Habra, Mouhammed Amir

Abstract Disclosure: S.R. Chacko: None. C.A. Villavicencio Torres: None. K. Yu: None. S.G. Waguespack: None. L. Lu: None. Z. Belaya: None. T. Bandgar: None. A. Sada: None. O. Ragnarsson: None. B. Altieri: None. A. Newman: None. P. Vibhatavata: None. M. Tóth: None. E.V. Varlamov: None. C. Badiu: None. A. Paissan: None. M. St-Jean: None. H. Falhammar: None. N. Imamudeen: None. L. Haberbosch: None. M. Bobrowicz: None. A. Tabarin: None. R. Shah: None. M.R. Gadelha: None. A. Peersen: None. W.F. Young: None. J. Kaplan: None. J. Varghese: None. M.A. Habra: None. O. Golounina: None. G.A. Melnichenko: None. A.R. Lila: None. C. Yamichannaiah: None. I. Bancos: None. Context: Cushing syndrome (CS) due to ectopic ACTH secretion (EAS) is a rare condition, associated with severe hypercortisolism and consequent morbidity and mortality. Its varied and often emergent presentation make diagnosis and treatment challenging. Objectives: 1.Characterize clinical and biochemical presentation of EAS. 2.Describe the scope of hypercortisolism-related complications, overall and CS-specific mortality. 3.Identify factors associated with CS-specific mortality. Methods: We conducted a multicenter retrospective cohort study in patients with EAS at 37 centers. Outcomes were clinical/biochemical severity scores, complications, overall and CS-specific mortality. Results: In 1053 patients [median age at diagnosis 52 years (IQR 37-64), 57% women], metastatic disease was present at diagnosis in 585 (56%). The most common sources of EAS were bronchial neuroendocrine neoplasm (NEN) (304, 29%), pancreatic NEN (114, 11%) and small cell lung carcinoma (114, 11%), with the source of EAS being occult in 192 (18%). Clinical and biochemical severity scores were severe in 475 (45%) and 873 patients (92%) respectively. Hypokalemia was present in 819 patients (78%) in the year prior to diagnosis. Of 342 patients (32%) who had IPSS, 301 (88%) suggested an ectopic source, 7 (2%) a pituitary source, and 23 (7%) were non-diagnostic. Of 595 patients who had both functional and cross-sectional imaging, discordant findings were seen in 122 (21%), concordant lesion was seen on both in 326 (55%), and no lesion in 147 (25%). Of those with discordant results, cross-sectional imaging was accurate in 66 (54%) and functional imaging in 56 (46%).Management included medical therapy alone in 237 (23%), surgical excision of the source of EAS in 158 (15%), bilateral adrenalectomy in 77 (7%) and multimodal therapies in 498 patients (47%). Complications within 5 years after diagnosis included hospitalization related to CS or its therapy in 351 (33%), infection in 337 (32%), thromboembolic event in 102 (10%), cardiovascular event in 83 (8%) and cerebrovascular event in 27 (3%). During a median follow-up of 35 months (IQR 20-122) from CS diagnosis, death occurred in 462 patients (44%), with the cause of death related to CS in 149 (14%). CS-specific mortality was higher in metastatic compared with non-metastatic disease (19% vs. 7%, P<0.001). On multivariable analysis of age, sex, clinical and biochemical severity, older age (HR 1.03, 95% CI: 1.02-1.04) and lower clinical severity score (HR 0.97, 95% CI: 0.94-0.99), were associated with higher CS-specific mortality. Conclusion: Our interim analysis, the largest worldwide, found that most patients with EAS had severe hypercortisolism and hypokalemia. Metastatic disease was present in 56%, and the source of EAS was occult in 18%. CS-related death occurred in 14%, emphasizing the need for urgent management. Presentation: Monday, July 14, 2025

Abstract Context The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood. Objective To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC. Design and Setting We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American-Australian-Asian Adrenal Alliance collaborative research group. Patients Patients aged ≥18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019. Intervention Performance (or not) of cytoreductive surgery of the primary tumor. Main outcome and measures A propensity score match was done using age and the number of organs with metastasis (≤2 or >2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients. Results Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (hazard ratio [HR] = 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR = 1.02; 95% CI, 1.00-1.03), hormone excess (HR = 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR = 0.41; 95% CI, 0.47-0.65). Conclusion Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival.

