Quality Versus Quantity: Using Scholarly Activity to Assess Otolaryngology Residency Candidates.

Selecting qualified candidates each year for residency positions has become more difficult in recent years, due to the sharp increase in Otolaryngology applicants. Although there are objective measures that can be used to directly compare medical students during the initial screening process, most information in the application is highly subjective and/or variable across institutions. Many programs count the total posters/presentations and publications to gauge scholarship. This measure of quantity may lead to negative bias toward those who have no home program, limited time outside of academics, and/or inadequate resources to engage in volunteer research. Evaluating the quality of research may be superior to quantity. A first-author publication is a viable proxy that demonstrates applicants have developed skills that set them apart from their peers. They likely possess non-clinical, translatable skills including internal motivation, self-regulation, curation of information, and task completion that map closely with qualities that make for excellent residents.

Systematic Review of CT Angiography in Guiding Management in Pediatric Oropharyngeal Trauma.

OBJECTIVES: Pediatric oropharyngeal trauma is common. Although most cases resolve uneventfully, there have been reports of internal carotid artery injury leading to devastating neurovascular sequelae. There is significant controversy regarding the utility of CT angiography (CTA) in children with seemingly minor oropharyngeal trauma. The goal of this study was to appraise changes in diagnosis and treatment based on CTA results. METHODS: A comprehensive search of PubMed, Embase, CINAHL, Scopus, the Cochrane Ear, Nose and Throat Disorders Group Trials Register, and the ClinicalTrials.gov database was performed following PRISMA guidelines. RESULTS: The search yielded 5,078 unique abstracts, of which 8 articles were included. A total of 662 patients were included, with 293 having any CT head/neck imaging, and 255 with CTA. Eleven injuries/abnormalities of the carotid were found on CTAs, comprising edema around the carotid (n = 8), potential intimal tear (n = 1), carotid spasm (n = 1), and carotid compression (n = 1). The pooled proportion of imaging findings on CTA that could lead to changes in clinical management was 0.00 (95% CI 0.00-0.43). Angiography was obtained in 10 patients, in 6 cases due to abnormal CTA. Angiography identified 1 patient with vessel spasm and two patients with carotid intima disruption without thrombus. No patient underwent vascular repair or suffered cerebrovascular injury. CONCLUSION: Imaging with CTA yielded radiological abnormalities in a few instances. These results do not support the routine use of CTA in screening pediatric oropharyngeal trauma when balanced against the risk of radiation, as it rarely resulted in management changes and was not shown to improve outcomes. LEVEL OF EVIDENCE: N/A Laryngoscope, 133:457-466, 2023.

Dual blockade of EGFR and CDK4/6 delays head and neck squamous cell carcinoma progression by inducing metabolic rewiring.

Despite preclinical success, monotherapies targeting EGFR or cyclin D1-CDK4/6 in Head and Neck squamous cell carcinoma (HNSCC) have shown a limited clinical outcome. Here, we aimed to determine the combined effect of palbociclib (CDK4/6) and afatinib (panEGFR) inhibitors as an effective strategy to target HNSCC. Using TCGA-HNSCC co-expression analysis, we found that patients with high EGFR and cyclin D1 expression showed enrichment of gene clusters associated with cell-growth, glycolysis, and epithelial to mesenchymal transition processes. Phosphorylated S6 (p-S6), a downstream effector of EGFR and cyclin D1-CDK4/6 signalling, showed a progressive increase from normal oral tissues to leukoplakia and frank malignancy, and associated with poor outcome of the patients. This increased p-S6 expression was drastically reduced after combination treatment with afatinib and palbociclib in the cell lines and mouse models, suggesting its utiliy as a prognostic marker in HNSCC. Combination treatment also reduced the cell growth and induced cell senescence via increasing reactive oxygen species with concurrent ablation of glycolytic and tricarboxylic acid cycle intermediates. Finally, our findings in sub-cutaneous and genetically engineered mouse model (K14-CreERtam;LSL-KrasG12D/+;Trp53R172H/+) studies showed a significant reduction in the tumor growth and delayed tumor progression after combination treatment. This study collectively demonstrates that dual targeting may be a critical therapeutic strategy in blocking tumor progression via inducing metabolic alteration and warrants clinical evaluation.

