Transsphenoidal Surgery For Cushing's Disease Research Articles

Predicting delayed remission in Cushing's disease using radiomics models: a multi-center study.

No multi-center radiomics models have been built to predict delayed remission (DR) after transsphenoidal surgery (TSS) in Cushing's disease (CD). The present study aims to build clinical and radiomics models based on data from three centers to predict DR after TSS in CD. A total of 122 CD patients from Peking Union Medical College Hospital, Xuanwu Hospital, and Fuzhou General Hospital were enrolled between January 2000 and January 2019. The T1-weighted gadolinium-enhanced MRI images and clinical data were used as inputs to build clinical and radiomics models. The regions of interest (ROI) of MRI images were automatically defined by a deep learning algorithm developed by our team. The area under the curve (AUC) of receiver operating characteristic (ROC) curves was used to evaluate the performance of the models. In total, 10 machine learning algorithms were used to construct models. The overall DR rate is 44.3% (54/122). According to multivariate Logistic regression analysis, patients with higher BMI and lower postoperative cortisol levels are more likely to achieve a higher rate of delayed remission. Among the 10 models, XGBoost achieved the best performance among all models in both clinical and radiomics models with AUC values of 0.767 and 0.819 respectively. The results from SHAP value and LIME algorithms revealed that postoperative cortisol level (PoC) and BMI were the most important features associated with DR. Radiomics models can be built as an effective noninvasive method to predict DR and might be useful in assisting neurosurgeons in making therapeutic plans after TSS for CD patients. These results are preliminary and further validation in a larger patient sample is needed.

Diurnal Range and Intra-patient Variability of ACTH Is Restored With Remission in Cushing's Disease.

Single ACTH measurements have limited ability to distinguish patients with Cushing's disease (CD) from those in remission or with other conditions. To investigate the changes in ACTH levels before and after transsphenoidal surgery (TSS) to identify trends that could confirm remission from CD and help establish ACTH cutoffs for targeted clinical trials in CD. Retrospective analysis of CD patients who underwent TSS from 2005 to -2019. Referral center. CD patients (n = 253) with ACTH measurements before and after TSS. TSS for CD. Remission after TSS. Remission was observed in 223 patients after TSS. Those in remission had higher ACTH variability at AM (P = .02) and PM (P < .001) time points compared to nonremission. The nonremission group had a significantly narrower diurnal range compared to the remission group (P = <.0001). A decrease in plasma ACTH of ≥50% from mean preoperative levels predicted CD remission after TSS, especially when using PM values. The absolute plasma ACTH concentration and ratio of preoperative to postoperative values were significantly associated with nonremission after multivariable logistic regression (adj P < .001 and .001, respectively). Our findings suggest that ACTH variability is suppressed in CD, and remission from CD is associated with the restoration of this variability. Furthermore, a decrease in plasma ACTH by 50% or more may serve as a predictor of remission post-TSS. These insights could guide clinicians in developing rational outcome measures for interventions targeting CD adenomas.

Surgery and perioperative management of patients with Cushing's disease.

Transsphenoidal surgery (TSS) is the initial treatment modality of first choice in Cushing's disease (CD). With microscopic TSS and endoscopic TSS, two operative techniques with equally favourable remission rates and operative morbidity are available. On average, remission is achieved with primary TSS in 80% of patients with microadenomas and 60% of patients with macroadenomas. The current literature indicates that remission rates in repeat TSS for microadenomas can also exceed 70%. Experience with TSS in CD plays an important role in the success rate and centralization in Pituitary Centres of Excellence has been proposed. Microadenoma stage, imaging-visible adenoma, confirmation of ACTH-positive adenoma on histopathology and noninvasiveness are positive predictors for postoperative remission. In postoperative management, a steroid-sparing protocol with early postoperative assessment of remission status is recommended. Convincing evidence suggests that prolonged postoperative prophylactic antithrombotic measures can significantly reduce the risk of postoperative thromboembolic events in CD. Prevention or successful treatment of cortisol withdrawal syndrome remains an unsolved issue that should be a focus of future research. The further development and broad availability of functional imaging hold promise for improved preoperative detection of microadenomas. Intraoperative identification of microadenomas by specific fluorescent targeting could be a promising future avenue for the treatment of patients with negative imaging.

