Objectives/Hypothesis
The presence of regional metastases in head and neck squamous cell carcinoma (HNSCC) patients is a common and adverse event associated with poor prognosis. Understanding the ...molecular mechanisms that mediate HNSCC metastasis may enable identification of novel therapeutic targets. E‐cadherin plays a key role in epithelial intercellular adhesion; its downregulation is a hallmark of the epithelial‐to‐mesenchymal transition (EMT) (an essential process during tumor progression); and it is associated with invasion, metastasis, and decreased survival. Inflammatory cytokines have been implicated in the progression of HNSCC. Herein, the mechanisms by which the inflammatory mediator, Interleukin‐1β (IL‐1β), might contribute to EMT in HNSCC is investigated.
The pathways involved in E‐cadherin regulation in HNSCC had not previously been defined. It is hypothesized that 1) inflammatory mediators upregulate cyclooxygenase‐2/prostaglandin E2 (COX‐2/PGE2), which then in turn regulate E‐cadherin expression in HNSCC; and 2) PGE2 downregulates E‐cadherin via transcriptional repressors of E‐cadherin (such as Snail) in HNSCC. The outcome of the proposed research will allow us to define how resistance to epidermal growth factor receptor (EGFR)‐selective tyrosine kinase inhibitors is mediated and whether the benefits of combination therapy are due to the capacity of COX‐2 inhibitors to increase E‐cadherin expression and thus create a more sensitive target for EGFR TK inhibition.
Study Design
Basic science, molecular biology, animal model, immunohistochemistry.
Methods
We evaluated the effect of IL‐1β on the molecular events of EMT in surgical specimens and HNSCC cell lines. We examined the correlation with tumor histologic features, and a severely compromised immunodeficient (SCID) xenograft model was used to assess the effects in vivo.
Results
COX‐2‐dependent pathways contribute to the modulation of E‐cadherin expression in HNSCC. An inverse relationship between COX‐2 and E‐cadherin was demonstrated in situ by double immunohistochemical staining of human HNSCC tissue sections. Treatment of HNSCC cells with IL‐1β caused the downregulation of E‐cadherin expression and upregulation of COX‐2 expression. This effect was blocked in the presence of COX‐2 small hairpin RNA (shRNA). IL‐1β ‐treated HNSCC cell lines demonstrated a significant decrease in E‐cadherin messenger RNA (mRNA) and an increase in the mRNA expression of the transcriptional repressor Snail. IL‐1β exposure led to enhanced Snail binding at the chromatin level. ShRNA‐mediated knockdown of Snail interrupted the capacity of IL‐1β to downregulate E‐cadherin. Snail overexpression in normal oral keratinocytes and HNSCC cells is sufficient to drive EMT and confers resistance to erlotinib. In a SCID xenograft model, HNSCC Snail overexpressing cells demonstrated significantly increased primary and metastatic tumor burdens.
Conclusions
The inflammatory mediator IL‐1β modulates Snail and thereby regulates COX‐2‐dependent E‐cadherin expression in HNSCC. This is the first report indicating the role of Snail in the inflammation‐induced promotion of EMT in HNSCC. This newly defined pathway for transcriptional regulation of E‐cadherin in HNSCC has important implications for targeted chemoprevention and therapy.
Level of Evidence
N/A Laryngoscope, 125:S1–S11, 2015
Objective: In vivo visualization and quantification of edema, or 'tissue swelling' following injury, remains a clinical challenge. Herein, we investigate the ability of reflective terahertz (THz) ...imaging to track changes in tissue water content (TWC)-the direct indicator of edema-by comparison to depth-resolved magnetic resonance imaging (MRI) in a burn-induced model of edema. Methods : A partial thickness and full thickness burns were induced in an in vivo rat model to elicit unique TWC perturbations corresponding to burn severity. Concomitant THz surface maps and MRI images of both burn models were acquired with a previously reported THz imaging system and T 2 -weighted MRI, respectively, over 270 min. Reflectivity was analyzed for the burn contact area in THz images, while proton density (i.e., mobile TWC) was analyzed for the same region at incrementally increasing tissue depths in companion, transverse MRI images. A normalized cross correlation of THz and depth-dependent MRI measurements was performed as a function of time in histologically verified burn wounds. Results : For both burn types, strong positive correlations were evident between THz reflectivity and MRI data analyzed at greater tissue depths (>258 μm). MRI and THz results also revealed biphasic trends consistent with burn edema pathogenesis. Conclusion : This paper offers the first in vivo correlative assessment of mobile TWC-based contrast and the sensing depth of THz imaging. Significance: The ability to implement THz imaging immediately following injury, combined with TWC sensing capabilities that compare to MRI, further support THz sensing as an emerging tool to track fluid in tissue.
Objective
To assess perioperative and readmission outcomes of patients undergoing head and neck cancer (HNCA) surgery at safety‐net hospitals (SNHs) in a modern cohort.
Study Design
Retrospective ...cohort study.
Setting
Nationwide Readmissions Database (NRD), 2010 to 2019.
Methods
All elective adult (≥18 years) admissions involving HNCA resection were identified from the NRD. To calculate safety‐net burden, the proportion of Medicaid or uninsured patients admitted to each hospital for any indication was tabulated annually, with centers in the highest quartile defined as SNHs. To perform risk adjustment in assessing perioperative and readmission outcomes, multivariable regression models were developed.
Results
Of an estimated 133,018 head and neck surgical patients, 26.5% (n = 35,268) received treatment at a SNH. Utilization of SNHs increased over the decade‐long study period, with 29.8% of individuals treated at these sites in 2019. After multivariable adjustment, several patient factors were noted to be associated with SNHs, including younger age, lower comorbidity burden, and income within the lowest quartile. Although incidence of adverse events decreased at both SNHs and non‐SNHs during the study period, treatment at SNHs remained associated with these events after risk adjustment (adjusted odds ratio: 1.17, 95% confidence interval: 1.08‐1.28, P < .001).
