Pencil Beam Scanning Proton Therapy as Single Vocal Cord Irradiation for Early-Stage Glottic Cancer.

Purpose: Single vocal cord irradiation (SVCI) is a promising technique to maintain excellent oncologic control and potentially improve upon toxicities for treatment of early-stage glottic squamous cell carcinomas. We sought to investigate whether pencil beam scanning (PBS) proton therapy could improve upon the already favorable dose gradients demonstrated with volumetric modulated arc therapy (VMAT) SVCI. Patients and Methods: A 64-year-old gentleman was treated in our department with 6X-flattening filter-free VMAT SVCI to 58.08 Gy in 16 fractions for a T1a well-differentiated squamous cell carcinoma of the left true vocal cord and tolerated it well with good local control. Comparative PBS plans were created in Raystation for the Varian ProBeam with clinical target volume (CTVs) generated to mimic the prescription target volume extent of the VMAT planning target volumes when accounting for PBS plan robustness (±3 mm translational shifts, 3.5% density perturbation). A 3-field single-field optimization plan was selected as dosimetrically preferable. Dosimetric variables were compared. Results: Several organs at risk doses improved with PBS, including the maximum and mean dose to ipsilateral carotids, maximum and mean dose to contralateral carotid, maximum dose to the spinal cord, maximum and mean dose to inferior constrictor/cricopharyngeus, maximum and mean dose to the uninvolved vocal cord, and mean dose to the thyroid gland. There are tradeoffs in skin dose depending on location relative to the target-with the highest and lowest isodoses extending more into the skin with the VMAT plan but with the moderate isodose lines covering a wider area with the PBS plan, but we deemed it tolerable regardless. Conclusion: SVCI is a promising strategy for maintaining the oncologic effectiveness of whole-larynx photon radiation while potentially improving upon the historic toxicity profile. The favorable dose distribution with PBS with respect to organs at risk dosimetry for PBS may allow for further improvements upon VMAT SVCI strategies. Clinical implementation of PBS SVCI may be considered.

Posterior Glottic Injury Following Prolonged Intubation in COVID-19 Patients.

OBJECTIVE: The objective of this study was to characterize the risk factors for posterior glottic injury (PGI) in patients with coronavirus disease 2019 (COVID-19) who underwent prolonged intubation. STUDY DESIGN: This was a case-control study designed to assess the risk factors associated with development of PGI in COVID-19 patients who underwent prolonged intubation. SETTING: This single-center study was conducted at a tertiary care academic hospital in a metropolitan area. METHODS: We retrospectively reviewed patients who underwent prolonged intubation (≥7 days) for COVID-19 and compared those with PGI to those without. Patient demographics, comorbidities, and intubation characteristics were compared. Factors associated with PGI development among COVID-19 patients were assessed using multivariate regression. RESULTS: We identified 56 patients who presented with PGI following prolonged intubation for COVID-19 and 60 control patients who underwent prolonged intubation for COVID-19 but did not develop PGI. On univariate analyses, the number of reintubations due to failed extubation efforts was significantly associated with development of PGI (odds ratio [OR], 2.9; 95% CI, 1.4-6.2). On multivariate analyses, patients with cardiovascular disease (OR, 3.3; 95% CI, 1.2-9.0); non-COVID-19 respiratory illnesses, which included obstructive sleep apnea and asthma (OR, 5.9; 95% CI, 2.0-17.8); and diabetes mellitus (OR, 11.6; 95% CI, 3.7-36.6) were more likely to develop PGI. CONCLUSION: Our results represent the largest case-control study investigating risk factors for PGI in the setting of prolonged intubation specific to COVID-19. Our study suggests a significant role of comorbidities associated with poor wound healing with development of PGI.

Response of Laryngopharyngeal Symptoms to Transoral Incisionless Fundoplication in Patients with Refractory Proven Gastroesophageal Reflux.

