Recurrence Of Cushing's Disease Research Articles

8117 Late-night Salivary Cortisol in the Diagnosis of Cushing's Disease Recurrence

Abstract Disclosure: A.E. Alexandre: None. P.C. Elias: None. M. De Castro: None. L.M. Mermejo: None. D.C. Aragon: None. A.C. Moreira: None. Cushing’s Disease (CD) remission following transsphenoidal surgery (TSS) is most often defined by low morning cortisol levels and the requirement of glucocorticoid (GC) replacement therapy. However, CD recurrence is not a well studied event. There is no standard definition of remission criteria and no accurate cutoff for biochemical tests on CD recurrence. Late-night salivary cortisol (LNSC) has been shown to have higher accuracy in confirming CD recurrence than urinary free cortisol and dexamethasone suppression test (DST). However, few studies addressed LNSC performance following remission after TSS. The study aimed to establish cutoff values of LNSC with higher sensitivity (S) and specificity (E) in CD recurrence diagnosis.In a retrospective cohort study of 65 patients with remitted CD after TSS, remission was defined as improvement of sign and symptoms related to CD and a plasma cortisol <5mcg/dL in 30 days following TSS. Eleven patients progressed to permanent adrenal insufficiency and were excluded from the study. All 54 patients had at least four LNSC sampling and a minimal follow-up of 24 months after TSS. LNSC was determined by RIA. A cutoff value of 270 ng/dl for LNSC is used for the diagnosis of CD. Patients were divided in three different groups: Overt Recurrence (OR): elevated LNSC and worsening of CD`s signs and symptoms. Remission (RM): normal LNSC and no clinical signs of CD recurrence. Biochemical Recurrence (BR): at least 2 elevated biochemical parameters (LNSC or DST) but no worsening of signs and symptoms associated with CD. The mean of the 2 LNSC last values when OR was diagnosed and the mean of 2 LNSC last values of follow up for RM patients were used to estimate the accuracy of LNSC for diagnosing recurrence using a ROC curve (AUC) and its 95% confidence interval. Of the 54 patients included, 46 females; 8 males; mean age at diagnosis: 32 years, (5 – 58 yrs); mean time of follow-up: 12.8 years (4 – 31.7 yrs). Thirteen were classified as OR, 18 as RM and 23 as BR; and mean time of GC use after TSS was: 8.7; 34 and 17 yrs, respectively, significantly lower in OR compared to RM (p:0.046). A LNSC cutoff value of 272 mcg/dL had sensitivity of 85% and specificity of 95% (AUC: 0.97; 95% IC = [0.93; 1,00]) for CD recurrence diagnosis. BR patients presented LSNC fluctuation along follow-up.LNSC is a useful tool for CD recurrence screening. Setting LSNC specific assay cutoff values might be needed. LSNC cutoff values were similar for the initial CD diagnosis, as well as for CD recurrence diagnosis. Shorter time of GC replacement may be an important predictor of CD recurrence. Patients with BR should be followed more carefully as they may be at higher risk of recurrence. Multiple LNSC sampling on successive days can be easily performed and may detect subtle changes in cortisol rhythm. Presentation: 6/1/2024

Budget impact analysis of cabergoline for medical treatment of Cushing's disease in Brazil.

The aim of this study was to estimate the budget impact of adding cabergoline to the Brazilian Unified Health System (SUS) formulary for the treatment of patients with Cushing's disease (CD) who do not achieve disease control after transsphenoidal surgery. We conducted a budget impact analysis (BIA) from the perspective of the Brazilian SUS over a 5-year time horizon. We compared two scenarios: ketoconazole (Scenario 1) versus including cabergoline as a treatment option (Scenario 2). All analyses were conducted using Microsoft Excel. Uncertainty was explored in univariate sensitivity analyses. The total costs were BRL $25,596,729 for Scenario 1 and BRL $32,469,169 for Scenario 2. The budget impact of adding cabergoline to the formulary for CD treatment within the SUS would be BRL $6,091,036 over 5 years. On univariate analyses, variations in the rates of surgical failure and CD recurrence had the greatest potential to affect the final costs associated with cabergoline. The estimated budget impact of adding cabergoline to the formulary for CD treatment within the Brazilian SUS would be about BRL $6 million. While cost savings cannot be expected, the budget impact of adding cabergoline would be lower than that of adding other treatment options for CD.

Postoperative Serum Cortisol and Cushing Disease Recurrence in Patients With Corticotroph Adenomas.

