Early detection of nasopharyngeal carcinoma: performance of a short contrast-free screening magnetic resonance imaging.

BACKGROUND: Although contrast-enhanced magnetic resonance imaging (MRI) detects early-stage nasopharyngeal carcinoma (NPC) not detected by endoscopic-guided biopsy (EGB), a short contrast-free screening MRI would be desirable for NPC screening programs. This study evaluated a screening MRI in a plasma Epstein-Barr virus (EBV)-DNA NPC screening program. METHODS: EBV-DNA-screen-positive patients underwent endoscopy, and endoscopy-positive patients underwent EGB. EGB was negative if the biopsy was negative or was not performed. Patients also underwent a screening MRI. Diagnostic performance was based on histologic confirmation of NPC in the initial study or during a follow-up period of at least 2 years. RESULTS: The study prospectively recruited 354 patients for MRI and endoscopy; 40/354 (11.3%) endoscopy-positive patients underwent EGB. Eighteen had NPC (5.1%), and 336 without NPC (94.9%) were followed up for a median of 44.8 months. MRI detected additional NPCs in 3/18 (16.7%) endoscopy-negative and 2/18 (11.1%) EGB-negative patients (stage I/II, n = 4; stage III, n = 1). None of the 24 EGB-negative patients who were MRI-negative had NPC. MRI missed NPC in 2/18 (11.1%), one of which was also endoscopy-negative. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MRI, endoscopy, and EGB were 88.9%, 91.1%, 34.8%, 99.4%, and 91.0%; 77.8%, 92.3%, 35.0%, 98.7%, and 91.5%; and 66.7%, 92.3%, 31.6%, 98.1%, and 91.0%, respectively. CONCLUSION: A quick contrast-free screening MRI complements endoscopy in NPC screening programs. In EBV-screen-positive patients, MRI enables early detection of NPC that is endoscopically occult or negative on EGB and increases confidence that NPC has not been missed.

The prevalence of gastroesophageal reflux disease and laryngopharyngeal reflux in patients with dysphagia after radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: The prevalence of gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) in post-irradiated patients with nasopharyngeal carcinoma (NPC) is unknown. MATERIALS AND METHODS: In a cross-sectional study, 31 NPC and 12 control patients completed questionnaires for GERD/LPR before esophageal manometry and 24-h pH monitoring. The DeMeester score and reflux finding score (RFS) were used to define GERD and LPR, respectively. Risk factors were identified. RESULTS: 51.6% of NPC and 8.3% of control patients, and 77.4% of NPC and 33% of control patients, were GERD-positive and LPR-positive, respectively. The GERD/LPR questionnaire failed to identify either condition in patients with NPC. No parameter differences in esophageal manometry or pneumonia incidence were noted between GERD/LPR-positive and GERD/LPR-negative patients. Post radiotherapy duration, high BMI, lack of chemotherapy, and dysphagia were positive risk factors for GERD/LPR. CONCLUSIONS: A high prevalence of GERD/LPR in patients with post-irradiated NPC exists, but reflux symptoms are inadequate for diagnosis.

A Hybrid Auricular Framework of Autologous Rib Cartilage and a Porous Polyethylene Implant for Reconstruction of Congenital Microtia: A Modification of Nagata's Technique.

Background: An implant (porous polyethylene) is an alternative to rib cartilage for microtia reconstruction but carries a risk of extrusion. Objective: To evaluate the outcome of a hybrid framework of implant with rib cartilage for microtia reconstruction. Methods: Patients who underwent Nagata's technique for microtia reconstruction were reviewed for complications and aesthetic score. In stage 1, a rib cartilage framework or a hybrid framework of implant with rib cartilage was used. In stage 2, the framework was elevated and supported by an implant for projection. Postoperative outcomes were reported for both groups. Results: Forty-four ears of 40 patients underwent surgery. Eleven ears received a rib auricular framework and 33 ears a hybrid auricular framework. The mean postoperative follow-up for the rib and hybrid groups was 76.3 and 43.1 months, respectively. No supporting postauricular implant extruded, whereas stainless-steel wires extruded in seven ears (15.9%). Five (15.2%) hybrid frameworks were removed due to infection or extrusion. Mean operating time was 2 h shorter in the hybrid group. Aesthetic outcomes were similar for both groups. Conclusion: A hybrid framework of rib and implant that requires less harvested cartilage is feasible for microtia reconstruction, but caution should be used due to its higher explantation rate.

