Simon R. Best

Prognostic significance of human papillomavirus in oropharyngeal squamous cell carcinomas

The human papillomavirus (HPV) has been identified as a causative factor in 20% to 25% of all head and neck squamous cell carcinomas (HNSCC). Ongoing research suggests that the presence of HPV DNA in HNSCC predicts a positive prognosis with respect to disease‐free and overall survival. However, most studies have been limited by the heterogeneity in treatment regimens and/or anatomic subsites of tumor origin. In this study, we correlate clinical outcomes with HPV status for patients with oropharyngeal carcinomas who were uniformly treated with a concurrent chemoradiation treatment protocol.

Administration of HPV DNA vaccine via electroporation elicits the strongest CD8+ T cell immune responses compared to intramuscular injection and intradermal gene gun delivery

DNA vaccines are an attractive approach to eliciting antigen-specific immunity. Intracellular targeting of tumor antigens through its linkage to immunostimulatory molecules such as calreticulin (CRT) can improve antigen processing and presentation through the MHC class I pathway and increase cytotoxic CD8+ T cell production. However, even with these enhancements, the efficacy of such immunotherapeutic strategies is dependent on the identification of an effective route and method of DNA administration. Electroporation and gene gun-mediated particle delivery are leading methods of DNA vaccine delivery that can generate protective and therapeutic levels of immune responses in experimental models. In this study, we perform a head-to-head comparison of three methods of vaccination--conventional intramuscular injection, electroporation-mediated intramuscular delivery, and epidermal gene gun-mediated particle delivery--in the ability to generate antigen-specific cytotoxic CD8+ T cell responses as well as anti-tumor immune responses against an HPV-16 E7 expressing tumor cell line using the pNGVL4a-CRT/E7(detox) DNA vaccine. Vaccination via electroporation generated the highest number of E7-specific cytotoxic CD8+ T cells, which correlated to improved outcomes in the treatment of growing tumors. In addition, we demonstrate that electroporation results in significantly higher levels of circulating protein compared to gene gun or intramuscular vaccination, which likely enhances calreticulins role as a local tumor anti-angiogenesis agent. We conclude that electroporation is a promising method for delivery of HPV DNA vaccines and should be considered for DNA vaccine delivery in human clinical trials.

The prevalence, diagnosis, and management of voice disorders in a National Ambulatory Medical Care Survey (NAMCS) cohort†‡§

The purpose of this study was to analyze the prevalence, presentation, and treatment of voice complaints (VC) using a national cohort of ambulatory care patients and describe how this care conforms to guidelines for the treatment of vocal disorders.

Biology of Human Papillomavirus Infection and Immune Therapy for HPV-Related Head and Neck Cancers

This article outlines the biology of human papillomavirus (HPV) infection of human mucosa and the cellular pathways that are altered through viral infection. The article provides a conceptual framework with which to understand the 2 major immunologic strategies to address HPV-related diseases: (1) prevention of primary HPV infection through the use of prophylactic vaccines and (2) treatment of established infection and diseases through therapeutic vaccines. Nonimmunologic therapy that targets cellular dysregulation induced by HPV infection is also discussed. The challenges in actualizing these conceptually attractive therapies on both a societal and biological level are examined.

Factors associated with pharyngoesophageal stricture in patients treated with concurrent chemotherapy and radiation therapy for oropharyngeal squamous cell carcinoma.

The purpose of this study was to elucidate factors associated with pharyngoesophageal strictures after treatment for head and neck squamous cell carcinoma (SCC).

Characterization of human papillomavirus type 11-specific immune responses in a preclinical model

Human papillomavirus (HPV) types 6 and 11 are associated with recurrent respiratory papillomatosis (RRP). Although a prophylactic vaccine has been developed that protects against HPV infection, a therapeutic vaccine is still needed for those patients infected with and/or suffering from persistent disease. Therefore, we developed a novel, therapeutic DNA vaccine targeting HPV‐11 and characterized the in vivo immunologic responses generated against HPV‐11 E6 and E7 after DNA vaccination in a preclinical model.

Risk Factors for Dysplasia in Recurrent Respiratory Papillomatosis in an Adult and Pediatric Population

Aim: Recurrent respiratory papillomatosis (RRP) is classically described as a benign neoplasm of the larynx caused by the low-risk human papillomavirus (HPV) viral subtypes. Nevertheless, transformation to dysplasia and invasive carcinoma can occur. We aimed to assess the prevalence of dysplasia and carcinoma-ex-papilloma in both adult-onset and juvenile-onset RRP and identify patient risk factors for this dysplastic transformation. Material and Methods: Ten-year retrospective chart review of a tertiary otolaryngology referral center. Patients with papilloma were identified from a review of a pathology database and clinical records. Patient demographics, pathologic data, and treatment history, including use of cidofovir as an adjunctive therapy for papilloma, were extracted from electronic medical records. Results: One hundred fifty-nine RRP patients were identified, 96 adult-onset (AORRP) and 63 juvenile-onset (JORRP) cases. Of this cohort, 139 (87%) had only benign papilloma as a pathologic diagnosis. In the AORRP cohort, 10 patients (10%) were diagnosed with dysplasia or carcinoma in situ in addition to papilloma, and 5 patients (5%) had malignant transformation to invasive carcinoma-ex-papilloma. There was a significantly higher age of disease onset for those with dysplasia or carcinoma versus those without dysplasia or carcinoma (56 vs 45 years old; P = .0005). Of the 63 JORRP patients, there were no cases of dysplasia but 3 (5%) cases of invasive carcinoma-ex-papilloma, all involving pulmonary disease. The JORRP patients with carcinoma-ex-papilloma had a younger average disease onset (2 vs 6 years old; P = .009) and a higher rate of tracheal involvement than those without carcinoma. Gender, smoking history, number of operations, or use of cidofovir showed no association with the development of dysplasia or carcinoma-ex-papillomatosis in either the AORRP or JORRP population. Conclusion: In a large series of RRP, age of disease onset is the strongest predictor of dysplastic transformation in the adult and pediatric population. Carcinoma-ex-papillomatosis was uniformly associated with pulmonary disease in the JORRP population in this series. No other demographic or behavioral factors, including adjunctive therapy with cidofovir, were statistically associated with dysplasia or carcinoma-ex-papilloma.

