MaryO

You know, I'm still not sure if the GH is worth it, even after almost 20 years (with some hiccups). I had to stop after I've had kidney cancer and flying with the stuff is such a pain due to the refrigeration (more about that here). One time we were going on a cruise out of New York so we were visiting our son first. I was in a hotel and I put the whole case in an ice bucket. The ice melted... I wasn't sure if the water had seeped into the injector pen or not so I threw it away and went on the cruise without it. I never noticed any bad effects from the week or so with no GH. So, last January when we went on another cruise, I didn't bother to take it with no ill effects. So, it doesn't seem like it's working for me but my endo (Dr. Salvatori at Johns Hopkins) is happy so I guess my non-schedule is ok. Maybe I'll just die sooner than I would have.

Authors Stasiak M , Witek P, Adamska-Fita E, Lewiński A Received 27 December 2023 Accepted for publication 20 March 2024 Published 8 April 2024 Volume 2024:16 Pages 35—42 DOI https://doi.org/10.2147/DHPS.S453105 Checked for plagiarism Yes Review by Single anonymous peer review Peer reviewer comments 2 Editor who approved publication: Dr Hemalkumar B Mehta Download Article [PDF] Magdalena Stasiak,1 Przemysław Witek,2 Emilia Adamska-Fita,1 Andrzej Lewiński1,3 1Department of Endocrinology and Metabolic Diseases, Polish Mother’s Memorial Hospital—Research Institute, Lodz, Poland; 2Department of Internal Medicine, Endocrinology and Diabetes, Medical University of Warsaw; Mazovian Brodnowski Hospital, Warszawa, Poland; 3Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, Lodz, Poland Correspondence: Magdalena Stasiak, Department of Endocrinology and Metabolic Diseases, Polish Mother’s Memorial Hospital—Research Institute, 281/289 Rzgowska Street, Lodz, 93-338, Poland, Tel +48502049292, Fax +48422711140, Email mstasiak33@gmail.com Abstract: Cushing’s disease (CD) is the most common cause of endogenous hypercortisolism. Osilodrostat was demonstrated to be efficient in treating CD, and the mean average dose required for CD control was < 11 mg/day. Potential differences in osilodrostat treatment between cortisol-producing adenoma (CPA) and CD have not been reported. The aim of this study was to present two patients with CPA in whom significant differences in the response to therapy compared to CD were found. We demonstrated a case of inverse response of cortisol levels with adrenal tumor progression during the initial dose escalation (Case 1). Simultaneously, severe exaggeration of hypercortisolism symptoms and life-threatening hypokalemia occurred. A further rapid dose increase resulted in the first noticeable cortisol response at a dose of 20 mg/day, and a full response at a dose of 45 mg/day. We also present a case that was initially resistant to therapy (Case 2). The doses required to achieve the first response and the full response were the same as those for Case 1. Our study demonstrated that osilodrostat therapy in patients with CPA may require a different approach than that in CD, with higher doses, faster dose escalation, and a possible initial inverse response or lack of response. Keywords: osilodrostat, adrenal adenoma, hypercortisolism, ACTH-independent, adverse events, hypokalemia Introduction Chronic persistent hypercortisolism is a life-threatening condition that requires effective treatment. Untreated exposure to excessive cortisol secretion leads to severely increased morbidity and mortality due to cardiovascular diseases, thromboembolic events, sepsis, visceral obesity, impairment of glucose metabolism, and dyslipidaea, as well as musculoskeletal disorders, such as myopathy, osteoporosis, and skeletal fractures. Moreover, neuropsychiatric disorders, such as impairment of cognitive function, depression, or mania, as well as impairment of reproductive function can frequently occur.1,2 Cushing’s disease (CD) – a disorder caused by a pituitary adenoma secreting adrenocorticotropic hormone (ACTH) – is the most common cause of hypercortisolism. Cushing’s syndrome (CS) includes all other causes of cortisol excess, including ectopic ACTH production as well as direct cortisol overproduction by adrenal adenoma (cortisol-producing adenoma [CPA]) or adrenocortical carcinoma (ACC). Approximately 10% of hypercortisolism cases result from CPA. The first line therapy is a surgical resection of the tumor, which is the source of hormone excess. However, in many patients surgery is not fully efficient and other therapies are required to reduce cortisol levels. Additionally, due to severe cardiovascular complications and unstable DM, the surgical approach sometimes entails unacceptable risk and it is frequently postponed until cortisol levels are lowered. Pharmacotherapy with steroidogenesis inhibitors reduces cortisol levels and improves the symptoms of hypercortisolism.1,2 As CD is the most common cause of cortisol excess, most studies have focused on the efficacy and safety of novel steroidogenesis inhibitors, including patients with CD only.3–6 This is exactly the case with osilodrostat – a new potent inhibitor of 11β-hydroxylase.3–6 More data are available for metyrapone efficacy and safety in CSA,7 as the drug has been available much longer than osilodrostat. A study by Detomas et al, which reported results of comparison of efficacy of metyrapone and osilodrostat, included 4 patients with adrenal CS, among whom one CPA patient was treated with osilodrostat.8 Osilodrostat is approved in the United States to treat CD in patients in whom pituitary surgery was not curative or is contraindicated.9 In Poland, osilodrostat therapy is available for patients with all kinds of endogenous hypercortisolism not curative with other approaches, within a national program of emergency access to drug technologies.10 Reports on osilodrostat application in CPA are highly valuable as data on potential differences in the treatment regimens between CD and CPA are scarce. Here, we present two patients with CPA in whom the response and doses of osilodrostat were different from those reported in patients with CD. The main purpose of this study was to demonstrate that the efficacy of osilodrostat in CPA is high, although initial resistance to treatment or even deterioration of hypercortisolism can occur during the application of lower doses of the drug. Materials and Methods Study Design and Patients We retrospectively analyzed medical files of two consecutive patients with CPA treated with osilodrostat. The analysis included medical history, laboratory and imaging results as well as a detailed reports of adverse events. Laboratory and Imaging Procedures Serum cortisol and ACTH levels were measured by electrochemiluminescence immunoassay (ECLIA) using a Cobas e601 analyzer (Roche Diagnostics, Indianapolis, IN, USA). UFC excretion was measured by chemiluminescent microparticle immunoassay (CMIA) using an Abbott Architect ci4100 analyzer (Abbott, Abbott Park, IL, USA). Cross-reactivity with 11-deoxycortisol for this method is very low (2.1% according to the manufacturer’s data). Potassium levels were measured by ion-selective electrode potentiometry using a Beckman Coulter DxC 700 AU Chemistry Analyzer (Beckman Coulter, Brea, CA, USA). Computed tomography (CT) imaging was performed using a Philips Ingenuity Core 128 system (Philips, the Netherlands). Ethics Procedures Informed consent was obtained from all subjects involved in the study. Written informed consent was obtained from the patients for publication of this paper. The approval of Institutional Ethics Committee was obtained to publish the case details (approval code KB 33/2023). Presentation of the Cases Case 1 A 51-year-old female was referred to our department in November 2021 because of CPA, disqualified from surgery because of severe hypertension with a poor response to antihypertensive therapy and uncontrolled DM despite high doses of insulin. Additionally, the patient presented with hyperlipidemia and severe obesity (BMI=50.7 kg/m2), gastritis, depression, and osteoarthritis. On admission, she complained of a tendency to gain weight, fragile skin that bruised easily, difficulty with wound healing, susceptibility to infections, and insomnia. Physical examination revealed a moon face with plethora, a buffalo hump, central obesity with proximal muscle atrophy, and purple abdominal striae. The CPA diagnosis was initially made two years earlier, but the patient did not qualify for surgery due to a hypertensive crisis. Soon after this episode, the SARS-CoV-2 pandemic began, and the patient was afraid of visiting any medical center because her son had died of COVID-19. Therefore, she was referred to our center for life-threatening hypercortisolism two years later. At the time of admission, computed tomography (CT) imaging revealed a right adrenal tumor of 34x24x37mm, with a basal density of 21 HU and a contrast washout rate typical for adenomas (83%). The size and CT characteristics were identical as they were two years earlier. High serum cortisol levels, undetectable ACTH concentrations, and a lack of physiological diurnal rhythm of cortisol secretion were observed (Table 1). Urinary free cortisol (UFC) excretion was 310 µg/24 h, with an upper normal limit (UNL) of 176 µg/24 h. No cortisol suppression was achieved in high-dose dexamethasone suppression test (DST) (Table 1). Other adrenal-related hormonal parameters were within normal ranges, with values as follows: DHEA-S 42.68 µg/dl, aldosterone 3.24 ng/mL, and renin 59.14 µIU/mL. Table 1 Laboratory Results Before Osilodrostat Therapy – Case 1 Due to multiple severe systemic complications, including uncontrolled hypertension, decompensated DM, and cardiac insufficiency, treatment with osilodrostat was introduced for life-saving pre-surgical management. Osilodrostat was started at a dose of 1 mg twice daily and gradually increased to 6 mg per day with actually an inverse response of serum cortisol level. The late-night cortisol level increased from 16 µg/dl to 25 µg/dl. As the full effect of the osilodrostat dose can occur even after a few weeks, the patient was discharged from hospital and instructed to contact her attending doctor immediately if any health deterioration was noticed. In the case of improvement in the patient’s condition, the next hospitalization was planned 3 weeks later. After three weeks of no contact with the patient, she was readmitted to our department with life-threatening escalation of hypercortisolism, severe hypokalemia, and further deterioration of hypertension, DM, cardiac insufficiency, dyspnea, and significant edemas, including facial edema. Treatments of hypertension, cardiac insufficiency, and DM were intensified, as presented in Table 2. Despite active potassium supplementation, life-threatening hypokalemia of 2.1 mmol/l occurred. Previously observed depression was exaggerated with severe anxiety and fear of death. The dose of osilodrostat was increased to 8 mg/day, and after three days of treatment a further elevation of serum cortisol was found, with an increase in UFC up to 9 × UNL (1546.2 µg/24 h). Due to an entirely unexpected inverse cortisol response, CT imaging was performed and revealed progression of the adenoma size to 39 × 36 × 40 mm, with a slight increase in density up to 27 HU as compared to the previous CT scan performed a month earlier (Figure 1). Table 2 Changes in the Most Important Parameters During Osilodrostat Therapy – Case 1 Figure 1 Progression of the adrenal adenoma size during the initial doses of osilodrostat: (a) CT scan directly before osilodrostat therapy – solid nodule 34x24x37 mm, basal density 21 HU; (b) CT scan during treatment with 8 mg of osilodrostat daily – solid nodule 39x36x40 mm, basal density of 27 HU. Considering the extremely high risk associated with such a rapid cortisol increase and related complications, decision of fast osilodrostat dose escalation was made. The dose was increased by 5 mg every other day, up to 45 mg per day, and, finally, a gradual decrease in the cortisol level (Table 2) was achieved, with UFC normalization to 168 µg/24 h. During dose escalation, no deterioration in the adverse effects (AEs) of osilodrostat was observed. Conversely, hypokalemia gradually improved despite a simultaneous reduction in potassium supplementation (Table 2). Facial edema decreased and the level of anxiety improved significantly. The course of hypertension severity as well as a summary of the main parameters controlled during treatment and the medications used are presented in Table 2. As soon as the cortisol level normalized, the patient was referred for surgery and underwent right adrenalectomy without any complications. Histopathology results confirmed a benign adenoma of the right adrenal gland (encapsulated, well-circumscribed tumor consisting of lipid-rich cells with small and uniform nuclei, mostly with eosinophilic intracytoplasmic inclusions). After surgery, hydrocortisone replacement therapy was administered. A few days after surgery, blood pressure and glucose levels gradually decreased, and the patient required reduction of antihypertensive and antidiabetic medications. After 22 months of follow-up, the patient’s general condition is good with no signs of recurrence. Antidepressant treatment is no longer required in this patient. Body mass index was significantly reduced to 40 kg/m2. The antihypertensive medication was completely discontinued, and the glucose level is controlled only with metformin. The patient still requires hydrocortisone substitution at a dose of 30 mg/day. Case 2 A 39-year-old female was referred to our department in November 2022 with a diagnosis of CPA and unstable hypertension, for which surgery was contraindicated. The patient was unsuccessfully treated with triple antihypertensive therapy (telmisartan 40 mg/day, nebivolol 5 mg/day, and lercanidipine 20 mg/day). The patient reported weight gain, muscle weakness, acne, fragile skin that bruised easily, and secondary amenorrhea. Other comorbidities included gastritis, hypercholesterolemia, and osteoporosis. Physical examination revealed typical signs of Cushing’s syndrome, such as abnormal fat distribution, particularly in the abdomen and supraclavicular fossae, proximal muscle atrophy, moon face, and multiple hematomas. A lack of a serum cortisol diurnal rhythm with high late-night serum cortisol and undetectable ACTH levels was found (Table 3). The short DST revealed no cortisol suppression (Table 3), and the UFC result was 725 µg/24 h, which exceeded the UNL more than four times. The serum levels of renin, aldosterone, and 24-h urine fractionated metanephrines were within the normal ranges. Computed tomography imaging revealed a left adrenal gland tumor measuring 25 × 26 × 22 mm, with a basal density of 32 HU and a washout rate typical for adenoma (76%). Table 3 Laboratory Results Before Osilodrostat Therapy – Case 2 Osilodrostat therapy was administered for preoperative management. The initial daily dose was 2 mg/day, increased gradually by 2 mg every day with no serum cortisol response (late night cortisol levels 15.8–18.5 µg/dl) and no AEs of the drug (Table 4). After the daily dose of osilodrostat reached 10 mg, it was escalated by 5 mg every other day, initially with no serum cortisol reduction. The dose was increased to 45 mg daily (with the lowest detected late-night serum cortisol of 9.6 µg/dl) (Table 4). Table 4 Changes in the Most Important Parameters During Osilodrostat Therapy – Case 2 After a week of administration of 45 mg daily, UFC normalization was achieved. Despite rapid dose escalation, no AEs were observed during the entire therapy period. Potassium levels were normal without any supplementation (the lowest detected serum potassium level was 3.9 mmol/l; all other results were over 4.0 mmol/l) (Table 4). After UFC normalization, left adrenalectomy was performed without complications. Histopathological examination revealed benign adrenal adenoma. Antihypertensive therapy was reduced only to 2.5 mg of nebivolol daily. The patient’s general condition improved significantly. Currently, hydrocortisone replacement therapy is administered at a dose of 15 mg/day. Discussion Osilodrostat is a novel potent steroidogenesis inhibitor whose efficacy and safety have been thoroughly analyzed in clinical trials of patients with CD, the most common cause of endogenous hypercortisolism. No clinical trial of osilodrostat therapy in CPA has been performed, as this disease constitutes only 10% of all cases of endogenous hypercortisolism. Moreover, osilodrostat is not approved by the FDA for hypercortisolism conditions other than CD.9 Therefore, data on potential differences in the treatment regimen are lacking. During the course of already reported trials in CD, osilodrostat doses were escalated slowly, every 2–3 weeks,3,5,6 with an excellent response to quite low doses of the drug.3–6 In the LINC 2 extension study the median average dose was 10.6 mg/day,5 while in the LINC 3 extension study and the LINC 4 study it was 7.4 mg/day and 6.9 mg/day, respectively.4,6 In most cases, a significant decrease of hypercortisolism was reported with the low doses of osilodrostat (4 or 10 mg/day). Moreover, some patients received 1 mg/day or even 1 mg every other day, with a good response.6 Even in rare cases of CD in whom initial short-term etomidate therapy was given at the beginning of osilodrostat therapy, due to highly severe life-threatening symptoms of hypercortisolism, the final effective dose of osilodrostat was much lower than that in our patients with CPA (25 mg/day vs 45 mg/day) and no increase of cortisol level was observed.11 It should be underlined that many cases of adrenal insufficiency during osilodrostat therapy in patients with CD have been reported,3–6,12,13 and – therefore – low initial dose with slow gradual dose escalation is recommended in patients with CD.1,6,13 In the cases presented here, CPA led to severe hypercortisolism, the complications of which constituted contraindications for surgery. Therefore, osilodrostat therapy was introduced as a presurgical treatment. In Case 1, the therapy was started at low doses according to the approved product characteristics.14 Due to the severity of hypertension, which was uncontrolled despite of active antihypertensive therapy, as well as to unstable DM, the doses were increased faster than recommended. Surprisingly, we immediately observed a gradual increase in hypercortisolism, in both serum cortisol levels and the UFC, with simultaneous burst of complications related to both hypercortisolism itself and 11β-hydroxylase inhibition. Life-threatening episodes of hypertensive crisis responded poorly to standard therapies. Severe exaggeration of cardiac insufficiency could probably be related to these episodes as well as to deep hypokalemia, which occurred despite potassium supplementation. Hypokalemia is a typical complication of treatment with 11β-hydroxylase inhibitors due to the accumulation of adrenal hormone precursors. However, Patient 1 required much higher doses of potassium supplementation, both parenteral and oral, than ever described during osilodrostat therapy.3–6,13 The dose of 20 mg/day of osilodrostat was the first one which led to noticeable cortisol reduction and a decrease in systolic blood pressure (SBP) to below 170 mmHg. Surprisingly, instead of the expected deterioration of hypokalemia, parenteral potassium administration could be stopped with an osilodrostat dose of 20 mg/day and oral supplementation was gradually reduced simultaneously with osilodrostat dose escalation. The reason why such severe hypokalemia occurred with low doses of osilodrostat and did not deteriorate further seems complex. One possible reason is the administration of high doses of potassium-saving antihypertensive drugs such as spironolactone and the angiotensin II receptor antagonist telmisartan. Additionally, one can consider other possible mechanisms, such as downregulation of the receptors of deoxycorticosterone (DOC) or other adrenal hormone precursors. However, this hypothesis requires further research and confirmation. Such an improvement of the potassium level during osilodrostat dose escalation was previously demonstrated in a patient with CD.11 Interestingly, in our Patient 2, no potassium supplementation was required during the whole time of osilodrostat therapy, although the doses were increased intensively up to the finally effective dose, which was the same (45 mg/day) as for Patient 1. In Patient 2, no actual response to doses lower than 20 mg/day was observed. UFC normalization was achieved after a week of administration of 45 mg/day, five weeks from the beginning of therapy. Although UFC normalization is not always required in pre-surgical treatment, clinical symptoms significantly improved in our patients only after the UFC upper normal level was achieved. The present paper is one of only a few reports focused on osilodrostat therapy in CPA, and the only one presenting a different therapy course as compared to patients with CD. No case of CPA resistance to low doses of osilodrostat has been described. It should be underlined that in our report “low doses” of osilodrostat were higher than the average mean doses of osilodrostat used in clinical trials in patients with CD.3–6 Therefore, they should not generally be considered low but only much lower than those which were effective in our patients. Malik and Ben-Shlomo presented a case of CPA treated with osilodrostat, with an immediate decrease in cortisol level at 4 mg/day and adrenal insufficiency symptoms after dose escalation to 8 mg/day.15 Similar to our two cases, their patient was a middle-aged female with normal results of all other adrenal parameters, such as renin, angiotensin, or metanephrine levels. However, a CT scan was not performed (or presented), while magnetic resonance imaging revealed an indeterminate adrenal gland mass without a typical contrast phase/out-of-phase dropout for adenoma.15 Therefore, different morphology of cortisol-secreting adrenal tumor can potentially be considered a reason of the different response to treatment. Tanaka et al performed a multicenter study on the efficacy and safety of osilodrostat in Japanese patients with non-CD Cushing’s syndrome.16 Five patients with CPA were included in the study, and none of them required osilodrostat doses higher than 10 mg/day to achieve UFC normalization. However, most of the patients presented by Tanaka et al were previously treated with metyrapone,16 whereas both of our patients were treatment-naive. Previous metyrapone therapy may be considered as a potential reason of better response to osilodrostat. This hypothesis was confirmed in the quoted study by Tanaka et al, who demonstrated that at week 12 the median percent changes in the mUFC values were higher in patients previously treated with metyrapone (–98.97%) than in treatment-naive cases (–86.65%).16 Detomas et al performed a comparison of efficacy and safety of osilodrostat and metyrapone, with one CPA patients included in a group treated with osilodrostat, however no data on a dose required for a disease control are available separately for this particular patient.8 To the best of our knowledge, no more CPA cases have been described and therefore no further comparison is available. Higher doses of osilodrostat were administered to a group of seven patients with hypercortisolism due to adrenocortical carcinoma (ACC) presented by Tabarin et al.17 A full control of hypercortisolism was achieved in one patient for each dose of 4, 8, 10, and 20 mg/day, and in three patients treated with 40 mg/day.17 These patients, however received other therapies including mitotane and chemotherapy, which can significantly modify the response to osilodrostat. Several authors have reported the phenomenon of a partial or total loss of response to osilodrostat.5,16,17 In such cases, a response to treatment was initially achieved and then lost during treatment with the same dose. A further increase in osilodrostat dose usually resulted in the response resumption.5,16,17 Such a situation could not be suspected in either of our cases. The presented cases provide a novel insight into modalities of treatment with osilodrostat in patients with CPA and demonstrate for the first time that an inverse cortisol response is possible in CPA cases, especially those with a higher CT density of adrenal adenoma. Such a situation should not be considered a contraindication to dose escalation. Conversely, the dose should be increased more intensively so as to achieve the initial efficacy threshold, which was 20 mg/day in both of our patients. The fully efficient dose that allowed UFC normalization was more than twice as high (45 mg/day in both cases). A similar approach should be applied in patients who do not respond to lower doses, such as Patient 2. The safety of osilodrostat therapy is strictly individual and not dose dependent in patients with CPA. Adverse events, including hypokalemia, severe hypertension, and edema, can be of life-threatening severity or may not occur regardless of the dose. Moreover, AEs of high severity may decrease with osilodrostat dose escalation. Our study demonstrated that osilodrostat is efficient and can be used in patients with CPA as a pre-surgical therapy if surgery is contraindicated due to hypercortisolism complications. Our study presented two cases of CPA treated with osilodrostat, and a small size of our group is the main limitation of this report. Future research is required to confirm our observations. Conclusion In some patients with CPA, the doses of osilodrostat required for disease control can be much higher than those previously reported. Acceleration of the dose increase can be fast, and the risk of overdosing, adrenal insufficiency, and later necessity of dose reduction seem to be much lower than it could be expected. Low initial doses (<20 mg/day in our study) can be entirely ineffective or can even cause exacerbation of hypercortisolism, whereas high doses (45 mg/day in the present study) are efficient in pre-surgery UFC normalization. AEs associated with osilodrostat can be rapid, with severe hypokalemia despite active potassium supplementation, or may not occur even if high doses of osilodrostat are applied. Therefore, close monitoring for potential AEs is necessary. Acknowledgments The abstract included some parts of this paper was presented at the European Congress of Endocrinology ECE2023 as a rapid communication. The abstract was published in the Endocrine Abstracts Vol. 90 [https://www.endocrine-abstracts.org/ea/0090/]. Funding The publication of this report was financially supported by the statutory funds of the Polish Mother’s Memorial Hospital – Research Institute, Lodz, Poland. Disclosure Professor Przemysław Witek reports personal fees from Investigator in the clinical trials paid by Novartis and Recordati Rare Diseases, outside the submitted work; lectures fees from Recordati Rare Diseases, Strongbridge, IPSEN. The authors report no other conflicts of interest in this work. References 1. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847–875. doi:10.1016/S2213-8587(21)00235-7 2. Pivonello R, Isidori AM, De Martino MC, et al. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4(7):611–629. doi:10.1016/S2213-8587(16)00086-3 3. 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. 2020;8(9):48–761. doi:10.1016/S2213-8587(20)30240-0 4. Fleseriu M, Newell-Price J, Pivonello R, et al. Long-term outcomes of osilodrostat in Cushing’s disease: LINC 3 study extension. Eur J Endocrinol. 2022;187(4):531–541. doi:10.1530/EJE-22-0317 5. Fleseriu M, Biller BMK, Bertherat J, et al. Long-term efficacy and safety of osilodrostat in Cushing’s disease: final results from a Phase II study with an optional extension phase (LINC 2). Pituitary. 2022;25(6):959–970. doi:10.1007/s11102-022-01280-6 6. Gadelha M, Bex M, Feelders RA, et al. Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab. 2022;107(7):e2882–e2895. doi:10.1210/clinem/dgac178 7. Daniel E, Aylwin S, Mustafa O, et al. Effectiveness of metyrapone in treating cushing’s syndrome: a retrospective multicenter study in 195 patients. J Clin Endocrinol Metab. 2015;100(11):4146–4154. doi:10.1210/jc.2015-2616 8. Detomas M, Altieri B, Deutschbein T, et al. Metyrapone versus osilodrostat in the short-term therapy of endogenous cushing’s syndrome: results from a single center cohort study. Front Endocrinol. 2022;13:903545. doi:10.3389/fendo.2022.903545 9. U.S. food and drug administration home page. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-adults-cushings-disease. Accessed March 22, 2023. 10. Agency for health technology assessment and tariff system home page. Available from: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja&uact=8&ved=2ahUKEwj6ypGbsfT9AhUMzYsKHTgAD2EQFnoECA8QAQ&url=https%3A%2F%2Fbipold.aotm.gov.pl%2Fassets%2Ffiles%2Fwykaz_tli%2FRAPORTY%2F2020_010.pdf&usg=AOvVaw3P2Q85gwi3JcxKkW3uxfOb. Accessed March 22, 2022. 11. Dzialach L, Sobolewska J, Respondek W, et al. Cushing’s syndrome: a combined treatment with etomidate and osilodrostat in severe life-threatening hypercortisolemia. Hormones. 2022;21(4):735–742. doi:10.1007/s42000-022-00397-4 12. Ekladios C, Khoury J, Mehr S, et al. Osilodrostat-induced adrenal insufficiency in a patient with Cushing’s disease. Clin Case Rep. 2022;10(11):e6607. doi:10.1002/ccr3.6607 13. Fleseriu M, Biller BMK. Treatment of Cushing’s syndrome with osilodrostat: practical applications of recent studies with case examples. Pituitary. 2022;25(6):795–809. doi:10.1007/s11102-022-01268-2 14. Summary of product characteristics. Available from: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwim1_KdsvT9AhVq-ioKHUZKAc4QFnoECA4QAQ&url=https%3A%2F%2Fwww.ema.europa.eu%2Fen%2Fdocuments%2Fproduct-information%2Fisturisa-epar-product-information_pl.pdf&usg=AOvVaw0S8nayCTdqNh1LsEcXVLEu. Accessed March 24, 2023. 15. Malik RB, Ben-Shlomo A. Adrenal cushing’s syndrome treated with preoperative osilodrostat and adrenalectomy. AACE Clin Case Rep. 2022;8(6):267–270. doi:10.1016/j.aace.2022.10.001 16. Tanaka T, Satoh F, Ujihara M, et al. A multicenter, Phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11β-hydroxylase inhibitor, in Japanese patients with endogenous Cushing’s syndrome other than Cushing’s disease. Endocr J. 2020;67(8):841–852. doi:10.1507/endocrj.EJ19-0617 17. Tabarin A, Haissaguerre M, Lassole H, et al. Efficacy and tolerance of osilodrostat in patients with Cushing’s syndrome due to adrenocortical carcinomas. Eur J Endocrinol. 2022;186(2):K1–K4. doi:10.1530/EJE-21-1008 © 2024 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms. Download Article [PDF]

