Patrick K Ha

Johns Hopkins Medicine, Baltimore, Maryland, United States

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Publications (83)362.02 Total impact

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    ABSTRACT: Adenoid cystic carcinomas (ACCs) of the salivary glands are challenging to understand, treat, and cure. To better understand the genetic alterations underlying the pathogenesis of these tumors, we performed comprehensive genome analyses of 25 fresh-frozen tumors, including whole genome sequencing, expression and pathway analyses. In addition to the well-described MYB-NFIB fusion which was found in 11 tumors (44%), we observed five different rearrangements involving the NFIB transcription factor gene in seven tumors (28%). Taken together, NFIB translocations occurred in 15 of 25 samples (60%, 95%CI=41-77%). In addition, mRNA expression analysis of 17 tumors revealed overexpression of NFIB in ACC tumors compared with normal tissues (p=0.002). There was no difference in NFIB mRNA expression in tumors with NFIB fusions compared to those without. We also report somatic mutations of genes involved in the axonal guidance and Rho family signaling pathways. Finally, we confirm previously described alterations in genes related to chromatin regulation and Notch signaling. Our findings suggest a separate role for NFIB in ACC oncogenesis and highlight important signaling pathways for future functional characterization and potential therapeutic targeting.
    No preview · Article · Feb 2016 · Cancer Prevention Research
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    ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) has a variety of causes. Recently, the human papilloma virus (HPV) has been implicated in the rising incidence of oropharyngeal cancer and has led to variety of studies exploring the differences between HPV-positive and HPV-negative HNSCC. The calcium-activated chloride channel TMEM16A is overexpressed in a variety of cancers, including HNSCC, but whether or not it plays different roles in HPV-positive and HPV-negative HNSCC is unknown. Here, we demonstrate that TMEM16A is preferentially overexpressed in HPV-negative HNSCC and that this overexpression of TMEM16A is associated with decreased patient survival. We also show that TMEM16A expression is decreased in HPV-positive HNSCC at the DNA, RNA, and protein levels in patient samples as well as cell lines. We demonstrate that the lower levels of TMEM16A expression in HPV-positive tumors can be attributed to both a combination of copy number alteration and promoter methylation at the DNA level. Additionally, our cellular data show that HPV-negative cell lines are more dependent on TMEM16A for survival than HPV-positive cell lines. Therefore, we suspect that the down-regulation of TMEM16A in HPV-positive HNSCC makes TMEM16A a poor therapeutic target in HPV-positive HNSCC, but a potentially useful target in HPV-negative HNSCC.
    Preview · Article · Nov 2015 · Scientific Reports
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    ABSTRACT: Background: Factors associated with disease-free survival (DFS) after salvage therapy for recurrent oropharyngeal squamous cell carcinoma (SCC) in the context of human papillomavirus (HPV) are poorly understood. Methods: A retrospective cohort analysis was conducted of patients with recurrent oropharyngeal SCC with known HPV tumor status who received salvage therapy. Results: Eighty-six patients were eligible for analysis. Sixty-four patients (74%) were HPV-positive. In multivariable analysis, HPV-positive tumor status (hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.13-0.71; p = .007), clinical response to any salvage therapy (HR = 0.29; 95% CI = 0.11-0.77; p = .01), and surgical salvage (HR = 0.38; 95% CI = 0.16-0.88; p = .02) were associated with improved overall survival (OS). Positive surgical margin was associated with worse DFS after salvage (HR = 8.43; 95% CI = 1.99-35.70; p = .004). Conclusion: For recurrent oropharyngeal SCC, HPV-positive tumor status, surgical salvage, and clinical response to salvage therapy are independently associated with improved OS, but not DFS after salvage. Surgical margin is the only independent predictor of DFS. © 2015 Wiley Periodicals, Inc. Head Neck, 2015.
