[Show abstract][Hide abstract] ABSTRACT: The presence of cervical lymph node metastases in head and neck squamous cell carcinoma (HNSCC) is the strongest determinant of patient prognosis. Owing to the impact of nodal metastases on patient survival, a system for sensitive and accurate detection is required. Clinical staging of lymph nodes is far less accurate than pathological staging. Pathological staging also suffers limitations because it fails to detect micrometastasis in a subset of nodal specimens. To improve the sensitivity of existing means of diagnosing metastatic disease, many advocate the use of molecular markers specific for HNSCC cells. MicroRNA (miRNA) are short noncoding segments of RNA that posttranscriptionally regulate gene expression. Approximately one third of all miRNA will exhibit substantial tissue specificity. Using a quantitative reverse transcription-polymerase chain reaction-based assay, we examined the expression of microRNA-205 (mir-205) across tissues and demonstrated that its expression is highly specific for squamous epithelium. We applied this assay to tissue samples, and we could detect metastatic HNSCC in each positive lymph node specimen, whereas benign specimens did not express this marker. When compared to metastases from other primary tumors, HNSCC-positive lymph nodes were distinguishable by the high expression of this marker. Using an in vitro lymphoid tissue model, we were able to detect as little as one squamous cell in a background of 1 million lymphocytes. By combining the sensitivity of quantitative reverse transcription-polymerase chain reaction with the specificity of mir-205 for squamous epithelium, we demonstrate a novel molecular marker for the detection of metastatic HNSCC.
[Show abstract][Hide abstract] ABSTRACT: Lingual tonsillar hypertrophy is an underappreciated cause of dysphagia and is believed to impede swallowing function by inhibition of laryngeal elevation and epiglottic inversion due to mechanical interference by bulky tongue base tissue. We present a case of severe dysphagia secondary to idiopathic tongue base hypertrophy that was treated with coblation lingual tonsillectomy and tongue base reduction.
We report a case and discuss the relevant literature regarding tongue base hypertrophy and surgical interventions to treat the enlarged base of the tongue.
Symptoms of dysphagia and globus sensation and signs of decreased epiglottic inversion and laryngeal penetration improved markedly after surgical reduction of hypertrophied lingual tonsillar tissue using coblation. Preoperative and postoperative clinical imaging and radiographs are presented to show the reduction of tongue base size, correlated with the patient's improved clinical function.
Coblation-assisted lingual tonsillectomy and tongue base reduction can successfully treat dysphagia secondary to tongue base hypertrophy.
The Annals of otology, rhinology, and laryngology 08/2008; 117(7):506-9. · 1.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine how vascular endothelial growth factor C (VEGF-C) affects tumor cell invasion and motility in squamous cell carcinoma of the head and neck (SCCHN).
A molecular biology study. The VEGF-C coding sequence was cloned into an expression vector and stably transfected into the SCCHN cell line SCC116 to create the SCC116-VEGFC line. RNA interference (RNAi) was used to block VEGF-C expression. An adenoviral system for expressing VEGF-C RNAi was developed and tested.
An academic hospital laboratory.
Relative VEGF-C RNA levels were determined by real-time quantitative reverse transcriptase-polymerase chain reaction, and protein expression was evaluated by Western blot. Cellular invasion was evaluated by 24-hour semipermeable membrane transit assay.
SCC116-VEGFC cells had markedly increased expression of VEGF-C protein and RNA compared with normal SCC116 controls. SCC116-VEGFC cells produced marked increases in cellular invasion and motility compared with SCC116 cells. Blockade of VEGF-C expression by transfection of a VEGF-C RNAi expression plasmid into both SCC116 and SCC116-VEGFC cells induced a 38% decrease in SCCHN invasion and motility as tested by a semipermeable membrane invasion assay. We developed an adenoviral expression system for VEGF-C RNAi, which also induced a dose-dependent decrease in cellular invasion in the highly invasive DM12 cell line.
These studies demonstrate that intracellular VEGF-C levels modulate in vitro SCCHN motility and invasion. Further work is needed to clarify the specific receptors and signaling pathways that are involved in SCCHN motility. Molecular therapies that inhibit the VEGF-C pathway may have clinical potential in the treatment of lymphatic metastasis in SCCHN.