Copeptin Levels Before and After Transsphenoidal Surgery for Cushing Disease: A Potential Early Marker of Remission.

Arginine-vasopressin and CRH act synergistically to stimulate secretion of ACTH. There is evidence that glucocorticoids act via negative feedback to suppress arginine-vasopressin secretion. Our hypothesis was that a postoperative increase in plasma copeptin may serve as a marker of remission of Cushing disease (CD). Plasma copeptin was obtained in patients with CD before and daily on postoperative days 1 through 8 after transsphenoidal surgery. Peak postoperative copeptin levels and Δcopeptin values were compared among those in remission vs no remission. Forty-four patients (64% female, aged 7-55 years) were included, and 19 developed neither diabetes insipidus (DI) or syndrome of inappropriate anti-diuresis (SIADH). Thirty-three had follow-up at least 3 months postoperatively. There was no difference in peak postoperative copeptin in remission (6.1 pmol/L [4.3-12.1]) vs no remission (7.3 pmol/L [5.4-8.4], P = 0.88). Excluding those who developed DI or SIADH, there was no difference in peak postoperative copeptin in remission (10.2 pmol/L [6.9-21.0]) vs no remission (5.4 pmol/L [4.6-7.3], P = 0.20). However, a higher peak postoperative copeptin level was found in those in remission (14.6 pmol/L [±10.9] vs 5.8 (±1.4), P = 0.03]) with parametric testing. There was no difference in the Δcopeptin by remission status. A difference in peak postoperative plasma copeptin as an early marker to predict remission of CD was not consistently present, although the data point to the need for a larger sample size to further evaluate this. However, the utility of this test may be limited to those who develop neither DI nor SIADH postoperatively.

Copeptin Levels Before and After Transsphenoidal Surgery for Cushing Disease: A Potential Marker of Remission

Abstract Objectives: Chronic hypercortisolemia suppresses AVP secretion. Copeptin makes up the C-terminal portion of the AVP precursor pre-pro-AVP, is released in stoichiometric amounts with AVP, and is a stable surrogate marker of AVP.A post-operative increase in plasma copeptin was hypothesized to be a marker of remission of Cushing Disease (CD). Methods: Plasma copeptin was obtained in patients with CD before and daily in the first week after transsphenoidal surgery (TSS), measured using the Brahm Kryptor Compact PLUS sandwich immunofluorescent assay. Urine output, serum sodium, urine specific gravity, and urine/serum osmolality were used to determine development of central diabetes insipidus (DI) and/or syndrome of inappropriate anti-diuretic hormone secretion (SIADH). Change in copeptin reflects pre-TSS to peak post-TSS copeptin levels. Statistical analyses were completed using non-parametric tests. Results are presented as median (inter-quartile range). Results: Forty-four patients (64% female, 7-55 years old) were included. After TSS, 8 (18%) developed DI, 13 (30%) developed SIADH, 4 (9%) developed both DI and SIADH, and 19 (43%) developed neither. Thirty-three patients had a follow-up at 3-6 months. Overall, there was no difference in peak post-TSS copeptin for patients in remission versus those not in remission [6.1 pmol/L (4.3-12.1) vs. 7.3 pmol/L (5.4-8.4), p=0.88]. There was, also, no difference in the copeptin change for those in remission versus not in remission [2.3 pmol/L (-0.5-8.2) vs. 0.1 pmol/L (-0.1-2.2), p=0.46]. When we excluded patients who developed a water balance disorder postoperatively, there was a difference in peak post-TSS copeptin for those in remission [10.2 pmol/L (6.9-21.0)] vs. those not in remission [5.4 pmol/L (4.6-7.3), p=0.032], but not in the change in copeptin for those in remission vs. not in remission [5.1 pmol/L (0.3-19.5) vs. 1.1 pmol/L (-0.1-2.2), p=0.39]. Conclusions: Post-TSS plasma copeptin may be a useful early marker to predict remission of CD after TSS. However, the utility of this test may be limited to those who do not develop water balance disorders post-operatively. Additional studies with larger sample sizes are needed to confirm these findings and to determine a post-operative plasma copeptin cutoff level that may predict remission of CD.

