Citations

Abstract The OmicsFootPrint framework addresses the need for advanced multi-omics data analysis methodologies by transforming data into intuitive two-dimensional circular images and facilitating the interpretation of complex diseases. Utilizing deep neural networks and incorporating the SHapley Additive exPlanations algorithm, the framework enhances model interpretability. Tested with The Cancer Genome Atlas data, OmicsFootPrint effectively classified lung and breast cancer subtypes, achieving high area under the curve (AUC) scores—0.98 ± 0.02 for lung cancer subtype differentiation and 0.83 ± 0.07 for breast cancer PAM50 subtypes, and successfully distinguished between invasive lobular and ductal carcinomas in breast cancer, showcasing its robustness. It also demonstrated notable performance in predicting drug responses in cancer cell lines, with a median AUC of 0.74, surpassing nine existing methods. Furthermore, its effectiveness persists even with reduced training sample sizes. OmicsFootPrint marks an enhancement in multi-omics research, offering a novel, efficient and interpretable approach that contributes to a deeper understanding of disease mechanisms.

Abstract Disclosure: J. Saini: None. B. Bahrani Fard: None. M. Suresh: None. R. Sandooja: None. Y. Hleibiehova: None. E. Atkinson: None. S. Achenbach: None. I. Bancos: None. Background: Patients with endogenous hypercortisolism experience glucocorticoid withdrawal syndrome (GWS) following curative surgery. The symptoms of GWS include fatigue, weakness, muscle aches, joint pain, mood changes, and sleep disturbance. Limited interventions have been explored to alleviate the symptoms of GWS and improve patients’ quality of life. The use of meditation as an intervention has been reported to enhance postsurgical recovery in patients with other conditions and offers a promising intervention for GWS. Objective: To determine the impact of a portable, wearable, electroencephalographic device (MUSE headband device) used for guided meditation practices on the quality of life of patients in the first 12 weeks post-surgery for endogenous hypercortisolism. Methods: We conducted a single-center prospective longitudinal study of adults with endogenous hypercortisolism undergoing curative surgery between 2018 and 2024. The patients were enrolled before the surgical intervention and were followed for 2 years. Only patients who completed at least 4 weeks of follow-up were included. The study comprised of 2 groups; (1) The interventional group included consecutive patients who were offered a MUSE headband with instructions to meditate for at least 10 minutes per day for 3 months (MUSE cohort) and (2) the comparison group included age-, sex-, clinical score, hypercortisolism type, and BMI-matched 3:1 patients (Referent cohort). Quality of life and symptoms of GWS were assessed with AddiQoL and Short Form-36 (SF-36) surveys. Results: At least 4 weeks post-surgical follow-up was completed by 27 patients in the MUSE cohort and 81 referent subjects. Age (median 51 vs 47 years), women (82% vs 84%), BMI (median 31 vs 32 kg/m2), the subtype of hypercortisolism (pituitary 48% vs 52%), clinical (median 16 vs 15) and biochemical (median 6 vs 7) severity scores were similar between the two groups (P>0.05 for all). At baseline, AddiQoL score was similar in groups (median of 66 vs 70, P=0.083), though symptoms of fatigue (92.6% vs 69.1%, P=0.015) and lightheadedness (37% vs 17.3%, P=0.033) were more frequent in MUSE cohort. After 12 weeks, 20 patients using MUSE demonstrated improvement compared to 67 no muse patients in the SF-36 physical component (mean delta 3.9 (SD 11.77) vs -2.19 (SD 9.67), P=0.010). The physical functioning SF-36 subcomponent (4.94 (8.77) vs 0.92 (9.24), P=0.048) and body pain SF-36 subcomponent (2.69 (11.89) vs -3.69 (8.32), P=0.008) domains improved in the MUSE intervention group, when compared to referent cohort. No significant improvement in SF-36 mental component scores was seen in both groups. Conclusions: The use of wearable electroencephalographic device for meditation was associated with improvement in the quality of life of patients recovering from hypercortisolism, particularly in the domains of body pain and physical functioning. Presentation: 6/3/2024

