Scott & White Memorial Hospital

Abstract Disclosure: M. Ahmed: None. A. Patel: None. S. Simon: None. Introduction: Adrenal hemorrhage in the context of Cushing’s syndrome is a rare but significant complication. There are many causes that can lead to adrenal hemorrhage, including adrenal tumors, coagulopathies, or infectious disease. Therefore, it is often difficult to determine the etiology. This report explores the case of a patient with cushingoid features presenting with spontaneous left adrenal hemorrhage. Case Presentation: A 47-year-old man with a history of hypertension and clinical features of Cushing’s syndrome, including abdominal striae, dorsal fat pad and 80-lb weight gain, presented with left upper quadrant and left flank pain. CT findings were consistent with active hemorrhage in the left upper quadrant, suspicious for an adrenal mass or nodule in origin. The patient underwent left superior adrenal artery embolization. Repeat CT Abdomen/Pelvis three days after embolization showed a stable left adrenal hematoma. Endocrinology and Infectious Disease were consulted to evaluate the etiology of the adrenal hemorrhage. Infectious work up which included HIV, hepatitis, fungal antibodies, Tb, CMV, Typhus, were all negative. Notable labs included an elevated 24-hour urine cortisol, normal salivary cortisol level, elevated cortisol level after a high dose dexamethasone suppression test, decreased ACTH levels, normal serum metanephrines and elevated serum normetanephrines. These findings indicated an adrenal source of excessive cortisol production. Given the acute presentation, lab and imaging findings, the differential diagnosis included adrenal adenoma, pheochromocytoma, or adrenocortical carcinoma. The patient was scheduled for outpatient monitoring and treatment, including repeat CT imaging and consultation to discuss left adrenalectomy. Discussion: Adrenal hemorrhage is rare and can result from a variety of causes. Literature review shows abdominal trauma, infections, surgery, angiography, adrenal venous thrombosis, adrenal tumors, coagulopathy, antiphospholipid syndrome, pheochromocytoma, and ACTH administration as some of the possible etiologies. This report explores the pathophysiology of adrenal artery rupture in the setting of Cushing’s syndrome. Various mechanisms, including vascular fragility, hypertension, increased intra-adrenal pressures from adenomas, arteriosclerotic changes and potential thrombosis, can contribute to the increased risk of hemorrhage. In summary, this case highlights the importance of considering the risk of adrenal hemorrhage in patients with adrenal masses and/or hypercortisolism. Detailed hormonal and imaging evaluations are crucial for accurate diagnosis and management. Presentation: Saturday, July 12, 2025

Abstract Racial disparities in triple-negative breast cancer (TNBC) outcomes have been reported. However, the biological mechanisms underlying these disparities remain unclear. We integrated imaging mass cytometry and spatial transcriptomics, to characterize the tumor microenvironment (TME) of African American (AA) and European American (EA) patients with TNBC. The TME in AA patients was characterized by interactions between endothelial cells, macrophages, and mesenchymal-like cells, which were associated with poor patient survival. In contrast, the EA TNBC-associated niche is enriched in T-cells and neutrophils suggestive of an exhaustion and suppression of otherwise active T cell responses. Ligand-receptor and pathway analyses of race-associated niches found AA TNBC to be “immune cold” and hence immunotherapy resistant tumors, and EA TNBC as ‘inflamed’ tumors that evolved a distinctive immunosuppressive mechanism. Our study revealed the presence of racially distinct tumor-promoting and immunosuppressive microenvironments in AA and EA patients with TNBC, which may explain the poor clinical outcomes. Statement of Significance We have uncovered distinct tumor-promoting and immunosuppressive microenvironments that may contribute to the observed disparities in patient outcomes. Our findings lay the groundwork for developing race-specific therapeutic interventions, potentially improving outcomes for patients with TNBC. Given that chemotherapy and anti-PD1 therapy are currently available treatments for TNBC, our finding of race-specific spatial multicellular niche-associated cell-cell interactions suggest that these treatments may have racially distinct response profiles among TNBC patients. Hence, our novel insights on molecular and cellular interactions in TNBC stratified by race has the potential to inform personalized treatment strategies. Citation Format: Qian Zhu, Akhila Balasubramanian, Jaya Ruth Asirvatham, Badrajee Piyarathna, Jaspreet Kaur, Nada Mohamed, Ling Wu, Megha Chatterjee, Stacy Wang, Niloufar Pourfarrokh, Uttam Rasaily, Yitian Xu, Junjun Zheng, Deborah Jebakumar, Arundathi Rao, Shu-hsia Chen, Yi Li, Eric Chang, Xiaoxian Li, Ritu Aneja, Xiang H.-F. Zhang, Arun Sreekumar. Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5320.

