Beta-adrenergic Blockade Research Articles

Nonselective beta blockade enhances gut microbiome diversity in a rodent model of trauma, hemorrhage, and chronic stress

BACKGROUND Traumatic injury leads to gut dysbiosis with changes in microbiome diversity and conversion toward a “pathobiome” signature characterized by a selective overabundance of pathogenic bacteria. The use of non-selective beta antagonism in trauma patients has been established as a useful adjunct to reduce systemic inflammation. We sought to investigate whether beta-adrenergic blockade following trauma would prevent the conversion of microbiome to a “pathobiome” phenotype. METHODS Sprague-Dawley rats (n = 6–8/group) were subjected to routine daily handling (naïve), lung contusion with hemorrhagic shock (LCHS), or LCHS with daily chronic stress (LCHS/CS), each with or without administration of intraperitoneal propranolol (BB) (10 mg/kg/day). Fecal microbiome was measured on Days 0, 7, and 14 using high-throughput 16S rRNA sequencing and QIIME2 bioinformatics analyses. Alpha- and beta-diversity and microbiome composition were assessed with significance defined as *p < 0.05. RESULTS Use of propranolol following LCHS or LCHS/CS demonstrated a significant increase in the number of bacterial species (Chao1 index), as well as overall richness and evenness (Shannon index) compared with their untreated counterparts at Day 7. By Day 14, these differences were no longer apparent between BB and untreated groups subjected to LCHS/CS. There was an abundance of commensal bacteria such as Oscillospiraceae and Clostridia in LCHS and LCHS/CS treated with BB after 7 days which persisted at 14 days. CONCLUSION These findings suggest a role for beta-antagonism in altering the diversity of the gut microbiome and the need for further studies to elucidate the cellular and molecular mechanisms underlying this intriguing connection of microbiome with trauma and beta-blockade.

Case report of laparoscopic adrenalectomy for a giant pheochromocytoma: medical and surgical challenge

Pheochromocytomas are rare adrenal tumors that can pose significant clinical challenges due to their potential for catecholamine release and hypertensive crises. We present a case of a large pheochromocytoma managed successfully through a laparoscopic adrenalectomy. A 66-year-old male presented with adrenal incidentaloma. Imaging revealed a sizable left adrenal mass (9.5 cm) consistent with a pheochromocytoma. Preoperative alpha- and beta-adrenergic blockade was initiated to optimize hemodynamic control. The patient underwent a laparoscopic adrenalectomy, with meticulous dissection and adrenal vein ligation to minimize catecholamine release during surgery. Post operatively, blood pressure and catecholamine levels normalized. Histopathological evaluation confirmed the diagnosis of pheochromocytoma with high pheochromocytoma of the adrenal gland scaled score (PASS) and grading of adrenal pheochromocytoma and paraganglioma (GAPP) scoring. Laparoscopic adrenalectomy proved to be a safe and effective approach for managing this large pheochromocytoma, resulting in improved blood pressure control and quality of life for the patient. This case underscores the importance of a multidisciplinary approach, including preoperative medical optimization and close postoperative monitoring, in the management of pheochromocytomas, and contributes to the growing body of evidence supporting laparoscopic techniques for these adrenal tumors.

8621 A Challenging Case of Preoperative Management of Pheochromocytoma Presenting With Recurrent Hypotension

Abstract Disclosure: N. Shripad: None. R. Osman: None. Introduction: Pheochromocytoma is a neuroendocrine tumor that clinically manifests due to the hypersecretion of catecholamines. Preoperative management typically involves alpha- and beta-adrenergic blockade. Patients commonly present with hypertension; however, in rare cases, patients may be hypotensive due to other comorbidities, posing a challenge to preoperative management. The following is a case of management of a pheochromocytoma with recurrent preoperative hypotension before the initiation of blood pressure-lowering agents. Case: A 47-year-old female presented to the hospital with dizziness and hypotension. The patient has a history of bilateral nephrectomy with left-sided adrenalectomy secondary to left-sided renal cell cancer and is hemodialysis-dependent. A right-sided pheochromocytoma was diagnosed a year ago on a follow-up CT scan done for monitoring renal cell cancer. The diagnosis was later confirmed with a DODATE scan and, eventually, a biopsy. Normetanephrine levels were between 581-735 pg/mL (0-88 pg/mL), with normal metanephrine levels. She denies having hyperadrenergic spells. She was started on metoprolol and doxazosin the year prior to presentation; however, she self-discontinued doxazosin after experiencing dizziness and palpitations on hemodialysis days. On admission, she was afebrile with a blood pressure of 103/66 mm Hg and a heart rate of 115 BPM. After an interdisciplinary decision was made for surgical resection, she was restarted on a lower dose of doxazosin (1 mg) and metoprolol was increased to the goal heart rate. Despite fewer hypotensive episodes on a reduced dose of doxazosin, the patient remained hypotensive on hemodialysis days. Salt tablets were started post-dialysis after clearance from nephrology, and an improvement in blood pressure was noted. She underwent a right adrenalectomy without receiving saline infusion before surgery due to concerns about volume overload. She was started on stress dose steroids due to her history of left adrenalectomy. She remained stable during and following surgery and did not require any vasopressor support. Discussion: Perioperative management of pheochromocytoma can be challenging in hypotensive patients and is poorly documented. Midodrine, an alpha-1 agonist that is typically used in dialysis-induced hypotension, is contraindicated in the setting of pheochromocytoma. We opted to manage our patient with a reduced dose of doxazosin and beta-blocker initially; however, with continued hypotensive episodes, the addition of salt tablets preoperatively on dialysis days helped to alleviate the hypotension. Although our patient did not require it, a preoperative overnight albumin infusion is a viable alternative to saline to prevent volume overload. Despite the limited literature, the patient was treated successfully through an interdisciplinary approach. Presentation: 6/3/2024