    No preview · Article · Nov 2015 · Head & Neck
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    ABSTRACT: Objectives/hypothesis: We hypothesized that personal characteristics of residents may affect how well competency is attained in a surgical residency. To this end, we examined two concepts of global trait emotional intelligence and learner autonomy profile and their factor relationship with competency outcomes in a residency program in otolaryngology-head and neck surgery. Study design: A cohort study prospectively gathered competency change scores for 1 year and retrospectively analyzed the factor associations. Methods: We measured two personal characteristics using the Trait Emotional Intelligence Questionnaire-Short Form and Learner Autonomy Profile-Short Form between 2013 and 2014 in a tertiary otolaryngology-head and neck residency program. We prospectively examined faculty-rated resident competency scores monitored in the same time period and correlated the personal attributes with cumulative competency improvement scores. Statistical analyses included factor correlations and univariate regression. Results: With a response rate of 64% (N = 16/25), we identified two statically significant predictors of competency improvement outcome attained by the end of the year. Regression analyses showed that emotionality factor of global trait emotional intelligence (P = .04) and learner autonomy profile (P < .01) were significant predictors for the higher improvement of aggregate competency outcome. Conclusions: Personal factors of individual residents can affect their improvement of overall competency. Practicing competency-based education should, therefore, include assessing individual resident factors as well as teaching clinical knowledge and technical skills. Level of evidence: NA Laryngoscope, 2015.
    No preview · Article · Nov 2015 · The Laryngoscope
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    ABSTRACT: Objective: Pharyngocutaneous fistula is a common complication in laryngectomy patients, particularly in previously irradiated cases. We initiated a comprehensive performance improvement intervention in all head and neck surgery patients intended to reduce postoperative infection and fistulae rates. We report our review of outcomes within laryngectomy patients. Study design: Case series with chart review. Setting: Academic tertiary referral center. Subjects: Nineteen laryngectomy patients at risk of postoperative fistula formation. Methods: We reviewed the medical records of all patients who had undergone laryngectomy procedures between January 2013 and April 2014. Clinicodemographic data were obtained, including history of diabetes, prior radiation therapy, type of reconstruction performed for closure of the pharyngeal defect, and the presence or absence of postoperative fistula. Results: The study population comprised 19 laryngectomy patients. Prior to implementation of our performance improvement intervention, 8 of 11 (73%) patients undergoing laryngectomy developed postoperative fistulae. After intervention, 0 of 8 patients developed fistulae (P = .002). Prior radiation, diabetes mellitus, and overall stage were not associated with a reduction in fistula rate (P > .05). Conclusion: Comprehensive uniform application of a standard antibiotic prophylaxis, surgical technique, perioperative care, and treatment of comorbid conditions can significantly reduce and potentially eliminate fistulae in laryngectomy patients who are especially at risk.
    No preview · Article · Oct 2015 · Otolaryngology Head and Neck Surgery
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    ABSTRACT: Objectives: The role of promoter methylation in the development of mucoepidermoid carcinoma (MEC) has not been fully explored. In this study, we investigated the epigenetic landscape of MEC. Methods: The Illumina HumanMethylation27 BeadChip array and differential methylation analysis were utilized to screen for epigenetic alterations in 14 primary MEC tumors and 14 matched normal samples. Bisulfite sequencing was used to validate these results, with subsequent quantitative Methylation-Specific PCR (qMSP) to validate chloride intracellular channel protein 3 (CLIC3) in a separate cohort. Furthermore, CLIC3 immunohistochemical (IHC) staining was performed in another separate cohort of MEC. Finally, clinical and pathological characteristics were statistically analyzed for correlation with methylation status of CLIC3 and CLIC3 IHC H-scores by Wilcoxon rank sum, Kruskall-Wallis, and X(2) test tests. Results: We obtained 6 significantly differentially methylated gene candidates demonstrating significant promoter hyper- or hypo-methylation from the array data. Using bisulfite sequencing, we found one gene, CLIC3, which showed differential methylation between MEC tumor and normal samples in a small validation cohort. qMSP analysis of the CLIC3 promoter in a separate validation set showed significantly lower methylation level in tumor than in normal. The level of CLIC3 methylation in MECs was not statistically correlated with clinical or pathological characteristics. However, IHC staining intensity and distribution of CLIC3 were significantly increased in MECs, compared with those of normal salivary gland tissues. Conclusions: Hypomethylation of CLIC3 promoter and its overexpression are significant events in MEC. Its functional role and potential therapeutic utility in MEC are worthy of further exploration.
