MTAP deficiency contributes to immune landscape remodelling and tumour evasion.

Methylthioadenosine phosphorylase (MTAP) deficiency occurs in various malignancies and is associated with poor survival in cancer patients. However, the mechanisms underlying tumour progression due to MTAP loss are yet to be elucidated. Utilizing integrated analyses of the transcriptome, proteome and secretome, we demonstrated that MTAP deficiency alters tumour-intrinsic, immune-related pathways and reprograms cytokine profiles towards a tumour-favourable environment. Additionally, MTAP-knockout cells exhibited a marked increase in the immune checkpoint protein PD-L1. Upon co-culturing primary T cells with cancer cells, MTAP loss-mediated PD-L1 upregulation inhibited T cell-mediated killing activity and induced several T cell exhaustion markers. In two xenograft tumour models, we showed a modest increase in average volume of tumours derived from MTAP-deficient cells than that of MTAP-proficient tumours. Surprisingly, a remarkable increase in tumour size was observed in humanized mice bearing MTAP-deficient tumours, as compared to their MTAP-expressing counterparts. Following immunophenotypic characterization of tumour-infiltrating leukocytes by mass cytometry analysis, MTAP-deficient tumours were found to display decreased immune infiltrates with lower proportions of both T lymphocytes and natural killer cells and higher proportions of immunosuppressive cells as compared to MTAP-expressing tumour xenografts. Taken together, our results suggest that MTAP deficiency restructures the tumour immune microenvironment, promoting tumour progression and immune evasion.

Stomal maturation does not increase the rate of tracheocutaneous fistulas.

OBJECTIVES/HYPOTHESIS: To determine the rate of persistent tracheocutaneous fistula (TCF) in pediatric patients managed with stomal maturation at the time of the tracheostomy. STUDY DESIGN: Retrospective chart analysis of all cases of tracheostomy performed at a tertiary pediatric care center between 2001 and 2011. METHODS: The use of stomal maturation, number of decannulations, number of persistent TCFs, timing of TCF repair, and the overall mortality were assessed. RESULTS: A total of 264 patients received tracheostomy between 2001 and 2011. Of the total, 173 (66%) underwent stomal maturation. Of those 173 patients, 89 patients (51% of maturation group) underwent planned decannulation. Forty seven (53%) of the 89 decannulated were found to have a persistent TCF in the stomal maturation group. These were diagnosed an average of 1.3 years (range, 4-43 months) after decannulation. Of the 91 patients (34% of the total) who did not undergo stomal maturation, 44 (48% of nonmaturation group) underwent planned decannulation. Twenty of the 44 patients decannulated (45%) were diagnosed with a residual TCF 8 to 28 months later. Both groups achieved similar rates of decannulation (51% maturation vs. 48% non-maturation [P = .80]) and TCF (27% maturation vs. 22% non-maturation [P = .44]). Overall, mortality rates were (32/173) 18% (matured) versus (26/91) 29% (nonmatured). No mortalities were tracheostomy related. The mean (standard deviation) time from operation to TCF closure among those with TCF was 4.0 (1.9) years. CONCLUSIONS: Comparable rates of persistent TCF with stomal maturation (27%) and without maturation (22%) were found in this single institution's 10-year experience. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2395-2398, 2016.

The role of gastric pepsin in the inflammatory cascade of pediatric otitis media.