Resection of Secreting Right Carotid Body Paraganglioma: 2-Dimensional Operative Video

Secreting carotid body paragangliomas are very rare entities that account for less than 1% of all tumors of the head and neck region. 1-3 These vascular lesions splay the internal and external carotid arteries as they enlarge and cause increased catecholamine production in affected individuals. Surgical resection is definitive treatment, but preoperative embolization of the tumor can decrease its vascular supply and aid in surgery. Patients undergoing treatment require preoperative administration of alpha and beta adrenergic blockade to avoid intraoperative and postoperative complications. In this case, a 49-year-old woman presented with a growing neck mass compatible with a carotid body tumor. Preoperative MRI demonstrated a lesion splaying the external and internal carotid arteries. Angiogram demonstrated a vascular tumor, which was embolized before surgery. The patient consented to the procedure and the publication of her case and images. The University of Utah does not require Institutional Review Board approval for the presentation of a single case. This step-by-step video illustrates the surgical resection of her secreting right carotid body paraganglioma. Skull base neurosurgeons must understand the anatomy of vessels and nerves of the neck to safely and successfully resect such tumors.

Abstract 732: Toward optimizing CXCR4 inhibition with beta adrenergic blockade to enhance chemotherapy response in acute myeloid leukemia

Abstract Introduction: CXCR4 is a chemokine receptor for CXCL12 that plays a critical role in homing of hematopoietic stem cells (HSCs) to the bone marrow microenvironment. The CXCR4 inhibitor plerixafor is used to increase mobilization of peripheral blood stem cells in combination with filgrastim. This pathway has also been investigated for applications in hematologic malignancies such as acute myeloid leukemia (AML), including clinical trials, with the goal of disrupting AML from the protective marrow environment. These have included use of plerixafor with 7+3 or MEC, BL-8040 with cytarabine, and ulocuplumab with MEC. For the ulocuplumab trial, at the study site of the authors, CR/CRi correlated with >10% CXCR4 expression (Becker et al. ASH 2014). The objective of this preclinical study is to identify the AML patient population most likely to respond to CXCR4 inhibition, and the role of combined beta-adrenergic blockade, as the latter has been shown pre-clinically to augment mobilization of HSCs when combined with a CXCR4 inhibitor, GPC-100 (Sukhtankar et al. PLoS One, 2023). Procedures: AML patient samples (N=124 including 90 blood and 34 bone marrow samples, and 21 with both) were obtained with informed consent on an IRB approved protocol. Multicolor flow cytometry was performed with sequential gating on blasts (by FSC/SSC, CD45/SSC, CD34 or phenotype), and leukemia stem cells (LSCs:CD34+CD38−,CD123+), then analysis for CXCR4 and beta-2 adrenergic receptor (ADRB2) surface expression. Correlations between CXCR4 expression and clinical characteristics including age, gender, new diagnosis vs. relapse, ELN2022 risk, cytogenetics, FLT3/NPM1 mutation status, CR1 duration, and overall survival were performed. GraphPad Prism9 was used for statistical analysis, and Mann Whitney test (two groups) and ordinary one-way ANOVA (>2 groups) were used for comparisons. Results: The range of CXCR4 expression by AML blasts is 0.05 to 99.7% (median 13.1%; mean 16.2%), and by AML LSCs 0 to 99% (median 2%, mean 15.7%). The expression by blasts and LSCs for each patient exhibited tight correlation, R2=0.88 p=1.23 × 10e-25). There was higher % expression of CXCR4 by both blasts and LSCs for new diagnosis, as compared to relapsed, patient samples (p=0.002). There was no correlation between level of CXCR4 expression and the other clinical features. For a subset of 20 patient samples analyzed for both CXCR4 and ADBR2 expression by AML blasts, ADBR2 expression ranged from 0.4 to 20.1%. For the samples that express ADBR2, there was high level expression of CXCR4, range 35.9 to 98.7% (median 78.4%, mean 76%). Conclusion: These studies support further investigation of whether simultaneous blockade of CXCR4 and ADBR2 may potentiate chemotherapy response in AML by limiting microenvironment mediated chemotherapy protection and reveal that patients with new diagnosis may be more susceptible to this approach. Citation Format: Brenda Loera, Chunxiao Zhang, Pina M. Cardarelli, Niña G. Caculitan, Sylvia Chien, Jin Dai, Vivian G. Oehler, Jianying Zhang, Guido Marcucci, Pamela S. Becker. Toward optimizing CXCR4 inhibition with beta adrenergic blockade to enhance chemotherapy response in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 732.