Differential mutation spectrum and immune landscape in African Americans versus Whites: A possible determinant to health disparity in head and neck cancer.

African Americans (AA) with Head and Neck Squamous Cell Carcinoma (HNSCC) have a worse disease prognosis than White patients despite adjusting for socio-economic factors, suggesting the potential biological contribution. Therefore, we investigated the genomic and immunological components that drive the differential tumor biology among race. We utilized the cancer genome atlas and cancer digital archive of HNSCC patients (1992-2013) for our study. We found that AA patients with HNSCC had a higher frequency of mutation compared to Whites in the key driver genes-P53, FAT1, CASP8 and HRAS. AA tumors also exhibited lower intratumoral infiltration of effector immune cells (CD8+, γδT, resting memory CD4+ and activated memory CD4+ T cells) with shorter survival than Whites. Unsupervised hierarchical clustering of differentially expressed genes demonstrated distinct gene clusters between AA and White patients with unique signaling pathway enrichments. Connectivity map analysis identified drugs (Neratinib and Selumetinib) that target aberrant PI3K/RAS/MEK signaling and may reduce racial disparity in therapy response.

Immunometabolic Alterations by HPV Infection: New Dimensions to Head and Neck Cancer Disparity.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, with high morbidity and mortality. Racial disparity in HNSCC is observed between African Americans (AAs) and whites, effecting both overall and 5-year survival, with worse prognosis for AAs. In addition to socio-economic status and demographic factors, many epidemiological studies have also identified factors including coexisting human papillomavirus (HPV) infection, primary tumor location, and a variety of somatic mutations that contribute to the prognostic incongruities in HNSCC patients among AAs and whites. Recent research also suggests HPV-induced dysregulation of tumor metabolism and immune microenvironment as the major regulators of HNSCC patient prognosis. Outcomes of several preclinical and clinical studies on targeted therapeutics warrant the need to elucidate the inherent mechanistic and population-based disparities underlying patient responses. This review systematically reports the underlying reasons for inconsistency in disease prognosis and therapy responses among HNSCC patients from different racial populations. The focus of this review is twofold: aside from discussing the causes of racial disparity, we also seek to identify the consequences of such disparity in terms of HPV infection and its associated mutational, metabolic, and immune landscapes. Considering the clinical impact of differential patient outcomes among AA and white populations, understanding the underlying cause of this disparity may pave the way for novel precision therapy for HNSCC.

Emerging therapeutic potential of graviola and its constituents in cancers.

Cancer remains a leading cause of death in the USA and around the world. Although the current synthetic inhibitors used in targeted therapies have improved patient prognosis, toxicity and development of resistance to these agents remain a challenge. Plant-derived natural products and their derivatives have historically been used to treat various diseases, including cancer. Several leading chemotherapeutic agents are directly or indirectly based on botanical natural products. Beyond these important drugs, however, a number of crude herbal or botanical preparations have also shown promising utility for cancer and other disorders. One such natural resource is derived from certain plants of the family Annonaceae, which are widely distributed in tropical and subtropical regions. Among the best known of these is Annona muricata, also known as soursop, graviola or guanabana. Extracts from the fruit, bark, seeds, roots and leaves of graviola, along with several other Annonaceous species, have been extensively investigated for anticancer, anti-inflammatory and antioxidant properties. Phytochemical studies have identified the acetogenins, a class of bioactive polyketide-derived constituents, from the extracts of Annonaceous species, and dozens of these compounds are present in different parts of graviola. This review summarizes current literature on the therapeutic potential and molecular mechanism of these constituents from A.muricata against cancer and many non-malignant diseases. Based on available data, there is good evidence that these long-used plants could have both chemopreventive and therapeutic potential. Appropriate attention to safety studies will be important to assess their effectiveness on various diseases caused or promoted by inflammation.

Afatinib radiosensitizes head and neck squamous cell carcinoma cells by targeting cancer stem cells.