IMPORTANCE: Otitis media is characterized as an ongoing inflammation with accumulation of an effusion in the middle ear cleft. The molecular mechanisms underlying the pathogenesis, particularly the inflammatory response, remain largely unknown. We hypothesize that aspiration of gastric contents into the nasopharynx may be responsible for the initiation of the inflammatory process or aggravate a preexisting condition. OBJECTIVE: To investigate the correlation of gastric pepsin A with inflammatory cytokines, bacterial infection, and clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 129 pediatric patients undergoing myringotomy with tube placement for otitis media at a tertiary care pediatric hospital. MAIN OUTCOMES AND MEASURES: Ear samples were tested for pepsin A; cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor; and bacterial culture inoculation. Data were analyzed by descriptive statistics and regression analysis to identify risk factors for the presence of pepsin A and to correlate pepsin A levels with cytokine levels, infection status, and clinical outcomes. RESULTS: Of the 129 patients, 199 ear samples were obtained; 82 samples (41%) and 64 patients (50%) were positive for pepsin A as measured by immunoassay. Pepsin A positivity correlated with age younger than 3.0 years (mean [SD], 2.3 [2.1] years in the positive group vs 3.3 [3.0] years in the negative group) and with all 3 cytokine levels (mean [SD] tumor necrosis factor, 29.5 [45.9] pg/mL in the positive group vs 13.2 [21.6] pg/mL in the negative group; IL-6, 6791.7 [9389.1] pg/mL in the positive group vs 2849.9 [4066.3] pg/mL in the negative group; and IL-8, 6828.2 [8122.3] pg/mL in the positive group vs 2925.1 [3364.5] pg/mL in the negative group [all P < .05]); however, logistic regression analysis showed that only IL-8 (odds ratio, 3.96; 95% CI, 1.3-12.0; P = .02) and age (odds ratio, 3.83; 95% CI, 1.2-12.7; P = .03) were significant independent variables. No statistically significant association was found with other parameters. Multiple linear regressions revealed that the levels of pepsin A were correlated with IL-8 levels (R2 = 0.248; P < .001) and the need for second or third tubes 6 to 12 months after the first (R2 = 0.102; P = .006). The presence of pepsin A in the middle ear was not associated with increased bacterial infection. Interleukin 8 was independent and significantly associated with both pepsin A levels and bacterial infection (R2 = 0.144 and 0.263, respectively; P = .001 for both). CONCLUSIONS AND RELEVANCE: Extraesophageal reflux as indicated by the presence of pepsin A is closely involved in the middle ear inflammatory process and may worsen the disease in some children; however, a proof of cause and effect between extraesophageal reflux and middle ear inflammation requires further investigation.

Section for Residents and Fellows-in-Training Leaders: Where Are They Now?

The purpose of this study was to examine the experiences of prior governing council (GC) members of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Section for Residents and Fellows-in-Training (SRF) and assess the impact of early Academy involvement. A survey was conducted via email on all prior AAO-HNS SRF GC members. The AAO-HNS SRF has elected 52 GC members since its 2003 inception. Each member served an average of 1.5 year-long terms. The mean time since completion of training is 4.1 years. A subspecialty fellowship was pursued in 86%. Fifty-seven percent practice in academic settings, with 3 members advancing to subspecialty division director within their department. More than half (58%) have served on an AAO-HNS committee, and most are frequent attendees of the annual meeting. All prior members felt involvement in the SRF GC was beneficial, enabling them to gain leadership skills and deeper understanding of the specialty.

A homozygous SLITRK6 nonsense mutation is associated with progressive auditory neuropathy in humans.

OBJECTIVES/HYPOTHESIS: SLITRK family proteins control neurite outgrowth and regulate synaptic development. In mice, Slitrk6 plays a role in the survival and innervation of sensory neurons in the inner ear, vestibular apparatus, and retina, and also influences axial eye length. We provide the first detailed description of the auditory phenotype in humans with recessive SLITRK6 deficiency. STUDY DESIGN: Prospective observational case study. METHODS: Nine closely related Amish subjects from an endogamous Amish community of Pennsylvania underwent audiologic and vestibular testing. Single nucleotide polymorphism microarrays were used to map the chromosome locus, and Sanger sequencing or high-resolution melt analysis were used to confirm the allelic variant. RESULTS: All nine subjects were homozygous for a novel nonsense variant of SLITRK6 (c.1240C>T, p.Gln414Ter). Adult patients had high myopia. The 4 oldest SLITRK6 c.1240C>T homozygotes had absent ipsilateral middle ear muscle reflexes (MEMRs). Distortion product otoacoustic emissions (DPOAEs) were absent in all ears tested and the cochlear microphonic (CM) was increased in amplitude and duration in young patients and absent in the two oldest subjects. Auditory brainstem responses (ABRs) were dys-synchronised bilaterally with no reproducible waves I, III, or V at high intensities. Hearing loss and speech reception thresholds deteriorated symmetrically with age, which resulted in severe-to-profound hearing impairment by early adulthood. Vestibular evoked myogenic potentials were normal in three ears and absent in one. CONCLUSION: Homozygous SLITRK6 c.1240C>T (p.Gln414Ter) nonsense mutations are associated with high myopia, cochlear dysfunction attributed to outer hair cell disease, and progressive auditory neuropathy.