Abstract PR-001: Beta-adrenergic blockade licenses the use of immunotherapy in primary brain tumors and brain metastases

Abstract Immunotherapy is less effective against intracranial metastases compared to extracranial metastases and ineffective against primary brain tumors such as glioblastoma. Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just locally at the tumor, but also outside the CNS. Importantly, systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Through this work we present a novel axis of immunosuppression in patients with intracranial tumors and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. We demonstrate that this survival benefit is driven by a remodeling of the tumor microenvironment, increasing NF-kB activity and resulting in an increase in cDC1s and CD8+ T cells, as well as an increase in CD40-CD40L signaling, suggesting the immune system is poised to respond to immunotherapy. Further, we demonstrate that beta-adrenergic blockade can overcome systemic immunosuppression to restore the capacity of T cells to respond to an immune stimulus. Using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently receiving beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of glioma, demonstrating that combining immunotherapy and propranolol, a widely prescribed FDA-approved beta-blocker, extended survival. Moving forward, we proffer that combination therapy with beta-blocker and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies. Citation Format: Selena Lorrey, Lucas Wachsmuth, Mackenzie Price, Corey Neff, Quinn Ostrom, Peter Fecci. Beta-adrenergic blockade licenses the use of immunotherapy in primary brain tumors and brain metastases [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-001.

A COMPARISON OF GUIDELINES FOR HEART TRANSPLANT CONSIDERATION BASED ON CPET DATA

https://youtu.be/tfol-46xG-o BACKGROUND The International Society for Heart and Lung Transplantation (ISHLT) recommends using peak oxygen uptake (VO2≤12 mL/kg/min), percent predicted peak VO2 (ppVO2≤50%), or the ventilation to carbon dioxide slope (VE/VCO2 slope>35) to guide listing for heart transplantation (HTx) in patients with heart failure with reduced ejection fraction (HFrEF). Data comparing the mortality rates between each of these thresholds is lacking. The purpose of this retrospective cohort study was to describe the 3-year mortality rate among patients with HFrEF based on the ISHLT recommendations. METHODS This was a secondary analysis of a combined cohort of patients (≥18 years) with HFrEF from Henry Ford Hospital (n=1,063) and the HF-ACTION study (n=1,772). The cohort was limited to patients who completed a cardiopulmonary exercise test on a treadmill and were prescribed a beta-adrenergic blockade at the time of the test. The primary outcome was probability of all-cause mortality at 3 years based on Kaplan-Meier estimates. Patients were censored at the date of HTx, left ventricular assist device implant, or last known alive. Mortality rates were calculated for patients with a peak VO2≤12 mL/kg/min, ppVO2≤50%, and VE/VCO2 slope>35. The cohort was stratified by sex, age, obesity (body mass index [BMI]> 30 kg/m2), and peak respiratory exchange ratio (RER). Mortality rates were compared to the 3-year mortality post HTx reported by ISHLT. RESULTS In our combined cohort (n=2,775; age=57±13 y; 19% women; 48% non-white), 3-year mortality for peak VO2≤12 mL/kg/min, ppVO2≤50%, and VE/VCO2 slope>35 was 30%, 31%, and 28%, respectively. Each of these are higher than the 3-year mortality post HTx (20%). Similar results were observed by age below/above 50 y, BMI < versus > 30 kg/m2, RER ≤ versus >1.05, and within men. However, among women the 3-year mortality was 18% for peak VO2≤12 mL/kg/min, 25% for ppVO2≤50%, and 21% for VE/VCO2 slope>35. CONCLUSIONS ISHLT recommendations to guide listing for HTx for peak VO2≤12 mL/kg/min, ppVO2≤50%, and VE/VCO2 slope>35 are associated with a higher 3-year mortality than patients post HTx irrespective of age, obesity, and RER. However, among women only ppVO2≤50% and VE/VCO2 slope>35 identify patients with 3-year mortality that is higher than HTx.