    No preview · Article · Oct 2015
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    ABSTRACT: The purpose of this study was to retrospectively review patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) for the presence of retropharyngeal lymph nodes (RPLNs) prior to treatment using positron emission tomography/computed tomography (PET/CT), and to determine if the presence of RPLNs is of utility in predicting outcomes. Retrospective review of patient data from a single institution. Two hundred thirty patients with a diagnosis of HPV-associated OPSCC were identified from 2002 to 2013. The presence of RPLNs was determined primarily from findings on PET/CT as reviewed in a standardized fashion by two neuroradiologists. Of the 230 patients, 165 had pretreatment PET/CT imaging available for review. There were a total of 16 patients (9.70%) with evidence of RPLNs. Among patients positive for RPLNs pretreatment, with an average follow-up of 2 years, there was a 5.2-times greater odds of having recurrence or death (31.3% vs. 8.1%, P = .004). When T and N stage were adjusted for with multiple regression, there was no significant association between RPLN status and recurrence free survival. This is a unique investigation utilizing PET/CT to classify RPLN status in HPV-associated OPSCC. RPLNs were relatively common in our HPV-associated OPSCC cohort at 9.70%, at the low end of the quoted positivity of 10% to 27% in all OPSCC. A combination of PET/CT is useful in identifying RPLNs. Prospective investigation will be needed to determine the sensitivity and specificity of PET/CT in identifying RPLNs, and the precise impact of RPLNs on HPV-associated OPSCC treatment and outcomes. 4. Laryngoscope, 2015. © 2015 The American Laryngological, Rhinological and Otological Society, Inc.
    No preview · Article · Jul 2015 · The Laryngoscope
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    ABSTRACT: To explore the potential of tumor-specific DNA as a biomarker for head and neck squamous cell carcinomas (HNSCC), we queried DNA from saliva or plasma of 93 HNSCC patients. We searched for somatic mutations or human papillomavirus genes, collectively referred to as tumor DNA. When both plasma and saliva were tested, tumor DNA was detected in 96% of 47 patients. The fractions of patients with detectable tumor DNA in early- and late-stage disease were 100% (n = 10) and 95% (n = 37), respectively. When segregated by site, tumor DNA was detected in 100% (n = 15), 91% (n = 22), 100% (n = 7), and 100% (n = 3) of patients with tumors of the oral cavity, oropharynx, larynx, and hypopharynx, respectively. In saliva, tumor DNA was found in 100% of patients with oral cavity cancers and in 47 to 70% of patients with cancers of the other sites. In plasma, tumor DNA was found in 80% of patients with oral cavity cancers, and in 86 to 100% of patients with cancers of the other sites. Thus, saliva is preferentially enriched for tumor DNA from the oral cavity, whereas plasma is preferentially enriched for tumor DNA from the other sites. Tumor DNA in saliva was found postsurgically in three patients before clinical diagnosis of recurrence, but in none of the five patients without recurrence. Tumor DNA in the saliva and plasma appears to be a potentially valuable biomarker for detection of HNSCC. Copyright © 2015, American Association for the Advancement of Science.
