Gigaxonin Suppresses Epithelial-to-Mesenchymal Transition of Human Cancer Through Downregulation of Snail.

Gigaxonin is an E3 ubiquitin ligase that plays a role in cytoskeletal stability. Its role in cancer is not yet clearly understood. Our previous studies of head and neck cancer had identified gigaxonin interacting with p16 for NFκB ubiquitination. To explore its role in cancer cell growth suppression, we analyzed normal and tumor DNA from cervical and head and neck cancers. There was a higher frequency of exon 8 SNP (c.1293 C>T, rs2608555) in the tumor (46% vs. 25% normal, P = 0.011) pointing to a relationship to cancer. Comparison of primary tumor with recurrence and metastasis did not reveal a statistical significance. Two cervical cancer cell lines, ME180 and HT3 harboring exon 8 SNP and showing T allele expression correlated with higher gigaxonin expression, reduced in vitro cell growth and enhanced cisplatin sensitivity in comparison with C allele expressing cancer cell lines. Loss of gigaxonin expression in ME180 cells through CRISPR-Cas9 or siRNA led to aggressive cancer cell growth including increased migration and Matrigel invasion. The in vitro cell growth phenotypes were reversed with re-expression of gigaxonin. Suppression of cell growth correlated with reduced Snail and increased e-cadherin expression. Mouse tail vein injection studies showed increased lung metastasis of cells with low gigaxonin expression and reduced metastasis with reexpression of gigaxonin. We have found an association between C allele expression and RNA instability and absence of multimeric protein formation. From our results, we conclude that gigaxonin expression is associated with suppression of epithelial-mesenchymal transition through inhibition of Snail. SIGNIFICANCE: Our results suggest that GAN gene exon 8 SNP T allele expression correlates with higher gigaxonin expression and suppression of aggressive cancer cell growth. There is downregulation of Snail and upregulation of e-cadherin through NFκB ubiquitination. We hypothesize that exon 8 T allele and gigaxonin expression could serve as diagnostic markers of suppression of aggressive growth of head and neck cancer.

Bilateral Endolymphatic Hydrops in a Patient With Migraine Variant Without Vertigo: A Case Report.

OBJECTIVE: To use modern high-resolution inner ear imaging modalities to evaluate for endolymphatic hydrops (EH) in a patient with migraine-associated fluctuating hearing loss without vertigo spells or dizziness. BACKGROUND: EH has been well described in patients with Meniere's disease on both human temporal bone studies and modern high-resolution imaging; however, there is no study to date, to our knowledge, that examines the presence of EH in a patient with migraine and bilateral hearing loss. We present the MRI findings using a sequence for detecting EH in a unique case of a patient experiencing migraine headaches accompanied by fluctuating hearing loss without vertigo. METHODS: Magnetic resonance imaging sequences included "cisternographic" three-dimensional T2, and delayed intravenous-enhanced three-dimensional fluid-attenuation inversion recovery (DIVE-3D-FLAIR) sequences, performed with 2350 ms (bright perilymph) and 2050 ms (bright endolymph) inversion times. The bright endolymph images were subtracted from bright perilymph images to create a composite image with bright perilymph, dark endolymph, and intermediate bone signals. RESULTS: A 40-year-old female presented with a left-sided sensorineural hearing loss and severe migraine headaches that began at age 12. For the past year, she experienced severe migraines with right-sided fluctuating sensorineural hearing loss, tinnitus, and aural fullness. Audiometry confirmed a drop of right-sided hearing at times of migraines and increased symptom severity. Vestibular testing was within normal limits. MRI demonstrated the presence of severe bilateral vestibular and cochlear EH. CONCLUSIONS: EH of both the cochlea and vestibule can be present in patients without Meniere's disease or vertigo. The relationship between migraine and Meniere's disease may be complex, as demonstrated in this patient with migraine-associated bilateral hearing loss with MRI documentation of severe bilateral EH. The fact that migraine can be associated with EH is important and demonstrates a potential relationship between the pathophysiology of migraine and that of EH. Given this patient's previous association of migraine and hearing loss at age 12, it appears that migrainous attacks occur simultaneously with the hearing loss, and may be potentially causative of the fluctuating hearing loss, mediated possibly through the development of EH. New imaging modalities allow for studies into the field of inner ear pathology, with significant implications for future research.