Toward better prediction of recurrence for Cushing’s disease: a factorization-machine based neural approach

Cushing's disease (CD) is a rare disease that occurs in 1.2–1.4 persons per million population per year. Recurrence prediction after transsphenoidal surgery (TSS) is important for determining individual treatment and follow-up strategies. Between 2000 and 2017, 354 CD patients with initial postoperative remission and long-term follow-up data were enrolled from Peking union medical college hospital (PUMCH) to predict recurrence, and PUMCH is one of the largest CD treatment centers in the world. We first investigated the effect of a factorization machine (FM)-based neural network to predict recurrence after TSS for CD. This method could automatically reduce a portion of the cross-feature selection work with acceptable parameters. We conducted a performance comparison of various algorithms on the collected dataset. To address the lack of interpretability of neural network models, we also used the local interpretable model-agnostic explanations approach, which provides an explanation in the form of relevant features of the predicted results by approximating the model behavior of the variables in a local manner. Compared with existing methods, the DeepFM model obtained the highest AUC value (0.869) and the lowest log loss value (0.256). According to the importance of each feature, three top features for the DeepFM model were postoperative morning adrenocorticotropic hormone level, age, and postoperative morning serum cortisol nadir. In the post hoc explanation phase, the above-mentioned importance-leading features made a great contribution to the prediction probability. The results showed that deep learning-based models could better aid neurosurgeons in recurrence prediction after TTS for patients with CD, and could contribute to determining individual treatment strategies.

Outcomes of pituitary surgery for Cushing's disease: a systematic review and meta-analysis.

Transsphenoidal surgery (TSS) is the first-line treatment for Cushing's disease (CD). This review aimed to synthesize the remission and recurrence rates following TSS for CD and identify predictors of these outcomes. Medline (1946-) and Embase (1947-) were searched until 23rd January 2019 for original studies. A meta-analysis was performed of remission and recurrence rates. Studies were excluded if patients had prior radiosurgery/radiotherapy, mixed pathologies or interventions without separated data, follow-up not reported or population size < 20. For recurrence rate syntheses, studies with follow-up < 6months were excluded. The search produced 2663 studies, of which n = 68 were included, involving 5664 patients. Remission rates after primary and revision TSS were 80% [77-82] and 58% [50-66] at last follow-up. After primary TSS, predictors of remission were micro- v macroadenomas (83% v 68%, p < 0.01), imaging-visible adenomas (81% v 69%, p < 0.01), adenomas confirmed on histopathology (87% v 45%, p < 0.01), absence of cavernous sinus invasion (80% v 30%, p < 0.01), postoperative serum cortisol (MSeC) nadir < 2μg/dL (< 55nmol/L; 95% v 46%, p < 0.01) and lower preoperative 24-h urine free cortisol (1250nmol v 1726nmol, p < 0.01). For revision TSS, predictors of remission were postoperative MSeC nadir < 2μg/dL (< 55nmol/L; 100% v 38%, p < 0.01) and operations for recurrence v persistence (80% v 54%, p < 0.01). Recurrence rates after primary and revision TSS were 18% [14-22] and 28% [16-42]. TSS is most effective in primary microadenomas, visible on preoperative imaging and without CS invasion, lower preoperative 24-h urine free cortisol and postoperative MSeC nadir < 2μg/dL (< 55nmol/L).

Determinants of outcome of transsphenoidal surgery for Cushing disease in a single-centre series.