    Full-text · Article · Jun 2015 · Science translational medicine
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    ABSTRACT: Objectives Salivary gland adenoid cystic carcinoma (ACC) is rare, aggressive, and challenging to treat. Many ACCs have a t(6;9) chromosomal translocation resulting in a MYB-NFIB fusion gene, but the clinical significance is unclear. The purposes of this study were to describe the clinicopathologic factors impacting survival and to determine the prevalence and clinical significance of MYB-NFIB fusion. Study DesignCase series. Methods Medical records of patients treated for ACC of the head and neck from 1974 to 2011 were reviewed and clinicopathologic data recorded. Fluorescence in situ hybridization (FISH) was used to detect MYB rearrangement in archival tumor tissue as a marker of MYB-NFIB fusion. ResultsOne hundred fifty-eight patients were included, with median follow-up 75.1 months. Median overall survival was 171.5 months (95% confidence interval [CI]=131.9-191.6), and median disease-free survival was 112.0 months (95% CI=88.7-180.4). Advanced stage was associated with decreased overall survival (adjusted p(trend)<0.001), and positive margins were associated with decreased disease-free survival (adjusted hazard ratio [aHR]=8.80, 95% CI=1.25-62.12, P = 0.029). Ninety-one tumors were evaluable using FISH, and 59 (65%) had evidence of a MYB-NFIB fusion. MYB-NFIB positive tumors were more likely than MYB-NFIB negative tumors to originate in minor salivary glands (adjusted prevalence ratios=1.51, 95% CI=1.07-2.12, P = 0.019). MYB-NFIB tumor status was not significantly associated with disease-free or overall survival (hazard ratio [HR]=1.53, 95% CI=0.77-3.02, P = 0.22 and HR=0.91, 95% CI=0.46-1.83, P = 0.80, respectively, for MYB-NFIB positive compared with MYB-NFIB negative tumors). Conclusion Stage and margin status were important prognostic factors for ACC. Tumors with evidence of MYB-NFIB fusion were more likely to originate in minor salivary glands, but MYB-NFIB tumor status was not significantly associated with prognosis. Level of Evidence4. Laryngoscope, 125:E292-E299, 2015
    No preview · Article · May 2015 · The Laryngoscope
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    ABSTRACT: Background: Human papillomavirus (HPV) tumor status and surgical salvage are associated with improved prognosis for patients with recurrent oropharyngeal squamous cell carcinoma (OPSCC). Current data regarding types of surgery and the impact of surgery for patients with distant metastatic disease are limited. Methods: A retrospective analysis of patients with recurrent OPSCC from 2 institutions between 2000 and 2012 was performed. p16 immunohistochemistry and/or in situ hybridization, as clinically available, were used to determine HPV tumor status. Clinical characteristics, distribution of recurrence site, and treatment modalities were compared by HPV tumor status. Overall survival (OS) was examined using Kaplan-Meier and Cox proportional hazards methods. Results: The current study included 108 patients with 65 locoregional and 43 distant metastatic first recurrences. The majority of patients were HPV-positive (80 patients). HPV-positive tumor status was associated with longer time to disease recurrence (P<.01). Anatomic site distribution of disease recurrences did not differ by HPV tumor status. HPV-positive tumor status (adjusted HR [aHR], 0.23; 95% confidence interval [95% CI], 0.09-0.58 [P = .002]), longer time to disease recurrence (≥ 1 year; aHR, 0.36; 95% CI, 0.18-0.74 [P = .006]), and surgical salvage (aHR, 0.26; 95% CI, 0.12-0.61 [P = .002]) were found to be independently associated with OS after disease recurrence. Surgical salvage was independently associated with improved OS compared with nonsurgical treatment among patients with both locoregional (aHR, 0.15; 95% CI, 0.04-0.56 [P = .005]) and distant (aHR, 0.19; 95% CI, 0.05-0.75 [P = .018]) metastatic disease recurrences. Conclusions: Surgical salvage was found to be associated with improved OS for patients with recurrent locoregional and distant metastatic OPSCC, independent of HPV tumor status. Further prospective data are needed to confirm the role of surgical salvage for distant metastases.