Quality of life and swallowing outcomes after early proactive swallowing rehabilitation by either transcutaneous neuromuscular electrical stimulation or exercise-based swallowing training in patients with nasopharyngeal carcinoma after radiotherapy.

Background: Exercise-based swallowing training (EBST) and transcutaneous neuromuscular electrical stimulation (TNMES) are common modalities used to treat late dysphagia after radiotherapy for nasopharyngeal carcinoma (NPC). We aimed to investigate and compare the efficacies of EBST and TNMES as proactive treatments administered early after radiotherapy. Methods: Patients with early post-radiotherapy NPC (n = 120) underwent either TNMES or EBST. Flexible endoscopic evaluation of swallowing (FEES), quality of life (QOL), and swallowing function questionnaires were completed before the intervention as well as immediately, 6, and 12 months after the intervention. Outcome measures included the scores for the swallowing function score (SFS), penetration and aspiration scale (PAS), dynamic imaging grade of swallowing toxicity (DIGEST), functional oral intake scale (FOIS), swallowing performance status scale (SPSS), pharyngeal motor impairment (PMI), pharyngeal function impairment (PFI), and functional assessment after cancer therapy-nasopharyngeal (FACT-NP) questionnaire. Results: Three months after radiotherapy, 31 and 34 patients underwent TNMES and EBST, respectively, and completed swallowing assessments at all four assessment timepoints. All patients showed post-radiotherapy impairments in the SFS, PAS, DIGEST, PMI, and PFI. Compared with the EBST group, the TNMES group showed significant improvements in the PFI and PMI scores, with small-to-medium effect sizes. Additionally, compared with the EBST group, the TNMES group demonstrated a trend toward slightly better improvements in the PAS, DIGEST, FOIS, and SPSS scores immediately and 6 months after the intervention. The SFS scores improved from baseline in both groups; however, the TNMES group showed an earlier improvement. Finally, the TNMES group showed better QOL according to the FACT-NP than the EBST group. Conclusion: Proactive TMNES and EBST are safe and feasible modalities for improving swallowing in patients with NPC when administered early after radiotherapy. Although TNMES showed better results than EBST, these results should be interpreted with caution given the study limitations. Level of evidence: 1B.

Plasma Epstein-Barr Virus DNA and Risk of Future Nasopharyngeal Cancer.

BACKGROUND: We previously conducted a prospective study to show that nasopharyngeal cancer (NPC) screening with circulating Epstein­Barr virus (EBV) DNA analysis can improve survival. However, the long-term significance of positive results in individuals without cancer was unclear. METHODS: We conducted a second-round screening at a median of 43 months after the initial screening. Participants with detectable plasma EBV DNA were retested in 4 weeks, and those with persistently positive results were investigated with nasal endoscopy and magnetic resonance imaging. RESULTS: Of the 20,174 volunteers who participated in the first-round screening, 17,838 (88.6%) were rescreened. Among them, 423 (2.37%) had persistently detectable plasma EBV DNA. Twenty-four patients were identified as having NPC. A significantly higher proportion of patients had stage I/II cancer than in a historical cohort (67% vs. 20%; chi-square test, P<0.001), and they had superior 3-year progression-free survival (100% vs. 78.8%). Compared with participants with undetectable plasma EBV DNA in the first round of screening, participants with transiently and persistently positive results in the first round were more likely to have a cancer identified in the second round, with relative risks of 4.4 (95% confidence interval, 1.3 to 15.0) and 16.8 (95% confidence interval, 5.7 to 49.6), respectively. CONCLUSIONS: Individuals with detectable plasma EBV DNA but without an immediately identifiable NPC were more likely to have the cancer identified in another round of screening performed 3 to 5 years later. (Funded by Kadoorie Charitable Foundation and others; ClinicalTrials.gov number, NCT02063399.)

