Moskaluk C.A.,University of Virginia |
Califano J.A.,Jr Head And Neck Center |
Ha P.K.,Jr Head And Neck Center
Clinical Cancer Research | Year: 2011
Purpose: Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy that is poorly understood. To look for relevant oncogene candidates under the control of promoter methylation, an integrated, genome-wide screen was conducted. Experimental Design: Global demethylation of normal salivary gland cell strains using 5-aza-2′-deoxycytidine (5-aza-dC) and trichostatin A (TSA), followed by expression array analysis was conducted. ACC-specific expression profiling was generated using expression microarray analysis of primary ACC and normal samples. Next, the two profiles were integrated to identify a subset of genes for further validation of promoter demethylation in ACC versus normal. Finally, promising candidates were further validated for mRNA, protein, and promoter methylation levels in larger ACC cohorts. Functional validation was then conducted in cancer cell lines. Results: We found 159 genes that were significantly re-expressed after 5-aza-dC/TSA treatment and overexpressed in ACC. After initial validation, eight candidates showed hypomethylation in ACC: AQP1, CECR1, C1QR1, CTAG2, P53AIP1, TDRD12, BEX1, and DYNLT3. Aquaporin 1 (AQP1) showed the most significant hypomethylation and was further validated. AQP1 hypomethylation in ACC was confirmed with two independent cohorts. Of note, there was significant overexpression of AQP1 in both mRNA and protein in the paraffinembedded ACC cohort. Furthermore, AQP1 was upregulated in 5-aza-dC/TSA-treated SACC83. Finally, AQP1 promoted cell proliferation and colony formation in SACC83. Conclusions: Our integrated, genome-wide screening method proved to be an effective strategy for detecting novel oncogenes in ACC. AQP1 is a promising oncogene candidate for ACC and is transcriptionally regulated by promoter hypomethylation. ©2011 AACR.
PubMed | Johns Hopkins Medical Institutions and Jr Head And Neck Center
Type: Journal Article | Journal: Cancer | Year: 2015
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.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.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.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.
Fraunfelder F.T.,Oregon Health And Science University |
Sciubba J.J.,Jr Head And Neck Center |
Mathers W.D.,Oregon Health And Science University
Journal of Ophthalmology | Year: 2012
The purpose of this paper is to review the possible role of polypharmacy in causing dry eye disease (DED), reflecting the complex interactions and complications associated with the use of multiple systemic and topical ocular medications. The pharmacological, physiological, anatomical, and histological mechanisms causing dry mouth differ little from those causing dry eye. Oral polypharmacy is the most common cause of dry mouth, but has not been investigated as a cause of dry eye. Topical ocular polypharmacy has been shown to cause DED. Information on drugs that likely cause or aggravate DED and the controversial role of preservatives in topical ocular medications are examined. Systemic or topical ocular medications and preservatives used in topical ocular drugs may cause dry eye through the drug's therapeutic action, ocular surface effects, or preservatives, and the effects probably are additive. Long-term use of topical ocular medications, especially those containing preservatives such as BAK, may play an important role in DED and the role of polypharmacy needs further study. We review possible ways to decrease the risk of medication-related dry eye. © 2012 Frederick T. Fraunfelder et al.
Tan M.,Johns Hopkins Medical Institutions |
Shao C.,Johns Hopkins Medical Institutions |
Bishop J.A.,Johns Hopkins Medical Institutions |
Feng Z.,Johns Hopkins Medical Institutions |
And 4 more authors.
Otolaryngology - Head and Neck Surgery (United States) | Year: 2014
Objectives. 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. Study design. Laboratory study, retrospective chart review. Setting. Academic medical center. Methods. DNA and RNA were isolated from ACC tumors and control salivary gland tissues. Quantitative methylationspecific 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. Results. 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. Conclusion. 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. © American Academy of Otolaryngology-Head and Neck Surgery Foundation 2014.
Durr M.L.,Johns Hopkins Medical Institution |
Mydlarz W.K.,Johns Hopkins Medical Institution |
Shao C.,Johns Hopkins Medical Institution |
Zahurak M.L.,Johns Hopkins Medical Institution |
And 9 more authors.
