ABSTRACT
Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is associated with significant mortality. The Val122Ile variant, highly prevalent in Black patients, portends poorer survival compared with other ATTR-CM subtypes. Although Val122Ile is biologically more aggressive, the contribution of race and socioeconomic status (SES) to disease outcomes in patients with ATTR-CM is undefined. Objectives: The aim of this study was to evaluate the impact of race and SES on clinical outcomes in patients with ATTR-CM. Methods: Patients with ATTR-CM who received care at Johns Hopkins Hospital between 2006 and 2022 were included. SES was assessed using area deprivation index (ADI). Associations of race and ADI with heart failure (HF) hospitalization and/or death were measured using multivariable logistic or Cox proportional hazards models. Results: Of 282 patients, 225 (80%) were men, and 129 (46%) were Black. Black vs White patients disproportionately constituted the highest ADI (most deprived) category (66% vs 28%; P = 0.004), and Black patients were more likely to have HF hospitalization or death over 5 years compared with White patients (log-rank P < 0.001). Among those with ADI >25, Black patients had a significantly greater hazard of HF hospitalization or death compared with White patients, independent of disease stage at diagnosis (HR: 2.77; 95% CI: 1.45-5.32; P = 0.002). Conclusions: Black patients with low SES may be at greater risk for underdiagnosis and adverse outcomes compared with White patients. Ongoing efforts are needed to improve outcomes in this subset of patients with ATTR-CM.
ABSTRACT
Brain radiation necrosis (RN) is a subacute or late adverse event following radiotherapy, involving an exacerbated inflammatory response of the brain tissue. The risk of symptomatic RN associated with stereotactic radiosurgery (SRS) as part of the treatment of brain metastases (BMs) has been a subject of recent investigation. The activation of the signal transducer and activator of transcription 3 (STAT3) was shown in reactive astrocytes (RA) associated with BMs. Given that the pathophysiological mechanisms behind RN are not fully understood, we sought to investigate the role of STAT3 among other inflammatory markers in RN development. A mouse model of RN using clinical LINAC-based SRS was designed to induce brain necrosis with the administration of 50 Gy in a single fraction to the left hemisphere using a circular collimator of 5 mm diameter. Immunohistochemistry and multiplex staining for CD4, CD8, CD68, GFAP, and STAT3 were performed. For validation, eleven patients with BMs treated with SRS who developed symptomatic RN and required surgery were identified to perform staining for CD68, GFAP, and STAT3. In the mouse model, the RN and perinecrotic areas showed significantly higher staining for F4/80+ and GFAP+ cells, with a high infiltration of CD4 and CD8 T-lymphocytes, when compared to the non-irradiated cerebral hemisphere. A high number of GFAP+pSTAT3+ and F4/80+pSTAT3+ cells was found in the RN areas and the rest of the irradiated hemisphere. The analysis of human brain specimens showed that astrocytes and microglia were actively phosphorylating STAT3 in the areas of RN and gliosis. Phosphorylated STAT3 is highly expressed in the microglia and RA pertaining to the areas of brain RN. Targeting STAT3 via inhibition represents a promising strategy to ameliorate symptomatic RN in BM patients undergoing SRS.