From all the news items I share, and the patients I talk to, it seems like not a lot of advancement is being made over the years. I hear about more people thinking that they have Cushing's after reading about some of the symptoms but it still seems hard for them to get to good doctors, to get diagnosed Hopefully, next year will be better news!

Even though I posted this in 2022 - the original website is still being redone. Probably it will be next year, too! LOL

Abstract Disclosure: C.M. Godar: None. E.B. Noble: None. N.O. Vietor: None. T.S. Knee: None. Background: Cushing’s syndrome may rarely present as an emergency known as Florid Cushing’s Syndrome. Patients can exhibit severe hyperglycemia, hypertension, hypokalemia, infections, and hypercoagulability. Cushing’s syndrome is a rare disease, and the constellation of clinical features can be overlooked if clinicians are not aware of the manifestations of hypercortisolism. We present the case of a patient with Cushing’s syndrome that went unrecognized with life-threatening sequelae. Case presentation: A 52-year-old woman with well-controlled type 2 diabetes and hypertension was admitted to the hospital for severe left lower extremity cellulitis. Prior to hospitalization she had noted rapid weight gain, fatigue, weakness, mental clouding, and moodiness. She was admitted for antibiotics and surgical debridement. The infection persisted despite broad spectrum antibiotics, multiple surgical debridements, and skin grafting. She became bacteremic, and extremity amputation was considered. She additionally developed hypertensive emergency, refractory hypokalemia, and hyperglycemia to 396 mg/dL. Exam was notable for facial plethora, supraclavicular fullness, dorsocervical fat pad, and violaceous abdominal striae. Cushing’s Syndrome was suspected, and labs revealed a significantly elevated random serum cortisol of 60.5mcg/dL (Ref 6.2-19.4), significantly elevated 24H urine cortisol of 2157mcg/24H (Ref 0-50), and ACTH elevated to 81.8pg/mL (Ref 7.2-63.3) that confirmed Cushing’s Disease. MRI sella and octreotide scans did not localize a lesion. Inpatient therapy included multiple antihypertensive agents, insulin drip, aggressive potassium repletion, and initiation of ketoconazole to reduce cortisol levels. Ketoconazole was maximally dosed and she underwent surgical exploration and removal of a small pituitary microadenoma. Following surgery, she developed transient adrenal insufficiency requiring hydrocortisone and she no longer required antihypertensives, insulin, or potassium therapy. Follow up 7 years later has revealed no recurrence of Cushing’s Disease. Discussion: Cushing’s Syndrome may present with a variety of clinical features and rarely may present as a medical emergency. Delay in diagnosis can lead to Florid Cushing’s Syndrome which carries high risk for morbidity and mortality. This case illustrates the need for clinician awareness of the features of Cushing’s Syndrome: hypertension, hyperglycemia, rapid weight gain, cushingoid exam features, hypokalemia, hirsutism, virilization, infection, and/or hypercoagulable state. Severe hypercortisolism was responsible for this patient’s refractory infection, and if not controlled, she likely would have endured a lower extremity amputation. Rapid detection with elevated random serum and/or urine cortisol and treatment with a cortisol-lowering agent is critical and lifesaving. Presentation: Thursday, June 15, 2023 Issue Section: Neuroendocrinology and Pituitary PDF This content is only available as a PDF.

