Prolonged Surgical Interval Following Chemotherapy in a Patient With Idiopathic Subglottic Stenosis (iSGS): Case Report and Brief Review of Literature

Objective: To report a case of a patient with idiopathic subglottic stenosis (iSGS) who no longer required surgical intervention for her disease following a chemotherapy regimen of carboplatin and doxorubicin for ovarian cancer. A brief review of the literature and discussion on the possible mechanism of action of chemotherapy agents affecting fibrosis is included. Methods: Case report and review of literature. Results: A 71-year-old Caucasian woman with iSGS was managed with serial endoscopic excision and dilation (n = 5) from 2013 to 2017 with an average dilation interval of 12.3 months. After a course of doxorubicin and carboplatin to treat her ovarian cancer, we observed that her airway stenosis surprisingly stabilized, and has no longer required a surgical dilation for 45 months, which signifies an increase of 33 months when compared to her averaged dilation interval (12.3 months) prior to her second course of chemotherapy. Conclusion: We present an iSGS patient whose fibrosis was arrested following carboplatin/doxorubicin treatment. While a single case, a possible mechanism is carboplatin/doxorubicin’s inhibition of pathologic CD4 lymphocytes that propagate laryngotracheal fibrosis. Further investigation of like mechanisms may allow for translation of local agents with inhibitory effects on CD4+ cells and/or fibroblasts as a novel therapy for airway fibrosis.

Intracellular Water Lifetime as a Tumor Biomarker to Monitor Doxorubicin Treatment via FFC-Relaxometry in a Breast Cancer Model

This study aims to explore whether the water exchange rate constants in tumor cells can act as a hallmark of pathology status and a reporter of therapeutic outcomes. It has been shown, using 4T1 cell cultures and murine allografts, that an early assessment of the therapeutic effect of doxorubicin can be detected through changes in the cellular water efflux rate constant kio. The latter has been estimated by analyzing the magnetization recovery curve in standard NMR T1 measurements when there is a marked difference in the proton relaxation rate constants (R1) between the intra- and the extra-cellular compartments. In cellular studies, T1 measurements were carried out on a relaxometer working at 0.5 T, and the required difference in R1 between the two compartments was achieved via the addition of a paramagnetic agent into the extracellular compartment. For in-vivo experiments, the large difference in the R1 values of the two-compartments was achieved when the T1 measurements were carried out at low magnetic field strengths. This task was accomplished using a Fast Field Cycling (FFC) relaxometer that was properly modified to host a mouse in its probe head. The decrease in kio upon the administration of doxorubicin is the result of the decreased activity of Na+/K+-ATPase, as shown in an independent test on the cellular uptake of Rb ions. The results reported herein suggest that kio can be considered a non-invasive, early and predictive biomarker for the identification of responsive patients immediately from the first doxorubicin treatment.

Abstract P440: Cardiac Tissue Chip Model Provides A Platform For Studying Age-related Cardiovascular Complications By Recapitulating Important Hallmarks Of Senescence And Myocardial Ischemia

Introduction: With the rise in the elderly population, there has been an exponential growth in cardiovascular diseases and age-related complications. This necessitates a platform for studying cardiovascular disease in the context of aging. Hypothesis: An engineered cardiac tissue model that can recapitulate critical aspects of aging can be used to study age-related diseases of the cardiovascular system. Methods: Senescence was induced in rat cardiomyoblasts using an acute low-dose doxorubicin treatment. The presence of important senescent markers in the cells like enlarged and flattened nuclei, increased ROS activity, elevated p53 production, DNA damage response foci, and increased expression of cell cycle inhibitor p16 INK4a was evaluated. These senescent cells were then used to engineer cardiac tissue, which was subjected to hemodynamic stresses associated with the pressure-volume changes in the heart. Myocardial ischemia was imposed in the aging cardiac tissue model using hypoxic treatment. Results: Under normal hemodynamic loading, the engineered cardiac tissue retained its cardiac cell characteristics and showed cell alignment along with age-related changes in structure and gene expression. The myocardial ischemic model of the tissue revealed major pathological hallmarks of the disease like increased cell death and natriuretic peptide expression. Conclusion: Our model and methodology provide an effective platform for studying the cardiovascular disease pathologies associated with aging and screening drugs against age-related complications.

Engineered Aging Cardiac Tissue Chip Model for Studying Cardiovascular Disease

Due to the rapidly growing number of older people worldwide and the concomitant increase in cardiovascular complications, there is an urgent need for age-related cardiac disease modeling and drug screening platforms. In the present study, we developed a cardiac tissue chip model that incorporates hemodynamic loading and mimics essential aspects of the infarcted aging heart. We induced cellular senescence in H9c2 myoblasts using low-dose doxorubicin treatment. These senescent cells were then used to engineer cardiac tissue fibers, which were subjected to hemodynamic stresses associated with pressure-volume changes in the heart. Myocardial ischemia was modeled in the engineered cardiac tissue via hypoxic treatment. Our results clearly show that acute low-dose doxorubicin treatment-induced senescence, as evidenced by morphological and molecular markers, including enlarged and flattened nuclei, DNA damage response foci, and increased expression of cell cycle inhibitor p16^INK4a, p53, and ROS. Under normal hemodynamic load, the engineered cardiac tissues demonstrated cell alignment and retained cardiac cell characteristics. Our senescent cardiac tissue model of hypoxia-induced myocardial infarction recapitulated the pathological disease hallmarks such as increased cell death and upregulated expression of ANP and BNP. In conclusion, the described methodology provides a novel approach to generate stress-induced aging cardiac cell phenotypes and engineer cardiac tissue chip models to study the cardiovascular disease pathologies associated with aging.

The implications of mitochondria in doxorubicin treatment of cancer in the context of traditional and modern medicine

Doxorubicin (DOX) is an antibiotic anthracycline extensively used in the treatment of different malignancies, such as breast cancer, lymphomas and leukemias. The cardiotoxicity induced by DOX is one of the most important pathophysiological events that limit its clinical application. Accumulating evidence highlights mitochondria as a central role in this process. Modulation of mitochondrial functions as therapeutic strategy for DOX-induced cardiotoxicity has thus attracted much attention. In particular, emerging studies investigated the potential of natural mitochondria-targeting compounds from Traditional Chinese Medicine (TCM) as adjunct or alternative treatment for DOX-induced toxicity. This review summarizes studies about the mechanisms of DOX-induced cardiotoxicity, evidencing the importance of mitochondria and presenting TCM treatment alternatives for DOX-induced cardiomyopathy.