Publications by authors named "Myung Woul Han"

38 Publications

Epigenetic regulation of p62/SQSTM1 overcomes the radioresistance of head and neck cancer cells via autophagy-dependent senescence induction.

Cell Death Dis 2021 Mar 5;12(3):250. Epub 2021 Mar 5.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Tumors are composed of subpopulations of cancer cells with functionally distinct features. Intratumoral heterogeneity limits the therapeutic effectiveness of cancer drugs. To address this issue, it is important to understand the regulatory mechanisms driving a subclonal variety within a therapy-resistant tumor. We identified tumor subclones of HN9 head and neck cancer cells showing distinct responses to radiation with different levels of p62 expression. Genetically identical grounds but epigenetic heterogeneity of the p62 promoter regions revealed that radioresistant HN9-R clones displayed low p62 expression via the creation of repressive chromatin architecture, in which cooperation between DNMT1 (DNA methyltransferases 1) and HDAC1 (histone deacetylases 1) resulted in DNA methylation and repressive H3K9me3 and H3K27me3 marks in the p62 promoter. Combined inhibition of DNMT1 and HDAC1 by genetic depletion or inhibitors enhanced the suppressive effects on proliferative capacity and in vivo tumorigenesis following irradiation. Importantly, ectopically p62-overexpressed HN9-R clones increased the induction of senescence along with p62-dependent autophagy activation. These results demonstrate the heterogeneous expression of p62 as the key component of clonal variation within a tumor against irradiation. Understanding the epigenetic diversity of p62 heterogeneity among subclones allows for improved identification of the functional state of subclones and provides a novel treatment option to resolve resistance to current therapies.
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http://dx.doi.org/10.1038/s41419-021-03539-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935951PMC
March 2021

Obesity Can Contribute to Severe Persistent Allergic Rhinitis in Children through Leptin and Interleukin-1β.

Int Arch Allergy Immunol 2021 Mar 3:1-7. Epub 2021 Mar 3.

Department of Occupational and Environmental Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.

Background: Obesity/overweight is associated with a higher risk of allergic rhinitis (AR) in children.

Objective: This study aimed at exploring the mechanisms by which obesity affects the severity of AR through leptin and interleukin (IL)-1β were investigated.

Methods: In all, 210 subjects with AR and 82 subjects without AR were included in this study. The levels of leptin and inflammatory biomarkers were measured in the serum to investigate the correlation with the severity of AR. Additionally, we analyzed whether changes in BMI regulate the severity of AR through serial follow-up of obese children.

Results: IL-1β, which is a biomarker of active inflammation in AR, was significantly higher in individuals with AR than in those without and higher in subjects in the obesity group than in those in the normal weight group. A regression analysis showed that the leptin level was associated with increased IL-1β expression in children with AR. In the multivariate analysis, only parental AR (9.2-fold increase in risk), elevated leptin (11.3-fold increase in risk), and high expression of IL-1β (5.8-fold increase in risk) emerged as significant risk factors of moderate to severe persistent allergic rhinitis. We also found that children with an increase or decrease in BMI showed changes in IL-1β and AR symptoms, which these changes were dependent on leptin and BMI.

Conclusions: These results suggest that obesity is an important risk factor for the exacerbation of symptoms and leptin can exacerbate inflammation as well as severe and persistent symptoms through IL-1β in AR.
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http://dx.doi.org/10.1159/000512920DOI Listing
March 2021

p53-dependent glutamine usage determines susceptibility to oxidative stress in radioresistant head and neck cancer cells.

Cell Signal 2021 Jan 31;77:109820. Epub 2020 Oct 31.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

The manner in which p53 maintains redox homeostasis and the means by which two key metabolic elements, glucose and glutamine, contribute to p53-dependent redox stability remain unclear. To elucidate the manner in which p53 deals with glucose-deprived, reactive oxygen species (ROS)-prone conditions in this regard, two isogenic cancer subclones (HN3R-A and HN3R-B) bearing distinct p53 mutations as an in vitro model of intratumoral p53 heterogeneity were identified. Following cumulative irradiation, the subclones showed a similar metabolic shift to aerobic glycolysis and increasing NADPH biogenesis for cellular defense against oxidative damage irrespective of p53 status. The radioresistant cancer cells became more sensitive to glycolysis-targeting drugs. However, in glucose-deprived and ROS-prone conditions, HN3R-B, the subclone with the original p53 increased the utilization of glutamine by GLS2, thereby maintaining redox homeostasis and ATP. Conversely, HN3R-A, the p53-deficient radioresistant subclone displayed an impairment in glutamine usage and high susceptibility to metabolic stresses as well as ROS-inducing agents despite the increased ROS scavenging system. Collectively, our findings suggest that p53 governs the alternative utilization of metabolic ingredients, such as glucose and glutamine, in ROS-prone conditions. Thus, p53 status may be an important biomarker for selecting cancer treatment strategies, including metabolic drugs and ROS-inducing agents, for recurrent cancers after radiotherapy.
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http://dx.doi.org/10.1016/j.cellsig.2020.109820DOI Listing
January 2021

Tristetraprolin Posttranscriptionally Downregulates TRAIL Death Receptors.

Cells 2020 08 7;9(8). Epub 2020 Aug 7.