Abstract Disclosure: J. Saini: None. R. Nathani: None. J. Larson: None. V. Fell: None. I. Bancos: None. Background: Surgical menopause due to bilateral salpingo-oophorectomy (BSO) at a younger age is associated with an increased risk of cardiovascular disease, cognitive decline, and increased mortality. Aging is associated with abnormalities in steroid metabolome, most notably an increased glucocorticoid to androgen ratio (“adrenal aging”). We hypothesized that in postmenopausal women of the same age, the duration of menopause is associated with adrenal aging. Objective: To determine the differences in the adrenal steroid metabolome of women with a history of BSO as compared to age-matched women following natural menopause. Methods: We conducted a single-center cross-sectional study in postmenopausal women with or without a history of BSO, between December 2020 to December 2022 Each participant collected 24-hour urine, which was analyzed for steroid profiling by liquid chromatography-tandem mass spectrometry (25 steroids). Exclusion criteria were inability to collect a 24h urine sample, exogenous glucocorticoid use, advanced malignancy, and chronic opioid use. Primary endpoints were glucocorticoid/androgen ratio, 11β-hydroxysteroid dehydrogenase type 2 activity (cortisol/cortisone, Tetrahydrocortisol (THF) + 5 α-tetrahydrocortisol (5 α-THF)/ Tetrahydrocortisone, THE) and 5 α-reductase type activity (Tetrahydrocortisol (THF)/5 α-tetrahydrocortisol (5 α-THF) and Etiocholanolone/Androsterone, Et/An). Results: A total of 245 women were enrolled: 124 women (median age of 66 years, IQR 63-72) with a history of BSO and 121 women (median age of 68 years, IQR 64-71) who underwent natural menopause (P=0.214). Median age at menopause was 44 years (IQR 41-46) in the BSO group, and 50 years (IQR 48-53) in the natural menopause group. History of hormone replacement therapy with estrogen was reported in 161 (66%) women, more frequently (92% vs 39%, P<0.001) and for a longer duration (median 12 years (IQR 6-16) vs 6 years (IQR 3-9), P<0.001) in in the BSO group, as compared to the natural menopause group. Although both groups had similar levels of urinary androgens (median 1387 vs 1686 mcg/24h, P=0.063) and total glucocorticoids (median 10877 vs 10277 mcg/24h, P=0.354), women with a history of BSO demonstrated a higher glucocorticoid/androgen ratio (median 7.9 (IQR 5.0-11.1) vs 6.7 (4.3-9.9), P=0.014), and a lower Et/An ratio (median 1.4 vs 1.6, P=0.045), but not THF/5aTHF ratio (median 1.7 vs 1.8, P=0.380) in comparison to women with natural menopause. No differences were found in other ratios. Conclusion: Women with a history of BSO demonstrated a higher glucocorticoid/androgen ratio in comparison to women undergoing natural menopause, suggestive of BSO-induced accelerated “adrenal aging”. Future studies need to examine associations between the abnormal steroid metabolome and increased cardiovascular morbidity, frailty, and mortality reported following BSO. Presentation: 6/3/2024

