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Recordati's Isturisa is expected to launch in the second or third quarter. (Getty) As part of a small 2019 deal, Italian drugmaker Recordati snagged a trio of underperforming Novartis endocrinology meds, including a late-stage candidate for Cushing's disease. Less than a year later, that drug is cleared for market after an FDA green light. The FDA on Friday approved Recordati's Isturisa (osilodrostat) to treat Cushing's disease—a rare disease in which patients' adrenal glands produce too much cortisol—in those who have undergone a prior pituitary gland surgery or are not eligible for one. Isturisa, a cortisol synthesis inhibitor, will come with the FDA's orphan drug designation, providing market exclusivity for seven years, Recordati said (PDF) in a release. The drug is expected to be commercially available in the second or third quarter. The FDA based its review on phase 3 data showing 86% of patients treated with Isturisa showed normal cortisol levels in their urine after eight weeks, compared with 29% of patients treated with placebo, the drugmaker said. Recordati is "actively building its commercial, medical, and market access teams" to accommodate Isturisa's launch through its recently created U.S. endocrinology business unit, it said. The drugmaker will launch the drug with a "comprehensive distribution model" through specialty pharmacies. Novartis, once the owner of Isturisa, turned the asset over to Recordati in 2019 as part of a $390 million offload of some of the Swiss drugmaker's endocrinology portfolio. Recordati received Signifor, long-acting sister Signifor LAR and Isturisa, positioned as a successor drug to Signifor. The purchase included milestone payments tied to Isturisa. Recordati talked up the buy of the Cushing's disease trio as a boon for its rare disease portfolio, calling it a "key and historical milestone" at the time. From https://www.fiercepharma.com/pharma/recordati-scores-fda-nod-for-cushing-s-disease-med-isturisa

Abstract Background Endoscopic endonasal surgery is the main transsphenoidal approach for pituitary surgery in many centers, however few studies compare the endoscopic and microscopic surgical approach with regard to long-term follow-up. This single-center study aimed to compare the two techniques over 15 years. Methods Medical records and magnetic resonance images from 40 patients with primary transsphenoidal surgery for Cushing’s disease at Sahlgrenska University Hospital between 2003 and 2018 were reviewed. Fourteen patients who underwent microscopic surgery and 26 patients who underwent endoscopic surgery were included in this study. Results In the microscopic group, 12 of 14 patients achieved endocrine remission, compared to 19 of 26 patients in the endoscopic group (n. s.). Three patients in each group developed a late recurrence. Complications were seen in 5 patients in the microscopic group and in 8 patients in the endoscopic group (n. s.). No serious complications, such as carotid artery damage, cerebrovascular fluid leakage, epistaxis, or meningitis, occurred in any group. The postoperative hospital stay was shorter in the endoscopic than the microscopic group. Conclusion Endoscopic endonasal surgery for Cushing’s disease showed no difference in remission, recurrence, and complication rates compared to the microscopic approach. The endoscopic group had a shorter postoperative hospital stay than the microscopic group, which in part may be due to the minimal invasiveness of the endoscopic approach. References (0) Cited by (0) Recommended articles (6) Research article Identifying obstructive sleep apnea in patients with epilepsy: A cross-sectional multicenter study Seizure, Volume 100, 2022, pp. 87-94 Show abstract Research article Nursing Home Characteristics Associated with High and Low Levels of Antipsychotic, Benzodiazepine, and Opioid Prescribing to Residents with Alzheimer’s Disease and Related Dementias: A Cross-Sectional Analysis Journal of the American Medical Directors Association, 2022 Show abstract Research article Association between sensory impairments and restricted social participation in older adults: A cross-sectional study Collegian, 2022 Show abstract Research article Percutaneous Intervertebral-Vacuum Polymethylmethacrylate Injection for Foraminal Stenosis with Degenerative Lumbar Scoliosis World Neurosurgery, 2022 Show abstract Research article Predictors of Emergency Department service outcome for people brought in by police: A retrospective cohort study International Emergency Nursing, Volume 63, 2022, Article 101188 Show abstract Research article Interdisciplinary Care Coordination in Chronic Viral Hepatitis C The Journal for Nurse Practitioners, 2022 Show abstract Conflicts of interest The authors have no conflicts of interest. Author statements Conceptualization: D. Farahmand, E. Backlund, O. Ragnarsson and P. Trimpou Data curation: Dan Farahmand, Erica Backlund, J. Carlqvist, T. Skoglund, T. Hallén, O. Ragnarsson, P. Trimpou. Formal Analysis: D. Farahmand, E. Backlund Funding acquisition: D. Farahmand Investigation: D. Farahmand, E. Backlund, O. Ragnarsson and P. Trimpou Methodology: D. Farahmand, E. Backlund, O. Ragnarsson and P. Trimpou Project administration: D. Farahmand, E. Backlund, O. Ragnarsson and P. Trimpou Supervision: D. Farahmand Writing – original draft: Penelope Trimpou Writing – review & editing: E. Backlund, O. Ragnarsson, T. Skoglund, T. Hallén, G. Gudnadottir, J. Carlqvist and D. Farahmand. View full text From https://www.sciencedirect.com/science/article/abs/pii/S1878875022009640

Recordati Rare Diseases, a US biopharma that forms part of the wider Italian group, has presented multiple positive data sets on Isturisa (osilodrostat) at the annual ENDO 2022 meeting in Atlanta, Georgia. Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. Among the data presented, the Phase III LINC 4 study demonstrated that Isturisa maintained normal mean urinary free cortisol long-term in patients with Cushing’s disease while the Phase III LINC 3 study found adrenal hormone levels changed during early treatment with the drug while stabilizing during long-term treatment. The ILLUSTRATE study also showed patients treated with a prolonged titration interval tended to have greater persistence with therapy. Mohamed Ladha, president and general manager for North America, Recordati Rare Diseases, said: “The data from these studies reinforces the efficacy and safety of Isturisa as a treatment for patients with Cushing’s disease. “We are pleased to share these data with the endocrine community and are excited to provide patients with a much-needed step forward in the management of this rare, debilitating, and potentially life-threatening condition.” Cushing’s disease is a rare, serious illness caused by a pituitary tumor that leads to overproduction of cortisol by the adrenal glands. Excess cortisol can contribute to an increased risk of morbidity and mortality. Treatment for the condition seeks to lower cortisol levels to a normal range. Isturisa, which was approved by the US Food and Drug Administration in March 2020, works by inhibiting 11-beta-hydroxylase, an enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland. From https://www.thepharmaletter.com/article/results-reinforce-efficacy-of-recordati-s-isturisa-in-cushing-s-disease

Abstract Cushing's disease causes numerous metabolic disorders, cognitive decline, and sarcopenia, leading to deterioration of the general health in older individuals. Cushing's disease can be treated with transsphenoidal surgery, but thus far, surgery has often been avoided in older patients. We herein report an older woman with Cushing's disease whose cognitive impairment and sarcopenia improved after transsphenoidal surgery. Although cognitive impairment and sarcopenia in most older patients show resistance to treatment, our case indicates that normalization of the cortisol level by transsphenoidal surgery can be effective in improving the cognitive impairment and muscle mass loss caused by Cushing's disease. References (27) 1. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of Cushing's syndrome: a population-based study. J Clin Endocrinol Metab 86: 117-123, 2001. 2. Starkman MN. Neuropsychiatric findings in Cushing syndrome and exogenous glucocorticoid administration. Endocrinol Metab Clin N Am 42: 477-488, 2013. 3. Chen YF, Li YF, Chen X, Sun QF. Neuropsychiatric disorders and cognitive dysfunction in patients with Cushing's disease. CMJ 26: 3156-3160, 2013. 4. Priego T, Martín AI, González-Hedström D, Granado M, López-Calderón A. Role of hormones in sarcopenia. Vitam Horm 115: 535-570, 2021. 5. Grossman R, Mukherjee D, Chaichana KL, et al. Complications and death among elderly patients undergoing pituitary tumour surgery. Clin Endocrinol 73: 361-368, 2010. 6. Tiemensma J, Kokshoom NE, Biermasz NR, et al. Subtle cognitive impairments in patients with long-term cure of Cushing's disease. J Clin Endocrinol Metab 95: 2699-2714, 2010. 7. Brunetti A, Fulham MJ, Aloj L, et al. Decreased brain glucose utilization in patients with Cushing's disease. J Nucl Med 39: 786-790, 1998. 8. Liu S, Wang Y, Xu K, et al. Brain glucose metabolism is associated with hormone level in Cushing's disease: A voxel-based study using FDG-PET. Neuroimage Clin 12: 415-419, 2016. 9. Cheng H, Gao L, Hou B, et al. Reversibility of The cerebral blood flow in Patients with Cushing's Disease after Surgery Treatment. Metabolism 104: 154050, 2020. 10. Forget H, Lacroix A, Somma M, Cohen H. Cognitive decline in patients with Cushing's syndrome. J Int Neuropsychol Soc 6: 20-29, 2000. 11. Kim KJ, Filosa JA. Advanced in vitro approach to study neurovascular coupling mechanisms in the brain microcirculation. J Physiol 590: 1757-1770, 2012. 12. McEwen BS, Bowles NP, Gray JD, et al. Mechanisms of stress in the brain. Nat Neurosci 18: 1353-1363, 2015. 13. Rajkowska G, Miguel-Hidalgo JJ. Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets 6: 219-233, 2007. 14. Iuchi T, Akaike M, Mitsui T, et al. Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. Circ Res 92: 81-87, 2003. 15. Cheng H, Gao L, Hou B, et al. Reversibility of the cerebral blood flow in patients with Cushing's disease after surgery treatment. Metabolism 104: 154050, 2020. 16. Frimodt-Møller KE, Møllegaard Jepsen JR, Feldt-Rasmussen U, et al. Hippocampal volume, cognitive functions, depression, anxiety, and quality of life in patients with Cushing syndrome. J Clin Endocrinol Metab 104: 4563-4577, 2019. 17. Siegel S, Kirstein CF, Grzywotz A, et al. Neuropsychological functioning in patients with cushing's disease and Cushing's syndrome. Exp Clin Endocrinol Diabetes 129: 194-202, 2021. 18. Chow Y, Masiak J, Mikołajewska E, et al. Limbic brain structures and burnout-A systematic review. Adv Med Sci 63: 192-198, 2018. 19. Starkman MN, Gebarski SS, Berent S, Schteingart DE. Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome. Biol Psychiatry 32: 756-765, 1992. 20. Goldberg AL, Tischler M, Demartina G, Griffin G. Hormonal regulation of protein degradation and synthesis in skeletal muscle. Fed Proc 39: 31-36, 1980. 21. Miller BS, Ignatoski KM, Daignault S, et al. A quantitative tool to assess degree of sarcopenia objectively in patients with hypercortisolism. Surgery 150: 1178-1185, 2011. 22. Delivanis D, Iñiguez-Ariza N, Zeb M, et al. Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas. Clin Endocrinol 88: 209-216, 2018. 23. Kim JH, Kwak MK, Ahn SH, et al. Alteration in skeletal muscle mass in women with subclinical hypercortisolism. Endocrine 61: 134-143, 2018. 24. Gonzalez Rodriguez E, Marques-Vidal P, Aubry-Rozier B, et al. Diurnal salivary cortisol in sarcopenic postmenopausal women: the OsteoLaus Cohort. Calcif Tissue Int 109: 499-509, 2021. 25. Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol 8: 748-761, 2020. 26. Lau D, Rutledge C, Aghi MK. Cushing's disease: current medical therapies and molecular insights guiding future therapies. Neurosurg Focus 38: E11, 2015. 27. Villar-Taibo R, Díaz-Ortega C, Sifontes-Dubo M, et al. Pituitary surgery in elderly patients: a safe and effective procedure. Endocrine 2: 814-822, 2021. From https://www.jstage.jst.go.jp/article/internalmedicine/advpub/0/advpub_8326-21/_article