First-line therapy of Cushing disease (CD) is transsphenoidal surgery (TSS) aimed to obtain a complete removal of the pituitary adenoma and remission of disease. To analyse the surgical outcome of patients with CD who underwent TSS in our Centre. Retrospective analysis on patients with CD who underwent TSS between 1990 and 2016. We analysed 102 TSS that included: 84 first TSS and 18 second and third TSS. The overall remission rate after surgery was 76.5%, with a significant higher percentage of remitted patients after the first TSS compared to the subsequent TSS (82% vs 50%, p = 0.014). The remission after the first TSS was significantly higher when performed by a dedicated surgical team (DST) (89.8% vs 71% p = 0.04) and when the immunohistochemical examination confirmed the adrenocorticotropic adenoma (87% vs 55%, p = 0.04). Neuroradiological findings influenced the surgical outcome in a non-significant manner. Post-TSS complications were reported in 32 patients, with no significant variation when TSS was performed by DST. In case of reintervention, remission of disease was obtained in 72.7% of microadenoma, while no remitted patients were observed in case of macroadenomas. The DST did not significantly improve the outcome. Cushing disease is characterized by a broad spectrum of neuroradiological presentation. Despite the availability of a DST make the TSS a safe and effective first-line treatment among all these patients, a precise pre-treatment evaluation is needed in order to define the aim of neurosurgery and to schedule the management of recurrent disease.

Transsphenoidal surgery in Cushing disease: The challenging microadenoma (Local experience)

Abstract Background: Cushing disease is uncommon challenging disease. The adenomas are usually small in size in most case making the disease diagnosis and management is sometimes difficult. In some cases, the tumor cannot be identified on imaging studies and in many cases the adenoma is eccentric in location adding more difficulties to the trans-sphenoid approach for excision of such tricky tumors. Object: to evaluate the challenge of diagnosis and trans-sphenoid surgery for ACTH pituitary microadenomas. Methods: 21 patients with ACTH secreting adenomas were involved in this retrospective study. All cases were operated up on via trans-sphenoid approach during the period from January 2009 till October 2015. All of them were microadenomas. All patients had obvious Cushing manifestations. In all cases magnetic resonance (MR) imaging and CT paranasal sinuses were performed. In this study: cases with macroadenomas and recurrent cases after previous trans-sphenoid approach or gamma knife radiosurgery were excluded. Results: Among the 21 patients; 14 were female and 7 weremale with age ranging from 21 to 44 years. The imaging study was positive for microadenoma in 18 patients while in 3 cases; no tumor was seen on the MRI imaging. All were operated via the trans-sphenoid approach (12 patients via the microscopic technique and other 9 patients via the endoscopic technique). The adenoma was successfully removed in 15 out of the 18 patients with evident adenoma on pre-operative MRI imaging while partial hypophysectomy were done in 5 cases without an evident adenoma on pre-operative MRI study or difficult adenoma identification. In one patient; the procedure was aborted because of sphenoid sinus abnormalities and the tumor was successfully removed via trans-cranial approach. Disease remission was achieved in 17 patients. In 4 patients; complete remission was not achieved and gamma knife radiosurgery was done after surgery. Disease progression occurred in two patients with initial remission and was treated gamma knife radiosurgery. 13 patients had an ACTH deficiency after surgery while other hormonal replacement therapy is needed in only 5 cases. CSF rhinorrhea occurred in 2 patients and was managed with transient lumbar drain without any subsequent morbidities. Transient diabetes insipidus occurred in 6 cases and was treated conservatively. Conclusions: The transsphenoidal approach ACTH secreting pituitary microadenomas is considered safe and effective for achieving disease remission despite the challenge of diagnosis and intra-operative tumor identification.

Outcomes of Primary Transsphenoidal Surgery in Cushing Disease: Experience of a Tertiary Center

To report the initial and long-term remission rates and related factors, secondary treatments, and outcomes of a series of patients with Cushing disease (CD). We included 147 consecutive adult patients with CD who underwent primary transsphenoidal surgery (TSS) between 1998 and 2014 in this study. Eighty-two were followed up in the Cerrahpasa Medical Faculty Endocrinology and Metabolism outpatient clinic. Patients were requested to attend a long-term remission assessment; 55 could be contacted, and data for the remaining 27 patients' last visit to the outpatient clinics were reviewed for early and late remission. Six patients were excluded from the study. Magnetic resonance imaging (MRI) findings and pathologic results including mitosis, Ki-67 levels, and P53 in immunostaining of all patients were evaluated. Data of 82 patients with CD with an average age of 36 years [interquartile range: 29-47] were analyzed with a mean follow-up of 7.5 years [interquartile range: 5-10].Overall initial remission rates were 72.3% after TSS. Among the 82 patients, 16 patients had Gamma Knife radiosurgery and 7 patients underwent adrenalectomy. After these additional treatments, the long-term remission rate was found as 69.7%. The highest remission rates were with microadenomas. Recurrence was most frequently seen in patients without tumor evidence on MRI. Patients with high Ki-67 levels had higher recurrence rates in long-term follow-up (P= 0.02). Life-long follow-up for patients with CD seems essential. Undetectable tumors on MRI before TSS and high Ki-67 immunopositivity were found as risk factors for tumor recurrence.