Oro-pharyngo-esophageal radionuclide scintigraphy predicts aspiration pneumonia risk and associated survival in post-irradiated nasopharyngeal carcinoma patients.

OBJECTIVE: To demonstrate that oro-pharyngo-esophageal radionuclide scintigraphy (OPERS) not only detects tracheobronchial aspiration after swallowing, but also quantifies the amount of aspiration and subsequent clearance. METHODS: Data collected between 2014 and 2019 were reviewed for aspiration pneumonia at 12 and 24-months after OPERS. The predictive value for aspiration pneumonia on flexible endoscopic evaluation of swallowing (FEES), videofluoroscopic swallowing study (VFSS), and OPERS, and the overall survival of patients with or without aspiration were determined. RESULTS: Thirty-seven patients treated with radiotherapy for nasopharyngeal carcinoma (NPC) were reviewed. The incidence of aspiration detected on FEES, VFSS, and OPERS was 78.4%, 66.7%, and 44.4%, respectively. Using VFSS as a gold standard, the sensitivity and specificity of OPERS for aspiration was 73.7% and 100%. The positive and negative predictive values for aspiration were 100% and 66.7%, respectively, with an overall accuracy of 82.8%. A history of aspiration pneumonia was one factor associated with a higher chance of subsequent aspiration pneumonia within 12 months (odds ratio: 15.5, 95% CI 1.67-145.8, p < .05) and 24 months (odds ratio: 23.8, 95% CI 3.69-152.89, p < .01) of the swallowing assessment. Aspiration detected by OPERS was a significant risk factor for future aspiration pneumonia at 12 and 24 months respectively. Significantly, better survival was associated with an absence of aspiration on OPERS only, but not on FEES or VFSS. CONCLUSION: OPERS predicts the safety of swallowing, the incidence of subsequent aspiration pneumonia, and the survival prognosis in post-irradiated NPC dysphagia patients. LEVEL OF EVIDENCE: 3.

Assessment of pharyngeal motor function using a novel velopharyngeal squeeze maneuver and a novel endoscopic pharyngeal contraction grade scale in patients with dysphagia after radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: To investigate a novel velopharyngeal squeeze maneuver (VPSM) and novel endoscopic pharyngeal contraction grade (EPCG) scale for the evaluation of pharyngeal motor function. METHODS: During endoscopic examination of 77 post-irradiated nasopharyngeal carcinoma patients and control subjects, VPSM was rated and lateral pharyngeal wall movement graded with EPCG scale during swallowing. Pharyngeal constriction ratio (PCR) measured by videofluoroscopy was used for correlation. RESULTS: VPSM and EPCG scale showed almost perfect intra-rater and inter-rater reliability (Kappa: >0.90). VPSM was present in 61% of patients suggesting good pharyngeal motor function. VPSM was predictive of EPCG scale (Wald statistic = 29.99, p < 0.001). EPCG scale also correlated strongly with PCR (r: 0.812) and was predictive for aspiration (odds ratio: 22.14 [95% CI 5.01-97.89, p < 0.001]). CONCLUSIONS: VPSM and EPCG scale are two novel tools to assess pharyngeal motor function, and both correlate well with pharyngeal contractility and aspiration.

Tubed Supraglottic Laryngeal Closure to Treat Chronic Aspiration After Radiotherapy for Head and Neck Cancer.