Archives of otolaryngology--head & neck surgery 05/2008; 134(4):355-62. · 1.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study was performed to compare the relative antineoplastic activity of 10 different non-steroidal anti-inflammatory drugs (NSAIDs) in clinical use, and to investigate the underlying mechanisms of this activity in a squamous cell carcinoma of the head and neck model (SCCHN). A standard 5-day MTT assay was used to calculate IC(50) values in UM-SCC-1 cells for 10 NSAIDs, including celecoxib, rofecoxib, sulindac sulfide, sulindac sulfone, indomethacin, ketoprofen, flurbiprofen, naproxen, piroxicam, and aspirin. Celecoxib, a COX-2 specific inhibitor, was by far the most potent NSAID, with an IC(50) of 39.9 +/- 1.1 microM, followed by sulindac sulfide (116.5 +/- 2.34 microM). Celecoxib and sulindac sulfide also induced more activation of caspase-3 than any other NSAID. Cell cycle analysis showed that celecoxib and sulindac sulfide both induced a 3-fold increase in G(1) phase distribution, and this correlated with strong induction of p21(waf1/cip1), inhibition of cyclin D1, and hypophosphorylation of Rb. Celecoxib and sulindac sulfide treatment induced strong downstream inhibition of E2F transactivating activity as determined by a luciferase reporter assay. These data demonstrate the wide range of activity of various NSAID agents, and reveal a mechanism of action through cell cycle inhibition and induction of apoptosis.
[Show abstract][Hide abstract] ABSTRACT: Celecoxib inhibits proliferation and induces apoptosis in human tumors, but the molecular mechanisms for these processes are poorly understood. In this study, we evaluated the ability of celecoxib to induce toxicity in head and neck squamous cell carcinomas (HNSCC) and explored the relationships between celecoxib-induced cell cycle inhibition and toxicity in HNSCC. Celecoxib inhibited the proliferation of UM-SCC-1 and UM-SCC-17B cells both in vitro and in vivo, accompanied by G(1) phase cell cycle arrest and apoptosis. Celecoxib induced p21(waf1/cip1) at the transcriptional level independent of wild-type p53 function, leading to decreased expression of cyclin D1 and hypophosphorylation of Rb, with subsequent marked downstream decreases in nuclear E2F-1 protein expression and E2F transactivating activity by luciferase reporter assay. Cell cycle phase-specific cytometric sorting showed that celecoxib induced clonogenic toxicity preferentially to cells within the S phase greater than G(1) and G(2) phases. Levels of p21(waf1/cip1) and cyclin D1 protein were reduced in the S phase compared with the G(1) and G(2) phases, suggesting a possible protective role for p21(waf1/cip1) expression in celecoxib toxicity. In conclusion, we show that celecoxib has marked antiproliferative activity against head and neck cancer cells through transcriptional induction of p21(waf1/cip1) and G(1) phase accumulation leading to S phase-specific clonogenic toxicity. We additionally show that a profound inhibition of nuclear E2F function provides a possible mechanism for this S phase-specific toxicity.
Cancer Research 05/2007; 67(8):3801-8. · 9.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sulindac sulfide and sulindac sulfone have demonstrated anti-neoplastic and chemo-preventive activity against various human tumors, but few studies have examined the relative effectiveness of these drugs against squamous cell carcinoma of the head and neck (SCCHN). These compounds are metabolites of the nonsteroidal anti-inflammatory drug sulindac and differ in their ability to inhibit cyclooxygenase-2 (COX-2) enzyme function. Sulindac sulfide (the sulindac metabolite with COX-2 inhibitory function) demonstrated strong cell growth inhibition as measured by MTT and growth assays in UM-SCC-1 and SCC-25 cells, while sulindac sulfone had only moderate effect. Growth inhibition by sulindac sulfide was associated with a significant increase in percent G cells and activation of caspase-3. Sulindac sulfide induced expression of p21wafl/cipl in a dose-dependent fashion, decreased cyclin D1 protein levels, and increased Rb hypophosphorylation. p21waf1/cip1 protein levels increased without a significant increase in wild-type p53, suggesting that sulindac sulfide induces a p53-independent pathway regulating p2lwafl/ciP1 protein levels in SCCHN. Sulindac sulfide also induced dose-dependent expression of PPAR-gamma. In contrast, sulindac sulfone did not significantly alter apoptosis, cell cycle distribution or G1 checkpoint protein expression at doses below 200 microM. These results demonstrate the differential activity of sulindac metabolites and support the hypothesis that sulindac sulfide induced perturbations in SCCHN cellular proliferation could be regulated both by p21waf1/cip1-dependent cytostatic and caspase-dependent cytotoxic pathways.