Department of Otorhinolaryngology, GangNeung Asan Hospital, University of Ulsan College of Medicine, Gangneung 25440, Korea.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has attracted attention as a potential candidate for cancer therapy. However, many primary cancers are resistant to TRAIL, even when combined with standard chemotherapy. The mechanism of TRAIL resistance in cancer cells has not been fully elucidated. The TRAIL death receptor (DR) 3'-untranslated region (3'-UTR) is reported to contain AU-rich elements (AREs) that are important for regulating DR mRNA stability. However, the mechanisms by which DR mRNA stability is determined by its 3'-UTR are unknown. We demonstrate that tristetraprolin (TTP), an ARE-binding protein, has a critical function of regulating DR mRNA stability. DR4 mRNA contains three AREs and DR5 mRNA contains four AREs in 3'-UTR. TTP bound to all three AREs in DR4 and ARE3 in DR5 and enhanced decay of DR4/5 mRNA. TTP overexpression in colon cancer cells changed the TRAIL-sensitive cancer cells to TRAIL-resistant cells, and down-regulation of TTP increased TRAIL sensitivity via DR4/5 expression. Therefore, this study provides a molecular mechanism for enhanced levels of TRAIL DRs in cancer cells and a biological basis for posttranscriptional modification of TRAIL DRs. In addition, TTP status might be a biomarker for predicting TRAIL response when a TRAIL-based treatment is used for cancer.
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http://dx.doi.org/10.3390/cells9081851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465502PMC
August 2020

Sex disparities in head & neck cancer driver genes: An analysis of the TCGA dataset.

Oral Oncol 2020 05 5;104:104614. Epub 2020 Mar 5.

Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada; Department of Oncology, University of Western Ontario, London, Ontario, Canada. Electronic address:

Objectives: Survival in head and neck squamous cell carcinoma (HNSCC) has been associated with patient sex, typically with males experiencing poorer outcomes. It is unclear if this disparity is based in divergent tumor biology. We analyzed the TCGA HNSCC cohort to uncover disparities in the somatic single nucleotide variation (SNV), copy number alteration (CNA) and mRNA abundance profiles between males and females. Critically, we stratified our results by tumor HPV status to control for this significant confounder.

Methods: SNV, CNA and mRNA abundance differences between males and females were compared separately for the HPV-positive (n = 67) and negative (n = 431) TCGA HNSCC cohorts. Overall survival outcomes were compared in males and females in both HPV-positive and HPV-negative subsets of patients.

Results: Females were found to have poorer overall survival than males (p = 0.048), largely due to higher rates of HPV-positive disease among men. SNV analysis revealed that in HPV-positive disease, there were no differences by sex after accounting for the false discovery rate (FDR). In HPV-negative tumors, BRWD3 mutations occurred more frequently in the tumors of female patients compared to males after adjusting for the FDR (p = 0.02). Further, HPV-negative BRWD3 mutant tumors were found to have significantly worse 5-year overall survival compared to wildtype on multivariate analysis (p = 0.02). There were 88 heterozygous deletions and 14 amplifications that were differentially altered between male and female HPV-negative tumors and associated with expression changes. Pathway analysis of these genes revealed that tumors from males were enriched in five pathways including chemokine and phosphophatidylinositol signaling.

Conclusions: Reanalysis of the TCGA HNSCC dataset stratified by sex revealed that males in this cohort had a significant survival advantage, due to a higher proportion of HPV-positive disease. Mutations in BRWD3 were more frequent in HPV-negative tumors of females and were associated with poorer overall survival. BRWD3 may represent a novel biomarker of patient outcomes, but will require additional validation.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104614DOI Listing
May 2020

Spleen tyrosine kinase expression is correlated with human papillomavirus in head and neck cancer.

Oral Oncol 2020 02 19;101:104529. Epub 2019 Dec 19.

Department of Otolaryngology, London Health Sciences Centre, London, Ontario, Canada; Department of Oncology, London Health Sciences Centre, London, Ontario, Canada. Electronic address:

Objectives: Spleen tyrosine kinase (SYK) is a promoter of cell survival in a variety of cell types, including normal and cancerous epithelial cells. We hypothesized that SYK would an important therapeutic target to inhibit for the treatment of HNSCC.

Materials And Methods: SYK protein abundance in patient tumours was evaluated. SYK protein and mRNA abundance was used to examine patient survival and human papillomavirus (HPV) status. Small-interfering RNAs and gene editing with CRISPR/Cas9 were used to evaluate SYK expression on proliferation in HNSCC cell lines. The potency of SYK inhibitor ER27319 maleate on cellular proliferation was tested using a panel of 28 HNSCC cell lines and in vivo in HNSCC patient-derived xenograft (PDX) models.

Results: Moderate to high protein expression of SYK was observed in 24% of patient tumors and high SYK expression was exclusively observed in HPV-positive samples (p < 0.001). SYK inhibition with RNA interference, gene editing or a SYK inhibitor (ER27319) decreased cell proliferation and migration. Treatment of PDXs with ER27319 maleate was observed to reduce tumour burden in vivo in two of three models.

Conclusions: HPV-positive HNSCC harbours high SYK protein levels. We demonstrate that proliferation, migration and overall burden of these tumours can be reduced by genetic or pharmacologic inhibition of SYK. Taken together, these data establish SYK as a therapeutic target for HNSCC.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104529DOI Listing
February 2020

Genomic and human papillomavirus profiling of an oral cancer cohort identifies TP53 as a predictor of overall survival.

Cancers Head Neck 2019 5;4. Epub 2019 Dec 5.

1Department of Otolaryngology - Head and Neck Surgery, Western University, London, ON Canada.

Background: The genomic landscape of head and neck cancer has been reported through The Cancer Genome Atlas project. We attempt to determine if high-risk human papillomavirus (HPV) or frequently mutated genes are correlated with survival in an oral cancer cohort.

Methods: Patient demographic data along with data from final pathology was collected. Tumor DNA was analyzed using a custom Illumina targeted sequencing panel. Five high-risk HPV types were tested by qPCR. Statistical analyses were used to identify associations between patient outcome and mutational status.

Results: High-risk HPV types were identified in 7% of cases; HPV status was not associated with survival. Mutations were identified in TP53, TERT promoter, & PIK3CA. Mutations in TP53 were significantly associated with poorer overall survival on multi-variate analysis ( = 0.03).