<div>Abstract<p>We hypothesized that signaling through multiple mitogen-activated protein kinase (MAPK) kinase (MKK) pathways is essential for the growth and vascularization of soft-tissue sarcomas, which are malignant tumors derived from mesenchymal tissues. We tested this using HT-1080, NCI, and Shac fibrosarcoma-derived cell lines and anthrax lethal toxin (LeTx), a bacterial toxin that inactivates MKKs. Western blots confirmed that LeTx treatment reduced the levels of phosphorylated extracellular signal-regulated kinase and p38 MAPK <i>in vitro</i>. Although short treatments with LeTx only modestly affected cell proliferation, sustained treatment markedly reduced cell numbers. LeTx also substantially inhibited the extracellular release of angioproliferative factors including vascular endothelial growth factor, interleukin-8, and basic fibroblast growth factor. Similar results were obtained with cell lines derived from malignant fibrous histiocytomas, leiomyosarcomas, and liposarcomas. <i>In vivo</i>, LeTx decreased MAPK activity and blocked fibrosarcoma growth. Growth inhibition correlated with decreased cellular proliferation and extensive necrosis, and it was accompanied by a decrease in tumor mean vessel density as well as a reduction in serum expression of angioproliferative cytokines. Vital imaging using high-resolution ultrasound enhanced with contrast microbubbles revealed that the effects of LeTx on tumor perfusion were remarkably rapid (<24 h) and resulted in a marked reduction of perfusion within the tumor but not in nontumor tissues. These results are consistent with our initial hypothesis and lead us to propose that MKK inhibition by LeTx is a broadly effective strategy for targeting neovascularization in fibrosarcomas and other similar proliferative lesions. [Mol Cancer Ther 2008;7(3):648–58]</p></div>

Gulf War Illness (GWI) has been reported in 25%-35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal models, the exposure to PB and permethrin resulted in similar changes in the gut microbiome as these found in GW veterans with GWI. Studies using animal models have also shown that phytochemicals like curcumin are beneficial in reducing the symptoms and that the extracellular vesicles (EV) released from gut bacteria and from the intestinal epithelium can both promote diseases and suppress diseases through the intercellular communication mechanisms. The intestinal epithelium cells produce EVs and these EVs of intestinal epithelium origin are found to suppress inflammatory bowel disease severity, suggesting the benefits of utilizing EV in treatments. On the contrary, EV from the plasma of septic mice enhanced the level of proinflammatory cytokines in vitro and neutrophils and macrophages in vivo, suggesting differences in the EV depending on the types of cells they were originated and/or influences of environmental changes. These studies suggest that targeting the EV that specifically have positive influences may become a new therapeutic strategy in the treatment of veterans with GWI.

BackgroundReversion of activated hepatic stellate cells (HSCs) to quiescence is likely to be a promising pathway in liver fibrosis regression. The development of senescence in HSCs during alcoholic liver injury may lead to liver compensation against fibrosis. The current study aims to characterize the functional role of miR‐34a regulated cellular senescence during alcohol‐associated hepatitis.MethodsSenescence related gene and miR‐34a expression was assessed using a PCR Array and/or real‐time PCR analysis. Cellular senescence in cultured HSCs were measured by SA‐β‐gal staining. Senescence mediators were defined in LPS treated hepatic stellate cells in vitro, and in TLR‐4 knockout mice or morpholino antisense oligomer against miR‐34a (miR‐34a Morpho/AS) treated mice with chronic ethanol feeding in vivo.ResultsWe identified that 5 weeks of ethanol feeding significantly increased the total liver histopathology score and miR‐34a expression, along with the activation of hepatic stellate cells marked by enhanced α‐SMA staining. Treatment of HSCs with LPS (20 ng/ml) for 24 hr significantly increased miR‐34a expression, along with the enhanced SA‐β‐gal activity, up‐regulated α‐SMA/Collagen A1 expression and increased cellular viability. Silencing of miR‐34a decreased LPS‐induced activation in HSCs by downregulation of fibrosis markers α‐SMA, Col1a1 and TIMP‐1, and increased SA‐β‐gal activity as well as the cellular senescence marker CCl2, whereas silencing of the LPS receptor, TLR4, decreased this marker in the same group of HSCs, suggesting anti‐miR‐34a reversed LPS‐mediated HSC activation through inducing cellular senescence. Furthermore, the expression of miR‐34a and verified miR‐34a related senescence marker CCl2 were significantly altered in hepatic stellate cells from ethanol‐fed mouse liver specimens compared to controls. TLR4 knockout mice and miR‐34a Morpho/AS treated mice displayed less sensitivity to alcoholic injury, along with enhanced SA‐β‐gal activity and CCl2 level in HSCs, and recovered expressions of α‐SMA, Col1a1 and TIMP‐1. Summary andConclusionOur results show that miR‐34a mediated cellular senescence is essential for the potential reversion from activated to quiescent hepatic stellate cells during alcohol‐associated hepatitis. These findings provide new insight into the function of microRNA regulatedcellular senescence in human HSCs and increase opportunities for the development of novel treatment paradigms for the management of alcohol‐associated liver diseases.