The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed. Key Takeaways A study of 78 patients who underwent elective transsphenoidal adenomectomy to remove a pituitary tumor or other lesions within the pituitary fossa at a single center in the UK suggests that postoperative plasma levels of copeptin — a surrogate marker for levels of arginine vasopressin (antidiuretic hormone) — can rule out development of central (neurogenic) diabetes insipidus caused by a deficiency of arginine vasopressin following pituitary surgery. The researchers suggest using as a cutoff a copeptin level of >3.4 pmol/L at postoperative day 1 to rule out diabetes insipidus. Such a cutoff yields the following: A high sensitivity of 91% for ruling out diabetes insipidus. A negative predictive value of 97%. Only 1 of 38 patients with a copeptin value >3.4 pmol/L at day 1 postoperatively developed diabetes insipidus. A low specificity of 55%, meaning that copeptin level is not useful for diagnosing diabetes insipidus Why This Matters An estimated 1% to 67% of patients who undergo pituitary gland surgery develop diabetes insipidus, often soon after surgery, although it is often transient. Diagnosing diabetes insipidus in such patients requires a combination of clinical assessment, the monitoring of fluid balance, and determining plasma and urine sodium and osmolality. Currently, clinical laboratories in the UK do not have assays for arginine vasopressin, which has a short half-life in vivo and is unstable ex vivo, even when frozen, and is affected by delayed or incomplete separation from platelets. Copeptin, an arginine vasopressin precursor, is much more stable and measurable by commercial immunoassays. The findings suggest that patients who have just undergone pituitary gland surgery and are otherwise healthy and meet the copeptin cutoff for ruling out diabetes insipidus could be discharged 24 hours after surgery and that there is no need for additional clinical and biochemical monitoring. This change would ease demands on the healthcare system. Study Design The study reviewed 78 patients who underwent elective transsphenoidal adenomectomy to remove a pituitary tumor from November 2017 to June 2020 at the John Radcliffe Hospital in Oxford, United Kingdom. Patients remained in hospital for a minimum of 48 hours after their surgery. Clinicians collected blood and urine specimens preoperatively and at day 1, day 2, day 8, and week 6 post surgery. The patients were restricted to 2 L of fluid a day postoperatively to prevent masking of biochemical abnormalities through compensatory drinking. Diabetes insipidus was suspected when patients' urine output was >200 mL/h for 3 consecutive hours or >3 L/d plus high plasma sodium (>145 mmol/L) and plasma osmolality (> 295 mosmol/kg) plus inappropriately low urine osmolality. Definitive diagnosis of diabetes insipidus was based on clinical assessment, urine and plasma biochemistry, and need for treatment with desmopressin (1-deamino-8-D-arginine vasopressin). Key Results The median age of the patients was 55, and 53% were men; 92% of the lesions were macroadenomas; the most common histologic type was gonadotroph tumor (47%). Among the 78 patients, 11 (14%) were diagnosed with diabetes insipidus postoperatively and required treatment with desmopressin; of these, seven patients (9%) continued taking desmopressin after 6 weeks (permanent diabetes insipidus), but the other four did not need to take desmopressin for more than a week. Patients who developed diabetes insipidus were younger than other patients (mean age, 46 vs 56), and 8 of the 11 patients who developed diabetes insipidus (73%) were women. Preoperative copeptin levels were similar in the two groups. At day 1, day 8, and 6 weeks postoperatively, copeptin levels were significantly lower in the diabetes insipidus group; there were no significant differences at day 2, largely because of an outlier result. An area under the receiver operating characteristic curve (AUC; C-statistic) analysis showed that on day 1 after surgery, copeptin levels could account for 74.22% of the incident cases of diabetes insipidus (AUC, 0.7422). On postop day 8, the AUC for copeptin was 0.8015, and after 6 weeks, the AUC associated with copeptin was 0.7321. Limitations Blood samples for copeptin tests from patients who underwent pituitary surgery were collected at specified times and were frozen for later analysis; performing the test in real time might alter patient management. The study may have missed peak copeptin levels by not determining copeptin levels sooner after pituitary gland surgery, inasmuch as other researchers have reported better predictive values for diagnosing diabetes insipidus from samples taken 1 hour after extubation or <12 hours after surgery. Disclosures The study did not receive commercial funding. The authors report no relevant financial relationships. This is a summary of a preprint research study, "Post-Operative Copeptin Analysis Predicts Which Patients Do Not Develop Diabetes Insipidus After Pituitary Surgery," by researchers from John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, in the United Kingdom. Preprints from Research Square are provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com. Read the article here: https://www.medscape.com/viewarticle/970357#vp_1

This article was originally published here Front Surg. 2022 Feb 2;8:806855. doi: 10.3389/fsurg.2021.806855. eCollection 2021. ABSTRACT PURPOSE: Currently, endoscopic transsphenoidal surgery (ETS) and microscopic transsphenoidal surgery (MTS) are commonly applied treatments for patients with pituitary adenomas. This meta-analysis was conducted to evaluate the efficacy and safety of ETS and MTS for these patients. METHODS: A computer search of Pubmed, Embase, Cochrane library, Web of Science, and Google Scholar databases was conducted for studies investigating ETS and MTS for patients with pituitary adenomas. The deadline is March 01, 2021. RevMan5.1 software was used to complete this meta-analysis after literature screening, data extraction, and literature quality evaluation. RESULTS: A total of 37 studies including 5,591 patients were included. There was no significant difference in gross tumor removal (GTR) and hormone-excess secretion remission (HES remission) between two groups [RR = 1.10, 95% CI (0.99-1.22), P = 0.07; RR = 1.09, 95% CI (1.00-1.20), P = 0.05]. ETS was associated with lower incidence of diabetes insipidus (DI) [RR = 0.71, 95% CI (0.58-0.87), P = 0.0008], hypothyroidism [RR = 0.64, 95% CI (0.47-0.89), P = 0.007], and septal perforation [RR = 0.32, 95% CI (0.13-0.79), P = 0.01] than those with MTS. CONCLUSION: This meta-analysis indicated that ETS cannot significantly improve GTR and HES remission. However, ETS could reduce the incidence of DI, hypothyroidism, and septal perforation without increasing the rate of other complications. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/#myprospero, identifier: CRD42021241217. PMID:35187049 | PMC:PMC8847202 | DOI:10.3389/fsurg.2021.806855