Conclusions: Mutations in TP53 were associated with poor patient survival. Expanding our sample size may identify further predictors of outcome to direct customized cancer care.
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http://dx.doi.org/10.1186/s41199-019-0045-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894507PMC
December 2019

Serum IL-1β can be a biomarker in children with severe persistent allergic rhinitis.

Allergy Asthma Clin Immunol 2019 18;15:58. Epub 2019 Sep 18.

3Department of Occupational and Environmental Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, 877 Bangeojinsunhwan-doro, Dong-gu, Ulsan, 44033 Republic of Korea.

Background: Allergic rhinitis (AR) is one of the most common diseases globally and usually persists throughout life. In the present study, we aimed to determine whether the expression of inflammatory biomarkers has a relationship with the severity of allergic rhinitis and with comorbid asthma or other allergic diseases in children.

Methods: For diagnosis of AR, the skin prick test was performed to measure the responses to 18 allergens. Blood levels of eosinophils and immunoglobulin E (IgE) were examined. We classified the patients into 2 groups based on the severity of the condition as Group 1 [intermittent AR (IAR) or mild persistent AR (PAR)] and Group 2 (moderate to severe PAR). To determine the expression of inflammatory biomarkers, in serum and several biomarkers (caspase-1, IL-1β, CCL-11, CCL-24 and IL-33) were measured in the serum using enzyme-linked immunosorbent assay (ELISA). Additionally, we analyzed the correlation between clinical variables and the expression of biomarkers (eosinophils count, IL-1β and CCL-24) and the severity of AR.

Results: We found that eosinophils count, IL-1β, a marker of activation of inflammasomes, and CCL-24 were significantly increased in the moderate to severe PAR group ( = 0.008,  = 0.003,  = 0.039). Additionally, the expressions of eosinophil count, IL-1β and CCL-24 were significantly higher in patients with active asthmatic symptoms than in those without these conditions. On univariate analysis, allergic rhinitis in sibling, paternal allergic rhinitis, high expression of eosinophils count, IL-1β and CCL-24, history of active asthma and atopy correlated with severity of AR. Multivariate analysis showed only paternal allergic rhinitis and high expression of IL-1β as significant risk factors of moderate to severe PAR with 6.4 fold and 4.7 fold-increase in risk, respectively ( = 0.011 and  = 0.030).

Conclusion: In conclusion, this study provides the first evidence that an excessive release of biologically active IL-1β may promote inflammation in severe PAR. It demonstrates that IL-1β can be a biomarker for active allergic diseases such as AR, asthma, and atopy. Moreover, this finding suggests that IL-1B should be investigated as a therapeutic target in severe PAR and other allergic diseases.
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http://dx.doi.org/10.1186/s13223-019-0368-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749717PMC
September 2019

Aggressive Thyroid Carcinoma Showing Thymus-Like Differentiation (CASTLE) With Lung Metastasis and Carotid Artery Invasion.

Ear Nose Throat J 2019 Oct-Nov;98(9):557-559. Epub 2019 Jul 8.

Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.

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http://dx.doi.org/10.1177/0145561319858056DOI Listing
April 2020

The role of CIP2A as a therapeutic target of rapamycin in radioresistant head and neck cancer with TP53 mutation.

Head Neck 2019 09 3;41(9):3362-3371. Epub 2019 Jul 3.

Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.

Background: CIP2A may activate multiple oncogenic proteins and promote the proliferation of various cancer cells.

Methods: We investigated that the role of CIP2A in radioresistant head and neck cancer (HNC) cell line with TP53 mutation and the effect of the rapamycin on the response of HN31 with TP53 mutation cells to irradiation related to CIP2A expression.

Results: CIP2A expression was stimulated by p53 mutation and critical for the inhibition of senescence induction in response to radiation. The treatment with radiation alone neither induced cytotoxicity in HN31 cells nor completely suppressed the activation of CIP2A. However, the combination of radiation and rapamycin increase the radiosensitivity through the induction of senescence with downregulation of CIP2A expression both in vivo and in vitro.

Conclusion: Our results suggest that CIP2A may serve as a therapeutic target of rapamycin through induction of senescence in radioresistant HNC with TP53 mutation.
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http://dx.doi.org/10.1002/hed.25868DOI Listing
September 2019

EphA3 maintains radioresistance in head and neck cancers through epithelial mesenchymal transition.

Cell Signal 2018 Jul 10;47:122-130. Epub 2018 Apr 10.

Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea. Electronic address:

Radiotherapy is a well-established therapeutic modality used in the treatment of many cancers. However, radioresistance remains a serious obstacle to successful treatment. Radioresistance can cause local recurrence and distant metastases in some patients after radiation treatment. Thus, many studies have attempted to identify effective radiosensitizers. Eph receptor functions contribute to tumor development, modulating cell-cell adhesion, invasion, neo-angiogenesis, tumor growth and metastasis. However, the role of EphA3 in radioresistance remains unclear. In the current study, we established a stable radioresistant head and neck cancer cell line (AMC HN3R cell line) and found that EphA3 was expressed predominantly in the radioresistant head and neck cancer cell line through DNA microarray, real time PCR and Western blotting. Additionally, we found that EphA3 was overexpressed in recurrent laryngeal cancer specimens after radiation therapy. EphA3 mediated the tumor invasiveness and migration in radioresistant head and neck cancer cell lines and epithelial mesenchymal transition- related protein expression. Inhibition of EphA3 enhanced radiosensitivity in the AMC HN 3R cell line in vitro and in vivo study. In conclusion, our results suggest that EphA3 is overexpressed in radioresistant head and neck cancer and plays a crucial role in the development of radioresistance in head and neck cancers by regulating the epithelial mesenchymal transition pathway.
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http://dx.doi.org/10.1016/j.cellsig.2018.04.001DOI Listing
July 2018

Low-Dose Radioactive Iodine Ablation Is Sufficient in Patients With Small Papillary Thyroid Cancer Having Minor Extrathyroidal Extension and Central Lymph Node Metastasis (T3 N1a): Reply.