    No preview · Article · Mar 2015 · Cancer
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    ABSTRACT: To determine if phosphodiesterase 5 (PDE5) inhibitors can augment immune function in patients with head and neck cancer through inhibition of myeloid-derived suppressor cells (MDSC). We performed a randomized, prospective, double blinded, placebo controlled, phase II clinical trial to determine the in vivo effects of systemic PDE5 inhibition on immune function in patients with head and neck squamous cell carcinoma (HNSCC). Tadalafil augmented immune response, increasing ex vivo T-cell expansion to a mean 2.4-fold increase compared with 1.1-fold in control patients (P = 0.01), reducing peripheral MDSC numbers to mean 0.81-fold change compared with a 1.26-fold change in control patients (P = 0.001), and increasing general immunity as measured by delayed type hypersensitivity response (P = 0.002). Tumor-specific immunity in response to HNSCC tumor lysate was augmented in tadalafil-treated patients (P = 0.04). These findings demonstrate that tadalafil augments general and tumor-specific immunity in patients with HNSCC and has therapeutic potential in HNSCC. Evasion of immune surveillance and suppression of systemic and tumor-specific immunity is a significant feature of head and neck cancer development. This study demonstrates that a PDE5 inhibitor, tadalafil, can reverse tumor-specific immune suppression in patients with head and neck cancer, with potential for therapeutic application. Clin Cancer Res; 21(1); 30-38. ©2015 AACR. ©2015 American Association for Cancer Research.
    Full-text · Article · Jan 2015 · Clinical Cancer Research
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    ABSTRACT: Purpose The purpose of this study was to determine the incidence of and risk factors for pharyngocutaneous fistula in patients undergoing total laryngectomy at a single institution. Materials and Methods The records of 59 patients undergoing primary or salvage total laryngectomy at our institution from 2001–2012 were retrospectively reviewed. Data collected included patient, tumor and treatment characteristics, and surgical technique. Risk factors were analyzed for association with pharyngocutaneous fistula formation. Results Twenty patients (34%) developed fistulas. Preoperative tracheostomy (OR 4.1; 95% CI 1.3-13 [p = 0.02]) and low postoperative hemoglobin (OR 9.1; 95% CI 1.1-78 [p = 0.04]) were associated with fistula development. Regarding surgical technique, primary sutured closure of the total laryngectomy defect had the lowest fistula rate (11%). In comparison, primary stapled closure and pectoralis onlay flap over primary closure had nonsignificantly increased fistula rates (43%, OR 6.0; 95% CI 1.0-37.3 [p = 0.06] and 25%, OR 2.7; 95% CI 0.4-23.9 [p = 0.38], respectively). Pectoralis flap incorporated into the suture line had a significantly increased fistula rate (50%, OR 7.1; 95% CI 1.4-46 [p = 0.02]). After stratification for salvage status, patient comorbidities were associated with fistula in non-salvage cases whereas disease-related characteristics were associated with fistula in salvage cases. Fistula development was associated with increased length of hospital stay (p < 0.001) and increased time before oral diet initiation (p < 0.001). Conclusions Pharyngocutaneous fistula is a common complication of total laryngectomy. Preoperative tracheostomy, postoperative hemoglobin, and surgical technique are important in determining the risk of fistula.
    No preview · Article · Sep 2014 · American Journal of Otolaryngology
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    ABSTRACT: Purpose: Tumor metastasis is the leading cause of death in patients with cancer. However, the mechanisms that underlie metastatic progression remain unclear. We examined TMEM16A (ANO1) expression as a key factor shifting tumors between growth and metastasis. Experimental design: We evaluated 26 pairs of primary and metastatic lymph node (LN) tissue from patients with squamous cell carcinoma of the head and neck (SCCHN) for differential expression of TMEM16A. In addition, we identified mechanisms by which TMEM16A expression influences tumor cell motility via proteomic screens of cell lines and in vivo mouse studies of metastasis. Results: Compared with primary tumors, TMEM16A expression decreases in metastatic LNs of patients with SCCHN. Stable reduction of TMEM16A expression enhances cell motility and increases metastases while decreasing tumor proliferation in an orthotopic mouse model. Evaluation of human tumor tissues suggests an epigenetic mechanism for decreasing TMEM16A expression through promoter methylation that correlated with a transition between an epithelial and a mesenchymal phenotype. These effects of TMEM16A expression on tumor cell size and epithelial-to-mesenchymal transition (EMT) required the amino acid residue serine 970 (S970); however, mutation of S970 to alanine does not disrupt the proliferative advantages of TMEM16A overexpression. Furthermore, S970 mediates the association of TMEM16A with Radixin, an actin-scaffolding protein implicated in EMT. Conclusions: Together, our results identify TMEM16A, an eight transmembrane domain Ca2+-activated Cl- channel, as a primary driver of the "Grow" or "Go" model for cancer progression, in which TMEM16A expression acts to balance tumor proliferation and metastasis via its promoter methylation.
