. However, the physiological adaptation and pathological conditions need further study.

Targeted analysis of Ubiquitin-Specific Peptidase (USP8) in a population of Iranian people with Cushing's disease and a systematic review of the literature.

OBJECTIVE: Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs. METHODS: Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases. RESULTS: In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas. CONCLUSION: Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies.

Long-term outcome of retroperitoneoscopic partial versus total adrenalectomy in patients with Cushing's syndrome.

BACKGROUND: We analyze the long-term outcome of surgery for Cushing's syndrome (CS) and the influence of the extent of surgical resection on the duration of postoperative cortisone substitution. METHODS: One-hundred forty-one patients (129 female, 12 males; mean age: 45.7 ± 12.8 years) operated between January 2000 to June 2020 were included in the analysis. Patients suffered from manifest (124) or subclinical (17) CS due to benign unilateral adrenal neoplasia. All tumors were removed by the posterior retroperitoneoscopic approach. 105 patients had total (TA) and 36 partial (PA) adrenalectomies. All patients were discharged with ongoing corticosteroid supplementation therapy. RESULTS: Follow-up data could be obtained for 83 patients. Twenty-four (1 male, 23 females; mean age 42.3 years) underwent PA and 59 TA (6 males, 53 females; mean age 44.6 years). Mean follow-up time was 107 ± 68 months (range: 6-243 months). The median duration of postoperative corticosteroid therapy was 9.5 months after PA and 11 months after TA (p = 0.1). Significantly, more patients after total adrenalectomy required corticosteroid therapy for more than 24 months (25% vs. 4%; p = 0.03). Recurrent ipsilateral disease occurred in one case after partial adrenalectomy and was treated by completion adrenalectomy. A case of contralateral recurrence associated with subclinical Cushing's syndrome was observed after total adrenalectomy. CONCLUSIONS: The risk of local recurrence after partial adrenalectomy in CS is low. Cortical-sparing surgery may shorten corticosteroid supplementation therapy after surgery.

Impact of etiology, sex, diabetes mellitus and remission status on erythrocytic profile in patients with cushing's syndrome: a large population database study.

PURPOSE: The study aimed to characterize the erythrocytic profile in patients with cushing's syndrome (CS) versus controls from the normal population according to etiology, sex, presence of diabetes mellitus (DM) and hypercortisolemia remission status. METHODS: This retrospective cohort analysis compared erythrocytic parameters between patients with CS of pituitary (CD) and adrenal (aCS) etiology and age, sex, body mass index (BMI) and socioeconomic status-matched controls in a 1:5 ratio. Laboratory values at baseline were calculated as mean values during the year preceding CS diagnosis, and over one year thereafter. RESULTS: The cohort included 397 CS patients (68.26% female; mean age 51.11 ± 16.85 years) and 1970 controls. Patients with CS had significantly higher baseline median levels of hemoglobin (Hgb) (13.70 g/dL vs. 13.12 g/dL [p < 0.0001]) and hematocrit (Hct) (41.64% vs. 39.80% [p < 0.0001]) compared to controls. These differences were observed for both CD and aCS and for both sexes. Patients who attained remission had Hgb and Hct levels comparable to controls (13.20 g/dL and 40.08% in patients with CD and aCS vs. 13.20 g/dL and 39.98% in controls). Meanwhile, those with persistent/recurrent disease maintained elevated levels. Patients with comorbid DM had similar Hgb but higher Hct (p = 0.0419), while patients without DM showed elevated erythrocytic values compared to controls (p < 0.0001). CONCLUSION: Our data illustrates that erythrocytic parameters are directly influenced by glucocorticoid excess as Hgb and Hct are higher in patients with CS, and normalize after remission. We have identified the influence of DM on erythrocytic parameters in patients with CS for the first time.

A medical chart audit to assess endocrinologist perceptions of the burden of endogenous Cushing's syndrome.

PURPOSE: This study was undertaken to assess the unmet needs within the endogenous Cushing's syndrome (CS) care paradigm from the endocrinologist's perspective, including data abstracted from patient charts. The study evaluated endocrinologists' perceptions on burden of illness and treatment rationale along with the long-term clinical burden of CS, tolerability of CS treatments, and healthcare resource utilization for CS. METHODS: Retrospective medical chart data from treated patients with a confirmed diagnosis of CS was abstracted using a cross-sectional survey to collect data from qualified endocrinologists. The survey included a case report form to capture patient medical chart data and a web-enabled questionnaire to capture practitioner-level data pertaining to endocrinologists' perceptions of disease burden, CS treatments, and treatment attributes. RESULTS: Sixty-nine endocrinologists abstracted data from 273 unique medical charts of patients with CS. Mean patient age was 46.5 ± 13.4 years, with a 60:40 (female:male) gender split. The mean duration of endogenous CS amongst patients was 4.1 years. Chart data indicated that patients experienced a high burden of comorbidities and symptoms, including fatigue, weight gain, and muscle weakness despite multi-modal treatment. When evaluating treatments for CS, endocrinologists rated improvement in health-related quality of life (HRQoL) as the most important treatment attribute (mean score = 7.8; on a scale of 1 = Not at all important to 9 = Extremely important). Surgical intervention was the modality endocrinologists were most satisfied with, but they agreed that there was a significant unmet treatment need for patients with CS. CONCLUSION: Endocrinologists recognized that patients with CS suffered from a debilitating condition with a high symptomatic and HRQoL burden and reported that improvement in HRQoL was the key treatment attribute influencing their treatment choices. This study highlights unmet needs for patients with CS. Patients with CS have a high rate of morbidity and comorbidity, even after treatment.