Cancer biology & therapy 02/2007; 6(1):30-9. · 3.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The practice of injection laryngoplasty under local anesthesia has become more common as both the indications for the procedure and the number of injectable substances increased. Modifications to the injection techniques used for vocal fold augmentation have been described over the last decade that reflect changes in the established percutaneous and transoral approaches. These percutaneous and transoral injection techniques for the treatment of dysphonia secondary to glottic incompetence are well described and provide an adequate approach for most cases. However, these traditional methods may be difficult to master, require great patient tolerance, and may be impossible to perform when anatomic or physiologic barriers exist. We describe a new application of the fiberoptic transnasal endoscope to perform laryngeal injection using a flexible needle through a port in the endoscope. This technique is easily mastered and readily tolerated by patients who would not be candidates for the other injection techniques under local anesthesia. We present our favorable experience with this technique and identify its shortcomings coupled with recommendations to address future technical modifications.
The Laryngoscope 01/2006; 115(12):2262-5. · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the long-term, health-related quality-of-life outcomes in patients with advanced head and neck cancer (HNC) treated with surgery and postoperative radiation therapy (SRT) or concurrent chemotherapy and radiation therapy (CRT).
Matched-pair study comparing patients with advanced HNC treated with SRT or CRT at least 12 months after treatment. Patients completed 2 validated surveys addressing HNC-specific outcomes and depressive symptoms and provided information on employment and tobacco and alcohol use. Results for the 2 groups were compared using paired-sample t test and chi2 analysis.
Patients with stage III or IV squamous cell carcinoma of the oropharynx, hypopharynx, and larynx who underwent SRT or received CRT.
Head and neck cancer-specific health-related quality of life from the Head and Neck Cancer Inventory and level of depressive symptoms from the Beck Depression Inventory.
The matching process resulted in 27 patients in each treatment group. The HNC-specific domain scores (with higher scores representing better outcomes) for CRT vs SRT were eating, 37.8 vs 40.8 (P = .69); speech, 65.1 vs 56.0 (P = .23); aesthetics, 80.3 vs 69.2 (P = .14); and social disruption, 69.7 vs 70.6 (P = .90). Overall health-related quality of life was 64.0 with SRT and 55.0 with CRT (P = .142). For the Beck Depression Inventory (with higher scores representing worse outcomes), patients who underwent SRT had a mean score of 9.6 compared with 11.6 for patients who received CRT (P = .42).
As nonsurgical means of treating HNC have become more aggressive and surgical techniques have become more focused on function preservation and rehabilitation, the overall health-related quality of life resulting from these different approaches is similar.
Archives of Otolaryngology - Head and Neck Surgery 11/2005; 131(10):879-85. · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oral melanoacanthoma is a rare condition that presents as a pigmented, painful lesion, most commonly on the buccal mucosa. Argon plasma coagulation is a new treatment option for benign oral lesions and is hypothesized to be efficacious for this rare mucosal disorder.
Treatment of a case and a review of the English-language literature were performed.
One patient received a diagnosis of oral melanoacanthoma, and argon plasma coagulation treatment resulted in ablation of the lesion with excellent mucosal healing. A review of the literature demonstrated that this lesion is most commonly associated with black (90.9%), adult female (69.7%) patients and is most commonly located on the buccal mucosa (64.7%).
Oral melanoacanthoma is a rare, benign mucosal lesion that may require surgical intervention for symptomatic relief. Argon plasma coagulation is a relatively safe and effective means of treating this lesion. Argon plasma coagulation treatment may be expanded to include other benign, superficial lesions of the oral mucosa.