TAMPA, Fla., Nov. 3, 2021 /PRNewswire/ -- The Carling Adrenal Center, a worldwide destination for the surgical treatment of adrenal tumors, becomes the first center to offer adrenal vein sampling and curative surgery in one visit. The novel protocol and diagnostic method for adrenal tumors will condense a 2–4-week process of localization of hyper-secreting adrenal tumors and subsequent curative surgery down to just one day. The innovative approach combines highly specialized adrenal vein sampling with rapid adrenal hormone lab testing and then consultation with the world's highest volume adrenal surgeon. If appropriate, a patient may even complete their mini-surgery during that same visit. Established by Dr. Tobias Carling in 2020, the Carling Adrenal Center located at the Hospital for Endocrine Surgery in Tampa FL, is the highest volume adrenal surgical center in the world. The Center now averages nearly 20 adrenal tumor patients every week that could benefit from this novel diagnostic and treatment approach to address a decades-long problem for patients with adrenal tumors. The Endocrine Society Clinical Practice Guideline recommends adrenal vein sampling (AVS) as the preferred method to select patients with primary hyperaldosteronism for an adrenalectomy. "The difficulty and complexity of testing and diagnosing adrenal tumors secreting excess aldosterone is the primary reason why less than 5% of these adrenal tumors are diagnosed and treated," says Dr. Carling. "By combining expertise in interventional radiology for adrenal vein sampling and rapid laboratory measurements of adrenal hormones with our unique international consulting capability, we can determine which adrenal gland is bad and whether or not the patient needs that adrenal gland removed." Adrenal vein sampling is performed through small catheters placed in very specific veins where blood samples are obtained from both adrenal veins and the inferior vena cava. In experienced centers, the bilateral adrenal veins are catheterized and sampled with a success rate exceeding 90%. Technical success is directly associated with operator experience, leading to the recommendation that the procedure only be performed by true experts or the test will very likely be of no help. Dr. Carling's very high volume of adrenal surgery for many years has allowed him to publish scientific studies demonstrating that in aldosterone-producing adenomas, there is a strong correlation between the imaging phenotype (i.e., what the tumor looks like on a CT scan), histology (what the tumor looks like under the microscope) and genotype (what gene is mutated in the tumor). This knowledge allows Dr. Carling and his team at the Hospital for Endocrine Surgery to predict who can go straight to surgery with an excellent outcome, and who may first need adrenal vein sampling to determine which adrenal gland is over-producing the hormone causing significant morbidity and mortality. With adrenal vein sampling proving lateralization, the next step is surgical removal of the adrenal tumor. Dr. Carling has more experience with all types of adrenal surgery than any surgeon in the United States, but especially with advanced, minimally invasive adrenal operations which are the best options for aldosterone-secreting adrenal tumors. A fellow of the American College of Surgeons, Dr. Carling is a member of both the American Association of Endocrine Surgeons (AAES) and the International Association of Endocrine Surgeons (IAES). Dr. Carling moved his world-renowned adrenal surgery program from Yale University to Tampa, Florida in early 2020 to start the Carling Adrenal Center. Here, patients needing adrenal surgery have access to the best practices and best techniques the world has to offer. In January 2022, the Carling Adrenal Center will unite with the Norman Parathyroid Center, the Clayman Thyroid Center and the Scarless Thyroid Surgery Center at the brand-new Hospital for Endocrine Surgery located in Tampa, Florida. About the Carling Adrenal Center: Founded by Dr. Tobias Carling, one of the world's leading experts in adrenal gland surgery, the Carling Adrenal Center is a worldwide destination for the surgical treatment of adrenal tumors. Dr. Carling spent nearly 20 years at Yale University, including 7 as the Chief of Endocrine Surgery before leaving in 2020 to open to Carling Adrenal Center, which performs more adrenal operations than any other hospital in the world. More about adrenal vein sampling for adrenal tumors can be found at the Center's website www.adrenal.com and here. (813) 972-0000. Contact: Julie Canan, Director of Marketing Carling Adrenal Center juliec@parathyroid.com SOURCE Carling Adrenal Center From https://www.prnewswire.com/news-releases/innovative-one-visit-adrenal-tumor-diagnosis-and-treatment-program-begins-in-tampa-301414465.html

This article was originally published here J Clin Endocrinol Metab. 2021 Sep 3:dgab659. doi: 10.1210/clinem/dgab659. Online ahead of print. ABSTRACT CONTEXT: Confirming a diagnosis of Cushing’s disease (CD) remains challenging yet is critically important before recommending transsphenoidal surgery for adenoma resection. OBJECTIVE: To describe predictive performance of preoperative biochemical and imaging data relative to post-operative remission and clinical characteristics in patients with presumed CD. DESIGN, SETTING, PATIENTS, INTERVENTIONS: Patients (n=105; 86% female) who underwent surgery from 2007-2020 were classified into 3 groups: Group A (n=84) pathology-proven ACTH adenoma; Group B (n=6) pathology-unproven but with postoperative hypocortisolemia consistent with CD, and Group C (n=15) pathology-unproven, without postoperative hypocortisolemia. Group A+B were combined as Confirmed CD and Group C as Unconfirmed CD. MAIN OUTCOMES: Group A+B was compared to Group C regarding predictive performance of preoperative 24-hour urinary free cortisol (UFC), late night salivary cortisol (LNSC), 1mg dexamethasone suppression test (DST), plasma ACTH, and pituitary MRI. RESULTS: All groups had a similar clinical phenotype. Compared to Group C, Group A+B had higher mean UFC (p<0.001), LNSC(p=0.003), DST(p=0.06), ACTH(p=0.03) and larger MRI-defined lesions (p<0.001). The highest accuracy thresholds were: UFC 72 µg/24hrs; LNSC 0.122 µg/dl, DST 2.70 µg/dl, and ACTH 39.1 pg/ml. Early (3-month) biochemical remission was achieved in 76/105 (72%) patients: 76/90(84%) and 0/15(0%) of Group A+B versus Group C, respectively, p<0.0001. In Group A+B non-remission was strongly associated with adenoma cavernous sinus invasion. CONCLUSIONS: Use of strict biochemical thresholds may help avoid offering transsphenoidal surgery to presumed CD patients with equivocal data and improve surgical remission rates. Patients with Cushingoid phenotype but equivocal biochemical data warrant additional rigorous testing. PMID:34478542 | DOI:10.1210/clinem/dgab659

Christina Tatsi, Maria E. Bompou, Chelsi Flippo, Meg Keil, Prashant Chittiboina, Constantine A. Stratakis First published: 25 August 2021 https://doi.org/10.1111/cen.14560 Abstract Objective Diagnostic workup of Cushing disease (CD) involves imaging evaluation of the pituitary gland, but in many patients no tumour is visualised. The aim of this study is to describe the association of magnetic resonance imaging (MRI) findings with the postoperative course of paediatric and adolescent patients with CD. Patients Patients with a diagnosis of CD at less than 21 years of age with MRI evaluation of the pituitary before first transsphenoidal surgery were included. Measurements Clinical, imaging and biochemical data were analysed. Results One hundred and eighty-six patients with paediatric or adolescent-onset CD were included in the study. Of all patients, 127 (68.3%) had MRI findings consistent with pituitary adenoma, while the remaining had negative or inconclusive MRI. Patients with negative MRI were younger in age and had lower morning cortisol and adrenocorticotropin levels. Of 181 patients with data on postoperative course, patients with negative MRI had higher odds of not achieving remission after the first surgery (odds ratio = 2.6, 95% confidence intervals [CIs] = 1.1–6.0) compared to those with positive MRI. In patients with remission after first transsphenoidal surgery, long-term recurrence risk was not associated with the detection of a pituitary adenoma in the preoperative MRI (hazard risk = 2.1, 95% CI = 0.7–5.8). Conclusions Up to one-third of paediatric and adolescent patients with CD do not have a pituitary tumour visualised in MRI. A negative MRI is associated with higher odds of nonremission after surgery; however, if remission is achieved, long-term risk for recurrence is not associated with the preoperative MRI findings. Full text at https://onlinelibrary.wiley.com/doi/full/10.1111/cen.14560

Rachel Acree, Caitlin M Miller, Brent S Abel, Nicola M Neary, Karen Campbell, Lynnette K Nieman Journal of the Endocrine Society, Volume 5, Issue 8, August 2021, bvab109, https://doi.org/10.1210/jendso/bvab109 Abstract Context Cushing syndrome (CS) is associated with impaired health-related quality of life (HRQOL) even after surgical cure. Objective To characterize patient and provider perspectives on recovery from CS, drivers of decreased HRQOL during recovery, and ways to improve HRQOL. Design Cross-sectional observational survey. Participants Patients (n = 341) had undergone surgery for CS and were members of the Cushing’s Support and Research Foundation. Physicians (n = 54) were Pituitary Society physician members and academicians who treated patients with CS. Results Compared with patients, physicians underestimated the time to complete recovery after surgery (12 months vs 18 months, P = 0.0104). Time to recovery did not differ by CS etiology, but patients with adrenal etiologies of CS reported a longer duration of cortisol replacement medication compared with patients with Cushing disease (12 months vs 6 months, P = 0.0025). Physicians overestimated the benefits of work (26.9% vs 65.3%, P < 0.0001), exercise (40.9% vs 77.6%, P = 0.0001), and activities (44.8% vs 75.5%, P = 0.0016) as useful coping mechanisms in the postsurgical period. Most patients considered family/friends (83.4%) and rest (74.7%) to be helpful. All physicians endorsed educating patients on recovery, but 32.4% (95% CI, 27.3-38.0) of patients denied receiving sufficient information. Some patients did not feel prepared for the postsurgical experience (32.9%; 95% CI, 27.6-38.6) and considered physicians not familiar enough with CS (16.1%; 95% CI, 12.2-20.8). Conclusion Poor communication between physicians and CS patients may contribute to dissatisfaction with the postsurgical experience. Increased information on recovery, including helpful coping mechanisms, and improved provider-physician communication may improve HRQOL during recovery. Read the entire article in the enclosed PDF. bvab109.pdf