OBJECTIVE: Patients with laryngopharyngeal reflux (LPR) symptoms may not respond to proton pump inhibitors (PPI) if they have an alternative laryngeal diagnosis or high-volume reflux. Transoral incisionless fundoplication (TIF) or TIF with concomitant hiatal hernia repair (cTIF) are effective in decreasing symptoms of gastroesophageal reflux disease (GERD) but are not well studied in patients with LPR symptoms. This prospective multicenter study assessed the patient-reported and clinical outcomes after TIF/cTIF in patients with LPR symptoms and proven GERD. METHODS: Patients with refractory LPR symptoms (reflux symptom index [RSI] > 13) and with erosive esophagitis, Barrett's esophagus, and/or pathologic acid reflux by distal esophageal pH testing were evaluated before and after a minimum of 6 months after TIF/cTIF. The primary outcome was normalization of RSI. Secondary outcomes were >50% improvement in GERD-Health-Related Quality of Life (GERD-HRQL), normalization of esophageal acid exposure time, discontinuation of PPI, and patient satisfaction. RESULTS: Forty-nine patients had TIF (n = 26) or cTIF (n = 23) with at least 6 months follow-up. Mean pre- and post TIF/cTIF RSI were 23.6 and 5.9 (mean difference: 17.7, P < .001). Post TIF/cTIF, 90% of patients had improved GERD-HQRL score, 85% normalized RSI, 75% normalized esophageal acid exposure time, and 80% discontinued PPI. No serious procedure-related adverse events occurred. Patient satisfaction was 4% prior to TIF/cTIF and 73% after TIF/cTIF (P < .001). CONCLUSION: In patients with objective evidence of GERD, TIF, or cTIF are safe and effective in controlling LPR symptoms as measured by normalization of RSI and improvement in patient satisfaction after TIF/cTIF. LEVEL OF EVIDENCE: Level 4.

Readability of Online Materials Related to Vocal Cord Leukoplakia.

OBJECTIVES: To assess readability and understandability of online materials for vocal cord leukoplakia. STUDY DESIGN: Review of online materials. SETTING: Academic medical center. METHODS: A Google search of "vocal cord leukoplakia" was performed, and the first 50 websites were considered for analysis. Readability was measured by the Flesch Reading Ease Score (FRES), Flesch-Kincaid Grade Level (FKGL), and Simple Measure of Gobbledygook (SMOG). Understandability and actionability were assessed by 2 independent reviewers with the PEMAT-P (Patient Education Materials Assessment Tool for Printable Materials). Unpaired t tests compared scores between sites aimed at physicians and those at patients, and a Cohen's kappa was calculated to measure interrater reliability. RESULTS: Twenty-two websites (17 patient oriented, 5 physician oriented) met inclusion criteria. For the entire cohort, FRES, FKGL, and SMOG scores (mean ± SD) were 36.90 ± 20.65, 12.96 ± 3.28, and 15.65 ± 3.57, respectively, indicating that materials were difficult to read at a >12th-grade level. PEMAT-P understandability and actionability scores were 73.65% ± 7.05% and 13.63% ± 22.47%. Statistically, patient-oriented sites were more easily read than physician-oriented sites (P < .02 for each of the FRES, FKGL, and SMOG comparisons); there were no differences in understandability or actionability scores between these categories of sites. CONCLUSION: Online materials for vocal cord leukoplakia are written at a level more advanced than what is recommended for patient education materials. Awareness of the current ways that these online materials are failing our patients may lead to improved education materials in the future.

Clinical Excellence in Otolaryngology-Head and Neck Surgery: Examples from the Published Literature.

OBJECTIVE/HYPOTHESIS: To apply the domains of clinical excellence, as published by the Miller-Coulson Academy of Clinical Excellence, to the field of otolaryngology-head and neck surgery (OHNS) as a framework for evaluating and improving clinical excellence. METHODS: A search of PubMed, Scopus, the Cochrane Library, and the National Institute for Health and Care Excellence (NICE) databases was performed and 229 publications were reviewed. RESULTS: Case reports and other articles were selected that exemplify each of the distinct domains of clinical excellence within our specialty. CONCLUSIONS: The Miller-Coulson Academy's domains of clinical excellence are relevant to OHNS and can provide a framework for fostering clinical excellence in otolaryngologists. The many examples of excellent care by otolaryngologists found in the published literature can inspire otolaryngologists to provide outstanding care to all patients consistently and to advance our specialty. LEVEL OF EVIDENCE: N/A Laryngoscope, 131:E2153-E2158, 2021.

Predictors of Tracheostomy Decannulation in Adult Laryngotracheal Stenosis.