In Cushing disease, the association between the rate of serum cortisol decline and recurrent disease after corticotroph adenoma removal has not been adequately characterized. To analyze postoperative serum cortisol and recurrence rates in Cushing disease. Patients with Cushing disease and pathology-confirmed corticotroph adenoma were retrospectively studied. Cortisol halving time was estimated using exponential decay modeling. Halving time, first postoperative cortisol, and nadir cortisol values were collected using immediate postoperative inpatient laboratory data. Recurrence and time-to-recurrence were estimated and compared among cortisol variables. A total of 320 patients met inclusion/exclusion criteria for final analysis, and 26 of those patients developed recurrent disease. Median follow-up time was 25 months (95% CI, 19-28 months), and 62 patients had ≥ 5 years follow-up time. Higher first postoperative cortisol and higher nadir were associated with increased risk of recurrence. Patients who had a first postoperative cortisol ≥ 50 µg/dL were 4.1 times more likely to recur than those with a first postoperative cortisol < 50 µg/dL (HR 4.1, 1.8-9.2; P = .0003). Halving time was not associated with recurrence (HR 1.7, 0.8-3.8, P = .18). Patients with a nadir cortisol ≥2 µg/dL were 6.6 times more likely to recur than those with a nadir cortisol of < 2 µg/dL (HR 6.6, 2.6-16.6, P < .0001). Postoperative nadir serum cortisol is the most important cortisol variable associated with recurrence and time-to-recurrence. Compared to first postoperative cortisol and cortisol halving time, a nadir < 2 µg/dL showed the strongest association with long-term remission and typically occurs within the first 24 to 48 hours after surgery.

Recurrent Cushing's Disease in Adults: Predictors and Long-Term Follow-Up.

Cushing's disease (CD) is characterized by endogenous hypercortisolism that is associated with increased mortality and morbidity. Due to high recurrence rates in CD, the determination of high-risk patients is of paramount importance. In this study, we aimed to determine recurrence rates and clinical, laboratory, and histological predictors of recurrence in a high volume single-center. This retrospective study included 273 CD patients operated in a single pituitary center between 1997 and 2020. The patients with early postoperative remission were further grouped according to recurrence status (recurrent and sustained remission groups). Demographic, radiologic, laboratory, pathologic, and follow-up clinical data of the patients were analyzed and compared between groups. The recurrence rate was 9.6% in the first 5 years; however, the overall recurrence rate was 14.2% in this study. Higher preoperative basal ACTH levels were significantly correlated with CD recurrence even with ACTH levels adjusted for tumor size, Ki-67 levels, and tumoral invasion. Recurrence rates were significantly higher in patients with ACTH levels higher than 55 pg/ml, tumor diameter>9.5 mm, and if adrenal axis recovery was before 6 months. The severity of hypercortisolism, morbidities, and demographic factors except age were not predictive factors of recurrence. Based on our study data, younger age at diagnosis, a diagnosis of osteoporosis, higher preoperative ACTH levels, larger tumor size, invasive behavior, higher Ki 67 index, and early recovery of the adrenal axis during the postoperative period attracted attention as potential predictors of recurrent disease.

Course of Cushing`s disease and treatment outcomes in correlation with pituitary MRI in children.