Two years later “My Dream Day“… I’d wake up refreshed and really awake at about 7:00AM and take the dog out (no more dog ) for a brisk run. Maybe do a Silver Sneakers online workout unless it's a water aerobics day. Get home about 8:00AM and start on my website work. Later in the morning, I’d get some bills paid – and there would be enough money to do so! After lunch, out with the dog again, then practice the piano some, practice my balalaika and tenor recorder son, read a bit, finish up the website work, teach a few piano students, work on my church job, then dinner. After dinner, check email, out with the dog, maybe handbell or choir practice, a bit of TV, then bed about 10PM Nothing fancy but NO NAPS. Work would be getting done, time for hobbies, the dog, 3 healthy meals. Just a normal life that so many take for granted. Or, do they? I would love to have enough money to retire from some of those jobs, to travel more, to cruise more...

Highlights Aim to identify independent risk factors for postoperative delirium after pituitary adenoma surgery. Select matched subjects by Propensity Score Matching to reduce potential biases caused by variables. Enhance preoperative communication to minimize the occurrence of delirium, for patients at high risk of postoperative delirium. Minimize surgery duration and general anesthesia, optimize perioperative sedation regimen. Reducing unnecessary or excessive protective physical restraints. Abstract Objectives The primary aim of this study is to explore the factors associated with delirium incidence in postoperative patients who have undergone endoscopic transsphenoidal approach surgery for pituitary adenoma. Methods The study population included patients admitted to Tianjin Huanhu Hospital's Skull Base Endoscopy Center from January to December 2022, selected through a retrospective cohort study design. The presence of perioperative delirium was evaluated using the 4 'A's Test (4AT) scale, and the final diagnosis of delirium was determined by clinicians. Statistical analysis included Propensity Score Matching (PSM), χ2 Test, and Binary Logistic Regression. Results A total of 213 patients were included in this study, and the incidence of delirium was found to be 29.58 % (63/213). Among them, 126 patients were selected using PSM (delirium:non-delirium = 1:1), ensuring age, gender, and pathology were matched. According to the results of univariate analysis conducted on multiple variables, The binary logistic regression indicated that a history of alcoholism (OR = 6.89, [1.60–29.68], P = 0.010), preoperative optic nerve compression symptoms (OR = 4.30, [1.46–12.65], P = 0.008), operation time ≥3 h (OR = 5.50, [2.01–15.06], P = 0.001), benzodiazepines for sedation (OR = 3.94, [1.40–11.13], P = 0.010), sleep disorder (OR = 3.86, [1.40–10.66], P = 0.009), and physical restraint (OR = 4.53, [1.64–12.53], P = 0.004) as independent risk factors for postoperative delirium following pituitary adenoma surgery. Conclusions For pituitary adenoma patients with a history of alcoholism and presenting symptoms of optic nerve compression, as well as an operation time ≥3 h, enhancing communication between healthcare providers and patients, improving perioperative sleep quality, and reducing physical restraint may help decrease the incidence of postoperative delirium. Introduction In clinical practice, patients admitted to the intensive care unit (ICU) during the postoperative period after endoscopic transsphenoidal tumorectomy of pituitary adenoma often experience episodes of delirium. According to a recent retrospective analysis conducted at a single center, the incidence of postoperative delirium among these patients was found to be 10.34 % (n = 360) [1]. Delirium is a common complication following neurosurgery, characterized by acute distraction, confusion in thinking, sleep disorders, and cognitive decline. The incidence of delirium in admitted patients after neurosurgery has been reported to be 19 %, with a range of 12 % to 26 % depending on clinical features and the methods used for delirium assessment [2], [3], [4]. The incidence of postoperative delirium varied across different types of neurosurgical diseases, as reported in a meta-analysis [2]. Specifically, the incidences were 8.0 % for patients with neurological tumors, 20 % for those undergoing functional neurosurgery, 24.0 % for microvascular decompression patients, 19.0 % for traumatic brain injury patients, 42.0 % for neurovascular patients, and 17.0 % for the mixed population undergoing neurosurgery procedures. Furthermore, the incidence rates of delirium in intensive care units (ICUs), general wards, or both combined were found to be 24.0 %, 17 %, and 18 %, respectively. The aforementioned issue not only leads to prolonged hospital stays and increased healthcare costs, but also exerts a significant impact on patient consciousness and cognitive function. Therefore, early and accurate identification of delirium in post-neurosurgical patients is crucial. However, due to frequent co-occurrence with primary brain injury, related complications can also lead to cognitive impairment or even decreased levels of consciousness, posing challenges for timely and precise identification of delirium. Currently, the primary focus lies in the prevention of delirium within the neurosurgical ICU setting. Early identification and comprehensive pre-surgical assessment are positively significant measures for preventing postoperative delirium occurrence [5], [6]. In this study, a retrospective cohort design was employed to collect pertinent data and statistically analyze the incidence of delirium, as well as its associated influencing factors, among patients admitted to the neurosurgical ICU for pituitary adenoma treatment. And now it is reported as follows. Section snippets Patient selection A retrospective cohort study design was employed to select 213 pituitary adenomas admitted to the Skull Base and Endoscopy Center of Tianjin Huanhu Hospital between January 2022 and December 2022 as the subjects for investigation, with a review of their medical records. The mean age was (50.03 ± 15.72) years, ranging from 20–79 years old (Fig. 1). Informed consent was obtained from all patients or their families, ensuring compliance with the requirements stated in the Declaration of Helsinki. Inclusion criteria a. Propensity score matching The present study enrolled a total of 213 patients with pituitary tumors, among whom 63 exhibited symptoms related to delirium while the remaining 150 did not. Consequently, the incidence rate of delirium was determined to be 29.58 % in this cohort of patients admitted to the intensive care unit following pituitary tumor surgery. The univariate analysis revealed no significant differences in age (≥65y old, 23.8 % vs. 23.3 %, P = 0.940) and gender (male, 49.2 % vs. 56.7 %, P = 0.318) between the Background of perioperative delirium in transsphenoidal endoscopic pituitary adenoma surgery The pituitary gland is situated within the sella turcica and comprises two distinct components. The anterior pituitary, known as the adenohypophysis, functions as an endocrine organ responsible for secreting growth hormone, prolactin, adrenocorticotropic hormone, thyrotropin, follicle-stimulating hormone and luteinizing hormone. On the other hand, the posterior pituitary, referred to as the neurohypophysis, serves as a direct extension of the hypothalamus and acts as a storage site for Conclusions To enhance the evaluation of postoperative patients at risk of delirium, it is anticipated that optimizing doctor-nurse-patient communication and minimizing unnecessary and indiscriminate protective measures will mitigate the incidence of delirium following pituitary tumor surgery. This study is a single-center prospective study conducted at our institution, which has several inherent limitations. A large-scale multicenter prospective study is anticipated to further investigate the associated Limitations There are multiple factors that influence the occurrence of delirium following neurosurgery. This retrospective study solely focused on analyzing and comparing general patient data, medical history, and potential perioperative factors contributing to delirium, without considering any other known or unknown variables in this analysis. The pituitary gland functions as a neuroendocrine organ involved in the regulation of neuroendocrine processes. Changes in hormone levels following surgery for Funding All authors affirm that this study was conducted without any fund support from external organizations. CRediT authorship contribution statement Shusheng Zhang: Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Yanan Chen: Writing – original draft, Investigation, Data curation. Xiudong Wang: Validation, Supervision, Project administration, Methodology, Conceptualization. Jun Liu: Software, Formal analysis, Data curation. Yueda Chen: Validation, Supervision, Methodology, Investigation. Guobin Zhang: Writing – review & editing, Validation, Supervision, Methodology, Conceptualization. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References (21) G. Sousa et al. Postoperative delirium in patients with history of alcohol abuse Rev Esp Anestesiol Reanim (2017) M. Terzaghi et al. Sleep disorders and acute nocturnal delirium in the elderly: a comorbidity not to be overlooked Eur J Intern Med (2014) S. Lee et al. Opioid and benzodiazepine use in the emergency department and the recognition of delirium within the first 24 hours of hospitalization J Psychosom Res (2022) A.J. Slooter et al. Delirium in critically ill patients Handb Clin Neurol (2017) E. Wang et al. Effect of perioperative benzodiazepine use on intraoperative awareness and postoperative delirium: a systematic review and meta-analysis of randomized controlled trials and observational studies Br J Anaesth (2023) E. Rollo et al. Physical restraint precipitates delirium in stroke patients J Neurol Sci (2021) H. Chen et al. The incidence and predictors of postoperative delirium after brain tumor resection in adults: A cross-sectional survey World Neurosurg (2020) J. Liu et al. Identifying hormones and other perioperative risk factors for postoperative delirium after endoscope-assisted transsphenoidal pituitary adenoma resection: A retrospective, matched cohort study Brain Behav (2023) P.R. Kappen et al. Delirium in neurosurgery: a systematic review and meta-analysis Neurosurg Rev (2022) J. Wang et al. Risk factors for the incidence of delirium in cerebrovascular patients in a Neurosurgery Intensive Care Unit: A prospective study J Clin Nurs (2018) There are more references available in the full text version of this article. From https://www.sciencedirect.com/science/article/abs/pii/S0967586824001279

Happy Birthday, Harvey!

It's Sunday again, so this is another semi-religious post so feel free to skip it I'm sure that many would think that Abide With Me is a pretty strange choice for my all-time favorite hymn, especially since it often shows up at funerals and memorial services. My dad was a Congregational (now United Church of Christ) minister so I was pretty regular in church attendance in my younger years. Some Sunday evenings, he would preach on a circuit and I'd go with him to some of these tiny churches. The people there, mostly older folks, liked the old hymns best - Fanny Crosby and so on. So, some of my "favorite hymns" are those that I sang when I was out with my Dad. Fond memories from long ago. In 1986 I was finally diagnosed with Cushing's after struggling with doctors and trying to get them to test for about 5 years. I was going to go into the NIH (National Institutes of Health) in Bethesda, MD for final testing and then-experimental pituitary surgery. I was terrified and sure that I wouldn't survive the surgery. Somehow, I found a 3-cassette tape set of Reader's Digest Hymns and Songs of Inspiration and ordered that. The set came just before I went to NIH and I had it with me. At NIH I set up a daily "routine" of sorts and listening to these tapes was a very important part of my day and helped me get through the ordeal of more testing, surgery, post-op and more. When I had my kidney cancer surgery, those tapes were long broken and irreplaceable, but I had replaced all the songs - this time on my iPod. Abide With Me was on this original tape set and it remains a favorite to this day. Whenever we have an opportunity in church to pick a favorite, my hand always shoots up and I request page 700. When someone in one of my handbell groups moves away, we always sign a hymnbook and give it to them. I sign page 700. I think that many people would probably think that this hymn is depressing. Maybe it is but to me it signifies times in my life when I thought I might die and I was so comforted by the sentiments here. This hymn is often associated with funeral services and has given hope and comfort to so many over the years - me included. If you abide in Me, and My words abide in you, you will ask what you desire, and it shall be done for you. ~John 15:7 Abide With Me Words: Henry F. Lyte, 1847. Music: Eventide, William H. Monk, 1861. Mrs. Monk described the setting: This tune was written at a time of great sorrow—when together we watched, as we did daily, the glories of the setting sun. As the last golden ray faded, he took some paper and penciled that tune which has gone all over the earth. Lyte was inspired to write this hymn as he was dying of tuberculosis; he finished it the Sunday he gave his farewell sermon in the parish he served so many years. The next day, he left for Italy to regain his health. He didn’t make it, though—he died in Nice, France, three weeks after writing these words. Here is an excerpt from his farewell sermon: O brethren, I stand here among you today, as alive from the dead, if I may hope to impress it upon you, and induce you to prepare for that solemn hour which must come to all, by a timely acquaintance with the death of Christ. For over a century, the bells of his church at All Saints in Lower Brixham, Devonshire, have rung out “Abide with Me” daily. The hymn was sung at the wedding of King George VI, at the wedding of his daughter, the future Queen Elizabeth II, and at the funeral of Nobel peace prize winner Mother Teresa of Calcutta in1997. Abide with me; fast falls the eventide; The darkness deepens; Lord with me abide. When other helpers fail and comforts flee, Help of the helpless, O abide with me. Swift to its close ebbs out life’s little day; Earth’s joys grow dim; its glories pass away; Change and decay in all around I see; O Thou who changest not, abide with me. Not a brief glance I beg, a passing word; But as Thou dwell’st with Thy disciples, Lord, Familiar, condescending, patient, free. Come not to sojourn, but abide with me. Come not in terrors, as the King of kings, But kind and good, with healing in Thy wings, Tears for all woes, a heart for every plea— Come, Friend of sinners, and thus bide with me. Thou on my head in early youth didst smile; And, though rebellious and perverse meanwhile, Thou hast not left me, oft as I left Thee, On to the close, O Lord, abide with me. I need Thy presence every passing hour. What but Thy grace can foil the tempter’s power? Who, like Thyself, my guide and stay can be? Through cloud and sunshine, Lord, abide with me. I fear no foe, with Thee at hand to bless; Ills have no weight, and tears no bitterness. Where is death’s sting? Where, grave, thy victory? I triumph still, if Thou abide with me. Hold Thou Thy cross before my closing eyes; Shine through the gloom and point me to the skies. Heaven’s morning breaks, and earth’s vain shadows flee; In life, in death, O Lord, abide with me. https://youtu.be/i5nbq_VEea0 http://cushieblog.files.wordpress.com/2012/04/maryo-butterfly-script1.gif

