Treatment Of Cushing's Disease Research Articles

THU213 Posterior Reversible Encephalopathy Syndrome As A Rare Presentation Of ACTH-dependent Cushing Syndrome In A Pediatric Patient

Abstract Disclosure: E.E. Bell-Sambataro: None. C. Tatsi: None. P. Chittiboina: None. S.A. Bowden: None. Background: Cushing disease (CD), caused by ACTH-secreting pituitary adenoma, is the most common cause of Cushing Syndrome (CS) in children > 5 years of age. Hypertension is reported in up to 50% of pediatric cases with CS. We report a challenging pediatric case with a rare presentation of hypertensive emergency associated with CD. Clinical Case: A 6-year-old female with 3 month-history of rapid weight gain (8 kg), round face, and hypertrichosis presented to emergency department for abdominal pain from nephrolithiasis and was noted to have severe hypertension. While in ED, she developed status epilepticus and altered mental status. Brain MRI findings were consistent with posterior reversible encephalopathy syndrome (PRES). Her hypertensive encephalopathy gradually improved with aggressive anti-hypertensive and anti-epileptic therapy. Further studies confirmed hypercortisolism with markedly elevated urine free cortisol of 1288 ug/day (<18 ug/day) and lack of diurnal variation of serum cortisol (8 AM cortisol of 47.9 ug/dL, midnight cortisol of 20.3 ug/dL). ACTH level of 23 pg/mL suggested ACTH-dependent CS. Low dose (1 mg) dexamethasone suppression test (DST) failed to suppress 8 am cortisol (31.4 ug/dL). High dose DST (120 mcg/kg) suppressed serum cortisol to 67%- borderline threshold for CD, likely due to increased dexamethasone clearance by anticonvulsant. Pituitary MRI did not reveal a visible lesion. Desmopressin stimulation test showed stimulation of ACTH by 700% and cortisol by 160% suggesting pituitary source. Inferior petrosal sinus sampling showed a mildly increased gradient in central to peripheral plasma ACTH of 1.7 at baseline (>2) and post-stimulation of 2.5 (>3). ACTH gradient did not reach cutoffs for pituitary source, likely due to insufficient catheterization of petrosal sinus from anatomically small blood vessels. Given her severity, she underwent surgical pituitary exploration. Postoperative morning cortisol was <5 mcg/dL, with decreased midnight salivary cortisol level obtained 2 months after surgery. She developed post-operative central hypothyroidism but did not have diabetes insipidus. She had a 4 kg weight loss with increased height percentile 5 months after surgery and remains under close monitoring. Conclusion: PRES is a clinical-radiographic disorder characterized by seizures, encephalopathy with neuroimaging findings of reversible cortical and subcortical vasogenic edema. Hypertension induced by marked hypercortisolism precipitated by pain is likely the etiologic factor. Prompt recognition and treatment of PRES are crucial to prevent further life-threatening complications and permanent neurological damage. Early diagnosis and treatment of CD are critical to prevent associated morbidities. Pituitary exploration by expert neurosurgery team should be considered in patients with MRI-negative CD. Presentation: Thursday, June 15, 2023

THU647 Patient With Successful Conception During Treatment For Cushing Disease: Case Report