Histone Deacetylase Inhibitor SAHA Is a Promising Treatment of Cushing Disease.

Remission failure following transsphenoidal surgery in Cushing disease (CD) from pituitary corticotroph tumors (CtTs) remains clinically challenging. Histone deacetylase inhibitors (HDACis) are antitumor drugs approved for clinical use, with the potential to affect adrenocorticotropin hormone (ACTH) hypersecretion by inhibiting pro-opiomelanocortin (POMC) transcription. Testing the efficacy of suberoylanilide hydroxamic acid (SAHA) on human and murine ACTH-secreting tumor (AtT-20) cells. Cell viability, ACTH secretion (enzyme-linked immunosorbent assay), apoptosis, and gene expression profile were investigated on AtT-20 cells. In vivo efficacy was examined in an athymic nude mouse AtT-20 xenograft model. SAHA efficacy against human-derived corticotroph tumor (hCtT) (n = 8) was tested in vitro. National Institutes of Health. SAHA (0.5 to 8 µM). AtT-20 and hCtT cell survival, in vitro/invivo ACTH measurements. SAHA (1 µM) reduced AtT-20 viability to 75% at 24 hours, 43% at 48 hours (analysis of variance; P = 0.002). Apoptosis was confirmed with elevated BAX/Bcl2 ratio and FACS. Intriguingly, early (3-hour) significant decline (70%; P < 0.0001) of secreted ACTH and diminished POMC transcription was observed with SAHA (1 µM). Microarray analysis revealed a direct association between liver X receptor alpha (LXRα) and POMC expression. Accordingly, SAHA reduced LXRα in AtT-20 cells but not in normal murine corticotrophs. Xenografted nude-mice tumor involution (126 ± 33/160 ± 35 vs 337 ± 49 mm3; P = 0.0005) was observed with 5-day intraperitoneal SAHA, with reversal of elevated ACTH (P < 0.0001). SAHA did not affect serum ACTH in nontumor mice. Lastly, we confirmed that SAHA (1 µM/24 h) decreased hCtT survival (78.92%; P = 0.0007) and ACTH secretion (83.64%; P = 0.03). Our findings demonstrate SAHA's efficacy in reducing survival and ACTH secretion in AtT-20 and hCtT cells, providing a potential intervention for recurrent/unremitting CD.

Normalized Early Postoperative Cortisol and ACTH Values Predict Nonremission After Surgery for Cushing Disease.

Perioperative increases in adrenocorticotropic hormone (ACTH) and cortisol mimic results of corticotropin-releasing hormone (CRH) stimulation testing. This phenomenon may help identify patients with residual adenoma after transsphenoidal surgery (TSS) for Cushing disease (CD). To predict nonremission after TSS for CD. Retrospective case-control study of patients treated at a single center from December 2003 until July 2016. Early and medium-term remission were assessed at 10 days and 11 months. Two hundred and ninety-one consecutive TSS cases from 257 patients with biochemical evidence of CD seen at a clinical center. Normalized early postoperative values (NEPVs) for cortisol and ACTH were calculated as immediate postoperative cortisol or ACTH levels minus preoperative post-CRH-stimulation test levels. Prediction of early nonremission was evaluated using logistic regression. Prediction of medium-term remission was assessed using Cox regression. Predictive ability was quantified by area under the receiver operating characteristic curve (AUROC). NEPVs for cortisol and ACTH predicted early nonremission [adjusted odds ratio (OR): 1.1; 95% confidence interval (CI): 1.0, 1.1; P = 0.016 and adjusted OR: 1.0; 95% CI: 1.0, 1.0; P = 0.048, respectively]. AUROC for NEPV of cortisol was 0.78 (95% CI: 0.61, 0.95); for NEPV of ACTH, it was 0.80 (95% CI: 0.61, 0.98). NEPVs for cortisol and ACTH predicted medium-term nonremission [hazard ratio (HR): 1.1; 95% CI: 1.0, 1.1; P = 0.023 and HR: 1.0; 95% CI: 1.0, 1.0; P = 0.025, respectively]. NEPVs for cortisol and ACTH predicted nonremission after TSS for CD.