As left atrial appendage occlusion devices (LAAO) implantation rates grow, continued evaluation on best patient practices is important. We report pooled Watchman outcomes at a multicenter Texas healthcare system with an emphasis on clinical outcomes and post-implantation anticoagulation with direct oral anticoagulants (DOACs) versus warfarin. Data for 163 patients with atrial fibrillation (AF) undergoing Watchman implantation was collected via retrospective chart review between June 2016 and June 2018. A Fisher's exact test was utilized to evaluate associations in bivariate comparisons of categorical data. Tests of non-inferiority, applied between DOACs and warfarin, utilized a ratio of 2. Outcomes were significant for similar rates of stroke, disabling stroke, major bleeds, and all-cause mortality when compared to published clinical trials. Most patients with cerebrovascular events were found to have >5mm peri-device leaks (PDLs), were on warfarin at the time of the event (75%), and all occurred within the first 6months post implant. A significant number of patients were discharged on DOACs (42%). DOACs were shown to be non-inferior to warfarin with respect to stroke (p = 0.0048), disabling stroke (p = 0.0383), gastrointestinal bleeding (p = 0.0287), mortality (p = 0.0165), and combined adverse outcomes (p = 0.0040). DOACs were associated with less combined adverse outcomes (p = 0.021). Our findings suggest that additional imaging or aggressive management of PDLs in Watchman recipients within the initial 6-month follow-up may aid in reducing stroke rates. Additionally, anticoagulation with DOACs' post Watchman implantation was found non-inferior to warfarin, with some evidence of lower risk for adverse outcomes favoring DOACs.

TPS586 Background: Chemoradiotherapy(CRT) is a SOC for patients with muscle invasive bladder cancer (MIBC) who refuse or are not fit for radical cystectomy. Radiotherapy and chemotherapy are known to increases the PD-L1 expression in bladder cancer. Based on these observations, we hypothesized that addition of atezolizumab to CRT will increase its efficacy. Methods: This is a randomized phase III trial testing CRT with and without atezolizumab for 6 months in 475 patients with MIBC. Pts will be stratified on performance status (0-1 vs. 2); clinical stage (T2 vs T3/T4a, chemotherapy(cisplatin vs 5FU+mitomycin vs gemcitabine); and radiation field (bladder only vs small pelvis). Patients will undergo biopsy 18 week from registration. If they have residual disease they will be taken off protocol treatment and can proceed with alternative SOC option including radical cystectomy. Patients will be followed for 5 years. The primary end point of the study is bladder intact event –free survival (BIEFS). The event is comprised of: recurrence or residual muscle-invasive bladder cancer at 18 weeks or later, clinical evidence of nodal or metastatic disease, radical cystectomy, or death due to any cause. This composite endpoint is reflective of the intent of bladder preservation strategy with radical cystectomy included as one of the outcomes. Secondary end points include overall survival, modified event free survival, pathologic response at 18 weeks, metastasis free survival, cancer specific survival, rate of salvage cystectomy, rate of adverse event and QOL & PRO end points. The expected 3 year BIEFS for the control arm is 52%. The study leadership concluded that a 12% improvement in this endpoint is meaningful for this patient population. With a sample size of 475 patients the study has 85% power to detect the improvement from 52% to 64% in the BIEFS at 3 years (hazard ratio=0.68). The study team will perform translational studies evaluating tumor tissue, whole blood and urine for molecular and immunologic markers of immune response and response to RT. Successful completion of this trial could lead to a new treatment paradigm for patients with muscle invasive bladder cancer. Clinical trial information: NCT03775265.