Clin Nucl Med 2018 08;43(8):633-634

Department of Nuclear Medicine Ulsan University Hospital University of Ulsan College of Medicine Ulsan, Korea Department of Surgery Ulsan University Hospital University of Ulsan College of Medicine Ulsan, Korea Department of Otorhinolaryngology Ulsan University Hospital University of Ulsan College of Medicine Ulsan, Korea Department of Internal Medicine Ulsan University Hospital University of Ulsan College of Medicine Ulsan, Korea Department of Pathology Ulsan University Hospital University of Ulsan College of Medicine Ulsan, Korea Department of Nuclear Medicine Ulsan University Hospital University of Ulsan College of Medicine Ulsan, Korea

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http://dx.doi.org/10.1097/RLU.0000000000002066DOI Listing
August 2018

Low-Dose Radioactive Iodine Ablation Is Sufficient in Patients With Small Papillary Thyroid Cancer Having Minor Extrathyroidal Extension and Central Lymph Node Metastasis (T3 N1a): Reply.

Clin Nucl Med 2018 08;43(8):635-636

Department of Nuclear Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea Department of Otorhinolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea Department of Nuclear Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea

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http://dx.doi.org/10.1097/RLU.0000000000002060DOI Listing
August 2018

Phosphorylation of PI3K regulatory subunit p85 contributes to resistance against PI3K inhibitors in radioresistant head and neck cancer.

Oral Oncol 2018 03 20;78:56-63. Epub 2018 Feb 20.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

Objectives: PI3K/Akt/mTOR pathway is commonly activated in most cancers and is correlated with resistance to anticancer therapies such as radiotherapy. Therefore, PI3K is an attractive target for treating PI3K-associated cancers.

Material And Methods: We investigated the basal expression and the expression after treatment of PI3K inhibitor or Src inhibitor of PI3K/Akt pathway-related proteins in AMC-HN3, AMC-HN3R, HN30 and HN31 cells by performing immunoblotting analysis. The sensitivity to PI3K inhibitors or Src inhibitor was analyzed by MTT assay and clonogenic assay. To determine the antitumoral activity of combination treatment with PI3K inhibitor and Src inhibitor, we used using xenograft mouse model.

Results: We found that PI3K regulatory subunit p85 was predominantly phosphorylated in radioresistant head and neck cancer cell line (HN31), which showed resistance to PI3K inhibitors. Next, we investigated mechanism through which PI3K p85 phosphorylation modulated response to PI3K inhibitors. Of note, constitutive activation of Src was found in HN31 cells and upon PI3K inhibitor treatment, restoration of p-Src was occurred. Src inhibitor improved the efficacy of PI3K inhibitor treatment and suppressed the reactivation of both Src and PI3K p85 in HN31 cells. Furthermore, downregulation of PI3K p85 expression by using a specific siRNA suppressed Src phosphorylation.

Conclusions: Together, our results imply the novel role of the PI3K regulatory subunit p85 in the development of resistance to PI3K inhibitors and suggest the presence of a regulatory loop between PI3K p85 and Src in radioresistant head and neck cancers with constitutively active PI3K/Akt pathway.
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http://dx.doi.org/10.1016/j.oraloncology.2018.01.014DOI Listing
March 2018

Low-Dose Radioactive Iodine Ablation Is Sufficient in Patients With Small Papillary Thyroid Cancer Having Minor Extrathyroidal Extension and Central Lymph Node Metastasis (T3 N1a).

Clin Nucl Med 2017 Nov;42(11):842-846

From the Departments of *Nuclear Medicine, †Surgery, ‡Otorhinolaryngology, §Internal Medicine, and ∥Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.

Purpose: The aim of this study was to evaluate the effectiveness of low-dose radioactive iodine (RAI) ablation in patients with small papillary thyroid cancer (PTC) exhibiting microscopic extrathyroidal extension (mETE) and central lymph node (CLN) metastasis.

Methods: Among patients who underwent RAI ablation between March 2007 and February 2014, those who had small PTCs (≤2 cm), as well as mETE and CLN metastasis (T3 N1a M0), were enrolled. Response to ablation and long-term outcomes were assessed and compared according to the administered RAI dose. Factors associated with unsuccessful ablation were also determined.

Results: A total of 180 patients were included in the study. Eighty-eight patients had been treated with 1110 MBq (low-dose group) and 92 with 2960 MBq (high-dose group) of RAI. There were no significant differences in the responses to ablation (P = 0.810) and long-term outcomes (P = 0.663) between both groups. Among all patients enrolled, 13 did not achieve successful ablation at long-term follow-up. Logistic regression found that a high ratio of metastatic nodes was a significant factor for predicting unsuccessful ablation.

Conclusions: Low-dose RAI ablation did not produce significantly different responses or long-term outcomes in patients with small PTCs exhibiting mETE and CLN metastasis. These findings suggest that low-dose ablation may be sufficient in this specific group of intermediate-risk patients, although careful selection is required for patients with a high ratio of metastatic nodes.
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http://dx.doi.org/10.1097/RLU.0000000000001812DOI Listing
November 2017

Homotypic Interaction of Stabilin-2 Plays a Critical Role in Lymph Node Metastasis of Tongue Cancer.

Anticancer Res 2016 12;36(12):6611-6618

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

Background/aim: Lymph node (LN) metastasis of solid types of tumors has important clinical significance and it is therefore critical to identify molecular biomarkers that would enable the selection of patients with LN metastases.