Cushing's disease (CD) is a rare disorder of a persistent cortisol excess caused by ACTH-secreting pituitary tumor (corticotropinoma). Transsphenoidal surgery (TSS) is a treatment of choice for СD, which effectiveness range is from 70 to 90%. Recurrence rate after successful treatment is about 25%. If surgical treatment is unsuccessful or recurrence appear, radiation treatment is the next therapeutic option, which effectiveness range is also 90%, but the hypopituitarism rate as side effect of treatment is higher. Preoperative predictors of remission and recurrence are still unexplored what leads to further investigations. Analysis of remission and recurrence rates of pediatric CD after successful treatment according to preoperative MRI and therapeutic option. We conducted a retrospective analysis of 90 pediatric patients with CD who were observed between 1992 and 2020 at the Endocrinology Research Centre. The most common clinical symptoms of CD were weight gain [94%] and growth retardation [72%]. Pituitary tumor was detected on radiological imaging in 53/90 patients [59%], there were no signs of visible adenoma in 37/90 of patients[41%]. 63 of 90 patients underwent TSS (70%), 27 patients underwent radiosurgery (30%). Remission rate after TSS was 71%[45/63], after radiosurgery - 85% [23/27]. There were no significant differences in remission rates after radical treatment according to preoperative MRI results (P=0.21 after TSS and P=0.87 after radiosurgery, х2 analysis). Recurrence after successful treatment was diagnosed in 10 patients. There were no significant differences in time to recurrence according to preoperative MRI results (P=0.055, х2 analysis). Time to recurrence was statistically different after TSS compared to radiosurgery (P=0.007, Kaplan-Meier analysis) and in the group with developed adrenal insufficiency in the early postoperative period (P=0.04, Kaplan-Meier analysis). Analysis of side effect of treatment showed that the frequency of growth hormone and gonadotrophin deficiency was statistically higher after radiosurgery (р&lt;0.01, Kruskel-Wallis ANOVA test). Diabetes insipidus was diagnosed only after TSS. Results of our study didn`t allow to use MRI-results as predictor of effectiveness treatment in pediatric CD. Therapeutic option has an impact on time to recurrence, not on recurrence rates. The frequency of growth hormone and gonadotrophin deficiency was statistically higher after radiosurgery compared to TSS. Further studies are needed to identify predictors of remission and recurrence in CD.&gt;&lt; 0.01, Kruskel-Wallis ANOVA test). Diabetes insipidus was diagnosed only after TSS. Results of our study didn`t allow to use MRI-results as predictor of effectiveness treatment in pediatric CD. Therapeutic option has an impact on time to recurrence, not on recurrence rates. The frequency of growth hormone and gonadotrophin deficiency was statistically higher after radiosurgery compared to TSS. Further studies are needed to identify predictors of remission and recurrence in CD.

Integrative Clinical, Radiological, and Molecular Analysis for Predicting Remission and Recurrence of Cushing Disease

Adrenocorticotropin (ACTH)-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus on remission and prevention of persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse. This work aimed to identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas. A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004 and 2018 with at least 2 years' follow-up. Clinical/biochemical variables were evaluated yearly. Molecular expression profile of the somatostatin/ghrelin/dopamine regulatory systems components and of key pituitary factors and proliferation markers were evaluated in tumor samples after the first surgery. Clinical variables including tumor size, time until diagnosis/first surgery, serum prolactin, and postsurgery cortisol levels were associated with tumor remission and relapsed disease. The molecular markers analyzed were distinctly expressed in ACTHomas, with some components (ie, SSTR1, CRHR1, and MKI67) showing instructive associations with recurrence and/or remission. Notably, an integrative model including selected clinical variables (tumor size/postsurgery serum cortisol), and molecular markers (SSTR1/CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a receiver operating characteristic curve with an area under the curve of 1 (P < .001). This study demonstrates that the combination of a set of clinical and molecular biomarkers in ACTHomas is able to accurately predict the clinical evolution and remission of patients. Consequently, the postsurgery molecular profile represents a valuable tool for clinical evaluation and follow-up of patients with ACTHomas.

The effects of cabergoline in the presurgical and recurrence periods of Cushing's disease patients.

The dopaminergic agonist cabergoline (CAB) has been used in the pharmacological treatment of Cushing's disease (CD). The effect is attributed to the frequent expression of the dopamine receptor subtype 2 in corticotroph tumors. However, in vivo studies have demonstrated the normalization of 24-h urinary cortisol (24-h UC) in approximately 30-40% of patients over the long term, mainly after surgical failure. To evaluate the effect of CAB as monotherapy in the early preoperative period and on the recurrence of CD. A single-center retrospective study was conducted in a tertiary referral center. Twenty-one patients with confirmed CD were included. The median age was 32 years (13-70), 86% were female, 10 had microadenomas, and 11 had macroadenomas. They were diagnosed from 1986 to 2016 and used CAB as monotherapy either in the preoperative period (n=7, CABi) or upon recurrence before any other treatment (n=14, CABr). A 'complete response' was considered 24-h UC normalization and a 'partial response' was considered a 24-h UC reduction of >50%. UC was obtained at the last follow-up evaluation. The normalization of late-night salivary cortisol (LNSC) after CAB use was evaluated in most patients, as well as the tumor diameter by pituitary MRI, before and after CAB treatment. Complete response was achieved in 29% (6/21) of subjects after 14.9±16.4 months of treatment, with an average dose of 2.2±1.0 mg/week. Partial response occurred in 9.5% (2/21). LNSC normalized in 35% (6/17) of patients, and no variation in tumor diameter before and after CAB use was observed (n=13): 6.8±6.8 vs. 7.2±7.1 mm. There was no normalization of 24-h-UC in the CABi subgroup at the end of the treatment, whereas 43% (6/14) of patients in the CABr subgroup reached complete response. The CABi subgroup was treated for 4.7±1.9 months, and the CABr subgroup was treated for 20.1±18.1 months. Both groups were administered similar doses of CAB (CABi 2.1±0.9 and CABr 2.3±1.1 mg/week). Interestingly, the difference between the subgroups' complete response was evident early on in the three months of treatment: no patients in the CABi subgroup vs. 6/10 (60%) in the CABr subgroup (p=0.035), despite a lower dose in the CABr subgroup (1.1 vs. 1.6; p=0.008). The normalization of LNSC occurred in 20% of the CABi subgroup and in 42% of the CABr subgroup. The normalization of 24-h UC and LNSC occurred in approximately 30% of all patients, mainly in those who used CAB for the recurrence of CD. Despite the small number of subjects in the CABi subgroup, the absence of hormone control in this subgroup discourages the use of this medication as primary therapy or as a preoperative treatment option.