Utility of Adrenocorticotropic Hormone in Assessing the Response to Transsphenoidal Surgery for Cushing’s Disease

To compare adrenocorticotrophic hormone (ACTH) and cortisol dynamics in subjects with Cushing's disease (CD) following transsphenoidal surgery (TSS) and to determine the value of early postoperative ACTH levels in predicting subsequent hypocortisolemia. Following TSS for CD, serum cortisol and plasma ACTH were measured every 6 hours in the absence of empiric glucocorticoid coverage. A total of 26 subjects (25 female) underwent 28 operations. Hypocortisolemia was achieved in 21 (81%) subjects after the initial TSS. Repeat TSS was performed in 2 subjects, resulting in hypocortisolemia in 1. Subjects who achieved hypocortisolemia had significantly lower ACTH levels by 19 hours postoperatively (P = .007). Plasma ACTH fell to <30 pg/mL in 86% and <20 pg/mL in 82% of subjects who subsequently achieved hypocortisolemia. Plasma ACTH declined to <30 pg/mL by a mean of 10 hours and to <20 pg/mL by 13 hours prior to hypocortisolemia. Follow-up data were available on 25 patients for a median of 23 months. Three subjects who achieved initial surgical remission had disease recurrence at 19, 24, and 36 months; all of these subjects had a postoperative nadir serum cortisol levels <3 μg/dL and plasma ACTH <20 pg/mL. Following TSS for CD, plasma ACTH declined prior to achievement of hypocortisolemia in most subjects. In the majority, the ACTH level reached a nadir of <20 pg/mL. Low early postoperative ACTH levels predict early hypocortisolemia but may not accurately predict long-term remission.

Predictors of resource utilization in transsphenoidal surgery for Cushing disease

The short-term cost associated with subspecialized surgical care is an increasingly important metric and economic concern. This study sought to determine factors associated with hospital charges in patients undergoing transsphenoidal surgery for Cushing disease in an effort to identify the drivers of resource utilization. The authors analyzed the Nationwide Inpatient Sample (NIS) hospital discharge database from 2007 to 2009 to determine factors that influenced hospital charges in patients who had undergone transsphenoidal surgery for Cushing disease. The NIS discharge database approximates a 20% sample of all inpatient admissions to nonfederal US hospitals. A multistep regression model was developed that adjusted for patient demographics, acuity measures, comorbidities, hospital characteristics, and complications. In 116 hospitals, 454 transsphenoidal operations were performed. The mean hospital charge was $48,272 ± $32,060. A multivariate regression model suggested that the primary driver of resource utilization was length of stay (LOS), followed by surgeon volume, hospital characteristics, and postoperative complications. A 1% increase in LOS increased hospital charges by 0.60%. Patient charges were 13% lower when performed by high-volume surgeons compared with low-volume surgeons and 22% lower in large hospitals compared with small hospitals. Hospital charges were 12% lower in cases with no postoperative neurological complications. The proposed model accounted for 46% of hospital charge variance. This analysis of hospital charges in transsphenoidal surgery for Cushing disease suggested that LOS, hospital characteristics, surgeon volume, and postoperative complications are important predictors of resource utilization. These findings may suggest opportunities for improvement.

