PD-1 blockade induces responses by inhibiting adaptive immune resistance.

Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.

Identification of Perinatal Risk Factors for Auditory Neuropathy Spectrum Disorder.

OBJECTIVES/HYPOTHESIS: To identify medical risk factors associated with auditory neuropathy spectrum disorder (ANSD). STUDY DESIGN: Retrospective case-control study. METHODS: During a 2-year period (2013-2014) patients with newly diagnosed ANSD were identified at a tertiary care facility. Twenty-two patients (n = 22) were identified aged 0.5 to 8.1 years. There were 15 males and seven females. Sixteen had bilateral, four had left-sided, and two had right-sided ANSD. Two age-matched, side-matched, and gender-matched control groups were then collected. The first group was 22 normal-hearing children (n = 22). The second was 22 children with sensorineural hearing loss (SNHL) (n = 22) who did not meet the criteria for ANSD. The chart of each subject was reviewed for the following five-predictor variables: prematurity, low birth weight, jaundice, use of mechanical ventilation, and administration of ototoxic medications. Analysis of variance was performed to analyze the prevalence of perinatal risk factors among the three groups. Multivariate linear regression was then applied. RESULTS: When comparing the ANSD group to both the normal-hearing and SNHL groups, the subjects with ANSD had statistically significant higher rates of prematurity, low birth weight, jaundice, and mechanical ventilation. Multiple regression analysis was performed to identify predictors of ANSD compared to each control group individually. Jaundice in the first month of life approached significance when comparing the ANSD group to the normal-hearing group, and was the only medical risk factor found to be statistically significant when comparing the ANSD group to the SNHL group. CONCLUSIONS: A history of neonatal hyperbilirubinemia was significantly more common in children with ANSD compared to children with severe SNHL. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:671-674, 2021.

Single Layer Biomaterial Repair of Frontal Sinus Encephalocele in a Pediatric Patient.

INTRODUCTION: Reconstruction of skull base defects are determined by size, location, and complexity of the defect. METHODS: Case report. CASE DISCUSSION: An 11-year old girl presented with a right frontoethmoidal encephalocele after an episode of meningitis. An endoscopic approach was performed with a Draf III to provide exposure. The skull base defect extended superolateral over the orbit, which limited the choice of reconstructive options. The defect was successfully repaired with a single layer onlay graft of bovine collagen matrix. CONCLUSIONS: Single layer repairs using commercial biomaterials should be considered where multilayer closure or vascularized flaps may not be possible. Laryngoscope, 131:E1750-E1752, 2021.

30-Day readmission rates, diagnoses, and risk factors following pediatric airway surgery.

BACKGROUND: In the last few decades, the increased survival of premature infants and critically ill children have led to the increased frequency and complexity of pediatric airway procedures. Minimizing readmission rates following these procedures is important to maximize health outcomes and cost effectiveness. This study examines the incidence, reasons, and risk factors for hospital readmissions following pediatric airway surgeries in a large, nationally representative sample. METHODS: Pediatric airway surgeries performed across 22 states in 2014 were identified using data from the Nationwide Readmissions Database (NRD). Airway surgeries were identified and categorized using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes into the following categories: tracheostomy, repair of larynx, repair of trachea, laryngeal excision, tracheal excision, bronchoscopy, laryngoscopy, laryngotracheal diagnostic procedures, other operations on larynx, and other operations on trachea. Univariate and multivariate analyses were used to identify factors significantly correlated with readmissions. RESULTS: 10,289 pediatric airway procedures over 7120 visits were identified. 954 readmissions were identified for an overall readmission rate of 13.4%. 613 of these readmissions were related to the initial procedure, yielding a relevant readmission rate of 8.6%. On univariate analysis, factors that varied significantly with readmission rates included number of diagnoses on record (OR 1.06), number of chronic conditions (OR 1.18), number of procedures (OR 1.07), public insurance status (OR 1.39), bottom quartile median household income in patient zip code (OR 1.29), teaching hospital status (OR 1.60), and chronic perinatal respiratory disease (OR 1.45). On multivariate analysis, significant predictors included number of diagnoses (OR 1.02), number of chronic conditions (OR 1.13), and bottom quartile median household income in patient zip code (OR 1.20). The most common categories for readmission were respiratory distress (36%), infection (24%), and pneumonia (14%). The top overall individual reasons for readmission were stenosis of larynx (7.3%) and pneumonia (5.9%). CONCLUSIONS: Pediatric airway surgeries have relatively high rates of readmission. Strategies to reduce readmissions should involve addressing health disparities and employing a multidisciplinary approach to improve care for medically complex patients.

Ankyloglossia superior syndrome: Case report and updated literature review.

Ankyloglossia superior (palatoglossal adhesion) is an extremely rare congenital condition with only 14 previously reported cases. When found in conjunction with other congenital abnormalities, such as cleft palate, gastrointestinal malformations, and limb malformations, this anomaly is considered part of ankyloglossia superior syndrome. We present a case of a newborn female found to have ankyloglossia superior syndrome. Surgical repair is also described. We review the available literature and discuss theories regarding the etiology of ankyloglossia superior syndrome. Clinicians should have a high degree of suspicion for other congenital anomalies when a neonate is found to have ankyloglossia superior.

Improving education under work-hour restrictions: comparing learning and teaching preferences of faculty, residents, and students.

BACKGROUND: Faced with work-hour restrictions, educators are mandated to improve the efficiency of resident and medical student education. Few studies have assessed learning styles in medicine; none have compared teaching and learning preferences. Validated tools exist to study these deficiencies. Kolb describes 4 learning styles: converging (practical), diverging (imaginative), assimilating (inductive), and accommodating (active). Grasha Teaching Styles are categorized into "clusters": 1 (teacher-centered, knowledge acquisition), 2 (teacher-centered, role modeling), 3 (student-centered, problem-solving), and 4 (student-centered, facilitative). STUDY DESIGN: Kolb's Learning Style Inventory (HayGroup, Philadelphia, Pennsylvania) and Grasha-Riechmann's TSS were administered to surgical faculty (n = 61), residents (n = 96), and medical students (n = 183) at a tertiary academic medical center, after informed consent was obtained (IRB # 06-0612). Statistical analysis was performed using χ(2) and Fisher exact tests. RESULTS: Surgical residents preferred active learning (p = 0.053), whereas faculty preferred reflective learning (p < 0.01). As a result of a comparison of teaching preferences, although both groups preferred student-centered, facilitative teaching, faculty preferred teacher-centered, role-modeling instruction (p = 0.02) more often. Residents had no dominant teaching style more often than surgical faculty (p = 0.01). Medical students preferred converging learning (42%) and cluster 4 teaching (35%). Statistical significance was unchanged when corrected for gender, resident training level, and subspecialization. CONCLUSIONS: Significant differences exist between faculty and residents in both learning and teaching preferences; this finding suggests inefficiency in resident education, as previous research suggests that learning styles parallel teaching styles. Absence of a predominant teaching style in residents suggests these individuals are learning to be teachers. The adaptation of faculty teaching methods to account for variations in resident learning styles may promote a better learning environment and more efficient faculty-resident interaction. Additional, multi-institutional studies using these tools are needed to elucidate these findings fully.