Zarina Brady, Aoife Garrahy, Claire Carthy, Michael W. O’Reilly, Christopher J. Thompson, Mark Sherlock, Amar Agha & Mohsen Javadpour BMC Endocrine Disorders volume 21, Article number: 36 (2021) Cite this article 160 Accesses Metricsdetails Abstract Background Transsphenoidal surgery (TSS) to resect an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment for Cushing’s disease (CD), with increasing usage of endoscopic transsphenoidal (ETSS) technique. The aim of this study was to assess remission rates and postoperative complications following ETSS for CD. Methods A retrospective analysis of a prospective single-surgeon database of consecutive patients with CD who underwent ETSS between January 2012–February 2020. Post-operative remission was defined, according to Endocrine Society Guidelines, as a morning serum cortisol < 138 nmol/L within 7 days of surgery, with improvement in clinical features of hypercortisolism. A strict cut-off of < 50 nmol/L at day 3 post-op was also applied, to allow early identification of remission. Results A single surgeon (MJ) performed 43 ETSS in 39 patients. Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). IPSS was carried out in 33 (85%) patients. The remission rates for initial surgery were 87% using standard criteria, 58% using the strict criteria (day 3 cortisol < 50 nmol/L). Three patients had an early repeat ETSS for persistent disease (day 3 cortisol 306-555 nmol/L). When the outcome of repeat early ETSS was included, the remission rate was 92% (36/39) overall. Remission rate was 94% (33/35) when patients with macroadenomas were excluded. There were no cases of CSF leakage, meningitis, vascular injury or visual deterioration. Transient and permanent diabetes insipidus occurred in 33 and 23% following first ETSS, respectively. There was one case of recurrence of CD during the follow-up period of 24 (4–79) months. Conclusion Endoscopic transsphenoidal surgery produces satisfactory remission rates for the primary treatment of CD, with higher remission rates for microadenomas. A longer follow-up period is required to assess recurrence rates. Patients should be counselled regarding risk of postoperative diabetes insipidus. Peer Review reports Introduction With an estimated annual incidence of 1.7 per million [1], Cushing’s disease is rare. Untreated, it poses serious complications including osteoporosis, hypertension, dyslipidaemia, insulin resistance, and hypercoagulability [2] and is associated with a 4.8 fold increase in mortality rate [3,4,5]. Patients who are in remission from CD have a mortality rate which decreases towards (although not reaching) that of the general population [6]. Endoscopic transsphenoidal surgery (ETSS) offers patients potential remission from Cushing’s disease, although long term surveillance is required as recurrence rates range from 5 to 22%% [7,8,9,10,11,12]. Since the first report in 1997 [13], the selective removal of an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma by endoscopic transsphenoidal surgery has gained popularity as the first line treatment for Cushing’s disease. The primary goal of ETSS treatment in Cushing’s disease is to produce disease remission and to provide long-term control, while minimising complications. Remission rates are dependent on tumour size, preoperative MRI, cavernous sinus invasion, intraoperative visualisation of the tumour and pre- and postoperative ACTH and cortisol concentration [11]. Several studies also report pituitary neurosurgeon experience as a major factor for operative success [2, 14, 15]. Reported remission and recurrence rates after TSS for CD vary widely according to the criteria utilised to define remission [11], and in some studies due to limited patient numbers or short follow-up periods. Indeed, there is no clear consensus on how best to define post-operative remission; an early morning serum cortisol concentration < 138 nmol/L (5μg/dl) within 7 days of TSS is quoted in the 2015 Endocrine Society Clinical Practice Guideline as indicative of remission [16]. A more strict day 3 cut-off of 50 nmol/L (1.8 μg/dl) has been reported in paediatric studies [17], and also included in the Endocrine Society Guideline [16]; the literature suggests this cut-off is associated with remission, and a low recurrence rate of approximately 10% at 10 years [14]. The main objective of this study was to assess the outcomes of endoscopic transsphenoidal surgery for Cushing’s disease in a tertiary pituitary centre; remission using two widely accepted criteria [16], recurrence and postoperative complications. Methods Study design This is a retrospective analysis of a prospectively-maintained database of patients operated on by a single neurosurgeon (MJ), via image-guided endoscopic transsphenoidal approach for Cushing’s disease. Patient data was gathered over 8 years (January 2012 to February 2020) and identified from the institution’s prospective database. Clinical and biochemical data during the follow-up period was reviewed. Approval was granted by the Hospital Audit Committee. Study population Patients were screened for Cushing’s syndrome by the presence of typical clinical features, together with failure to adequately suppress cortisol to < 50 nmol/L following overnight dexamethasone suppression test (ONDST) and/or elevated late night salivary cortisol (LNSF) concentration and/or elevated 24 h urinary free cortisol measurements. As per standard guidelines, Cushing’s disease was diagnosed on the basis of elevated serum ACTH measurements, along with confirmatory hormone responses to peripheral corticotropin releasing hormone (CRH) test and inferior petrosal sinus sampling (IPSS). Patients with previous TSS prior to the study period were excluded. Surgical procedure A single neurosurgeon subspecialising in endoscopic pituitary and anterior skull base surgery, M.J, carried out all ETSS surgical procedures. The surgical technique has been described in detail in publications by Cappabianca et al. (1998, 1999) and Jho et al. (1997, 2000, 2001) [13, 18,19,20,21]. In summary, the procedure consists of a binostril endoscopic transsphenoidal approach. A selective adenomectomy was performed on patients with adenomas noted on pre-operative MRI. In cases of negative pre-operative MRI, exploration of the pituitary gland was performed. To confirm the diagnosis of ACTH-secreting adenoma or hyperplasia, all specimens removed underwent histopathological and immunohistochemical staining for pituitary hormones. Postoperative assessment Patients received empiric oral hydrocortisone on day 1 and on the morning of day 2 post-operatively, prior to assessment of 0800 h serum cortisol on day 3. A blood sample for serum cortisol was drawn at 0800 h on the morning of day 3, if clinically stable, prior to administration of hydrocortisone. The Endocrine Society Clinical Practice Guideline define post-operative biochemical remission as morning serum cortisol < 138 nmol/L (5μg/dl) within 7 days postoperatively [16], ‘standard criteria’. In our institution, we also apply a biochemical cut-off of < 50 nmol/L (1.8 μg/dl) at day 3 postoperatively to allow early indication of biochemical remission, ‘strict criteria’. If serum cortisol on day 3 is 50–138 nmol/L, serial measurements are taken daily to determine if cortisol will fall further, and assessment for improvement/resolution of clinical sequalae of hypercortisolaemia made (such as improvement in blood pressure or glycaemic control), before repeat endoscopic transsphenoidal surgery is considered. Transient cranial diabetes insipidus (DI) was defined as the development of hypotonic polyuria postoperatively requiring at least one dose of desmopressin [22], which resolved prior to discharge. Permanent DI was confirmed by water deprivation test according to standard criteria [23]. Thyroid stimulating hormone (TSH) deficiency was defined by low fT4 with either low or inappropriately normal TSH. Growth hormone (GH) deficiency was confirmed using either Insulin Tolerance Test or Glucagon Stimulation Test [24]. Gonadotrophin deficiency was defined in premenopausal women as amenorrhoea with inappropriately low FSH and LH concentration, and in postmenopausal patients as inappropriately low FSH and LH concentration. Recovery of hypothalamic-pituitary-adrenal axis was assessed by short synacthen (250 μg) test or insulin tolerance test 3 months post-operatively, and every 3–6 months thereafter in cases of initial fail or borderline result. Patients were assessed annually for recurrence of Cushing’s disease, recurrence was defined by failure to suppress cortisol to < 50 nmol/L following an 1 mg overnight dexamethasone suppression test, an elevated late night salivary cortisol (LNSF) or urinary free cortisol (UFC) in patients no longer taking hydrocortisone. Laboratory analysis Prior to 2019, serum cortisol was measured using a chemiluminescent immunoassay with the Beckman Coulter UniCel Dxl 800. Intra-assay CV for serum cortisol was 8.3, 5 and 4.6% at concentrations of 76, 438 and 865 nmol/L, respectively. From January 2019 onwards, serum cortisol was measured using Elecsys® Cortisol II assay on the Roche Cobas e801; intra-assay precision for serum cortisol was 1.2, 1.1 and 1.6% at concentrations of 31.8, 273 and 788 nmol/L, respectively. Statistics Data are expressed as median (range) and number (%). The Fishers Exact test was used to compare categorical variables between groups. All p-values were considered statistically significant at a level < 0.05. Statistical analysis was performed using GraphPad Prism 8 statistical software (GraphPad Software, La Jolla, California, USA). Results Demographics Forty-three endoscopic transsphenoidal procedures were performed in 39 patients. Demographics are summarised in Table 1. Median (range) age was 37 years (8–75), 30 were female. Median (range) duration of symptoms was 24 months (6–144), 72% (28/39) had hypertension, and 28% (11/39) had type 2 diabetes. Table 1 Summary of demographics and post-operative outcomes Full size table Preoperative imaging and IPSS Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). No adenoma was identified in 17 patients (44%). IPSS was carried out in 33 (85%) patients. Postoperative remission Post-operative outcomes are summarised in Table 1 and Fig. 1. Using standard criteria (0800 h serum cortisol < 138 nmol/l within 7 days of operation and improvement in clinical features of hypercortisolism), postoperative remission rates for initial surgery were 87% (34/39) for the entire group and 89% (31/35) when patients with macroadenomas were excluded, Fig. 1. Three patients had an early repeat ETSS for persistent disease; day 3 serum cortisol ranged from 306 to 555 nmol/L and interval to repeat ETSS from 10 days–3 months. When the outcome of early repeat ETSS was factored in, overall remission rate was 92% (36/39) overall, and 94% (33/35) when patients with macroadenomas were excluded. Fig. 1 Schema of patients who underwent ETSS. *Day 3 cortisol was not measured in one patient due to intercurrent illness requiring treatment with intravenous glucocorticoids Full size image Using strict criteria of early remission (day 3 serum cortisol concentration < 50 nmol/L), postoperative remission rates were 58% (22/38) overall, and 62% (21/34) excluding macroadenomas. Including the three patients with early repeat ETSS, remission rate was 61% (23/38) overall, and 65% excluding macroadenomas (22/34). Day 3 cortisol was not measured in one patient due to intercurrent illness requiring treatment with intravenous glucocorticoids. Eleven patients (28%) had a cortisol measurement between 50 and 138 nmol/L on day 3, seven of whom had received metyrapone therapy prior to ETSS. Six patients had serial measurements of 0800 h cortisol up to a maximum follow-up of 14 days post-op, serum cortisol concentration fell after day 3 in all six patients. Ten (91%) were glucocorticoid-dependent at 3 months based on synacthen/ITT; 0800 h cortisol had fallen to < 50 nmol/L in six patients. Predictors of remission No statistical difference was found in the rates of remission in those patients with or without tumour target on preoperative MRI, using either strict criteria for remission (12/21 target vs 10/17 no target, p > 0.99) or standard criteria (19/22 target vs 15/17 no target, p > 0.99). Similar results were found when the four patients with macroadenoma were excluded. Persistent disease Five patients (13%) had persistent hypercortisolaemia after the initial endoscopic transsphenoidal surgery (Table 2). Three patients underwent a repeat early endoscopic transsphenoidal surgery, Fig. 1. Remission rate after repeat early ETSS was 67% (2/3) using standard criteria, and 33% (1/3), using the strict criteria. Of the patients with persistent disease following repeat ETSS, one received radiosurgery, while the other has been commenced on medical therapy, with a view to refer for radiotherapy. Table 2 Outcome of five patients with persistent hypercortisolaemia after initial ETSS Full size table Postoperative complications The rate of transient diabetes insipidus after first ETSS was 33% (13/39), while permanent diabetes insipidus occurred in 23% (9/39). Postoperatively, there were five cases of new thyroid stimulating hormone deficiency (13%) and four cases of gonadotrophin deficiency (10%) (in pre-menopausal females). There were no cases of postoperative CSF leak, no cases of meningitis and no visual complications. There were no other complications. Recurrence No patients were lost to follow-up. Over a median (range) duration of follow-up of 24 (4–79) months, one patient had recurrence of Cushing’s disease. Pre-operative MRI had shown a macroadenoma; serum cortisol on day 3 after the initial ETSS was 71 nmol/L, which fulfilled standard criteria for remission, but not the more strict criteria. The patient underwent a second ETSS 13 months later. No tumour was visible intra-operatively so no tissue was removed, day 3 serum cortisol concentration was 308 nmol/L and the patient was commenced on a trial of metyrapone. Recovery of the hypothalamic-pituitary-adrenal axis Recovery of the hypothalamic-pituitary-adrenal axis occurred in nine patients (27%), at median 13 (3–27) months post-operatively. There was no statistical difference in rates of recovery of HPA axis in patients with day 3 cortisol < 50 nmol/l, and those who only passed standard criteria for remission (< 138 nmol/l) [7/20 (follow-up 25 (3–59) months) versus 2/11 (follow-up 16 (3–79) months) respectively, p = 0.43]. One patient died 5 weeks post-operatively; post-mortem revealed bilateral haemorrhagic adrenal necrosis. Discussion Reported remission rates following ETSS in patients with Cushing’s disease (CD) vary widely, predominantly due to differences