Conclusion
SNHs continue to provide valuable specialty care to underserved populations, often with limited financial resources. Despite promising results from prior decades demonstrating comparable perioperative outcomes, the present study noted increased adverse events following HNCA surgery at these sites. Such findings underscore the need for continued advocacy to secure necessary funding for these centers.
Objective/Hypothesis
Utilization of flaps for reconstruction of large head and neck cancer (HNCA) defects has become more prevalent. The present study aimed to assess the impact of center experience ...as measured by annual hospital caseload on mortality, major complications, resource utilization, and 90‐day readmissions following HNCA resection with flap reconstruction.
Study Design
Non‐Randomized Controlled Cohort Study.
Methods
All adult patients undergoing elective HNCA resection with flap reconstruction were identified utilizing the 2010 to 2018 Nationwide Readmissions Database. Hospitals were subsequently classified as low‐, medium‐, or high‐volume based on annual institutional surgical caseload tertiles. Multivariable regression models were implemented to assess the independent association of hospital volume with the outcomes of interest.
Results
Over the nine‐year study period, the proportion of HNCA resection with flap reconstruction gradually increased (12.8% in 2010 vs. 17.3% in 2018, P < .001). Although increasing hospital volume did not alter the odds of mortality, patients treated at high‐volume centers were less likely to experience both surgical (adjusted odds ratio AOR 0.81, 95% confidence interval CI 0.67–0.97, P = .025) and medical complications (AOR 0.70, 95% CI 0.57–0.85, P < .001). Furthermore, these patients had shorter hospitalizations (−2.1 days, 95% CI −2.7 to −1.4 days, P < .001) and decreased costs (−$8,100, 95% CI −11,400 to −4,700, P < .001) compared to counterparts at low‐volume centers. However, hospital volume did not impact 90‐day readmissions.
Conclusion
Patients undergoing HNCA resection with flap reconstruction at high‐volume centers were less likely to experience surgical and medical complications while incurring shorter hospitalizations and lower costs. Implementation of volume standards may be appropriate to improve outcomes in this surgical population.
Level of Evidence
3 Laryngoscope, 132:1381–1387, 2022
Recently, induction chemotherapy has gained favor for managing locally advanced sinonasal malignancies. In this Trio Best Practices paper, we review the evidence surrounding the application of ...induction chemotherapy for definitive management of locally advanced sinonasal squamous cell carcinoma.
Objective
Esthesioneuroblastoma is an uncommon malignancy of the sinonasal tract arising from the olfactory epithelium. Surgical management of the primary site, often via an endoscopic approach, with ...or without adjuvant radiation, is often curative. There is growing but ultimately limited data regarding management of the neck and the risk of nodal metastases. In this study, we examine the incidence and patterns of esthesioneuroblastoma‐related cervical nodal metastases using the Surveillance, Epidemiology, and End Results (SEER) database.
Methods
The SEER registry was queried for all patients with esthesioneuroblastomas diagnosed between 1973 and 2012. Patient data was then analyzed with respect to age, sex, race, modified Kadish stage, grade, survival functions, and nodal disease including specific nodal basins.
Results
Three hundred and eighty‐one cases of esthesioneuroblastoma with information on nodal metastases were identified. The overall cervical nodal metastasis rate was 8.7%. Level II metastases were most common (6.6%). A total of 4.5% of cases presented with multiple positive nodal basins. Male sex (P = 0.009) and higher tumor grade (P = 0.009) correlated with the presence of level II metastases. There was no association of primary tumor site to the presence of nodal metastases (P > 0.05). The presence of nodal disease significantly predicted poorer overall (P = 0.001) and disease‐specific survival (P = 0.017).
Conclusion
The incidence of nodal metastases in esthesioneuroblastoma at diagnosis is rare, and elective management of the neck remains controversial. Primary tumor site does not appear to predict metastases at specific nodal basins. Higher tumor grade may be a harbinger of eventual nodal metastases.
Level of Evidence
NA Laryngoscope, 129:1025–1029, 2019
To determine the current epidemiology and management trends for patients with vestibular schwannomas (VS).
Retrospective cohort study.
The Surveillance, Epidemiology, and End Results (SEER) tumor ...registry.
The SEER database was queried to identify patients diagnosed with VS from 1973 to 2015. Demographics, patient and tumor characteristics, and treatment methods were analyzed.
A total of 14,507 patients with VS were identified. The mean age at diagnosis was 55 ± 14.9 years. Age-adjusted incidence from 2006 to 2015 was 1.4 per 100,000 per year and remained relatively stable. Incidence across age varied with sex, as younger women and older men had increased incidences comparatively. A higher percentage of patients underwent surgery alone (43%), followed by observation (32%), radiation alone (23%), and combined radiation and surgery (2%). Age 65 and older was associated with observation (odds ratio OR 1.417; p = 0.029) whereas age 20 to 39 and 40 to 49 were associated with surgery (OR 2.013 and 1.935; p < 0.001). Older age was associated with radiation. Larger tumor size was associated with surgery and combined treatment. African American patients and American Indian or Alaskan Native patients were more likely to undergo observation than surgery.
The overall incidence of VS is 1.4 per 100,000 per year and has remained relatively stable. There is a trend toward more conservative management with observation, which may be secondary to earlier diagnosis given widespread use of magnetic resonance imaging. Further studies are necessary to investigate differences in disease patterns and disparities in management.
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