p14ARF protein expression is a predictor of both relapse and survival in squamous cell carcinoma of the anterior tongue.

PURPOSE: The INK4A-ARF locus at chromosome 9p21 is frequently altered in head and neck squamous cell carcinoma (SCC) and encodes two distinct tumor suppressors, p16(INK4A) and p14(ARF). This study addressed the role of p14(ARF) as a potential prognostic marker in this disease. EXPERIMENTAL DESIGN: p14(ARF) protein expression was assessed by immunohistochemistry in a cohort of 140 patients with SCC of the anterior tongue. Using univariate and multivariate Cox's proportional hazards models, the outcomes examined were time to disease recurrence or death, with or without clinicopathologic covariates, including nodal status, disease stage, treatment status, Ki-67 staining, and molecular markers with known functional or genetic relationships with p14(ARF) (p16(INK4A), p53, pRb, p21(WAF1/CIP1), E2F-1). RESULTS: On multivariate analysis, p14(ARF) positivity (nucleolar p14(ARF) staining and/or nuclear p14(ARF) staining in >/=30% of tumor cells) was an independent predictor of improved disease-free survival (DFS; P = 0.002) and overall survival (OS; P = 0.002). This was further enhanced when p14(ARF) positivity was cosegregated with positive (>/=1%) p16(INK4A) staining (DFS, P < 0.001; OS, P < 0.001). Patients whose cancers were p14(ARF) negative and p53 positive (>50%) had the poorest outcome (DFS, P < 0.001; OS, P < 0.001) of any patient subgroup analyzed. CONCLUSIONS: These data show that in patients with SCC of the tongue, combined nuclear and nucleolar expression of p14(ARF) protein predicts for improved DFS and OS independent of established prognostic markers.

Deregulated cyclin D1 expression is associated with decreased efficacy of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in head and neck squamous cell carcinoma cell lines.

PURPOSE: Despite promising initial results, recent Phase III trials of the selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib ("Iressa"; AstraZeneca, Wilmington, Delaware) in advanced head and neck squamous cell carcinoma (HNSCC) have been equivocal. Cyclin D1, an EGFR target gene, is frequently overexpressed in HNSCC, has been implicated in its pathogenesis, and is strongly associated with poor prognosis in this disease. Therefore, we examined the relationship between deregulated cyclin D1 expression and sensitivity to gefitinib to determine whether this frequently occurring oncogenic change affected the cellular response to gefitinib. EXPERIMENTAL DESIGN: A panel of six EGFR-overexpressing HNSCC cell lines was used to correlate CCND1 gene copy number, cyclin D1 expression, and response to gefitinib. The effect of constitutive overexpression of cyclin D1 was assessed by establishing stably transfected clonal SCC-9 cell lines. RESULTS: Three of six cell lines displayed cyclin D1 amplification and/or overexpression, and these cell lines were resistant to gefitinib. SCC 9 clones overexpressing cyclin D1 continued to proliferate and maintained their S-phase fraction when treated with gefitinib, whereas empty vector control clones and the parental SCC 9 cells were profoundly inhibited and displayed marked reductions in S-phase. The resistance of cyclin D1-overexpressing clones and cyclin D1-amplified cell lines was associated with maintenance of cyclin D1 expression after gefitinib treatment. CONCLUSIONS: These data suggest that deregulated cyclin D1 overexpression may be associated with resistance of HNSCC to EGFR inhibitors. Therefore, the role of cyclin D1 as a marker of therapeutic response and its utility as a prognostic marker in HNSCC warrant additional analysis.

Overexpression of E2F-1 is associated with increased disease-free survival in squamous cell carcinoma of the anterior tongue.