in criteria used to define remission [11]. There is no uniform consensus on the criteria used to define ‘remission’, with institutions using a combination of biochemical and clinical criteria; this makes comparing surgical outcome studies challenging. The normal corticotroph cells of the pituitary gland are suppressed due to sustained hypercortisolaemia, therefore following successful removal of the ACTH-secreting adenoma, serum ACTH and cortisol concentrations should fall postoperatively. A morning serum cortisol concentration < 138 nmol/L (5 μg/dl) within 7 days of ETSS is usually indicative of remission, and this biochemical cut-off is quoted in the Endocrine Society Clinical Practice Guideline [16], and many surgical outcome studies [8, 11, 25]. Other studies have applied a more strict serum cortisol cut-off of < 50 nmol/L (1.8 μg/L) at day 3 postoperatively to allow early indication of biochemical remission [10, 11, 26,27,28]; the literature suggests this cutoff is associated with remission, and a low recurrence rate of approximately 10% at 10 years [14]. Our practice is to apply this latter approach; if serum cortisol on day 3 is 50–138 nmol/L, serial measurements are taken daily to determine if cortisol will fall further, and assessment for improvement/resolution of clinical signs of hypercortisolaemia made, before repeat endoscopic transsphenoidal surgery is considered. It is important to ensure that serum cortisol has reached a nadir, before further intervention is considered. In this single-centre single-surgeon study, we report two very different remission rates using these two widely accepted criteria. Our remission rate, including those patients who had an early second ETSS, using standard guidelines, is 92%, on par with other larger studies [7, 8, 11, 25, 29]. When patients with corticotroph macroadenomas were excluded, the remission rate was even higher at 94%. In comparison, when we applied the more strict criteria of day 3 cortisol < 50 nmol/L, the remission rate was considerably lower at 61%. This criteria is in place in our institution so that we can safely identify patients who have early signs of remission to facilitate discharge on day 3 post-operatively; however reporting these rates in isolation lead to a misleadingly low remission rate compared to the more lenient criteria proposed by the Endocrine Society [16]. Evidence has suggested that higher day 3 cortisol concentration is associated with greater risk of recurrence of CD. A recent retrospective cohort analysis of 81 ETSS for CD by Mayberg et al. reported significantly higher recurrence rates in patients with post-operative cortisol nadir between 58 and 149 nmol/L (2.1–5.4 μg/dL) compared with those with cortisol < 55 nmol/L (2 μg/dL) (33% vs 6%, p = 0.01) [30]. Recurrence of CD was low in our series at 3%, and occurred in a patient with a corticotroph macroadenoma, which have been shown to be associated with higher rates of recurrence [31]. On post-operative assessment, serum cortisol fell between the two criteria for remission and if remission was strictly defined as a day 3 cortisol < 50 nmol/L, then this patient had in fact persistent hypercortisolaemia. This case highlights the difficulty when comparing studies reporting ETSS outcomes in CD – the distinction between persistent post-operative hypercortisolism and early recurrence of CD is not always clear-cut, and is dictated by the local protocol. Whilst our recurrence data are encouraging in comparison to other reports on CD recurrence, which published rates of up to 22% [11], longer term follow-up is necessary before recurrence rates can be accurately defined. The criteria used to define long term recurrence of CD also varies widely in the literature; a large systematic review (n = 6400) by Petersenn et al. (2015) reported decreased recurrence rates when studies used UFC with ONDST vs. UFC only, and UFC with morning serum cortisol vs. UFC only [11]. This highlights the requirement for standardization of remission and recurrence criteria, for consistency in clinical practice and in the literature. The post-operative surgical complication rate in our series was very low, with no cases of CSF leak, vascular injury or visual compromise. Other published case series have reported incidence rates for CSF leakage and meningitis of 0–7.2% and 0–7.9% [2, 12, 32, 33] respectively. Postoperative meningitis is strongly associated with CSF leakage [34]. Some studies suggest that the endoscopic approach results in higher rates of carotid artery injury compared with the microscopic approach, which could be attributed to the nature of the extended lateral approach [35]. However, in this series of 43 ETSS, we report no cases of surgical related carotid artery injury, similar to other studies reporting 0% serious morbidity or mortality due to carotid artery injury [33, 36]. Finally, postoperative visual disturbance is a major concern, as it can be life changing for patients. Factors linked with visual complications include tumour size, patient age and any pre-existing visual conditions [37,38,39]. Visual deterioration after TSS for Cushing’s disease has been reported to occur in some large case series at rates of 1.9% [32] and 0.86% [12]. There were no cases of postoperative visual disturbance in our series. While the surgical complication rate was low, our endocrine complication rate was higher than that reported in other studies, particularly the rate of DI. Transient DI occurred in 33% of cases, and permanent DI in 23%. These relatively high rates of transient DI may be due to the diagnostic criteria used in our protocol; we defined transient post-operative DI as one episode of hypotonic polyuria in the setting of normal or elevated plasma sodium concentration, requiring at least one dose of desmopressin. In contrast, some studies discount any polyuria which lasts less than 2 days [10], while others require the documentation of hypernatremia for the diagnosis of DI [40]. These more stringent criteria will not capture cases of mild transient DI; therefore it is not surprising that the rates of transient DI reported in a 2018 meta-analysis were lower than that in our study, 11.3% [29]. The rates of permanent DI in our study merits particular attention. TSS for CD has been shown to be associated with a higher risk of post-operative DI [41, 42]. It may be that a more aggressive surgical approach resulted in high remission rates, but at a cost of higher rates of DI. All patients are reviewed post-operatively in the National Pituitary Centre, where there is a low threshold for water deprivation testing and/or 3% saline testing. We did not routinely re-test patients for resolution of DI after their initial water deprivation test at 3 months, and it is possible that some cases subsequently resolved after 3 months [41, 43]. Regardless, the rate reported in this study is significant, and emphasises the importance of counselling the patient about the risk of DI long-term. Strengths and limitations The reporting of two remission rates based on widely accepted criteria is a strength of this study, and allows for direct comparison of our outcomes with other studies. All ETSS were performed by a single pituitary surgeon; while this removes bias from surgeon experience, the disadvantage of this is that the sample size is relatively low. Furthermore, because we included patients who were recently operated on to maximise numbers for analysis of surgical complications, the follow-up period is relatively short. A longer follow-up is required to comment accurately on recurrence of CD. We did not have full ascertainment of longitudinal post-operative data including dexamethasone suppression tests, and this has highlighted the need for protocolised follow-up to allow for consistency when reporting our results. Conclusion Endoscopic transsphenoidal surgery in patients with Cushing’s disease offers excellent remission rates and low morbidity. Remission rates are much higher when standard criteria [morning serum cortisol < 138 nmol/L (5μg/dl) within 7 days postoperatively] are used compared with day 3 cortisol < 50 nmol/l. Higher remission rates were found for patients with microadenomas. Patients should be counselled regarding risk of post-operative endocrine deficiencies, in particular permanent diabetes insipidus. Longer follow-up is required to accurately assess recurrence rates. Availability of data and materials The data that support the findings of this study are not publicly available due to restrictions by General Data Protection Regulation (GDPR), but are available from the corresponding author on reasonable request. Abbreviations TSS: Transsphenoidal surgery ACTH: Adrenocorticotropic hormone CD: Cushing’s disease ETSS: Endoscopic transsphenoidal surgery ONDST: Overnight dexamethasone suppression test LNSF: Late night salivary cortisol CRH: Corticotropin releasing hormone IPSS: Inferior petrosal sinus sampling DI: Diabetes insipidus TSH: Thyroid stimulating hormone GH: Growth hormone UFC: Urinary free cortisol References 1. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of cushing's syndrome: a population-based study. J Clin Endocrinol Metab. 2001;86(1):117–23. CAS PubMed PubMed Central Google Scholar 2. Broersen LHA, van Haalen FM, Biermasz NR, et al. 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Biomarkers in a majority of Cushing’s syndrome patients with surgically induced disease remission showed a high rate of bone turnover and greater bone mineral density one and two years later, a study reports. Before treatment, these patients were found to have greater bone degradation and poorer bone formation, as can be common to disease-related bone disorders. Researchers believe their work is the first study of its kind, “and the data obtained will be instrumental for clinicians who care for patients with Cushing’s syndrome.” The study, “The Effect of Biochemical Remission on Bone Metabolism in Cushing’s Syndrome: A 2‐Year Follow‐Up Study,” was published in the Journal of Bone and Mineral Research. Two common co-conditions of Cushing’s syndrome are osteopenia, a loss of bone mass, and osteoporosis, in which the body makes too little bone, loses too much bone, or both. Studies suggest up to 80% of people with Cushing’s have evidence of reduced bone mineral density affecting the entire skeleton. However, few risk factors to predict bone health have been identified so far, and guidelines for osteoporosis management due to Cushing’s are lacking. Uncertainty as to the natural course of osteoporosis once a diagnosis of Cushing’s syndrome has been made is also still evident. Investigators at the University of Munich, reportedly for a first time, analyzed the natural course of bone mineral density and bone turnover (recycling) in a group of people with endogenous Cushing’s syndrome — which refers to the disease caused by excess cortisol in the bloodstream, often due to a tumor in the adrenal or pituitary glands. They examined medical records of 89 Cushing syndrome patients with a mean age of 44, of which 74% were women. Of these, 65% had pituitary Cushing’s (Cushing’s disease), 28% had adrenal, and 7% had ectopic Cushing’s, which is caused by tumors outside the adrenal or pituitary glands. A group of 71 age- and sex-matched healthy participants were included as controls. In all patients, blood samples were collected at the time of diagnosis (baseline) and one and two years after removing one or both adrenal glands or moving tumors affecting the pituitary gland. Blood samples were analyzed for biomarkers related to bone formation and degradation (resorption). At the study’s beginning, the mean levels of two bone formation markers, osteocalcin and intact PINP, were significantly decreased in patients compared with controls, whereas the bone formation marker alkaline phosphatase was increased. Both markers for bone degradation — called CTX and TrAcP — were also high, which demonstrated “increased bone resorption and decreased bone formation in [Cushing’s syndrome],” the team wrote. While bone markers were similar in participants with a reduced bone mass relative to those with a normal bone mass, bone mineral density was lower overall. Bone mineral density was significantly lower in the neck and spine compared with the femur (thigh bone). Normal bone mineral density was reported in 28 (32%) patients, while 46 (52%) had osteopenia, and the remaining 15 (17%) lived with osteoporosis. A history of low-trauma bone fractures due to osteoporosis occurred in 17 (19%) patients, taking place shortly before diagnosis in more than half of these (58%) people, and more than two years before a Cushing’s diagnosis in the remaining group (42%). Compared to patients without fractures, those with fractures had a significantly lower T‐score, a bone density measure that represents how close a person is to average peak bone density. While Cushing’s subtype, age, or body mass index (BMI, body fat based on height) did not differ between groups, men had a significantly higher risk of fractures than women (35% of men vs. 14% of women). Both disease severity and duration did not contribute to fractures rates, but urinary free cortisol (a circulating cortisol measure) was significantly higher in patients with a low T‐score. At the one year after tumor removal, which led to Cushing’s remission based on blood tests, a significant increase in bone formation markers was reported. These biomarkers decreased slightly at two years post-surgery, but remained elevated. At the beginning of the study, bone resorption markers were mildly increased, which rose further one year after surgery before returning almost to normal levels by two years. In parallel, bone density measures conducted in 40 patients showed a matching increase in T-score, particularly in the spine. After two years, bone mineral density improved in 78% of patients, and T-scores improved in 45% of them. No fractures occurred after Cushing’s treatment, and there was no significant correlation between bone turnover markers and better bone mineral density. “This study analyzes for the first time in a comprehensive way bone turnover markers during the course of [Cushing’s syndrome],” the researchers wrote. “Our data suggest that the phase immediately after remission from [Cushing’s syndrome] is characterized by a high rate of bone turnover, resulting in a spontaneous net increase in bone mineral density in the majority of patients.” These results “will influence future therapeutic strategies in patients” with Cushing’s syndrome, they added. Steve Bryson PhD Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone. From https://cushingsdiseasenews.com/2021/02/19/successful-cushings-surgery-leads-to-better-bone-density-study-finds/