The Annals of otology, rhinology, and laryngology 10/2005; 114(9):677-80. · 1.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Organ preservation protocols in head and neck squamous cell carcinoma (HNSCC) are limited by tumors that fail to respond. We observed that larynx preservation and response to chemotherapy is significantly associated with p53 overexpression, and that most HNSCC cell lines with mutant p53 are more sensitive to cisplatin than those with wild-type p53. To investigate cisplatin resistance, we studied two HNSCC cell lines, UM-SCC-5 and UM-SCC-10B, and two resistant sublines developed by cultivation in gradually increasing concentrations of cisplatin. The cisplatin-selected cell lines, UM-SCC-5PT and UM-SCC-10BPT, are 8 and 1.5 times more resistant to cisplatin than the respective parental cell lines, respectively. The parental lines overexpress p53 and contain p53 mutations but the cisplatin-resistant cell lines do not, indicating that cells containing mutant p53 were eliminated during selection. Bcl-x(L) expression increased in the cisplatin-resistant lines relative to the parental lines, whereas Bcl-2 expression was high in the parental lines and decreased in the cisplatin-resistant lines. Thus, cisplatin selected for wild-type p53 and high Bcl-x(L) expression in these cells. We tested a small-molecule BH3 mimetic, (-)-gossypol, which binds to the BH3 domain of Bcl-2 and Bcl-x(L), for activity against the parental and cisplatin-resistant cell lines. At physiologically attainable levels, (-)-gossypol induces apoptosis in 70% to 80% of the cisplatin-resistant cells but only in 25% to 40% of the parental cells. Thus, cisplatin-resistant cells seem to depend on wild-type p53 and Bcl-x(L) for survival and BH3 mimetic agents, such as (-)-gossypol, may be useful adjuncts to overcome cisplatin resistance in HNSCC.
Molecular Cancer Therapeutics 08/2005; 4(7):1096-104. · 6.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate differences in gene expression profiles between oral cavity/oropharynx squamous cell carcinoma (OC/OP SCC) primary tumors that have metastasized to cervical lymph nodes and nonmetastatic OC/OP SCC tumors.
Oligonucleotide microarray analysis of primary tumors was used to produce gene expression profiles. Profile comparisons between metastatic and nonmetastatic tumors were performed using principal component analysis, t test, and fold change differences. A similar comparison between metastatic tumors and noncancer oral mucosa samples was performed to ensure tumor origin.
A prospective cohort of 20 patients with previously untreated OC/OP SCC who underwent pathologic staging following surgical resection and lymphadenectomy.
Of the approximately 9600 genes profiled, 101 demonstrated significant expression differences between the metastatic and nonmetastatic tumors (fold change > or =1.5; P<.01). Among this subset, 57 genes also exhibited significant differences between metastatic tumors and normal mucosa samples (fold change > or =1.5; P<.05). This profile included genes related to the extracellular matrix, adhesion, motility, inflammation, and protease inhibition. Collagen type 11 alpha-1 (COL11A1) demonstrated the greatest differential expression between metastatic and nonmetastatic OC/OP SCC tumors (fold change=7.61; P=.002). Tissue inhibitor of metalloproteinase 1 (TIMP-1) also demonstrated increased expression in metastatic tumors (fold change=3.3; P=.003).
Metastatic OC/OP SCC has a distinct gene expression profile compared with nonmetastatic OC/OP SCC and normal oral mucosa. This metastatic profile includes genes related to the extracellular matrix, adhesion, motility, and protease inhibition. Knowledge gained through tumor gene expression profiling may facilitate early detection of aggressive tumors and targeted therapeutic interventions.
Archives of Otolaryngology - Head and Neck Surgery 03/2004; 130(3):295-302. · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tissue microarrays are a powerful new tissue-conserving technology in the study of cancer, allowing simultaneous study of a large number of tumor specimens. We sought to ascertain the utility of tissue microarrays in head and neck cancer pathology using squamous cell carcinoma of the larynx as a model system. Whole-specimen slides from 44 different laryngeal squamous cell carcinomas were stained for p53 expression. Microarrays were then generated by taking six 0.6-mm core biopsies from each of the 44 specimens. The whole sections and the microarrays were independently scored for p53 expression. Twenty-three (53%) of the 44 tumor specimens were positive for p53. Forty-four of the 264 core biopsies (17%) were not given a score because of the lack of tumor cells. Seventy-eight percent of the individual discs on the microarray had scores in agreement with those of the whole-section slides. Among biopsy discs with tumor cells present, 94.5% were in agreement with the whole-section slide. The average probability that four randomly chosen biopsy discs, considered together, would accurately identify the presence of p53 staining in a whole section was 0.97 (95% CI.93-1.0). We conclude that tissue microarrays for squamous cell carcinomas can accurately represent immunohistochemical results of whole-slide specimens when four or more samples are used. Tissue microarrays are an important technique that may be applied to immunohistochemical studies of head and neck cancer.