Abstract Disclosure: C. Iweha: None. E.K. Babler: None. M. Castillo: None. Introduction Cushing Disease (CD) is an endocrine disorder that predominantly affects women of childbearing age and is characterized by excess secretion of adrenocorticotropic hormone (ACTH) with hypercortisolism. We report a case of a woman with ACTH-dependent hypercortisolism treated with pasireotide who had a successful pregnancy while on treatment. Clinical Case A 27-year-old woman presented to the initial consult on 9/01/2011 with a 4-year history of ongoing symptoms of hirsutism, diaphoresis, oligomenorrhea, myalgia, and acne. A physical exam revealed an overweight female with mild facial acne and hirsutism. Family history included autoimmune disease in mother (lupus and multiple sclerosis). She was frustrated by the lack of a definitive diagnosis over 4 years; she was anxious and using multiple medications, including anxiolytics and analgesics, without relief of symptoms. Patient did not use alcohol and never smoked. Labs revealed initial morning (AM) cortisol = 26.9 µg/dL (normal range: 5-23 µg/dL) and ACTH = 14 pg/mL (normal: 6-58 pg/mL); 24-hour urinary cortisol was 110.6 µg/24 h (normal:<100 µg/dL) and serum ACTH =8 pg/mL. Low-dose (1 mg) dexamethasone suppression test reduced AM cortisol to 1.7 µg/dL and ACTH of 8 pg/mL. No evidence of adrenal adenoma on abdominal CT or pituitary adenoma on brain MRI, and IPSS confirmed diagnosis. Based on hypercortisolism and normal ACTH level, diagnosis was ACTH-dependent CD. We advised the patient to join a clinical trial for pasireotide, and she began treatment on 1/3/2013. She presented for follow-up on 6/17/2014 and reported improvement of some symptoms on 0.6 mg pasireotide twice daily, the highest dose she could tolerate. She reported experiencing chronic pain; medications included prescription analgesics, muscle relaxants, and anxiolytics. On 6/23/2015, our patient returned for a follow-up when she was 5.5 months pregnant. While on pasireotide, she became pregnant and subsequently left the study and discontinued treatment. She reported recurrence of hirsutism, acne, fatigue, and hyperemesis with discontinuation of pasireotide. Patient returned twice more during pregnancy and had a successful delivery and healthy infant. Clinical Conclusions Successful conception and pregnancy are unusual with CD due to fertility-inhibiting hormonal effects of excess cortisol. Some medications for CD impede pregnancy through their mechanism (eg, mifepristone). Our patient conceiving while on treatment is promising for women with CD. Although her CD symptoms returned when pasireotide was discontinued, she delivered a healthy infant; limited pasireotide data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Our case underscores the potential for successful conception for women with CD when cortisol levels are normalized with treatment that avoids suppressing menstruation. Presentation: Thursday, June 15, 2023

Neuromedin B receptor as a potential therapeutic target for corticotroph adenomas.

Cushing's disease (CD) results from autonomous adrenocorticotropic hormone (ACTH) secretion by corticotroph adenomas, leading to excessive cortisol production, ultimately affecting morbidity and mortality. Pasireotide is the only FDA approved tumor directed treatment for CD, but it is effective in only about 25% of patients, and is associated with a high rate of hyperglycemia. Neuromedin B (NMB), a member of the bombesin-like peptide family, regulates endocrine secretion and cell proliferation. Here, we assessed NMB and NMB receptor (NMBR) expression in human corticotroph adenomas and the effects of NMBR antagonist PD168368 on murine and human corticotroph tumors. To investigate NMB and NMBR expression, real-time qPCR and immunostaining on human pathological specimens of corticotroph, non-functional and somatotroph adenomas were performed. The effects of PD168368 on hormone secretion and cell proliferation were studied in vitro, in vivo and in seven patient-derived corticotroph adenoma cells. NMB and NMBR were expressed in higher extent in human corticotroph adenomas compared with non-functional or somatotroph adenomas. In murine AtT-20 cells, PD168368 reduced proopiomelanocortin (Pomc) mRNA/protein expression and ACTH secretion as well as cell proliferation. In mice with tumor xenografts, tumor growth, ACTH and corticosterone were downregulated by PD168368. In patient-derived adenoma cells, PD168368 reduced POMC mRNA expression in four out of seven cases and ACTH secretion in two out of five cases. A PD168368-mediated cyclin E suppression was also identified in AtT-20 and patient-derived cells. NMBR antagonist represents a potential treatment for CD and its effect may be mediated by cyclin E suppression.

Cushing disease in pediatrics: an update.