The dismal prognosis of locally advanced and metastatic squamous cell carcinoma of the head and neck (HNSCC) is primarily due to the development of resistance to chemoradiation therapy (CRT). Deregulation of Epidermal Growth Factor Receptor (EGFR) signaling is involved in HNSCC pathogenesis by regulating cell survival, cancer stem cells (CSCs), and resistance to CRT. Here we investigated the radiosensitizing activity of the pan-EGFR inhibitor afatinib in HNSCC in vitro and in vivo. Our results showed strong antiproliferative effects of afatinib in HNSCC SCC1 and SCC10B cells, compared to immortalized normal oral epithelial cells MOE1a and MOE1b. Comparative analysis revealed stronger antitumor effects with afatinib than observed with erlotinib. Furthermore, afatinib enhanced in vitro radiosensitivity of SCC1 and SCC10B cells by inducing mesenchymal to epithelial transition, G1 cell cycle arrest, and the attenuating ionizing radiation (IR)-induced activation of DNA double strand break repair (DSB) ATM/ATR/CHK2/BRCA1 pathway. Our studies also revealed the effect of afatinib on tumor sphere- and colony-forming capabilities of cancer stem cells (CSCs), and decreased IR-induced CSC population in SCC1 and SCC10B cells. Furthermore, we observed that a combination of afatinib with IR significantly reduced SCC1 xenograft tumors (median weight of 168.25 ± 20.85 mg; p = 0.05) compared to afatinib (280.07 ± 20.54 mg) or IR alone (324.91 ± 28.08 mg). Immunohistochemical analysis of SCC1 tumor xenografts demonstrated downregulation of the expression of IR-induced pEGFR1, ALDH1 and upregulation of phosphorylated γH2AX by afatinib. Overall, afatinib reduces tumorigenicity and radiosensitizes HNSCC cells. It holds promise for future clinical development as a novel radiosensitizer by improving CSC eradication.

Structural and functional consequences of succinate dehydrogenase subunit B mutations.

Mitochondrial dysfunction, due to mutations of the gene encoding succinate dehydrogenase (SDH), has been implicated in the development of adrenal phaeochromocytomas, sympathetic and parasympathetic paragangliomas, renal cell carcinomas, gastrointestinal stromal tumours and more recently pituitary tumours. Underlying mechanisms behind germline SDH subunit B (SDHB) mutations and their associated risk of disease are not clear. To investigate genotype-phenotype correlation of SDH subunit B (SDHB) variants, a homology model for human SDH was developed from a crystallographic structure. SDHB mutations were mapped, and biochemical effects of these mutations were predicted in silico. Results of structural modelling indicated that many mutations within SDHB are predicted to cause either failure of functional SDHB expression (p.Arg27*, p.Arg90*, c.88delC and c.311delAinsGG), or disruption of the electron path (p.Cys101Tyr, p.Pro197Arg and p.Arg242His). GFP-tagged WT SDHB and mutant SDHB constructs were transfected (HEK293) to determine biological outcomes of these mutants in vitro. According to in silico predictions, specific SDHB mutations resulted in impaired mitochondrial localisation and/or SDH enzymatic activity. These results indicated strong genotype-functional correlation for SDHB variants. This study reveals new insights into the effects of SDHB mutations and the power of structural modelling in predicting biological consequences. We predict that our functional assessment of SDHB mutations will serve to better define specific consequences for SDH activity as well as to provide a much needed assay to distinguish pathogenic mutations from benign variants.

Prognosis for Spontaneous Resolution of OSA in Children.

