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The 8p11‐p12 amplicon occurs in approximately 15% of breast cancers in aggressive luminal B‐type tumors. Previously, we identified WHSC1L1 as a driving oncogene from this region. Here, we demonstrate that over‐expression of WHSC1L1 is linked to over‐expression of ERα in SUM‐44 breast cancer cells and in primary human breast cancers. Knock‐down of WHSC1L1, particularly WHSC1L1‐short, had a dramatic effect on ESR1 mRNA and ERα protein levels. SUM‐44 cells do not require exogenous estrogen for growth in vitro; however, they are dependent on ERα expression, as ESR1 knock‐down or exposure to the selective estrogen receptor degrader fulvestrant resulted in growth inhibition. ChIP‐Seq experiments utilizing ERα antibodies demonstrated extensive ERα binding to chromatin in SUM‐44 cells under estrogen‐free conditions. ERα bound to ERE and FOXA1 motifs under estrogen‐free conditions and regulated expression of estrogen‐responsive genes. Short‐term treatment with estradiol enhanced binding of ERα to chromatin and influenced expression of many of the same genes to which ERα was bound under estrogen‐free conditions. Finally, knock‐down of WHSC1L1 in SUM‐44 cells resulted in loss of ERα binding to chromatin under estrogen‐free conditions, which was restored upon exposure to estradiol. These results indicate the SUM‐44 cells are a good model of a subset of luminal B breast cancers that have the 8p11‐p12 amplicon, over‐express WHSC1L1, and over‐express ERα, but are independent of estrogen for binding to chromatin and regulation of gene expression. Breast cancers such as these, that are dependent on ERα activity but independent of estradiol, are a major cause of breast cancer mortality., Highlights SUM44 is a model cell line for ERα positive breast cancer with the 8p11 amplicon.WHSC1L1 is a driving oncogene from the 8p11 amplicon in SUM44 cells.SUM44 breast cancer cells have high ERα expression, regulated by WHSC1L1 knockdown.ERα is required for growth and survival of SUM44 cells but is estrogen‐independent.WHSC1L1 knock‐down re‐sensitizes ERα to estradiol for binding to essential genes.

Providing image guidance in a 3-dimensional (3D) format, visually more in keeping with the operative field, could potentially reduce workload and lead to faster and more accurate navigation. We wished to assess a 3D virtual-view surgical navigation prototype in comparison to a traditional 2D system.Thirty-seven otolaryngology surgeons and trainees completed a randomized crossover navigation exercise on a cadaver model. Each subject identified three sinonasal landmarks with 3D virtual (3DV) image guidance and three landmarks with conventional cross-sectional computed tomography (CT) image guidance. Subjects were randomized with regard to which side and display type was tested initially. Accuracy, task completion time, and task workload were recorded.Display type did not influence accuracy (P0.2) or efficiency (P0.3) for any of the six landmarks investigated. Pooled landmark data revealed a trend of improved accuracy in the 3DV group by 0.44 millimeters (95% confidence interval [0.00-0.88]). High-volume surgeons were significantly faster (P0.01) and had reduced workload scores in all domains (P0.01), but they were no more accurate (P0.28).Real-time 3D image guidance did not influence accuracy, efficiency, or task workload when compared to conventional triplanar image guidance. The subtle pooled accuracy advantage for the 3DV view is unlikely to be of clinical significance. Experience level was strongly correlated to task completion time and workload but did not influence accuracy.N/A. Laryngoscope, 126:1510-1515, 2016.

64 Cu-porphysome nanoparticles enable superior delineation of neoplastic tissues, metastatic lymph nodes, and vascular drainage on head and neck cancer orthotopic rabbit model using positron emission tomography imaging. Additionally, the nanoparticles exhibit selective fluorescence activation in tumor and metastatic lymph nodes, which permits intraoperative real-time visualization of disease tissues to precisely define surgical margins and prevents collateral damage during surgeries.

Salivary duct carcinoma is rare, with distinct morphology and behavior. We reviewed our institutional experience with salivary duct carcinoma, aiming to characterize clinical behavior and treatment outcomes.All salivary duct carcinomas treated curatively between 1999 and 2010 were reviewed. Overall survival (OS), locoregional control, distant control, and patterns of failure were analyzed. Multivariate analysis identified predictors of OS.Fifty-four patients with salivary duct carcinoma (parotid gland = 49; submandibular gland = 5) were included in the analysis. Fifty-three patients underwent primary surgery, and 48 (89%) received postoperative radiotherapy (RT; median dose = 60 Gy). Median follow-up was 5.7 years. The 5-year OS, locoregional control, and distant control were 43%, 70%, and 48%, respectively. Nine local (6 involving facial nerve), 10 regional, and 28 distant failures were identified. Multiple pathologic involved lymph nodes (pN2b/N2c) predicted reduced OS (hazard ratio [HR] = 3.6; p = .02).Distant recurrence is common. Presence of pN2b/N2c disease is associated with reduced OS. Local recurrence frequently involves the facial nerves. © 2015 Wiley Periodicals, Inc. Head Neck 38: E820-E826, 2016.

There are limited data on whether recurrent human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) is associated with higher surgical salvage rates. The purpose of this study was to determine the success rate of salvage surgery for locally recurrent oropharyngeal cancer and factors influencing the outcome, including p16 status.All patients who underwent salvage surgery for locally recurrent or persistent oropharyngeal cancer after (chemo)radiotherapy between 2000 and 2012 were included. The Kaplan-Meier analysis was used to determine overall survival (OS) and recurrence-free survival (RFS). Univariable analysis was performed using Cox proportional hazards regression.Thirty-four patients underwent salvage surgery. Five patients (14.7%) were tracheostomy dependent and 22 (64.7%) were gastrostomy tube dependent after salvage surgery. Postoperative complications occurred in 15 patients. RFS after salvage surgery was 28% and 19% at 3 and 5 years, respectively. The presence of nodal disease at the time of local recurrence, close or positive margins, and lymphovascular invasion were the only factors associated with worse survival on univariable analysis. HPV status based on p16 testing was not associated with either OS or RFS.Surgical salvage for oropharyngeal SCC after failure of radiotherapy (+/- chemotherapy) is feasible. Patients who may benefit from surgery include those without regional recurrence and/or those in whom negative margins can be obtained. However, patients may be tracheotomy or gastrostomy tube dependent. The p16 status did not seem to have prognostic impact in the salvage setting; however, larger series are required to assess this relationship. © 2015 Wiley Periodicals, Inc. Head Neck 38: E658-E664, 2016.

Clinical practice guidelines (cpgs) are systematically developed statements designed to assist practitioners and patients in making decisions about appropriate heath care interventions. Clinical practice guidelines are expensive and time-consuming to create. A cpg on concurrent chemotherapy with radiation therapy (ccrt) was developed in Ontario at a time when treatment approaches for head-and-neck cancer were changing significantly. An assessment of treatments and outcomes based on electronic and chart data obtained from a population-based study of 571 patients with oropharynx cancer treated in Ontario (2003&ndash, 2004) was combined with a review of relevant knowledge transfer (publications and presentations at major meetings) to understand variation in adherence to a cpg. In 9 Ontario cancer treatment centres, ccrt was used for 55% of all patients with oropharyngeal cancer, however, at the centres individually, that proportion ranged from 82% to 39%. Furthermore, there was no agreement on the chemotherapy regimen: 2&ndash, 4 years later (a period during which newer regimens were emerging), only 4 of 9 centres were following the guideline for most patients. When outcomes of treated patients were compared for centres with &ldquo, higher&rdquo, and &ldquo, lower&rdquo, use of ccrt, no difference in survival was observed (p = 0.64). At a time of treatment evolution, the new guideline was controversial, and there are many reasons for the mixed adherence. An estimation of adherence should be included during both development and review of guidelines.

Intraoperative imaging technologies including computed tomography and fluorescence optical imaging are becoming routine tools in the cancer surgery operating room. They constitute an enabling platform for high performance surgical resections that assure local control while minimizing morbidity. New contrast agents that can increase the sensitivity and visualization power of existing intraoperative imaging techniques will further enhance their clinical benefit. We report here the development, detection and visualization of a dual-modality computed tomography and near-infrared fluorescence nano liposomal agent (CF800) in multiple preclinical animal models of cancer. We describe the successful application of this agent for combined preoperative computed tomography based three-dimensional surgical planning and intraoperative target mapping (>200 Hounsfield Units enhancement), as well as near-infrared fluorescence guided resection (>5-fold tumor-to-background ratio). These results strongly support the clinical advancement of this agent for image-guided surgery with potential to improve lesion localization, margin delineation and metastatic lymph node detection.