Cushing disease (CD) is the main cause of endogenous Cushing syndrome (CS) and is produced by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma. Its relevance in pediatrics is due to the retardation of both growth and developmental processes because of hypercortisolism. In childhood, the main features of CS are facial changes, rapid or exaggerated weight gain, hirsutism, virilization, and acne. Endogenous hypercortisolism should be established after exogenous CS has been ruled out based on 24-hour urinary free cortisol, midnight serum or salivary cortisol, and dexamethasone suppression test; after that, ACTH dependence should be established. The diagnosis should be confirmed by pathology. The goal of treatment is to normalize cortisol level and reverse the signs and symptoms. Treatment options include surgery, medication, radiotherapy, or combined therapy. CD represents a challenge for physicians owing to its multiple associated conditions involving growth and pubertal development; thus, it is important to achieve an early diagnosis and treatment in order to control hypercortisolism and improve the prognosis. Its rarity in pediatric patients has led physicians to have limited experience in its management. The objective of this narrative review is to summarize the current knowledge about the pathophysiology, diagnosis, and treatment of CD in the pediatric population.

Ketoconazole as second-line treatment for Cushing's disease after transsphenoidal surgery: systematic review and meta-analysis.

The first-line treatment for Cushing's disease is transsphenoidal surgery for pituitary tumor resection. Ketoconazole has been used as a second-line drug despite limited data on its safety and efficacy for this purpose. The objective of this meta-analysis was to analyze hypercortisolism control in patients who used ketoconazole as a second-line treatment after transsphenoidal surgery, in addition to other clinical and laboratory criteria that could be related to therapeutic response. We searched for articles that evaluated ketoconazole use in Cushing's disease after transsphenoidal surgery. The search strategies were applied to MEDLINE, EMBASE, and SciELO. Independent reviewers assessed study eligibility and quality and extracted data on hypercortisolism control and related variables such as therapeutic dose, time, and urinary cortisol levels. After applying the exclusion criteria, 10 articles (one prospective and nine retrospective studies, totaling 270 patients) were included for complete data analysis. We found no publication bias regarding reported biochemical control or no biochemical control (p = 0.06 and p = 0.42 respectively). Of 270 patients, biochemical control of hypercortisolism occurred in 151 (63%, 95% CI 50-74%) and no biochemical control occurred in 61 (20%, 95% CI 10-35%). According to the meta-regression, neither the final dose, treatment duration, nor initial serum cortisol levels were associated with biochemical control of hypercortisolism. Ketoconazole can be considered a safe and efficacious option for Cushing's disease treatment after pituitary surgery. https://www.crd.york.ac.uk/prospero/#searchadvanced, (CRD42022308041).

Development of Human Pituitary Neuroendocrine Tumor Organoids to Facilitate Effective Targeted Treatments of Cushing's Disease.

(1) Background: Cushing's disease (CD) is a serious endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that stimulates the adrenal glands to overproduce cortisol. Chronic exposure to excess cortisol has detrimental effects on health, including increased stroke rates, diabetes, obesity, cognitive impairment, anxiety, depression, and death. The first-line treatment for CD is pituitary surgery. Current surgical remission rates reported in only 56% of patients depending on several criteria. The lack of specificity, poor tolerability, and low efficacy of the subsequent second-line medical therapies make CD a medical therapeutic challenge. One major limitation that hinders the development of specific medical therapies is the lack of relevant human model systems that recapitulate the cellular composition of PitNET microenvironment. (2) Methods: human pituitary tumor tissue was harvested during transsphenoidal surgery from CD patients to generate organoids (hPITOs). (3) Results: hPITOs generated from corticotroph, lactotroph, gonadotroph, and somatotroph tumors exhibited morphological diversity among the organoid lines between individual patients and amongst subtypes. The similarity in cell lineages between the organoid line and the patient's tumor was validated by comparing the neuropathology report to the expression pattern of PitNET specific markers, using spectral flow cytometry and exome sequencing. A high-throughput drug screen demonstrated patient-specific drug responses of hPITOs amongst each tumor subtype. Generation of induced pluripotent stem cells (iPSCs) from a CD patient carrying germline mutation CDH23 exhibited dysregulated cell lineage commitment. (4) Conclusions: The human pituitary neuroendocrine tumor organoids represent a novel approach in how we model complex pathologies in CD patients, which will enable effective personalized medicine for these patients.