    Full-text · Article · Jun 2014 · Clinical Cancer Research
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    ABSTRACT: Objective A standardized assay to determine the HPV status of head and neck squamous cell carcinoma (HNSCC) specimens has not yet been established, particularly for cytologic samples. The goal of this study was to determine whether the hybrid capture-2 (HC-2) assay, already widely used for the detection of high risk HPV in cervical brushings, is applicable to cytologic specimens obtained from patients with suspected HNSCCs. Materials and methods Fine needle aspirates (FNA) of cervical lymph nodes were pre-operatively obtained from patients with suspected HNSCCs and evaluated for the presence of HPV using the HC-2 assay. HPV analysis was performed on the corresponding resected tissue specimens using p16 immunohistochemistry (IHC) and HR-HPV in situ hybridization (ISH). A cost analysis was performed using the Center for Medicare & Medicaid Services. Results HPV status of the cervical lymph node metastases was correctly classified using the HC-2 assay in 84% (21/25) of cases. Accuracy was improved to 100% when cytologic evaluation confirmed the presence of cancer cells in the test samples. The estimated cost savings to CMS using the HC-2 assay ranged from $113.74 to $364.63 per patient. Conclusions HC-2 is a reliable method for determining the HPV status of HNSCCs. Its application to HNSCCs may reduce costs by helping to localize the primary site during the diagnostic work-up as well as decrease the interval time of determining the HPV status which would be relevant for providing prognostic information to the patient as well as determining eligibility for clinical trials targeting this unique patient population.
    Full-text · Article · Jun 2014 · Oral Oncology
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    ABSTRACT: Although human papillomavirus detection in cervical lymph nodes of head and neck squamous cell cancers (HNSCC) of unknown primary site (UP) is indicative of a primary tumor of the oropharynx (OP), localization can remain elusive. Therefore, we investigated ultrasonography (US) for the identification of the primary tumor. Eligible cases had HNSCC of UP after evaluation by a head and neck surgical oncologist. Controls were healthy volunteers. Transcervical and intraoral ultrasonography was performed by a standard protocol using convex (3.75-6.0MHz and 5-7.5MHz) transducers. US findings were compared with operative examination (exam under anesthesia, direct laryngoscopy) and biopsies. The primary outcome of interest was the presence or absence of a lesion on US. 10 cases and 20 controls were enrolled. PET/CT scans were negative/nonspecific (9), or suspicious (1) for a primary lesion. On US, predominantly hypoechoic (9 of 10) lesions were visualized consistent with base of tongue (n=7) or tonsil (n=3) primary tumors. On operative examination, 5 of 10 were appreciated. Two additional primaries were confirmed with biopsies "directed" by preoperative US. This represents an overall diagnostic rate of 70%, which is 20% higher than our detection rate for 2008-2010. The three cases in which a suspicious lesion was visualized on US, yet remained UP despite further interventions, could represent false positives, misclassification or operator variability. No lesions were suspected among the controls. Ultrasound has promise for detection of UPs of the OP and therefore warrants further investigation.