Future curative cancer chemotherapies have to overcome tumor cell heterogeneity and plasticity. To test the hypothesis that the tumor suppressor maspin may reduce microenvironment-dependent prostate tumor cell plasticity and thereby modulate drug sensitivity, we established a new schematic combination of two-dimensional (2D), three-dimensional (3D), and suspension cultures to enrich prostate cancer cell subpopulations with distinct differentiation potentials. We report here that depending on the level of maspin expression, tumor cells in suspension and 3D collagen I manifest the phenotypes of stem-like and dormant tumor cell populations, respectively. In suspension, the surviving maspin-expressing tumor cells lost the self-renewal capacity, underwent senescence, lost the ability to dedifferentiate in vitro, and failed to generate tumors in vivo. Maspin-nonexpressing tumor cells that survived the suspension culture in compact tumorspheres displayed a higher level of stem cell marker expression, maintained the self-renewal capacity, formed tumorspheres in 3D matrices in vitro, and were tumorigenic in vivo. The drug sensitivities of the distinct cell subpopulations depend on the drug target and the differentiation state of the cells. In 2D, docetaxel, MS275, and salinomycin were all cytotoxic. In suspension, while MS275 and salinomycin were toxic, docetaxel showed no effect. Interestingly, cells adapted to 3D collagen I were only responsive to salinomycin. Maspin expression correlated with higher sensitivity to MS275 in both 2D and suspension and to salinomycin in 2D and 3D collagen I. Our data suggest that maspin reduces prostate tumor cell plasticity and enhances tumor sensitivity to salinomycin, which may hold promise in overcoming tumor cell heterogeneity and plasticity. Cancer Res; 75(18); 3970–9. ©2015 AACR.

The aim of this study was to demonstrate the role of advanced fabrication technology across a broad spectrum of head and neck surgical procedures, including applications in endoscopic sinus surgery, skull base surgery, and maxillofacial reconstruction. The initial case studies demonstrated three applications of rapid prototyping technology are in head and neck surgery: i) a mono-material paranasal sinus phantom for endoscopy training ii) a multi-material skull base simulator and iii) 3D patient-specific mandible templates. Digital processing of these phantoms is based on real patient or cadaveric 3D images such as CT or MRI data. Three endoscopic sinus surgeons examined the realism of the endoscopist training phantom. One experienced endoscopic skull base surgeon conducted advanced sinus procedures on the high-fidelity multi-material skull base simulator. Ten patients participated in a prospective clinical study examining patient-specific modeling for mandibular reconstructive surgery. Qualitative feedback to assess the realism of the endoscopy training phantom and high-fidelity multi-material phantom was acquired. Conformance comparisons using assessments from the blinded reconstructive surgeons measured the geometric performance between intra-operative and pre-operative reconstruction mandible plates. Both the endoscopy training phantom and the high-fidelity multi-material phantom received positive feedback on the realistic structure of the phantom models. Results suggested further improvement on the soft tissue structure of the phantom models is necessary. In the patient-specific mandible template study, the pre-operative plates were judged by two blinded surgeons as providing optimal conformance in 7 out of 10 cases. No statistical differences were found in plate fabrication time and conformance, with pre-operative plating providing the advantage of reducing time spent in the operation room. The applicability of common model design and fabrication techniques across a variety of otolaryngological sub-specialties suggests an emerging role for rapid prototyping technology in surgical education, procedure simulation, and clinical practice.

Cone-beam computed tomography (CBCT) with a flat-panel detector represents a promising modality for intraoperative imaging in interventional procedures, demonstrating sub-mm three-dimensional (3D) spatial resolution and soft-tissue visibility. Measurements of patient dose and in-room exposure for CBCT-guided head and neck surgery are reported, and the 3D imaging performance as a function of dose and other acquisition/reconstruction parameters is investigated. Measurements were performed on a mobile isocentric C-arm (Siemens PowerMobil) modified in collaboration with Siemens Medical Solutions (Erlangen, Germany) to provide flat-panel CBCT. Imaging dose was measured in a custom-built 16 cm cylindrical head phantom at four positions (isocenter, anterior, posterior, and lateral) as a function of kVp (80-120 kVp) and C-arm trajectory ("tube-under" and "tube-over" half-rotation orbits). At 100 kVp, for example ("tube-under" orbit), the imaging dose was 0.059 (isocenter), 0.022 (anterior), 0.10 (posterior), and 0.056 (lateral) mGy/ mAs, with scans at approximately 50 and approximately 170 mAs typical for visualization of bony and soft-tissue structures, respectively. Dose to radiosensitive structures (viz., the eyes and thyroid) were considered in particular: significant dose sparing to the eyes (a factor of 5) was achieved using a "tube-under" (rather than "tube-over") half-rotation orbit; a thyroid shield (0.5 mm Pb-equivalent) gave moderate reduction in thyroid dose due to x-ray scatter outside the primary field of view. In-room exposure was measured at positions around the operating table and up to 2 m from isocenter. A typical CBCT scan (10 mGy to isocenter) gave in-air exposure ranging from 29 mR (0.26 mSv) at 35 cm from isocenter, to

Background. Surgery for squamous cell carci- noma (SCC) arising or extending to the hypopharynx is generally reserved for advanced disease or salvage. The prognosis of patients requiring pharyngectomy is poor, and the perioperative morbidity is significant. The aim of the present study is to describe the disease-related and treatment-related outcomes of patients undergoing primary and salvage pharyngectomy for cancer of the hypopharynx and larynx over a 10-year period from a single institution. Methods. We retrospectively reviewed 138 partial and cir- cumferential pharyngectomies performed at a tertiary referral center between 1992 and 2002. There were 31 females and 107 males. The median age was 62 years (range, 27-81 years), and mean follow-up was 3.6 years. Salvage pharyngectomy for radi- ation failure was performed in 72 patients (52%), and in 66 patients (48%) pharyngectomy was performed as the primary treatment. Results. The 5-year overall survival rate after salvage phar- yngectomy was 31% and after primary pharyngectomy was 38%. The 5-year disease-specific survival (DSS) for salvage was 40% and after primary surgery was 45%. The 5-year local and regional control rates for salvage pharyngectomy were 71% and 70%, respectively, and for primary pharyngectomy were 79% and 67%, respectively. The perioperative mortality rate was 3.6%, and the combined morbidity rate was 70%. Postoperative hypocalcemia developed in 44% of patients, a pharyngocutane- ous fistula developed in 31% of patients, and the long-term stric- ture rate was 15%. Variables adversely affecting DSS on univari- ate analysis were nodal metastases (p ¼ .044), extracapsular spread (ECS) (p ¼ .006), poorly differentiated tumors (p ¼ .015), lymphovascular invasion (p ¼ .042), and positive tumor margins (p ¼ .026). ECS (p ¼ .023) was the only independent prognostic variable on multivariable analysis; however, there was a trend toward significance for nodal metastases (p ¼ .064) and tumor differentiation (p ¼ .079). Conclusion. This study demonstrates that both salvage pharyn- gectomy and primary surgery for advanced disease are viable options with high locoregional control. However, this represents a high-risk group in terms of both operative morbidity and survival. Patients with nodal metastases, ECS, and poorly differentiated tumors are likely to succumb to their disease and should be selected for adjuvant therapy when possible. V C 2006 Wiley Peri- odicals, Inc. Head Neck 28: 671-677, 2006

The purpose of this study was to evaluate the individual and combined relationship of comorbidity and performance status (PS) on head and neck squamous cell carcinoma (HNSCC) survival.Six hundred patients with HNSCC were prospectively recruited. Comorbidity and PS were measured using the Charlson Comorbidity Index (CCI) and the Eastern Cooperative Oncology Group (ECOG) Scale. Outcomes were overall survival (OS) and cancer-specific survival (CSS).A total of 48.3% of the patients had at least 1 comorbidity, and 42.3% had impaired PS at baseline. There was no correlation between CCI and ECOG (Spearman's ρ = 0.033; p = .42). In multivariate analysis, CCI score was significantly associated with OS (p = .01). ECOG was not associated with OS, but seems to act as an effect modifier in the association between comorbidity and OS. CCI and ECOG were not associated with CSS.CCI and ECOG scores both provide prognostic information in predicting OS in HNSCC, but a significant association with CSS was not observed.