Postoperative basal cortisol level as an indicator of pituitary surgery success in Cushing's disease treatment: a single centre retrospective study

Postoperative basal cortisol level as an indicator of pituitary surgery success in Cushing's disease treatment: a single centre retrospective study

Cushing's disease: role of bilateral adrenalectomy.

Laparoscopic bilateral adrenalectomy (BAD) is one of the treatments of Cushing's Disease (CD), but its indications and outcome is debated. The literature on BAD was reviewed as part of a work performed for the Cushing's disease guideline. The surgical morbidity of BAD is reported between 10 and 18% and no mortality has been reported in the largest series. Because of the endocrine sacrifice it will be mostly performed after a multidisciplinary team discussion in selected cases of refractory CD (mostly after failure of pituitary surgery and/or medical treatment). It is also frequently discussed in female patients desiring pregnancy. Corticotroph tumor progression occurs in 40% of the patients but is in most patients manageable when detected early by a careful long term monitoring with pituitary MRI and ACTH assays after BAD. BAD is a safe and effective treatment of CD used in specific situations and requiring long term monitoring.

A 3-Dimensional Printed Patient-Specific Surgical Guide to Facilitate Transsphenoidal Hypophysectomy in Dogs.

ObjectiveHypophysectomy in dogs is a difficult surgery that requires specific learning and training. We aimed to evaluate the accuracy of a 3-dimensional printed patient-specific surgical guide to facilitate choosing the entry point in the basisphenoid bone before approaching the sella turcica during transsphenoidal hypophysectomy in dogs.MethodsTwo canine cadavers and 8 dogs undergoing transsphenoidal hypophysectomy for Cushing's disease treatment, involving design and fabrication of a 3-dimensional printed guide. The ideal entry point in the basisphenoid bone outer cortical layer was determined in each dog pre-operatively; its anatomical location was described with a set of measurements then compared to post-operative computed tomography measures describing the location of the outer cortical window created in the basisphenoid bone.ResultsSeveral guide designs were proposed, and a consensus reached based on surgeons' experience performing hypophysectomy. The device chosen could be applied to the size and shape of skulls encountered in this case series. The pre-planned measurements were comparable to post-operative measurement (there was also no statistical difference), with median of differences <0.1 mm, which we judged as clinically acceptable.Clinical SignificanceHypophysectomy in dogs is a challenging procedure that has a learning curve and needs to be performed by specialist neurosurgeons. We propose that a low-profile 3-dimensional printed surgical guide can aid the specialist neurosurgeon to locate the burring site of the outer cortical layer of the basisphenoid bone at a pre-defined location and with good accuracy. It does not alleviate the need to understand the anatomy of the region and to know how to create a slot within the basisphenoid bone, which remains essential to enter the sella turcica. This device could help specialist veterinary neurosurgeons wishing to be trained to perform hypophysectomy.

Role of Radiation in the treatment of Cushing Disease.

In Cushing disease (CD), radiation therapy (RT) is mostly used in the adjuvant setting in patients who have failed transsphenoidal surgery or have recurrent CD. Stereotactic radiotherapy (SRT) is administered as either single or several sessions, and the most commonly used modalities include photon source (Gamma Knife, CyberKnife, and LINAC) or heavy particles (protons). In multicenter studies, Gamma Knife SRT can lead to biochemical control in 80%, with medial time to remission approximately 15 mos, and 70% recurrence free at 10 years. Conventional RT (CRT) consists of administration of small daily fractions over six weeks, with cumulative dose of 45-50Gy. Biochemical control is achieved in up to 64% of patients with CRT. Choice of radiation modality includes convenience for patients (SRT is more convenient) and proximity to critical structures. Both forms of RT can result in hypopituitarism. RT remains an important modality for the treatment of patients with CD.

Treatment of recurrent and persistent Cushing's disease after first transsphenoidal surgery: lessons learned from an international meta-analysis.