PURPOSE: Overexpression of E2F-1 is associated with increased invasiveness in head and neck squamous cell carcinoma cell lines in vitro, but its significance in vivo is unknown. This study sought to determine the relationship between E2F-1 and retinoblastoma protein (pRb) expression and disease outcome in squamous cell carcinoma (SCC) of the anterior tongue. EXPERIMENTAL DESIGN: pRb and E2F-1 protein expression was assessed by immunohistochemistry in a cohort of 145 patients with SCC of the anterior tongue. The outcomes examined were time to disease recurrence or death. The relationships between E2F-1 or pRb expression and outcome were assessed by univariate and multivariate Cox's proportional hazards model, with or without clinicopathological covariates, including nodal status, disease stage, treatment status, and molecular markers (cyclin D1, p16(INK4A), and Ki-67) previously measured in this cohort. RESULTS: On univariate analysis, increased expression of E2F-1 (>35% of positive-stained nuclei) was associated with increased disease-free survival (DFS; hazard ratio [HR]: 0.35; P = 0.04) and increased overall survival (OS; HR: 0.33; P = 0.06). Decreased expression of pRb (<50% positive nuclei) was associated with increased DFS (HR: 1.81; P = 0.06) but not with OS (P = 0.11). However, when considered simultaneously with other significant factors, i.e. lymph node status, p16(INK4A) protein expression, and histopathological grade, in the multivariate Cox's proportional hazards model, the additional contributions of E2F-1 and/or pRb expression to DFS and OS were not statistically significant. CONCLUSIONS: These data demonstrate that in patients with SCC of the tongue, overexpression of E2F-1 is associated with increased DFS and OS. However, this association is not independent of lymph node status, tumor grade, and p16(INK4A) expression. Among the cell cycle-regulatory molecules studied, p16(INK4A) expression is the most predictive molecular marker of disease outcome.

Neck dissection of level IIb: is it really necessary?

OBJECTIVES: To determine whether resection of level IIb is necessary in elective or therapeutic neck dissections. STUDY DESIGN: Prospective case series. METHODS: Level IIb nodes were analyzed for micrometastases as separate specimens in 160 neck dissections on 148 patients with squamous cell carcinoma of the head and neck. RESULTS: In 106 elective neck dissections (N0 necks) from upper aerodigestive tract (UADT) and skin/parotid squamous carcinoma primaries, level IIb was involved in 4.5% and 33%, respectively. In 54 therapeutic neck dissections (N+ necks) from UADT and skin/parotid squamous carcinoma primaries, level IIb was involved in 25% and 71%, respectively. Apart from skin/parotid squamous carcinoma primaries, level IIb was never involved unless level IIa was also involved. CONCLUSIONS: Level IIb nodes can be left in situ in UADT primary carcinomas in nontonsillar N0 necks without significantly compromising regional clearance of micrometastases.

Novel approach of medialization thyroplasty with arytenoid adduction performed under general anesthesia with a laryngeal mask.

OBJECTIVE: To objectively assess the voice outcomes of patients with unilateral vocal fold paralysis treated with medialization thyroplasty and arytenoid adduction suture. STUDY DESIGN: Case series of patients who underwent medialization thyroplasty and arytenoid adduction suture. Preoperative and postoperative voice testing was performed and the data were compared by statistical analysis. SETTING: Tertiary referral teaching hospital in Sydney, Australia. SUBJECTS: All patients had a unilateral vocal fold paralysis, with a large posterior glottic gap and vocal symptoms affecting their quality of life. METHODS: Thirteen patients with a diagnosis of a unilateral vocal fold paralysis with a large posterior glottic gap, vocal symptoms, and total denervation of the vocal fold underwent medialization thyroplasty and arytenoid adduction suture. The surgery was performed in a novel method under a general anesthetic using a laryngeal mask and with direct intraoperative endoscopic feedback. Preoperative and postoperative measures of voice performance were compared, including acoustic analysis (fundamental frequency, speech intensity against quiet and loud background noise, speech rate) and aerodynamic assessment (airflow, maximum phonation time). RESULTS: Medialization thyroplasty with arytenoid adduction suture significantly improved aerodynamic assessment and phonation duration for both male and female subjects overall. There were 2 of 13 treatment failures. Median follow-up time was 6 months. CONCLUSION: Preliminary results indicate that in selected patients with vocal fold paralysis, medialization thyroplasty with arytenoid adduction suture leads to significant improvements in objective voice measures. Longer follow-up data are required to further quantify the voice outcomes after this procedure.

Innominate artery hemorrhage following tracheostomy.

OBJECTIVES: To review the clinical presentation, predisposing factors, prevention strategies, management, and outcomes of innominate artery hemorrhage following tracheostomy. STUDY DESIGN AND SETTING: We report the case of an 80-y-old patient who experienced sudden massive innominate artery hemorrhage 11 days post tracheostomy. We review the literature and present recommendations for management and prevention. RESULTS: Emergency median sternotomy with ligation and resection of the affected segment was performed with no neurological or vascular sequelae. CONCLUSIONS AND SIGNIFICANCE: The risk of innominate artery hemorrhage may be minimized with simple measures. Management by ligation and resection of the pathological segment of artery has superior outcomes to primary vascular reconstruction with maintenance of blood flow. Bypass procedures are not routinely required and have not been shown to confer any significant benefit. Resection without reconstruction is associated with a surprisingly low incidence of neurological sequelae.