Presented by Georgios A. Zenonos, MD Assistant Professor of Neurological Surgery Associate Director, Center for Skull Base Surgery University of Pittsburgh Medical Center 200 Lothrop Street, Pittsburgh PA, 15217 Presbyterian Hospital, Suite B400 Register Now! After registering you will receive a confirmation email containing information about joining the Webinar. Date: Wednesday July 1, 2020 Time: 3:00 PM Pacific Daylight Time, 6:00 PM Eastern Daylight Time

Braun LT, Fazel J, Zopp S Journal of Bone and Mineral Research | May 22, 2020 This study was attempted to assess bone mineral density and fracture rates in 89 patients with confirmed Cushing's syndrome at the time of diagnosis and 2 years after successful tumor resection. Researchers ascertained five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. Via chemiluminescent immunoassays, they assessed bone turnover markers osteocalcin, intact procollagen‐IN‐propeptide, alkaline bone phosphatase, CrossLaps, and TrAcP 5b in plasma or serum. For comparison, they studied 71 gender‐, age‐, and BMI‐matched patients in whom Cushing's syndrome had been excluded. The outcomes of this research exhibit that the phase immediately after surgical remission from endogenous CS is defined by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients. Read the full article on Journal of Bone and Mineral Research.

Cushing syndrome, a rare endocrine disorder caused by abnormally excessive amounts of the hormone cortisol, has a new pharmaceutical treatment to treat cortisol overproduction. Osilodrostat (Isturisa) is the first FDA approved drug who either can’t undergo pituitary gland surgery or have undergone the surgery but still have the disease. The oral tablet functions by blocking the enzyme responsible for cortisol synthesis, 11-beta-hydroxylase. “Until now, patients in need of medications…have had few approved options, either with limited efficacy or with too many adverse effects. With this demonstrated effective oral treatment, we have a therapeutic option that will help address patients' needs in this underserved patient population," said Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health Sciences University. Cushing disease is caused by a pituitary tumor that releases too much of the hormone that stimulates cortisol production, adrenocorticotropin. This causes excessive levels of cortisol, a hormone responsible for helping to maintain blood sugar levels, regulate metabolism, help reduce inflammation, assist in memory formulation, and support fetus development during pregnancy. The condition is most common among adults aged 30-50 and affects women 3 times more than men. Cushing disease can lead to a number of medical issues including high blood pressure, obesity, type 2 diabetes, blood clots in the arms and legs, bone loss and fractures, a weakened immune system, and depression. Patients with Cushing disease may also have thin arms and legs, a round red full face, increased fat around the neck, easy bruising, striae (purple stretch marks), or weak muscles. Side effects of osilodrostat occurring in more than 20% of patients are adrenal insufficiency, headache, nausea, fatigue, and edema. Other side effects can include vomiting, hypocortisolism (low cortisol levels), QTc prolongation (heart rhythm condition), elevations in adrenal hormone precursors (inactive substance converted into hormone), and androgens (hormone that regulated male characteristics). Osilodrostat’s safety and effectiveness was evaluated in a study consisting of 137 patients, of which about 75% were women. After a 24-week period, about half of patients had achieved normal cortisol levels; 71 successful cases then entered an 8-week, double-blind, randomized withdrawal study where 86% of patients receiving osilodrostat maintained normal cortisol levels, compared with 30% who were taking a placebo. In January 2020, the European Commission also granted marketing authorization for osilodrostat. From https://www.ajmc.com/newsroom/patients-with-cushing-have-new-nonsurgical-treatment-option

