Faculty Bibliography

OBJECTIVE:It has been postulated that treatment outcomes are similar between transoral robotic surgery (TORS) and definitive chemoradiation (CRT) for oropharyngeal squamous cell carcinomas (OPSCC). We compared oncologic and quality of life (QOL) outcomes between definitive CRT and definitive TORS. MATERIALS AND METHODS:An observational comparison study was performed on 92 patients treated with TORS±adjuvant therapy and 46 patients treated with definitive CRT between July 2005 and January 2016. The Kaplan Meier method was used for survival analyses, and the Mann-Whitney test was used to compare QOL scores between groups. RESULTS:All patients had T0-T2 and N0-N2 disease, although CRT patients had higher clinical staging (p<0.001). HPV+ disease was present in 79% (n=73) of TORS patients and 91% (n=19) of tested CRT patients. Median follow-up was 22.1months (range: 0.33-83.4). There were no significant differences in locoregional control or overall survival between CRT and TORS groups. Definitive TORS resulted in better saliva-related QOL than definitive CRT at 1, 6, 12, and 24months (p<0.001, p=0.025, p=0.017, p=0.011). Among TORS patients, adjuvant therapy was associated with worse QOL in the saliva domain at 6, 12, and 24months (p<0.001, p<0.001, p=0.007), and taste domain at 6 and 12months (p=0.067, p=0.008). CONCLUSION:Definitive CRT and definitive TORS offer similar rates of locoregional control, overall survival, and disease-free survival in patients with early stage OPSCC. TORS resulted in significantly better short and long-term saliva-related QOL, whereas adjuvant therapy was associated with worse saliva and taste-related QOL compared to TORS alone.

UNLABELLED:Achieving stable and desirable changes in tip rotation (TR) and tip projection (TP) is among the primary goals of modern day rhinoplasty. The tongue-in-groove (TIG) technique is one technique in rhinoplasty used to improve TR and/or TP. Performing TIG endonasally using a permanent suture can be quite cumbersome as the suture needs to be buried under the skin. We describe a variation of TIG technique for endonasal rhinoplasty using a permanent suture buried in small columellar skin incisions. The technique details are described and the postoperative changes in TR and TP are analyzed for the degree of change and longevity. A retrospective review of the preoperative and postoperative photographs of 12 patients treated with the endonasal TIG technique were analyzed for changes in TR and TP. Out of 12 patients, there were seven females (58.3%) and five males (41.7%), with age ranging from 17 to 49 years. The follow-up ranged from 6 months to 53 months, with mean follow-up of 12.1 months. All patients were treated by the senior author in a major New York City hospital. Postoperative changes in TR and TP were compared by measuring the nasolabial angle as well as the Goode ratio using a photo editing software. Using a t-test and a p-value criteria of 0.05, the difference between the preoperative and postoperative TR (p = 0.0069) and TP (p = 0.026) was found to be statistically significant. None of the study patients developed any complications related to the use of a permanent suture material during the follow-up period. Our modified TIG technique is a quick, reliable, and safe option in the surgical armamentarium to achieve desired changes in TR and/or TP. LEVEL OF EVIDENCE/METHODS: 4.

OBJECTIVE: Optic gliomas are characterized as pilocytic astrocytoma (PA) or pilomyxoid astrocytoma (PMXA). Prominent chondroid myxoid matrix is typical of PMXA but not PA. We investigated the composition of myxoid matrix and its role in vasculariztion of optic gliomas. MATERIAL-METHODS: We reviewed clinicopathological data of 120 patients with optic glioma diagnosed at NYU Langone Medical Center from 1996 to 2014.We analyzed microvascular density (MVD), perfusion, hypoxia and proliferation by immunohistochemistry and ultrastructural features by electron microscopy. Liquid chromatography-mass spectrometry (LC-MS) was performed to identify components of the myxoid matrix in PMXA. RESULTS: PMXA showed significantly lowerMVD by CD34 (8.1 vs 14.5, pvalue < 0.002) and Erg (7 vs. 13.6, p-value 0.003) than PA, however GLUT-1 showed equal distribution. Electron microscopy showed that PMXA contains both regular blood vessels with endothelial lining and channels completely lacking endothelia and smooth muscle. LC-MS stratified optic gliomas into three distinct groups. We identified 5389 proteins of which 188 were differentially expressed in the three groups (p < 0.05, Benjamini-Hochberg adjustment). Between PAand PMXA,most of differentially expressed proteins (146/188) displayed a positive fold change (increasing in PMXA relative to PA), and a minority (42/188) showed a negative fold change. Abundant extracellular matrix proteins were a chondroitin sulfate proteoglycan versican (VCAN 3.7-fold increase Q=0.000463) and its paralog vertebrate Hyaluronan and Proteoglycan Link Protein 1 (HAPLN1, 22-fold increase from the PA to the PMXA group Q=4.60x10-7). CONCLUSIONS: Optic gliomas develop endothelium-independent channels evocative invertebrate blood supply. The myxoid matrix is composed of VCAN and linking paralog HAPLN1. Targeting the myxoid matrix may provide novel avenues for therapy of optic gliomas and PMA