Beta-Adrenergic Blockade in Advanced Non-Small Cell Lung Cancer Patients Receiving Immunotherapy: A Multicentric Study.

Introduction The standard treatment of cancer has dramatically improved with immune checkpoint inhibitors (ICIs). Despite their proven advantage, many patients fail to exhibit a meaningful and lasting response. The beta-adrenergic signalling pathway may hold significant promise due to its role in promoting an immunosuppressive milieu within the tumour microenvironment.Inhibiting β-adrenergic signalling could enhance ICI activity; however, blocking this pathway for this purpose has yielded conflicting results. The primary objective of this study was to evaluate the effect of beta-blocker use on overall survival and progression-free survival during ICI therapy. Methods A multicentric, retrospective, observational study was conducted in four Portuguese institutions. Patients with advanced non-small cell lung cancer treated with ICIs between January 2018 and December 2019 were included. Those using beta blockers for non-oncological reasons were compared with non-users. Results Among the 171 patients included, 36 concomitantly received beta blockers and ICIs. No significant increase was found in progression-free survival among patients who took β-blockers (HR 0.74, 95% confidence interval (CI) 0.48-1.12, p = 0.151), and no statistically significant difference was found in overall survival. An apparent trend was observed towards better outcomes in the beta-blocker group, with a median overall survival of 9.93 months in the group not taking β-blockers versus 14.90 months in the β-blocker group (p = 0.291) and a median progression-free survival of 5.37 in the group not taking β-blockers versus 10.87 months in the β-blocker group (p = 0.151). Nine (25%) patients in the beta-blocker group and 16 (12%) in the non-beta-blocker group were progressive disease-free at the end of follow-up. This difference between the two groups is statistically significant (p = 0.047). Conclusion Our study found no statistically significant evidence that beta blockers enhance the effectiveness of immunotherapy. Using adrenergic blockade to modulate the immune system shows promise, warranting the need to develop prospective clinical studies.

Beta-adrenergic blockade increases pulmonary vascular resistance and causes exaggerated hypoxic pulmonary vasoconstriction at high altitude: a physiological study.

An increasing number of hypertensive persons travel to high altitude (HA) while using antihypertensive medications such as beta-blockers. Nevertheless, while hypoxic exposure initiates an increase in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), the contribution of the autonomic nervous system is unclear. In animals, beta-adrenergic blockade has induced pulmonary vasoconstriction in normoxia and exaggerated hypoxic pulmonary vasoconstriction (HPV) and both effects were abolished by muscarinic blockade. We thus hypothesized that in humans, propranolol (PROP) increases Ppa and PVR in normoxia and exaggerates HPV, and that these effects of PROP are abolished by glycopyrrolate (GLYC). In seven healthy male lowlanders, Ppa was invasively measured without medication, with PROP and PROP+GLYC, both at sea level (SL, 488m) and after a 3-week sojourn at 3454m altitude (HA). Bilateral thigh-cuff release manoeuvres were performed to derive pulmonary pressure-flow relationships and pulmonary vessel distensibility. At SL, PROP increased Ppa and PVR from (mean±SEM) 14±1 to 17±1mmHg and from 69±8 to 108±11 dyn s cm-5 (21% and 57% increase, P=0.01 and P<0.0001). The PVR response to PROP was amplified at HA to 76% (P<0.0001, P[interaction]=0.05). At both altitudes, PROP+GLYC abolished the effect of PROP on Ppa and PVR. Pulmonary vessel distensibility decreased from 2.9±0.5 to 1.7±0.2 at HA (P<0.0001) and to 1.2±0.2 with PROP, and further decreased to 0.9±0.2% mmHg-1 with PROP+GLYC (P=0.01). Our data show that beta-adrenergic blockade increases, and muscarinic blockade decreases PVR, whereas both increase pulmonary artery elastance. Future studies may confirm potential implications from the finding that beta-adrenergic blockade exaggerates HPV for the management of mountaineers using beta-blockers for prevention or treatment of cardiovascular conditions.