The molecular mechanisms underlying salivary gland tumorigenesis remain unclear. In order to identify genetic changes that occur during the development of invasive adenocarcinoma from normal salivary gland, we used the Smgb-Tag transgenic mouse model. This transgene induces the progressive development of dysplasia to invasive adenocarcinoma in the submandibular salivary gland. Gene expression patterns from 20 submandibular glands (two normal, nine dysplasia and nine adenocarcinoma samples) were assessed using a mouse 15 K cDNA array. Unsupervised hierarchical clustering was used to group gene expression based on 157 differentially expressed genes distinguishing between dysplasias and adenocarcinomas. Further analysis identified 25 significantly overexpressed and 28 underexpressed cDNA sequences in adenocarcinoma as compared to dysplasia. Differential expression of five genes (Lcn2, Ptn, Cd24a, Mapk6 and Rnps1) was validated by quantitative real-time RT-PCR in a total of 48 mouse salivary gland tissues (seven histologically normal, 13 dysplasias and 28 adenocarcinomas), including the 20 samples analyzed by cDNA arrays. Immunohistochemical analysis was used to validate the expression of Ptn and Cd24a at the protein level in a subset of 16 mouse salivary glands (four normal, five dysplasia and seven adenocarcinoma samples), as well as in 23 human submandibular gland tumors (16 pleomorphic adenomas, three adenoid cystic carcinomas, one acinic cell carcinoma, one adenocarcinoma NOS, one myoepithelial and one mucoepidermoid carcinoma). We thus demonstrated that the Smgb-Tag transgenic mouse model is a useful tool for the identification of genes that are deregulated in salivary gland adenocarcinomas. Our data suggest that Ptn and Cd24a may be genetic markers associated with salivary gland tumorigenesis and/or progression.

Squamous cell carcinomas of the head and neck (HNSCC) and of the cervix (CC) are particularly sensitive to the apoptotic effects of lovastatin in vitro. In this Phase I study, the safety and maximum related dose (MTD) of lovastatin was evaluated in these specific clinical settings. This was a Phase I open-label study to determine the recommended Phase II dose (RPTD) of lovastatin in advanced HNSCC or CC. This study involved a dose and duration escalation of lovastatin starting at 5/mg/kg/day x 2 weeks, every 21 days, until the MTD was reached. Plasma samples were collected for pharmacokinetic analysis. All 26 patients enrolled were evaluable. Dose-limiting toxicity (DLT) consisting of reversible muscle toxicity was seen at 10 mg/kg/day x 14 days. Toxicity may be related to relative renal insufficiency. The MTD was determined to be 7.5 mg/kg/day x 21 days, every 28 days. The low lipid levels experienced on study did not translate into adverse events. Biologically relevant plasma lovastatin levels were obtained. No objective responses were seen but the median survival of patients on study was 7.5 months (mean 9.2 +/- 1.5 months). Stable disease (SD) for more than 3 months was seen in 23% of patients. One patient achieved SD and clinical benefit for 14 months on study and a further 23 months off treatment. The disease stabilisation rate of 23% seen in these end-stage patients is encouraging. We conclude that the administration of lovastatin at 7.5 mg/kg/day for 21 consecutive days on a 28-day schedule is well tolerated in patients with good renal function and warrants further clinical evaluation.

Objective: Oral cancer elicits considerable distress in both the pre and post-treatment periods. This paper details the development, validation and pilot-testing of a psychoeducational intervention for oral cancer patients. Method: An educational booklet covering information about oral cancer and its treatment and effective coping strategies was developed by a multi-disciplinary team. It was evaluated by patient focus groups and content/educational experts, delivered to subjects in pre and post-operative presentations by a health educator, and pilot-tested in a randomized controlled trial versus standard care. Results: Pilot data from 19 subjects (10 psychoeducation, nine standard care) indicates that the intervention is feasible and highly acceptable. At follow-up the intervention group showed a gain in knowledge, less body image disturbance, lower anxiety and a trend toward higher wellbeing. Conclusion: This program, which is currently being evaluated in a larger RCT with extended follow-up, should prove useful in reducing the psychosocial burden of oral cancer and its treatment. Copyright © 2003 John Wiley & Sons, Ltd.

Background. We evaluated the feasibility of using quantitative real-time polymerase chain reaction (PCR) in monitoring Epstein-Barr virus (EBV) DNA concentrations in cell-free plasma of patients with localized nonmetastatic nasopharyngeal carcinoma (NPC) treated with chemoradiation. Methods. Cell-free plasma EBV DNA was quantified in six patients with locally advanced, nonmetastatic nasopharyngeal cancer (NPC) who underwent chemoradiation therapy (CRT) and correlated with magnetic resonance imaging (MRI), positron emission tomography (PET) scans, and clinical course. Results. The mean concentration of EBV DNA was 24,610 copies/mL, 682 copies/mL, and 64.5 copies/mL in the pretreatment, posttreatment, and last follow-up samples, respectively. Four of the six patients had normal PET scans and reduction of EBV DNA copy numbers to minimal levels after treatment and, despite equivocal posttreatment MRI scans, are clinically free of recurrent disease. Two of the six patients had elevated EBV DNA copy numbers immediately after treatment, but a metastatic workup was clear at the time; both subsequently relapsed with distant metastases 5 and 11 months later. Although the posttreatment PET scans were abnormal in both of these cases, they were not predictive of the subsequent sites of tumor relapse. Conclusions. To our knowledge, this is the first report on the correlation between EBV DNA levels and PET scan results in patients with NPC. Reductions in EBV DNA levels and normal PET scans after treatment were consistent among patients who had residual abnormality on MRI images. Persistently elevated EBV DNA levels and abnormal PET scans after treatment suggest residual disease. Further evaluations are required to determine the relative contributions of these two novel techniques in predicting residual disease in locally advanced NPC. © 2004 Wiley Periodicals, Inc. Head Neck26: 815–822, 2004

Our purpose was to classify OSCCs based on their gene expression profiles, to identify differentially expressed genes in these cancers and to correlate genetic deregulation with clinical and histopathologic data and patient outcome. After conducting proof-of-principle experiments utilizing 6 HNSCC cell lines, the gene expression profiles of 20 OSCCs were determined using cDNA microarrays containing 19,200 sequences and the BTSVQ method of data analysis. We identified 2 sample clusters that correlated with the T3-T4 category of disease (p = 0.035) and nodal metastasis (p = 0.035). BTSVQ analysis identified a subset of 23 differentially expressed genes with the lowest QE scores in the cluster containing more advanced-stage tumors. Expression of 6 of these differentially expressed genes was validated by quantitative real-time RT-PCR. Statistical analysis of quantitative real-time RT-PCR data was performed and, after Bonferroni correction, CLDN1 overexpression was significantly correlated with the cluster containing more advanced-stage tumors (p = 0.007). Despite the clinical heterogeneity of OSCC, molecular subtyping by cDNA microarray analysis identified distinct patterns of gene expression associated with relevant clinical parameters. Application of this methodology represents an advance in the classification of oral cavity tumors and may ultimately aid in the development of more tailored therapies for oral carcinoma.

Objectives/Hypothesis: The objective was to introduce microarray technology and its applications in cancer research to the head and neck clinician. Study Design: Literature review combined with methodology and examples from the authors' experiences with microarray analysis of tumors of the head and neck. Methods: Search of literature and the authors' experience was made for technical details, alternative methods of data analysis, available bioinformatics tools, and applications of microarrays in cancer research. Results: Microarrays allow the simultaneous analysis of the expression of thousands of genes. The use of a well-developed microarray study design leads to informative results. There are various bioinformatics resources widely available to aid in the analysis of microarray data. However, there is not yet a gold standard for analysis because this methodology is still evolving. Conclusion: Microarray studies may allow researchers to identify genetic changes relevant to diagnosis and prognosis in patients with head and neck cancer. Although still relatively new, this powerful methodology has immense potential to aid in understanding of the genetic changes that are important in head and neck cancer.

