Faculty Bibliography

OBJECTIVES/HYPOTHESIS: Although clinical dogma suggests the value of laryngeal visualization (flexible laryngoscopy and stroboscopy) in dysphonic patients, recently published clinical guidelines suggest that, in many cases, history and/or physical examination are sufficient to guide clinical decision-making regarding the timing of such examinations. We sought to prospectively quantify the diagnostic accuracy of history, laryngoscopy, and stroboscopy using direct laryngoscopy as the gold standard. STUDY DESIGN: Expert survey. METHODS: Six laryngologists were presented with vignettes including history and physical examination (HPE), laryngosocpy, and stroboscopy. Questions regarding diagnosis, the certainty of diagnosis, and subsequent management plans were posed. Operative findings via direct laryngoscopy were employed as a comparator. RESULTS: The diagnostic accuracy of HPE was quite low (5%). The accuracy of diagnosis increased substantially following laryngeal imaging; 68.3% for both flexible laryngoscopy and stroboscopy. Particular diagnoses were more consistently identified; cancer, for example, was much more accurately identified on laryngoscopy (100%) and stroboscopy (100%) rather than HPE alone (33%). Cancer was selected as the diagnosis in 10 of 60 HPEs, though was only correct once and missed in five cases. In contrast, no diagnoses of cancer were missed following laryngoscopic and/or stroboscopic examinations. CONCLUSION: These findings confirm the value of laryngeal visualization (flexible laryngoscopy and stroboscopy) in dysphonic patients, and the lack of accuracy of history and physical examination in determining the diagnosis in patients with hoarseness. Laryngoscope, 2013.

Primary malignant melanoma arising from the eustachian tube is extremely rare. We report the case of a 63-year-old white man who presented with a 1-month history of left-sided hearing loss and aural fullness. Flexible fiberoptic laryngoscopy detected a blue-purple mass that appeared to arise from the left lateral nasopharynx. Computed tomography demonstrated an enhancing mass arising from an orifice of the left eustachian tube. The tumor was debulked endoscopically and was confirmed to have originated in the left eustachian tube. Histologically, the tumor was made up of heavily pigmented pleomorphic spindle cells with frequent mitoses. The tumor cells were immunohistochemically positive for S-100 protein, HMB-45, Melan-A, and PNL-2. The final diagnosis was a mucosal malignant melanoma. We also performed a nested polymerase chain reaction assay for several genes of interest, including CTLA-4, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F, PLZF, Foxp3, RORgammat, CD27, and CD70. These genes have been studied mainly in cutaneous melanomas, especially for the development of immunotherapy, but only very limited studies have been done on mucosal melanomas. Our investigation found upregulation of CTLA-4, IL-17A, IL-17C, and IL-17E. Based on our finding of CTLA-4 upregulation, it may be suggested that our patient might have had low antitumor immunity and that he might have benefited from CTLA-4 blockade. On the other hand, upregulation of IL-17A and IL-17E might reflect increased antitumor immunity, which could suggest that patients with a mucosal melanoma might benefit from immunomodulators associated with the effect of Th17. These genes also have great potential to help melanoma patients obtain tailored treatment, and they can be used as biomarkers for predicting prognosis.

ABSTRACT: Preoperative nasoalveolar molding (NAM) in combination with primary gingivoperiosteoplasty (GPP) reduces the need for secondary alveolar bone grafting by 60% in patients with unilateral cleft lip and palate (CL/P). Herein, we investigate the efficacy of NAM and primary GPP in patients with bilateral CL/P. All patients (n = 38) with bilateral CL/P who underwent NAM and primary GPP from 1988 to 1998 with at least 14 years of follow-up were included in this study. Panoramic and periapical radiographs were used to assess dentoalveolar bone formation. A total of 38 patients were identified with median follow-up of 18 years (range 14-26 years). Of the 27 patients who underwent bilateral GPP, 14 (51%) patients had successful dentoalveolar bone formation bilaterally and 13 (49%) had unilateral bone formation. No patient had a bilateral failure. Of the 11 patients who underwent unilateral GPP, 7 (63%) patients had successful dentoalveolar bone formation. Bilateral successful dentoalveolar bone formation following primary bilateral GPP has a dependent probability of 52% and a conditional probability of 82%.

ABSTRACT: The incidence of postoperative complications in cleft care is low. In this 19-year retrospective analysis of cleft lip and palate patients treated with preoperative nasoalveolar molding, we examine the incidence of postoperative oronasal fistulae. The charts of 178 patients who underwent preoperative nasoalveolar molding by the same orthodontist/prosthodontist team and primary cleft lip/palate repair by the same surgeon over a 19-year period were reviewed. Millard, Mohler, Cutting, or Mulliken-type techniques were used for cleft lip repairs. Oxford-, Bardach-, or von Langenbeck-type techniques were used for cleft palate repairs. One nasolabial fistula occurred after primary cleft lip repair (0.56% incidence) and was repaired surgically. Four palatal fistulae (3 at the junction between soft and hard palate and 1 at the right anterior palate near the incisive foramen) occurred, but 3 healed spontaneously. Only 1 palatal fistula (0.71%) required surgical repair. All 5 fistulae occurred within the first 8 years of the study period, with 4 (80%) of 5 occurring within the first 3 years. Although fistula rate may be related to surgeon experience and the evolution of presurgical techniques, nasoalveolar molding in conjunction with nasal floor closure contributes to a low incidence of oronasal fistulae.