High Resolution MRI Shows Presence of Endolymphatic Hydrops in Patients Still Symptomatic After Endolymphatic Shunt Surgery.

OBJECTIVE: Endolymphatic hydrops has been well described in patients with Ménière's syndrome; however, causation has not been established. Decompression of the endolymphatic sac has been proposed as a means to relieve hydrops and improve vertigo symptoms, but the efficacy of the surgery is debated. Until recently, there have been few objective measures of efficacy other than patients' subjective symptoms. Recent archival human temporal bone studies have shown that patients continue to have hydrops after shunt surgery. We propose using high-resolution magnetic resonance imaging (MRI) to determine the efficacy of endolymphatic shunt surgery (ELS) in patients who continue to experience vertigo. PATIENTS: Four patients presented with continued vertigo after ELS. INTERVENTIONS: Magnetic resonance imaging sequences included "cisternographic" three-dimensional T2, and delayed intravenous-enhanced three-dimensional fluid-attenuation inversion recovery (DIVE-3D-FLAIR) sequences, performed with 2350 ms (bright perilymph) and 2050 ms (bright endolymph) inversion times. The bright endolymph images were subtracted from bright perilymph images to create a composite image with bright perilymph, dark endolymph, and intermediate bone signals. MAIN OUTCOME MEASURES: MRI finding of endolymphatic hydrops. RESULTS: In all five affected ears in four patients who continued to experience severe vertigo, hydrops was found on high resolution MRI on the operated ear. The appearance on MRI was no different than in patients with endolymphatic hydrops (EH) who have not had surgery. CONCLUSIONS: The present study demonstrates the persistence of endolymphatic hydrops in patients who have failed ELS. Future studies evaluating for the presence or absence of endolymphatic hydrops in patients who claim to obtain relief from ELS.

A review of gigaxonin mutations in giant axonal neuropathy (GAN) and cancer.

Gigaxonin, the product of GAN gene localized to chromosome 16, is associated with the early onset neuronal degeneration disease giant axonal neuropathy (GAN). Gigaxonin is an E3 ubiquitin ligase adaptor protein involved in intermediate filament processing in neural cells, and vimentin filaments in fibroblasts. Mutations of the gene cause pre-neural filaments to accumulate and form giant axons resulting in the inhibition of neural cell signaling. Analysis of the catalog of somatic mutations in cancer, driver DB and IDGC data portal databases containing 21,000 tumor genomic sequences has identified GAN patient mutations in cancer cell lines and primary tumors. The database search has also shown the presence of identical missense and nonsense gigaxonin mutations in GAN and colon cancer. These mutations frequently occur in the domains associated with protein homodimerization and substrate interaction such as Broad-Complex, Tramtrack and Bric a brac (BTB), BTB associated C-terminal KELCH (BACK), and KELCH repeats. Analysis of the International HapMap Project database containing 1200 normal genomic sequences has identified a single nucleotide polymorphism (SNP), rs2608555, in exon 8 of the gigaxonin sequence. While this SNP is present in >40 % of Caucasian population, it is present in less than 10 % of Japanese and Chinese populations. Although the role of gigaxonin polymorphism is not yet known, CFTR and MDR1 gene studies have shown that silent mutations play a role in the instability and aberrant splicing and folding of mRNAs. We believe that molecular and functional investigation of gigaxonin mutations including the exon 8 polymorphism could lead to an improved understanding of the relationship between GAN and cancer.

HPV-Positive Oropharyngeal Carcinoma: A Systematic Review of Treatment and Prognosis.