Patients And Methods: We evaluated the expression of stabilin-2 in primary oral tongue tumors and metastatic LNs using immunohistochemical staining. The correlation between risk factors and nodal metastasis was assessed and disease-free survival was analyzed.

Results: Stabilin-2 expression remained a significant predictor of LN metastasis and the factor affecting recurrence in tongue cancer. Most importantly, all metastatic tumors of tongue, lung, stomach and colon cancers stained positive for stabilin-2 and stabilin-2 was expressed strongly in the sinusoidal endothelial cell of metastatic LNs.

Conclusion: Stabilin-2 can play a critical role in the first entrapping step of LN metastasis through homotypic interaction with the lymphatic endothelium and appears to be a tumor biomarker predicting for LN metastasis in patients with solid tumors.
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http://dx.doi.org/10.21873/anticanres.11267DOI Listing
December 2016

Impact of adenotonsillectomy on nocturnal enuresis in children with sleep-disordered breathing: A prospective study.

Laryngoscope 2016 05 1;126(5):1241-5. Epub 2016 Mar 1.

Department of Otorhinolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.

Objectives/hypothesis: To investigate the relationship between sleep-disordered breathing (SDB) and nocturnal enuresis (NE) in children and to prospectively evaluate the effectiveness of adenotonsillectomy on resolving enuresis in indicated SDB patients with NE.

Methods: We prospectively collected data from 183 children (121 males, mean age 8.17 ± 2.84 years) who underwent adenotonsillectomy to treat SDB between July 2011 and July 2013, and analyzed the prevalence of NE. Before and 3 months after surgery, all parents were requested to answer a self-reported SDB scale questionnaire (22 questions, 0-22 points) and a NE questionnaire (episodes of enuresis per month). Paired t test, Student t test, and Chi-square test were used to analyze the data.

Results: Overall prevalence of NE was 9.3% (17 patients) preoperatively and 1.5% postoperatively (four patients). After adenotonsillectomy, prevalence of NE and the mean SDB scale were significantly decreased (both P values < 0.001). After adenotonsillectomy, 13 of the 17 NE patients (76.5%) showed complete resolution. There was significantly higher prevalence of NE in patients with obstructive sleep apnea (OSA) than those without OSA (13.1%, 14 of 107 vs. 3.9%, 3 of 76; P = 0.036).

Conclusion: There is strong association between NE and SDB, and adenotonsillectomy can markedly improve enuresis in the majority of children with NE and SDB.

Levels Of Evidence: 4. Laryngoscope, 126:1241-1245, 2016.
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http://dx.doi.org/10.1002/lary.25934DOI Listing
May 2016

Oxidative stress in schoolchildren with allergic rhinitis: propensity score matching case-control study.

Ann Allergy Asthma Immunol 2015 Nov 12;115(5):391-5. Epub 2015 Sep 12.

Department of Otorhinolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea; Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea. Electronic address:

Background: Oxidative stress is defined as an imbalance between the level of reactive oxygen species and antioxidant mechanisms. Compared with asthma, the role of oxidative stress in allergic rhinitis (AR) has received little attention.

Objective: To investigate the association between overall systemic oxidative stress and AR.

Methods: We used a propensity score matching case-control study and selected 90 children who had experienced AR in the previous year. This AR group was then matched with 90 healthy children who comprised the control group. Propensity score matching, a statistical matching technique that accounts for the conditional probability of receiving an exposure given a vector of measured covariates, is used to reduce selection bias and potential confounders in observational study. Serum total antioxidant status (TAS) and total oxidant status (TOS) levels were determined using a commercially available assay kit. Medical records and personal information were also reviewed.

Results: No statistically significant differences were found between patients with regard to age, sex, height, weight, educational level of parent, monthly household income, or distance of home from a main road. The mean TAS and TOS levels in the patient group were significantly higher than those of the control group (P = .03 and .048, respectively). The oxidative stress index, which is defined as the ratio of TOS to TAS, also increased in the AR group with statistical propensity (P = .08). In a multivariate logistic analysis, only TAS and TOS levels were significantly associated with increased risk of allergic rhinitis.

Conclusion: Patients with AR have systemically elevated oxidative stress and systemically elevated TAS levels.
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http://dx.doi.org/10.1016/j.anai.2015.07.022DOI Listing
November 2015

Prognostic factors and outcome analysis of salivary duct carcinoma.

Auris Nasus Larynx 2015 Dec 28;42(6):472-7. Epub 2015 May 28.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea. Electronic address:

Objective: Salivary duct carcinoma (SDC) is highly aggressive, with high rates of recurrence and nodal and distant metastases. The aim of the current study was to evaluate the clinical implication of EGFR and HER2 expression for predicting prognosis and to identify the factors associated with outcome.

Methods: The medical records of 28 patients with SDC underwent surgery and adjuvant RT. Expression of c-erbB-2 and EGFR was determined immunohistochemically on the 25 SDC specimens. Disease-free survival (DFS), overall survival (OS) and distant metastasis-free survival (DMFS) were analyzed.

Results: Three-year DFS, OS and DMFS rates were 38.3%, 78.1% and 45.7%, respectively. Expression of c-erbB-2 and EGFR was seen in 64% and 40%. c-erbB-2 and EGFR expression did not correlate with recurrence or metastasis. Advanced N classification and perineural invasion (PNI) were significant predictors of DFS and DMFS.

Conclusion: c-erbB-2 and EGFR expression did not correlate with recurrence or metastasis. Despite aggressive surgery and RT, approximately 50% of SDCs failed systemically. More effective therapy to inhibit distant metastases in patients with advanced N classification and PNI should be considered.
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http://dx.doi.org/10.1016/j.anl.2015.04.005DOI Listing
December 2015

Epithelial-mesenchymal transition: clinical implications for nodal metastasis and prognosis of tongue cancer.