Abstract Avascular necrosis (AVN), also called osteonecrosis, stems from blood supply interruption to the bone and is often idiopathic. It has risk factors like trauma, alcohol, and corticosteroids. AVN in the talus (AVNT) is less common than in the femoral head. Most cases of talar osteonecrosis are associated with trauma, while a smaller proportion is linked to systemic conditions such as sickle cell disease or prolonged prednisone use. Glucocorticoids are a key nontraumatic cause. We report a middle-aged woman with Cushing’s syndrome symptoms, such as hypertension and moon face, since her youth. A few years ago, she experienced pain and swelling in her ankle, which was diagnosed as atraumatic AVNT and treated with hindfoot fusion. Years later, she was diagnosed with Cushing’s disease caused by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma in laboratory tests and imaging, which was resected in 2020. She experienced significant weight loss, and her Cushing’s syndrome symptoms were relieved after tumor resection. Mechanisms behind AVN in hypercortisolism involve fat cell hypertrophy, fat embolization, osteocyte apoptosis, and glucocorticoid-induced hypertension. Traditional X-rays may miss early AVN changes; MRI is preferred for early detection. Although there are some cases of femoral AVN caused by endogenous hypercortisolism in the literature, as far as we know, this is the first case of AVNT due to Cushing’s disease. AVNT treatment includes conservative approaches, hindfoot fusion, and core decompression. Cushing’s disease is a rare cause of AVNT, and a multidisciplinary approach aids in the rapid diagnosis of elusive symptoms. Introduction Avascular necrosis (AVN), also known as osteonecrosis, is a condition arising from the temporary interruption or permanent cessation of blood supply to a bone, leading to tissue necrosis or its demise. While AVN is frequently idiopathic, certain established risk factors are known including trauma, alcohol abuse, and the use of exogenous corticosteroids [1]. While not as prevalent as in the femoral head, AVN of the talus (AVNT) in the ankle presents a painful and disabling issue for patients and poses a challenging dilemma for orthopedic surgeons [2]. About 75% of cases of talar osteonecrosis stem from traumatic injuries, while approximately 25% of nontraumatic instances are typically associated with systemic conditions such as sickle cell disease or prolonged use of prednisone, which impede blood flow. [3] The use of glucocorticoids is one of the most important non-traumatic causes of AVN. Nevertheless, there are some case reports where AVN in the femoral head is reported as a manifestation of endogenous hypercortisolism, particularly associated with Cushing's syndrome [4-12]. In this article, we describe the case of a middle-aged woman who was diagnosed with idiopathic severe progressive AVNT for two years. She had retrogradely diagnosed masked symptoms of Cushing’s disease since her youth, but the diagnosis was confirmed after undergoing ankle arthrodesis. Case Presentation A 43-year-old woman visited our office in June 2018 with a complaint of severe pain and swelling in her left ankle, which had persisted for the past two years. She had hypertension since her youth and blurry vision since 2013 but had no other significant medical or family history. She was also diagnosed with major depressive disorder (MDD) in 2015 when she lost her husband. She had no history of smoking, alcohol consumption, or addiction. She had not experienced any significant trauma during this period and sought consultations from various specialties, including neurology, psychology, internal medicine, nephrology, rheumatology, and orthopedics. She had received a platelet-rich plasma (PRP) injection in the ankle, but it did not improve her symptoms. Despite undergoing various diagnostic workups, no precise diagnosis had been established. Back in 2013, she remembers suddenly experiencing blurry vision in her right eye. This condition underwent a misdiagnosis, which almost led to a loss of vision. She had been struggling with her eye problems until her last visit, during which she received intravitreal bevacizumab injections. Additionally, she previously had iron deficiency anemia, which was treated with ferrous sulfate before 2018. In our first visit, during the physical examination, the pain was localized in the ankle mortise with some posterolateral pain along the course of the peroneal tendons posterior to the fibula. Based on the physical examination and available ankle radiographs, we diagnosed AVNT. The patient subsequently underwent ankle arthroscopy through the standard anterior portals, the joint was cleaned, the synovium was shaved, and a small incision was conducted for peroneal assessment; this procedure revealed a subchondral collapse and extensive necrosis in the talus. Following the procedure, she experienced a partial improvement in her symptoms. However, six months later, she returned with a recurrence of symptoms (Figure 1). Upon further inquiry, she mentioned that her symptoms had recurred a month ago when she was dancing at a family party. Radiographs showed a stress fracture in her fibula and extensive AVNT. This diagnosis was confirmed through a CT scan, MRI, and bone scan (Figure 2). Figure 1: Ankle X-ray six months after arthroscopy Pain had reduced for four months, then pain increased with activity and disabled her after a night of dancing. Subchondral fracture and fibular stress fracture are evident (A and B, respectively). Figure 2: MRI, CT scan, and technetium-99m (Tc-99m) bone scan Coronal MRI confirmed avascular necrosis of the talar dome with subchondral fracture (A and B, respectively). CT scan (C) and Tc-99 bone scan (D) images also revealed the pathologies. In the second visit after arthroscopy, upon confirmation of a fibular stress fracture and significant subchondral collapse, and following a discussion of the next available options with the patient, the second procedure was performed as an ankle arthrodesis with an anterior approach. A 6 cm longitudinal incision was made anteriorly, and through the plane between the tibialis anterior and extensor hallucis longus, the ankle joint was accessed. Joint preparation was done with an osteotome, ensuring a bleeding surface on both sides. Then, manual compression with provisional pin fixation in the corrective position was performed. The fusion was planned at less than 5 degrees of valgus, 10 degrees of external rotation, and approximately 10 degrees of plantar flexion, suitable for the high-heeled shoes that she was using in her daily living activities. After confirming fluoroscopy in two planes, final 6.5 mm cannulated cancellous screws were used, and fixation was augmented with an anterior molded 4.5 mm narrow dynamic compression plate (DCP), according to our previously published anterior ankle fusion technique [13]. The foot was placed in a splint for 10 days, after which stitches were removed, and a cast was applied for four weeks. Then, walking with gradual, as-tolerated weight-bearing was initiated (Figure 3). Three months after surgery, she was pain-free, and by the sixth month, she could walk without any boot or brace, only using high-heeled shoes. Figure 3: Post-operative radiographies Six months after the ankle surgery, a huge osteonecrosis and fibular stress fracture were managed with an acceptable, painless ankle fusion (not solid) despite the remaining necrosis (A and B, respectively). In 2024, four years after the tumor resection, complete healing of talus necrosis and solid fusion were achieved (C and D, respectively). In 2020, two years after her ankle surgery, she was referred to an endocrinologist due to excessive weight gain and hirsutism. The biochemical assessment revealed the following: cortisol (8 AM) (chemiluminescence immunoassay (CLIA)) was 96 µg/dl (normal range: 4.82 - 19.5 µg/dl), and it was 22.1 µg/dl after overnight dexamethasone (normal range: < 1.8 µg/dl). Adrenocorticotropic hormone (ACTH) (CLIA) was 44.4 pg/ml (normal range: 7.2-63.3 pg/ml), and cortisol measured 5.7 µg/dl after the 48-hour low-dose dexamethasone suppression test (normal < 5 µg/dl). The results, along with symptoms (Table 1), are documented in the laboratory tests (Table 2). She was diagnosed with Cushing’s syndrome, which was subsequently confirmed as Cushing's disease due to an ACTH-producing pituitary adenoma observed in the MRI and Brain CT (Figure 4). Sign/symptom Severity Weight Gain Severe Hirsutism Severe Hypertension Severe Easy bruising Severe Depression Severe Moon face Moderate (masked with makeup) Lethargy Moderate Headache Moderate Peripheral edema _ Buffalo hump _ Myopathy _ Acne _ Purple striae _ Table 1: Cushing's disease symptoms and signs The hyphens in the table indicate that the patient does not have those symptoms or signs. Laboratory test Result Reference range Cortisol (8 AM) (CLIA) 96 µg/dl 4.82-19.5 µg/dl Cortisol (8 AM) (after overnight dexamethasone) (CLIA) 22.1 µg/dl <1.8 µg/dl ACTH (CLIA) 44.4 pg/ml 7.2-63.3 pg/ml Cortisol after 48 hours of LDDST (CLIA) 5.7 µg/dl < 5 µg/dl Table 2: Laboratory tests CLIA: chemiluminescence immunoassay; ACTH: adrenocorticotropic hormone; LDDST: low-dose dexamethasone suppression test Figure 4: Brain MRI Finally, a pituitary adenoma was diagnosed using a Brain MRI as the cause of Cushing’s disease symptoms (A and B). Finally, she underwent a tumor resection and had a dramatic response after treatment (30 kg weight loss). She revealed that she had Cushing’s syndrome symptoms since she was young. These symptoms included a puffy face, which she covered with makeup, high blood pressure, and hirsutism. In January 2024, four years after her brain surgery, during our last visit, her symptoms had significantly improved. She reported no problems with her ankle, and talus necrosis was completely healed, with a solid fusion achieved in radiographs (Figure 3). Discussion As far as we are aware, this case presentation represents the first instance of AVNT attributed to Cushing’s disease in the existing literature. Nevertheless, some individuals with endogenous Cushing's syndrome have been reported to experience AVN of the femoral head [4-12]. Cushing's syndrome is an uncommon endocrine condition marked by manifestations of hypercortisolism. The predominant cause is often an adenoma in the anterior pituitary gland that produces ACTH, referred to as Cushing's disease [14]. The presentation of Cushing's syndrome can vary significantly in both adults and children, influenced by the extent and duration of hypercortisolemia. However, the typical signs and symptoms of Cushing's syndrome are widely known [15]. Although some individuals may perceive these alterations as normal and physiological, the disease can go unnoticed for an extended period, as in our case, in which it remained undiagnosed for more than 20 years. However, it is known that steroid use is a significant contributing factor to the occurrence of bone osteonecrosis, accounting for up to 40% of non-traumatic instances of AVN [16]. The mechanisms leading to AVN due to either endogenous hypercortisolism or excess exogenous glucocorticoids are not completely understood. There are just some hypotheses that suggest that the hypertrophy of fat cells, embolization of fat, and osteocytes' apoptosis result in impaired blood flow in the bone, ultimately causing ischemic tissue necrosis [17]. An alternative proposed theory suggests that elevated levels of glucocorticoids may cause insulin resistance and subsequently contribute to AVN [18]. Traditional X-rays often fail to detect the initial changes of AVN (as observed in our case). MRI stands as the preferred method for identifying AVN in its early phases, providing an opportunity for timely therapeutic interventions [19,20]. In an analysis of 321 cases of AVNT, the predominant treatment modalities included conservative therapies (n = 104), hindfoot fusion (n = 62), and core decompression (n = 85) [21]. These approaches reflect the primary methods employed in contemporary clinical practice for addressing AVNT. After all, we confirmed the AVNT diagnosis using MRI and bone scan and managed it with hindfoot fusion. Subsequently, the underlying issue, endogenous hypercortisolism due to an ACTH-producing pituitary adenoma, was identified and treated through resection of the tumor (Figure 5). Figure 5: Case report timeline * Avascular necrosis in the talus Conclusions Cushing’s syndrome is a rare endocrine disorder characterized by excessive cortisol levels, commonly caused by an ACTH-producing adenoma in the pituitary gland, known as Cushing’s disease. Cushing’s disease may be one of the rare causes of AVNT. To the best of our knowledge, this is the first instance of AVNT due to Cushing’s disease described in the literature. Since atraumatic AVNT is rare in itself, a multidisciplinary approach can lead us to a more rapid and proper diagnosis, as each symptom may be masked or considered rare within its subspecialty field. References Chang CC, Greenspan A, Gershwin ME: Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum. 1993, 23:47-69. 10.1016/s0049-0172(05)80026-5 Zhang H, Fletcher AN, Scott DJ, Nunley J: Avascular osteonecrosis of the talus: current treatment strategies. Foot Ankle Int. 2022, 43:291-302. 10.1177/10711007211051013 Parekh SG, Kadakia RJ: Avascular necrosis of the talus. J Am Acad Orthop Surg. 2021, 29:e267-78. 10.5435/JAAOS-D-20-00418 Belmahi N, Boujraf S, Larwanou MM, El Ouahabi H: Avascular necrosis of the femoral head: an exceptional complication of Cushing's disease. Ann Afr Med. 2018, 17:225-7. 10.4103/aam.aam_75_17 Salazar D, Esteves C, Ferreira MJ, Pedro J, Pimenta T, Portugal R, Carvalho 😧 Avascular femoral necrosis as part of Cushing syndrome presentation: a case report. J Med Case Rep. 2021, 15:287. 10.1186/s13256-021-02882-7 Alaya Z, Braham M, Bouajina E: Aseptic femur head necrosis revealing Cushing's disease: a rare presentation. J Clin Surg Res. 2020, 1:10.31579/2768-2757/002 Phillips KA, Nance EP Jr, Rodriguez RM, Kaye JJ: Avascular necrosis of bone: a manifestation of Cushing's disease. South Med J. 1986, 79:825-9. 10.1097/00007611-198607000-00011 Koch CA, Tsigos C, Patronas NJ, Papanicolaou DA: Cushing's disease presenting with avascular necrosis of the hip: an orthopedic emergency. J Clin Endocrinol Metab. 1999, 84:3010-2. 10.1210/jcem.84.9.5992 Modroño N, Torán CE, Pavón I, Benza ME, Guijarro G, Navea 😄 Cushinǵs syndrome and avascular hip necrosis: presentation of two patients [Article in Spanish]. Rev Clin Esp (Barc). 2014, 214:e93-6. 10.1016/j.rce.2014.05.003 Camporro F, Bulacio E, Gutiérrez Magaldi I: Bilateral osteonecrosis of the hip secondary to endogenous Cushing's syndrome due to a recently-diagnosed carcinoid tumour of the lung [Article in Spanish]. Med Clin (Barc). 2016, 147:228. 10.1016/j.medcli.2016.03.042 Ha JS, Cho HM, Lee HJ, Kim SD: Bilateral avascular necrosis of the femoral head in a patient with asymptomatic adrenal incidentaloma. Hip Pelvis. 2019, 31:120-3. 10.5371/hp.2019.31.2.120 Anand A, Jha CK, Singh PK, Sinha U, Ganesh A, Bhadani PP: Avascular necrosis of femur as a complication of Cushing's syndrome due to adrenocortical carcinoma. Am Surg. 2023, 89:2701-4. 10.1177/00031348221129510 Gharehdaghi M, Rahimi H, Mousavian A: Anterior ankle arthrodesis with molded plate: technique and outcomes. Arch Bone Jt Surg. 2014, 2:203-9. Lindholm J, Juul S, Jørgensen JO, et al.: Incidence and late prognosis of cushing's syndrome: a population-based study. J Clin Endocrinol Metab. 2001, 86:117-23. 10.1210/jcem.86.1.7093 Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125 Konarski W, Poboży T, Konarska K, Śliwczyński A, Kotela I, Hordowicz M, Krakowiak J: Osteonecrosis related to steroid and alcohol use-an update on pathogenesis. Healthcare (Basel). 2023, 11:1846. 10.3390/healthcare11131846 Chan KL, Mok CC: Glucocorticoid-induced avascular bone necrosis: diagnosis and management. Open Orthop J. 2012, 6:449-57. 10.2174/1874325001206010449 Hartmann K, Koenen M, Schauer S, Wittig-Blaich S, Ahmad M, Baschant U, Tuckermann JP: Molecular actions of glucocorticoids in cartilage and bone during health, disease, and steroid therapy. Physiol Rev. 2016, 96:409-47. 10.1152/physrev.00011.2015 Kaste SC, Karimova EJ, Neel MD: Osteonecrosis in children after therapy for malignancy. AJR Am J Roentgenol. 2011, 196:1011-8. 10.2214/AJR.10.6073 Pierce TP, Jauregui JJ, Cherian JJ, Elmallah RK, Mont MA: Imaging evaluation of patients with osteonecrosis of the femoral head. Curr Rev Musculoskelet Med. 2015, 8:221-7. 10.1007/s12178-015-9279-6 Gross CE, Haughom B, Chahal J, Holmes GB Jr: Treatments for avascular necrosis of the talus: a systematic review. Foot Ankle Spec. 2014, 7:387-97. 10.1177/1938640014521831 From https://www.cureus.com/articles/221491-talus-avascular-necrosis-as-a-rare-complication-of-cushings-disease-a-case-report?score_article=true#!/