OBJECTIVES/HYPOTHESIS: To evaluate the long-term swallowing outcomes after surgical treatment for chronic aspiration in patients treated with radiotherapy for head and neck cancer. STUDY DESIGN: This was a retrospective study. METHODS: The data of patients who underwent radiotherapy for head and neck cancer and who subsequently required a laryngectomy or a tubed supraglottic laryngeal closure (TSLC) for recurrent aspiration pneumonia between 2004 and 2017 were retrieved from a tertiary referral hospital dysphagia clinic. The Functional Oral Intake Scale (FOIS) and the Swallowing Performance and Status Scale (SPSS) were used to assess swallowing function. RESULTS: Of the 17 patients who required surgery for chronic aspiration secondary to radiotherapy for head and neck cancer, two underwent a laryngectomy and 15 a TSLC. During a mean follow-up of 77 months, the FOIS and SPSS scores significantly improved at 12, 24, and 36 months after laryngectomy and TSLC relative to the baseline (P < .05). Both patients who underwent laryngectomy and 11 of the 15 (73.3%) who underwent a TSLC resumed oral feeding. Both laryngectomy patients had episodes of recurrent aspiration pneumonia after surgery due to leakage through the tracheoesophageal puncture or prosthesis, whereas none of the TSLC patients had these episodes. CONCLUSION: A tubed supraglottic laryngeal closure, which is a reversible procedure that preserves the larynx and allows for natural phonation, should be considered an alternative to laryngectomy for the control of chronic aspiration. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1234-E1243, 2021.

Perceptual Voice and Speech Analysis after Supraglottic Laryngeal Closure for Chronic Aspiration in Head and Neck Cancer.

OBJECTIVES/HYPOTHESIS: To evaluate the voice and speech outcomes after tubed supraglottic laryngeal closure (TSLC) surgery to treat chronic aspiration after radiotherapy for head and neck cancer. STUDY DESIGN: A retrospective case-control study. METHODS: The data of patients who underwent radiotherapy for head and neck cancer and who later required total laryngectomy or TSLC for chronic aspiration between 2004 and 2017 were retrieved from a dysphagia clinic. Preoperative and postoperative voice and speech were assessed by the GRBAS and INFVo rating scales. Control subjects who underwent radiotherapy alone or total laryngectomy with a tracheoesophageal prosthesis for other indications were recruited for comparison. RESULTS: Of 15 patients who underwent a TSLC with a mean age of 57.3 years (45-75 years), 13 were male and 2 female. All patients had a history of nasopharyngeal carcinoma. The success rate of speech production using their own larynx following an intact TSLC was 64%. There was no statistically significant difference in voice and speech ratings between preoperative and TSLC subjects on the GRBAS (P = .32) and INFVo scales (P = .57), although the quality of voice appeared to deteriorate after TSLC. However, the INFVo scale for impression, intelligibility and unsteadiness of the voice after TSLC was statistically significantly better than for laryngectomy with tracheoesophageal speech. CONCLUSIONS: A tubed supraglottic laryngeal closure controls chronic aspiration while preserving the larynx for phonation, and results in a better voice and speech quality than a laryngectomy with a voice prosthesis. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1616-E1623, 2021.

Overcoming developing world challenges of cochlear implantation: Chinese perspective.

PURPOSE OF REVIEW: Over a short period, China has adopted cochlear implants and emerged as a burgeoning market. This represents a valuable case study for emerging countries in terms of planning, initiating, and growing cochlear implant programs. RECENT FINDINGS: Although many challenges such as funding, establishing infrastructure, and recipient community support have been addressed, many more remain. Consistent rapid escalation in numbers has been driven by push-and-pull factors. Federal, state, and private funding have all played a role. SUMMARY: The review highlights the massive need for hearing rehabilitation that currently exists in China. The shortfall can only be addressed by a purposeful and coordinated approach involving government policy, The China Disabled Persons Federation, the industry partnering with hearing and medical professionals and the deaf community.

Analysis of Plasma Epstein-Barr Virus DNA to Screen for Nasopharyngeal Cancer.