Predictive value of preoperative magnetic resonance imaging of the pituitary for surgical cure in cushing’s disease

Cushing's disease (CD) is caused by ACTH-secreting pituitary adenoma. Transsphenoidal surgery (TSS) is the treatment of choice. CD diagnosis must be based on biochemical confirmation of hypercortisolemia and visualization of pituitary tumor on magnetic resonance imaging (MRI). Diagnostic problems are associated with equivocal or even normal MRI. In such situations, some neurosurgical centers perform a diagnostic sellar exploration. The purpose of this study was to evaluate the relationship between the results of preoperative MRI of the pituitary and efficacy of TSS for CD. A prospective study enrolling 36 consecutive patients with biochemically confirmed CD operated on and then followed up for at least 18 months. 23 of 36 patients (63,9%) were cured. Persistent CD was confirmed in 13 patients (36,1%). A difference was demonstrated between both groups with reference to the preoperative MR findings. In the cured group there was a significantly greater number of patients with precisely visualized pituitary microadenoma whereas in the non-cured group there was a significantly greater number of patients with pituitary macroadenoma or equivocal result of MRI (p=0.036). Precise localization of corticotroph microadenoma on the preoperative MRI may be considered as one of predictive factors positively prognosticating cure after TSS for CD.

Sequential hormonal changes in 21 patients with recurrent Cushing's disease after successful pituitary surgery

To describe the sequence of hormonal changes during recurrence of Cushing's disease (CD) after successful transsphenoidal surgery (TSS). Retrospective study in a single center. We studied 101 of the 127 patients treated by TSS for CD between 1996 and 2009, who had hypocortisolism or eucortisolism for at least 3 months post-TSS. We arbitrarily defined 'overt recurrence', as presence of two classical parameters of excess cortisol (increased midnight--either serum or salivary--and 24 h urinary cortisol (UC)), leading to further specific therapeutic action, and 'mild recurrence', as presence of a single classical parameter, leading to simple surveillance. Of the 101 patients, 21 (20.8%) presented with recurrence, 'mild' or 'overt', during long-term follow-up (median 50.4 months, range 7-99). Recurrence occurred less frequently (16.8 vs 50%, P=0.02), and later (mean 44.7 months, median 43, range 7-94 vs mean 21.5 months, median 17, range 3-61, P=0.05), in patients with early post-TSS hypocortisolism compared with those with eucortisolism. Increase in midnight cortisol occurred in a mean time of 38.2 months, while UC elevation was observed at 50.6 months. Vasopressin analogs and CRH tests were eventually positive in 85 and 93% of all patients respectively; a positive response to one of the two dynamic tests preceded the increase in midnight cortisol or UC in 71 and 64% of the patients respectively. A positive response to vasopressin analogs and/or CRH tests occurs early in recurrence, followed by an increase in midnight cortisol, while UC elevation is at a later stage.

Transsphenoidal surgery for Cushing disease: experience with 136 patients.

This is a retrospective study of 136 patients with Cushing disease treated with transsphenoidal microsurgery. To evaluate factors influencing immediate postoperative results and long-term outcomes. Data regarding clinical presentation, endocrine evaluation, imaging studies, surgical technique, immediate postoperative biochemical remission (IPBR), and long-term results were entered into a database and analyzed statistically. IPBR was based on biochemical evidence of adrenal cortical insufficiency and clinical evidence of such insufficiency. IPBR for the entire series was 83.4%. In microadenomas, IPBR was 89.8% with a mean immediate postoperative plasma cortisol (IPPC) of 2.1 μg/dL (range, <0.5-5.3). Positive magnetic resonance imaging (MRI) was associated with 18 times greater odds of finding microadenoma at surgery (P < .001) and with 4.1 times greater odds of IPBR (P = .07). In patients with a negative MRI, a positive inferior petrosal sinus sampling (IPSS) test was associated with 93% of IPBR (P = .004). IPBR in macroadenomas was 30.7%. Of patients followed for 12 months or longer, 34.8% required glucocorticoid replacement for the duration of follow-up. The mean follow-up in microadenomas was 68.4 months with a 9.67% incidence of recurrences. The estimated actuarial incidence of recurrences increased with the passage of time and IPPC of greater than 2 μg/dL was associated with higher incidence of recurrences, although without statistical significance (P = .08). In microadenomas, a positive MRI and positive IPSS test were associated with a higher incidence of IPBR. Recurrences increased with the passage of time, and an IPPC of greater than 2 μg/dL may be associated with higher incidence of recurrences.