Presented by Varun Kshettry, MD Director, Advanced Endoscopic & Microscopic Neurosurgery Cleveland Clinic Lerner College of Medicine Register Now After registering you will receive a confirmation email with details about joining the webinar. Date: Tuesday, February 18, 2020 Time: 10:00 AM - 11:00 AM Pacific Standard Time, 1:00 PM - 2:00 PM Eastern Standard Time Learning Objectives: Discuss patient expectations for pituitary surgery and recovery Discuss best practices to minimize risk of complications What questions to ask your medical providers Presenter Bio Dr. Varun R. Kshettry, a neurosurgeon specializing in skull base and pituitary disorders at the Cleveland Clinic. He is also the director of the Advanced Endoscopic & Microscopic Neurosurgery Laboratory. He is an assistant professor of neurosurgery at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr. Kshettry received his BA in philosophy at the University of Pennsylvania. He earned his medical degree from Northwestern University. He completed his residency training at the Cleveland Clinic, during which he performed a research fellowship in skull base & microsurgical anatomy at Ohio State University. He then performed a clinical fellowship in minimally invasive cranial base & pituitary surgery at Thomas Jefferson University under Dr. James Evans. Dr. Kshettry has authored more than 100 peer-reviewed publications and book chapters and is an editor for a book entitled Endoscopic and Keyhole Cranial Base Surgery. He serves as an editor or reviewer for multiple neurosurgical journals. He serves on the Value-Based Healthcare Committee for the North American Skull Base Society. He serves as faculty director for the Cleveland Clinic Pituitary Tumor Board and is an investigator in several multi-center pituitary clinical trials. Dr. Kshettry collaborates closely with pituitary endocrinologists, neuro-ophthalmologists, otolaryngologists, pituitary pathologists, and radiation oncologists for multi-disciplinary care for patients with pituitary diseases.

Approximately 20% of a cohort of adults with Cushing’s syndrome experienced at least one thrombotic event after undergoing pituitary or adrenal surgery, with the highest risk observed for those undergoing bilateral adrenalectomy, according to findings from a retrospective analysis published in the Journal of the Endocrine Society. “We have previously showed in a recent meta-analysis that Cushing’s syndrome is associated with significantly increased venous thromboembolic events odds vs. the general population, though the risk is lower than in patients undergoing major orthopedic surgery,” Maria Fleseriu, MD, FACE, professor of neurological surgery and professor of medicine in the division of endocrinology, diabetes and clinical nutrition in the School of Medicine at Oregon Health & Science University and director of the OHSU Northwest Pituitary Center, told Healio. “However, patients undergoing many types of orthopedic surgeries have scheduled thromboprophylaxis, especially postsurgery, which is not the standard of care in patients with Cushing’s syndrome. In this study, we wanted to look in more detail at the rates of all thrombotic events, both arterial and venous, in patients at our specialized pituitary center over more than a decade.” In a retrospective, longitudinal study, Fleseriu and colleagues analyzed data from 208 individuals with Cushing’s syndrome undergoing surgical (pituitary, unilateral and bilateral adrenalectomy) and medical treatment at a single center (79.3% women; mean age at presentation, 45 years; mean BMI, 33.9 kg/m²; 41.8% with diabetes). Individuals with severe illness and immediate mortality were excluded. Thromboembolic events (myocardial infarction, deep venous thrombosis [DVT], and pulmonary embolism or stroke) were recorded at any point up until last patient follow-up. Researchers assessed all patients who received anticoagulation in the immediate postoperative period and up to 3 months after surgery, recording doses and complications for anticoagulation. Within the cohort, 39 patients (18.2%) experienced at least one thromboembolic event (56 total events; 52% venous), such as extremity DVT (32%), cerebrovascular accident (27%), MI (21%), and pulmonary embolism (14%). Of those who experienced a thromboembolic event, 40.5% occurred within 60 days of surgery. Researchers found that 14 of 36 patients who underwent bilateral adrenalectomy experienced a thromboembolic event, for an OR of 3.74 (95% CI, 1.69-8.27). Baseline 24-hour urinary free cortisol levels did not differ for patients with or without thromboembolic event after bilateral adrenalectomy. “Despite following these patients over time, results almost surprised us,” said Fleseriu, also an Endocrine Today Editorial Board Member. “The risk of thromboembolic events in patients with Cushing’s syndrome was higher than we expected, approximately 20%. Many patients had more than one event, with higher risk at 30 to 60 days postoperatively. Use of a peripherally inserted central catheter line clearly increased risk of upper extremity DVT.” Among 197 patients who underwent surgery, 50 (25.38%) received anticoagulation after surgery with 2% experiencing bleeding complications. “We clearly need to understand more about what happens in patients with Cushing’s syndrome for all comorbidities, but especially thrombosis, and find the factors that predict higher risk and use anticoagulation in those patients,” Fleseriu said. “We have shown that among patients who had anticoagulation, risks were minimal. We also have to think more about timelines for these thromboembolic events and the duration of anticoagulation, and probably to expand it up to 30 to 60 days postoperatively if there are no contraindications, especially for patients undergoing bilateral adrenalectomy.” Fleseriu cautioned that the findings do not necessarily suggest that every individual with Cushing’s syndrome needs anticoagulation therapy, as the study was retrospective. Additionally, sex, age, BMI, smoking status, estrogen or testosterone supplementation, diabetes and hypertension — all known factors for increased thrombosis risk among the general population — were not found to significantly increase the risk for developing a thromboembolic event, Fleseriu said. “As significantly more patients have exogenous Cushing’s syndrome than endogenous Cushing’s syndrome and many of these patients undergo surgeries, we hope that our study increased awareness regarding thromboembolic risks and the need to balance advantages of thromboprophylaxis with risk of bleeding,” Fleseriu said. – by Regina Schaffer For more information: Maria Fleseriu, MD, FACE, can be reached at fleseriu@ohsu.edu. Disclosure: Fleseriu reports she has received research funding paid to her institution from Novartis and Strongbridge and has received consultant fees from Novartis and Strongbridge. From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7Bce267e5a-0d32-4171-abc8-34369b455fcf%7D/risk-for-thrombotic-events-high-after-cushings-syndrome-surgery

