Search

Objectives/Hypothesis The endoscopic endonasal approach (EEA) for nasopharyngectomy is an alternative to the maxillary swing approach (MSA) for selected recurrent nasopharyngeal carcinomas (NPC). We compare the access between these approaches. Methods Three cadaver specimens were used to compare access volumes of the EEA and MSA. Exposure volumes were calculated using image guidance registration to cone beam computed tomography and tracking of accessible tissue with volumetric quantification. The area of exposure to the carotid artery was measured. Results The MSA provided higher volumes for access volume compared with the EEA (66.6 vs 39.1 cm3, p = 0.009). The working area was larger in the MSA (80.2 vs 56.9 cm2, p = 0.06). The exposure to the carotid artery was higher in the MSA (1.88 vs 1.62 cm2, p = 0.04). The MSA provided larger volume of exposure for tumors of the parapharyngeal space with exposure below the palate. Conclusions This study suggests that the MSA for nasopharyngectomy provides a larger volume of exposure. However, much of the increased exposure relates to exposure of the parapharyngeal space below the palate. The EEA provides adequate access to superior anatomical structures.

Background The primary purpose of this study was to describe variations in incidence rates, resections rates, and types of surgical resection for patients diagnosed with laryngeal and hypopharyngeal cancers in Ontario. Methods All laryngeal and hypopharyngeal cancer cases in Ontario (2003-2010) were identified from the Ontario Cancer Registry (n = 3034). Variations in incidence rates, resection rates, and type of surgical resection were compared by sex, age group, neighborhood income, community population, health region, and physician specialty. Results Incidence rates per 100 000 vary significantly by sex, age, neighborhood income, and community size. Women, the elderly (75+ years), those in the higher income quintiles, and those living in larger communities were significantly less likely to receive a laryngectomy procedure. Conclusions Laryngeal and hypopharyngeal cancer incidence rates vary by sex, age, neighborhood income, community size, and health region. Resection rates vary by age, sex, and health region. These disparities warrant further evaluation to improve the quality of delivered care in Ontario.

Background Intraoperative image guidance during transoral robotic surgery (TORS) is hampered by imaging-friendly instrumentation and intraoperative positioning. The purpose of this study was to develop and validate an accurate image-guidance system for TORS. Methods A custom radiolucent mouth retractor was fabricated from biocompatible material (Med-610; Stratasys, Minneapolis, MN). Teflon beads were placed in the oropharynx and carotid arteries of 3 cadavers. CT scans were obtained in the preoperative and intraoperative positions. Displacement of targets between preoperative and intraoperative scans was measured. Surgical navigation was based on the open-source Image-Guided Surgery Toolkit. Target registration error (TRE) was determined by measuring the distance between the tracker and bead registered to preoperative versus intraoperative scans. Results The inferior oropharyngeal targets demonstrated the greatest displacement between positions. A significant reduction in TRE was observed when registering the tracker to the intraoperative compared to the preoperative scan. Conclusion This study describes an accurate intraoperative image-guidance system for TORS.