OBJECTIVE: Predictors of tracheostomy decannulation in patients with laryngotracheal stenosis are not fully known, making prognosis difficult. The aim was to identify predictors of tracheostomy decannulation in adult patients with acquired stenosis of the larynx and/or trachea who were tracheostomy dependent. STUDY DESIGN: Case series. SETTING: Academic teaching hospital. METHODS: A total of 103 consecutive adult patients with laryngotracheal stenosis who were tracheostomy dependent and seen by the otolaryngology clinic from January 1, 2013, to August 2, 2018, were included. Exclusion criteria included age <18 years, history of laryngeal cancer or head and neck radiation, or history of laryngeal fracture. The primary outcome was the presence of tracheostomy at last follow-up. The patients' etiology of stenosis, comorbid conditions, and characteristics of the stenosis were analyzed to determine if there was a statistically significant relationship with decannulation. RESULTS: A total of 103 patients were included: 67% of patients were women and the average age was 53.5 years. Sixty-four patients (62%) were successfully decannulated. In multivariate analysis, patients who were successfully decannulated presented to the otolaryngology clinic earlier after tracheostomy was performed, were more likely to have been intubated due to trauma, and were less likely to have gastroesophageal reflux disease. In patients with subglottic or tracheal stenosis, those with granulation tissue without firm scar were more likely to be decannulated, and those who underwent rigid dilation were less likely to be decannulated. CONCLUSION: Early evaluation by an otolaryngologist may increase the likelihood of tracheostomy decannulation in patients with laryngotracheal stenosis. Patient comorbidities may assist in predicting which patients will be successfully decannulated.

SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2.

Comparison of tumors from The Cancer Genome Atlas (TCGA) reveals that head and neck squamous cell carcinomas (HNSCC) harbor the most frequent genomic amplifications of Fas-associated death domain (FADD), with or without Baculovirus inhibitor of apoptosis repeat containing BIRC2 (cIAP1), affecting about 30% of patients in association with worse prognosis. Here, we identified HNSCC cell lines harboring FADD/BIRC2 amplifications and overexpression by exome sequencing, RT-PCR, and Western blotting. In vitro, FADD or BIRC2 siRNA knockdown inhibited HNSCC displaying amplification and increased expression of these genes, supporting their functional importance in promoting proliferation. Birinapant, a novel SMAC mimetic, sensitized multiple HNSCC lines to cell death by agonists TNFα or TRAIL and inhibited cIAP1>XIAP>IAP2. Combination of birinapant and TNFα induced sub-G0 DNA fragmentation in sensitive lines and birinapant alone also induced significant G2-M cell-cycle arrest and cell death in UM-SCC-46 cells. Gene transfer and expression of FADD sensitized resistant UM-SCC-38 cells lacking FADD amplification to birinapant and TNFα, supporting a role for FADD in sensitization to IAP inhibitor and death ligands. HNSCC varied in mechanisms of cell death, as indicated by reversal by inhibitors or protein markers of caspase-dependent apoptosis and/or RIPK1/MLKL-mediated necroptosis. In vivo, birinapant inhibited tumor growth and enhanced radiation-induced TNFα, tumor responses, and host survival in UM-SCC-46 and -11B xenograft models displaying amplification and overexpression of FADD+/- BIRC2 These findings suggest that combination of SMAC mimetics such as birinapant plus radiation may be particularly active in HNSCC, which harbor frequent FADD/BIRC2 genomic alterations. Cancer Res; 76(18); 5442-54. ©2016 AACR.

Combination effects of SMAC mimetic birinapant with TNFα, TRAIL, and docetaxel in preclinical models of HNSCC.

OBJECTIVES/HYPOTHESIS: Head and neck squamous cell carcinoma (HNSCC) cells are resistant to cell death induced by tumor necrosis factor ligands such as tumor necrosis factor α (TNFα) or TNF-related apoptosis-inducing ligand (TRAIL) and cytotoxic chemotherapies. Recently, genetic alterations in cell death pathways, including inhibitor of apoptosis proteins, have been demonstrated in HNSCC. We investigated the effects of birinapant, a novel, second mitochondria-derived activator of caspases (SMAC)-mimetic that targets inhibitor of apoptosis proteins, alone and in combination with TNFα, TRAIL, or chemotherapy docetaxel. STUDY DESIGN: Experimental study using human HNSCC cell lines in vitro and xenograft mouse model in vivo. METHODS: A panel of HNSCC cell lines with varying genetic alterations in cell death pathway components were treated with birinapant ± TNFα, TRAIL, and docetaxel and were assessed for effects on cell density, cell cycle, and death. Synergism was determined at varying concentrations of treatments using the Chou-Talalay method. Combination studies using birinapant ± docetaxel were performed in a xenograft mouse model. RESULTS: Birinapant, alone or in combination with TNFα or TRAIL, decreased cell density in cell lines, with IC50 s ranging from 0.5 nM to > 1 µM. Birinapant alone or with TNF significantly increased subG0 cell death in different lines. Docetaxel showed synergism with birinapant ± TNFα in vitro. Birinapant monotherapy-inhibited growth in a tumor xenograft model resistant to docetaxel, and combination treatment further delayed growth. CONCLUSIONS: Birinapant alone or in combination with TNFα or TRAIL and docetaxel decreased cell density, increased cell death, and displayed antitumor activity in a preclinical HNSCC xenograft exhibiting aberrations in cell death pathway components and docetaxel resistance.