BACKGROUND: Circulating cell-free Epstein-Barr virus (EBV) DNA is a biomarker for nasopharyngeal carcinoma. We conducted a prospective study to investigate whether EBV DNA in plasma samples would be useful to screen for early nasopharyngeal carcinoma in asymptomatic persons. METHODS: We analyzed EBV DNA in plasma specimens to screen participants who did not have symptoms of nasopharyngeal carcinoma. Participants with initially positive results were retested approximately 4 weeks later, and those with persistently positive EBV DNA in plasma underwent nasal endoscopic examination and magnetic resonance imaging (MRI). RESULTS: A total of 20,174 participants underwent screening. EBV DNA was detectable in plasma samples obtained from 1112 participants (5.5%), and 309 (1.5% of all participants and 27.8% of those who initially tested positive) had persistently positive results on the repeated sample. Among these 309 participants, 300 underwent endoscopic examination, and 275 underwent both endoscopic examination and MRI; of these participants, 34 had nasopharyngeal carcinoma. A significantly higher proportion of participants with nasopharyngeal carcinoma that was identified by screening had stage I or II disease than in a historical cohort (71% vs. 20%, P<0.001 by the chi-square test) and had superior 3-year progression-free survival (97% vs. 70%; hazard ratio, 0.10; 95% confidence interval, 0.05 to 0.18). Nine participants declined to undergo further testing, and 1 of them presented with advanced nasopharyngeal carcinoma 32 months after enrollment. Nasopharyngeal carcinoma developed in only 1 participant with negative EBV DNA in plasma samples within 1 year after testing. The sensitivity and specificity of EBV DNA in plasma samples in screening for nasopharyngeal carcinoma were 97.1% and 98.6%, respectively. CONCLUSIONS: Analysis of EBV DNA in plasma samples was useful in screening for early asymptomatic nasopharyngeal carcinoma. Nasopharyngeal carcinoma was detected significantly earlier and outcomes were better in participants who were identified by screening than in those in a historical cohort. (Funded by the Kadoorie Charitable Foundation and the Research Grants Council of the Hong Kong government; ClinicalTrials.gov number, NCT02063399 .).

Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations.

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.

Clinical performance of a new magnetic bone conduction hearing implant system: results from a prospective, multicenter, clinical investigation.

OBJECTIVE: The aim of the investigation was to prospectively evaluate, in a multicenter setting, the clinical performance of a new magnetic bone conduction hearing implant system. METHODS: The test device was the Cochlear Baha Attract System (Cochlear Bone Anchored Solutions AB, Mölnlycke, Sweden). Instead of the skin-penetrating abutment of traditional bone conduction hearing implants, the test device uses an implantable and an external magnet to transmit sound from the sound processor (SP) through intact skin to the skull bone. Twenty-seven adult patients with a conductive or mild mixed hearing loss or single-sided sensorineural deafness were included in the clinical investigation across four investigational sites. The patients were followed for 9 months after implantation. The study evaluated efficacy in terms of hearing performance compared with unaided hearing and with hearing with the SP on a softband. Patient benefit, soft tissue status, device retention, and safety parameters were monitored continuously throughout the investigation. RESULTS: Surgery and healing was uneventful. Statistically significant improvements in audibility and speech understanding in noise and quiet were recorded for the test device compared with preoperative unaided hearing. Speech recognition was similar or better than tests performed with the same SP on a softband. Good soft tissue outcomes were reported, without major pressure-related complications. At the end of the investigation, all patients continued to use and benefit from the device. CONCLUSION: The test device provides good hearing performance in patients with a conductive hearing loss or single-sided sensorineural deafness, with good wearing comfort and minimal soft tissue complications.

The cross-talk between estrogen receptor and peroxisome proliferator-activated receptor gamma in thyroid cancer.