The Postoperative Basal Cortisol and CRH Tests for Prediction of Long-Term Remission from Cushing's Disease after Transsphenoidal Surgery

Selective adenomectomy via transsphenoidal surgery induces remission of Cushing's disease (CD) in most patients. Although an undetectable postoperative serum cortisol (<2 μg/dl) has been advocated as an index of remission, there is no consensus on predictors of recurrence. We hypothesized that patients with subnormal cortisol (2-4.9 μg/dl) might achieve long-term remission and that postoperative responses to CRH might predict recurrence. We prospectively studied CD patients with initial remission after adenomectomy or hemihypophysectomy (n = 14). Long-term recurrence (n = 39) or remission (n = 293) was assigned by laboratory results, glucocorticoid dependence, or patient survey at a mean of 10.6 yr after surgery. Postoperatively, morning cortisol was measured on d 3-5, and cortisol and ACTH responses to ovine CRH were assessed around d 10. Follow-up duration was median 11 yr (range 1-22.8 yr). Fewer patients achieved a cortisol nadir below 2 μg/dl (87%) than below 5 μg/dl (98%), yet recurrence rates were similar (<2 μg/dl, 9.5%; <5 μg/dl, 10.4%; 2-4.9 μg/dl, 20%; not significant). CRH-stimulated cortisol (P < 0.002) and ACTH (P = 0.04) values were higher for the recurrence than the remission group. However, no basal or stimulated ACTH or serum or urine cortisol cutoff value predicted all who later recurred. A postoperative cortisol below 2 μg/dl predicts long-term remission after transsphenoidal surgery in CD. Remission in those with intermediate d 3-5 postoperative cortisol values (2-4.9 μg/dl) suggests that these patients do not require immediate reoperation. However, because no single cortisol cutoff value excludes all patients with recurrence, all require long-term clinical follow-up.

Remission after transsphenoidal surgery for Cushing disease

In a recent study, Valassi et al. describe a subset of patients with Cushing disease with delayed remission after transsphenoidal adenomectomy. The investigators suggest that expectant management and close observation could eliminate unnecessary interventions in these patients. Could their findings change the clinical management of patients with hypercorticism after transsphenoidal adenomectomy?

A Combined Dexamethasone Desmopressin Test as an Early Marker of Postsurgical Recurrence in Cushing’s Disease

Recurrence of Cushing's disease (CD) after transsphenoidal surgery (TSS) occurs in about 25% of cases. Twenty percent of patients with immediate postsurgical corticotroph deficiency will present late recurrence. The aim of the study was to evaluate a coupled dexamethasone desmopressin test (CDDT) as a predictor of recurrence of CD. We conducted a prospective bicenter study (Marseille and Grenoble, France). We studied 38 patients treated by TSS for CD with a mean follow-up of 60 months. We evaluated 24-h urinary free cortisol, ACTH, and cortisol plasmatic levels and performed low-dose dexamethasone suppression test and CDDT 3 to 6 months after surgery and then yearly. After CDDT, ACTH ratio (ACTHr) was defined as (PeakACTH - BaseACTH)/BaseACTH. Cortisol ratio (Cortisolr) was defined as (PeakCortisol - BaseCortisol)/BaseCortisol. Basal values were observed after low-dose dexamethasone suppression test. Receiver operator characteristics curve defined ACTHr and Cortisolr giving the best sensitivity and specificity associated with recurrence. Ten patients presented recurrence. ACTHr and Cortisolr were superior or equal to 0.5 in all patients with recurrence and in three of 28 patients in remission (100% sensitivity, 89% specificity). The test became positive in eight of 10 patients with recurrence 6-60 months before classical markers of hypercortisolism. Six patients with immediate postsurgical corticotroph deficiency presented recurrence. All of them presented CDDT positivity during the 3 yr after surgery, and recurrence 6 to 60 months after CDDT positivity. CDDT is an early predictor of recurrence of CD and could be of particular interest in the first 3 yr after surgery, by selecting patients at high risk of recurrence despite falsely reassuring classical hormonal markers.