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Background. Transsphenoidal surgery is the treatment of choice for Cushing's disease. Successful surgery is associated with subnormal postoperative serum cortisol concentrations and cortisoluria levels, which may guide decisions regarding immediate reoperation. Remission is defined as the biochemical reversal of hypercortisolism with the re-emergence of diurnal circadian rhythm. Methods. A single-center prospective cohort study was conducted among thirty-three patients who underwent transsphenoidal pituitary surgery for Cushing's disease. Postoperative surgical outcomes, daily morning cortisolemia, and 24 h urinary-free cortisol from the first to the fifth morning were evaluated. Results. All patients underwent surgery, with a remission rate of 81.2%. Of the 26 patients who achieved early remission, 92% remained in remission. Two patients (7.7%) showed recurrence of Cushing's disease during a mean follow-up of 81.7 months. Early postoperative hypocortisolism suggests complete removal of the tumor, correlating with high rates of remission (p < 0.001). Also, in 12.5% of patients with early cortisol values >138 nmol/L, there was a gradual late remission. Conclusions. In our cohort of patients, the endoscopic transsphenoidal approach was safe and effective in the treatment of Cushing's disease. We demonstrated that serum and urinary cortisol concentrations did not experience significant fluctuations from the first to the fifth day. This constitutes an accurate predictor of durable remission, comprising a distinctive finding in the intermediate term by our team. [ABSTRACT FROM AUTHOR]

The majority of corticotroph adenomas are benign but some are locally invasive, demonstrate high rates of recurrence, and exhibit a relatively poor response to often repeated surgical, medical, and radiation treatment. Herein, we summarize the currently known somatic and genetic mutations and other molecular factors that influence the pathogenesis of these tumors and discuss currently available therapies. Although recent molecular studies have advanced our understanding of the pathogenesis and behavior of these refractory corticotroph adenomas, these insights do not reliably guide treatment choices at present. Development of additional diagnostic tools and novel tumor-directed therapies that offer efficacious treatment choices for patients with refractory corticotroph adenomas are needed.

Background. Transsphenoidal surgery is the treatment of choice for Cushing’s disease. Successful surgery is associated with subnormal postoperative serum cortisol concentrations and cortisoluria levels, which may guide decisions regarding immediate reoperation. Remission is defined as the biochemical reversal of hypercortisolism with the re-emergence of diurnal circadian rhythm. Methods. A single-center prospective cohort study was conducted among thirty-three patients who underwent transsphenoidal pituitary surgery for Cushing’s disease. Postoperative surgical outcomes, daily morning cortisolemia, and 24 h urinary-free cortisol from the first to the fifth morning were evaluated. Results. All patients underwent surgery, with a remission rate of 81.2%. Of the 26 patients who achieved early remission, 92% remained in remission. Two patients (7.7%) showed recurrence of Cushing’s disease during a mean follow-up of 81.7 months. Early postoperative hypocortisolism suggests complete removal of the tumor, correlating with high rates of remission (p < 0.001). Also, in 12.5% of patients with early cortisol values >138 nmol/L, there was a gradual late remission. Conclusions. In our cohort of patients, the endoscopic transsphenoidal approach was safe and effective in the treatment of Cushing’s disease. We demonstrated that serum and urinary cortisol concentrations did not experience significant fluctuations from the first to the fifth day. This constitutes an accurate predictor of durable remission, comprising a distinctive finding in the intermediate term by our team.

Introduction: Endogenous Cushing's syndrome (CS) is a rare, severe disease that can cause multiple systemic involvements and behavioral problems due to excessive cortisol production. Structural changes can be noted in the brain magnetic resonance imaging (MRI) scans of these cases. Cases: A 9-year-old girl and a 13-year-old boy were admitted with hypercortisolism. In the female patient, altered consciousness was prominent along with cerebral and cerebellar brain atrophy, and findings indicating posterior reversible encephalopathy syndrome were detected in the brain MRI. Although the male patient's neurological examination was normal, significant cerebral atrophy was seen in the brain MRI. Case 1 was diagnosed as having ectopic ACTH syndrome (EAS) due to a thymic carcinoid tumor. Case 2 underwent a pulmonary lobectomy upon detection of a bronchial lesion in the Ga-68 DOTATATE PET/CT scan while being examined for EAS due to a lack of suppression in the high-dose dexamethasone suppression test. However, hypercortisolism persisted despite the removal of the bronchial lesion, and subsequently, a diagnosis of Cushing's disease was established following bilateral inferior petrosal sinus sampling. Discussion: Endogenous hypercortisolism may cause brain atrophy of varying severity. The central nervous system findings can be overlooked in children with CS. More comprehensive studies are needed to better understand the behavioral changes caused by the effects on the brain and to evaluate whether these changes are reversible. In addition, identifying the source of hypercortisolism can be difficult due to a lack of experience related to the rarity of the disease in children. [ABSTRACT FROM AUTHOR]