Abstract Disclosure: R.J. Auchus: Consulting Fee; Self; Neurocrine Biosciences, Inc., Crinetics Pharmaceuticals, OMass Therapeutics, H Lundbeck A/S, Adrenas Therapeutics. Research Investigator; Self; Neurocrine Biosciences, Inc., Diurnal, Crinetics Pharmaceuticals, Spruce Biosciences. O. Hamidi: Advisory Board Member; Self; Corcept Therapeutics, Recordati Rare Diseases, Amryt Pharma, Neurocrine Biosciences, Inc., Xeris, Lantheus. R. Pivonello: Advisory Board Member; Self; Corcept Therapeutics, Recordati AG, Crinetics Pharmaceuticals, H. Lundbeck A/S. Research Investigator; Self; Corcept Therapeutics, Recordati AG, Strongbridge Biopharma, Neurocrine Biosciences, Inc. I. Bancos: Consulting Fee; Self; Corcept Therapeutics, Recordati Rare Diseases, HRA Pharmaceuticals, Neurocrine Biosciences, Inc., Diurnal, Spruce Biosciences, Sparrow Pharmaceuticals, Adrenas Therapeutics. Research Investigator; Self; Recordati Rare Diseases. G. Russo: Advisory Board Member; Self; Novartis Pharmaceuticals, Sandoz, Diurnal. Speaker; Self; Novartis Pharmaceuticals, Sandoz, Diurnal. S.F. Witchel: Research Investigator; Self; Neurocrine Biosciences, Inc. A.M. Isidori: Research Investigator; Self; Pfizer, Inc., Merck Serono, HRA Pharmaceuticals, Recordati AG, Corcept. P. Rodien: Consulting Fee; Self; Pfizer, Inc., Novo Nordisk, Lilly USA, LLC, Ipsen, HRA Pharmaceuticals, IBSA Pharma, Recordati Rare Diseases. U. Srirangalingam: Advisory Board Member; Self; Diurnal. Speaker; Self; Diurnal. F.W. Kiefer: Advisory Board Member; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. Speaker; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. H. Falhammar: Consulting Fee; Self; Diurnal, Roche Diagnostics, Neurocrine Biosciences, Inc., H Lundbeck A/S, Adrenas Therapeutics. D.P. Merke: Research Investigator; Self; Diurnal, Adrenas Therapeutics, Neurocrine Biosciences, Inc. N. Reisch: Consulting Fee; Self; Diurnal, Crinetics Pharmaceuticals, Neurocrine Biosciences, Inc., Spruce Biosciences, H Lundbeck A/S. J. Sturgeon: Employee; Self; Neurocrine Biosciences, Inc. E. Roberts: Employee; Self; Neurocrine Biosciences, Inc. V.H. Lin: Employee; Self; Neurocrine Biosciences, Inc. J.L. Chan: Employee; Self; Neurocrine Biosciences, Inc. R. Farber: Employee; Self; Neurocrine Biosciences, Inc.. Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a genetic disorder characterized by cortisol deficiency and excess adrenal androgens, typically requires management with supraphysiological glucocorticoid (GC) doses. Crinecerfont is a novel oral CRF1 antagonist that reduced elevated adrenocorticotropic hormone and adrenal androgens in patients with 21OHD in 14-day open-label Phase 2 studies. This Phase 3 study (CAHtalyst: NCT04490915) evaluated whether crinecerfont can reduce daily GC dose while maintaining androgen control in adults with 21OHD. Methods: Adults (≥18 years) with 21OHD, stable GC regimens at doses >13 mg/m2/d in hydrocortisone equivalents (HCe), and normal or elevated androstenedione (A4) were randomized (2:1) to crinecerfont 100 mg BID or placebo for 24 weeks. GC dosing was maintained stable for 4 weeks, followed by a planned GC down-titration over 8 weeks to achieve a GC dose of 8-10 mg/m2/d. GC doses were adjusted as needed during the last 12 weeks to maintain A4 control (≤120% of baseline or ≤upper limit of normal [ULN]) by week 24. Results: In the 182 randomized participants (51% male, mean age 31 years), demographics and baseline characteristics were similar between treatment arms (122 crinecerfont, 60 placebo). Mean GC dose at baseline was 17.6 mg/m2/d HCe (32 mg/d), with 58% on HC alone, 29% taking predniso[lo]ne, and 13% taking dexamethasone; mean pre-GC A4 (620 ng/dL) was elevated >2-3-fold the ULN. Over 95% of participants completed the double-blind treatment period. At week 24, the crinecerfont arm had a significantly greater percent reduction in GC dose while maintaining A4 control vs placebo (-27% vs -10%; least squares mean difference [LSMD]: -17%; p<0.0001) (primary endpoint). At week 4 (end of GC-stable period), a greater reduction in A4 prior to the morning GC dose was observed with crinecerfont vs placebo (LSMD: -345 ng/dL; p<0.0001) (key