Background. Our aim was to review the presenta- tion, treatment, and outcome of patients with metastatic cu- taneous squamous cell carcinoma involving the parotid gland at a tertiary referral center. Methods. We performed a retrospective chart review of the cancer registry at the Princess Margaret Hospital, Toronto, from 1970 to 2001. All patients had a previously untreated metastatic cutaneous head and neck squamous cell carcinoma involving the parotid gland. A minimal follow-up of 1 year was mandatory for inclusion in the study. Results. Fifty-six white patients (43 men and 13 women), with a median age of 76 years (range, 49-97 years), were eligible for inclusion. The disease in all patients was retro- spectively staged according to a new system. Twenty patients had P1 disease, 14 had P2, and 22 had P3. Therapy included surgery and adjuvant external beam radiation in 37 patients, single-modality external beam radiation in 12, and surgery alone in seven patients. The overall recurrence rate was 29%. The disease-specific survival was significantly worse in patients treated with external beam radiation alone (p 6 cm (p < .01) and the presence of facial nerve involvement (p < .01) were poor prognostic factors. Conclusions. Metastatic cutaneous squamous cell carcino- ma to the parotid gland is an aggressive neoplasm that requires combination therapy. The presence of a lesion in excess of 6 cm or with facial nerve involvement is associated with a poor prognosis. A 2004 Wiley Periodicals, Inc. Head Neck 26: 727-732, 2004

Background. Microvascular free tissue transfer has become an accepted and versatile method of reconstruction in the head and neck region, offering a one-stage procedure and thus reducing the number and length of hospital stays. Many of the patients requiring head and neck free flaps are elderly, with concomitant medical problems, including respiratory and cardiovascular compromise, and are therefore potentially at higher risk of adverse outcomes. In addition, they frequently have a history of heavy alcohol and cigarette consumption, which can compound the risks. Methods. We analyzed a series of 288 intraoral free flap reconstructions and arbitrarily divided them into four groups depending on age: 70. These reconstructions were all performed for malignant lesions. Preoperative medical problems, including ischemic heart disease, hypertension, chronic obstructive pulmonary disease, peripheral vascular disease, and diabetes, were assessed and compared among the different age groups. Conclusions. Our results suggest that free flap surgery is a safe technique in elderly patients with comparable surgical complications to a younger patient population. As a result of concomitant medical problems, however, postoperative medical complications are more frequent in the older age groups, with a resultant increase in length of hospital stay. © 2003 Wiley Periodicals, Inc. Head Neck 25: 549–553, 2003

Total laryngectomy or laryngopharyngectomy remains the procedure of choice for advanced laryngeal/hypopharyngeal carcinoma, either as a primary procedure or as salvage following irradiation alone or concurrent chemoradiation therapy. Over the past 25 years there has been significant improvement in the rehabilitation of these patients, with speech restoration that has dramatically altered and improved their quality of life. This article reviews postlaryngectomy voice rehabilitation with a historical background as well as the present state-of-the-art tracheoesophageal shunt voice with an artificial valve. Finally, this article reviews and compares artificial valve prostheses as to their voice characteristics, patient satisfaction, complications associated with the procedure, and devices used at a center in Europe (The Netherlands Cancer Institute, Amsterdam) and a North American center (The Wharton Head and Neck Center, Princess Margaret Hospital, University of Toronto, Canada).

Background. The purpose of this study was to examine the psychosocial impact of disfigurement, gender, and social support after surgical treatment of head and neck cancer. Method. Eighty-two ambulatory head and neck cancer patients, 6 months or more after treatment and free of active disease were assessed. Ratings of disfigurement were obtained using a valid and reliable 9-point scale developed for the study. Standardized measures of social support, depressive symptoms, well-being, and life happiness were used. Results. The sample as a whole displayed high levels of life happiness, low levels of depression, and positive feelings of well-being. Women demonstrated higher levels of depression and lower life happiness; subjects with greater disfigurement were more depressed. Social support seemed to buffer the impact of greater levels of disfigurement on well-being for women but not for men. Conclusion. These results suggest that women with head and neck cancer who experience low social support and face disfiguring treatment are at greatest risk for psychosocial dysfunction. © 2003 Wiley Periodicals, Inc. Head Neck 25: 103–112, 2003

The effect of tremor on phonation is to modulate an otherwise steady sound source in its amplitude, fundamental frequency, or both. The severity of untreated vocal tremor has been reported to change under certain conditions that may be related to muscle tension. In order to better understand the phenomenon of vocal tremor, its acoustic properties were examined as individuals volitionally altered their pitch and loudness. These voice conditions were anticipated to alter the tension of the intrinsic laryngeal muscles. The voices of 10 individuals with a diagnosis of vocal tremor were recorded before participating in a longitudinal treatment study. They produced vowels at low and high pitch and loudness levels as well as in a comfortable voice condition. Acoustic analyses quantified the amplitude and frequency modulations of the speakers' voices across the various conditions. Individual speakers varied in the way the pitch and loudness changes affected their tremor, but the following statistically significant effects for the speakers as a group were observed: Higher pitch phonation was associated with a more rapid rate for both amplitude and frequency modulations. Amplitude modulation became faster for louder phonation. Low-pitched phonation led to decreases in the extent of amplitude tremor. Varying pitch led to dramatic changes in the phase relationship between amplitude and frequency modulation in some of the speakers, whereas this effect was not apparent in other speakers.

Background A combination of molecular cytogenetic and expression array analysis has been performed on head and neck squamous cell carcinoma (HNSCC) of the oral cavity and supraglottis. These studies were performed to identify consensus regions of chromosomal imbalance and structural rearrangement to determine whether genes located in these genomic regions are subject to alterations in gene expression. Such combinatorial studies may help to identify recurrent patterns of altered gene expression in the context of specific chromosomal changes. Methods Comparative genomic hybridization (CGH) was used to identify net genomic imbalances and spectral karyotyping (SKY) to visualize the numerical and structural chromosomal changes in metaphase preparations. Expression microarray analysis of HNSCC cell lines and primary tongue tumors was also performed to identify genes that were commonly overexpressed or underexpressed compared with adjacent normal tissue. Results CGH detected gains at 3q (64%), 8q (45%) and 6q22-qter (45%) and losses at 18q22-qter (27%). SKY analysis of seven cell lines identified frequent structural rearrangement of the following chromosomal regions: 3q, 5p13–q11.2, 5q32–q34, 7p12–q11.2, 8p12–q12, 9p, 10p, 13p13–q12, 14q11.1–q11.2, 15p13–q11.2, 16p11.1–q11.1, 18q22–q23, and 22p13–q11.2. Consistent deregulation of interleukin 8, integrin alpha-6, c-MYC, epithelial discoidin domain receptor 1, and sterol regulatory element binding protein were apparent by expression analysis. Interestingly, some of these genes map to regions of genomic imbalance and chromosomal rearrangement as determined by our molecular cytogenetic analysis. Conclusions In this small study, a combinatorial analysis using SKY, CGH, and microarray provides a model linking the changes in gene expression to changes in chromosomal dosage and structure. This approach has identified a subset of genetic changes that provide new opportunities for investigating the genetic basis of tumorigenesis in HNSCC. © 2002 Wiley Periodicals, Inc. Head Neck 24: 874–887, 2002

PURPOSE: The benefits of recording the tumor, node, and metastasis (TNM) stages of cancer patients are well accepted, but little is known about how accurately this is performed. An audit was performed to determine the accuracy of recorded stage and to act as a baseline before the implementation of an education program. PATIENTS AND METHODS: All new patient referrals to Princess Margaret Hospital between July 1 and August 31, 1997, were reviewed. An audit panel composed of five health record technicians (HRTs) and 10 doctors was assembled. Each auditor reviewed 10% of the health record. If there was a discrepancy between the stage in the health record and the auditor stage, then the final stage was determined by the audit committee. Analysis of the agreement between the health record, the physician auditor, the HRT auditor, and the final stage was performed. RESULTS: A total of 855 patients were referred with a new diagnosis of a malignancy for which there was a TNM stage system; 833 patients (97.4%) had a stage assigned. There was agreement between the health record stage and final stage in 80% (95% confidence interval [CI], 77% to 82%) of cases for clinical stage, compared with 90% (95% CI, 87% to 92%) for pathologic stage. Of the major site groups, lung was the least accurately recorded. The most common major discrepancies were due to the recording of X when a definite category could be assigned. CONCLUSION: This audit demonstrates the importance of staging and provides impetus to develop staging guidelines and education programs.

