Ethics and Palliation in Head and Neck Surgery.

Head and neck cancer is a potentially traumatizing disease with the potential to impact many of the functions which are core to human life: eating, drinking, breathing, and speaking. Patients with head and neck cancer are disproportionately impacted by socioeconomic challenges, social stigma, and difficult decisions about treatment approaches. Herein, the authors review foundational ethical principles and frameworks to guide care of these patients. The authors discuss specific challenges including shared decision-making and advance care planning. The authors further discuss palliative care with a discussion of the role of surgery as a component of palliation.

Survival analysis of patients with advanced hypopharyngeal cancer comparing patients who received primary surgery to those who received chemoradiation: An analysis of the NCDB.

INTRODUCTION: The objective of this study was to use the American College of Surgeons' National Cancer Database (NCDB) to examine the association between primary treatment and overall survival (OS) among patients with locoregionally advanced hypopharyngeal cancer. METHODS: 6,055 adult patients diagnosed between 2004 and 2015 with stage III or IV, M0, hypopharyngeal squamous cell carcinoma were identified within the NCDB. Patients who received primary chemoradiation (CRT) were compared to those that received surgery with adjuvant radiation or chemoradiation (S + Adj). OS was compared between treatment groups using Kaplan-Meier analyses, propensity score adjustment, and Cox regression analyses. RESULTS: The median survival was 22.7 months (IQR 11.0-49.0). The S + Adj group had a significantly higher comorbidity score, higher grade disease, and more advanced stage disease than the CRT group. S + Adj was associated with significantly improved survival when compared to CRT (p < 0.0001). A propensity score adjusting for facility type, facility location, care at multiple facilities, histology, and T stage was developed. S + Adj was associated with longer survival (HR: 0.72, 95% CI: 0.64-0.80) when compared to CRT in a multivariable Cox regression analysis (adjusting for age, race and ethnicity, insurance status, a comorbidity index, diagnosis year, treatment delay, N stage, and the propensity score). S + Adj was associated with significantly improved survival among those with T2 disease (p = 0.02), T3 disease (p = 0.02), and T4 disease (p < 0.0001) in sensitivity analyses examining these subcohorts independently. CONCLUSIONS: Among patients with advanced hypopharyngeal cancer reported in NCDB, treatment with S + Adj was associated with longer survival compared to those treated with primary CRT.

Treatment sequence and survival in locoregionally advanced hypopharyngeal cancer: A surveillance, epidemiology, and end results-based study.

OBJECTIVES/HYPOTHESIS: The objective of this study was to examine the association between modality of primary treatment and survival among patients with locoregionally advanced hypopharyngeal cancer. STUDY DESIGN: Retrospective cohort. METHODS: There were 2,328 adult patients diagnosed with stage III or IV, M0, hypopharyngeal squamous cell carcinoma identified within the Surveillance, Epidemiology and End Results (SEER) registry (years 2004-2015). Patients who received primary chemoradiation (CRT) were compared to those who received surgery with either adjuvant radiation therapy (S + RT), or surgery with adjuvant CRT (S + CRT). The latter primary surgery group (S + Adj) was also analyzed collectively. Overall survival (OS) and disease-specific survival (DSS) were assessed using Kaplan-Meier analyses and Cox regression models using a propensity score to adjust for factors associated with treatment allocation. RESULTS: Median survival was 20 months (interquartile range [IQR] = 10-45) with CRT and 25 months (IQR = 10-47) with S + Adj (P < .001). S + Adj had higher-grade cancers and more advanced T staging (P < .001). S + CRT was associated with longer OS (hazard ratio [HR] = 0.70, 95% confidence interval [CI]: 0.59-0.84) and DSS (HR = 0.66, 95% CI: 0.54-0.82) after adjusting for age, gender, race, subsite, grade, and stage. S + RT was associated with longer DSS than CRT (HR = 0.75, 95% CI: 0.57-0.99) but not OS (HR = 0.82, 95% CI: 0.66-1.04). S + Adj was associated with longer DSS in T1/T2 disease (P = .04) and T4 disease (P = .0003), but did not reach significance among patients with T3 disease (P = .06). CONCLUSIONS: Among patients with advanced hypopharyngeal cancer reported in the SEER database, treatment with S + Adj was associated with longer DSS and OS compared to those treated with primary CRT. LEVEL OF EVIDENCE: 2b Laryngoscope, 130:2611-2621, 2020.

Correction: MiR-21 in Extracellular Vesicles Leads to Neurotoxicity via TLR7 Signaling in SIV Neurological Disease.

[This corrects the article DOI: 10.1371/journal.ppat.1005032.].