OBJECTIVE: Human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma is increasing in incidence and appears to exhibit improved response to treatment and better survival than that of HPV- head and neck squamous cell carcinoma. The purpose of this systematic review was to examine the current literature regarding treatment and prognosis of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) and identify whether type of treatment (primarily surgery vs primarily radiation) significantly affects survival rates. DATA SOURCES: PubMed and Cochrane Library databases. REVIEW METHODS: A computerized search of the PubMed and Cochrane Library databases was performed to identify English-language articles published between January 1, 2000, and October 21, 2014. Studies were included only if they were prospective or retrospective observational series of OPSCC patients that reported HPV status, treatment regimen, and survival outcomes. Outcomes were determined for HPV+ and HPV- OPSCC patients, with subanalyses according to the type of treatment received. RESULTS: Fifty-six articles were eligible for this review. In the HPV+ analysis, the unadjusted hazard rate ratio (HR) for surgery vs radiation treatment was 1.33 (P = .114). Nine confounders were considered, and HRs were adjusted for each covariate. While HRs were almost all >1 for all covariates, none of the HRs was statistically significant at P < .05. The HR for HPV- OPSCC was higher for radiation than surgery. CONCLUSIONS: HPV+ OPSCC has an improved prognosis and lower rates of adverse events when compared with HPV- OPSCC. HPV- OPSCC had significantly worse outcomes when treated with primary radiation as compared with primary surgery. There was no statistically significant difference in HRs for HPV+ OPSCC with primary radiation vs primary surgery treatment.

A comparative study of cricotracheal resection and staged laryngotracheoplasty for adult subglottic stenosis.

OBJECTIVE: Cricotracheal resection (CTR) and laryngotracheoplasty (LTP) are open surgical treatments for severe subglottic stenosis. This study aims to compare the applications and outcomes of these techniques. METHOD: Patients with subglottic stenosis at a tertiary academic institution from 2000 to 2012 were identified by diagnosis codes. Patients who underwent LTP or CTR were included. Records were reviewed for treatment data and outcomes. Patients with a history of head and neck malignancy or stenosis without cricoid involvement were excluded. RESULT: Sixty-one and 20 patients underwent LTP and CTR, respectively. When comparing patients receiving LTP and CTR, there was a significant difference in stenosis etiology (P=.014). The groups were similar in Cotton-Myer grade (P=.102). At last follow-up, 80.3% of LTP patients and 90.0% of CTR patients were decannulated. On multivariate analysis, there was a significant association between stenosis grade and decannulation in the LTP group (P=.01). Decannulation was not associated with stenosis grade in the CTR group. In both groups, there was no significant association between decannulation and sex, stenosis etiology, or stenosis length. CONCLUSION: Cricotracheal resection and LTP have both shown excellent long-term decannulation rates. Etiology and stenosis grade are likely to be determining factors when recommending specific surgical interventions for subglottic stenosis.

Staged laryngotracheoplasty in adult laryngotracheal stenosis: predictors of long-term decannulation.

IMPORTANCE: This study reviews a single center's experience of performing staged laryngotracheoplasty (LTP) for the treatment of laryngotracheal stenosis with the ultimate goal of attaining long-term airway patency without restenosis. OBJECTIVE: To identify staged LTP as an efficacious surgical treatment option for laryngotracheal stenosis. DESIGN, SETTING, AND PARTICIPANTS: From January 2000 to January 2012, patients at a tertiary care academic institution presenting with diagnoses of laryngeal or laryngotracheal stenosis were retrospectively identified. Medical records from adult patients were inspected, and patient demographics, clinical data, and clinical outcomes were recorded. All patients undergoing staged LTP were initially included. Patients with history of head and neck malignant neoplasm were excluded. INTERVENTIONS: Staged LTP. MAIN OUTCOMES AND MEASURES: The primary outcome was long-term decannulation, defined as decannulation for duration of at least 6 months. RESULTS: Sixty-one patients were included in this study. The mean (SD) patient age was 47.1 (16.7) at the time of first-stage LTP and had a mean (range) follow-up of 5.32 (0.5-17.3) years from the first-stage reconstruction. Etiology of stenosis included prolonged intubation in 27 patients (44%), autoimmune disease in 9 (15%), idiopathic causes in 11 (18%), blunt laryngeal trauma in 10 (16%), and other causes in 4 (7%). Forty-nine patients (80%) were successfully decannulated, while to date 12 (20%) remain tracheostomy or tympanostomy tube dependent. Univariate analyses showed no significant association between decannulation and age (P = .35), sex (P = .52), history of intubation (P = .22), surgeon (P = .20), etiology of stenosis (P = .91), or length of stenosis (P = .31). Multivariate logistic regression analysis showed a significant inverse relationship between grade of stenosis and probability of decannulation (P = .01). CONCLUSIONS AND RELEVANCE: Staged LTP is an option for the reconstruction laryngotracheal stenosis. Our experience shows excellent decannulation rates in the selected patients with stenosis, many of whom have failed treatment with other surgical modalities.