Targeted sequencing of cell-free (cfDNA) and circulating tumor DNA (ctcDNA) from blood enables detection of cancer-related mutations using minimally-invasive sample collection methods, and may make early detection of cancer possible, as well as improve monitoring of disease burden in translational research studies. We have developed a series of targeted panels for detection of multiple cancer-related mutations. The panels are designed to efficiently amplify damaged or short fragments of DNA derived from FFPE and cfDNA/ctcDNA, where hundreds of primer pairs can be amplified in a single tube from overlapping targets using only 10 ng input material, making these panels ideal for limiting liquid biopsy samples. A panel which covers known “hotspot” mutations in 56 oncology-related genes has been used in a pilot research study to monitor gynecological cancer in 11 women in a longitudinal study, which found a correlation between the presence of cancer mutations and morbidity and mortality. In 2 of 11 women, the initial absence of mutations above 1% allele-frequency was followed by the appearance of mutations in 1-3 genes at allele frequencies of 5-78% in the later time point. These 2 patients experienced increased morbidity or mortality. In 9 of the 11 women, no mutations were observed, and 6 remain in remission, while 3 are living with cancer. In an effort to further improve both workflow and performance, we are developing two technologies to incorporate into the panel design for future studies. The first will normalize library yield during PCR amplification for simple library pooling, which eliminates the requirement for library quantification and minimizes the time from sample to sequence. The second technology is a molecular ID (MID) system to tag each amplicon uniquely to allow data tracking to individual DNA fragments from the sample, and to increase confidence in variant calling by filtering PCR and sequencing errors. By incorporating technologies that reduce steps in the workflow, the likelihood of error is minimized, and combined with methods that increase confidence in low frequency variant calling, an ideal workflow for liquid biopsy samples is created. Citation Format: Jonathan C. Irish, Cassie A. Schumacher, Navya Nair, Olga Camacho-Vanegas, Jordan Rose- Figura, Ashley Wood, Sukhinder Sandhu, Sushma Chaluvadi, Sergey Chupreta, Laurie Kurihara, Timothy Harkins, John A. Martignetti, Vladimir Makarov. Targeted next-generation sequencing of cell-free tumor DNA to longitudinally monitor cancer burden and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5392. doi:10.1158/1538-7445.AM2017-5392

Background We set out to determine the accuracy of 3D-navigated mandibular and maxillary osteotomies with the ultimate aim to integrate virtual cutting guides and 3D-navigation into ablative and reconstructive head and neck surgery. Methods Four surgeons (two attending, two clinical fellows) completed 224 unnavigated and 224 3D-navigated osteotomies on anatomical models according to preoperative 3D plans. The osteotomized bones were scanned and analyzed. Results Median distance from the virtual plan was 2.1 mm unnavigated (IQR 2.6 mm, ≥3 mm in 33%) and 1.2 mm 3D-navigated (IQR 1.1 mm, ≥3 mm in 6%) (P

Background The use of near-infrared (NIR) fluorescence imaging with indocyanine green (ICG) for sentinel lymph node (SN) mapping has been investigated in lung cancer; however, this has not been fully adapted for minimally invasive surgery (MIS). The aim of our study was to develop a minimally invasive SN mapping integrating pre-operative electro-magnetic navigational bronchoscopy (ENB)-guided transbronchial ICG injection and intraoperative NIR thoracoscopic imaging. Methods A NIR thoracoscope was used to visualize ICG fluorescence. ICG solutions in a 96-well plate and ex vivo porcine lungs were examined to optimize ICG concentrations and injection volumes. Transbronchial ICG injection (n=4) was assessed in comparison to a traditional transpleural approach (n=3), where after thoracotomy an ICG solution (100μL at 100μg/mL) was injected into the porcine right upper lobe for SN identification. For further translation into clinical use, transbronchial ICG injection prior to thoracotomy followed by NIR thoracoscopic imaging was validated (n=3). ENB was used for accurate targeting in two pigs with a pseudo-tumor. Results The ICG fluorescence at 10 μg/mL was the brightest among various concentrations, unchanged by the distance between the thoracoscope and ICG solutions. Injected ICG of no more than 500μL showed a localized fluorescence area. All 7 pigs showed a bright paratracheal lymph node within 15 minutes post-injection, with persistent fluorescence for 60 minutes. The antecedent transbronchial ICG injection succeeded in SN identification in all 3 cases at the first thoracoscopic inspection within 20 minutes post-injection. The ENB system allowed accurate ICG injection surrounding the pseudo-tumors. Conclusions ENB-guided ICG injection followed by NIR thoracoscopy was technically feasible for SN mapping in the porcine lung. This promising platform may be translated into human clinical trials and is suited for MIS.

Skull base chondrosarcoma arises from endochondral bone in the cerebellopontine angle, paranasal sinuses, parasellar area, and clivus. Chordoma arises from ectopic notochord remnants, and approximately a third are within the skull base.1 Although both tumors are generally indolent and considered low grade, they are locally destructive, invasive, and fatal if not properly managed. The focus of this report is on skull base chordoma and chondrosarcoma. Surgery is the first line of therapy, with the aim to maximally debulk gross tumor.2 Optimally, a gross total resection (GTR) is performed; however, in the skull base, the location is such that critical structures are inevitably intricate to the tumor position, making an en bloc, or GTR, often not possible. In fact, residual tumor is often left intentionally as a consequence of preserving function depending on where the tumor is, and subtotal resection (STR) is often the postoperative result. Regardless of the extent of resection, local failure rates with surgery alone can be significant, and adjuvant radiation is considered a standard therapeutic option postoperatively. Within the radiation oncology department at the University of Toronto, our practice has been to offer all patients with skull base chordoma and chondrosarcoma adjuvant radiotherapy. As the therapeutic intent of radiation is to reduce the risk of local recurrence and increase survival, high doses of radiation are required, as these tumors are considered relatively radioresistant.3,4 However, similar to surgery, the inherent proximity to several organs at risk (OAR) presents a major challenge with respect to covering the target volume with the prescribed high dose. While we often make sacrifices to respect the OAR radiation tolerance, we also frequently allow greater dose exposure than traditionally deemed acceptable. Hence, radiation is also a high-risk procedure and requires treatment in centers with experienced practitioners. The historical inability of previous linear accelerator technology to shape and modulate the radiation beam is why largely ineffective low doses of radiation (ranging from 40 to 54 Gy in 1.8–2.0 Gy/d fraction sizes) were delivered, and yielded suboptimal local control (LC) rates.5 As a result, some even questioned the role of radiation altogether, in particular for chordoma. As proton therapy became available for medical use, chordoma and chondrosarcoma were amongst the first to be considered for this technology. The advantage for protons compared with conventional radiation lies in the dose profile, which allows a predictable edge in the dose fall-off with minimal exit dose.6 As a result, protons allow for higher doses to be deposited adjacent to the OAR, hence protons have become a standard of care. Over the last decade, photon-based linear accelerator technology has undergone a transformation. Multileaf collimators (MLCs) allow for intensity modulated radiotherapy (IMRT), while on-board image-guidance (IG) systems permit near-real-time tracking during delivery, and robotic technology has been incorporated to ensure millimeter precision in dose delivery. Ultimately, this translates into the ability to create sophisticated dose distributions with steep dose gradients that differentially dose the OAR and target, a reduction in the planning target volume margin, and excellent precision in the delivery, such that several centers have adopted IG-IMRT for skull base chordoma and chondrosarcoma, delivering equivalent doses to those typical of proton therapy.7–10 We report initial outcomes using high-dose IG-IMRT.

In 2004, Cancer Care Ontario's (CCO) role changed from providing direct cancer service to oversight, with a mission to improve the performance of the cancer system by driving quality, accountability and innovation in all cancer-related services. Since then, CCO has built a model for province-wide quality improvement and oversight--the Performance Improvement Cycle--that exemplifies the key elements of the Excellent Care for All Act, 2010. While ensuring that quality of the cancer system is by necessity a continuous process, the approach taken thus far has achieved measurable results and will continue to form the basis of CCO's future work. Clinician engagement has been critical to the success of CCO's approach to quality oversight and improvement. CCO uses a variety of formal and informal clinical engagement structures at each step of the Performance Improvement Cycle, and has developed operational processes to support quality improvement, and educational and mentorship programs to build clinician leadership capacity in that area. An example of sustained quality improvement in system performance is illustrated in a case study of the surgical treatment of prostate cancer. The improvement was achieved with strong collaboration across CCO's surgery and pathology clinical programs, with support from informatics staff.