BACKGROUND: Estrogen receptor (ER) and peroxisome proliferator-activated receptor gamma (PPARγ) are associated with thyroid tumorigenesis and treatment. However, the interaction between them has not been studied. METHODS: The impact of ER over-expression or down-expression by DNA/small interfering RNA (siRNA) transfection, ERα agonists, and the ERß agonist diarylpropiolnitrile (DPN) on PPARγ expression/activity was examined in papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC) cells. The effects of PPARγ modulation by rosiglitazone (RTZ), a PPARγ ligand, and of PPARγ siRNA on ER expression were determined. Cellular functions reflected by cell proliferation and migration were assayed. Apoptosis was analyzed by terminal deoxynucleotidyl transferase dUTP nick-end labeling, and apoptotic-related proteins were evaluated by Western blot analysis. RESULTS: PPARγ protein and activity were reduced by the over-expression of either ERα or ERß, whereas repression of ERα or ERß increased PPARγ expression. The administration of RTZ counteracted the effects of ER and also reduced their expression, particularly in PTC cells. Moreover, knockdown of PPARγ increased ER expression and activity. Functionally, ERα activation offset the inhibitory effect of PPARγ on cellular functions, but ERß activation aggregated it and induced apoptosis, particularly in PTC cells. Finally, the interaction between ERß and PPARγ enhanced the expression of proapoptotic molecules, such as caspase-3 and apoptosis-inducing factor. CONCLUSIONS: This study provides evidence supporting a cross-talk between ER and PPARγ. The reciprocal interaction between PPARγ and ERß significantly inhibits the proliferation and migration of thyroid cancer cells, providing a new therapeutic strategy against thyroid cancer.

Early detection of nasopharyngeal carcinoma by plasma Epstein-Barr virus DNA analysis in a surveillance program.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is prevalent in Southeast Asia. Over the last decade, plasma Epstein-Barr virus (EBV) DNA has been developed as a tumor marker for NPC. In this study, the authors investigated whether plasma EBV DNA analysis is useful for NPC surveillance. METHODS: In total, 1318 volunteers ages 40 to 60 years were prospectively recruited. Plasma EBV DNA and serology for viral capsid antigen immunoglobulin A (IgA) were measured. Participants who had detectable plasma EBV DNA or positive IgA serology underwent nasal endoscopic examination and a follow-up plasma EBV DNA analysis in approximately 2 weeks. All participants were followed for 2 years to record the development of NPC. RESULTS: Three individuals with NPC were identified at enrolment. All of them were positive for EBV DNA and remained positive in follow-up analysis. Only 1 of those patients was positive for EBV serology. In 1 patient who had NPC with a small tumor confined to the mucosa, the tumor was not detectable on endoscopic examination. Because of a 2-fold increase in plasma EBV DNA on the follow-up analysis, that patient underwent magnetic resonance imaging, which revealed the tumor. Among the participants who did not have NPC but had initially positive plasma EBV DNA results, approximately 66% had negative EBV DNA results after a median of 2 weeks. CONCLUSIONS: Plasma EBV DNA analysis proved useful for detecting early NPC in individuals without a clinical suspicion of NPC. Repeating the test in those who had initially positive results differentiated those with NPC from those who had false-positive results. Cancer 2013. © 2013 American Cancer Society.

The tumor suppressor UCHL1 forms a complex with p53/MDM2/ARF to promote p53 signaling and is frequently silenced in nasopharyngeal carcinoma.