OBJECTIVES: To determine the frequency and consequences of patient-reported post-thyroidectomy voice disorder (PTVD) after surgery for thyroid cancer. STUDY DESIGN: Retrospective review of data gathered from a survey. PARTICIPANTS: Members of the Thyroid Cancer Survivors' Association (ThyCa). METHODS: ThyCa members were asked about their thyroid disease and surgery, voice disturbance, impact on quality of life, treatment, and non-identifying demographics in a 36-item electronic questionnaire. Patients with preoperative voice disturbance or vocal fold immobility and those reporting postoperative vocal fold paralysis were excluded. RESULTS: A total of 4426 members responded (37% response rate), and PTVD was reported by 51.1% of responders. Most were temporary (85.9%), with a minority reporting permanent hoarseness. Rates of postoperative dysphonia were similar between the extent of surgery and histology. Patients with PTVD predominantly characterized their impairment as loss of loudness and an inability to shout or sing. Nearly a quarter of patients reporting PTVD identified detrimental impact to their professional or personal lives. Only 57 patients (3.4%) were offered voice therapy; however, more than two-thirds of them (73.7%) experienced at least partial improvement. CONCLUSIONS: We report the results of a large-scale patient survey to underscore the commonness of postoperative hoarseness and its impact on patients. LEVEL OF EVIDENCE: 4.

OBJECTIVES/OBJECTIVE:To compare hearing outcomes in patients with far advanced otosclerosis (FAO) undergoing cochlear implantation to an age-matched group of controls, to describe the effects of cochlear ossification on hearing, and to review the adverse effects of implantation in patients with FAO. HYPOTHESIS/OBJECTIVE:Hearing performance in patients with FAO after cochlear implantation is comparable to similarly treated postlingually deafened adults without FAO. Ossification or retrofenestral otosclerosis does not predict poor hearing outcomes. Modiolar-hugging technology reduces postoperative facial nerve stimulation. STUDY DESIGN/METHODS:Retrospective chart review. SETTING/METHODS:Academic neurotologic tertiary referral center. PATIENTS/METHODS:Thirty patients with FAO, who metaudiological criteria for cochlear implantation, were compared to 30 age-matched controls, postlingually deafened by non-otosclerotic causes. MAIN OUTCOME MEASURES/METHODS:Audiometric pre- and postoperative speech reception threshold, word, and sentence scores were analyzed. The presence of retrofenestral findings on computed tomography or intraoperative cochlear ossification were noted. RESULTS:In the FAO group, radiographic abnormalities were noted in 26.4% of patients. Intraoperative ossification requiring drillout was seen in 29.4% of patients. None developed postoperative facial nerve stimulation. There was no difference between the FAO and control groups in the mean short-term and long-term postoperative speech reception threshold, word, and sentence scores (P = .77). The presence of radiographic abnormalities did not predict hearing outcome. Intraoperative cochlear ossification was not associated with worse short-term word and sentence scores (P = .58 and 0.79, respectively), and for the long-term hearing outcome (P = .24). CONCLUSIONS:In patients with FAO, effective and safe hearing rehabilitation can be accomplished with cochlear implantation.

OBJECTIVE:To show that sialoendoscopy is both a safe and effective alternative to traditional treatments for juvenile recurrent parotitis and sialolithiasis. DESIGN/METHODS:Retrospective medical chart review. SETTING/METHODS:Two major pediatric tertiary care centers. PATIENTS/METHODS:Eighteen pediatric patients. INTERVENTIONS/METHODS:A total of 33 sialendoscopic procedures on 27 glands. MAIN OUTCOME MEASURES/METHODS:Indications for surgery, age at onset of symptoms, age at procedure, sex, intraoperative findings, complications, recurrences, need for additional procedures, and follow-up interval. RESULTS:Juvenile recurrent parotitis was the most common indication for sialendoscopy (12 of 18) followed by sialolithiasis (4 of 18). Ten of 12 patients with juvenile recurrent parotitis were asymptomatic after 1 or 2 sialendoscopies (8 patients and 2 patients, respectively). There were 6 minor complications. Three patients ultimately required gland excision for disease management. CONCLUSION/CONCLUSIONS:Sialoendscopy is safe and effective as a treatment for pediatric salivary gland disorders.

The epidermal growth factor receptor (EGFR) signaling pathway is frequently dysregulated in a variety of human malignancies. As a result, agents have been developed to selectively inhibit the tyrosine kinase function of EGFR (EGFR-TKI) for cancer therapy. However, the clinical efficacy of these drugs to date has been limited by both acquired and intrinsic resistance. Macroautophagy, a process of intracellular proteolysis, has been shown to be activated in response to EGFR targeted therapy. However, the specific role of the induction of autophagy remains controversial. Here we show that autophagy is induced in a dose-dependent manner by in vitro treatment of multiple cancer cell lines with EGFR-TKI. Additionally, we find that in cells highly resistant to EGFR-TKI, autophagy is not robustly activated and that co-treatment of these cells with rapamycin, a known inducer of autophagy, can partially restore sensitivity to EGFR-TKI. Finally, we demonstrate that, in resistant cell lines, EGFR-TKI sensitivity can be further inhibited by siRNA-mediated depletion of the critical autophagy protein ATG7. Thus, our data suggests that defective autophagy may be an EGFR-TKI resistance mechanism and that activation of autophagy may be a viable strategy to augment the cytotoxic effect of EGFR-TKIs.

UNLABELLED:Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as "undruggable." We developed a decoy targeting STAT3 and conducted a phase 0 trial. Expression levels of STAT3 target genes were decreased in head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexaethylene glycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development. SIGNIFICANCE/CONCLUSIONS:This is the fi rst study of a STAT3-selective inhibitor in humans and the fi rst evidence that a transcription factor decoy can be modifi ed to enable systemic delivery. These findings have therapeutic implications beyond STAT3 to other “undruggable” targets in human cancers.