Transsphenoidal surgery (TSS) is the first-line treatment for patients with Cushing's Disease (CD). Recurrence rates after a first TSS range between 3 and 22% within 3years. Management of recurrent or persistent CD may include repeat TSS or stereotactic radiosurgery (SRS). We performed a meta-analysis to explore the overall efficacy of TSS and SRS for patients with CD after an initial surgical intervention. EMBASE, PubMed, SCOPUS, and Cochrane databases were searched from their dates-of-inception up to December 2021. Inclusion criteria were comprised of patients with an established diagnosis of CD who presented with persistent or biochemically recurrent disease after a first TSS for tumor resection and were treated with a second TSS or SRS. Search criteria yielded 2,116 studies of which 37 articles from 15 countries were included for analysis. Mean age ranged between 29.9 and 47.9years, and mean follow-up was 11-104months. TSS was used in 669 (67.7%) patients, while SRS was used in 320 (32.4%) patients, and remission rates for CD were 59% (95%CI 0.49-0.68) and 74% (95%CI 0.54-0.88), respectively. There was no statistically significant difference in the remission rate between TSS and SRS (P = 0.15). The remission rate of patients with recurrent CD undergoing TSS was 53% (95%CI 0.32-0.73), and for persistent CD was 41% (95%CI 0.28-0.56) (P = 0.36). Both TSS and SRS are possible approaches for the treatment of recurrent or persistent CD after a first TSS. Our data show that either TSS or SRS represent viable treatment options to achieve remission for this subset of patients.

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

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

Molecular mechanisms involved in somatostatin receptor regulation in corticotroph tumors: the role of cytoskeleton and USP8 mutations.

Adrenocorticotropic hormone (ACTH)-secreting pituitary tumors mainly express somatostatin receptor 5 (SSTR5) since SSTR2 is downregulated by the elevated levels of glucocorticoids that characterize patients with Cushing's disease (CD). SSTR5 is the molecular target of pasireotide, the only approved pituitary tumor-targeted drug for the treatment of CD. However, the molecular mechanisms that regulate SSTR5 are still poorly investigated. This review summarizes the experimental evidence supporting the role of the cytoskeleton actin-binding protein filamin A (FLNA) in the regulation of SSTR5 expression and signal transduction in corticotroph tumors. Moreover, the correlations between the presence of somatic USP8 mutations and the expression of SSTR5 will be reviewed. An involvement of glucocorticoid-mediated β-arrestins modulation in regulating SSTRs expression and function in ACTH-secreting tumors will also be discussed.

Superiority of endoscopic transsphenoidal pituitary surgery to microscopic transseptal pituitary surgery for treatment of Cushing's disease.

This study aims to compare the efficacy and safety of endoscopic transsphenoidal pituitary surgery and microscopic transseptal pituitary surgery in the treatment of Cushing's disease (CD). A total of 46 patients with CD were randomized into endoscopic group and microscopic group, with 23 cases in each group. The endoscopic group received the endoscopic transsphenoidal pituitary surgery, and the microscopic group received the microscopic transseptal pituitary surgery. The retrospective data, surgical outcomes, surgical cure rates, and complications in two groups were compared. Compared with microscopic group, the operative time was significantly shorter (p<0.05), the estimated blood loss was significantly less (p<0.05), and the hospital stay was significantly shorter (p<0.05) in endoscopic group. The surgical cure rate in endoscopic and microscopic groups was 69.56% and 60.86%, respectively, with no significant difference between the two groups (p>0.05). The incidence of complications in endoscopic group was significantly lower than that in microscopic group (p<0.01). For the treatment of CD, the efficacy of endoscopic transsphenoidal pituitary surgery is basically the same as that of traditional microscopic transseptal pituitary surgery. However, the endoscopic surgery can further shorten the operative time, reduce the estimated blood loss, shorten the hospital stay, and reduce the complications.

Surgical outcome of transsphenoidal surgery in Cushing's disease: a case series of 1106 patients from a single center over 30 years.