PURPOSE: Nasopharyngeal carcinoma is prevalent in southern China and Southeast Asia, with distinct geographic and ethnic distribution. One candidate susceptibility locus has been identified at 4p11-14, with the associated candidate gene(s) not identified yet. This study investigated the role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in nasopharyngeal carcinoma pathogenesis. EXPERIMENTAL DESIGN: UCHL1 expression and methylation were examined in nasopharyngeal carcinoma. Furthermore, the mechanism of its tumor-suppressive function was elucidated in nasopharyngeal carcinoma cells. RESULTS: Through genomewide expression profiling, we identified UCHL1, a 4p14 gene normally expressed in normal upper respiratory tract tissues, being silenced in all nasopharyngeal carcinoma cell lines. Its silencing is mediated by CpG methylation because UCHL1 promoter methylation was detected in all silenced cell lines, and pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. UCHL1 methylation was also frequently detected in primary tumors but only weakly detected in few normal nasopharyngeal tissues, indicating that the methylation-mediated silencing of UCHL1 is important in nasopharyngeal carcinoma pathogenesis. Ectopic UCHL1 expression dramatically inhibited the growth of nasopharyngeal carcinoma cells through promoting tumor cell apoptosis. We further found that UCHL1 formed a complex with p53/p14(ARF)/Mdm2 p53 binding protein homolog (mouse), MDM2 and activated the p53 signaling pathway. UCHL1 expression extended p53 and p14(ARF) protein half-life and shortened MDM2 protein half-life. CONCLUSIONS: These results indicate that UCHL1 could deubiquitinate p53 and p14(ARF) and ubiquitinate MDM2 for p53 stabilization to promote p53 signaling, thus involved in nasopharyngeal carcinoma pathogenesis, whereas it is frequently silenced in this tumor.

Laryngopharyngeal sensory deficits and impaired pharyngeal motor function predict aspiration in patients irradiated for nasopharyngeal carcinoma.

OBJECTIVES/HYPOTHESIS: To assess the contribution of laryngopharyngeal sensory deficits and impaired pharyngeal motor function to aspiration in patients irradiated for nasopharyngeal carcinoma. STUDY DESIGN: A retrospective study at a tertiary referral university teaching hospital. METHODS: One hundred consecutive patients who underwent radiotherapy for nasopharyngeal carcinoma referred to a dysphagia clinic underwent sensory testing of their laryngopharynx and endoscopic evaluation of their swallowing. The sensory threshold of the laryngopharynx was determined, the pharyngeal contraction assessed, and the status of the larynx and hypopharynx documented before and after swallowing. The presence of laryngeal penetration and aspiration was noted. RESULTS: The average time from radiation therapy to assessment was 10.2 years, and the mean duration of swallowing symptoms was 27 months. Laryngopharyngeal sensation was deficient in 89% of patients and the pharyngeal contraction impaired in 93% patients. Laryngeal penetration and aspiration occurred in 87% and 74% of patients, respectively. Aspiration was associated with food residue in the pyriform fossae after swallowing (P < .001) and impaired pharyngeal contraction (P < .001), but not with laryngopharyngeal sensory deficiency. There was no association between a laryngopharyngeal sensory deficit and impaired pharyngeal contraction. CONCLUSIONS: Impaired pharyngeal contraction and food bolus clearance from the hypopharynx during swallowing are more important than laryngopharyngeal sensory deficiency in predicting aspiration in patients who underwent radiotherapy for nasopharyngeal carcinoma.

OPCML is a broad tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation.

BACKGROUND: Identification of tumor suppressor genes (TSGs) silenced by CpG methylation uncovers the molecular mechanism of tumorigenesis and potential tumor biomarkers. Loss of heterozygosity at 11q25 is common in multiple tumors including nasopharyngeal carcinoma (NPC). OPCML, located at 11q25, is one of the downregulated genes we identified through digital expression subtraction. METHODOLOGY/PRINCIPAL FINDINGS: Semi-quantitative RT-PCR showed frequent OPCML silencing in NPC and other common tumors, with no homozygous deletion detected by multiplex differential DNA-PCR. Instead, promoter methylation of OPCML was frequently detected in multiple carcinoma cell lines (nasopharyngeal, esophageal, lung, gastric, colon, liver, breast, cervix, prostate), lymphoma cell lines (non-Hodgkin and Hodgkin lymphoma, nasal NK/T-cell lymphoma) and primary tumors, but not in any non-tumor cell line and seldom weakly methylated in normal epithelial tissues. Pharmacological and genetic demethylation restored OPCML expression, indicating a direct epigenetic silencing. We further found that OPCML is stress-responsive, but this response is epigenetically impaired when its promoter becomes methylated. Ecotopic expression of OPCML led to significant inhibition of both anchorage-dependent and -independent growth of carcinoma cells with endogenous silencing. CONCLUSIONS/SIGNIFICANCE: Thus, through functional epigenetics, we identified OPCML as a broad tumor suppressor, which is frequently inactivated by methylation in multiple malignancies.