For bilateral cochlear implant (CI) patients, electrodes that receive the same frequency allocation often stimulate locations in the left and right ear that do not yield the same perceived pitch, resulting in a pitch mismatch. This pitch mismatch may be related to degraded binaural abilities. Pitch mismatches have been found for some bilateral CI users and the goal of this study was to determine whether pitch mismatches are prevalent in bilateral CI patients, including those with extensive experience with bilateral CIs. To investigate this possibility, pitch matching was conducted with 16 bilateral CI patients. For 14 of the 16 participants, there was a significant difference between those electrodes in the left and right ear that yielded the same pitch and those that received the same frequency allocation in the participant's clinical map. The results suggest that pitch mismatches are prevalent with bilateral CI users. The results also indicated that pitch mismatches persist even with extended bilateral CI experience. Such mismatches may reduce the benefits patients receive from bilateral CIs.

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.

IMPORTANCE:The elective management of no clinical or radiologic evidence of lymph node metastasis in the neck (cN0) in early stage T1-T2 oral tongue squamous cell carcinoma (OTSCC) has been the subject of much debate during the past 3 decades and continues to be controversial. OBJECTIVE:To systematically review the literature and carry out a meta-analysis of studies that compared elective neck dissection (END) with observation in patients with early-stage T1-T2 OTSCC and cN0 neck. DATA SOURCES:The MEDLINE, Scopus, Google scholar, and Cochrane databases were systematically searched for articles published between January 1, 1970, and June 1, 2015. Search terms used were squamous cell carcinoma, oral tongue, mobile tongue, T1, T2, early stage, elective neck dissection, no neck treatment, observation, wait and watch, node-negative neck, and N0 neck. STUDY SELECTION:Controlled clinical trials, prospective and retrospective cohorts, case-control studies, and case series that compared END with observation in patients with early-stage T1-T2 OTSCC who had no clinical or radiologic evidence of lymph node metastasis to the neck were eligible for inclusion in this meta-analysis. All patients included had a histopathologic diagnosis of SCC and at least 6 months of follow-up. Regional (neck) nodal recurrence, overall survival (OS), and disease-specific survival (DSS) were tested. DATA EXTRACTION AND SYNTHESIS:Four researchers independently extracted information on population characteristics, outcomes of interest, and study design. Discrepancies were resolved by consensus. Fixed effects were used to determine hazard ratios (HRs) and odds ratio (ORs) were used for studies including samples without substantial heterogeneity; random effects were evaluated for samples with significant heterogeneity. RESULTS:A total of 20 retrospective and 3 prospective randomized studies that met the inclusion criteria, with a total of 3244 patients, were included in the meta-analysis The results showed that END significantly reduced risk of regional recurrence (random-effects model: OR, 0.32; 95% CI, 0.22-0.46; P < .001) and improved DSS (fixed-effects model: HR, 0.49; 95% CI, 0.33-0.72; P < .001) compared with management by observation. However, END did not significantly improve OS (random-effects model: HR, 0.71; 95% CI, 0.41-1.22; P = .21). CONCLUSIONS AND RELEVANCE:The findings of this systematic review and meta-analysis indicate that END can significantly reduce the rate of regional nodal recurrence and improve DSS in patients with cT1T2N0 OTSCC.

