Ian E. Cole

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.

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.

Spasmodic dysphonia: clinical features and effects of botulinum toxin therapy in 169 patients-an Australian experience.

Adductor spasmodic dysphonia (SD) is a focal laryngeal dystonia, characterised by strangled, effortful speech with breaks in pitch and phonation. Injection of laryngeal muscles with BTX is widely used in the treatment of SD. A consecutive series of 169 patients with SD, of whom 144 were treated with BTX injections, seen at St. Vincents Hospital between 1983 and 1999 were studied prospectively. Patients underwent neurological, quantitative voice and otolaryngological assessment. Females (62.1%) outnumbered males (37.9%) and the mean age at diagnosis was 56 years (range 19-88). Adductor SD (89.4%) was more frequent than abductor SD (1.8%) or mixed SD (4.7%). Stridor was present in 14 patients (8.3%) and in 7 was the sole manifestation of the laryngeal dystonia. The median treatment outcome score was excellent in 63.2%, very good in 18.5%, satisfactory in 14.7% and unsatisfactory in 3.5%. Poorer treatment outcome was associated with abductor SD (OR = 4.69, CI [1.23, 17.92] p=0.024] and age >65 (OR = 2.83, CI [0.95, 8.42] p=0.049). Mild post-injection paralytic dysphonia was associated with longer lasting treatment (4.42 vs. 3.62 months p<0.001) and superior treatment outcome rating (1.37 vs. 1.81 p<0.001). We conclude that BTX injections are highly effective and severe adverse events are rare. Older age and abductor SD may confer a relatively poorer treatment outcome. Mild post-injection paralytic dysphonia may be a marker for more effective and lasting treatment in adductor SD.

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, p16INK4A and p14ARF. This study addressed the role of p14ARF as a potential prognostic marker in this disease. Experimental Design: p14ARF protein expression was assessed by immunohistochemistry in a cohort of 140 patients with SCC of the anterior tongue. Using univariate and multivariate Coxs 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 p14ARF (p16INK4A, p53, pRb, p21WAF1/CIP1, E2F-1). Results: On multivariate analysis, p14ARF positivity (nucleolar p14ARF staining and/or nuclear p14ARF 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 p14ARF positivity was cosegregated with positive (≥1%) p16INK4A staining (DFS, P < 0.001; OS, P < 0.001). Patients whose cancers were p14ARF 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 p14ARF protein predicts for improved DFS and OS independent of established prognostic markers.

Elective percutaneous (rapitrac) tracheotomy: Results of a prospective trial

A prospective trial was carried out to assess the incidence of complications from percutaneous tracheotomies by the Rapitrac method performed by one member of an otolaryngology unit and to compare them to the dissection method over the same time period. The first 32 patients had a Rapitrac carried out blindly. Three had paratracheal or anterior tracheal insertions, one of which resulted in death of the patient. The procedure was aborted in 5 patients (16%) because of difficulty introducing the curved needle. Primary hemorrhage, damage to the posterior wall, and surgical emphysema occurred in 2 (6%) patients each. Because of the high rate of complications due to the blind nature of the procedure, the following 23 procedures were carried out using a fiberoptic bronchoscope inserted through the endotracheal tube. This procedure resulted in only 2 minor complications and is recommended if the Rapitrac technique of percutaneous tracheotomy is the method of choice.

Salvage vertical partial laryngectomy for radiation failure in early glottic carcinoma.

Background:  Partial laryngectomy after failure of radiotherapy for early glottic cancer is an accepted surgical salvage procedure. However,there have been only a few studies on recurrent disease or long‐term survival.

The clinical spectrum of laryngeal dystonia includes dystonic cough: Observations of a large series

Laryngeal dystonia is a movement disorder of the muscles within the larynx, which most commonly manifests as spasmodic dysphonia (SD). Rarer reported manifestations include dystonic respiratory stridor and dyscoordinate breathing. Laryngeal dystonia has been treated successfully with botulinum neurotoxin (BTX) injections since 1984. We reviewed prospectively collected data in a consecutive series of 193 patients with laryngeal dystonia who were seen at St. Vincents Hospital between 1991 and 2011. Patient data were analyzed in Excel, R, and Prism. Laryngeal dystonia manifested as SD (92.7%), stridor (11.9%), dystonic cough (6.2%), dyscoordinate breathing (4.1%), paroxysmal hiccups (1.6%), and paroxysmal sneezing (1.6%). There were more women (68.4%) than men (31.6%), and the average age at onset was 47 years. A positive family history of dystonia was present in 16.1% of patients. A higher incidence of extra‐laryngeal dystonia (ie, torticollis and blepharospasm) and concurrent manifestations of laryngeal dystonia were present in patients with dystonic cough, dyscoordinate breathing, paroxysmal sneezing, and hiccups than in other patients (P = 0.003 and P < 0.0001, respectively). The average starting dose of BTX decreased from 2.3 to 0.5 units between 1991 and 2011. The median treatment rating was excellent across all subgroups. Patients with adductor SD, stridor, extra‐laryngeal dystonia and male patients had relatively better treatment outcomes. Technical failures were rare (1.1%). Dysphonia secondary to vocal cord paresis followed 38.7% of treatments. Laryngeal dystonia manifests predominantly as SD, but other manifestations include stridor, dyscoordinate breathing, paroxysmal cough, hiccups, and sneezing. BTX injections are very effective across all subgroups. Severe adverse events are rare.

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.

LMO4 expression in squamous cell carcinoma of the anterior tongue

LMO4 expression in squamous cell carcinoma of the anterior tongue DOI: 10.1111/j.1365-2559.2011.03765.x Sir: Ninety per cent of head and neck cancers are squamous cell carcinomas (SCC), the majority representing SCC of the anterior tongue. Understanding the biology of these SCC may assist in the clinical management of the disease and reveal novel potential targets for therapy. LMO4 is a member of the LIM-only (LMO) family of transcriptional regulators, consisting of LMO1–4. These proteins act as molecular adaptors, providing a scaffold for multiprotein complexes of DNA binding factors and transcriptional regulatory proteins, which play essential roles in cell fate determination, tissue patterning and organ development. Aberrant expression of LMO4 has been demonstrated in a number of cancer types, with particular attention being paid to its prognostic value and contribution towards tumorigenesis.