Outcomes of Transsphenoidal Surgery in Cushing Disease Patients with Negative Pituitary Magnetic Resonance Imaging Findings: A Single-Center Experience

Transsphenoidal surgery (TSS) is a first-line treatment for Cushing disease (CD). However, a subset of patients with CD have no visible adenoma on magnetic resonance imaging (MRI), and whether MRI results affect surgical outcomes is controversial. The aim of this study was to compare the surgical outcomes of CD patients with negative MRI findings to those of patients with positive MRI findings. The clinical features and outcomes of CD patients who underwent TSS between January 2000 and July 2019 at Peking Union Medical College Hospital were collected from medical records. The clinical, endocrinologic, histopathologic, surgical outcomes, and a minimum 12-month follow-up of 125 consecutive CD patients with negative MRI findings were compared with those of 1,031 consecutive CD patients with MRI-visible adenomas. The total remission rate was 73.3% after TSS, and 11.8% of patients experienced recurrence. Of 1,031 patients with MRI-visible adenomas, postoperative remission was achieved in 762 patients (73.9%), and the recurrence of CD was observed in 94 (12.3%) patients. Of the 125 patients with negative MRI findings, postoperative remission was achieved in 85 (68%) patients, and recurrence was observed in 6 (7.1%) patients. The remission rate and recurrence rate were not significantly different between patients with negative MRI findings and those with positive MRI findings (all P>.05). The remission rate was not significantly different between patients who did or did not undergo bilateral inferior petrosal sinus sampling (BIPSS) in patients with negative MRI findings (P>.05). In the patients with negative MRI findings who underwent BIPSS, the remission rate of patients with positive BIPSS results was not different from that in patients with negative BIPSS results (P>.05). The lack of prior TSS, the detection of a tumor during operation, and pathologic confirmation of adenoma were associated with a higher surgical remission rate in patients with negative MRI findings (all P<.05). Similar results were observed in the patients with positive MRI findings (all P<.05). In addition, the major perioperative complications, including intraoperative cerebrospinal fluid leakage, hypopituitarism, and transient diabetes insipidus, were not related to the MRI results (all P>.05). The remission rate and recurrence rate were not different between patients with negative MRI findings and those with positive MRI findings. If CD is clearly diagnosed according to biochemical tests, radiologic examinations, and BIPSS, we recommend TSS as the first-line treatment for patients, even if the MRI results are negative.

Postoperative Day 1 Morning Cortisol Value as a Biomarker to Predict Long-term Remission of Cushing Disease.

Recurrence of Cushing disease (CD) can occur even decades after surgery. Biomarkers to predict recurrence of CD after surgery have been studied but are inconclusive. The aim of our study was to identify specific biomarkers that can predict long-term remission after neurosurgery. Identification of specific biomarkers to predict long-term remission of CD was performed by logistic regression analysis followed by Kaplan-Meier survival analysis, using recurrence as the dependent variable. A total of 260 patients with CD identified from our institutional research patient data registry search tool and from patients who presented to our longitudinal multidisciplinary clinic between May 2008 and May 2018 underwent statistical analysis. Data on clinical features, neuro-imaging study, pathology, biochemistry, and treatments were collected by reviewing digital chart records. Postoperative cortisol as a biomarker to predict long-term remission after surgical treatment for CD. By logistic regression analysis, postoperative day 1 (POD1) morning (5-10 am) serum cortisol, female sex, and proliferative index had significant association with CD recurrence (odds ratio [OR] = 1.025, 95% CI: 1.002-1.048, P = .032). In contrast, the postoperative nadir cortisol (OR = 1.081, 95% CI: 0.989-1.181, P = .086), urinary free cortisol (OR = 1.032, 95% CI: 0.994-1.07, P = .098), and late night salivary cortisol (OR = 1.383, 95% CI: 0.841-2.274, P = .201) had no significant correlation with recurrence. A significant association between POD1 morning serum cortisol and long-term CD remission was verified by Kaplan-Meier analysis when using POD1 morning serum cortisol <5 μg/dL as the cut-off. The POD1 morning serum cortisol level has a significant association with CD recurrence.