Importance: Septal deviation commonly occurs in patients with cleft lip and palate (CLP); however, the contribution of the cartilaginous and bony septum to airway obstruction in skeletally mature patients is poorly understood. Objectives: To describe the internal nasal airway anatomy of skeletally mature patients with CLP and to determine the contributors to airway obstruction. Design, Setting, and Participants: This single-center retrospective review included patients undergoing cone-beam computed tomography (CBCT) from November 1, 2011, to July 6, 2015, at the cleft lip and palate division of a major academic tertiary referral center. Patients met inclusion criteria for the study if they were at least 15 years old at the time of CBCT, and images were used only if they were obtained before Le Fort I osteotomy and/or formal septorhinoplasty. Twenty-four skeletally mature patients with CLP and 16 age-matched control individuals were identified for the study. Main Outcomes and Measures: Septal deviation and airway stenosis were measured in the following 3 coronal sections: at the cartilaginous septum (anterior nasal spine), bony septum (posterior nasal spine), and midpoint between the anterior and posterior nasal spine. The perpendicular plate of the ethmoid bone and vomer displacement were measured as angles from the vertical plane at the coronal section of maximal septal deviation. The site of maximal septal deviation was identified. Results: Among the 40 study participants, 26 were male. The mean (SD) age was 21 (5) and 23 (6) years for patients with CLP and controls, respectively. Septal deviation in patients with CLP was significantly worse than that of controls at the anterior nasal spine (2.1 [0.5] vs 0.8 [0.2] mm; P < .05) and posterior nasal spine (2.9 [0.5] vs 1.0 [0.3] mm; P < .01) and most severe at the midpoint (mean [SD], 4.4 [0.6] vs 2.1 [0.3] mm; P < .01). The point of maximal septal deviation occurred in the bony posterior half of the nasal airway in 27 of 40 patients (68%). The CLP bony angular deviation from the vertical plane was significant in the CLP group compared with the control group (perpendicular plate of the ethmoid bone, 14 degrees [2 degrees ] vs 8 degrees [1 degrees ]; vomer, 34 degrees [5 degrees ] vs 13 degrees [2 degrees ]; P < .05 for both), and vomer deviation was significantly associated with anterior nasal airway stenosis (r = -0.61; P < .01). Conclusions and Relevance: Skeletally mature patients with CLP have significant septal deviation involving bone and cartilage. Resection of the bony and cartilaginous septum should be considered at the time of definitive cleft rhinoplasty. Level of Evidence: NA.

Fragile X Syndrome (FXS) is the leading form of inherited intellectual disability. It is caused by the transcriptional silencing of FMR1, the gene which codes for the Fragile X Mental Retardation Protein (FMRP). Patients who have FXS exhibit numerous behavioral and cognitive impairments, such as attention-deficit/hyperactivity disorder, obsessive compulsive disorder, and autistic-like behaviors. In addition to these behavioral abnormalities, FXS patients have also been shown to exhibit various deficits in communication such as abnormal sentence structures, increased utterances, repetition of sounds and words, and reduced articulation. These deficits can dramatically hinder communication for FXS patients, exacerbating learning and cognition impairments while decreasing their quality of life. To examine the biological underpinnings of these communication abnormalities, studies have used a mouse model of the Fragile X Syndrome; however, these vocalization studies have resulted in inconsistent findings that often do not correlate with abnormalities observed in FXS patients. Interestingly, a detailed examination of frequency modulated vocalizations that are believed to be a better assessment of rodent communication has never been conducted. The following study used courtship separation to conduct a detailed examination of frequency modulated ultrasonic vocalizations (USV) in FXS mice. Our analyses of frequency modulated USVs demonstrated that adult FXS mice exhibited longer phrases and more motifs. Phrases are vocalizations consisting of multiple frequency modulated ultrasonic vocalizations, while motifs are repeated frequency modulated USV patterns. Fragile X mice had a higher proportion of "u" syllables in all USVs and phrases while their wildtype counterparts preferred isolated "h" syllables. Although the specific importance of these syllables towards communication deficits still needs to be evaluated, these findings in production of USVs are consistent with the repetitive and perseverative speech patterns observed in FXS patients. This study demonstrates that FXS mice can be used to study the underlying biological mechanism(s) mediating FXS vocalization abnormalities.