secondary endpoint). At week 24, a higher percentage of participants reached a protocol-defined physiological GC dose (≤11 mg/m2/d) while maintaining A4 control with crinecerfont (63% vs 18% for placebo; p<0.0001) (key secondary endpoint). The most common treatment-emergent adverse events (AEs) in the crinecerfont arm were fatigue (25% vs 15% for placebo), headache (16% vs 15%), and COVID-19 (14% vs 9%). There were few serious AEs (3% overall), with none assessed as related to the study drug. Conclusions: Crinecerfont, an oral CRF1 antagonist, represents a novel treatment option to improve androgen control for patients with 21OHD. In the largest interventional Phase 3 study conducted to date in adults with 21OHD, crinecerfont led to a significant reduction in A4 while GC dose was stable, enabling a significant percent reduction in GC dose while maintaining A4 control at 24 weeks. Crinecerfont was overall well tolerated. Presentation: 6/1/2024

Abstract Disclosure: B. Graner: None. D.Z. Erickson: None. D. Donegan: None. Introduction: Pituitary lesions are a common incidental finding on brain MRI, the majority of which are cystic. The natural history and management of cystic pituitary lesions have not been clearly established. Purpose: The purpose of this study is to determine the natural history of incidentally identified cystic pituitary lesions, risk factors for growth and the proportion of patients who develop clinically significant symptoms requiring surgical intervention. Methods: Pituitary MRI reports between 01/01/2015 and 12/31/2022 in patients aged 18 years and older were searched for using Dig Our Radiology Information System (DORIS) using the words “cyst” or “cystic.” Additional inclusion criteria included a follow-up pituitary MRI of at least one year duration, clinical evaluation by Endocrinology, and the presence of a cystic pituitary lesion. Patients with non-contrast exams, excessive pituitary hormone secretion, and surgery within 1 year of presentation were excluded. Patient demographics, imaging characteristics of the lesion and clinical outcomes were collected. All pituitary MRI exams were reviewed by a single neuroradiologist. Results: A total of 157 MRIs in 56 patients with a mean age of 48 ±15 years were included, 39 (70%) were female. The mean follow-up was 2.3 ± 1.4 years. The most common indication for MRI was headache (n= 18, 32%). There was no significant difference in mean maximum (max) diameter at last follow-up compared to baseline (7.45 ±4.23 vs 7.04 ±4.35 mm, p=0.06) or mean cyst volume (197.08 ±252.68 vs 201.43 ±326.18 mm3). Nine (16%) of the lesions increased in volume with a mean change in volume of 105 ±133.64 mm3/yr, note 11 (20%) decreased volume and 36 (64%) remained the same size. Using univariate logistic regression, the odds of cyst growth was greater the larger the max diameter (p= 0.03) or volume was at baseline (p= 0.02)/ Female sex (p=0.32), age at diagnosis (p=0.70) or whether the lesion was thought to be a Rathke cleft cyst or a cystic adenoma (p=0.80) were not associated with increased odds of growth. The risk of growth was higher (42 vs 9%, p=0.016) and the volume change per year was greater (67.2 ±134 vs -7 ±28 mm3, p=0.04) in those with a baseline max diameter of >10 mm. Surgery was performed in 4 patients (7%), 3 of which demonstrated lesion growth (baseline size 12-15 mm and growth rates of 59-341mm3/yr). Pathology revealed one Rathke cleft cyst, one cystic adenoma and fibrotic pituitary changes. The fourth surgical patient opted for resection at an outside facility without a demonstrated increase in size (Rathke cleft cyst). Conclusion: The majority of incidentally found cystic pituitary lesions do not increase after an average follow-up 2-3 years. Growth necessitating surgical intervention was only required in 5% of patients over the study period. A pituitary cyst >10 mm at diagnosis was associated with an increased risk of growth and therefore warrants closer follow-up. Presentation: 6/1/2024