Recovery of hypothalamic-pituitary-adrenal axis in paediatric Cushing disease.

The postoperative period of Cushing disease (CD) is complicated by a phase of adrenal insufficiency (AI). Factors that influence the duration of AI and its prognostic significance for CD recurrence in children have not been extensively studied. We investigated whether clinical or biochemical factors contribute to the duration of AI, and the correlation of the recovery process with the risk for recurrence. Patients with paediatric-onset CD who were followed up for at least 3months after transsphenoidal surgery (TSS) (n=130) were included in the study. Multivariable Cox proportional hazards analysis was used to assess the association of biochemical and clinical factors with the duration of AI. Overall, 102 patients recovered adrenal function during their follow-up. Median time to recovery was 12.7months [95% confidence intervals (CI): 12.2-13.4]. On multivariable analysis, clinical (age, gender, disease duration, puberty stage, BMI z-score, tumour size, invasion of the cavernous sinus and year of surgery) and biochemical (midnight cortisol and morning ACTH) factors did not correlate with the time to recovery, except for increase in recovery time noted with increase in urinary free cortisol (UFC) [hazard ratio (HR): 0.94; 95% CI: 0.89-0.99]. Among patients who eventually recovered adrenal function, the risk for CD recurrence was associated with the time to recovery (HR: 0.86; 95% CI: 0.75-0.99). Recovery of adrenal function in patients with CD after TSS may not be associated with most clinical and biochemical factors in the preoperative period except for total cortisol excretion. Earlier recovery is associated with higher risk for recurrence, which has implications for the patients' follow-up and counselling.

OR23-03 Post-Operative Day One Morning Cortisol Value as a Biomarker to Predict the Recurrence of Cushing Disease

Tumor removal by transsphenoidal surgery (TSS) is the first line treatment for Cushing disease (CD). However, recurrence is relatively common. A one week post-operative (post-op) nadir cortisol has been used as a biomarker to predict recurrence1. We identified 299 CD patients from our longitudinal multidisciplinary clinic or our institutional RPDR search tool who met biochemical diagnostic criteria1 and had undergone TSS between May 2008 and May 2018, to evaluate post-op cortisol levels as biomarkers to predict long-term remission and to characterize clinical features of Cushing syndrome. Predictors of recurrence were identified with logistic regression, using recurrence as the dependent variable, and a Kaplan-Meier survival curve analysis was performed to compare long-term remission after TSS among the 202 patients who reached initial remission and had at least 1 year of follow-up. The post-op day 1 morning (AM) cortisol had significant association with CD recurrence (OR=1.025, 95%CI:1.002-1.048, p=0.032). The time to recurrence was significantly longer in patients with post-op day 1 AM cortisol <5 μg/dL. In contrast, one week post-op nadir cortisol (OR=1.081, 95%CI: 0.989-1.181, p=0.086), urinary free cortisol (OR=1.032,95%CI: 0.994-1.07, p=0.098), or late night salivary cortisol (OR=1.383, 95%CI:0.841-2.274, p=0.201) had no significant correlation with recurrence. There were no significant differences in time to recurrence for post-op day 2 AM cortisol <5 μg/dL. Among patients who developed post-op adrenal insufficiency, recurrence was significantly lower if glucocorticoid replacement continued for more than one year. In addition, tumor proliferative index (MIB-1) had a significant correlation with recurrence (OR=1.287, 95%CI:1.106-1.498, p=0.001). The most common symptoms and signs of initial presentation of CD were weight gain (91.6%), central obesity (79.6%), menstrual disorders (77.9%), round face (65.9%), hypertension (63.2%), mood disorders (60.2%), dorsocervical fat deposition (59.9%), supraclavicular fat deposition (59.9%), osteoporosis (58.9%), fatigue (58.2%), bruising (55.9%) and facial hirsutism (54.2%). Most of the best discriminating CD features did not have high sensitivity, such as purple striae (31.4%), facial plethora (33.4%) and proximal muscle weakness (30.8%). Our data show that post-op day one morning cortisol level above 5 μg/dL had significant association with recurrence. In contrast, the one week post-op nadir cortisol level had no significant value to predict recurrence. Our data also suggest that nonspecific symptoms and signs of CD are more common than stereotypical signs. Reference: Nieman LK, et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015; 100:2807-2831

Persistent cortisol response to desmopressin predicts recurrence of Cushing's disease in patients with post-operative corticotropic insufficiency.