Background Endometrial cancer is the most common gynecologic malignancy, and its incidence and associated mortality are increasing. Despite the immediate need to detect these cancers at an earlier stage, there is no effective screening methodology or protocol for endometrial cancer. The comprehensive, genomics-based analysis of endometrial cancer by The Cancer Genome Atlas (TCGA) revealed many of the molecular defects that define this cancer. Based on these cancer genome results, and in a prospective study, we hypothesized that the use of ultra-deep, targeted gene sequencing could detect somatic mutations in uterine lavage fluid obtained from women undergoing hysteroscopy as a means of molecular screening and diagnosis. Methods and Findings Uterine lavage and paired blood samples were collected and analyzed from 107 consecutive patients who were undergoing hysteroscopy and curettage for diagnostic evaluation from this single-institution study. The lavage fluid was separated into cellular and acellular fractions by centrifugation. Cellular and cell-free DNA (cfDNA) were isolated from each lavage. Two targeted next-generation sequencing (NGS) gene panels, one composed of 56 genes and the other of 12 genes, were used for ultra-deep sequencing. To rule out potential NGS-based errors, orthogonal mutation validation was performed using digital PCR and Sanger sequencing. Seven patients were diagnosed with endometrial cancer based on classic histopathologic analysis. Six of these patients had stage IA cancer, and one of these cancers was only detectable as a microscopic focus within a polyp. All seven patients were found to have significant cancer-associated gene mutations in both cell pellet and cfDNA fractions. In the four patients in whom adequate tumor sample was available, all tumor mutations above a specific allele fraction were present in the uterine lavage DNA samples. Mutations originally only detected in lavage fluid fractions were later confirmed to be present in tumor but at allele fractions significantly less than 1%. Of the remaining 95 patients diagnosed with benign or non-cancer pathology, 44 had no significant cancer mutations detected. Intriguingly, 51 patients without histopathologic evidence of cancer had relatively high allele fraction (1.0%–30.4%), cancer-associated mutations. Participants with detected driver and potential driver mutations were significantly older (mean age mutated = 57.96, 95% confidence interval [CI]: 3.30–∞, mean age no mutations = 50.35; p-value = 0.002; Benjamini-Hochberg [BH] adjusted p-value = 0.015) and more likely to be post-menopausal (p-value = 0.004; BH-adjusted p-value = 0.015) than those without these mutations. No associations were detected between mutation status and race/ethnicity, body mass index, diabetes, parity, and smoking status. Long-term follow-up was not presently available in this prospective study for those women without histopathologic evidence of cancer. Conclusions Using ultra-deep NGS, we identified somatic mutations in DNA extracted both from cell pellets and a never previously reported cfDNA fraction from the uterine lavage. Using our targeted sequencing approach, endometrial driver mutations were identified in all seven women who received a cancer diagnosis based on classic histopathology of tissue curettage obtained at the time of hysteroscopy. In addition, relatively high allele fraction driver mutations were identified in the lavage fluid of approximately half of the women without a cancer diagnosis. Increasing age and post-menopausal status were associated with the presence of these cancer-associated mutations, suggesting the prevalent existence of a premalignant landscape in women without clinical evidence of cancer. Given that a uterine lavage can be easily and quickly performed even outside of the operating room and in a physician’s office-based setting, our findings suggest the future possibility of this approach for screening women for the earliest stages of endometrial cancer. However, our findings suggest that further insight into development of cancer or its interruption are needed before translation to the clinic., Navya Nair and colleagues describe a screening method for early identification of endometrial cancer. This method also reveals cancer mutations in women without cancer., Author Summary Why Was This Study Done? Endometrial cancer is the most common gynecologic malignancy in the United States. When detected early, endometrial cancer survival rates are improved. There are no screening methods that can detect either pre-malignant lesions or early-stage cancers. What Did the Researchers Do and Find? We conducted a prospective study in 107 women where uterine lavage fluid was analyzed for genetic mutations using ultra-deep, panel-based next-generation sequencing (NGS). Seven of the 107 women were identified by gold-standard histopathology as having endometrial cancer. All seven, even those with microscopic cancer foci, had significant cancer-associated gene mutations detected in their lavage fluid. Fifty-one women without histopathologic evidence of cancer had high allele fraction cancer-associated mutations. What Do These Findings Mean? This study provides the first evidence for the ability of an NGS-based approach to prospectively detect early-stage, microscopic endometrial cancer. Our study identified a previously unknown but highly prevalent landscape of driver and potential driver mutations in women who did not have histopathologic evidence of endometrial cancer. These findings suggest that while NGS-based analysis of uterine lavage can achieve the necessary sensitivity for endometrial cancer screening, further insights into the steps leading to endometrial cancer development and/or its interruption are still needed before this goal can be achieved. These findings, based on ultra-deep sequencing, may also have implications for understanding the development and clonal expansion of somatic cancer-driver mutations in apparently non-diseased tissues.

Poorly differentiated sinonasal malignancies are amongst the hardest differential diagnoses in pathology, owing to the large number of rare entities that arise there. Complicating the matter is that most pathologists, including those with experience in head and neck pathology, have little experience in any one of these rare entities. Most patients with sinonasal carcinoma present with locally advanced disease and in the past a combination of chemotherapy, radiotherapy, and surgery would usually be recommended without the specific disease subtype playing a large part of the decision making. However, in the era of “precision medicine” and targeted therapies, the specific tumour subtype and an accurate diagnosis will become increasingly important even for the so-called “undifferentiated carcinoma”. Specific entities that tend to enter into the differential diagnosis include olfactory neuroblastoma, sinonasal undifferentiated carcinoma (SNUC), and non-keratinizing squamous cell carcinoma (viral and non-viral). However, recent new entities, such as NUT-midline carcinoma also have to be considered. Recently it was found that a subset of tumours originally diagnosed as one of the aforementioned entities all demonstrated loss of the ubiquitously expressed protein Integrase Interactor 1 (INI1; SMARCB1). These tumours were often basaloid with at least partial rhabdoid differentiation and most were considered a part of the SNUC spectrum. In this report, we describe two additional cases of INI1-deficient sinonasal carcinoma prospectively identified, both of which appeared to have a marked response to neo-adjuvant chemoradiation, a finding not previously described.