Abstract Disclosure: A.L. McKenna: None. S. Thota-Kammili: None. K. Grennan: None. S. Rao: None. It is known that thyroid dysfunction is an adverse effect of tyrosine kinase inhibitors (TKIs) via inhibition of the vascular endothelial growth factor receptor (VEGFR). The VEGF signaling pathway is important in regulating angiogenesis in tumors and normal tissue. As a highly vascularized gland, it is expected the thyroid may be compromised because of VEGFR inhibitors. Proposed mechanisms of thyroid dysfunction include capillary regression and constriction leading to reduced vascular perfusion to the gland. Bevacizumab is a monoclonal antibody that targets VEGF and inhibits activation of VEGFR, reducing angiogenesis; interestingly, this is not commonly reported in the literature. Here we present a case where bevacizumab altered thyroid function in a patient with pre-existing primary hypothyroidism. A 60-year-old woman presented with worsening hypothyroidism. She reported a history of nonautoimmune primary hypothyroidism diagnosed in her early 20s; she still had an intact thyroid with no history of head/neck radiation. In the months leading to the presentation, she had been receiving maintenance chemotherapy with 5 fluorouracil and bevacizumab every 2 weeks for metastatic duodenal carcinoma. Prior to starting chemotherapy, she had been on a steady dose of 112 mcg of levothyroxine (LT4) daily. After 6 months on chemotherapy, she reported symptoms of fatigue and hair loss. Workup revealed an elevated TSH of 41 mIU/L (reference 0.3-4.2 mIU/L). She denied any significant changes in weight or malabsorption issues. Aside from the chemotherapy, no other new medications were introduced. Her LT4 dose was increased to 137 mcg daily, and 3 months later, there was improvement in TSH to 6.5 mIU/L as well as her symptoms. At this point, bevacizumab was briefly on hold for 2 months due to an upcoming procedure, hence there was no change to LT4 to avoid over correction. Her TSH normalized and was trending lower while bevacizumab was on hold. Once bevacizumab resumed, LT4 was preemptively increased to 150 mcg daily. Four months after resuming bevacizumab, her TSH remains within the normal reference range on 150 mcg LT4. It is hypothesized that this VEGF blocker led to worsening of her underlying hypothyroidism.Given the shared down regulation in the VEGF signaling pathway, it would be expected that TKIs and monoclonal antibodies against VEGF would share similar adverse reactions to the thyroid. However, to our knowledge, there have been limited reports of bevacizumab induced thyroid dysfunction in the literature. Explanations to this may include the more targeted VEGF inhibition with bevacizumab versus the inhibition of multiple kinase receptors from the TKIs. Further research into this will be needed. This case demonstrates that bevacizumab can impact thyroid function and thyroid labs may need to be monitored at the onset and during VEGF inhibitor therapies. Presentation: 6/3/2024

Abstract Disclosure: O. Hamidi: Advisory Board Member; Self; Corcept, Neurocrine Biosciences, Amryt Pharma, Recordati Rare Diseases, Lantheus, Xeris. B.H. Salama: None. P. Dogra: None. A.P. Dackiw: None. F. Nwariaku: None. A. Islam: None. A. Mehta: None. S.C. Oltmann: None. S. Mirfakhraee: None. T. McKenzie: None. T.R. Foster: None. M. Lyden: None. B.M. Dy: None. I. Bancos: None. Introduction: Patients with mild autonomous cortisol secretion (MACS) are at risk for adrenal insufficiency (AI) after unilateral adrenalectomy. We aimed to determine the prevalence, predictors, and duration of AI after unilateral adrenalectomy for