Cushing's disease (CD) may recur despite corticotropic insufficiency (COI) following pituitary surgery. The predictive value of the desmopressin test (DT) for recurrence in this setting remains controversial. We have evaluated whether the disappearance of the response to DT predicts a low probability recurrence in a large cohort of patients with post-operative COI. Multicentre retrospective study. Ninety-five patients with CD (women 82%, age 41 ± 14 years), responding preoperatively to DT and with early post-operative COI (08 00 am cortisol: <138 nmol/L), underwent a DT within 3 months post-surgery. Association between DT findings and the prediction of recurrence was tested using regression and ROC analyses. Recurrence occurred in 17/95 patients within 29 to 91 months. The cortisol peak (327, 95% CI (237-417) vs 121 (79-164) nmol/L, P = 0.0001) and absolute increment during DT (208 (136-280) vs 56 (22-90) nmol/L, P = 0.005) were greater in the recurrence vs remission group. Cortisol peak (AUC: 0.786 (0.670-0.902)) and increment (0.793 (0.672-0.914)) yielded a higher prognostic performance for recurrence than did the early post-operative 08 00 am cortisol (0.655 (0.505-0.804)). In the context of COI, cortisol peak >100 nmol/L and increment >30 nmol/L had a high negative predictive value (94, 95% CI (88-100) and 94, (88-100), respectively). Patients with a cortisol peak ≤100 nmol/L (vs >100) or an increment ≤30 nmol/L (vs >30) were less likely to have CD recurrence (odds ratios: 0.12, 95% CI (0.03-0.41) and 0.11 (0.02-0.36), respectively). The disappearance of the response to the post-operative DT was independently associated with a lower odds of CD recurrence and offers an incremental prognostic value, which may help to stratify patients with COI and refine their follow-up according to the risk of recurrence.

Long-term outcome in patients after treatment for Cushing's disease in childhood.

IntroductionCushing’s disease (CD) is a rare cause of hypercortisolemia presenting a major diagnostic and therapeutic challenge. Data on pituitary function in long-term follow-up after CD treatment in childhood is limited.AimLong-term assessment of patients of the Children’s Memorial Health Institute (CMHI) after CD treatment in childhood.Materials and methodsRetrospective analysis of 29 CD patients, mean age at the time of diagnosis 13.46 yrs. The long-term follow-up (FU) was done by: 1) obtaining the data from a patient’s questionnaire (75% of adult patients); 2) using the data from the last clinic visit for patients who did not respond to the questionnaire and for current CMHI patients. The average long-term FU from transsphenoidal pituitary surgery (TSS) was 10.23 yrs.ResultsAt the latest FU: 18 patients (62%) had long-term disease remission after TSS1, 2 patients (6.9%) after TSS2, 1 patient (3.4%) after the post-TSS radiotherapy (XRT) cycle and 3 patients (10.3%) after bilateral adrenalectomy (BA). One patient (3.4%) died after TSS2 due to postoperative complications, 1 patient (3.4%) had persistent disease at latest FU, in 1 patient (3.4%) the long-term FU was not possible to perform. CD recurrence occurred in 4 out of 28 patients (14%) at an average time 3.6 yrs. from definitive treatment. One patient (3.4%) after BA was operated because of Nelson's syndrome. Two patients (6.9%) were suspected of relapse at latest assessment. At the time of the last evaluation, 17 patients (63%) were on levothyroxine therapy since definitive treatment, 16 patients (59%) were on hydrocortisone treatment, 10 patients (37%) were taking sex hormones replacement, 4 patients (15%)—antidiuretic hormone.ConclusionsRelatively large number of patients after CD treatment in childhood have hormonal pituitary deficits as well as mood and cognitive disorders. CD recurrence can occur even after a long time post effective treatment.

Hypercortisolemia Recurrence in Cushing's Disease; a Diagnostic Challenge.