PLoS ONE | Year: 2010
Background: Methylation profiling of tumor suppressor gene (TSGs) promoters is quickly becoming a powerful diagnostic tool for the early detection, prognosis, and even prediction of clinical response to treatment. Few studies address this in salivary gland tumors (SGTs); hence the promoter methylation profile of various TSGs was quantitatively assessed in primary SGT tissue to determine if tumor-specific alterations could be detected. Methodology: DNA isolated from 78 tumor and 17 normal parotid gland specimens was assayed for promoter methylation status of 19 TSGs by fluorescence-based, quantitative methylation-specific PCR (qMSP). The data were utilized in a binary fashion as well as quantitatively (using a methylation quotient) allowing for better profiling and interpretation of results. Principal Findings: The average number of methylation events across the studied genes was highest in salivary duct carcinoma (SDC), with a methylation value of 9.6, compared to the normal 4.5 (p≤0.0003). There was a variable frequency and individual methylation quotient detected, depending on the TSG and the tumor type. When comparing normal, benign, and malignant SGTs, there was a statistically significant trend for increasing methylation in APC, Mint 1, PGP9.5, RAR-β and Timp3. Conclusions/Significance: Screening promoter methylation profiles in SGTs showed considerable heterogeneity. The methylation status of certain markers was surprisingly high in even normal salivary tissue, confirming the need for such controls. Several TSGs were found to be associated with malignant SGTs, especially SDC. Further study is needed to evaluate the potential use of these associations in the detection, prognosis, and therapeutic outcome of these rare tumors. © 2010 Durr et al.
Gold D.,Jr Head And Neck Center
Otolaryngologic Clinics of North America | Year: 2012
Patients with head and neck cancer (HNC) suffer disproportionate psychosocial distress because of the nature of the tumor site, the possible impact on facial appearance and function, and the symptom burden resulting from treatment. Unmet psychosocial needs can negatively impact many aspects of care, from compliance to successful survivorship. This article reviews the challenges that patients with HNC confront throughout the disease trajectory from diagnosis to treatment, recovery, and long-term survivorship. It also provides a framework for understanding psychosocial adjustment and quality of life both for the general population of patients with HNC, and those with human papillomavirus-related diagnoses. © 2012 Elsevier Inc.
Blanco R.G.F.,Jr Head And Neck Center |
Fakhry C.,Jr Head And Neck Center |
Ha P.K.,Jr Head And Neck Center |
Ryniak K.,Jr Head And Neck Center |
And 4 more authors.
Journal of Laparoendoscopic and Advanced Surgical Techniques | Year: 2013
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. © 2013, Mary Ann Liebert, Inc.
Bishop J.A.,The Johns Hopkins Medical Institutions |
Yonescu R.,The Johns Hopkins Medical Institutions |
Batista D.,The Johns Hopkins Medical Institutions |
Yemelyanova A.,The Johns Hopkins Medical Institutions |
And 3 more authors.
Head and Neck Pathology | Year: 2014
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. © 2014 Springer Science+Business Media New York.
PubMed | Johns Hopkins Medical Institutions and Jr Head And Neck Center
Type: Journal Article | Journal: Surgical pathology clinics | Year: 2016
The most common malignancy to involve the oral cavity and oropharynx is squamous cell carcinoma (SCC). Because these oral cancers share an origin from the squamous epithelium, the pathology of oral SCC might be expected to be uniform and its diagnosis repetitive. In reality, the morphologic diversity in SCC, along with the propensity for reactive processes of the oral cavity to mimic SCC histologically, renders its diagnosis one of the more challenging in surgical pathology. This article discusses variants of oral and oropharyngeal SCC and highlights those features that help distinguish human papillomavirus-related from human papillomavirus-unrelated SCC.
PubMed | Jr Head And Neck Center
Type: Journal Article | Journal: The Laryngoscope | Year: 2015
The objective of this study was to evaluate the effectiveness of nystatin and Biotne() mouthwash Oral Rinse for controlling Candida in total laryngectomy (TL) patients with a tracheosophageal voice prosthesis (TEP) because Biotne() mouthwash Oral Rinse is a less costly alternative to nystatin and requires less adherence time.Randomized, unblinded, crossover trial.Twenty-one TL patients were randomized to receive nystatin followed by Biotne() mouthwash Oral Rinse, or the reverse order, after a basic oral-care phase (i.e., brushing teeth, cleaning dentures). A Provox() 2, 22.5 French TEP, which is an indwelling silicone voice prosthesis, was placed at the beginning of each phase. Patients were provided with oral care instructions at randomization and medication-specific instructions with each treatments initiation. TEPs were processed and evaluated for Candida growth as colony-forming units (CFUs). Wilcoxon signed-rank tests were used for comparisons between treatments.Fifteen patients were available for comparisons of Candida counts (6 received nystatin; 9 received Biotne() mouthwash first). Overall, the median log10 (CFUs) remained high regardless of treatment (no medication: 8.9; nystatin: 8.7; Biotne() mouthwash: 8.4). However, the median counts for both nystatin and Biotne() mouthwash Oral Rinse were lower than those for no medication (difference :-0.9 and -0.3, respectively), although only nystatin was significantly lower (P=0.02). There was no significant difference between the two treatments (P=0.22). Overall, median medication-adherence was high (97%), and Biotne() mouthwash adherence was significantly higher than that of nystatin (: 7.6%; P=0.03).Nystatin and Biotne() mouthwash Oral Rinse had similar CFU levels, with nystatin showing a significant improvement over usual oral care. Biotne() mouthwash is a less costly alternative to nystatin, with a less complex treatment protocol that might make it preferable to patients and clinicians.1b