IMMU-49. BETA-ADRENERGIC BLOCKADE LICENSES THE USE OF IMMUNOTHERAPY IN PRIMARY AND METASTATIC BRAIN TUMORS

Abstract Immunotherapy is less effective against intracranial metastases compared to extracranial metastases and ineffective against primary brain tumors such as glioblastoma. Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just locally at the tumor, but also outside the CNS. Importantly, systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Through this work we present a novel axis of immunosuppression in patients with intracranial tumors and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success.Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. We demonstrate that this survival benefit is driven by a remodeling of the tumor microenvironment with an increase in cDC1s and CD8+ T cells, as well as an increase in CD40-CD40L signaling, suggesting the immune system is poised to respond. Further, we demonstrate that beta-adrenergic blockade can overcome systemic immunosuppression to restore the capacity of T cells to respond to an immune stimulus. Further, using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently receiving beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of glioma, demonstrating that combining immunotherapy and propranolol, a widely-prescribed FDA-approved beta-blocker, extended survival. Moving forward, we suggest that combination therapy with beta-blocker and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.

THU523 A Rare Case Of Functional Cervical Paraganglioma: Case Report

Abstract Disclosure: V.D. Oliveira: None. G.C. Vaccarezza: None. A.E. Vieira: None. N.M. Scalissi: None. A.R. dos Santos: None. P.R. Lazarini: None. A.B. Suehara: None. C. Olivati: None. J.V. Lima: None. INTRODUCTION: Head and neck paragangliomas (HNPGL) are rare tumors arising from cells associated with parasympathetic ganglia. Catecholamine hypersecretion is founded in less than 5% of the patients. Evidence is growing that about 50% of the HNPGL are associated with hereditary syndromes. CASE REPORT: Male patient, 34 years old, previously healthy, presented with a 1-year history of jaw pain and hypoacusis, associated with progressive symptoms of dysphagia, facial paralysis, dysphonia and hoarseness. He also had a 2-month history of hypertension and palpitations. On physical examination, the patient had deficits in cranial nerves (CN) VII, VIII, IX, X, XI and XII and blood pressure of 150x90mmHg. Head and neck MRI showed an expansive lesion occupying the right jugular foramen extending above the cistern at the cerebellopontine angle and below the carotid space in the ipsilateral infratemporal fossa, reaching 50% of the internal carotid artery and extending into the right internal auditory canal, suggestive of glomus jugulare paraganglioma. Laboratory examination showed normetanephrines 9.1 mmol/L (VR &amp;lt; 0.9), confirming catecholamine-secreting paraganglioma. Next Generation Sequence (NGS) genetic testing evaluating 24 genes (ATM, DLST, EGLN1, EGLN2, FH, EPAS1 (HIF2A), HRAS, KIF1B , MAX, MDH2, MEN1 , MERTK , MET, NF1, RET, SLC25A11, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53 and VHL) was positive for the pathogenic variant c.166_170del:p.(Pro56Tyfs*5) of the SHDB gene. Patient with no family history of paraganglioma. Alpha-adrenergic blockade was started with doxazosin and, after two weeks, beta-adrenergic blockade with propranolol. After 3 months, he underwent preoperative embolization 48 hours before surgery with total tumor resection. Patient did not require antihypertensive drugs after surgery. CONCLUSIONS: We reported a case of a young patient diagnosed with catecholamine secreting HNPGL that carries pathogenic variant of SHDB. Presentation: Thursday, June 15, 2023