Thanks to AI, this year I was able to see a whole lot of zebras outside a hospital

Corcept Therapeutics Incorporated (NASDAQ: CORT), a commercial-stage company engaged in the discovery and development of medications to treat severe endocrinologic, oncologic, metabolic and neurologic disorders by modulating the effects of the hormone cortisol, today announced completion of enrollment in GRADIENT, a Phase 3 trial of its proprietary selective cortisol modulator relacorilant in patients with Cushing’s syndrome (hypercortisolism) caused by an adrenal adenoma or adrenal hyperplasia. “Hypercortisolism with adrenal etiology affects many patients and is associated with serious cardiometabolic comorbidities, including hypertension and hyperglycemia, and increased risk of premature death,” said Bill Guyer, PharmD, Corcept’s Chief Development Officer. “GRADIENT is the first prospective placebo-controlled study to be conducted exclusively in these patients with Cushing’s syndrome. We expect data from GRADIENT in the fourth quarter of this year.” GRADIENT is a randomized, double-blind, placebo-controlled trial conducted at sites in the United States, Europe and Israel. One-hundred thirty-seven patients were randomized 1:1 to receive relacorilant or placebo for 22 weeks. Primary endpoints are improvement in glucose metabolism and hypertension. About Cushing’s Syndrome (Hypercortisolism) Cushing’s syndrome is caused by excessive activity of the hormone cortisol. Endogenous Cushing’s syndrome is an orphan disease that most often affects adults aged 20-50. Symptoms vary, but most patients experience one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper-body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing’s syndrome can affect every organ system and can be lethal if not treated effectively. About Relacorilant Relacorilant is a selective cortisol modulator that binds to the glucocorticoid receptor (GR), but does not bind to the body's other hormone receptors. Corcept is studying relacorilant in a variety of serious disorders, including ovarian, adrenal and prostate cancer and Cushing’s syndrome. Relacorilant is proprietary to Corcept and is protected by composition of matter, method of use and other patents. Relacorilant has orphan drug designation in the United States and the European Union for the treatment of Cushing’s syndrome. About Corcept Therapeutics For over 25 years, Corcept’s focus on cortisol modulation and its potential to treat patients across a wide variety of serious disorders has led to the discovery of more than 1,000 proprietary selective cortisol modulators. Corcept’s advanced clinical trials are being conducted in patients with hypercortisolism, solid tumors, amyotrophic lateral sclerosis (ALS) and liver disease (NASH). In February 2012, the company introduced Korlym, the first medication approved by the U.S. Food and Drug Administration for the treatment of patients with Cushing’s syndrome. Corcept is headquartered in Menlo Park, California. For more information, visit Corcept.com. Forward-Looking Statements Statements in this press release, other than statements of historical fact, are forward-looking statements based on our current plans and expectations that are subject to risks and uncertainties that might cause our actual results to differ materially from those such statements express or imply. These risks and uncertainties include, but are not limited to, our ability to operate our business; risks related to the study and development of Korlym as well as relacorilant, miricorilant, dazucorilant and our other product candidates, including their clinical attributes, regulatory approvals, mandates, oversight and other requirements; and the scope and protective power of our intellectual property. These and other risks are set forth in our SEC filings, which are available at our website and the SEC’s website. In this press release, forward-looking statements include those concerning the development of relacorilant as a treatment for Cushing’s syndrome, and design, timing and expectations regarding our GRADIENT trial. We disclaim any intention or duty to update forward-looking statements made in this press release. From https://finance.yahoo.com/news/corcept-completes-enrollment-phase-3-120000179.html

Wow - a lot has happened since I first shared this post. If you look at the timestamp, I'm writing this at 4:20 am and I've been awake for an hour, even though I'm exhausted. I have been back on Growth Hormone although it doesn't seem to do me any good. I also had my knee replaced last March and I shared more about that in Bee’s Knees: TKR, Finally! I plan to get the other one done, presumably after next summer.

Comment from the blog: Thank you Mary. I had surgery to remove pituitary tumor caused by Cushings in 2013. I am just starting to see some returning symptoms. Chronic stiff neck bloating belly gummy eyes. It feels like I am wearing a bras that is 5 times too small for me but I don’t have a bras on. A tightness across my back. 4 days ago one red spot showed up that I know is bleeding under the skin but I never knew the name of it. Now I know it is purpura because of this diagram. I know enough now that anything that looks strange on my body I take pictures of to show the doctor. Having your site is reassuring. I am still learning from it.

Even though this was from two years ago, I don't think that there have been any significant changes in the many symptoms of Cushing's. Today's News Item proclaimed loftily But will enough doctors actually allow patients to get that far or will they still blow them off?

PET/MRI could become the diagnostic method of choice over MRI alone for identifying small pituitary tumors associated with Cushing disease, according to a study published March 21 in the Journal of Nuclear Medicine. In patients diagnosed with the disease yet who had inconclusive MRI results, PET/MRI was positive in 100% of cases, noted lead author Ilanah Pruis, a doctoral student at Erasmus University Medical Center in Rotterdam, Netherlands. “This multimodal imaging technique provides a welcome improvement for diagnosis, planning of surgery, and clinical outcome in patients with Cushing disease,” the authors wrote. Cushing disease is characterized by small tumors in pituitary glands, which causes them to secrete excess cortisol, the authors explained. While it is a rare disease, over time it can cause severely disabling conditions, such as high blood pressure or type II diabetes. Currently, guidelines recommend the use of MRI and inferior petrosal sinus sampling (IPSS) to diagnose these tumors. IPSS is an invasive procedure in which cortisol hormone levels are sampled from the veins that drain the pituitary gland. In up to 40% of patients, however, MRI is inconclusive, as the lesions are smaller than 10 millimeters in diameter. Even advanced MRI techniques, such as dynamic perfusion imaging, can leave small lesions undetected in up to one third of patients, the authors noted. In preclinical work, PET imaging using a radiotracer named F-18 FET has been shown to bind with high affinity to a molecular target in pituitary tumors, and in this study, the researchers aimed to test this technique combined with MRI in a multimodal approach. The researchers analyzed results from 22 patients (68% women; mean age 48 years) who underwent F-18 FET PET/MRI at Erasmus MC between February 2021 and December 2022. All patients showed a clear pituitary tumor F-18 FET-PET/MRI, whereas reading of the MRI alone yielded a suspected lesion in only 50%, the authors found. T1-weighted postgadolinium MR images (A and C) and F-18 FET-PET/MR images (B and D) centered at pituitary before (A and and after (C and D) transsphenoidal surgery. This patient with Cushing disease showed clear focal uptake (B) but no clear lesion on previously obtained and accompanying MRI (A). Postoperative tissue analysis did confirm resection of small pituitary adenoma/PitNET, and postoperative F-18 FET-PET showed no residual uptake (D). Image courtesy of the Journal of Nuclear Medicine. Importantly, 16 patients underwent treatment based on the results -- either surgery, Gamma Knife, or CyberKnife therapy -- with 12 of these patients achieving short-term remission, the authors noted. “[F-18 FET-PET/MRI] is of great clinical value because it allows precision surgery and targeted Gamma Knife or CyberKnife therapy,” the group wrote. The researchers noted that only one previous study evaluated F-18 FET-PET/MRI in these patients and that their study was limited, given the relatively small number of patients. “Future studies will be directed at head-to-head comparisons of the performance of F-18 FET- PET and other diagnostic techniques, including advanced MRI sequences… preferably in patients at the time of initial clinical presentation,” the authors concluded. A link to the full study can be found here. From https://www.auntminnie.com/clinical-news/molecular-imaging/article/15667496/petmri-may-improve-diagnosis-of-cushing-disease

Please join in a Virtual Town Hall Meeting on Cushing's Awareness Day! Mark your calendars for Monday, April 8, 2024, from 7 - 8 pm EST as we shed light on Cushing's syndrome with two incredible people who are living with this condition. Gain valuable insights, hear personal stories, and learn more about Cushing's syndrome from those who understand it firsthand. Don't miss this opportunity to connect, learn and show your support. Register now to secure your spot: https://www.eventbrite.com/.../cushings-awareness-day.... Let's come together to raise awareness and foster understanding. #CushingsAwareness

Comment from https://cushieblog.com/2024/04/01/day-1-cushings-awareness-challenge-2016/ Great post which sums up the doctor patient relationship quite well. And by extension my marital relationship as my husband believed the doctor. I finished my memoir and am happy to say I covered all those points. An agent read my first chapter and asked me to send her the full manuscript. I am waiting for her to read it and get back to me. I’m with you. More people need to know about this illness. I’m hoping to get my story published. You are doing such a wonderful job of awareness. Thank you for your tireless work Mary O.

Somehow, the fact that April 1 was fast approaching slipped my mind this year but here we are. Every month seems to be Cushing’s Awareness Month as more and more people are learning about Cushing's. It doesn’t seem like the diagnostic process is getting any easier, though. I read posts on here, on Facebook, in my inbox and people still aren’t getting the answers they need from doctors. I’ve had my license tags (CUSH1E) for many years and just last week someone mentioned them - and I could share about Cushing’s once again. They make is so easy to start a conversation. While American actress Amy Schumer is spreading the word about Cushing’s in general, I think that in some ways she is hurting things for everyone else. CBS News reports that “she says she now feels ‘reborn’ after her diagnosis, and while some forms of Cushing can be fatal, she has a type that ‘will just work itself out.’” How many others will try to get diagnosed and only be told not to worry, that it “will just work itself out”?