BACKGROUND: Adenotonsillectomy (AT) is commonly performed for childhood OSA syndrome (OSAS), but little is known about prognosis without treatment. METHODS: The Childhood Adenotonsillectomy Trial (CHAT) randomized 50% of eligible children with OSAS to a control arm (watchful waiting), with 7-month follow-up symptom inventories, physical examinations, and polysomnography. Polysomnographic and symptomatic resolution were defined respectively by an apnea/hypopnea index (AHI) <2 and obstructive apnea index (OAI) <1 and by an OSAS symptom score (Pediatric Sleep Questionnaire [PSQ]) < 0.33 with ≥ 25% improvement from baseline. RESULTS: After 194 children aged 5 to 9 years underwent 7 months of watchful waiting, 82 (42%) no longer met polysomnographic criteria for OSAS. Baseline predictors of resolution included lower AHI, better oxygen saturation, smaller waist circumference or percentile, higher-positioned soft palate, smaller neck circumference, and non-black race (each P < .05). Among these, the independent predictors were lower AHI and waist circumference percentile < 90%. Among 167 children with baseline PSQ scores ≥ 0.33, only 25 (15%) experienced symptomatic resolution. Baseline predictors were low PSQ and PSQ snoring subscale scores; absence of habitual snoring, loud snoring, observed apneas, or a household smoker; higher quality of life; fewer attention-deficit/hyperactivity disorder symptoms; and female sex. Only lower PSQ and snoring scores were independent predictors. CONCLUSIONS: Many candidates for AT no longer have OSAS on polysomnography after 7 months of watchful waiting, whereas meaningful improvement in symptoms is not common. In practice, a baseline low AHI and normal waist circumference, or low PSQ and snoring score, may help identify an opportunity to avoid AT. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00560859; URL: www.clinicaltrials.gov.

Overexpression of miR-210 is associated with SDH-related pheochromocytomas, paragangliomas, and gastrointestinal stromal tumours.

miR-210 is a key regulator of response to hypoxia. Pheochromocytomas (PCs) and paragangliomas (PGLs) with germline SDHx or VHL mutations have pseudohypoxic gene expression signatures. We hypothesised that PC/PGLs containing SDHx or VHL mutations, and succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumours (GISTs), would overexpress miR-210 relative to non-SDH or -VHL-mutated counterparts. miR-210 was analysed by quantitative PCR in i) 39 PC/PGLs, according to genotype (one SDHA, five SDHB, seven VHL, three NF1, seven RET, 15 sporadic, one unknown) and pathology (18 benign, eight atypical, 11 malignant, two unknown); ii) 18 GISTs, according to SDHB immunoreactivity (nine SDH-deficient and nine SDH-proficient) and iii) two novel SDHB-mutant neurosphere cell lines. miR-210 was higher in SDHx- or VHL-mutated PC/PGLs (7.6-fold) compared with tumours without SDHx or VHL mutations (P=0.0016). miR-210 was higher in malignant than in unequivocally benign PC/PGLs (P=0.05), but significance was lost when benign and atypical tumours were combined (P=0.08). In multivariate analysis, elevated miR-210 was significantly associated with SDHx or VHL mutation, but not with malignancy. In GISTs, miR-210 was higher in SDH-deficient (median 2.58) compared with SDH-proficient tumours (median 0.60; P=0.0078). miR-210 was higher in patient-derived neurosphere cell lines containing SDHB mutations (6.5-fold increase) compared with normal controls, in normoxic conditions (P<0.01). Furthermore, siRNA-knockdown of SDHB in HEK293 cells increased miR-210 by 2.7-fold (P=0.001) under normoxia. Overall, our results suggest that SDH deficiency in PC, PGL and GISTs induces miR-210 expression and substantiates the role of aberrant hypoxic-type cellular responses in the development of these tumours.

Longer length Baha™ abutments decrease wound complications and revision surgery.

OBJECTIVES/HYPOTHESIS: To study the complication rates of skin overgrowth, infection, and the need for revision surgery in longer length Baha™ abutments. STUDY DESIGN: Prospective observational cohort study compared with a retrospective historical control. METHODS: After the University of Nebraska Medical Center (UNMC) Institutional Review Board approval was obtained, data was collected from a prospective 8.5-mm abutment study group of 21 subjects with informed consent from October 2011 through October 2012, and was compared to a retrospective 5.5-mm abutment historical cohort of 23 patients who had undergone Baha™ by the same surgeon from May 2010 to October 2011. Patient demographics, body mass index (BMI), smoking status, and wound complications (skin overgrowth, infection, the need for revision surgery) were statistically investigated and compared between the groups. RESULTS: Forty-four patients were studied. The groups were similar in smoking status, diabetes, and a female preponderance. The 8.5-mm abutment group was older (P = 0.012). The average BMI for both groups was classified as overweight and nearly obese (BMI 28.8). Rates of infection, skin overgrowth, and the need for revision surgery related to wound complications were significantly decreased in the longer 8.5-mm abutment group (P = 0.020, P = 0.012, P = 0.007, respectively). BMI did not correlate with decreased infection, skin overgrowth, and the need for revision surgery based on abutment length as hypothesized (P = 0.214, P = 0.206, P = 0.408). CONCLUSIONS: The 8.5-mm abutment lends to decreased complications postoperatively, including infection, skin overgrowth, and the need for revision surgery. LEVEL OF EVIDENCE: 3b.