Polymorphous low-grade adenocarcinoma (PLGA) and cribriform adenocarcinoma of minor salivary gland (CAMSG) are low-grade carcinomas arising most often in oral cavity and oropharynx, respectively. Controversy exists as to whether these tumors represent separate entities or variants of one spectrum, as they appear to have significant overlap, but also clinicopathologic differences. As many salivary carcinomas harbor recurrent translocations, paired-end RNA sequencing and FusionSeq data analysis was applied for novel fusion discovery on two CAMSGs and two PLGAs. Validated rearrangements were then screened by fluorescence in situ hybridization (FISH) in 60 cases. Histologic classification was performed without knowledge of fusion status and included: 21 CAMSG, 18 classic PLGA, and 21 with "mixed/indeterminate" features. The RNAseq of 2 CAMSGs showed ARID1A-PRKD1 and DDX3X-PRKD1 fusions, respectively, while no fusion candidates were identified in two PLGAs. FISH for PRKD1 rearrangements identified 11 additional cases (22%), two more showing ARID1A-PRKD1 fusions. As PRKD2 and PRKD3 share similar functions with PRKD1 in the diacylglycerol and protein kinase C signal transduction pathway, we expanded the investigation for these genes by FISH. Six additional cases each showed PRKD2 and PRKD3 rearrangements. Of the 26 (43%) fusion-positive tumors, there were 16 (80%) CAMSGs and 9 (45%) indeterminate cases. A PRKD2 rearrangement was detected in one PLGA (6%). We describe novel and recurrent gene rearrangements in PRKD1-3 primarily in CAMSG, suggesting a possible pathogenetic dichotomy from "classic" PLGA. However, the presence of similar genetic findings in half of the indeterminate cases and a single PLGA suggests a possible shared pathogenesis for these tumor types.

A freehand, non-contact diffuse optical tomography (DOT) system has been developed for multimodal imaging with intraoperative cone-beam CT (CBCT) during minimally-invasive cancer surgery. The DOT system is configured for near-infrared fluorescence imaging with indocyanine green (ICG) using a collimated 780 nm laser diode and a nearinfrared CCD camera (PCO Pixelfly USB). Depending on the intended surgical application, the camera is coupled to either a rigid 10 mm diameter endoscope (Karl Storz) or a 25 mm focal length lens (Edmund Optics). A prototype flatpanel CBCT C-Arm (Siemens Healthcare) acquires low-dose 3D images with sub-mm spatial resolution. A 3D mesh is extracted from CBCT for finite-element DOT implementation in NIRFAST (Dartmouth College), with the capability for soft/hard imaging priors (e.g., segmented lymph nodes). A stereoscopic optical camera (NDI Polaris) provides real-time 6D localization of reflective spheres mounted to the laser and camera. Camera calibration combined with tracking data is used to estimate intrinsic (focal length, principal point, non-linear distortion) and extrinsic (translation, rotation) lens parameters. Source/detector boundary data is computed from the tracked laser/camera positions using radiometry models. Target registration errors (TRE) between real and projected boundary points are ~1-2 mm for typical acquisition geometries. Pre-clinical studies using tissue phantoms are presented to characterize 3D imaging performance. This translational research system is under investigation for clinical applications in head-and-neck surgery including oral cavity tumour resection, lymph node mapping, and free-flap perforator assessment.

A significant proportion (up to 62%) of oral squamous cell carcinomas (OSCCs) may arise from oral potential malignant lesions (OPMLs), such as leukoplakia. Patient outcomes may thus be improved through detection of lesions at a risk for malignant transformation, by identifying and categorizing genetic changes in sequential, progressive OPMLs. We conducted array comparative genomic hybridization analysis of 25 sequential, progressive OPMLs and same-site OSCCs from five patients. Recurrent DNA copy number gains were identified on 1p in 20/25 cases (80%) with minimal, high-level amplification regions on 1p35 and 1p36. Other regions of gains were frequently observed: 11q13.4 (68%), 9q34.13 (64%), 21q22.3 (60%), 6p21 and 6q25 (56%) and 10q24, 19q13.2, 22q12, 5q31.2, 7p13, 10q24 and 14q22 (48%). DNA losses were observed in >20% of samples and mainly detected on 5q31.2 (35%), 16p13.2 (30%), 9q33.1 and 9q33.29 (25%) and 17q11.2, 3p26.2, 18q21.1, 4q34.1 and 8p23.2 (20%). Such copy number alterations (CNAs) were mapped in all grades of dysplasia that progressed, and their corresponding OSCCs, in 70% of patients, indicating that these CNAs may be associated with disease progression. Amplified genes mapping within recurrent CNAs (KHDRBS1, PARP1, RAB1A, HBEGF, PAIP2, BTBD7) were selected for validation, by quantitative real-time PCR, in an independent set of 32 progressive leukoplakia, 32 OSSCs and 21 non-progressive leukoplakia samples. Amplification of BTBD7, KHDRBS1, PARP1 and RAB1A was exclusively detected in progressive leukoplakia and corresponding OSCC. BTBD7, KHDRBS1, PARP1 and RAB1A may be associated with OSCC progression. Protein-protein interaction networks were created to identify possible pathways associated with OSCC progression. © The Author 2014. Published by Oxford University Press. All rights reserved.

A partial glossectomy can affect speech production. The goal of this study was to investigate the effect of the presence of a tumour as well as the glossectomy surgery on the patients' production of tongue twisters with the sounds [t] and [k]. Fifteen patients with tongue cancer and 10 healthy controls took part in the study. The outcome measures were the patients' speech acceptability, rate of errors, the time needed to produce the tongue twisters, pause duration between item repetitions and the tongue shape during the production of the consonants [t] and [k] before and after surgery. The patients' speech acceptability deteriorated after the surgery. Compared to controls, the patients' productions of the tongue twisters were slower but not more errorful. Following the surgery, their speed of production did not change, but the rate of errors was higher. Pause duration between items was longer in the patients than in the controls but did not increase from before to after surgery. Analysis of the patients' tongue shapes for the productions of [t] and [k] indicated a higher elevation following the surgery for the patients with flap reconstructions. The results demonstrated that the surgical resection of the tongue changed the error rate but not the speed of production for the patient. The differences in pause duration also indicate that the tumour and the surgical resection of the tongue may impact the phonological planning of the tongue twister.

Objective To determine, using patient- and observer-rated facial disfigurement measures, whether a lateral rhinotomy imparts significant aesthetic morbidity. Design Retrospective and subject-controlled study in a large, tertiary-referral, academic otolaryngology department. Twenty-one consecutive patients who had undergone lateral rhinotomy for the treatment of inverted papilloma were studied in the long-term. Main Outcome Measures Scores on the following: (1) the novel Patient-Rated Facial Disfigurement Analogue Scale questionnaire and (2) the reliable and validated Observer-Rated Facial Disfigurement 9-Point Likert Scale. Results Patients rated their facial appearance as minimally altered and significantly less apparent to others. The observers in this study, a surgeon (J.C.I.) and a psychiatrist (M.R.K.), rated the patients' facial disfigurement as minimally visible. Patients seem to rate how apparent their appearance is to others in a similar fashion to observers. The observer-rated facial disfigurement scale used is valid and reliable. Conclusion Patient- and observer-rated facial disfigurement measures suggest that a lateral rhinotomy does not impart significant aesthetic morbidity.

We compared the management and outcome of glottic cancer in Ontario, Canada to that in the Surveillance, Epidemiology and End Results (SEER) Program areas in the United States to determine whether the greater use of primary radiotherapy with surgery reserved for salvage in Ontario was associated with similar survival and better larynx retention rates than the U.S. approach where primary surgery is used more often. Electronic, clinical and hospital data were linked to cancer registry data and supplemented by chart review where necessary. Initial treatment and survival in patients diagnosed in the SEER areas from 1988 through 1994 were compared to patients from Ontario diagnosed from 1982 through 1995. Actuarial laryngectomy rates were compared for patients over 65 at diagnosis in the two regions. Analyses were conducted over all cases and stratified by disease stage. In localized disease (T1 or T2), conservative treatment was the most common initial treatment in both regions, although total laryngectomy was used more often in SEER than Ontario (6.2% vs. 0.2%, respectively, P P ⩽ .001). Over all cases, the relative survival rate was 80% in Ontario at 5 years compared to 78% in SEER ( P = .33). In localized disease, the relative survival rates were 4 to 5% higher in Ontario from the second year on, while in advanced disease 2 to 3% higher rates in SEER did not approach statistical significance. Actuarial laryngectomy rates at 3 years differed between the two regions, with a 4% higher rate in SEER ( P = .01). In localized disease, 12.6% of Ontario patients had a laryngectomy by 3 years postdiagnosis compared to 17.9% in SEER ( P = .05). In advanced disease, the rates were 63.3% and 79.2%, respectively ( P = .07). There are large differences in the management of glottic cancer between the SEER areas of the U.S. and Ontario and no evidence that a policy emphasizing radiotherapy with surgery reserved for salvage is associated with worse survival. Ultimate laryngectomy rates are lower in Ontario for localized disease and may be lower for advanced disease. Conservation treatment should be used for localized disease while the treatment decision in advanced disease may be especially sensitive to patient values for voice retention versus initial cure.