Cushing’s disease (CD) is associated with an increased risk of venous thromboembolic events. The purpose of this review is to discuss preventive strategies for post-operative thrombosis in CD patients and their impact on patient outcomes. A systematic review under PRISMA guidelines was conducted within PubMed, Embase, Web of Science, and Cochrane databases through July 2022. Of the 3207 papers retrieved, seven articles were included in this systematic review. Four hundred forty-eight patients were presented in the reviewed studies and the overall reported mortality was 2.67% (12/448). Three studies utilized prophylaxis methods including graduated compression stockings (GCS) and early ambulation (EA) while the remaining four studies only used anticoagulation medicine. Only 20 patients received pre-operative prophylactic treatment, while 366 patients received post-operative prophylaxis which was delivered either immediately after surgery or at different time intervals within 2 days following the surgery. Thrombotic events mainly occurred within two to 3 months after surgery. Overall, a higher frequency of thromboembolic events and mortality was observed in the control groups in comparison to groups receiving prophylaxis. A combination of anticoagulation, EA, and GCS might reduce thrombotic events and mortality in CD patients after treatment. Although the early commencement of a prophylactic anticoagulation regimen on the same day of surgery and continuing up to 3 months seems beneficial, the application of a prophylactic regimen should be utilized with caution since the number of included studies was insufficient to draw a strong conclusion, as well as neither prospective study nor randomized controlled trials existed. [ABSTRACT FROM AUTHOR]

BackgroundCushing disease (CD), although rare, is a life-threatening disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, which leads to excess adrenal-derived cortisol. Efficacious and safe medical therapies that control both hormonal hypersecretion and pituitary corticotroph tumor growth remain an unmet need in the management of CD. Translational research in pituitary tumors has been significantly hampered by limited quantities of surgically resected tissue for ex vivo studies, and unavailability of human pituitary tumor cell models.MethodsTo characterize human corticotroph tumors at the cellular level, we employed single cell RNA-sequencing (scRNA-seq) to study 4 surgically resected tumors. We also used microarrays to compare individualized paired consecutive culture passages to understand transcriptional shifts as in vitro cultures lost ACTH secretion. Based on these findings, we then modified our in vitro culture methods to develop sustained ACTH-secreting human corticotroph tumoroid cultures.FindingsscRNA-seq identified 4 major cell populations, namely corticotroph tumor (73.6%), stromal (11.2%), progenitor (8.3%), and immune cells (6.8%). Microarray analysis revealed striking changes in extracellular matrix, cell adhesion and motility-related genes concordant with loss of ACTH secretion during conventional 2D culture. Based on these findings, we subsequently defined a series of crucial culture nutrients and scaffold modifications that provided a more favorable trophic and structural environment that could maintain ACTH secretion in in vitro human corticotroph tumor cultures for up to 4 months.InterpretationOur human corticotroph tumoroid model is a significant advance in the field of pituitary tumors and will further enable translational research studies to identify critically needed therapies for CD.FundingThis work was partly funded by NCI P50-CA211015 and the Warley Trust Foundation.

Objective: Transsphenoidal surgery (TSS) is the first-line treatment for Cushing’s disease. The objectives of the study were to determine remission and recurrence rates after TSS for Cushing’s disease, identify factors that predict these outcomes, and define the threshold for postoperative morning serum cortisol (MSeC) that most accurately predicts sustained remission. Methods: Records were retrospectively reviewed for consecutive adults undergoing TSS for Cushing’s disease at a tertiary centre (1990–2019). Remission was defined as MSeC