Risks of radiation versus risks from injury: a clinical decision analysis for the management of penetrating palatal trauma in children.

OBJECTIVES/HYPOTHESIS: Penetrating palatal trauma in children presents a diagnostic dilemma regarding the small but severe risk of injury to carotid vessels. Decisions regarding which children require computed tomography with angiography must be balanced against the risk of radiation-induced malignancy. Our objectives were to compare outcomes between children with and without computed tomography with angiography in the evaluation of palatal trauma and to identify thresholds where the ideal strategy changes in the management of children with palatal trauma through sensitivity analyses. STUDY DESIGN: Decision analytic techniques were used to compare management strategies for penetrating palatal trauma. METHODS: We assigned utilities to the following outcomes: 1) perfect health, 2) future malignancy, 3) carotid injury diagnosed by computed tomography with angiography, and 4) delayed diagnosis of stroke. We calculated outcomes when the risk of stroke ranged from 0.01% to 5.0% for a hypothetical cohort of 10,000 injured children. RESULTS: Not obtaining computed tomography with angiography is the optimal strategy when the stroke risk is less than 4.5%. In two-way sensitivity analyses that consider a range of probabilities of radiation-induced malignancy and stroke, not obtaining computed tomography with angiography on all patients dominates as a strategy until the risk of stroke exceeds 2.3%, and the risk of malignancy is under 0.24%. Routine imaging would introduce 20 additional malignancies for each additional stroke diagnosed. CONCLUSIONS: Routine use of computed tomography with angiography for well-appearing children with palatal trauma should be reconsidered, as the risk of radiation-induced malignancy may outweigh the benefit of identifying the rare carotid injury. LEVEL OF EVIDENCE: 2b.

Bacteriology of the paranasal sinuses in pediatric cystic fibrosis patients.

OBJECTIVES: To review the characteristic microbiology of the paranasal sinuses in patients with cystic fibrosis who undergo endoscopic sinus surgery. To examine the subtypes of organisms cultured from the maxillary sinuses and determine their sensitivity to antibiotic therapy. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care children's hospital. METHODS: Sinus cultures were obtained from 51 patients with cystic fibrosis during endoscopic sinus procedures between 2000 and 2004 at a tertiary care children's hospital. A retrospective chart review was undertaken to obtain culture and sensitivity data of the sinus contents. RESULTS: The most common bacteria isolated was Staphylococcus aureus (71%), followed by Pseudomonas aeruginosa (PSA) (27%), Haemophilus influenzae (21%), Staphylococcus non-aureus (16%) and Streptococcus viridans (12%). Streptococcus pneumoniae and Moraxella catarrhalis were rarely isolated (2% and 0% respectively). Twenty-nine percent of the patients with cultures positive for PSA were of the mucoid variant. Only one patient had culture positive Escherichia coli. Antibiotic resistance among the more common organisms cultured from the sinus samples is also listed. CONCLUSION: Staph. aureus is the most common isolate in the sinuses of this pediatric CF population followed by P. aeruginosa and H. influenzae. Although many isolates are pansensitive, some isolates are panresistant.

Comparison of postoperative pain in pediatric patients undergoing coblation tonsillectomy versus cautery tonsillectomy.