MACS, and to compare baseline and peak cortisol post cosyntropin stimulation test (CST) in diagnosing AI. Methods: We conducted a dual-center retrospective cohort study of patients with MACS who underwent unilateral adrenalectomy and were evaluated with postoperative cosyntropin stimulation test (CST). AI was diagnosed when postoperative morning cortisol was <10μg/dL and/or CST peak cortisol was <18μg/dL. Baseline and CST peak cortisol levels were considered concordant when both met corresponding cut-offs. Biochemical (BSS) and clinical (CSS) severity scores for hypercortisolism were calculated. Results: In 100 adults with MACS (77% women, median age 56 years, interquartile range [IQR] 48-63), median adenoma size was 2.8 cm (IQR, 2.2-3.7), and 25 (25%) had bilateral nodules. Median BSS was 3 (IQR, 2-5) and median CSS was 4 (IQR, 2-8). After adrenalectomy, AI was diagnosed in 56 (56%) patients. AI was associated with higher BSS, larger tumor size, but not age, sex, BMI, tumor laterality. Baseline and CST peak cortisol levels were concordant in 76% of cases. In 14% of cases morning cortisol was <10μg/dL but CST peak cortisol was ≥18μg/dL, and in 10% of cases morning cortisol was ≥10μg/dL, but CST peak cortisol was <18μg/dL. On a multivariable analysis that included age, sex, BMI, BSS, laterality, and tumor size, only higher BSS (odd ratio [OR] = 1.6 per 1 point) was associated with postoperative baseline cortisol <10μg/dL (P<0.05 for all). Independent predictors of CST peak cortisol <18μg/dL were BSS (OR 1.5 per 1 point) and unilateral adenoma (OR 3.7). During a median postoperative follow up of 13 months, 33 (59%) patients recovered from AI. Median time to recovery was 6.0 months, with AI recovery in 28% of patients by 2 months, 42% by 3 months, 53% by 6 months, and 64% by 12 months. Conclusions: Prevalence of postoperative AI in MACS was 56%. Only 76% of patients had concordant baseline and CST peak cortisol, with peak CST cortisol being more commonly abnormal in patients treated for unilateral MACS. Patients with larger adenomas and higher BSS were at higher risk for AI. Patients with MACS should be counseled about the risk and duration of AI after adrenalectomy. Presentation: 6/3/2024

Abstract Disclosure: J. Hewlett: None. S. Mohan: None. C.J. Davidge-Pitts: None. J. Abeykoon: None. R. Go: None. D.Z. Erickson: None. Objective: Erdheim-Chester Disease (ECD) is a multisystem histiocytic disorder which can infiltrate the pituitary gland, often leading to endocrine dysfunction. Central Arginine Vasopressin Deficiency (cAVP-D) commonly affects ECD patients, and those harboring BRAFV600E are reported to have an increased risk. Insufficient data exist about the risk associated with other mutations, and if cAVP-D or pituitary imaging improves with targeted therapies (TT). Methods: We conducted a review of a prospectively maintained database of adults with ECD treated at a tertiary center between 1992-2023. Objectives of this study were to identify mutations associated with cAVP-D and assess for improvement in cAVP-D (remission of disease or decrease in dose of desmopressin) or pituitary gland involvement (via MRI imaging) following TT for ECD. Results: Of 148 patients with ECD, the majority were male (98, 66.2%) and the mean age at diagnosis was 56.5 years [range: 19-82]. Median length of follow-up was 24 months (95% CI, 17 to 27). Of 121 (81.8%) patients with molecular testing results, 89 (73.6%) harbored a somatic mutation. 67 of 89 (75.3%) carried BRAF mutations, with BRAFV600E in 61 (91.0%) and missense mutations/fusions in 6 (9.0%). 22 of 89 (24.7%) patients harbored other somatic mutations, with MAP2K1 in 13 (14.6%) being the most common. 