Background There is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC. Methods A retrospective case series describing the use of LEN/PEM as salvage therapy in patients with progressive/metastatic ACC. Results Eight patients were treated with the LEN/PEM combination therapy. Half were female, and the median age at time of diagnosis was 38 years (range 21–49). Three (37.5%) patients had hormonally active ACC. The median number of prior lines of systemic therapy was 4 (range 2–9). Six (75%) patients had had disease progression on prior CPIs and five (62.5%) patients had progressed on prior MKI therapy. The median progression-free survival was 5.5 months (95% CI 1.8–not reached) and median duration of therapy was 8.5 months (range 2–22). Two (25%) patients had a partial response, one (12.5%) patient had stable disease, and five (62.5%) patients had progressive disease. None of the eight patients stopped therapy because of adverse events. Conclusions In our small cohort of heavily pretreated patients with ACC, the combination of LEN/PEM was associated with objective responses in a subset of patients without significant toxicity. This combination should be formally investigated in phase II clinical trial with robust correlative studies to identify predictors for response.

Abstract Objectives Localization of ectopic ACTH‐secreting tumours causing Cushing syndrome (ECS) is essential for clinical management, yet often difficult. [ 68 Ga]‐DOTATATE PET/CT ([ 68 Ga]‐DOTA‐(Tyr 3 )‐octreotate)] is an FDA‐approved high‐resolution diagnostic tool for imaging neuroendocrine tumours. Data on the clinical utility of [ 68 Ga]‐DOTATATE in patients with ECS, however, are scarce. The objectives of this study were to determine the efficacy for ECS localization and the clinical benefit of [ 68 Ga]‐DOTATATE imaging. Method We conducted a retrospective review of all cases with ECS evaluated with [ 68 Ga]‐DOTATATE from November 2016 through October 2018 at three referral centres. The clinical benefit of [ 68 Ga]‐DOTATATE was based on detection of new tumours and resultant changes in management. Results Over the study period, 28 patients with ECS underwent [ 68 Ga]‐DOTATATE: 17 for identification of the primary tumour and 11 during follow‐up. [ 68 Ga]‐DOTATATE identified the suspected primary ECS in 11/17 patients (65%). Of these, nine patients underwent surgery: eight with confirmed ECS (5 bronchial, 1 thymic, 1 pancreatic and 1 metastatic neuroendocrine tumour of unknown primary origin) and one patient with a false‐positive scan (adrenal gland). Of the 11 patients with ECS who underwent [ 68 Ga]‐DOTATATE evaluation during follow‐up, the study led to changes in clinical management in 7/11 (64%) patients. Conclusions [ 68 Ga]‐DOTATATE is sensitive in detecting primary and metastatic ECS, often identifies occult tumours after conventional imaging, and impacts clinical care in the majority of patients.

Adrenal cortical hyperplasia manifests radiologically as a non-malignant growth, or enlargement, of the adrenal glands, specifically the cortex, although the cortex cannot be definitively identified by conventional imaging. Controlled by the pituitary gland, the adrenal cortex drives critical processes, such as the production of cortisol, mineralocorticoid and sex hormones. Any disruption in the multiple enzymes and hormones involved in these pathways may cause serious or life-threatening symptoms, often associated with anatomical changes in the adrenal glands. Diagnosis and treatment of adrenal cortical hyperplasia requires a thorough clinical evaluation. As imaging has become more robust so has its role in the diagnosis and treatment of adrenal conditions. CT has been the primary modality for adrenal imaging owing to reproducibility, temporal and spatial resolution and broad access. MRI serves a complimentary role in adrenal imaging and can be used to further evaluate indeterminate CT findings or serve as an adjunct tool without the use of ionizing radiation. Ultrasound and fluoroscopy (genitography) are most commonly used in children and foetuses to evaluate congenital adrenal hyperplasia. This article will discuss the clinical presentation, laboratory workup and imaging features of adrenal cortical hyperplasia, both congenital and acquired.