Modern Pathology 01/2004; 16(12):1181-8. · 6.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Induction chemotherapy and definitive radiation therapy in advanced laryngeal cancer has been shown to achieve survival rates that are similar to total laryngectomy and postoperative radiation therapy. In patients with advanced laryngeal cancer, quality of life can be significantly enhanced by treatment regimens that preserve the larynx. However, which patients will respond best to organ preservation protocols remains unknown. The Bcl-2 family proteins are involved in control of apoptosis and, potentially, tumor response to chemotherapy.
Retrospective analysis of immunohistochemical tumor characteristics and clinical outcome.
To determine whether Bcl-2 family proteins were predictive of successful organ preservation, immunohistochemical analysis of tissue specimens from 47 patients with advanced laryngeal cancer from the U.S. Department of Veterans Affairs Cooperative Study Program (VA CSP-268) were evaluated for the expression of Bcl-2, Bcl-X(L), and Bax protein expression. Tumor response was classified as either complete or partial/nonresponse after induction chemotherapy. Protein expression was correlated with tumor response, organ preservation, and overall patient survival.
The Bcl-2 protein was expressed at high levels in only 15% of specimens, but five of seven tumors with high Bcl-2 showed complete response (P = .10). The majority of tumors expressed high levels of Bcl-X(L) (74%). Reduced expression of Bcl-X(L) was associated with a complete response (P = .143) and with larynx preservation (P = .06). Most patients (81%) had increased levels of Bax expression. Reduced expression of Bax was associated with a complete response rate (P = .074), but there was no correlation between Bax expression and larynx preservation.
The findings indicate that laryngeal cancer cells typically produce high levels of only one of the apoptosis protective proteins, Bcl-2 or Bcl-X(L). Prospective studies of larger numbers of patients are under way to determine whether Bcl-X(L) expression will be a useful marker predicting larynx preservation.
The Laryngoscope 05/2002; 112(4):638-44. · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oral cancer has been identified as a significant public health threat. Systematic evaluation of the impact of this disease on the US population is of great importance to health care providers and policy makers.
This study used the National Cancer Data Base (NCDB) to evaluate associations between demographic and disease characteristics, treatment, and survival for patients with oral cavity cancer in the United States. Of patients diagnosed between 1985 and 1996, 58,976 were extracted from the NCDB. ANOVAs were performed on selected cross-tabulations, and relative survival was used to calculate outcome.
Median age of patients was 64.0 years. Men made up 60.2% of patients. Pathologic diagnosis was squamous cell carcinoma (SCC) in 86.3% of cases. Younger patients had a much higher frequency of non-SCC, and this was related to survival in these patients. African-Americans (independent of income), lower income patients, and patients with higher grade disease were seen more frequently with advanced-stage SCC. Five-year relative survival for SCC cases was lower for older patients, men, and African-Americans.
This study addressed many issues related to oral cancer that have been previously discussed in the literature. The demographic, site, stage, histologic, and survival data available for this large number of cases in the NCDB allowed an accurate characterization of the contemporary status of oral cancer in the United States.
Head & Neck 03/2002; 24(2):165-80. · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Verrucous carcinoma is distinguished by controversy regarding appropriate diagnosis and treatment. This study provides a contemporary survey of demographics, patterns of care, and outcome for this disease in the United States.
The National Cancer Data Base had 2350 cases of verrucous carcinoma of the head and neck diagnosed between 1985 and 1996. Statistical procedures included chi-square analyses, Student t tests, and relative survival.
Tumors originated most frequently in the oral cavity (55.9%) and larynx (35.2%). Although most patients were male (60.0%), oral cavity tumors were more common among older females. The most prevalent treatment was surgery alone (69.7%), followed by surgery combined with irradiation (11.0%) and irradiation alone (10.3%). For oral cavity tumors, surgery alone was more common among early (85.8%) than advanced cases (56.9%); a larger proportion of advanced disease received radiation alone or surgery and irradiation combined. Most laryngeal tumors were treated with surgery (60.3% for early and 55.6% for advanced disease), but a higher proportion received radiation alone or surgery combined with radiation compared with oral cavity cases. Five-year relative survival was 77.9%. For localized disease, survival after surgery was 88.9% compared with 57.6% after irradiation.
Demographic differences implicate different mechanisms of carcinogenesis for verrucous carcinoma arising in the oral cavity and the larynx. Although selection bias may account for the differences observed, patients receiving initial treatment with surgery had better survival than those treated with irradiation, especially for cases originating in the oral cavity.
Cancer 08/2001; 92(1):110-20. · 4.90 Impact Factor