35 (23.6%) patients were diagnosed with cAVP-D, and the median onset of polyuria and polydipsia prior to diagnosis of ECD was 51 months (95% CI, -120 to -6). Molecular testing was performed in 28 patients with cAVP-D: 17 (60.7%) harbored BRAF mutation and 3 (10.7%) MAP2K1 mutation. There was no significant association between the presence of cAVP-D and MAP2K1 (p=0.69, 95% CI, -0.08 to 0.21). The association between cAVP-D and BRAF did not reach statistical significance (p=0.07, 95%CI, -0.03 to 0.38). Additionally, there was no association between BRAF and timing of cAVP-D symptoms before ECD diagnosis (p=0.08, 95% CI -163.4 to 10.3). Pituitary MRI was available in 32 patients with cAVP-D (91.4%) showing infundibular involvement in 17 (53.1%) and loss of the posterior bright spot in 5 (15.6%). 28 (80%) patients with cAVP-D received systemic therapy, 18 (64.3%) of whom received TT. One patient with cAVP-D was able to discontinue desmopressin. Improvement of pituitary MRI was noted in 7 (21.9%), among whom 4 received TT, 2 received systemic non-TT, and 1 was lost to follow-up. There was no significant MRI improvement associated with TT (p=0.67, 95% CI -0.30 to 0.42). Conclusion: In this large cohort of patients with ECD, of whom the majority underwent molecular testing, we identified no association between MAP2K1 mutation and cAVP-D, and no impact of TT on the clinical course or MRI findings associated with cAVP-D. BRAF mutation carriers were more likely to have cAVP-D and more likely to have onset of symptoms closer to ECD diagnosis, but the results did not reach statistical significance. Presentation: 6/2/2024

Abstract Disclosure: M. Fleseriu: Consulting Fee; Self; Novo Nordisk, Amryt Pharma Holdings Ltd, Ascend Therapeutics (A Besins Healthcare company). Speaker; Self; Xeris Pharmaceuticals, Inc., RECORDATI_RARE_DISEASES_INC., Ipsen Pharma SAS. S.L. Samson: Advisory Board Member; Self; Amryt. Research Investigator; Self; Amryt. N. Biermasz: Advisory Board Member; Self; Recordati, Pfizer Global R&D. Grant Recipient; Self; Macro Registry Grant, Amryt. C.J. Strasburger: Advisory Board Member; Self; Sandoz, Ipsen, Recordati. Consulting Fee; Self; Ascendis, Amryt, Novo Nordisk, Merck, Sandoz, Recordati. Speaker; Self; Ipsen, Novo Nordisk, HRA-Pharma. S. Fuchs Orenbach: Employee; Self; Chiesi Global Rare Diseases. J.A. Crompton: Employee; Self; Chiesi Global Rare Diseases. S. Melmed: Advisory Board Member; Self; Ionis, Crinetics. Consulting Fee; Self; Ipsen. Grant Recipient; Self; Pfizer. Background: Treatment with oral octreotide capsules (OOC) was evaluated in three phase 3 trials (CH-ACM-01, OPTIMAL, MPOWERED) in patients with acromegaly who previously tolerated and responded to the injectable somatostatin receptor ligands (iSRLs) octreotide and lanreotide. Results demonstrated efficacy and safety despite differences in trial design. Pooling data from all three trials can provide further insight into the biochemical response, symptom improvement, and safety profile of OOC. Objective: Analyze the biochemical changes, symptom control, and safety of OOC through a pooled analysis of phase 3 clinical trial datasets. Methods: Patients included were aged ≥18 years with acromegaly and responded biochemically to iSRL therapy before the initiation of OOC (defined as IGF-I <1.3 × ULN and mean integrated GH <2.5 ng/mL for CH-ACM-01 and MPOWERED, and IGF-I ≤1.0 × ULN for OPTIMAL). Data analyzed were from the following periods: baseline until the end of the double-blind placebo-controlled phase of OPTIMAL (36 weeks); the run-in phase of MPOWERED (26 weeks); end of dose escalation (2-5 months; efficacy data) and end of fixed dose phase (up to 7 months, safety data) for CH-ACM-01. Effect of prior iSRL dose was analyzed using a random effects meta-analysis. Symptom severity was scored using the Acromegaly Index of Severity (AIS) tool. Results: Efficacy, symptom, and safety data were available for 318, 194, and 329 