Abstract Here, we present the case of a 40-year-old man in whom the diagnosis of ectopic adrenocorticotropin (ACTH) syndrome went unrecognized despite evaluation by multiple providers until it was ultimately suspected by a nephrologist evaluating the patient for edema and weight gain. On urgent referral to endocrinology, screening for hypercortisolism was positive by both low-dose overnight dexamethasone suppression testing and 24-hour urinary free cortisol measurement. Plasma ACTH values confirmed ACTH-dependent Cushing syndrome. High-dose dexamethasone suppression testing was suggestive of ectopic ACTH syndrome. Inferior petrosal sinus sampling demonstrated no central-to-peripheral gradient, and 68Ga-DOTATATE scanning revealed an avid 1.2-cm left lung lesion. The suspected source of ectopic ACTH was resected and confirmed by histopathology, resulting in surgical cure. While many patients with Cushing syndrome have a delayed diagnosis, this case highlights the critical need to increase awareness of the signs and symptoms of hypercortisolism and to improve the understanding of appropriate screening tests among nonendocrine providers. ACTH-dependent Cushing syndrome, ectopic ACTH, ectopic Cushing syndrome, glucocorticoid excess Issue Section: Case Report Introduction Even in the face of overt clinical signs and symptoms of hypercortisolism, diagnosing Cushing syndrome requires a high index of suspicion, and people with hypercortisolism experience a long road to diagnosis. In a recent meta-analysis including more than 5000 patients with Cushing syndrome, the mean time to diagnosis in all Cushing syndrome, including Cushing disease and ectopic adrenocorticotropin (ACTH) syndrome, was 34 months (1). Reasons for delayed diagnosis are multifactorial, including the nonspecific nature of subjective symptoms and objective clinical signs, as well as notorious challenges in the interpretation of diagnostic testing. Furthermore, the health care system's increasingly organ-specific referral patterns obfuscate multisystem disorders. Improving the recognition of and decreasing time to diagnosis in Cushing syndrome are critical factors in reducing morbidity and mortality. Here, we present the case of a patient who, despite classic signs of Cushing syndrome as well as progressive physical and mental decline, remained undiagnosed for more than 3 years while undergoing repeated evaluation by primary care and subspecialty providers. The case (1) highlights the lack of awareness of Cushing syndrome as a potential unifying diagnosis for multiorgan system problems; (2) underscores the necessity of continued education on the signs and symptoms of hypercortisolism, appropriate screening for hypercortisolism, and early referral to endocrinology; and (3) provides an opportunity for systemic change in clinical laboratory practice that could help improve recognition of pathologic hypercortisolism. Case Presentation In August 2018, a previously healthy 40-year-old man with ongoing tobacco use established care with a primary care provider complaining that he had been ill since the birth of his son 13 months prior. He described insomnia, headaches, submandibular swelling, soreness in his axillary and inguinal regions, and right-sided chest discomfort (Fig. 1). Previously, he had been diagnosed with sinusitis, tonsillitis, and allergies, which had been treated with a combination of antibiotics, antihistamines, and intranasal glucocorticoids. He was referred to otolaryngology where, in the absence of cervical lymphadenopathy, he was diagnosed with sternocleidomastoid pain with recommendations to manage conservatively with stretching and massage. A chest x-ray demonstrated a left apical lung nodule. Symptoms continued unabated throughout 2019, now with a cough. Repeat chest x-ray demonstrated opacities lateral to the left hilum that were attributed to vascular structures. Figure 1. Open in new tabDownload slide Timeline of development of subjective symptoms and objective clinical findings preceding diagnosis and surgical cure of ectopic Cushing syndrome. In May 2020, increasingly frustrated with escalating symptoms, the patient transitioned care to a second primary care provider and was diagnosed with hypertension. He complained of chronic daily headaches that prompted brain imaging with magnetic resonance imaging (MRI), which noted findings consistent with left maxillary silent sinus syndrome. He was sent back to otolaryngology, which elected to proceed with sinus surgery. During this time, he suffered a fibular fracture for which he was evaluated by orthopedic surgery. In the second half of 2020, he was seen by neurology to evaluate his chronic headaches and paresthesias with electromyography demonstrating a left ulnar mononeuropathy consistent with cubital tunnel syndrome. His primary care provider diagnosed him with fibromyalgia for which he started physical therapy, and he was referred to a pain clinic for cognitive behavioral therapy. Unfortunately his wife, dealing with her husband's increasing cognitive and personality changes including irritability and aggression, filed for divorce. At the end of 2020, the patient developed bilateral lower extremity edema and was prescribed hydrochlorothiazide, subsequently developing hypokalemia attributed to diuretic use. With worsening bilateral lower extremity edema and new dyspnea on exertion, he was evaluated for heart failure with an echocardiogram, which was unremarkable. Over the next several months, he gained approximately 35 pounds (∼16 kg). It was in the setting of weight gain that he was first evaluated for hypercortisolism with random serum cortisol of 22.8 mcg/dL (629 nmol/L) and 45.6 mcg/dL (1258 nmol/L) in the late morning and mid-day, respectively. No reference range was provided for the times of day at which these laboratory values were drawn. Although these serum cortisol values were above provided reference ranges for other times of day, they were not flagged as abnormal by in-house laboratory convention, and they were overlooked. The search for other etiologies of his symptoms continued. In early 2021, diuretic therapy and potassium supplementation were escalated for anasarca. He developed lower extremity cellulitis and received multiple courses of antibiotics. Skin biopsy performed by dermatology demonstrated disseminated Mycobacterium and later Serratia (2), prompting referral to infectious disease for management. Additional subspecialty referrals included rheumatology (polyarthralgia) and gastroenterology (mildly elevated alanine transaminase with planned liver biopsy). In July 2021, he was evaluated for edema by nephrology, where the constellation of subjective symptoms and objective data including hypertension, central weight gain, abdominal striae, fracture, edema, easy bruising, medication-induced hypokalemia, atypical infections, and high afternoon serum cortisol were noted, and the diagnosis of Cushing syndrome was strongly suspected. Emergent referral to endocrinology was placed. Diagnostic Assessment At his first clinic visit with endocrinology in June 2021, the patient’s blood pressure was well-controlled on benazepril. Following weight gain of 61 pounds (∼28 kg) in the preceding 2 years, body mass index was 33. Physical examination demonstrated an ill-appearing gentleman with dramatic changes when compared to prior pictures (Fig. 2), including moon facies, dorsocervical fat pad, violaceous abdominal striae, weeping lower extremity skin infections, an inability to stand without assistance from upper extremities, and depressed mood with tangential thought processes. Figure 2. Open in new tabDownload slide Photographic representation of physical changes during the years leading up to diagnosis of ectopic Cushing syndrome in June 2021 and after surgical resection of culprit lesion. Diagnostic workup for hypercortisolism included a morning cortisol of 33.4 mcg/dL (922 nmol/L) (normal reference range, 4.5-22.7 mcg/dL) and ACTH of 156 pg/mL (34 pmol/L) (normal reference range, 7.2-63 pg/mL) following bedtime administration of 1-mg dexamethasone, and 24-hour urine free cortisol of 267 mcg/24 hours (737 nmol/24 hours) (normal reference range, 3.5-45 mcg/24 hours). Morning serum cortisol and plasma ACTH following bedtime administration of 8-mg dexamethasone were 27.9 mcg/dL (770 nmol/L) and 98 pg/mL (22 pmol/L), respectively. Given concern for potential decompensation, he was hospitalized for expedited work-up. Brain MRI did not demonstrate a pituitary lesion (Fig. 3), and inferior petrosal sinus sampling under desmopressin stimulation showed no central-to-peripheral gradient (Table 1). He underwent a positron emission tomography–computed tomography 68Ga-DOTATATE scan that demonstrated a 1.2-cm left pulmonary nodule with radiotracer uptake (Fig. 4). Figure 3. Open in new tabDownload slide A, Precontrast and B, postcontrast T1-weighted sagittal magnetic resonance imaging of the sella. Images were affected by significant motion degradation, precluding clear visualization of the pituitary gland on coronal imaging. Figure 4. Open in new tabDownload slide 68Ga-DOTATATE imaging. A, Coronal and B, axial views of the chest after administration of radiopharmaceutical. Arrow in both panels indicates DOTATATE-avid 1.2-cm left lung lesion. Table 1. Bilateral petrosal sinus and peripheral adrenocorticotropin levels preintravenous and postintravenous injection of desmopressin acetate 10 mcg Time post DDAVP, min Left petrosal ACTH Left petrosal:peripheral ACTH Right petrosal ACTH Right petrosal:peripheral ACTH Peripheral ACTH Left:right petrosal ACTH 0 172 pg/mL (37.9 pmol/L) 1.1 173 pg/mL (38.1 pmol/L) 1.2 150 pg/mL (33.0 pmol/L) 1.0 3 288 pg/mL (63.4 pmol/L) 1.8 292 pg/mL (64.3 pmol/L) 1.8 162 pg/mL (35.7 pmol/L) 1.0 5 348 pg/mL (76.6 pmol/L) 1.8 341 pg/mL (75.1 pmol/L) 1.8 191 pg/mL (42.1 pmol/L) 1.0 10 367 pg/mL (80.8 pmol/L) 1.3 375 pg/mL (82.6 pmol/L) 1.3 278 pg/mL (61.2 pmol/L) 1.0 Abbreviations: ACTH, adrenocorticotropin; DDAVP, desmopressin acetate. Open in new tab Treatment The patient was started on ketoconazole 200 mg daily for medical management of ectopic ACTH-induced hypercortisolism while awaiting definitive surgical treatment. Within a month of initial endocrinology evaluation, he underwent thoracoscopic left upper lobe wedge resection with intraoperative frozen histopathology section consistent with a well-differentiated neuroendocrine tumor and final pathology consistent with a well-differentiated neuroendocrine tumor. Staining for ACTH was positive (Fig. 5). Postoperative day 1 morning cortisol was 1.4 mcg/dL (39 nmol/L) (normal reference range, 4.5-22.7 mcg/dL). He was started on glucocorticoid replacement with hydrocortisone and was discharged from his surgical admission on hydrocortisone 40 mg in the morning and 20 mg in the afternoon. Figure 5. Open in new tabDownload slide Lung tumor histopathology. A, The tumor was epicentered around a large airway (asterisk) and showed usual architecture for carcinoid tumor. B, The tumor cells had monomorphic nuclei with a neuroendocrine chromatin pattern, variably granulated cytoplasm, and a delicate background vascular network. By immunohistochemistry, the tumor cells were strongly positive for C, synaptophysin; D, CAM5.2; and E, adrenocorticotropin. F, Ki-67 proliferative index was extremely low (<1%). Outcome and Follow-up Approximately 12 days after discharge, the patient was briefly readmitted from the skilled nursing facility where he was receiving rehabilitation due to a syncopal event attributed to hypovolemia. This was felt to be secondary to poor oral intake in the setting of both antihypertensive and diuretic medications as well as an episode of emesis earlier in the morning precluding absorption of his morning hydrocortisone dose. Shortly after this overnight admission, he was discharged from his skilled nursing facility to home. In the first month after surgery, he lost approximately 30 pounds (∼14 kg) and had improvements in sleep and mood. Eight months after surgery, hydrocortisone was weaned to 10 mg daily. Cosyntropin stimulation testing holding the morning dose showed 1 hour cortisol 21.5 mcg/dL (593 nmol/L). Hydrocortisone was subsequently discontinued. In June 2022, 1 year following surgery, 3 sequential midnight salivary cortisol tests were undetectable. At his last visit with endocrinology in June 2023, he felt well apart from ongoing neuropathic pain in his feet and continued but improved mood disturbance. Though his health has improved dramatically, he continues to attribute his divorce and substantial life disruption to his undiagnosed hypercortisolism. Discussion Endogenous neoplastic hypercortisolism encompasses a clinical spectrum from subclinical disease, as is common in benign adrenal cortical adenomas, to overt Cushing syndrome of adrenal, pituitary, and ectopic origin presenting with dramatic clinical manifestations (3) and long-term implications for morbidity and mortality (4). Even in severe cases, a substantial delay in diagnosis is common. In this case, despite marked hypercortisolism secondary to ectopic ACTH syndrome, the patient's time from first symptoms to diagnosis was more than 3 years, far in excess of the typical time to diagnosis in this subtype, noted to be 14 months in 1 study (1). He initially described a constellation of somatic symptoms including subjective neck swelling, axillary and inguinal soreness, chest discomfort, and paresthesias, and during the year preceding diagnosis, he developed hypertension, fibular fracture, mood changes, weight gain, peripheral edema, hypokalemia, unusual infections, and abdominal striae. Each of these symptoms in isolation is a common presentation in the primary care setting, therefore the challenge arises in distinguishing common, singular causes from rare, unifying etiologies, especially given the present epidemics of diabetes, obesity, and associated cardiometabolic abnormalities. By Endocrine Society guidelines, the best discriminatory features of Cushing syndrome in the adult population are facial plethora, proximal muscle weakness, abdominal striae, and easy bruising (5). Furthermore, Endocrine Society guidelines suggest evaluating for Cushing disease when consistent clinical features are present at a younger-than-expected age or when these features accumulate and progress, as was the case with our patient (5). However, even when the diagnosis is considered, the complexities of the hypothalamic-pituitary-adrenal axis make selection and interpretation of screening tests challenging outside the endocrinology clinic. We suspect that in most such situations, a random serum cortisol measurement is far more likely to be ordered than a validated screening test, such as dexamethasone suppression testing, urine free cortisol, and late-night salivary cortisol per Endocrine Society guidelines (5). Although random serum cortisol values are not considered a screening test for Cushing syndrome, elevated values can provide a clue to the diagnosis in the right clinical setting. In this case, 2 mid-day serum cortisols were, by in-house laboratory convention, not flagged as abnormal despite the fact that they were above the upper limit of provided reference ranges. We suspect that the lack of electronic medical record flagging of serum cortisol values contributed to these values being incorrectly interpreted as ruling out the diagnosis. Cushing syndrome remains among the most evasive and difficult diagnoses in medicine due to the doubly difficult task of considering the disorder in the face of often protean signs and symptoms and subsequently conducting and interpreting screening tests. The challenges this presents for the nonendocrinologist have recently been recognized by a group in the United Kingdom after a similarly overlooked case (6). We believe that our case serves as a vivid illustration of the diagnostic hurdles the clinician faces and as a cautionary tale with regard to the potential downstream effects of a delay in diagnosis. Standardization of clinical laboratory practices in flagging abnormal cortisol values is one such intervention that may aid the busy clinician in more efficiently recognizing laboratory results suggestive of this diagnosis. While false-positive case detection is a significant downside to this approach, given the potential harm in delayed or missed diagnosis, the potential benefits may outweigh the risks. Learning Points People with Cushing syndrome frequently experience a prolonged time to diagnosis, in part due to lack of recognition in the primary care and nonendocrine subspecialty settings of the constellation of clinical findings consistent with hypercortisolism. Endocrine Society guidelines recommend against random serum cortisol as initial testing for Cushing syndrome in favor of dexamethasone suppression testing, urine free cortisol, and late-night salivary cortisol. Increased awareness of Cushing syndrome by primary care providers and specialists in other fields could be an important and impactful mechanism to shorten the duration of symptom duration in the absence of diagnosis and hasten cure where cure is achievable. We suggest clinical laboratories consider standardizing flagging abnormal cortisol values to draw attention to ordering providers and perhaps lower the threshold for endocrinology referral if there is any uncertainty in interpretation, especially in the context of patients with persistent symptoms and elusive diagnoses. Acknowledgments We are grateful to the patient for allowing us to present his difficult case to the community with the hopes of improving time to diagnosis for patients with hypercortisolism. Contributors All authors made individual contributions to authorship. J.M.E., E.M.Z., and K.R.K. were involved in the diagnosis and management of this patient. B.C.M., J.M.E., E.M.Z., and K.R.K. were involved in manuscript submission. S.M.J. performed and analyzed histopathology and prepared the figure for submission. All authors reviewed and approved the final draft. Funding No public or commercial funding. Disclosures J.M.E. was on the editorial board of JCEM Case Reports at the time of initial submission. Informed Patient Consent for Publication Signed informed consent obtained directly from the patient. Data Availability Statement Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study. References 1 Rubinstein G , Osswald A , Hoster E , et al. Time to diagnosis in Cushing's syndrome: a meta-analysis based on 5367 patients . J Clin Endocrinol Metab . 2020 ; 105 ( 3 😞 dgz136 . Google Scholar Crossref PubMed WorldCat 2 Park MA , Gaghan LJ , Googe PB , Klein KR , Mervak JE . Disseminated cutaneous Mycobacterium chelonae infection as a presenting sign of ectopic adrenocorticotropic hormone syndrome . JAAD Case Rep . 2021 ; 18 : 79 ‐ 81 . Google Scholar Crossref PubMed WorldCat 3 Reincke M , Fleseriu M . Cushing syndrome: a review . JAMA . 2023 ; 330 ( 2 😞 170 ‐ 181 . Google Scholar Crossref PubMed WorldCat 4 Puglisi S , Perini AME , Botto C , Oliva F , Terzolo M . Long-term consequences of Cushing's syndrome: a systematic literature review . J Clin Endocrinol Metab . 2024; 109 ( 3 😞 e901 ‐ e909 . Crossref PubMed WorldCat 5 Nieman LK , Biller BMK , Findling JW , et al. The diagnosis of Cushing's syndrome: an Endocrine Society clinical practice guideline . J Clin Endocrinol Metab . 2008 ; 93 ( 5 😞 1526 ‐ 1540 . Google Scholar Crossref PubMed WorldCat 6 Scoffings K , Morris D , Pullen A , Temple S , Trigell A , Gurnell M . Recognising and diagnosing Cushing's syndrome in primary care: challenging but not impossible . Br J Gen Pract . 2022 ; 72 ( 721 😞 399 ‐ 401 . Google Scholar Crossref PubMed WorldCat Abbreviations ACTH adrenocorticotropin MRI magnetic resonance imaging © The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com From https://academic.oup.com/jcemcr/article/2/3/luae034/7618559?login=false