Transsphenoidal surgery (TSS) is the first-line treatment for patients with Cushing's disease (CD). However, the reported remission rates of patients who received TSS vary widely between different studies, and the predictors of surgical outcomes remain controversial. The present study analyzed the early outcome of TSS in a large population of patients with CD at a single center, and identified potential predictors of initial remission of TSS in patients with CD. The clinical features and surgical outcomes of CD patients who underwent TSS between 1988 and 2018 at Peking Union Medical College Hospital (PUMCH) were collected and analyzed from their medical records. Of the 1604 CD patients who underwent TSS at PUMCH between February 1988 and October 2018, 1106 patients had complete medical data and pathological results. After surgery, the overall postoperative initial remission rate was 72.5, and 27.5% of patients maintained persistent hypercortisolism. The initial remission rate of patients with preoperative noninvasive adenoma based on MRI (77.1%), intraoperative noninvasiveness (72.5%), microadenoma (74.3%), pathological confirmation (76.4%), and first TSS (73.9%) was significantly higher than that in patients with preoperative invasive adenoma (53.0%), intraoperative invasiveness (60.7%), macroadenomas (65.9%), pathologically negative (49.7%), and repeat TSS (56.0%), respectively (all P < 0.05). The initial remission rate in patients with pseudocapsule-based extracapsular resection (88.1%), MRI-visible adenoma (74.2%) was higher than that in patients without pseudocapsule-based extracapsular resection (77.1%), and with MRI-negative results (64.5%), respectively, but did not reach statistical significance (All P > 0.05). Striking, there was no significant differences in initial remission rates between patients who underwent selective adenomectomy and enlarged adenomectomy (P > 0.05). Whereas, the initial remission rates in patients who underwent partial hypophysectomy only was 51.0%, which was much lower than that in patients underwent selective adenomectomy and enlarged adenomectomy (P < 0.05). The TSS is a safe and effective procedure for the treatment of CD. Whereas, preoperative invasiveness based on MRI, intraoperative invasiveness, macroadenomas pathologically negative, and repeat TSS are related to lower initial remission rates.

Perioperative Tranexamic Acid for ACTH-Secreting Pituitary Adenomas: Implementation Protocol Results and Trial Prospectus

Primary resection of adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma has become a front-line standard-of-care treatment for Cushing disease. However, surgical intervention can be challenging because of elevated blood pressure, as well as direct cortisol impacts on endothelial cells, vascular permeability, and tissue friability-potentially resulting in increased intraoperative bleeding. Tranexamic acid (TXA) is a well-studied, widely used intravenous hemostatic; however, the potential benefit during resection of ACTH-secreting pituitary adenoma is unstudied. The purpose of this study was to define an institutional protocol for perioperative administration of TXA in patients undergoing endoscopic endonasal approach for resection of ACTH-secreting pituitary adenoma, and to study the implementation of our novel protocol in a prospective fashion. Criteria for preoperative TXA were defined by age, medical history, and risk factors. Descriptive statistics were reported for all patients receiving perioperative TXA. Thirty patients met inclusion criteria and underwent perioperative administration of TXA, using a standardized dosing protocol of a 10 mg/kg bolus in 30 minutes prior to incision, followed by maintenance infusion of 2 mg/kg/hour for the duration of the procedure. No incidence of myocardial infarction or postoperative thromboembolic events were noted. Subjective assessments indicated satisfaction with the patient selection protocol, and meaningful reduction in the extent of intraoperative bleeding. Perioperative TXA represents a potentially efficacious approach for control of intraoperative bleeding during endonasal resection of ACTH-secreting tumors. Careful preoperative patient selection is emphasized, given the potential for thromboembolic complications; however, initial experience with our institutional protocol suggests a favorable risk/benefit profile when this treatment is applied judiciously.

Abstract #999926: Effect of Dosing and Titration of Osilodrostat on Efficacy and Safety in Patients With Cushing's Disease (CD): Results From Two Phase III Trials (LINC3 and LINC4)

Two Phase III studies (LINC3 NCT02180217; LINC4 NCT02697734), showed that osilodrostat, a potent oral 11β-hydroxylase inhibitor, is an effective treatment for CD. Reductions in cortisol levels during osilodrostat therapy can lead to hypocortisolism, which may be mitigated by slow dose uptitration. We assessed the effect of the different dose titration schedules in LINC3 and LINC4 on hypocortisolism-related AEs.