    No preview · Article · May 2014 · Oral Oncology
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    ABSTRACT: High risk human papillomavirus (HPV) is firmly established as an important cause of oropharyngeal carcinoma. Recent studies have also implicated HPV as a cause of mucoepidermoid carcinoma (MEC)-a tumor of salivary gland origin that frequently harbors MAML2 translocations. The purpose of this study was to determine the prevalence of transcriptionally active HPV in a large group of MECs and to determine whether HPV infection and the MAML2 translocation are mutually exclusive events. Break-apart fluorescence in situ hybridization for MAML2 was performed on a tissue microarray containing 92 MECs. HPV testing was performed using RNA in situ hybridization targeting high risk HPV mRNA E6/E7 transcripts. Of the 71 MECs that could be evaluated by FISH, 57 (80 %) harbored the MAML2 rearrangement. HPV was not detected in any of the 57 MECs that contained a MAML2 rearrangement, in any of the 14 MECs that did not contain the rearrangement, or in any of the 21 MECs where MAML2 status was unknown. High risk HPV does not appear to play any significant role in the development of MEC. It neither complements nor replaces MAML2 translocation in the tumorigenesis of MEC.
    No preview · Article · Apr 2014 · Head and Neck Pathology
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    ABSTRACT: Aquaporin-1 (AQP1) is a candidate oncogene that is epigenetically modified in adenoid cystic carcinoma (ACC). We sought to (1) assess AQP1 promoter methylation and expression in an ACC cohort, (2) identify correlations between AQP1 and clinical outcomes, and (3) explore the role of AQP1 in tumor progression in vitro. Laboratory study, retrospective chart review. Academic medical center. DNA and RNA were isolated from ACC tumors and control salivary gland tissues. Quantitative methylation-specific polymerase chain reaction (PCR) was performed on bisulfite-treated DNA. Quantitative reverse transcription PCR was performed after cDNA synthesis. Cell lines stably overexpressing an AQP1 plasmid or empty vector were generated. Cell scratch and Matrigel invasion assays were performed. Retrospective chart review was performed for collection of clinical information. Methylation results from 77 tumors and 30 controls demonstrated that AQP1 was hypomethylated in tumors (P < .0001). Fifty-eight tumors (75.3%) displayed AQP1 hypomethylation compared with controls. AQP1 expression levels assessed in 58 tumors and 23 controls demonstrated a trend toward increased expression in tumors (P = .08). Univariate analysis revealed that AQP1 hypermethylation was associated with increased overall survival. No associations between AQP1 expression level and survival were found. AQP1 overexpression did not affect cell migratory or invasive capacities in vitro. AQP1 promoter hypomethylation is common in ACC, and AQP1 tends to be overexpressed in these tumors. Increased AQP1 methylation is associated with improved prognosis on univariate analysis, but expression is not associated with outcomes. Further in vitro studies are necessary to clarify the role of AQP1 in ACC.
    No preview · Article · Feb 2014 · Otolaryngology Head and Neck Surgery
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    ABSTRACT: Base of tongue (BOT) is a difficult subsite to examine clinically and radiographically. Yet, anatomic delineation of the primary tumor site, its extension to adjacent sites or across midline, and endophytic vs. exophytic extent are important characteristics for staging and treatment planning. We hypothesized that ultrasound could be used to visualize and describe BOT tumors. Transcervical ultrasound was performed using a standardized protocol in cases and controls. Cases had suspected or confirmed BOT malignancy. Controls were healthy individuals without known malignancy. 100% of BOT tumors were visualized. On ultrasound BOT tumors were hypoechoic (90.9%) with irregular margins (95.5%). Ultrasound could be used to characterize adjacent site involvement, midline extent, and endophytic extent, and visualize the lingual artery. No tumors were suspected for controls. Ultrasonography can be used to transcervically visualize BOT tumors and provides clinically relevant characteristics that may not otherwise be appreciable.