Objective Postoperative data on Cushing’s disease (CD) are equivocal in the literature. These discrepancies may be attributed to different series with different criteria for remission and variable follow-up durations. Additional data from experienced centers may address these discrepancies. In this study, we present the results obtained from 96 endoscopic transsphenoidal surgeries (ETSSs) for CD conducted in a well-experienced center. Methods Pre- and postoperative data of 96 ETSS in 87 patients with CD were included. All cases were handled by the same neurosurgical team between 2014 and 2022. We obtained data on remission status 3−6 months postoperatively (medium-term) and during the latest follow-up (long-term). Additionally, magnetic resonance imaging (MRI) and pathology results were obtained for each case. Results The mean follow-up duration was 39.5±3.2 months. Medium and long-term remission rates were 77% and 82%, respectively. When only first-time operations were considered, the medium- and long-term remission rates were 78% and 82%, respectively. The recurrence rate in this series was 2.5%. Patients who showed remission between 3−6 months had higher longterm remission rates than did those without initial remission. Tumors >2 cm and extended tumor invasion of the cavernous sinus (Knosp 4) were associated with lower postoperative remission rates. Conclusion Adenoma size and the presence/absence of cavernous sinus invasion on preopera-tive MRI may predict long-term postoperative remission. A tumor size of 2 cm may be a supporting criterion for predicting remission in Knosp 4 tumors. Further studies with larger patient populations are necessary to support this finding. Key Words: Complete remission · Neuroendoscopy · Pituitary-dependant Cushing syndrome · Treatment outcome. Go to : INTRODUCTION Cushing’s disease (CD) is characterized by excessive secretion of adrenocorticotropic hormone (ACTH) by a corticotropic adenoma in the pituitary gland. In patients with CD whose hypercortisolism is inadequately corrected, morbidity and mortality can increase by up to 4.8 times due to Cushingrelated complications such as osteoporosis, hypertension, dyslipidemia, insulin resistance, and hypercoagulability [11,18]. Endoscopic transsphenoidal surgery (ETSS), the first-line treatment for CD [7], is performed to decrease complications while achieving remission and long-term disease control. Previous studies on CD have reported varying remission rates between 45% and 95% and recurrence rates ranging from 3−66% [2,4,9,16,21,30]. This wide range of differences can be primarily attributed to differences in surgical experience among centers: centers with higher surgical experience have fewer postoperative complications and higher remission rates [4,6]. However, despite initial remission, patients with CD may eventually experience recurrence. The mean recurrence rate at the 5-10-year follow-up is 23% for microadenomas and 33% for macroadenomas [19,23,30]. Since the postoperative rates in the literature are variable, additional data from experienced centers may be necessary to resolve these discrepancies. In this study, we present the medium- and long-term follow-up data from 96 operations for CD that were conducted in a center with a high level of experience for ETSS. Go to : MATERIALS AND METHODS The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Basaksehir Cam and Sakura City Hospital (No. 2022185). Informed consent was obtained from all patients. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This retrospective study included pre and postoperative data of 96 ETSS performed in 87 patients with CD (Fig. 1). CD was diagnosed based on unsuppressed cortisol levels (>1.8 µg/dL) following the 1-mg dexamethasone suppression test, high levels of urinary free cortisol, or late night salivary cortisol and plasma ACTH levels >20 pg/mL [28]. Between 2014 and 2022, all surgeries were conducted by the experienced neurosurgical team (Ö.G., O.T., B.E., E.A.) responsible for endoscopic transsphenoidal procedures at the Pituitary Research Center. The surgeries were performed under perioperative glucocorticoid coverage. Fig. 1. Number of operations and patients included in the study. Size, cavernous sinus invasion, sellar and suprasellar infiltration of adenoma on preoperative magnetic resonance imaging (MRI) scans, residual tumor on postoperative MRI scans, postoperative complications, pathology results, remission and recurrence status, and additional postoperative management were evaluated in addition to patients’ demographic data. For follow-up assessments, data obtained 3−6 months postoperatively and during the latest follow-up were included. Three different classifications obtained during radiologic evaluation using MRI were used for pituitary adenomas : 1) maximum size of tumor (MST) : 0−5 mm (group 1), 6−10 mm (group 2), 11−20 mm (group 3), and >20 mm (group 4); 2) Knosp classification : for evaluation of cavernous sinus invasion [22]; and 3) modified Hardy classification : for evaluation of sellar and suprasellar infiltrations [20,39]. In cases of CD without a lesion or with a lesion <6 mm on MRI, confirmation of the central origin and lateralization was provided by inferior petrosal sinus sampling (IPSS) with corticotropin-releasing hormone stimulation [25,26,29]. Under neuronavigation guidance, pure ETSS surgical interventions were performed for all patients by a single surgical team using the Medtronic StealthStation™ S7 and S8 systems (Medtronic, Minneapolis, MN, USA) together with 4-mm 0°, 30°, and 45° rigid optical instruments and an endoscope. A nasal decongestant spray was administered 1 hour before the operation. The sphenoid ostium was detected from both nostrils, and a bi-nostril approach was used by resecting the posterior nasal septum. After sphenoidectomy, the standard sellar approach was used for lesions in the sellar region. The details of these surgical procedures are described in previous study [14]. Selective adenectomy with ETSS was performed for preoperatively localized and visible tumors, whereas hemihypophysectomy was performed for non-lesional cases. In cases with cavernous sinus-invading tumors, particularly Knops 3-4, the defect which was created by the tumor on the medial wall of anterior cavernous sinus was identified and, it was expanded for resection of the tumor tissue within the cavernous sinus. If a defect was not visible, blunt-ended hook-shaped dissectors were used to create a defect on the medial wall, allowing access for the tumor to enter the cavernous sinus. Hematoxylin and Eosin (H&E) and immunohistochemistry staining were performed for the specimens obtained during ETSS. Adenomas showing positive immunohistological staining for ACTH were diagnosed histologically as corticotropinomas. CD was considered to be in remission when the cases showed basal cortisol levels <5 µg/dL or suppressed cortisol levels (≤1.8 µg/dL) following the 1-mg dexamethasone suppression test, 3-6 months postoperation, and during the latest follow-up. The study protocol was approved by the ethics committee of our institution. Data were statistically analyzed using the SPSS 15.0 package (IBM Corp., Armonk, NY, USA). The chi-square test was used for categorical variables. Sample distribution was evaluated with the Kolmogorov-Smirnov test. Continuous independent variables with a normal distribution were compared using the Student’s t-test. Continuous variables with non-normal distributions were compared using the Mann-Whitney U test. p<0.05 was considered statistically significant. A Kaplan-Meier survival analysis was conducted to determine probability and time to recurrence in cases with initial remission. Go to : RESULTS Demographic data A total of 96 ETSS were performed for 87 patients with CD. Of the 87 patients, 68 (79%) were female, and 19 (21%) were male. The mean patient age was 42.2±12.9 years, and the mean duration of follow-up was 39.5±3.2 months. Of the 96 surgeries, 79 (82%) were performed for the first time, six (6%) were performed for residual tumors, and 11 (12%) were performed following a recurrence of the disease. Eight of the 17 patients who underwent reoperations had undergone their first operation at another center. Preoperative imaging Table 1 shows the maximum tumor size on preoperative pituitary MRI before each surgical procedure. Preoperative IPSS for lateralization was performed in 42 operations (44%), all of which were first-time cases. Knosp classification based on preoperative pituitary MRI and the modified Hardy classification is presented in Table 1. Table 1. Preoperative pituitary magnetic resonance imaging scans Number of tumors (n=96) Maximum tumor size  Group 1, 0−5 mm 41 (42.7)  Group 2, 6−10 mm 24 (25.0)  Group 3, 11−20 mm 20 (20.8)  Group 4, >20 mm 11 (11.5) Knosp classification  Grade 0 52 (54.2)  Grade 1 22 (22.9)  Grade 2 6 (6.3)  Grade 3 8 (8.3)  Grade 4 8 (8.3) Modified Hardy classification  0   A 41 (42.8)   B -   C -   D -   E -  1   A 14 (14.6)   B -   C -   D -   E 4 (4.2)  2   A 5 (5.2)   B -   C -   D -   E 5 (5.2)  3   A 1 (1.0)   B 2 (2.1)   C -   D -   E 1 (1.0)  4   A 1 (1.0)   B -   C -   D 1 (1.0)   E 3 (3.1)  NA 18 (18.8) Values are presented as number (%). Invasion : 0, sella normal; 1, sella focally expanded and tumor ≤10 mm; 2, sella enlarged and tumor ≥10 mm; 3, localized perforation of the sellar floor; 4, diffuse destruction of the sellar floor. Suprasellar extension : A, no suprasellar extension; B, anterior recesses of the third ventricle obliterated; C, floor of the third ventricle grossly displaced with parasellar extension; D, intracranial (intradural) : anterior, middle or middle fossa; E, into/beneath the cavernous sinus (extradural). NA : not available Postoperative results Remission was achieved between the 3rd and 6th months in 74 (77%) of the 96 operations, and long-term remission in 79 operations (82%). Among all 96 operations, eight (8%) concluded with a residual tumor. Regarding only first-time operations, five (6%) of the 79 concluded with a postoperative residual tumor. Of the 79 first-time operations, there were 62 cases (78%) of remission between 3 and 6 months. Two (2.5%) of these 79 operations involved recurrence during follow-up, while 60 (97%) showed sustained remission. Those with sustained remission had a median disease-free survival time of 31 months (interquartile range, 14-64) during long-term followup, two cases with recurrence had their recurrence 49 and 54 months after their operation. Survival analysis of cases with remisson and recurrence is presented in Fig. 2. CD persisted after 17 (21.5%) of the 79 first operations. Fig. 2. Survival analysis after the first operation in cases with remission at 3-6 months. Dashed line represents cases with recurrence and, straight line represents cases with sustained remission during long-term follow-up. Ten (13%) of the 79 cases underwent reoperation; two were due to recurrence, and eight due to disease persistence. In five cases (29%), the patients were initially unresponsive but showed remission later during the long-term follow-up. Remission was achieved with stereotactic radiosurgery (STRS) and medical treatment in one of these cases, with only STRS in two and only medical treatment in two cases. At the latest follow-up visit, the total number of cases showing remission after the first operation was 65 (82%). Additional details regarding the results of the first operations are provided in Fig. 3. Fig. 3. Results of the cases who had operation for the first time. Of the 18 reoperations, the results for one case were excluded since the patient was operated at another center. After the reoperation (n=17), the medium and long-term remission rates were 71% (n=12) and 77% (n=13), respectively. The 3-6-month remission rate did not differ significantly between first-time and reoperations (p=0.5). Residual tumors were present in three cases (18%) after reoperation. Of the early non-responders, one case showed remission after STRS, and none of the responders showed recurrence during long-term follow-up. Additional details regarding the results of reoperations are provided in Fig. 4. Fig. 4. Results of the reoperations in our center. Remission rates based on tumor size are presented in Table 2. The initial remission rates of the tumors in MST group 4 were significantly lower than those in the other MST groups (MST 1 vs. 4, p=0.01; MST 2 vs. 4, p=0.001; and MST 3 vs. 4, p=0.006). Comparisons of the other MST groups showed no significant differences. When adenomas were stratified using the 10-mm cut-off, the remission rates did not differ significantly (remission rate, 81% for adenomas <10 mm and 68% for adenomas ≥10 mm; p=0.2). Postoperative residual tumors were observed in five of the 11 tumors (46%) >2 cm (MST group 4) and in one tumor in each of MST groups 1-3 (2%, 4%, and 5%, respectively, p<0.001). Reoperation rate was 17% (n=7) for adenomas ≤5 mm, 18% (n=10) for adenomas ≥6 mm (p=0.9), and 27% (n=3) for adenomas >20 mm (among all grades, p=0.3). Table 2. Comparison of remission rates in preoperative pituitary magnetic resonance imaging scans 3−6-month remission Long-term remission Maximum tumor size  Group 1, 0−5 mm (n=41) 31 (75.6) 33 (80.5)  Group 2, 6−10 mm (n=24) 22 (91.7) 22 (91.7)  Group 3, 10−20 mm (n=20) 17 (85.0) 17 (85.0)  Group 4, >20 mm (n=11) 4 (36.4) 7 (63.6)  p-value 0.003* 0.200 Knops classification  0 (n=52) 41 (78.8) 44 (84.6)  1 (n=22) 21 (95.5) 21 (95.5)  2 (n=6) 4 (66.7) 3 (50.0)  3 (n=8) 7 (87.5) 7 (87.5)  4 (n=8) 1 (12.5) 4 (50.0)  p-value <0.001* 0.010* Modified Hardy classification  0   A (n=41) 32 (78.0) 34 (82.9)  1   A (n=14) 12 (85.7) 12 (85.7)  2   E (n=4) 3 (75.0) 3 (75.0)   A (n=5) 5 (100.0) 5 (100.0)  3   E (n=5) 2 (40.0) 2 (40.0)   A (n=1) 1 (100.0) 1 (100.0)   B (n=2) 2 (100.0) 2 (100.0)  4   E (n=1) 0 (0.0) 0 (0.0)   A (n=1) 1 (100.0) 1 (100.0)   D (n=1) 0 (0.0) 0 (0.0)   E (n=3) 1 (33.3) 3 (100.0)  p-value 0.10 0.06 Pathology result  Corticotropinoma (+) (n=71) 58 (81.7) 60 (84.5)  Corticotropinoma (-) (n=25) 16 (64.0) 19 (76.0)  p-value 0.07 0.30 Values are presented as number (%). Invasion : 0, sella normal; 1, sella focally expanded and tumor ≤10 mm; 2, sella enlarged and tumor ≥10 mm; 3, localized perforation of the sellar floor; 4, diffuse destruction of the sellar floor. Suprasellar extension : A, no suprasellar extension; B, anterior recesses of the third ventricle obliterated; D, intracranial (intradural) with anterior, middle, or middle fossa; E, into/beneath the cavernous sinus (extradural). * Statistically significant p-value Remission rates based on Knosp and Hardy classifications are presented in Table 2, respectively. The medium-term remission rates in Knosp group 4 were significantly lower than the rates in the other groups (Knosp 0 vs. 4, p<0.001; Knosp 1 vs. 4, p<0.001; Knosp 2 vs. 4, p=0.04; and Knosp 3 vs. 4, p=0.003). Additionally, the medium-term remission rate of tumors in Knosp group 2 was lower than that in Knosp group 1 (p=0.04). However, remission rates did not differ significantly among the other groups. Comparing invasive (Knosp 3 and 4) and noninvasive (Knosp 0, 1, and 2) tumors, remission rates within 3-6 months were 50% and 83% in the invasive and noninvasive groups, respectively. We further stratified cases with tumor size ≥20 mm (n=11) using Knosp classification; one case (9%) was Knosp 0, one case (9%) was Knosp 1, two cases (18%) were Knosp 3, and seven cases (64%) were Knosp 4 tumors. For ≥20 mm, all cases with Knosp 0, 1, and 3 tumors achieved remission within 3-6 months postoperatively, while none of the cases with Knosp 4 tumors had remission (p=0.01). All the cases with Knosp 0, 1, and 3 tumors sustained remission, and three cases with Knosp 4 tumor later achieved long-term remission (p=0.3). Of the cases that achieved long-term remission, two underwent STRS, and one had medical therapy with additional STRS. Of the 96 tissue specimens obtained during ETSS, 71 (74%) stained positive for ACTH and were histologically identified as corticotropic adenomas, while 25 (26%) were negative. Remission rates based on the pathology results are compared in Table 2. Of the lesions with conclusive findings on MRI (≥6 mm lesions), 89% (n=49) were pathologically confirmed as corticotropinomas, whereas 54% (n=22) of those with inconclusive MRI f indings were pathologically conf irmed (p<0.001). Among the lesions that showed negative results for both conclusive MRI findings (≤5 mm) and pathologic confirmation (negative for a corticotropinoma) (n=19), 12 (63%) showed remission at 3-6 months and 14 (74%) showed remission during long-term follow-up. During the exploration of the cavernous sinus in one patient (1%), postoperative lateral gaze paralysis of the eye developed due to right abducens nerve palsy. The patient was treated with anti-inflammatory doses of steroids, and the symptom completely resolved within 1 month. In three other patients (3%), severe epistaxis was observed in the postoperative period, 1 to 3 weeks after surgery. Nasal packing was applied for 3 days. Additionally, three patients (3%) experienced postoperative rhinorrhea. To address this issue, a reconstruction of the skull base was performed using fat tissue