Otolaryngol Head Neck Surg 2015 Jan 11;152(1):80-6. Epub 2014 Nov 11.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea

Objective: The development of biomarkers for the prediction of lymph node metastasis and prognosis is critical for deciding the treatment modality of tongue cancer. The purpose of our study is to investigate the clinical implications of epithelial-mesenchymal transition (EMT) expression in tongue cancer.

Study Design: Historical cohort study

Setting: Tertiary-care hospital.

Subjects And Methods: The study included 95 subjects with tongue cancer who underwent wide excision and neck dissection. According to characteristics of immunohistochemical staining for E-cadherin and vimentin, we classified the tumors as complete EMT phenotype, incomplete EMT phenotype, or epithelial phenotype. The correlation between risk factors and nodal metastasis was assessed, and disease-free survival (DFS) was analyzed.

Results: Positive lymph nodes were detected in 46 (48.4%) patients and was found to correlate significantly with depth of invasion ≥ 4 mm and EMT expression on multivariate analysis (P = .030, P = .022, respectively). The mean follow-up period of all patients was 96.3 months (range, 6-149 months). Overall 5-year DFS was 61.7%. On multivariate analysis, the only factors affecting DFS were nodal stage and EMT expression (P = .033, P = .021, respectively).

Conclusions: Our study reveals that EMT expression is a significant biomarker for predicting lymph node metastasis and tumor recurrence in tongue cancer. Evaluation of EMT expression in tongue cancer can allow therapy to be offered accordingly.
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http://dx.doi.org/10.1177/0194599814556061DOI Listing
January 2015

Development of TRAIL resistance by radiation-induced hypermethylation of DR4 CpG island in recurrent laryngeal squamous cell carcinoma.

Int J Radiat Oncol Biol Phys 2014 Apr;88(5):1203-11

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea. Electronic address:

Purpose: There are limited therapeutic options for patients with recurrent head and neck cancer after radiation therapy failure. To assess the use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a salvage chemotherapeutic agent for recurrent cancer after radiation failure, we investigated the effect of clinically relevant cumulative irradiation on TRAIL-induced apoptosis.

Methods And Materials: Using a previously established HN3 cell line from a laryngeal carcinoma patient, we generated a chronically irradiated HN3R isogenic cell line. Viability and apoptosis in HN3 and HN3R cells treated with TRAIL were analyzed with MTS and PI/annexin V-FITC assays. Western blotting and flow cytometry were used to determine the underlying mechanism of TRAIL resistance. DR4 expression was semiquantitatively scored in a tissue microarray with 107 laryngeal cancer specimens. Methylation-specific polymerase chain reaction and bisulfite sequencing for DR4 were performed for genomic DNA isolated from each cell line.

Results: HN3R cells were more resistant than HN3 cells to TRAIL-induced apoptosis because of significantly reduced levels of the DR4 receptor. The DR4 staining score in 37 salvage surgical specimens after radiation failure was lower in 70 surgical specimens without radiation treatment (3.03 ± 2.75 vs 5.46 ± 3.30, respectively; P<.001). HN3R cells had a methylated DR4 CpG island that was partially demethylated by the DNA demethylating agent 5-aza-2'-deoxycytidine.

Conclusion: Epigenetic silencing of the TRAIL receptor by hypermethylation of a DR4 CpG island might be an underlying mechanism for TRAIL resistance in recurrent laryngeal carcinoma treated with radiation.
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http://dx.doi.org/10.1016/j.ijrobp.2013.12.016DOI Listing
April 2014

Autophagy inhibition can overcome radioresistance in breast cancer cells through suppression of TAK1 activation.

Anticancer Res 2014 Mar;34(3):1449-55

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olymhic-Ro 43-Gil, Songpa-Gu, Seoul 138-736, Republic of Korea. and Seong Who Kim, MD, Ph.D., Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine Seoul, Republic of Korea. E-mail:

Background/aim: Autophagy is frequently activated in radioresistant cancer cells. In the present study, we evaluated the role of autophagy and transforming growth factor-activated kinase 1 (TAK1) in radioresistance.

Materials And Methods: TAK1 phosphorylation in MDA-MB231 breast cancer cells was evaluated by western blotting. The regulatory effects of the TAK1 inhibitor and autophagy inhibitor were assessed by cell morphology, cell survival and induction of apoptosis.

Results: Radiation induced the phosphorylation of TAK1, whereas the inhibition of TAK1 activity enhanced the cytotoxicity of radiation in MDA-MB231 cells. Autophagy inhibitors significantly enhanced radiation-induced apoptosis of MDA-MB231 cells. This augmentation in radiosensitivity seemed to result from the suppression of TAK1 activation.

Conclusion: Inhibition of autophagy enhanced radiosensitivity through suppression of radiation-induced TAK1 activation, suggesting that the modulation of TAK1-induced autophagy may be a good therapeutic strategy to treat radioresistant breast cancer.
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March 2014

Prolonged autophagy by MTOR inhibitor leads radioresistant cancer cells into senescence.

Autophagy 2013 Oct 13;9(10):1631-2. Epub 2013 Aug 13.

Department of Biochemistry and Molecular Biology; Biomedical Research Center; University of Ulsan College of Medicine; Seoul, Korea.