Objectives: A pilot study was designed to analyze lymphoid cell infiltration in Epstein-Barr virus–positive (EBV + ) nasopharyngeal carcinomas (NPCs) and to determine whether this pattern of infiltration is consistent with non-EBV + head and neck carcinomas or with solid EBV + tumors in other locations. Study design: We performed a retrospective analysis of archived NPCs and oral cavity carcinomas. Methods: Immunohistochemical staining of the archive material for various markers (CD3, CD8, UCHL-1, S-100, and intercellular adhesion molecule) was performed. Polymerase chain reaction techniques to establish the presence of the EBV genome were used. Cells in different locations were counted under a light microscope by 2 of the authors. Results: The infiltration pattern of NPCs was different from that of oral cavity carcinomas. Stromal infiltration was significantly denser in oral cavity carcinomas. Tumor nest infiltration was more pronounced in NPCs. The pattern of infiltration was comparable with what has been described for other solid EBV + tumors. Conclusions: The immune response to NPCs is likely to be strongly influenced by the presence of the EBV genome. The pattern of infiltration is similar to that of other non-head and neck EBV + solid tumors and different from that of EBV − head and neck carcinomas.

BACKGROUND The objectives of this study were 1) to describe patterns of use of computed tomography (CT) in laryngeal carcinoma, and 2) to characterize the contribution of CT to the T classification of laryngeal carcinoma. METHODS The study population comprised 1195 patients with laryngeal carcinoma diagnosed from 1982 through 1995 chosen randomly from the Ontario provincial cancer registry. A chart review was conducted to obtain data on each case. Patient-related, tumor-related, and health-system-related factors were analyzed to identify factors associated with the use of CT. Descriptions of clinical exams and CT reports were reviewed to see how CT information modified T classification. Actuarial local control and cause specific survival curves were plotted by clinical T classification without and with CT to evaluate stage migration. The percentage of the variance in outcome explained by T classification in a Cox analysis was used to evaluate whether the prognostic accuracy of T classification was improved with the use of information from CT. RESULTS Patients with glottic (20.1%) and supraglottic (41.7%) carcinoma underwent CT. The use of CT increased over time in glottic and supraglottic carcinoma combined from 17.2% in 1982–5 to 33.9% in 1991–5. Computed tomography was used less often in older patients with a 16% (95% confidence interval, 5– 27%) decrease in the odds of having CT with each 10-year age increment. Computed tomography use varied considerably across the cancer center regions in Ontario. Computed tomography altered the T classification in 20.2% of those patients who had CT, with most being “upstages.” Stage migration due to CT was demonstrated. Using information from CT in the assignment of T classification for 27.8% of this study population did not make a significant contribution to the ability of T classification to predict outcome over the entire group. CONCLUSIONS There is large variation in the use of CT among different age groups and regions. The ability to compare outcomes by stage across geographic areas is compromised when the use of CT varies. Cancer 2001;91:394–407. © 2001 American Cancer Society.

In this cross-sectional study, the sensibility, test-retest reliability, and validity of the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire were assessed in patients who underwent neck dissection.Sensibility was assessed with a questionnaire. Test-retest reliability was performed with completion of the DASH questionnaire 2 weeks after initial completion; validity, by evaluating differences in scores between patients undergoing different types of neck dissections and correlating DASH scores with Neck Dissection Impairment Index (NDII) scores.The DASH questionnaire met sensibility criteria. For test-retest reliability analysis, the intraclass coefficient was 0.91. The DASH questionnaire showed differences between patients who underwent accessory nerve-sacrifice and nerve-sparing neck dissection. DASH questionnaire scores strongly correlated with NDII scores (r = -0.86).Although this study provides preliminary data on some psychometric properties of the DASH questionnaire in patients who have undergone a neck dissection, further assessment of responsiveness and other properties are required.

Background Several questionnaires have been used to evaluate shoulder disability after neck dissection. The purpose of this study was to review these measures and highlight their strengths and weaknesses. Methods A literature review was performed to identify measures of shoulder disability after head and neck cancer surgery. These measures were evaluated in terms of their methods of development and assessment of their psychometric properties. Results Seven questionnaires were identified. Several of the other questionnaires have been well developed but have not had their psychometric properties assessed in the head and neck cancer population. Each questionnaire has its strengths and weaknesses. Conclusion The strengths and weaknesses of the shoulder disability questionnaires should be considered when deciding which questionnaire to use. Efforts should be focused on using well-designed questionnaires that have been assessed in this patient population rather than developing or using other questionnaires. © 2013 Wiley Periodicals, Inc. Head Neck, 36: 1453–1458, 2014

This study was designed to validate and standardize a method for unilateral nasal nitric oxide (NO) measurement. Fourteen healthy volunteers and 11 patients who had undergone unilateral medial maxillectomy were enrolled. Nasal NO was measured unilaterally by means of a dual pump system, and bilateral nasal NO was measured by aspirating air through the nasal airway in series. The median unilateral NO output was 195 nL/min on the surgical side and 291 nL/min on the contralateral, surgically untreated side (p = .006). The NO output was not significantly different between nostrils in the control group (p = .82). With the bilateral technique, there was no significant difference between the surgery group and the healthy-subjects group (p = .72). The unilateral nasal NO technique is sensitive in determining unilateral differences in nasal NO production. The NO outputs from the nostrils were similar in normal subjects regardless of the nasal cycle, but were significantly lower on the operated side in the unilateral nasal surgery group.

Objective/Hypothesis The immortalizing enzyme telomerase has been linked to carcinogenesis and is being targeted as a novel molecular marker. This study investigated telomerase expression in patients with laryngeal squamous cell carcinoma and correlated telomerase activity with conventional prognostic parameters. Study Design A consecutive series of patients with laryngeal squamous cell carcinoma undergoing surgical salvage for persistent or progressive disease after failed radiation therapy. Methods Twenty patient samples of laryngeal squamous cell carcinoma and 20 adjacent histologically normal mucosal samples were assayed using the telomeric repeat amplification protocol (TRAP) method for detection of telomerase activity. The leukemic cell line, K562, acted as a positive control and the human fibroblast line, Hs21Fs, as a negative control. A sample was classified as telomerase positive when an RNase-sensitive hexameric repeat ladder was observed. Absence of laddering was considered a negative result. Results Seventeen of 20 (85%) tumor samples and 4 of 20 (20%) adjacent histologically normal samples were telomerase positive. No statistically significant difference was observed when densitometric readings were compared by T category, tumor grade, or site (by ANOVA). Conclusions Although telomerase activity is present in laryngeal cancer, levels of activation do not correlate with conventional parameters used for prognostication. Our study indicates that the marker may be a useful adjunctive method in the diagnosis of malignancy after radiation failure.

Background Facial disfigurement is considered to be one of the most distressing aspects of head and neck cancer and its treatment, but it has been the focus of little systematic study. Existing studies have yielded conflicting results about the psychosocial impact of disfigurement. No studies to date have examined disfigurement using a valid and reliable observer-rated measure. The purpose of the current study was to examine the validity (convergent and discriminant) and the inter-rater reliability of a novel nine-point observer-rated disfigurement scale. Methods The sample consisted of 74 ambulatory head and neck cancer patients more than 6 months post treatment. Ratings of disfigurement were assigned independently by surgical and nonsurgical raters. Validity was assessed by comparing the association between disfigurement ratings and sociodemographic and illness treatment variables. Reliability was assessed by examining the concordance between the surgical and nonsurgical ratings. Results Disfigurement ratings were not associated with several sociodemographic variables, supporting the discriminant validity of the scale. Disfigurement was significantly related to a diagnosis of oral cancer, a history of adjunctive radiation, the type of surgical procedure performed, the degree of physical dysfunction, and the presence of postoperative complications. Observer ratings of disfigurement were significantly related to patient ratings of disfigurement. These findings support the convergent validity of the disfigurement scale. Inter-rater reliability of the scale was high (intraclass correlation coefficient = .91). Conclusion The study provides preliminary evidence for the validity and inter-rater reliability of a novel nine point observer-rated disfigurement scale that may be useful in evaluating the impact of disfigurement on quality of life in head and neck cancer. © 2000 John Wiley & Sons, Inc. Head Neck 22: 132–141, 2000.

