Analysis of the Vascular Phenotype of the ENT1-null mouse

Adenosine is important in the regulation of vascular tone and the Equilibrative Nucleoside Transporter 1 (ENT1) is a regulator of adenosine concentrations. Thus, changes in ENT1 expression and activity may alter vascular tone regulation. We therefore examined the cardiovascular phenotype of ENT1-null (ENT1-/-) as compared to wild type mice (ENT1+/+). Heart rates (HRs) and blood pressures (BPs) of ENT1-/- and ENT1+/+ littermate male mice were obtained while conscious and anaesthetized, and metabolic data were collected over a 24 hr period. Vascular reactivity was assessed in aortic ring segments obtained from 3 month old ENT1-/- and ENT1+/+ mice during both normoxic and hypoxic conditions. Gene expression was obtained using qPCR. KCl administration mediated significantly greater constriction (~32% increase independent of tension applied or age) in ENT1-/- rings compared to ENT1+/+. However, no significant differences between the two genotypes were observed for the different receptor agonists. KCl works independent of receptors and carries out direct vasoconstriction via depolarization whereas receptor agonists work indirectly through cellular signaling mechanisms. In hypoxic conditions, ENT1-/- mice exhibited diminished response to phenylephrine following pretreatment with increasing concentration of adenosine as well as in the presence of ENT1 inhibitor NBMPR suggesting an ENT1 independent effect of NBMPR. Length tension curves on the aortas were carried out and resulted in ­­ an increase in ENT1-/-curve when the same tension was applied. HR and BP analysis showed elevated blood pressure while the mice were conscious. Morphological assessment of vascularized tissues was performed using H&E and Alizarin Red Staining. Visualization of H&E stain yielded significant differences in luminal area however no significant differences were seen in arterial wall thickness between ENT1+/+ and ENT1-/- mice at the age of 3 months. Alizarin Red staining yielded no evidence of calcium deposits in the arterial walls. The enhanced effect of KCl in ENT1-/- aortic rings suggests a physiological difference in the regulation of the vasoconstriction response. The increased blood pressure coupled with the stiffening of the aortic wall suggests an increase on the mechanical load of the heart, possibly the early stages of hypertension. The studies suggest a vascular phenotype associated with a loss of ENT1. This model will continue to aid in unraveling the role of adenosine in vascular regulation

Outcomes of Dupilumab treatment in patients presenting with severe asthma or chronic rhinosinusitis with nasal polyps, over the age of 65

Introduction: Dupilumab is an IL-4/13 inhibitor that has been successfully implemented in the treatment of severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). The safety and efficacy of Dupilumab has not been reported for these indications in patients over the age of 65. This study aims to determine the long-term benefits of dupilumab while detailing adverse effects. Methods: This study is a single institution retrospective review of patients receiving dupilumab for severe asthma and/or CRSwNP from 2018 to present. Charts were reviewed for patient demographics, Sino-nasal Outcome Test (SNOT-22) scores, asthma control test (ACT) scores, polyp scores, and adverse effects. We reported the findings of patients over the age of 65 whose first biologic was dupilumab. Results: Thirty-one patients over the age of 65 were identified (mean = 72.2), 18 (58.1%) of whom are female. Twelve (38.7%) presented with severe asthma, 7 (22.6%) with CRSwNP and 12 (38.7%) with both severe asthma and CRSwNP. Compared to baseline, there was a significant difference observed within patients in mean ACT (17.8 to 20.3; n=13, p=0.002), SNOT-22 (40.5 to 23.4; n=10, p= 0.015), and polyp scores (3.06 to 1.13; n=8, p=0.010) post-treatment initiation. Seven patients (22.6%) reported adverse reactions that may or may not be related to dupilumab. Adverse reactions included ophthalmologic (1), musculoskeletal (1), dermatologic (2) and other (2) which included lower extremity edema, tinnitus, hair loss, and TMJ pain. Zero patients reported allergic reactions. Four of the 7 patients who experienced adverse reactions chose to continue dupilumab therapy, while 3 discontinued. Conclusions: Patients over 65 on dupilumab showed improvement in asthma and CRSwNP symptoms. There were significant improvements in ACT, SNOT-22, and nasal polyp scores withing 9 months of therapy initiation. The majority did not experience any adverse effects, demonstrating the value of dupilumab treatment in this patient cohort

Evaluating Quality of Life and Functional Outcomes in Salvage Surgery for Head and Neck Cancer

Background: Unique challenges surround treatment for residual or recurrent head and neck squamous cell carcinoma (HNSCC). Of the limited treatment options for residual or recurrent HNSCC, salvage surgery is often the best option. However, salvage surgery can result in significant morbidity, affecting both quality of life (QoL) and functional outcomes. Few studies have examined QoL outcomes following salvage surgery in the setting of HNSCC. Objectives: To analyze head and neck related quality of life and functional outcomes in patients with head and neck cancer who underwent salvage surgery. Methods: In this IRB approved study, FACT-HN Version 4 was administered pre-operatively and 6 months post-operatively to patients undergoing salvage surgery for HNSCC between November 4, 2014 and April 27, 2020. Retrospective cohort analysis was performed on this population with major outcome being postoperative QoL score. Functional outcomes included postoperative tracheostomy and feeding tube status. QoL outcomes were compared with paired t-tests. Univariate logistic regression was used to determine characteristics associated with presence of permanent tracheostomy and feeding tube, defined as presence greater than 30 days. Results: Overall, 25 patients undergoing salvage surgery for HNSCC were included in this analysis. Primary tumor sites were larynx/hypopharynx (44.0%), oral cavity (24.0%), oropharynx (20.0%), salivary (4.0%), skin (4.0%), and unknown primary (4.0%). Salvage surgeries consisted of total laryngectomy (36.0%), definitive neck dissection (24.0%), mandibulectomy (16.0%), parotidectomy (8.0%), with total laryngectomy/total glossectomy, radical tonsillectomy, TORS base of tongue excision, and transoral laser laryngeal excision all comprising 4% of cases. Total QoL scores were not significantly different preoperatively to postoperatively (mean 108.7, 95% CI=97.7 to 119.7 vs. 103.8, 95% CI: 93.1 to 114.5; P=0.436, with maximum total score of 148). Patients with lower preoperative Emotional Well-Being (EWB) subscores demonstrated significantly worse EWB subscores postoperatively (postoperative mean: 17.0, 95% CI: 14.5 to 19.4 vs. 21.7, 95% CI: 20.0 to 23.4; P=0.002). Of patients who underwent tracheostomy tube placement, 53.8% (N=7/13) remained tracheostomy dependent long-term (\u3e30 d). Of patients who underwent feeding tube placement, 81.0% (N=17/21) remained feeding tube dependent long-term (\u3e30 d). Tracheostomy and feeding tubes remained in place with median durations of 3.02 months (range 0.16 to 20.55) and 10.13 months (range 0 to 24.89), respectively. All patients with T3/4 disease undergoing salvage surgery required long-term feeding tube (N=6). Conclusions: This study provides important information about quality of life and functional outcomes for patients undergoing salvage surgery for HNSCC. There is a high rate of long-term tracheostomy and feeding tube dependence following salvage surgery. While no difference was found in head and neck related quality of life total score and sub-scores at 6 months postoperatively, general emotional well-being preoperatively was most associated with general emotional well-being postoperatively. This information should be taken into consideration when counseling and managing patients with residual or recurrent HNSCC