Voice quality in laryngotracheal stenosis: impact of dilation and level of stenosis.

Objective: To assess the impact of suspension microlaryngoscopy with balloon dilation on voice-related quality of life (V-RQOL) in laryngotracheal stenosis (LTS). Methods: Retrospective chart review of LTS patients dilated at a tertiary-care academic hospital from 2010 to 2013. Data were obtained and then analyzed. LTS was stratified by (1) subglottic or tracheal stenosis and (2) multilevel stenosis (MLS; glottic and subglottic/tracheal). Pre- and postoperative V-RQOL and grade, roughness, breathiness, asthenia, strain (GRBAS) scores were compared. The number and frequency of balloon dilation procedures over the lifetime were secondary outcome variables. Results: Thirty-eight patients were identified: 26 subglottic/tracheal and 12 multilevel. Of these, 71.4% required multiple dilations, with greatest dilations/patient for multilevel stenosis (4.8). V-RQOL improved in the 27 patients with completed pre- and postoperative scores from a mean of 70.4 to 80 (P = .025). Pre/postoperative V-RQOLs for tracheal/subglottic (mean, 82.8/93.8) were significantly higher (P = .0001/.0001) than multilevel stenosis (48/55.3). Voice quality-of-life improvement was significant for the subglottic/tracheal cohort (P = .036) but not for the MLS group. GRBAS was performed pre- and postoperatively in 10 patients with improvement in all domains except breathiness. Conclusion: Laryngotracheal stenosis is associated with dysphonia. Patients with glottic involvement have significantly worse voice quality of life than those with tracheal/subglottic stenosis. Endoscopic balloon dilation improves V-RQOL in patients with subglottic/tracheal stenosis.

Prevalence, Characteristics, and Management of Swallowing Disorders following Cerebellopontine Angle Surgery:

Objective. To describe swallowing disorders encountered after cerebellopontine angle surgery and to explore variables associated with increased incidence of postoperative dysphagia. Study Design. Case series with chart review. Setting. Single academic medical institution. Subjects and Methods. Chart review of 181 consecutive patients undergoing surgical excision of cerebellopontine angle pathology from January 2008 to December 2010 at the Johns Hopkins Hospital. Presence and characteristics of dysphagia were determined by review of speech pathologist reports. Other clinical variables were extracted from the electronic medical record, and statistical analyses were applied to determine factors associated with postoperative dysphagia. Results. Immediate postoperative dysphagia was identified in 57 of 181 patients (31%). Oral, oropharyngeal, and pharyngeal deficits accounted for 51%, 37%, and 12% of dysphagic symptoms, respectively. Facial nerve weakness in the immediate postoperative period was noted in 91% of dysphagic subjects compared with 43% of those without. Mean House-Brackmann score for dysphagic individuals was 4 compared with 2 in the nondysphagic group. Diet alterations were required for 65% of dysphagic individuals, and an additional 9% required tube feeding. Common findings during videofluoroscopic swallowing studies were pharyngeal residue, reduced pharyngeal constriction, and anterior bolus loss. Abnormal penetration-aspiration scores (≥3) were found in 59% of those undergoing videofluoroscopic swallow studies. Conclusions. Oral and pharyngeal swallowing deficits are commonly encountered after cerebellopontine angle surgery. Consultation with the speech-language pathologist appears most critical for any individuals demonstrating postoperative cranial nerve dysfunction, particularly for those with evidence of facial nerve weakness. Early consultation may help to manage short- and long-term functional difficulties.

Risk Factors for Vagal Palsy following Cerebellopontine Angle Surgery

Objective Describe the incidence, risk factors, and outcomes of postoperative vagal palsy in patients undergoing surgical excision of cerebellopontine angle (CPA) tumors. Study Design Case series with chart review. Setting Academic tertiary care center. Subjects and Methods One hundred eighty-one consecutive patients undergoing surgical excision of CPA pathology from January 1, 2008, to December 31, 2010, at Johns Hopkins Hospital. Postoperative unilateral vagal palsy was identified by laryngoscopy or videofluoroscopy, and clinical variables were collected from medical records. Results Postoperative unilateral vagal palsy was identified in 19 of 181 (10%) patients. Vocal fold motion impairment (VFMI) in combination with pharyngeal palsy was more common than VFMI or pharyngeal palsy alone. Those with vagal palsy had a larger mean tumor size (30 mm) than those without vagal palsy (20 mm, P = .0002) and a significantly longer mean hospital stay (9 vs 5 days, P < .0001). Vagal palsy was not associated with tumor pathology, prior treatment (stereotactic radiation or prior surgery), or surgical approach (suboccipital craniotomy vs translabyrinthine approach). Significant rates of aspiration were observed in patients with vagal palsy (67%). Conclusion Voice and swallowing function can be affected by surgical excision of pathology of the CPA. Tumor size is an independent risk factor for postoperative vagal palsy, which in turn has important consequences for prolonged hospital stay, aspiration, and voice and swallowing impairment.