FRI264 A Case Of Composite Pheochromocytoma And Ganglioneuroma

Abstract Disclosure: D. He: None. J. Pullman: None. S. Stefan: None. B.Y. Wong: None. Background: Pheochromocytomas are catecholamine-secreting tumors that arise from chromaffin cells in the adrenal medulla or paraganglia. Representing 1-9% of pheochromocytomas, composite pheochromocytomas are rare tumors composed of pheochromocytoma and neural tumor components such as neuroblastoma, ganglioneuroblastoma, ganglioneuroma or peripheral nerve sheath tumor1. We present a case of composite pheochromocytoma and ganglioneuroma. Clinical Case: A 69-year-old man presented with recurrent dyspnea at rest, diaphoresis and tachycardia. He was diagnosed with heart failure with reduced ejection fraction and management included metoprolol 50 mg daily. On work-up, he was incidentally found to have a 1.2 cm left upper lobe lung lesion and an indeterminate 2.4 cm right adrenal mass on CTA chest. PET/CT scan showed an intensely avid left upper lobe lung nodule and a right adrenal mass with mild FDG uptake (SUV max 3.8). MRI abdomen demonstrated a 3.1 cm right adrenal lesion with a mildly thickened enhancing rim and a central enhancing nodular component suspicious for pheochromocytoma, metastases, schwannoma or ganglioneuroma. He then had a stroke with mild residual right-sided weakness. Oncological work-up of his lung and adrenal lesions eventually directed tissue sampling to biopsy of the adrenal lesion and pathology was consistent with pheochromocytoma. Subsequent biochemical evaluation revealed elevated plasma metanephrines of 194 pg/mL (&amp;lt;= 57 pg/mL), plasma normetanephrines of 474 pg/mL (&amp;lt;= 148 pg/mL), 24-hour urine metanephrines of 389 mcg (90-315 mcg) and 24-hour urine normetanephrines of 428 mcg (122-676 mcg). Pre-operatively, he was placed on phenoxybenazmine 10 mg twice daily and metoprolol 62.5 mg every 8 hours. The patient then underwent right adrenalectomy. The tumor nodule was adherent to and dissected off the inferior vena cava. Pathology showed composite pheochromocytoma with a small component of ganglioneuroma. Conclusion: This rare case of a composite pheochromocytoma with ganglioneuroma was diagnosed through histopathology as composite pheochromocytomas are clinically and radiographically indistinguishable from pheochromocytomas1. Management of composite pheochromocytomas with ganglioneuroma is similar to the management of pheochromocytomas, and surgical resection remains the first line treatment. Combined alpha and beta-adrenergic blockade is recommended to prevent intraoperative hypertensive crisis. However, more studies are needed to further understand these rare composite pheochromocytomas.

FRI207 Challenges Of Pheochromocytoma Management In A Heart Failure Patient

Abstract Disclosure: M. Novitskaya: None. M. Sonbol: None. S. Jafri: None. J. Monye: None. E. Japp: None. Introduction: Successful management of pheochromocytoma in patients with heart failure requires a careful balance between blood pressure control and appropriate perioperative volume resuscitation. Clinical Case: A 38-year-old male with heart failure with reduced ejection fraction (EF 15-20%), HTN, and polysubstance use disorder presented with dyspnea and subsequent in-house PEA arrest. Whole body CT showed an incidental 7.3 cm left adrenal mass. Laboratory work-up was notable for elevated plasma free metanephrines 47.30 nmol/L (n&amp;lt;0.89) and normetanephrines 39.8 nmol/L (n&amp;lt;0.49). Medical management of presumed pheochromocytoma was initiated with doxazosin. Left and right heart catheterization showed elevated intracardiac filling pressures (mmHg): RA 10, RV 66/5 (12), PA 55/29 (43), PCWP 35. Subsequent coronary angiogram was aborted due to hypertensive emergency and flash pulmonary edema for which he required IV hydralazine 20 mg, furosemide 80 mg, labetalol 30 mg, verapamil 5 mg, nitroglycerin 800 mg bolus then gtt at 100 mcg/min to achieve hemodynamic stability. He reached the preoperative BP goal after up titration of doxazosin to 12 mg daily and carvedilol to 25 mg twice daily. He subsequently underwent left adrenalectomy. Intraoperatively, the patient’s abdomen was insufflated to 13 mmHg given his reduced EF, and he received 2 L crystalloid prior to adrenal vein division. After a left adrenalectomy, he developed hypotension despite receiving an additional 3 L crystalloid, and was started on norepinephrine, epinephrine, and vasopressin gtt. Postoperatively, he remained intubated for two days due to distributive shock. With continued diuresis, mean arterial pressure recovered to &amp;gt;65 mmHg and he was extubated. He was successfully discharged on metoprolol succinate 25 mg, spironolactone 25 mg and losartan 25 mg daily. Clinical Lessons: Preoperative management of pheochromocytoma involves alpha-adrenergic blockade followed by beta-adrenergic blockade to target a BP of &amp;lt;130/80. A high sodium diet is recommended after adequate alpha-adrenergic blockade, and volume resuscitation is started preoperatively due to vasodilation after adrenalectomy. Successful management of patients with pheochromocytoma and heart failure requires extra attention to BP and volume status. Our patient’s case was complicated by severe HTN during cardiac catheterization resulting in flash pulmonary edema, and postoperative hypotension requiring vasopressor support due to loss of circulating catecholamines. His estimated risk of morbidity/mortality from adrenalectomy was &amp;gt;25% due to these factors. Multidisciplinary collaboration among endocrinologists, cardiologists, anesthesiologists, surgeons, and perfusionists is crucial to optimize patient outcomes. This patient case adds to the literature in presenting a positive adrenalectomy outcome in a patient with heart failure. Presentation: Friday, June 16, 2023

Association of Discontinuing Preinjury Beta-Adrenergic Blockade Medications With Mortality in Severe Blunt Traumatic Brian Injury.