Radiotherapy is one of the well-established therapeutic modalities for cancer treatment. However, the emergence of cells refractory to radiation is a major obstacle to successful treatment with radiotherapy. Many reports suggest that inhibitors targeting the mechanistic target of rapamycin (MTOR) can sensitize cancer cells to the effect of radiation, although by which mechanism MTOR inhibitors enhance the efficacy of radiation toward cancer cells remains to be elucidated. Our studies indicate that a potent and persistent activation of autophagy via inhibition of the MTOR pathway, even in cancer cells where autophagy is occurring, can trigger premature senescence, cellular proliferation arrest. Combined treatment of MTOR inhibitor and radiation induce heterochromatin formation, an irreversible growth arrest and an increase of senescence-associated GLB1 (β-galactosidase) activity, which appear to result from a constant activation of TP53 and a restoration in the activity of retinoblastoma 1 protein (RB1)-E2F1. Thus, this study provides evidence that promoting cellular senescence via inhibition of the MTOR pathway may serve as an avenue to augment radiosensitivity in cancer cells that initiate an autophagy-survival mode to radiotherapy.
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http://dx.doi.org/10.4161/auto.25879DOI Listing
October 2013

Radioresistant cancer cells can be conditioned to enter senescence by mTOR inhibition.

Cancer Res 2013 Jul 30;73(14):4267-77. Epub 2013 May 30.

Department of Biochemistry and Molecular Biology, Otolaryngology, and Biomedical Research Center, Asan Medical Center, University of Ulsan, Ulsan, Korea.

Autophagy is frequently activated in radioresistant cancer cells where it provides a cell survival strategy. The mTOR inhibitor rapamycin activates autophagy but paradoxically it also enhances radiosensitivity. In this study, we investigated the mechanisms of these opposing actions in radiation-resistant glioma or parotid carcinoma cells. Radiation treatment transiently enhanced autophagic flux for a period of 72 hours in these cells and treatment with rapamycin or the mTOR inhibitor PP242 potentiated this effect. However, these treatments also increased heterochromatin formation, irreversible growth arrest, and premature senescence, as defined by expression of senescence-associated β-galactosidase activity. This augmentation in radiosensitivity seemed to result from a restoration in the activity of the tumor suppressor RB and a suppression of RB-mediated E2F target genes. In tumor xenografts, we showed that administering rapamycin delayed tumor regrowth after irradiation and increased senescence-associated β-galactosidase staining in the tumor. Our findings suggest that a potent and persistent activation of autophagy by mTOR inhibitors, even in cancer cells where autophagy is occurring, can trigger premature senescence as a method to restore radiosensitivity.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-3516DOI Listing
July 2013

Quantitative shear wave elastography in the evaluation of metastatic cervical lymph nodes.

Ultrasound Med Biol 2013 Jun 27;39(6):935-40. Epub 2013 Feb 27.

Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

Our aim was to compare the diagnostic performance of shear wave elastography (SWE) with that of gray-scale ultrasound (US) in differentiating metastatic from benign lymph nodes in patients with head and neck malignancies. Maximum shear elasticity modulus (maxSM) was measured on SWE. The reference standard was pathologic diagnosis after surgery. We examined 67 lymph nodes (34 metastatic, 33 benign) from 15 patients (8 men and 7 women; mean age, 54.2 years). The maxSM value was significantly higher for metastatic than benign lymph nodes (41.06 ± 36.34 kPa vs. 14.22 ± 4.19 kPa, p < 0.0001) at a cutoff level of 19.44 kPa. Accuracy, sensitivity and specificity were 94, 91 and 97%, respectively, for SWE, and 91, 88 and 94%, respectively, for gray-scale US. Multiple regression analysis showed that the maxSM value (r = 0.882) and gray-scale US criteria (r = 0.837) were independent variables. SWE may be a valuable quantitative reproducible method for characterizing cervical lymph nodes.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2012.12.009DOI Listing
June 2013

Diagnostic accuracy of computed tomography findings for patients undergoing salvage total laryngectomy.

Acta Otolaryngol 2013 Jun 28;133(6):620-5. Epub 2013 Feb 28.

Department of Otolaryngology, Ulsan University Hospital, Ulsan, Republic of Korea.

Conclusions: Computed tomography (CT) imaging has clear limitations for the diagnosis of cartilage invasion or tumor spread in recurrent laryngeal cancer. Alternative methods of pretreatment assessment are needed for recurrent laryngeal cancer.

Objectives: The diagnosis and staging of recurrent laryngeal cancer, previously treated by radiation therapy (RT), remains challenging. Practically, surgeons need to depend on imaging to predict which patients will have a chance for conservation salvage laryngectomy. The purpose of the present study was to determine the accuracy of preoperative CT performed for recurrent laryngeal carcinoma evaluation following RT.

Methods: This retrospective review identified 32 patients who underwent salvage total laryngectomy after RT from 1998 to 2010. For our radiologic classification of the thyroid cartilage, we analyzed the conditions as normal, sclerosis, invasion, penetration, and extralaryngeal spread and categorized the state of the arytenoids and cricoid into three possible conditions: normal, sclerosis, and destruction. Radiographic findings were correlated with pathology findings.

Results: Sensitivity and specificity for the detection of the thyroid cartilage infiltration were 57% and 94%, 50% and 89% for the cricoid cartilage, and 33% and 76% for arytenoid cartilage, respectively. The accuracy of recurrent tumor classification was 59.4%. Three carcinomas were over-staged and 10 were under-staged.
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http://dx.doi.org/10.3109/00016489.2012.761352DOI Listing
June 2013

p16 immunohistochemistry alone is a better prognosticator in tonsil cancer than human papillomavirus in situ hybridization with or without p16 immunohistochemistry.

Acta Otolaryngol 2013 Mar 6;133(3):297-304. Epub 2012 Nov 6.

Departments of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Conclusions: p16 immunohistochemistry (IHC) status correlated with less exposure to smoking and/or alcohol in Korean patients with locally advanced tonsillar squamous cell carcinoma (TSCC), and was an independent prognostic factor for survival.

Objective: TSCC is more likely to be human papillomavirus (HPV)-positive than other head and neck squamous cell carcinoma (HNSCC) subtypes. The objective of this study was to ascertain the HPV status of TSCC in Korean patients and to determine its relationship with clinical parameters and prognosis.