Traumatic brain injury increases levels of miR-21 in extracellular vesicles: implications for neuroinflammation.

Traumatic brain injury (TBI) is an important health concern and effective treatment strategies remain elusive. Understanding the complex multicellular response to TBI may provide new avenues for intervention. In the context of TBI, cell-cell communication is critical. One relatively unexplored form of cell-cell communication in TBI is extracellular vesicles (EVs). These membrane-bound vesicles can carry many different types of cargo between cells. Recently, miRNA in EVs have been shown to mediate neuroinflammation and neuronal injury. To explore the role of EV-associated miRNA in TBI, we isolated EVs from the brain of injured mice and controls, purified RNA from brain EVs, and performed miRNA sequencing. We found that the expression of miR-212 decreased, while miR-21, miR-146, miR-7a, and miR-7b were significantly increased with injury, with miR-21 showing the largest change between conditions. The expression of miR-21 in the brain was primarily localized to neurons near the lesion site. Interestingly, adjacent to these miR-21-expressing neurons were activated microglia. The concurrent increase in miR-21 in EVs with the elevation of miR-21 in neurons, suggests that miR-21 is secreted from neurons as potential EV cargo. Thus, this study reveals a new potential mechanism of cell-cell communication not previously described in TBI.

Systems Perturbation Analysis of a Large-Scale Signal Transduction Model Reveals Potentially Influential Candidates for Cancer Therapeutics.

Dysregulation in signal transduction pathways can lead to a variety of complex disorders, including cancer. Computational approaches such as network analysis are important tools to understand system dynamics as well as to identify critical components that could be further explored as therapeutic targets. Here, we performed perturbation analysis of a large-scale signal transduction model in extracellular environments that stimulate cell death, growth, motility, and quiescence. Each of the model's components was perturbed under both loss-of-function and gain-of-function mutations. Using 1,300 simulations under both types of perturbations across various extracellular conditions, we identified the most and least influential components based on the magnitude of their influence on the rest of the system. Based on the premise that the most influential components might serve as better drug targets, we characterized them for biological functions, housekeeping genes, essential genes, and druggable proteins. The most influential components under all environmental conditions were enriched with several biological processes. The inositol pathway was found as most influential under inactivating perturbations, whereas the kinase and small lung cancer pathways were identified as the most influential under activating perturbations. The most influential components were enriched with essential genes and druggable proteins. Moreover, known cancer drug targets were also classified in influential components based on the affected components in the network. Additionally, the systemic perturbation analysis of the model revealed a network motif of most influential components which affect each other. Furthermore, our analysis predicted novel combinations of cancer drug targets with various effects on other most influential components. We found that the combinatorial perturbation consisting of PI3K inactivation and overactivation of IP3R1 can lead to increased activity levels of apoptosis-related components and tumor-suppressor genes, suggesting that this combinatorial perturbation may lead to a better target for decreasing cell proliferation and inducing apoptosis. Finally, our approach shows a potential to identify and prioritize therapeutic targets through systemic perturbation analysis of large-scale computational models of signal transduction. Although some components of the presented computational results have been validated against independent gene expression data sets, more laboratory experiments are warranted to more comprehensively validate the presented results.

MiR-21 in Extracellular Vesicles Leads to Neurotoxicity via TLR7 Signaling in SIV Neurological Disease.

Recent studies have found that extracellular vesicles (EVs) play an important role in normal and disease processes. In the present study, we isolated and characterized EVs from the brains of rhesus macaques, both with and without simian immunodeficiency virus (SIV) induced central nervous system (CNS) disease. Small RNA sequencing revealed increased miR-21 levels in EVs from SIV encephalitic (SIVE) brains. In situ hybridization revealed increased miR-21 expression in neurons and macrophage/microglial cells/nodules during SIV induced CNS disease. In vitro culture of macrophages revealed that miR-21 is released into EVs and is neurotoxic when compared to EVs derived from miR-21-/- knockout animals. A mutation of the sequence within miR-21, predicted to bind TLR7, eliminates this neurotoxicity. Indeed miR-21 in EV activates TLR7 in a reporter cell line, and the neurotoxicity is dependent upon TLR7, as neurons isolated from TLR7-/- knockout mice are protected from neurotoxicity. Further, we show that EVs isolated from the brains of monkeys with SIV induced CNS disease activates TLR7 and were neurotoxic when compared to EVs from control animals. Finally, we show that EV-miR-21 induced neurotoxicity was unaffected by apoptosis inhibition but could be prevented by a necroptosis inhibitor, necrostatin-1, highlighting the actions of this pathway in a growing number of CNS disorders.