Cushing's disease recurrence following successful pituitary surgery is common and merits prompt and careful diagnosis, as untreated hypercortisolism leads to increased morbidity and mortality. However, an established recurrence definition has not been forthcoming. This poses a diagnostic challenge especially early in the course of returning hypercortisolemia and/or in the presence of non-neoplastic hypercortisolemia. A late-night salivary cortisol (LNSC) test is the first test to reveal abnormal results, however, has limitations related to assay performance as well as individual patient variability. Dexamethasone suppression tests and 24-h urinary free cortisol (UFC) results are next to reveal abnormal results. Other tests including, corticotropin-releasing hormone (CRH) stimulation test and combined CRH-dexamethasone test, as well as desmopressin stimulation test with/without dexamethasone are also used, although, none have proven to be the preeminent diagnostic test for recurrence determination. There is a possible role for these tests in predicting recurrence in patients who have experienced remission, though, this also remains challenging due to lack of established cutoff values. This article details and summarizes evidence about different diagnostic tests currently used to diagnose and predict Cushing's disease recurrence.

Recovery of Adrenal Function after Pituitary Surgery in Patients with Cushing Disease: Persistent Remission or Recurrence?

Background: Cushing disease (CD) represents the principal cause of endogenous hypercortisolism. The first-line therapy of CD is surgical removal of the ACTH-secreting pituitary adenoma, which is generally followed by adrenal insufficiency (AI). Objective: To analyze the recovery of AI in patients with CD after pituitary surgery in relation with recurrence and persistent remission of CD. Patients and Methods: We performed a retrospective analysis of patients with CD who met the following inclusion criteria: adult age, presence of AI 2 months after the surgical intervention, and a minimum follow-up of 3 years after the surgical intervention. Results: Sixty-one patients were followed for a median of 6 years. Ten (16.4%) patients recurred during follow-up. The patients who restored adrenal function did so after a median time of 19 months, with a significantly shorter time in the recurrence group (12.5 vs. 25 months, p = 0.008). All 10 patients who recurred recovered their adrenal function within 22 months. The recovery rate of AI in the persistent remission group was 37.3% (19/51) at 3 years and 55.8% (24/43) at 5 years. In all patients the duration of AI was negatively associated with disease recurrence. Conclusion: The duration of postsurgical AI in patients with recurrent CD is significantly shorter than that in patients with persistently remitted CD, and this parameter may be a useful predictor of recurrence. Patients showing a normal pituitary-adrenal axis within 2 years after surgery should be strictly monitored as they are at higher risk of disease relapse.

Large Genomic Aberrations in Corticotropinomas Are Associated With Greater Aggressiveness.

Genomic losses/gains are associated with cancer progression and prognosis. In pituitary adenomas, analyses of copy number variations (CNVs) have shown that a subset of adenomas have higher genomic variability. However, whether CNVs are associated with tumor aggressiveness and prognosis has not been determined. We hypothesized that somatic CNVs of pituitary tumors may play a role in the progression and aggressiveness of pituitary corticotropinomas in children and adolescents. Paired germline and tumor DNA samples from 27 pediatric patients with Cushing disease (CD), were subjected to whole exome sequencing. Somatic CNVs were identified using the ExomeDepth tool. Clinical, histological, and biochemical data from the patients were collected and correlated with the results of the CNV analysis. Chromosomal instability, involving 23% to 59% of the tumor genome, was noted in 5 of the 27 samples (18.5%). The patients with tumors showing chromosomal instability had similar clinical and biochemical characteristics to the remaining patients, except for tumor size, which was larger (median size 18 mm vs 5.5 mm, P = 0.005). Tumors with chromosomal instability were also associated with a higher rate of invasion of the cavernous sinus (P = 0.029). There was insufficient information on persistence or recurrence of CD to determine whether the risk was higher in those with chromosomal instability. A subgroup of corticotropinomas demonstrates chromosomal instability that is associated with markers of aggressiveness of these adenomas. It appears that more genomic gains/losses in a few, rare corticotropinomas may predict poorer prognosis for pediatric patients with CD.

Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas.

somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been described in patients with Cushing's disease (CD). The aim of the study is to verify whether USP8 mutation may predict early and late outcome of pituitary surgery in patients with CD operated at a single institution. We performed a retrospective genetic analysis of 92 adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. Specimens were screened for USP8 hotspot mutations in the exon 14 with Sanger sequencing. Hormonal and surgical data were compared between USP8 variant carriers and wild-type tumors. USP8 variants were detected in 22 adenomas (23.9%) with higher prevalence in women (28.9% vs. 5.3% in men; p < 0.05). No significant difference in hormonal levels and tumoral features in relation to USP8 status was observed. Interestingly, USP8-variant carriers were more likely to achieve surgical remission than wild-type adenomas (100% vs. 75.7%; p = 0.01). Conversely, recurrence of CD occurred in 23% of USP8-mutated patients and in 13% of patients with wild-type adenoma. The recurrence-free survival did not differ significantly between the two groups (p = 0.42). ACTH-secreting pituitary adenomas carrying somatic USP8 mutations are associated with a greater likelihood of surgical remission in patients operated by a single neurosurgeon. Recurrence rates are not related with USP8-variant status.

