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      An early post-operative ACTH suppression test can safely predict short- and long-term remission after surgery of Cushing’s disease

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          Abstract

          Purpose

          The present study evaluates the usefulness of an ACTH suppression test shortly after surgery, and to determine optimal cut-off values of included laboratory analyses, in predicting short- and long-term remission after surgery of Cushing’s disease.

          Methods

          A 48 h suppression test with betamethasone 2 mg/day applied after 45 transphenoidal adenomectomies in 28 patients was evaluated. Receiver operating characteristic (ROC)-curves were created for the included assays: plasma cortisol, plasma adrenocorticotropic hormone (ACTH) and urinary free cortisol (UFC). Plasma levels of cortisol and ACTH were measured both at 24 and 48 h. Youden’s index was used to determine cut-off with the highest sensitivity and specificity in predicting short- (3 months) and long-term (5 years or longer) remission. The area under curve (AUC) illustrated the clinical accuracy of the different assays.

          Results

          Plasma cortisol after 24 h with betamethasone was most accurate in predicting both short- and long-term remission. 3 months remission with cut-off 107 nmol/L: sensitivity 0.85, specificity 0.94, positive predictive value (PPV) 0.96 and AUC 0.92 (95% CI 0.85–1). 5 years remission with cut-off 49 nmol/L: sensitivity: 0.94, specificity 0.93, PPV 0.88, AUC 0.98 (95% CI 0.95–1). Analyses of ACTH or UFC did not improve diagnostic accuracy.

          Conclusions

          A 48 h, 2 mg/day betamethasone suppression test after transphenoidal surgery of Cushing’s disease could predict short- and long-term remission with a high accuracy. Suppression of plasma cortisol after 24 h with betamethasone to values excluding Cushings disease in the diagnostic setting yielded the highest accuracy in predicting long-term remission.

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          Most cited references22

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          Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline.

          The objective is to formulate clinical practice guidelines for treating Cushing's syndrome.
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            Long-term remission rates after pituitary surgery for Cushing's disease: the need for long-term surveillance.

            There have been a few reports on long-term remission rates after apparent early remission following pituitary surgery in the management of Cushing's disease. An undetectable postoperative serum cortisol has been regarded as the result most likely to predict long-term remission. Our objective was to assess the relapse rates in patients who underwent transsphenoidal surgery in order to determine whether undetectable cortisol following surgery was predictive of long-term remission and whether it was possible to have long-term remission when early morning cortisol was measurable but not grossly elevated. Endocrinological factors associated with late relapse were also studied. We reviewed the long-term outcome in 63 patients who had pituitary surgery for the treatment of Cushing's disease between 1979 and 2000. Case notes were reviewed and the current clinical and biochemical status assessed. Our usual practice was that early after the operation, an 08:00 h serum cortisol was measured 24 h after the last dose of hydrocortisone. This was followed by a formal low-dose dexamethasone suppression test. Current clinical status and recent 24-h urinary free cortisol values were used as an index of activity of the Cushing's disease. If there was evidence suggesting relapse, a low-dose dexamethasone suppression test was performed. In many patients, sequential collections of early morning urine specimens for urinary cortisol to creatinine ratio were also performed in an attempt to diagnose cyclical and intermittent forms of recurrent hypercortisolism. We did this if there was conflicting endocrine data, or if patients were slow to lose abnormal clinical features. Mean age at diagnosis was 40.3 years (range 14-70 years). Mean follow-up up time was 9.6 years (range 1-21 years). Forty-five patients (9 males/36 females) achieved apparent remission immediately after surgery and were subsequently studied long term. Of these 45 patients, four have subsequently died while in remission from hypercortisolism. Ten of the remaining 41 patients have relapsed. Of those 10, six demonstrated definite cyclical cortisol secretion. Two of the 10 had undetectable basal serum cortisol levels in the immediate postoperative period. Thirty-one patients are still alive and in remission. Fourteen (45%) of the 31 who remained in remission had detectable serum cortisol levels (> 50 nmol/l) immediately postoperatively, and remain in remission after a mean of 8.8 years. Our relapse rate was therefore 10/45 (22%), after a mean follow-up time of 9.6 years, with mean time to relapse 5.3 years. The overall remission rate of 56% (35/63) at 9.6 years follow-up is disappointing and merits some re-appraisal of the widely accepted principle that pituitary surgery must be the initial treatment of choice in pituitary-dependent Cushing's syndrome. Following pituitary surgery, careful ongoing expert endocrine assessment is mandatory as the incidence of relapse increases with time and also with increasing rigour of the endocrine evaluation. A significant number of our patients were shown to have relapsed with a cyclical form of hypercortisolism.
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              Diagnosis and management of Cushing's syndrome: results of an Italian multicentre study. Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis.