Methods: The locally advanced TSCCs of 79 patients who were treated between 2000 and 2008 were tested by p16 IHC and HPV in situ hybridization (ISH) with a tissue microarray.

Results: Sixty-three patients (80%) were positive for p16 IHC, while 54 (68%) were positive by HPV ISH. p16 IHC status correlated significantly with lower exposure to smoking and alcohol (p < 0.05) but did not correlate with T and N stage classification, histological differentiation, age, or gender. The p16-positive group had a significantly higher 5-year overall survival rate in comparison with the p16-negative group (78% vs 63%, hazard ratio (HR) = 0.347, 95% CI = 0.14, 95% Cp = 0.025). p16 IHC was a favorable independent prognostic factor for overall survival, even after adjustment for age and T stage (HR = 0.283, 95% CI = 0.103, 95% p = 0.015).
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http://dx.doi.org/10.3109/00016489.2012.741327DOI Listing
March 2013

Detection of the primary lesion in patients with cervical metastases from unknown primary tumors with narrow band imaging endoscopy: preliminary report.

Head Neck 2013 Jan 8;35(1):10-4. Epub 2012 Apr 8.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background: We investigated whether the addition of narrow band imaging (NBI) to standard diagnostic workups could enhance the detection of primary lesions in patients with carcinoma of unknown primary (CUP).

Methods: Thirty patients with CUP underwent NBI endoscopy and fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) after thorough conventional diagnostic workups between 2009 and 2011. Sites suspected of harboring primary tumors, as determined by NBI and/or FDG-PET/CT, were biopsied for histologic confirmation.

Results: Occult primary tumors were identified in 33.3% (10/30), including 13.3% (4/30) by NBI and 20.0% (6/30) by FDG-PET/CT. All of diagnosed lesions by NBI were confirmed histologically as squamous cell carcinomas with T1 classification and identified at 2 supraglottis, 1 hypopharynx, and 1 esophagus, respectively.

Conclusions: NBI endoscopy may be a useful method for detecting primary tumors, especially for small and superficial squamous cell carcinomas of the upper aerodigestive tract, after conventional workup in patients with CUP.
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http://dx.doi.org/10.1002/hed.22901DOI Listing
January 2013

Patterns of lymph node metastasis and their influence on outcomes in patients with submandibular gland carcinoma.

J Surg Oncol 2012 Sep 27;106(4):475-80. Epub 2012 Mar 27.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background And Objectives: Little is known about lymph node metastasis and the extent of neck dissection (ND) in patients with submandibular gland (SMG) carcinoma. We therefore evaluated the metastatic topography of neck lymph nodes in patients with SMG carcinoma and the influence of metastases on tumor recurrence and patient survival.

Methods: The pattern of lymph node spread was analyzed in 64 patients with SMG carcinoma treated from January 1994 to January 2009. Disease-free survival (DFS), overall survival (OS), and distant metastasis-free survival (DMFS) were calculated, and the clinicopathological factors associated with each were analyzed.

Results: Positive pathological lymph nodes were detected in 31 (48.4%) patients and was found to correlate significantly with histologic grade (P<0.001) on univariate analysis. Eight patients (19.5%) had occult cervical metastases. The 5-year DFS, OS, and DMFS rates were 46.8, 56.2, and 58.5%, respectively, and 23 patients (35.9%) experienced systemic failure. Multivariate analyses revealed that T-classification (P=0.043) and N-classification (P=0.006) were significantly independent predictors of DFS, whereas only N-classification (P=0.049) was significantly associated with DMFS.

Conclusions: Elective ND should be recommended for preoperatively suspected high-grade malignancy in SMG carcinoma. Patients with nodal metastasis should receive more effective therapy to hinder recurrence and distant metastasis.
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http://dx.doi.org/10.1002/jso.23100DOI Listing
September 2012

Long-term voice outcomes after thyroplasty for unilateral vocal fold paralysis.

Arch Otolaryngol Head Neck Surg 2012 Apr 19;138(4):347-51. Epub 2012 Mar 19.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Objectives: To investigate the long-term clinical efficacy and stability of thyroplasty type I for unilateral vocal cord palsy, and to identify the appropriate timing of posttreatment evaluations for determination of long-term voice outcome. Study

Design: Single-institution retrospective study.

Setting: Academic tertiary referral centers in Korea.

Patients: Forty patients with unilateral vocal cord palsy who underwent thyroplasty from January 1, 1996, through December 31, 2006, and were followed up for at least 5 years after the surgical procedure.

Interventions: Thyroplasty type I under local anesthesia.

Main Outcome Measures: Acoustic and aerodynamic analyses of voice were performed on the day before the operation and at preset intervals afterward. Two blinded speech-language pathologists performed the perceptual evaluation.

Results: The GRBAS scale (grade of hoarseness, roughness, breathiness, asthenia, and strain) values showed significant improvement at 6 months after the operation (P < .05); these improvements continued up to 1 year and were maintained 5 years after the operation. Acoustic measurements of shimmer and jitter began to show significant improvement at 6 months after the operation, and fundamental frequency and noise harmonic ratios evidenced significant improvement at 1 year (P < .05); these improvements were maintained, to a significant extent, at 5 years after the operation. Aerodynamically, the maximum phonation time, glottal flow rate, and peak subglottic pressure improved significantly from before the operation to 6 months and 1 year after the operation, attaining near-normal values at 1 year afterward (P < . 05)

Conclusions: Thyroplasty type I may provide evidence that voice outcome progressively evolves during the first years after the surgical procedure, and that subsequent vocal improvement presented long-lasting stabilization. To assess the long-term voice quality, it may be enough to perform the voice evaluation at 1 year after the procedure.
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http://dx.doi.org/10.1001/archoto.2012.42DOI Listing
April 2012