No abstract

Head and neck cancer is disfiguring and deadly, and contemporary treatment has fallen short in terms of morbidity and mortality. The rich immune infiltrate within these tumors designates them as prime candidates for immunotherapy and success with these drugs has been documented for recurrent and metastatic head and neck cancer. Still, single-agent immunotherapy has generated either only transient responses or durable response in only a minority subset of patients. Mapping the immune escape mechanisms enacted by head and neck cancer within the tumor microenvironment allows for rational design of strategies to overcome this tolerance. We outline the immune pathway derangements within the head and neck cancer microenvironment and discuss combination treatment strategies to overcome the limitations of immunologic monotherapy.

This large study of CBTs demonstrates the value of preoperatively determining tumor dimensions and how far the tumor is located from the base of the skull. DTBOS and tumor volume, when used in combination with the Shamblin grade, better predict bleeding and cranial nerve injury risk. Furthermore, surgical resection before expansion toward the base of the skull reduces complications as every 1-cm decrease in the distance to the skull base results in 1.8 times increase in >250 mL of blood loss and 1.5 times increased risk of cranial nerve injury.

No abstract

Leukocidin ED (LukED) is a bicomponent pore-forming toxin produced by Staphylococcus aureus that lyses host cells by targeting the chemokine receptors CC chemokine receptor type 5 (CCR5), CXCR1, CXCR2, and DARC. In addition to its role as a receptor for LukED, CCR5 is the major coreceptor for primary isolates of human immunodeficiency virus type 1 (HIV-1) and has been extensively studied. To compare how LukED and HIV-1 target CCR5, we analyzed their respective abilities to use CCR5/CCR2b chimeras to mediate cytotoxicity and virus entry. These analyses showed that the second and third extracellular loops (ECL) of CCR5 are necessary and sufficient for LukED to target the receptor and promote cell lysis. In contrast, the second ECL of CCR5 is necessary but not sufficient for HIV-1 infectivity. The analysis of CCR5 point mutations showed that glycine-163 is critical for HIV-1 infectivity, while arginine-274 and aspartic acid-276 are critical for LukED cytotoxicity. Point mutations in ECL2 diminished both HIV-1 infectivity and LukED cytotoxicity. Treatment of cells with LukED did not interfere with CCR5-tropic HIV-1 infectivity, demonstrating that LukED and the viral envelope glycoprotein use nonoverlapping sites on CCR5. Analysis of point mutations in LukE showed that amino acids 64 to 69 in the rim domain are required for CCR5 targeting and cytotoxicity. Taking the results together, this study identified the molecular basis by which LukED targets CCR5, highlighting the divergent molecular interactions evolved by HIV-1 and LukED to interact with CCR5.

The objective of this study was to determine temporal trends of dysphagia diagnoses in hospitalized children. This is a retrospective observational study from the 1997-2012 Kids' Inpatient Database (KID) conducted in the setting of weighted hospitalizations in a KID participating center. More than 6 million pediatric admissions were captured in each triennial KID report. Main outcomes included triennial rates of dysphagia diagnosis in hospitalized pediatric patients, and secondary outcomes included rates of dysphagia in premature and low-birthweight infants. Dysphagia diagnoses were coded in 5107/6607653 (0.08%) of these admissions in 1997, rising to 27,464/6,675,222 (0.41%) in 2012 (p < 0.001). The portion of these diagnoses in premature neonates has been increasing over time from 162/9551 (1.7%) in 2003 to 1027/27,464 (3.7%) by 2012 (p < 0.001). Similarly, low-birthweight children constituted 40/5107 (0.8%) of dysphagia diagnoses in 1997, a number that increased to 762/27,464 (2.8%) in 2012. Rates of dysphagia are increasing nationally, particularly in premature and low-birthweight infants, which may represent an increase alongside other neuroanatomic abnormalities. This growing problem illustrates the need for better data on the comparative efficacy of diagnostic and treatment modalities.

No abstract

2574 Background: Oral cavity squamous cell carcinoma (OCSCC) is a highly prevalent surgically-treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer, but has not been validated in the neoadjuvant presurgical setting. Methods: A Simon two stage design was used in this single-arm, Phase II clinical trial with a preplanned analysis after completion of stage one. The first stage included 9 patients with stage II-IVA OCSCC who received 3-4 biweekly doses of 3mg/kg Nivolumab (anti-programmed death 1 [PD-1]) followed by definitive surgical resection for cure. The primary endpoint was overall response rate to treatment. Secondary endpoints were safety and feasibility. Results: Presurgical Nivolumab therapy resulted in an overall response rate of 44% (95% CI: 14-79%) with four patients having >30% reduction in tumor size consistent with partial response. An additional patient had stable disease while the remaining four patients progressed through treatment. Neoadjuvant Nivolumab was not associated with delays in definitive surgical treatment. There were no grade 3-4 adverse events and no treatment interruptions. At median follow up of 10 months (2-16), there were 4 recurrences in 3 patients and one death. Objective response by RECIST 1.1 criteria on interval imaging predicated eventual pathologic response in 100% of patients. Conclusions: Neoadjuvant presurgical PD-1 blockade is associated with encouraging response rate and demonstrates feasibility and safety for OCSCC. Clinical trial information: NCT03021993.