    Full-text · Article · Jan 2014 · PLoS ONE
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    ABSTRACT: MicroRNA-21 (miRNA-21) has proto-oncogenic properties, though no miRNA-21 specific targets have been found in head and neck squamous cell carcinoma (HNSCC). Further study of miRNA-21 and its specific targets is essential to understanding HNSCC biology. miRNA expression profiles of 10 HNSCC and 10 normal mucosa samples were investigated using a custom miRNA microarray. 13 HNSCC and 5 normal mucosa primary tissue specimens underwent mRNA expression microarray analysis. To identify miRNA-21 downstream targets, oral keratinocyte cells were subjected to microarray analysis after miRNA-21 transient transfection. miRNA and mRNA expression were validated by RT-qPCR in a separate cohort of 16 HNSCC and 15 normal mucosal samples. Microarray and bioinformatics analyses were integrated to identify potential gene targets. In vitro assays looked at the function and interaction of miRNA-21 and its specific gene targets. miRNA-21 was upregulated in HNSCC and stimulated cell growth. Integrated analyses identified Clusterin (CLU) as a potential miRNA-21 gene target. CLU was downregulated after forced expression of miRNA-21 in normal and HNSCC cell lines. The activity of a luciferase construct containing the 3'UTR of CLU was repressed by the ectopic expression of miRNA-21. CLU was also found to be downregulated in primary HNSCC and correlated with miRNA-21 over-expression. A CLU variant 1 (CLU-1) was the predominant splice variant in HNSCC, and showed growth suppression function that was reversed by miRNA-21 over-expression. CLU is a specific, functional target of oncogenic miRNA-21 in HNSCC. CLU-1 isoform is the predominant growth suppressive variant targeted by miRNA-21.
    Preview · Article · Dec 2013 · Clinical Cancer Research
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    ABSTRACT: Objective: To report a single institution's experience with transoral robotic surgery (TORS) and its clinical outcomes. This was a retrospective study carried out at a university-affiliated teaching hospital. Subjects and methods: Forty-four consecutive TORS patients with benign and malignant diseases were reviewed. Data on demographics, clinical parameters, and diet were collected. Surgical margins, local and regional recurrence, distant metastasis, 2-year disease-free survival rate, and 2-year survival data were reviewed for the malignant cases. Results: Nine benign and 35 proven squamous cell carcinoma (SCCA) cases underwent TORS. The set-up time was 17.12 minutes (range, 10-40 minutes), and operative time was 53 minutes (range, 10-300 minutes). Average length of stay was 2.5 days. There were seven (6.8%) grade 3 surgical complications. Surgical infection rate was 2.3%. Benign cases were on a regular diet after TORS. Of the malignant cases, 94% were taking peroral diet immediately after the TORS procedure. There were no intraoperative complications and no 30-day postoperative mortalities. The mean follow-up time was 25.2 months (range, 16-38 months) for malignant disease. The SCCA sites were in the oropharynx (30/35), larynx (2/35), and unknown primary with neck metastasis (3/35). Unknown primary patients were excluded in the surgical margin analyses. Negative margins were achieved in 91% of cases. The local and regional recurrence rates were 6.3% (2/32) and 3.1% (1/32), respectively. Two patients (6.3%) developed distant metastasis. Oropharyngeal SCCA cases were reviewed, of which 23 were human papillomavirus (HPV)/p16 positive and 7 were HPV/p16 negative. The 2-year actual survival for HPV-positive and -negative patients was 96% (22/23) and 86% (6/7), respectively. The 2-year disease-free survival for HPV-positive and -negative cases was 91% (21/23) and 71.4% (5/7), respectively. All malignant cases that underwent TORS received postoperative adjuvant therapy. Conclusions: TORS is a safe procedure with minimal complications and acceptable clinical and functional outcomes.
    No preview · Article · Oct 2013 · Journal of Laparoendoscopic & Advanced Surgical Techniques

Publication Stats

2k Citations
362.02 Total Impact Points

Institutions

  • 2002-2015
    • Johns Hopkins Medicine
      • Department of Otolaryngology - Head and Neck Surgery
      Baltimore, Maryland, United States
    • Johns Hopkins University
      • • Department of Otolaryngology - Head and Neck Surgery
      • • Department of Surgery
      Baltimore, Maryland, United States
  • 2009-2014
    • Greater Baltimore Medical Center
      Baltimore, Maryland, United States