              The past 45 yr' experience with Cushing's syndrome (CS) has led to the awareness of its complex nature and, by the same token, brought about an increase in the diagnostic and therapeutic dilemmas. We carried out a retrospective multicentre study on the diagnostic work-up and treatment in 426 patients with CS, subdivided as follows: 288 with Cushing's disease (CD), 80 with an adrenal adenoma, 24 with an adrenal carcinoma, 25 with ectopic ACTH and/or CRH secretion, and 9 with ACTH-independent nodular adrenal hyperplasia. Normal urinary free cortisol (UFC) values among multiple collections were recorded in about 10% of patients with CS. In 28% of patients with ACTH-independent CS, basal ACTH concentrations were within the normal range but did not respond to CRH stimulation. Measurement of ACTH levels by immunoradiometric assay, rather than by RIA, offered a greater chance of recognizing patients with ACTH-independent CS or ectopic secretion. A 50% increase in ACTH or cortisol levels after CRH yielded a diagnostic accuracy of 86% and 61%, respectively, in the differential diagnosis of ACTH-dependent CS. An 80% decrease in cortisol levels after 8 mg dexamethasone overnight, or in UFC values after the classical 2-day administration, excluded an ectopic secretion but carried a low negative predictive value given the high number of nonsuppressors among patients with CD. Pituitary imaging identified an adenoma in 61% of patients with CD. At inferior petrosal sinus sampling, an ACTH centre: periphery gradient after CRH less than 3, correctly classified all patients with ectopic secretion but misdiagnosed 15% of 76 patients with CD. Transsphenoidal pituitary surgery, the standard therapy for CD, resulted in complete remission (appearance of clinical signs of adrenal insufficiency associated with low/normal UFC excretion and, when available, low/normal morning plasma ACTH and cortisol levels) in 69% of patients. The overall relapse rate after pituitary surgery was 17%. The probability of relapse-free survival, as assessed by Kaplan-Meier analysis, was 95% at 12 months, 84% at 2 yr, and 80% at 3 yr. Risk of relapse was significantly correlated with postoperative baseline plasma ACTH and cortisol peak after CRH. No relapses were observed among patients who did not respond to CRH. Other therapeutic approaches for CD, such as pituitary irradiation and medical therapy, resulted in normalization of cortisol secretion in about half of treated cases. In summary, an accurate selection of the available diagnostic tools leads to the correct diagnosis in the majority of patients with CS. The therapeutic options for CD, adrenal carcinoma, and ectopic secretion are, as yet, not fully satisfactory. The high incidence of relapse after pituitary surgery calls for a prolonged follow-up.
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                Author and article information

                Contributors
                0046 46 172145 , erik.uvelius@med.lu.se
                Journal
                Pituitary
                Pituitary
                Pituitary
                Springer US (New York )
                1386-341X
                1573-7403
                23 July 2018
                23 July 2018
                2018
                : 21
                : 5
                : 490-498
                Affiliations
                [1 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Neurosurgery, Department of Clinical Sciences Lund, Skåne University Hospital, , Lund University, ; EA-Blocket Plan 3, 221 85 Lund, Sweden
                [2 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Laboratory Medicine, Department of Clinical Chemistry & Pharmacology, , Lund University, ; Lund, Sweden
                [3 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Department of Clinical Sciences, Skåne University Hospital, , Lund University, ; Lund, Sweden
                Author information
                http://orcid.org/0000-0002-5399-3830
                Article
                902
                10.1007/s11102-018-0902-6
                6132983
                30039432
                3dc70bce-7724-49a6-946d-4802e48a9658
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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                © Springer Science+Business Media, LLC, part of Springer Nature 2018

                Medicine
                acth-secreting pituitary adenoma,cushing disease,pituitary adenoma,pituitary neoplasms/surgery,transphenoidal surgery,recurrence,treatment outcome

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