Beta-adrenergic receptor blocker (BB) administration has been shown to improve survival after traumatic brain injury (TBI). However, studies to date that observe a benefit did not distinguish between continuation of preinjury BB versus de novo initiation of BB. To determine the effect of continuation of preinjury BB and de novo initiation of BB on risk-adjusted mortality and complications for patients with TBI. Trauma quality collaborative data (2016-2021) were analyzed. Patients were excluded with hospitalization <48 hours, direct admission, or penetrating injury. Severe TBI was identified as a head abbreviated injury scale (AIS) value of 3 to 5. Patients were placed into 4 groups based on the preinjury BB use and administration of BB during hospitalization. Propensity score matching was used to create 1:1 matched cohorts of patients for comparisons. Odd ratios of mortality accounting for hospital clustering were calculated. A sensitivity analysis was performed excluding patients with AIS >2 injuries in all other body regions to create a cohort of isolated TBI patients. A total of 15,153 patients treated at 35 trauma centers were available for analysis. Patients were divided into 4 cohort groupings related to preinjury BB use and postinjury receipt of BB. The odds of mortality was significantly reduced for patients with a TBI on a preinjury BB who had the medication continued in the acute setting (as compared with patients on preinjury BB who did not) (odds ratio [OR], 0.73; 95% confidence interval [CI], 0.54-0.98; P = 0.04). Patients with a TBI who were not on preinjury BB did not benefit from de novo initiation of BB with regard to mortality (OR, 0.83; 95% CI, 0.64-1.08; P = 0.2). In the sensitivity analysis, excluding polytrauma patients, patients on preinjury BB who had BB continued had a reduction in mortality when compared with patients in which BB was stopped following a TBI (OR, 0.65; 95% CI, 0.47-0.91; P = 0.01). Continuing BB is associated with reduced odds of mortality in patients with a TBI on preinjury BB. We were unable to demonstrate benefit from instituting beta blockade in patients who are not on a BB preinjury.

SYST-05 BETA-ADRENERGIC BLOCKADE LICENSES THE USE OF IMMUNOTHERAPY IN PRIMARY AND METASTATIC BRAIN TUMORS

Abstract Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just at the tumor but also outside the CNS. The systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Brain tumor patients, particularly those with metastatic disease, represent a patient population that is on the rise and in need of targeted treatment approaches. Through this work we present a novel axis of immunosuppression in brain tumor patients and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. Using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently on beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of both glioma and melanoma brain metastases, demonstrating that combining immunotherapy and propranolol, a widely-prescribed FDA-approved beta-blocker, extended survival. Moving forward, we suggest that combination therapy with propranolol and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.

Among Patients Taking Beta-Adrenergic Blockade Therapy, Use Measured (Not Predicted) Maximal Heart Rate to Calculate a Target Heart Rate for Cardiac Rehabilitation.

Among patients in cardiac rehabilitation (CR) on beta-adrenergic blockade (βB) therapy, this study describes the frequency for which target heart rate (THR) values computed using a predicted maximal heart rate (HR max ), correspond to a THR computed using a measured HR max in the guideline-based heart rate reserve (HR reserve ) method. Before CR, patients completed a cardiopulmonary exercise test to measure HR max , with the data used to determine THR via the HR reserve method. Additionally, predicted HR max was computed for all patients using the 220 - age equation and two disease-specific equations, with the predicted values used to calculate THR via the straight percent and HR reserve methods. The THR was also computed using resting heart rate (HR) +20 and +30 bpm. Mean predicted HR max using the 220 - age equation (161 ± 11 bpm) and the disease-specific equations (123 ± 9 bpm) differed ( P < .001) from measured HR max (133 ± 21 bpm). Also, THR computed using predicted HR max resulted in values that were infrequently within the guideline-based HR reserve range calculated using measured HR max . Specifically, 0 to ≤61% of patients would have had an exercise training HR that fell within the guideline-based range of 50-80% of measured HR reserve . Use of standing resting HR +20 or +30 bpm would have resulted in 100% and 48%, respectively, of patients exercising below 50% of HR reserve . A THR computed using either predicted HR max or resting HR +20 or +30 bpm seldom results in a prescribed exercise intensity that is consistent with guideline recommendations for patients in CR.