OBJECTIVE: To compare postoperative pain scores between monopolar electrocautery and coblation subcapsular tonsillectomy. STUDY DESIGN: Prospective double-blind randomized study. SETTING: Tertiary care children's hospital. SUBJECTS AND METHODS: Between December 2004 and April 2008, 61 children, ages 4 to 20 years (mean age, 10 years; SD, 4 years), were randomized to have one tonsil removed by electrocautery and the other tonsil removed by coblation. Subjects used the FACES scale to rate pain on each side immediately postoperatively, 2 days postoperatively, and 2 weeks postoperatively. Postoperative hemorrhage was also tracked. RESULTS: Coblation tonsillectomy resulted in statistically less pain than electrocautery immediately after surgery, but this difference was not clinically significant. CONCLUSIONS: Pediatric pain is similar following monopolar electrocautery or coblation subcapsular tonsillectomy.

Minimally invasive endoscopic management of subglottic stenosis in children: success and failure.

OBJECTIVE: To assess the efficacy and safety of endoscopic management of subglottic stenosis both as a primary and as an adjunctive treatment in the pediatric population. METHODS: Retrospective review of pediatric patients with subglottic stenosis undergoing endoscopic airway procedures at a tertiary care pediatric medical center. Outcomes were assessed by systematic review to determine the success and failure of the endoscopic approach. RESULTS: Forty patients (22 male, 18 female) underwent endoscopic interventions for a diagnosis of subglottic airway stenosis between 2003 and 2006. Age ranged from 22 days old to 20 years old. Recorded degree of subglottic stenosis ranged from 10% to 99%. Fifty-three percent (21/40) had a history of prematurity, and 40% (16/40) had secondary airway diagnoses. Twenty-four patients underwent an endoscopic intervention initially (including laser or dilation, with or without topical mitomycin treatment), including four patients who underwent tracheostomy prior to the first endoscopic intervention. Sixteen underwent laryngotracheoplasty initially, including ten patients who underwent tracheostomy prior to the laryngotracheoplasty. Endoscopic treatment resulted in resolution of symptoms, and/or decannulation, and no further need for an open procedure in 58% of patients. Of the 24 patients undergoing endoscopic interventions initially, 14 patients underwent two or more endoscopic interventions, and 10 patients subsequently required tracheostomy or laryngotracheoplasty. When endoscopic procedures were used as an adjunct to laryngotracheoplasty, 60% (12/20) had resolution of symptoms, underwent decannulation, and did not require tracheostomy or revision laryngotracheoplasty. CONCLUSIONS: The endoscopic approach can be successful in the management of properly selected patients with subglottic stenosis, either as the initial treatment modality or as an adjunctive treatment in cases of re-stenosis after open airway surgery. The likelihood of success with a minimally invasive procedure as the primary treatment decreases with worsening initial grade of subglottic stenosis.

Maize DELLA proteins dwarf plant8 and dwarf plant9 as modulators of plant development.

DELLA proteins are nuclear-localized negative regulators of gibberellin signaling found ubiquitously throughout higher plants. Dominant dwarfing mutations of DELLA proteins have been primarily responsible for the dramatic increases in harvest index of the 'green revolution'. Maize contains two genetic loci encoding DELLA proteins, dwarf plant8 (d8) and dwarf plant 9 (d9). The d8 gene and three of its dominant dwarfing alleles have been previously characterized at the molecular level. Almost 20 years after the initial description of the mutant, this investigation represents the first molecular characterization of d9 and its gibberellin-insensitive mutant, D9-1. We have molecularly, subcellularly and phenotypically characterized the gene products of five maize DELLA alleles in transgenic Arabidopsis. In dissecting the molecular differences in D9-1, a critical residue for normal DELLA function has been uncovered, corresponding to E600 of the D9 protein. The gibberellin-insensitive D9-1 was found to produce dwarfing and, notably, earlier flowering in Arabidopsis. Conversely, overexpression of the D9-1 allele delayed flowering in transgenic maize, while overexpression of the d9 allele led to earlier flowering. These results corroborate findings that DELLA proteins are at the crux of many plant developmental pathways and suggest differing mechanisms of flowering time control by DELLAs in maize and Arabidopsis.