Recurrent Cushing disease (CD) is characterized by the reappearance of clinical and hormonal aspects of hypercortisolism that occur more than 6 months after an initial post-treatment remission. We performed a systematic review and meta-analysis to synthesize the evidence about remission and complication rates after transsphenoidal surgery (TSS) radiotherapy (RT) and medical therapy (MT) in recurrent CD patients. A quantitative systematic review was performed. Article selection was performed by searching MEDLINE (using PubMed), and Cochrane electronic bibliographic databases through 2020. We noted 61 articles described therapeutic management of recurrent CD patients with representative outcome. A total of 723 patients received different therapeutic modality for their recurrent CD. The remission rates were 0.65 (95% confidence interval [CI] 0.60–0.70), 0.57 (95% CI 0.51–0.63), and 0.75 (95% CI 0.60–0.86) in the TSS, RT, and MT subgroups, respectively. The total remission rate after therapeutic approaches on recurrent CD patients was 0.64 (95% CI 0.60–0.68). A test for subgroup differences revealed there was a statistically significant difference between different subgroups (P = 0.01). The post hoc test showed that in comparison with RT, TSS (P = 0.0344) and MT (P = 0.0149) had a higher rate of remission. However, there was no statistically significant difference between separate therapeutic modalities in terms of complications including diabetes insipidus (P = 1.0) and hypopituitarism (P = 0.28). Compared MT and TSS, RT has a statistically lower rate of remission. Although there is robust superiority of surgery over RT, interpretation of MT data must considered with caution due to the small number of included cases and wide CI range. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To define the incidence and risk factors of postoperative sodium alterations in pediatric patients undergoing transsphenoidal surgery (TSS) for adrenocorticotropic hormone and growth hormone secreting pituitary adenomas. STUDY DESIGN: We retrospectively reviewed 160 patients ≤18 years of age who had TSS for pituitary adenomas at our institution from 1999 to 2017. Variables included daily serum sodium through postoperative day 10, urine specific gravity, and medications administered. We examined associations between sex, repeat surgery, manipulation of the posterior pituitary (PP), tumor invasion into the PP, tumor type and size, cerebrospinal fluid (CSF) leak, lumbar drain insertion, body mass index, puberty, and development of diabetes insipidus (DI) or syndrome of inappropriate antidiuretic hormone secretion (SIADH). RESULTS: Mean age was 12.9 ± 3.4 years (female = 81). Patients had adrenocorticotropic hormone (150/160) and growth hormone (10/160) producing adenomas. Forty-two (26%) patients developed DI. Among the 37 of 160 who required desmopressin acutely, 13 of 37 required it long term. Risk of long-term need for desmopressin was significantly higher in patients who had CSF leak 9 of 48 (P = .003), lumbar drain 6 of 30 (P = .019), manipulation 11 of 50 (P

CONTEXT: Achievement of hypocortisolemia following transsphenoidal surgery (TSS) for Cushings disease (CD) is associated with successful adenoma resection. However, up to one-third of these patients recur. OBJECTIVE: We assessed whether delay in reaching post-operative cortisol nadir may delineate patients at risk of recurrence for CD following TSS. METHODS: A retrospective review of 257 patients who received 291 TSS procedures for CD at NIH, between 2003 and 2016. Early biochemical remission (serum cortisol nadir

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BackgroundThe utility of circadian cortisol variation in estimating the degree of hypercortisolemia in different forms of endogenous Cushing syndrome (CS) has not been evaluated in children yet.MethodsA retrospective cohort study, including children who underwent surgery due to CS (n = 115), was divided into children with a pituitary adenoma (Cushing disease) (n = 88), primary adrenal CS (n = 21), or ectopic adrenocorticotropin- or corticotropin-releasing hormone (ACTH-/CRH)-secreting tumors (n = 6). Circadian plasma cortisol measurements were obtained at 11: 30 p.m. and at midnight, and at 7: 30 and 8: 00 a.m. The ratios between the morning and late-night concentrations were calculated.ResultsPlasma cortisol early-morning and midnight (AM/PM) ratios negatively correlated with 24-h urinary free cortisol (UFC) collections among the full study population and in each of the individual etiologies. Plasma ACTH concentrations positively correlated with plasma cortisol AM/PM ratios among patients with ACTH-independent CS. Finally, patients with primary pigmented nodular adrenocortical disease showed no correlation between UFC collections and the plasma cortisol AM/PM ratio, in contrast with other etiologies for primary adrenal CS, which showed a strong negative correlation between them.ConclusionOur study shows the association between the plasma cortisol AM/PM ratio and the degree of hypercortisolemia in children with CS.

Objective: Our objective is to present a case of Cushing’s disease (CD) with 2 adrenocorticotropic hormone (ACTH)-secreting pituitary tumors. Multiple monohormonal pituitary tumors are rare. This case supports a consideration of repeat transsphenoidal surgery (TSS) in patients with initial surgical failure. Methods: Salivary, 24-h urine, serum cortisol testing, and magnetic resonance imaging (MRI) were used to diagnose CD. Treatment included TSS and postoperative hydrocortisone. Results: A 36-year-old woman followed for hypothyroidism presented with a new left supraclavicular fossa swelling and underwent Cushing’s syndrome screening. The levels of late-night salivary cortisol were 0.636 and 0.316 μg/dL, 24-h urine cortisol was 162 μg/24 h, cortisol after 1-mg dexamethasone suppression was 14.0 μg/dL, and serum morning cortisol was 26.4 μg/dL with ACTH of 66.7 pg/mL. A 7-mm hypoenhancing anterior pituitary lesion was noted on pituitary MRI. The cortisol level was 2.7 μg/dL after an 8-mg dexamethasone suppression. She underwent TSS, and her histopathology read as pituitary adenoma staining positive for ACTH. No residual tumor was seen intraoperatively. Postoperative morning serum cortisol was 17.9 μg/dL, and ACTH level was 79 pg/mL. Repeat TSS revealed a second adenoma previously unseen on MRI, which also stained positive for ACTH. Postoperative morning cortisol was 0.7 μg/dL, and ACTH was