Is there a common cause for paediatric Cushing's disease?

According to recent literature, somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are the most common changes in patients with Cushing's disease (CD). Data on the frequency of these mutations in the paediatric population are limited. The aim of the presented study was to determine the frequency of the USP8 gene mutations in a group of paediatric patients with CD treated at the Children's Memorial Health Institute (CMHI). Eighteen patients (nine females) with CD were treated at CMHI, Warsaw, Poland between 1993 and 2019. All patients underwent transsphenoidal surgery (TSS) as a primary treatment for CD. The average age of all patients at TSS was 13.10 years (5.42-17.25). DNA was extracted from formalin-fixed paraffin-embedded resected tumour tissue. Sanger sequencing was performed on DNA sequence corresponding to the exon 14 of USP8 gene. The mean age at diagnosis of CD was 13.08 years, and the average duration of symptoms before diagnosis was 2.96 years. All patients were operated at CMHI by the same neurosurgeon. Fifteen out of 18 patients (83.33%) had initial biochemical remission after a single TSS procedure (post-operative serum cortisol < 1.8 μg/dL). The result of genetic testing was negative for all samples at the hotspot area of the USP8 gene. The current retrospective study demonstrates that mutations in the USP8 gene may not be as common a cause of paediatric Cushing's disease, as previously reported.

The quality of life in adult patients treated for Cushing's disease in childhood.

Numerous studies assessed the quality of life (QoL) of adult patients after Cushing's disease (CD) treatment. Available professional literature reveals that hypercortisolemia caused by CD may negatively impact the mood and social life. However, data on QoL of adult patients after CD treatment in childhood are scarce. Aim of the study: To study the QoL of adult patients treated for CD in childhood. Eighteen out of 29 adult patients diagnosed in childhood with CD and/or treated at one center participated in asurvey and completed WHO Quality of Life-BREF questionnaire. The influence of selected prognostic factors for the QoL has been analyzed. Patients data were compared with acontrol group with the same age and sex. Participants (10 women and 8 men) were at the mean age of 28.93 years (19.75-40.33). No significant difference in the QoL was noted between analyzed patients and controls. Patients with hypopituitarism had lower results in domain 4 in comparison with patients without hypopituitarism (p=0.31) and lower results in domain 2 in comparison with the control group (p=0.045). Patients with ahigher age at disease onset had lower results of the QoL in domain 1 (p=0.031). During long-term follow-up the QoL of patients after CD treatment in childhood is not significantly different wit QoL of healthy controls. Further studies are needed to expand the knowledge of factors that may contribute to the QoL in CD patients who were treated in childhood.

Pneumocystis pneumonia can complicate medical treatment of hypercortisolism even in outpatients with Cushing's disease

Several cases of Pneumocystosis pneumonia (PCP) have been reported in patients with hypercortisolism, mainly in patients with severe ectopic ACTH syndrome (EAS). We report 2 cases of PCP that did not develop until after starting treatment with metyrapone, one of which occurred in an outpatient with Cushing's disease (CD) without pulmonary symptoms before medical treatment for CD. Patient 1 presented as an outpatient with CD and severe hypercortisolism but nonetheless in good general condition. Treatment with metyrapone was started before pituitary surgery. Patient 2 had EAS due to prostate cancer. Respiratory failure in the two patients occurred 4 days and 30 days, respectively, after the start of metyrapone treatment. In both cases, chest CT showed bilateral interstitial infiltrates, and Pneumocystis jirovecii was found on bronchoalveolar lavage (BAL). A literature review was performed to identify risk factors for PCP in patients with CD: we identified 20 other cases of PCP in patients treated for hypercortisolism, including 16 patients with EAS. Ninety percent of patients had free urinary cortisol greater than 6 times the upper limit of normal (ULN). In conclusion, onset of PCP after initiation of anticortisolic therapy is not limited to patients with EAS, and may occur in CD patients with elevated cortisol levels, even if the patient remains in good general condition and has no pulmonary symptoms before treatment. In such patients, routine prophylactic treatment with trimethoprim/sulfamethoxazole (TMP/SMX) should be considered.