The roles and limitations of computed tomography in the preoperative assessment of sinonasal inverted papillomas.

BACKGROUND: Preoperative radiological assessment of sinonasal inverted papilloma (SNIP) is important in the planning of surgical treatment. This study investigates the roles and limitations of preoperative plain computed tomography (CT) scan in the preoperative assessment of SNIP. METHODS: Plain CT scans from 30 patients with SNIP were reviewed retrospectively by a radiologist who had no prior knowledge of the final surgical findings. Disease at each sinus was judged by the CT findings of opacity and additional signs. The overall disease was staged according to the staging system proposed by Krouse. All of the findings were compared with the final disease extent and staging confirmed by intraoperative and histological findings. RESULTS: Using opacity with additional signs for diagnosis, the range of accuracy of CT diagnosis for each sinus involvement was 83-97%. Staging by plain CT was concordant with postoperative staging in 80% of patients. Among the additional signs, focal hyperostosis or "bony strut" had the highest positive predictive value (100%) of tumor origin. CONCLUSION: Focal hyperostosis or bony strut is the most important CT sign predicting the origin of tumor. Although using multiple CT diagnostic signs provides a reasonable assessment of tumor origin and extent, accurate tumor mapping was still impossible because of inadequate differentiation of tumor from inflammatory pathologies. This drawback may be overcome by a complementary MRI scan. Since preoperative CT staging was inaccurate in 20% of cases, surgical planning should be flexible to provide for the need of the intraoperative findings.

The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas.

Aberrant activation of the wingless-type- (Wnt)-signaling pathway is common in many cancers including nasopharyngeal (NPC) and esophageal squamous cell (ESCC) carcinomas, both prevalent in Southern China and Southeast Asia. However, the molecular mechanism leading to this abnormality is still obscure. Wnt inhibitory factor-1 (WIF1) is a secreted antagonist of the Wnt pathway, and is recently shown to be inactivated by epigenetic mechanism in some tumors. Here, we examined whether WIF1 is also inactivated epigenetically in NPC and ESCC. With semiquantitative reverse transcription-PCR and methylation-specific PCR, we detected WIF1 downregulation or silencing in 6/6 of NPC and 12/19 of ESCC cell lines, which is well correlated with its methylation status. Methylation was further confirmed by high-resolution bisulfite genomic sequencing. Methylation was also frequently observed in a large collection of primary tumors of NPC (85%, 55/65) and ESCC (27%, 25/92), with WIF1 expressed and unmethylated in normal NPC and esophageal cell lines and normal tissues. Treatment of 5-aza-2'-deoxycytidine demethylated WIF1 and induced its expression in NPC and ESCC cell lines, highlighting a direct role of epigenetic inactivation. Ectopic expression of WIF1 in NPC and ESCC tumor cells resulted in significant inhibition of tumor cell colony formation, similar to TP53, and also significant downregulation of beta-catenin protein level in NPC cells. Thus, WIF1 functions as a tumor suppressor for both NPC and ESCC through suppressing the Wnt-signaling pathway, but is frequently silenced by epigenetic mechanism in a tumor-specific way. Our study indicates that epigenetic inactivation of WIF1 contributes to the aberrant activation of Wnt pathway and is involved in the pathogenesis of both tumors. WIF1 methylation could also serve as a specific biomarker for these tumors.