Written by Kathleen Doheny with Maria Fleseriu, MD, FACE, and Vivien Herman-Bonert, MD Cushing's disease, an uncommon but hard to treat endocrine disorder, occurs when a tumor on the pituitary gland, called an adenoma—that is almost always benign—leads to an overproduction of ACTH (adrenocorticotropic hormone), which is responsible for stimulating the release of cortisol, also known as the stress hormone. Until now, surgery to remove the non-cancerous but problematic tumor has been the only effective treatment. Still, many patients will require medication to help control their serum cortisol levels, and others cannot have surgery or would prefer to avoid it. Finally, a drug proves effective as added on or alternative to surgery in managing Cushing's disease. Photo; 123rf New Drug Offers Alternative to Surgery for Cushing's Disease Now, there is good news about long-term positive results achieved with pasireotide (Signifor)—the first medication to demonstrate effectiveness in both normalizing serum cortisol levels and either shrinking or slowing growth of tumors over the long term.1,2 These findings appear in the journal, Clinical Endocrinology, showing that patients followed for 36 months as part of an ongoing study had improved patient outcomes for Cushing’s disease.2 "What we knew before this extension study was—the drug will work in approximately half of the patients with mild Cushing's disease," says study author Maria Fleseriu, MD, FACE, director of the Northwest Pituitary Center and professor of neurological surgery and medicine in the division of endocrinology, diabetes and clinical nutrition at the Oregon Health and Sciences University School of Medicine. “Pasireotide also offers good clinical benefits," says Dr. Fleseriu who is also the president of the Pituitary Society, “which includes improvements in blood pressure, other signs and symptoms of Cushing’s symptom], and quality of life.”2 What Symptoms Are Helped by Drug for Cushing's Disease? Among the signs and symptoms of Cushing’s disease that are lessened with treatment are:3 Changes in physical appearance such as wide, purple stretch marks on the skin (eg, chest, armpits, abdomen, thighs) Rapid and unexplained weight gain A more full, rounder face Protruding abdomen from fat deposits Increased fat deposits around the neck area The accumulation of adipose tissue raises the risk of heart disease, which adds to the urgency of effective treatment. In addition, many individuals who have Cushing’s disease also complain of quality of life issues such as fatigue, depression, mood and behavioral problems, as well as poor memory.2 As good as the results appear following the longer term use of pasireotide,2 Dr. Fleseriu admits that in any extension study in which patients are asked to continue on, there are some built-in limitations, which may influence the findings. For example, patients who agree to stay on do so because they are good responders, meaning they feel better, so they’re happy to stick with the study. “Fortunately, for the patients who have responded to pasireotide initially, this is a drug that can be continued as there are no new safety signals with longer use," Dr. Fleseriu tells EndocrineWeb, "and when the response at the start is good, very few patients will lose control of their urinary free cortisol over time. That's a frequent marker used to monitor patient's status. For those patients with large tumors, almost half of them had a significant shrinkage, and all the others had a stable tumor size." What Are the Reasons to Consider Drug Treatment to Manage Cushing’s Symptoms The extension study ''was important because we didn't have any long-term data regarding patient response to this once-a-month treatment to manage Cushing's disease," she says. While selective surgical removal of the tumor is the preferred treatment choice, the success rate in patients varies, and Cushing's symptoms persist in up to 35% of patients after surgery. In addition, recurrent rates (ie, return of disease) range from 13% to 66% after individuals experience different durations remaining in remission.1 Therefore, the availability of an effective, long-lasting drug will change the course of therapy for many patients with Cushing’s disease going forward. Not only will pasireotide benefit patients who have persistent and recurrent disease after undergoing surgery, but also this medication will be beneficial for those who are not candidates for surgery or just wish to avoid having this procedure, he said. Examining the Safety and Tolerability of Pasireotide This long-acting therapy, pasireotide, which is given by injection, was approved in the US after reviewing results of a 12-month Phase 3 trial.1 In the initial study, participants had a confirmed pituitary cause of the Cushing's disease. After that, the researchers added the optional 12-month open-label, extension study, and now patients can continue on in a separate long-term safety study. Those eligible for the 12-month extension had to have mean urinary free cortisol not exceeding the upper limit of normal (166.5 nanomoles per 24 hour) and/or be considered by the investigator to be getting substantial clinical benefit from treatment with long-action pasireotide, and to demonstrate tolerability of pasireotide during the core study.1 Of the 150 in the initial trial, 81 participants, or 54% of the patients, entered the extension study. Of those, 39 completed the next phase, and most also enrolled in another long-term safety study—these results not yet available).2 During the core study, 1 participants were randomly assigned to 10 or 30 mg of the drug every 28 days, with doses based on effectiveness and tolerability. When they entered the extension, patients were given the same dose they received at month.1,2 Study Outcomes Offer Advantages in Cushing’s Disease Of those who received 36 months of treatment with pasireotide, nearly three in four (72.2%) had controlled levels of urinary free cortisol at this time point.2 Equally good news for this drug was that tumors either shrank or did not grow. Of those individuals who started the trial with a measurable tumor (adenoma) as well as those with an adenoma at the two year mark (35 people), 85.7% of them experienced a reduction of 20% or more or less than a 20% change in tumor volume. No macroadenomas present at the start of the study showed a change of more than 20% at either month 24 or 36.2 Improvements in blood pressure, body mass index (BMI) and waist circumference continued throughout the extension study.1 Those factors influence CVD risk, the leading cause of death in those with Cushing's.4 As for adverse events, most of the study participants, 91.4%, did report one or more complaint during the extension study—most commonly, it was high blood sugar, which was reported by nearly 40% of participants.2. This is not surprising when you consider that most (81.5%) of the individuals participating in the extension trial entered with a diagnosis of diabetes or use of antidiabetic medication, and even more of them (88.9%) had diabetes at the last evaluation.1 This complication indicates the need for people with Cushing’s disease to check their blood glucose, as appropriate. Do You Have Cushing’s Disese? Here's What You Need to Know Women typically develop Cushing’s disease more often than men. What else should you be aware of if you and your doctor decide this medication will help you? Monitoring is crucial, says Dr. Fleseriu, as you will need to have your cortisol levels checked, and you should be on alert for any diabetes signals, which will require close monitoring and regular follow-up for disease management. Another understanding gained from the results of this drug study: "This medication works on the tumor level," she says. "If the patient has a macroadenoma (large tumor), this would be the preferred treatment." However, it should be used with caution in those with diabetes given the increased risk of experiencing high blood sugar. The researchers conclude that "the long-term safety profile of pasireotide was very favorable and consistent with that reported during the first 12 months of treatment. These data support the use of long-acting pasireotide as an effective long-term treatment option for some patients with Cushing's Disease."1 Understanding Benefits of New Drug to Treat Cushing's Diseease Vivien S. Herman-Bonert, MD, an endocrinologist and clinical director of the Pituitary Center at Cedars-Sinai Medical Center in Los Angeles, agreed to discuss the study findings, after agreeing to review the research for EndocrineWeb. As to who might benefit most from monthly pasireotide injections? Dr. Herman-Bonert says, "any patient with Cushing's disease that requires long-term medical therapy, which includes patients with persistent or recurrent disease after surgery." Certainly, anyone who has had poor response to any other medical therapies for Cushing's disease either because they didn't work well enough or because the side effects were too much, will likely benefit a well, she adds. Among the pluses that came out of the study, she says, is that nearly half of the patients had controlled average urinary free cortisol levels after two full years, and 72% of the participants who continued on with the drug for 36 months were able to remain in good urinary cortisol control .1 As the authors stated, tumor shrinkage was another clear benefit of taking long-term pasireotide. That makes the drug a potentially good choice for those even with large tumors or with progressive tumor growth, she says. It’s always good for anyone with Cushing’s disease to have an alterative to surgery, or a back-up option when surgery isn’t quite enough, says Dr. Herman-Bonert. The best news for patients is that quality of life scores improved,1 she adds. Dr Herman-Bonert did add a note of caution: Although the treatment in this study is described as ''long-term, patients will need to be on this for far longer than 2 to 3 years," she says. So, the data reported in this study may or may not persist, and we don’t yet know what the impact will be 10 or 25 years out. Also, the issue of hyperglycemia-related adverse events raises a concern, given the vast majority (81%) of patients who have both Cushing’s disease and diabetes. Most of those taking this drug had a dual diagnosis—having diabetes, a history of diabetes, or taking antidiabetic medicine. If you are under care for diabetes and you require treatment for Cushing’s disease, you must be ver mindful that taking pasireotide will likely lead to high blood sugar spikes, so you should plan to address this with your healthcare provider. Dr. Fleseriu reports research support paid to Oregon Health & Science University from Novartis and other 0companies and consultancy fees from Novartis and Strongbridge Biopharma. Dr. Herman-Bonert has no relevant disclosures. The study was underwritten by Novartis Pharma AG, the drug maker. From https://www.endocrineweb.com/news/pituitary-disorders/62449-cushings-disease-monthly-injection-good-alternative-surgery

Levels of adrenocorticotropic hormone (ACTH) in circulation after pituitary surgery may help predict which Cushing’s disease patients will achieve early remission and which will eventually see the disease return, a study shows. Also, the earlier that patients reached their lowest peak of ACTH levels, the better their long-term outcomes. The study, “Prognostic usefulness of ACTH in the postoperative period of Cushing’s disease,” was published in the journal Endocrine Connections. Removing the pituitary tumor through a minimally invasive surgery called transsphenoidal surgery is still the treatment of choice for Cushing’s disease patients. But not all patients enter remission, and even among those who do, a small proportion will experience disease recurrence. While cortisol levels have been suggested as a main predictor of remission and recurrence, there is no consensus as to which cutoff point should be used after surgery, or the best time for measuring this hormone. Because Cushing’s disease is caused by an ACTH-producing tumor in the pituitary gland, and ACTH has a short half-life (approximately 10 minutes), it is expected that ACTH levels drop markedly within a few hours after surgery. Thus, a group of researchers in Spain aimed to determine whether blood levels of ACTH could be useful for predicting remission of Cushing’s disease both immediately after surgery (defined as less than 72 hours) and in the long term. Researchers analyzed 65 patients with Cushing’s disease who had undergone transsphenoidal surgery (seven required a second intervention) between 2005 and 2016. Remission within three months was seen in 56 of 65 cases; late disease recurrence was seen in 18 of 58 cases. Investigators measured the ACTH nadir concentration (defined as the lowest concentration) and the time taken to reach nadir levels after surgery, as well as the plasma ACTH concentration before hospital discharge. While ACTH levels had no predictive value, the team found that people who went into remission had significantly lower ACTH nadir levels and ACTH levels at discharge. On the other hand, levels of ACHT nadir and at discharge were significantly higher for people who experienced a relapse, compared to those who remained in remission. Using artificial intelligence algorithms, the researchers further found that ACTH nadir, ACTH at discharge, and cortisol nadir values were all of great relevance to predict remission within three months. Analysis indicated that using a cutoff point of 3.3 pmol/L of ACTH after surgery and before discharge gave the best sensitivity and specificity for predicting a patient’s prognosis. Researchers further found that the time patients took to reach their ACTH nadir, regardless of nadir levels, also influenced their outcomes. In fact, patients reaching this nadir in less than than 46 hours more likely achieved early remission. And taking longer than 39 hours to reach the ACTH nadir was significantly more frequent in patients who experienced recurrence. This indicates that the time to ACTH nadir is an important measure for prognosis. “In the immediate postoperative period of patients with [Cushing’s disease], the ACTH concentration is of prognostic utility in relation to late disease remission,” the researchers said. Overall, “we propose an ACTH value <3.3 pmol/L as a good long-term prognostic marker in the postoperative period of CD. Reaching the ACTH nadir in less time is associated to a lesser recurrence rate,” the study concluded. PATRICIA INACIO, PHD EDITOR Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York. From https://cushingsdiseasenews.com/2019/08/29/acth-levels-after-surgery-help-predict-remission-recurrence-in-cushings-study-suggests/

Presented by Nathan T Zwagerman MD Director of Pituitary and Skull base surgery Department of Neurosurgery Medical College of Wisconsin After registering you will receive a confirmation email with details about joining the webinar. Date: Wednesday, August 21, 2019 Time: 10:00 AM - 11:00 AM Pacific Daylight Time 1:00 PM - 2:00 PM Eastern Daylight Time Webinar Description: Learning Objectives: Describe the signs and symptoms of Cushing's Disease Describe the work up for patients with Cushing's Disease Understand the goals, risks, and expected outcomes for treatment Describe alternative treatments when surgery is not curative. Presenter Bio: Dr. Zwagerman is a Professor of Neurosurgery at the Medical College of Wisconsin. He did his undergraduate work in psychology at Calvin College in Grand Rapids, Michigan. He earned his medical degree at Wayne State University in Detroit. He did his fellowship in endoscopic and open cranial base surgery, and then his residency in neurological surgery at the University of Pittsburgh Medical Center.