harvested from the leg, fascia lata graft, and tissue adhesive material. These patients were monitored with a lumbar drain for 1 week. Among the patients who developed rhinorrhea, one patient also developed meningitis and received intravenous antibiotic therapy for about 3 weeks and, the situation compeletly resolved during follow-up. The postoperative complications are summarized in Table 3. Comparison of various characteristics of the cases with and without medium and long-term remission are presented in Table 3, respectively. Table 3. Comparison of cases with and without remission, postoperative complications 3−6-month remission Long-term remission Number of cases (n=96) Remission (+) (n=74) Remission (-) (n=22) p-value Remission (+) (n=79) Remission (-) (n=17) p-value Operation 0.500 0.08  First time 62 (83.8) 17 (77.3) 66 (83.5) 13 (76.5)  Re-operation 12 (16.2) 5 (22.7) 13 (16.5) 4 (23.5) Tumor characteristics 0.003* 0.20  MST   Grade 1 31 (42.0) 10 (45.0) 33 (41.8) 8 (47.1)   Grade 2 22 (30.0) 2 (9.0) 22 (27.8) 2 (11.8)   Grade 3 17 (23.0) 3 (14.0) 17 (21.5) 3 (17.6)   Grade 4 4 (5.0) 7 (32.0) 7 (8.9) 4 (23.5)  Knosp classification <0.001* 0.01*   0 41 (56.0) 11 (50.0) 44 (55.5) 9 (53.0)   1 21 (28.0) 1 (4.5) 21 (26.5) 2 (12.0)   2 4 (5.0) 2 (9.0) 3 (4.0) 1 (6.0)   3 7 (10.0) 1 (4.5) 7 (9.0) 1 (6.0)   4 1 (1.0) 7 (32.0) 4 (5.0) 4 (23.0)  Hardy classification 0.09 0.06   0A 32 (43.2) 9 (41.0) 34 (43.0) 7 (41.0)   1A 12 (16.2) 2 (9.0) 12 (15.0) 2 (12.0)   1E 3 (4.0) 1 (4.5) 3 (4.0) 1 (6.0)   2A 5 (6.7) 0 (0.0) 5 (6.0) 0 (0.0)   2E 2 (2.7) 3 (14.0) 2 (3.0) 3 (17.0)   3A 1 (1.4) 0 (0.0) 1 (1.0) 0 (0.0)   3B 2 (2.7) 0 (0.0) 2 (3.0) 0 (0.0)   3E 0 (0.0) 1 (4.5) 0 (0.0) 1 (6.0)   4A 1 (1.4) 0 (0.0) 1 (1.0) 0 (0.0)   4D 0 (0.0) 1 (4.5) 0 (0.0) 1 (6.0)   4E 1 (1.4) 2 (9.0) 3 (4.0) 0 (0.0)   NA 15 (20.3) 3 (13.5) 16 (20.0) 2 (12.0) Postoperative  Complication 0.900 0.30   (+) 10 (13.5) 3 (13.6) 12 (15.2) 1 (5.9)   (-) 64 (86.5) 19 (86.4) 67 (84.8) 16 (94.1)  Pathologic diagnosis 0.070 0.30   Corticotropinoma 58 (78.4) 13 (59.1) 60 (75.9) 11 (64.7)   Negative 16 (21.6) 9 (40.9) 19 (24.1) 6 (35.3)  Remission during long-term F/U <0.001*   (+) 72 (97.3) 7 (31.8)   (-) 2 (2.7) 15 (68.2)  Residual tumor 0.001*   (+) 3 (3.8) 5 (29.4)   (-) 76 (96.2) 12 (70.6)  Remission during long-term F/U <0.001*   (+) 72 (91.1) 2 (11.8)   (-) 7 (8.9) 15 (88.2) Postoperative complication  DI-temporary 4 (4.2)  DI-permanent 4 (4.2)  Meningitis 1 (1.0)  CSF leak 3 (3.1)  Epistaxis 3 (3.1)  Cranial nerve palsy, transient 1 (1.0) Hypopituitarism 4 (4.2)  Hypocortisolism 2 (2.1)  Hypothyroidisim 2 (2.1) Values are presented as number (%). *Statistically significant p-values. MST : maximum size of tumor, NA : not available, F/U : follow up, DI : diabetes insipidus, CSF : cerebrospinal fluid Go to : DISCUSSION This study reported an overall postoperative 3-6 month remission rate of 77% and a long-term remission rate of 82% after 3 years of follow-up. The initial and long-term remission rates after first operations were 78% and 82%, respectively, with a recurrence rate of 2.5% over a follow-up period of 3-3.5 years. Additionally, our findings revealed that tumor size >2 cm and extended tumor invasion of the cavernous sinus (Knosp 4) might be associated with lower postoperative remission rates. Patients who showed remission within 3-6 months showed higher rates of long-term remission than those in patients without initial remission. Pituitary surgery is the first-line treatment modality for CD. ETSS is a safe and less invasive method for treating pituitary adenomas; therefore, it has been increasingly preferred in CD [5,15]. However, the postsurgical outcomes in patients with CD have shown variable remission and recurrence rates [2,4,9,16,17,21,30]. These discrepancies may be attributable to differences in population and number of cases involved in the studies, tumor characteristics, criteria for remission and recurrence used by the centers, laboratory parameters, time of evaluation and followup durations, surgical and imaging techniques used by different centers, and neurosurgical expertise. In this study, we present the medium- and long-term postoperative results of 96 ETSS procedures performed in 87 patients. The medium-term results (obtained 3-6 months postoperation) were preferred to immediate results since a subset of cases may show delayed remission, and immediate postoperative results could be misleading in almost 6% of cases [37]. The overall medium-term remission rate was 77%, consistent with the results published by Serban et al. [34], who reported an overall remission rate of 77% 2 months postoperation. A larger series of 1106 cases reported an immediate remission rate of 72.5% within 7 days postoperation; however, this rate decreased to 67% after delayed remission rates and recurrences 56 months postoperation were considered [12]. The long-term remission rate obtained over a median period of 3 years was 82% in our series. The increased long-term remission rate was attributed to reoperations, additional medical therapies, and the use of STRS in those who did not show remission initially. Of the 96 procedures, 79 were performed for the first time. The medium-term remission rate after first operations was 78%. Recent studies have reported remission rates of 74-82% after first operations [12,34]. The recurrence rates reported previously varied between 3% and 66% [5,12,34]. However, the duration of follow-up differed among the studies. Dai et al. [12] and Brady et al. [5] reported recurrence rates of 12% and 3%, respectively, after a follow-up period of 2 years. In contrast, Serban et al. [34] reported a recurrence rate of 17% after a longer followup duration of 6 years. In this series, after a median follow-up period of 3 years, the overall recurrence rate was 2.5%. Residual tumors were observed in five cases (6%), and the reoperation rate after the first operation was 13%. Including the eight patients admitted for reoperation after having undergone their first surgery in another center, 17 cases involved reoperations in our center. Of these cases, 71% (n=12) showed remission between 3-6 months postoperation, while none showed recurrence; thus, the long-term remission rate was 77%. Residual tumors were detected in three cases (18%), and the disease persisted in four (24%) of these 17 reoperated cases. Previous studies have reported remission rates of 22-75% after repeated surgery in CD [5,12,34,38]. Although the success rates after reoperations were lower than those in first-time operations in some studies [38], the remission rates after the first and reoperations did not differ significantly in our study. Tumor size has been reported to contribute to the success of transsphenoidal surgery [12,34], with microadenomas showing a higher success rate after surgery [5,12,34]. Our remission rates for micro- and macroadenomas were similar to those reported by Dai et al. [12] : 81% for adenomas <10 mm and 68% for adenomas ≥10 mm. However, the statistical significance of our study differed from that in the series presented by Dai et al. [12] (p=0.2 vs. p=0.002). This may be due to the large difference in the number of cases included in the two studies and the differences in size scales for tumors ≥10 mm. In our series, when the tumors were stratified further by the tumor size, the medium-term remission rate further decreased to 36% for tumors ≥20 mm in size, although the remission rates for other groups <20 mm were all above 75% (p=0.003). Sharifi et al. [35] classified pituitary MRI scans in CD showing a tumor size <6 mm as “inconclusive” because incidentalomas are frequent among tumors in this size range, and this size is not indicative of CD. Previously published series reported that the rate of inconclusive MRI scans in CD was 36-64%, and the remission rates varied between 50% and 71% for those with an inconclusive MRI scan [10,24,27,32,33]. In our series, 54% of the preoperative MRI scans were inconclusive. In the series presented by Sharifi et al. [35] and some other series [8,12,32,36], no significant difference was observed between the remission rates of CD cases with and without a conclusive MRI.This finding is controversial since other studies showed decreased remission rates with preoperative inconclusive MRIs [13,40]. Similar to the results reported by Sharifi et al. [35], we did not find a statistically significant difference between the remission rates of tumors <6 mm and those between 6-20 mm. However, a significant difference was observed between tumors <6 mm and those ≥20 mm. Residual tumors were more frequent after operating tumors >20 mm compared to those <20 mm, but the number of reoperations did not differ among the groups. Additionally, tumors >20 mm were primarily Knosp 4 (64%), probably contributing to lower remission rates in this group. Interestingly, two Knosp 3 cases had postoperative remission within 3-6 months without additional intervention. In these two cases, the surgical team explored the cavernous sinus and could resect the tumor. However, complete excision was not feasible with Knosp 4 tumors, where there is a complete encasement of the intracavernous internal carotid artery. Thus, a tumor size of 20 mm may be supportive data in predicting non-remission in the presence of complete cavernous sinus infiltration. Cavernous sinus invasion, determined by the Knosp classification, and sellar invasion and/or suprasellar extension, determined by the Hardy-Wilson classification, indicate the radiologic status of local invasion in cases of pituitary tumors [20,22,39]. Invasion to surrounding structures and tissues may be a limiting factor for postoperative remission of pituitary tumors. In the series presented by Dai et al. [12], remission rates of corticotropinomas with Knosp grade 4 (definitive cavernous sinus invasion) dropped to 53% from a remission rate of 77% for corticotropinomas with less likely or no cavernous sinus invasion (p<0.001). Similarly, our results showed that both medium- and long-term remission rates for Knosp grade 4 tumors decreased to 13% and 50%, respectively, and were lower than the remission rates in other grades (p<0.001 and p=0.01, respectively). While remission rates in Knosp group 3 were not inferior to noninvasive tumors, remission rates in Knosp group 4 were lower than all the other groups. In this regard, the extent of invasion may be more determinative. In contrast, in our series, the modified Hardy classification did not show a significant effect on postoperative remission rates in medium- and long-term follow-up assessments. Araujo-Castro et al. [3] had previously shown that for pituitary adenomas, the Hardy-Wilson classification lacked utility in predicting postoperative remission compared to the Knosp classification. The difference in the utility of these classifications for predicting postoperative remission may be due to differences in accessing tissues during surgery. In the present series, 74% (n=71) of tissues were histologically proven to be corticotropinomas, while 26% (n=25) did not show histologic confirmation. Medium- and long-term remission rates did not differ between histologically proven and unproven CD cases (medium-term remission rates, 82% vs. 64%, p=0.07; long-term remission rates, 85% vs. 76%, p=0.3). A conclusive finding of an adenoma on MRI increased the rate of histologic proof of corticotropinoma in our series, implying that adenomas showing a ≥6-mm lesion on MRI more frequently stained positive for ACTH. In previous studies 12-53% of CD did not have postoperative pathologic identification and the rate increased in those with a preoperative inconclusive MRI [25,31,38]. However, this did not have a significant influence on our remission rates. The remission rates did not decrease even for CD cases that were not conclusively detected on MRI and could not be histologically proven. On the other hand, in previous studies, ACTH positivity was higher, and the lack of proof for a corticotropinoma decreased the remission rates [1,12,31,32,34]. The higher remission rates despite reduced localization with MRI and/or lower rates of histologic confirmation in our series may be explained by the successful preoperative IPSS lateralization, surgical exploration, and hemi-hypophysectomy procedure. Furthermore, tumor tissues might have been aspirated along with blood and other materials through the suction tube, potentially resulting in less histological confirmation despite postoperative remission of CD. Additionally, tumor tissues might have been aspirated along with blood and other materials through the suction tube, potentially resulting in less histological confirmation despite postoperative remission of CD. The total rate of complications in this series was 20%, and the most frequent complication was diabetes insipidus (DI; 8%, both permanent and temporary). The incidence of hypopituitarism was relatively lower (4%), mainly involving hypocortisolism and hypothyroidism. Recent studies have shown postoperative DI rates of 25-66% and hypothyroidism rates of 11-23% [5,34]. Although our neurosurgical team was experienced in conducting pituitary surgeries, other factors may have resulted in these differences. Since not all the cases were postoperatively followed in our center, with some patients lost to follow-up, there may be missing data. Comparing cases with and without remission in the medium term, cases of remission frequently involved adenomas >20 mm and less cavernous sinus invasion. Additionally, cases that achieved medium-term remission showed long-term remission more frequently. In the long term, those showing remission had less cavernous sinus invasion and residual tumors compared to those without remission. Therefore, we may conclude that a tumor size of 20 mm may predict medium-term remission, while the absence of/less cavernous sinus invasion, early remission, and absence of residual tumor may predict long-term remission. This study had limitations. First, the retrospective nature of the study and the limited number of cases, which was inevitable due to the low incidence of CD, may have distorted our results. Although the same neurosurgical team operated on all patients, they were followed up pre and postoperatively at different endocrinology centers, causing difficulty in obtaining the full postoperative data of certain cases. Lastly, some patients recently underwent ETSS; thus, they had a shorter follow-up period. However, we intend to present the longer-term outcomes of all patients in a separate study. Although ETSS is the first-line treatment for CD, previous studies on the use of ETSS for CD have reported a wide range of remission and recurrence rates, which can be primarily attributed to differences in the surgical experience levels among centers. This trend highlights the need for additional data from experienced centers to resolve the discrepancies in the existing data. Therefore, we present medium- and long-term follow-up data from 96 operations for CD conducted in a center with a high level of experience for ETSS. We believe our study makes a significant contribution to the literature because the findings reconfirm the usefulness of ETSS for the treatment of CD and highlight the importance of the size of the adenoma and presence/absence of cavernous sinus invasion on preoperative MRI in predicting long-term remission postoperatively. Go to : CONCLUSION ETSS is a safe and effective method for the treatment of CD. Some characteristics of adenomas, such as size, cavernous sinus invasion, and postoperative residue, may predict long-term remission. A tumor size of 2 cm may be a supporting criterion for predicting remission status in the presence of complete cavernous sinus infiltration. Further studies with larger patient populations are necessary to support this finding. Go to : Notes Conflicts of interest No potential conflicts of interest relevant to this study exist. Informed consent Informed consent was obtained from all individual participants included in this study. Author contributions Conceptualization : BE, MB, EH; Data curation : EA, OH, DT, MM; Formal analysis : LŞP, DAB, DT, İÇ; Funding acquisition : OT, ÖG, DAB; Methodology : LŞP, İÇ, MM, ÖG; Project administration : BE, SÇ, EH; Visualization : EA, OT, OH; Writing - original draft : BE, MB, SÇ; Writing - review & editing : BE, EH Data sharing None Preprint None Go to : Acknowledgements This manuscript was edited by a certified English Proofreading Service (Editage). Go to : References 1. Acebes JJ, Martino J, Masuet C, Montanya E, Soler J : Early post-operative ACTH and cortisol as predictors of remission in Cushing’s disease. Acta Neurochir (Wien) 149 : 471-477; discussion 477-479, 2007 2. Aranda G, Enseñat J, Mora M, Puig-Domingo M, Martínez de Osaba MJ, Casals G, et al : Long-term remission and recurrence rate in a cohort of Cushing’s disease: the need for long-term follow-up. Pituitary 18 : 142-149, 2015 3. 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World Neurosurg 77 : 525-532, 2012 From https://jkns.or.kr/journal/view.php?doi=10.3340/jkns.2023.0100

I would have hoped that you could get better answers in the UK. I'm in the US - Virginia. Our doctors aren't very good, either