patients, respectively. The overall response rate was 65% with no effect of prior iSRL dose (p>0.05). Mean (SD) IGF-I change from baseline was +0.17 (0.32; n=214), +0.19 (0.39; n=81), and +0.22 (0.57; n=23) for patients with baseline IGF-I levels ≤1 × ULN, 1 to <1.3 × ULN, and ≥1.3 × ULN. Twenty percent (16/81) and 35% (8/23) of patients with baseline IGF-I of 1 to <1.3 x ULN and ≥1.3 x ULN shifted to an improved category of response. There was a median decrease of one symptom per patient (p<0.05) and a mean decrease of 0.8 in AIS (p<0.05). The proportion of OOC responders reporting ≤1, 2, or 3 moderate/severe acromegaly symptoms at baseline and month 6 decreased from 56% to 39%, 32% to 20%, and 20% to 12%. At month 6, improvement was seen for all individual symptoms (joint pain, swelling, sweating, fatigue, headache) of moderate/severe grade and was significant for joint pain (36% to 22%) and swelling (15% to 10%) (p<0.02). Most adverse events (AEs) were gastrointestinal (GI) in nature (54%, n=179/329) with a median onset and duration of 15 and 12 days for first reported GI events. Conclusion: Pooled analysis confirms overall maintenance of biochemical control in patients previously responding to iSRL therapy, with decreased symptom burden in OOC responders. OOC was generally well tolerated with no new safety signals. GI-related AEs were largely transient. These results support OOC as a therapeutic option for treating acromegaly. Presentation: 6/3/2024

Abstract Disclosure: C.A. Villavicencio Torres: None. I. Bancos: None. Background: Adrenocortical carcinoma (ACC) is a rare malignancy with an estimated annual incidence of 0.7-2 cases per million per year. Scarce data are available on rare histological variants of ACC. Objective: To describe the clinical presentation and outcomes of patients diagnosed with oncocytic, sarcomatoid and myxoid ACC variants. Methods: Retrospective single center cohort study, 1992-2021 of patients with rare histological ACC variant. Results: A total of 20 patients were diagnosed with oncocytic (17, 85%), sarcomatoid (2, 10%), or myxoid (1, 5%) ACC. Median age of diagnosis was 47 years (range 17-80), and 14 (70%) were women. All patients had unilateral ACC (12, 60% left) with a median tumor size of 11 cm (range 4-29). Adrenal hormone excess was documented in 10 (50%) patients, mostly with either glucocorticoid or androgen excess. ENSAT stage I, II, III, and IV was documented in 2 (10%), 10 (50%), 6 (30%), and 2 (10%) patients, respectively. All patients were treated with adrenalectomy (laparoscopic in 5 and open in 15). In addition, patients were treated with mitotane (10, 50%), radiation (7, 35%), and chemotherapy (5,25%). Mitotane was administered for a median of 12 months (range 4-31) and was discontinued mainly due to side effects in 9 (90%) patients. Patients were followed for a median follow up of 6.5 years (range 0.4-12). In addition to 2 patients who presented with ENSAT stage IV metastatic disease, metastatic disease developed in additional 6 (30%) patients who initially presented with localized ACC (3 stage 2, 3 stage 3, 5 oncocytic, 1 sarcomatoid). Metastatic sites included lung (n=2), omentum (n=1), duodenum (n=1), liver (n=4), and bones (n=1). At the end of follow up, 11 (55%) patients remained disease free (53% oncocytic, 50% sarcomatoid, 100% myxoid), 5 (25%) patients were alive with metastatic ACC (23% oncocytic, 50% sarcomatoid), and 4 patients died of ACC (median time to death 21 months (range 10-50) post-adrenalectomy). Conclusions: Patients with oncocytic, sarcomatoid, and myxoid ACC may have a better prognosis than in reported literature. Larger multicenter studies are needed to identify patient and tumor-specific factors that guide management to assure improved outcomes in these very rare patients. Presentation: 6/2/2024