Review article: Research on dengue during World War II revisited.

Much of the basic clinical information about dengue infection comes from experimental human studies conducted in the 1920s and 1940s. Albert Sabin's original laboratory records from one such study were bequeathed to Duane J. Gubler. These records were reviewed and 150 experiments were included in our analyses. Persons were inoculated with dengue virus 1 (DENV-1) and DENV-2. Median fever duration was shorter in primary DENV-2 infections compared with DENV-1, although maximum temperature and severity of illness were comparable. At 1.5-9 months after primary infection, 20 persons were inoculated with the heterologous serotype. Only one person inoculated with a heterologous serotype at < 8 weeks showed development of a clinical infection with a maximum temperature of 38°C, and 7 (88%) of 8 persons inoculated with a heterologous serotype at 4-9 months post-primary infection showed development of fever. On average, persons had a shorter incubation period in secondary infection compared with primary infection.

Chemoprevention of head and neck squamous cell carcinoma through inhibition of NF-κB signaling.

Nuclear factor-kappa B (NF-κB) transcription factors regulate cellular processes such as inflammation and cell survival. The NF-κB pathway is often activated with development and progression of head and neck squamous cell carcinoma (HNSCC). As such, NF-κB represents an attractive target for chemoprevention. HNSCC involves progression of lesions from premalignant to malignant, providing a window of opportunity for intervention with chemopreventive agents. Appropriate chemopreventive agents should be inexpensive, nontoxic, and target important pathways involved in the development of HNSCC. Several such agents that inhibit the NF-κB pathway have been investigated in HNSCC. Retinoids have been studied most extensively but have shown limited potential in human trials. Epidermal growth factor receptor inhibitors and PI3K-mTOR inhibitors may benefit a subset of patients. Other agents such as green tea extract and curcumin are appealing because they are generally regarded as safe. In contrast, there is evidence that Vitamin E supplementation may actually increase mortality of cancer patients. Repurposed drugs such as cyclooxygenase (COX) inhibitors and antidiabetic drugs are an emerging area of interest. Future research to develop agents with lower toxicity and higher specificity for the NF-κB pathway, and to target these therapies to individual patient genetic signatures should help to increase the utility of chemoprevention in HSNCC.

Wnt pathway reprogramming during human embryonal carcinoma differentiation and potential for therapeutic targeting.

BACKGROUND: Testicular germ cell tumors (TGCTs) are classified as seminonas or non-seminomas of which a major subset is embryonal carcinoma (EC) that can differentiate into diverse tissues. The pluripotent nature of human ECs resembles that of embryonic stem (ES) cells. Many Wnt signalling species are regulated during differentiation of TGCT-derived EC cells. This study comprehensively investigated expression profiles of Wnt signalling components regulated during induced differentiation of EC cells and explored the role of key components in maintaining pluripotency. METHODS: Human embryonal carcinoma cells were stably infected with a lentiviral construct carrying a canonical Wnt responsive reporter to assess Wnt signalling activity following induced differentiation. Cells were differentiated with all-trans retinoic acid (RA) or by targeted repression of pluripotency factor, POU5F1. A Wnt pathway real-time-PCR array was used to evaluate changes in gene expression as cells differentiated. Highlighted Wnt pathway genes were then specifically repressed using siRNA or stable shRNA and transfected EC cells were assessed for proliferation, differentiation status and levels of core pluripotency genes. RESULTS: Canonical Wnt signalling activity was low basally in undifferentiated EC cells, but substantially increased with induced differentiation. Wnt pathway gene expression levels were compared during induced differentiation and many components were altered including ligands (WNT2B), receptors (FZD5, FZD6, FZD10), secreted inhibitors (SFRP4, SFRP1), and other effectors of Wnt signalling (FRAT2, DAAM1, PITX2, Porcupine). Independent repression of FZD5, FZD7 and WNT5A using transient as well as stable methods of RNA interference (RNAi) inhibited cell growth of pluripotent NT2/D1 human EC cells, but did not appreciably induce differentiation or repress key pluripotency genes. Silencing of FZD7 gave the greatest growth suppression in all human EC cell lines tested including NT2/D1, NT2/D1-R1, Tera-1 and 833K cells. CONCLUSION: During induced differentiation of human EC cells, the Wnt signalling pathway is reprogrammed and canonical Wnt signalling induced. Specific species regulating non-canonical Wnt signalling conferred growth inhibition when targeted for repression in these EC cells. Notably, FZD7 repression significantly inhibited growth of human EC cells and is a promising therapeutic target for TGCTs.