POST HOC ERGO PROPTER HOC? NOT EVERYTHING THAT HAPPENS AFTER COVID-19 IS LONG COVID. OR, THE MANY MASQUERADES OF PHEOCHROMOCYTOMA

Objective: A seemingly endless list of symptoms and conditions are being labeled as long COVID or post-COVID syndrome, but not everything that happens after a COVID-19 episode can be attributed to it. We hereby present a clinical case in which pheochromocytoma was masquerading as long COVID. Design and method: Review of the patient's clinical record and the relevant literature. Results: A previously healthy, non-smoker, 57-year-old woman was admitted in October 2020 with fever, dyspnea and asthenia. She was diagnosed with SARS-CoV-2 bilateral bronchopneumonia and required oxygen therapy but not assisted ventilation or intensive care. Three months after discharge the patient was asymptomatic but in the two following years she progressively developed symptoms of confusion, dizziness, inability to concentrate, gait instability, tachycardia, palpitations, anxiety and insomnia. The syndrome was labeled as post-COVID and in March 2022 began treatment with alprazolam and propranolol. Subsequently she complained of severe non-pulsatile holocranial headache accompanied by vertigo, nausea and skin pallor. In October 2022 she was admitted in Emergency Care with a BP reading of 226/118 mmHg, HR 132 bpm, ECG: sinus rhythm without repolarization anomalies. She was referred to our Outpatient Hypertension Clinic for workup of suspected secondary hypertension. Physical exam: BMI 27.3 kg/m2, BP 156/94 mmHg, FC 112 lpm, normal cardiopulmonary auscultation, no murmurs or oedema. Lab: Plasma glucose, ionogram, lipid profile, blood count, free T4, TSH, aldosterone, renin, ARR, NT-pro-BNP: normal, metanephrines 876/1238 pg/mL, albuminuria 56 mg/g Cr. Echocardiography: slight LVH (13 mm septum and posterior wall) with preserved function. Abdominal CT: Left adrenal mass, 54 mm, hyperdense, heterogeneous. MIBG scintigraphy: hyperintense left adrenal uptake without additional anomalies. After standard presurgical conditioning the patient underwent laparoscopic adrenalectomy, uneventfully. Pheochromocytoma was pathologically confirmed, without suggestion of malignancy (Ki-67 &lt;2%). Three months afterwards the patient is normotensive and asymptomatic without medication, with normal plasma metanephrines. Conclusions: The clinical presentation of pheochromocytoma may be atypical and sometimes bizarre. Sustained hypertension may be absent, but the paradoxical hypertensive response to beta-adrenergic blockade is highly suggestive. Anyhow, a ‘post-COVID syndrome’ label may be masking unrelated and solvable serious diseases.

Combination beta-adrenergic blockade and immunotherapy for the treatment of primary and metastatic brain cancer.

e14017 Background: Brain tumors present a unique challenge to immunotherapeutic success, as immune responses in patients with brain tumors are suppressed both within the tumor microenvironment and peripherally. The systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Brain tumor patients, particularly those with primary brain tumors like glioblastoma, represent a population in dire need of more thoughtful, targeted treatment approaches. Through this work we present an immunosuppressive axis specifically activated in the context of intracranial malignancies that inhibits immunotherapeutic success in these patients. We demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. More specifically, beta-adrenergic signaling is known to suppress immune responses in various contexts. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. Methods: Using the SEER Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently on beta-blocker therapy. Results: We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of both glioma and melanoma brain metastases, demonstrating that combining immunotherapy and propranolol, a highly-prescribed FDA-approved beta-blocker, extended survival. Conclusions: Moving forward, we suggest that combination therapy with propranolol and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.

Beta1-receptor blockade attenuates atherosclerosis progression following traumatic brain injury in apolipoprotein E deficient mice.

Traumatic brain injury (TBI) is associated with cardiovascular mortality in humans. Enhanced sympathetic activity following TBI may contribute to accelerated atherosclerosis. The effect of beta1-adrenergic receptor blockade on atherosclerosis progression induced by TBI was studied in apolipoprotein E deficient mice. Mice were treated with metoprolol or vehicle following TBI or sham operation. Mice treated with metoprolol experienced a reduced heart rate with no difference in blood pressure. Six weeks following TBI, mice were sacrificed for analysis of atherosclerosis. Total surface area and lesion thickness, analyzed at the level of the aortic valve, was found to be increased in mice receiving TBI with vehicle treatment but this effect was ameliorated in TBI mice receiving metoprolol. No effect of metoprolol on atherosclerosis was observed in mice receiving only sham operation. In conclusion, accelerated atherosclerosis following TBI is reduced with beta-adrenergic receptor antagonism. Beta blockers may be useful to reduce vascular risk associated with TBI.

Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer.

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated β2-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or β2-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting β2-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive β2-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.