Background Functional and aesthetic restoration of total lip and chin defects can be achieved using the composite radial forearm—palmaris longus tendon free flap. Objective To present the technique we use and our experience with this form of reconstruction in 10 consecutive patients with total lip and chin defects who were surgically treated between 1992 and 1998. Methods The palmaris longus tendon acting as a sling over which the flap is draped is responsible for long-term maintenance of vertical lip height and lip support. The factors responsible for this are the long-term maintenance of vertical lip height and lip support and the transfer of facial muscle activity to the neolip. Results All patients were satisfied with their final reconstructive result.Oral competence for deglutition and speech was achieved in all patients in our case series, with no incidence of drooling. Conclusion We recommend the use of the composite radial forearm—palmaris longus tendon free flap for this type of reconstructive surgery.

Background The population in New Zealand is a heterogeneous mix of Caucasians (80%), Maori (9%), and Polynesians (10%). It is believed that the Polynesians are of Chinese descent and may harbor the same high incidence of nasopharyngeal carcinoma (NPC). In addition, it is not known whether the Epstein-Barr virus (EBV) is as closely associated with the development of NPC in Polynesians as it is in those of Chinese origin. Methods This study reexamines the associative correlation between EBV and NPC with two methods of genetic detection, polymerase chain reaction (PCR) and in-situ hybridization (ISH). In addition, geographic heterogeneity was analyzed to determine whether there are differences in the prevalence of EBV in NPCs among the ethnic mixed populations found in New Zealand. Nasopharyngeal biopsy specimens from 20 patients with NPC and 36 controls were obtained from Auckland. Results With PCR, EBNA-1, a genomic sequence of EBV in NPC samples was able to be detected with 76.5% sensitivity and 96.7% specificity. By use of ISH, EBV was detected in NPC tissue with 82.4% sensitivity and 100% specificity. Conclusion There seems to be no geoanthropologic differences in terms of the association of EBV with NPC. © 2000 John Wiley & Sons, Inc. Head Neck 22: 505–508, 2000.

Background A variety of free flaps have been successfully used for mandible reconstruction. This study compared the short- and long-term results of using the free iliac crest and fibula flaps. Methods We conducted a retrospective analysis of 117 patients who underwent mandibular reconstruction, 59 patients with iliac crest and 58 with free fibula. Accurate long-term functional assessment was possible in 31 cases in the iliac crest group and in 48 patients with fibular reconstruction. Anterior or combined anterolateral defects formed 72% and 64% in the iliac crest and fibula groups, respectively. The remainder were pure lateral defects. In both series, a skin paddle was included to provide either lining, skin cover, or both in 77% of the cases, whereas in 23% bone only was used. Results Complications included two perioperative deaths and three flap losses in the iliac crest group and five flap losses in the fibula group. Long-term functional and cosmetic assessment showed no statistically significant differences in oral continence (p > 0.9), speech (p = 0.57), and contour results (p = 0.80) between the two groups. However, oral deglutition was statistically significantly better in the fibula free flap group (p = 0.009). Conclusion Although the fibula free flap is the flap of choice, the iliac crest is an excellent and reliable complementary flap for mandibular reconstruction. © 1999 John Wiley & Sons, Inc. Head Neck 21: 639–647, 1999.

Objective: To investigate the effects of medialization laryngoplasty on laryngeal airway resistance at various clinically relevant flow rates. Study Design: This study was conducted using a total of 13 laboratory experiments. Two of the experiments were used to validate the cadaveric model employed. Eleven experiments were used to quantify airway resistance relative to increasing medialization laryngoplasty stent size. Methods: With autopsy consent the authors obtained 13 consecutive and anatomically complete larynges for experimentation. A thyrotomy window measuring 8 × 6 mm was made on the left side of the thyroid cartilage. A #4 laryngeal mask was secured to the pharyngeal airway with sutures. Eleven experiments were conducted at the same flow rates using increasingly larger stents from 1 mm to 11 mm in size. Using the Bernoulli equation, the pressure measured at the proximal end of the laryngeal mask is representative of the pressure drop across the airway. The experimental model was validated in two experiments using flow rates between 5 and 50 L/min and stents measured at 5, 10, 15, and 20 mm. Results: Average results from the 11 experiments indicate that at increasing levels of medialization, from 0 to 11 mm, there is essentially the same pressure drop across the larynx at a given flow rate. Conclusion: At physiologic airflow rates in a cadaveric model, medialization laryngoplasty implants of 11 mm or less seem to have no obvious effect on airway resistance.

Background The supraomohyoid neck dissection (SOHND) is often performed in patients with cancer of the oral cavity, where there is no clinical or radiologic evidence of regional metastases. When on pathologic examination positive neck nodes are found, however, some consider it a curative operation, whereas others regard it as a staging procedure only. Methods We retrospectively reviewed 43 patients with cancer of the oral cavity who had a SOHND during the period from 1991 to 1994. All patients were staged as having N0 disease and had a total of 48 SOHNDs (38 unilateral, 5 bilateral). The follow-up period was at least 2 years. Results Seven of 48 N0-staged necks showed occult metastasis (15%). Two of these patients received postoperative radiotherapy. One of 7 (14%) patients with pathologic node-positive disease on the SOHND side developed recurrent ipsilateral neck disease during the follow-up period, whereas 4 (10%) recurrences developed in 41 necks that were pathologically staged as N0. Survival was 88% for patients with pathologically N0 necks versus 86% for patients with pathologically N+; disease. Conclusion Supraomohyoid neck dissection is an effective staging procedure; however, in this group of patients, neck recurrence and patient survival after SOHND appear not to be related to pathology N stage. Also, SOHND with or without adjuvant radiotherapy appears to control the neck in the majority of patients, attesting to therapeutic efficacy. A prospective study is needed, however, to see if a "wait and see" policy does not achieve similar long-term outcome.

Background. The incidence of internal jugular vein thrombosis (IJVT) following a modified neck dissection remains uncertain. The effect of, or consequences following, IJVT upon pedicled and free flap head and neck reconstructions remains unexplored. Methods. Twenty-nine preserved internal jugular veins in 24 patients undergoing modified neck dissection were available for prospective study. All patients required a pedicled or free flap reconstruction and received a modified, unilateral or bilateral cervical lymphadenectomy. The patency of all jugular veins was determined preoperatively and postoperatively using a combination of computed tomography (CT) scanning, high-resolution ultrasound, and color-flow Doppler (CFD). Results. The IJVT rate was 14%. The presence of a pedicled myocutaneous flap and left-sided jugular dissections may represent risks to the postoperative patency of the internal jugular vein. Preoperative radiotherapy did not appear to impact negatively upon the thrombosis rate. Conclusions. Thrombosis of the internal jugular vein may result in significant morbidity for the postoperative oncologic patient. An internal jugular-dependent-free-tissue transfer may risk venous compromise of the flap, whereas the use of a pedicled flap may place the jugular at increased risk for thrombosis. Strategies for deep venous system microvascular recipient recruitment in the head and neck are discussed. Wherever possible, we employ two deep venous systems, the internal jugular, and subclavian (via the external jugular) for flap drainage.

Objective: To evaluate the results and functional outcome associated with fibular free flap reconstruction of orofacial and mandibular defects. Design: We conducted a retrospective analysis of 50 consecutive fibular free flaps during a 3-year period. Forty patients were available for follow-up, which ranged from 4 to 39 months. Setting: Academic tertiary care referral medical center. Patients: Fifty consecutive mandibular reconstructions using the fibular free flap were performed on 47 patients. Thirty-five patients (74%) underwent primary reconstruction. Sixty-six percent of the mandibular defects were anterior or combined anterolateral types; the remainder were pure lateral defects. In 38 patients (81%), a skin paddle was included with the flap to provide either a mucosal lining or skin cover, whereas in only 9 patients (19%), bone was used alone. Main Outcome Measures: Factors reflecting functional properties and processes as well as complications of the upper aerodigestive tract were evaluated clinically and radiographically. Results: Four flaps required reexploration as emergencies, and none were successfully salvaged (8.5% failure). Three patients underwent further free vascularized fibula transfer with 1 failure. During follow-up, swallowing was normal in 25 patients (64%), oral continence was normal or almost normal in 26 patients (67%), and speech was normal or easily intelligible in 35 patients (90%). Aesthetic results were excellent or acceptable in 37 patients (95%). Conclusions: Our results reveal that the vascularized fibular free flap is very suitable with an excellent success rate for reconstructing both the composite or simple long-spanned mandibular defect. The overlying skin island is reliable and provides lining or coverage for intraoral and extraoral defects. Superior functional and cosmetic results are expected in the majority of patients, while donor site morbidity is minimal. Arch Otolaryngol Head Neck Surg. 1997;123:939-944