American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: Diagnosis of Recurrence in Cushing Disease

ACTH = adrenocorticotropic hormone AI = adrenal insufficiency CD = Cushing disease CDDT = coupled dexamethasone desmopressin test CR = circadian rhythm CRH = corticotropin-releasing hormone GC = glucocorticoid GCR = global clinical response HPA = hypothalamic-pituitary-adrenal LDDST = low-dose dexamethasone suppression test LNSC = late-night salivary cortisol ODST = overnight dexamethasone suppression test TSS = trans-sphenoidal surgery.

Adrenocorticotropic hormone levels before treatment predict recurrence of Cushing's disease.

Cushing's disease (CD) is the most common cause of endogenous Cushing's syndrome. Transsphenoidal surgery (TSS) is the first choice of treatment. Predicting prognosis after treatment can benefit further strategies of management, but currently there is no convenient predictor. This study aims to investigate characteristic changes after treatment and to identify potential prognostic predictors. We retrospectively studied the records of CD patients presenting to the National Taiwan University Hospital, Taipei, Taiwan between 1992 and 2011. They were categorized according to treatment response. Clinical features and examination findings were compared between groups. Forty-one patients with CD were included. The follow-up time was 0.26-19.3years. The time interval between the onset of symptoms and diagnosis was 2.1-120.0months. The initial remission rate of CD after the first treatment was 82.9%. Mean body mass index (BMI) was 27.4kg/m2 before treatment and 26.0kg/m2 3months after treatment. The patients in remission had a greater decrease in BMI after treatment and lower dehydroepiandrosterone sulfate (DHEAS) levels before treatment, compared with the recurrent group (both p<0.05). Adrenocorticotropic hormone (ACTH) levels before treatment showed a significant positive correlation with recurrent diseases (p<0.05). A larger decrease in BMI after treatment and lower DHEAS levels before treatment were noted for the patients who stayed in CD remission. Higher ACTH levels before treatment predicted a recurrence of CD. These are potentially simple and practical predictors of prognosis.

Postsurgical Recurrent Cushing Disease: Clinical Benefit of Early Intervention in Patients with Normal Urinary Free Cortisol

To assess the performance of biochemical markers in the detection of recurrent Cushing disease (CD), as well as the potential benefit of early intervention in recurrent CD patients with elevated late-night salivary cortisol (LNSC) and normal urinary free cortisol (UFC). The design was a single-center, retrospective chart review. Patients treated by the authors from 2008-2013 were included. Recurrence was defined by postsurgical remission of CD with subsequent abnormal LNSC, UFC, or dexamethasone suppression test (DST). We identified 15 patients with postsurgical recurrent CD after initial remission; all but one underwent testing with LNSC, DST, and UFC. Although 12 of 15 patients had normal UFC at time of recurrence, DST was abnormal in 11 of 15, and all 14 patients with LNSC results had ≥1 elevated measurement. Nine patients (7 with normal UFC) showed radiologic evidence of a pituitary tumor at time of recurrence. Among the 14 patients with available follow-up data, 12 have demonstrated significant improvement since receiving treatment. Five patients underwent repeat pituitary surgery and 4 achieved clinical and biochemical remission. Eight patients received mifepristone or cabergoline, and 6 showed clinical and/or biochemical improvement. Three patients (2 with prior mifepristone) underwent bilateral adrenalectomy and 2 demonstrated significant clinical improvements. LNSC is more sensitive than UFC or DST for detection of CD recurrence. Prompt intervention when LNSC is elevated, despite normal UFC, may yield significant clinical benefit for many patients with CD. Early treatment for patients with recurrent CD should be prospectively evaluated, utilizing LNSC elevation as an early biochemical marker. ACTH = adrenocorticotropic hormone CD = Cushing disease CS = Cushing syndrome CV = coefficient of variation DST = dexamethasone suppression test IPSS = inferior petrosal sinus sampling LNSC = late-night salivary cortisol QoL = quality of life TSS = transsphenoidal adenoma resection UFC = urinary free cortisol.