The primary purpose of this study was to examine whether angiosarcoma outcomes differ for the scalp and face.We conducted a retrospective outcomes analysis of 50 patients with cutaneous angiosarcoma treated by curative intent identified from the Princess Margaret Cancer Centre Registry (from 1958 to 2014).Median survival was 26 months (95% confidence interval [CI], 17.6-34.6) and median follow-up 29 months. For the scalp and face, respectively, the 5-year locoregional control rate was 9% and 53% (p = .04); the recurrence-free survival (RFS) rate was 5% and 27% (p = .017); and the overall survival (OS) rate was 9% and 26% (p = .017). Scalp lesions were larger, more likely to be multifocal, and presented more rapidly once noticed. In multivariate Cox proportional hazards analysis, scalp location was independently prognostic for mortality (hazard ratio [HR], 2.10; 95% CI, 1.03-4.28; p = .04).Scalp angiosarcoma has worse survival than angiosarcoma of the face. Scalp angiosarcoma tends to be larger at presentation, which may be because it is not noticed until more advanced. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1205-1211, 2017.

Patients being treated at higher case volume hospitals or by higher case volume physicians appear to have better outcomes. This volume-outcome relationship is reviewed for oncologic and non-oncologic surgery with a focus on head and neck oncology. The impact of these research findings on health policy and health-care organization in Ontario, Canada, is then outlined. Lastly, future directions for quality improvement in surgical oncology are reviewed in the context of a universal health-care system. These include surgeon report cards, pre-operative checklists, linking funding and remuneration to the quality of delivered care, and the use of process improvement techniques.

Unlike papillary thyroid carcinoma, medullary thyroid carcinoma is insensitive to adjuvant treatment with radioactive iodine. The clinical management of patients with advanced or metastatic disease remains challenging since no effective systemic adjuvant therapy is available. We aimed to identify markers of aggressive disease and novel drugable protein targets that would provide systemic adjuvant treatment for patients with advanced medullary thyroid carcinoma. We therefore examined morphologic features of aggressive behavior and the expression of 41 proteins involved in apoptosis, cell cycle, angiogenesis, inflammation, cell adhesion, tumor-specific markers, and WNT, SHH, and AKT pathways using tissue microarray from 23 patients with medullary thyroid carcinoma. Protein expression was determined using computerized image analysis software. Statistical analysis was carried out to correlate clinical data with the average score for each marker. Angioinvasion proved to be the most reliable predictor of disease recurrence and death. The rate of angioinvasion was 43 %. All angioinvasive medullary thyroid carcinomas had locoregional and/or distant metastasis; 60 % of angioinvasive medullary thyroid carcinomas developed distant metastasis. We identified expression of several potentially important protein targets such as COX-1/2, Bcl-2a, Gst-π, Gli-1, Gli-2, Gli-3, and Bmi-1 that may be therapeutically targeted in medullary thyroid carcinoma. More importantly, the immunohistochemical profile of SSTRs in medullary thyroid carcinoma may also have clinical relevance for the administration of peptide receptor radionuclide treatment. Successful outcome of clinical trials directed against these novel targets would provide much needed systemic adjuvant treatment for patients with advanced medullary thyroid carcinoma, and our data suggest the possibility of stratifying patients who are likely to require adjuvant therapy before their burden of disease precludes successful therapeutic effect.

The causative role of human papillomavirus (HPV) in a subset of squamous cell carcinomas of the oropharynx (OSCC) is now well established with HPV-16 being detected in approximately 92 % of HPV-positive OSCC in North America. Recently HPV has also been found in some non-squamous oropharyngeal carcinomas including adenosquamous carcinomas, neuroendocrine carcinomas, and undifferentiated “lymphoepithelioma-like” carcinomas. Herein, we report a HPV-16 positive adenocarcinoma NOS arising in the base of the tongue of a non-smoker, 64 year-old male. To our knowledge, this is the first time this association has been clearly documented. The adenocarcinoma was diffusely positive for p16 and HPV-16 was demonstrated by in situ hybridization and linear array analysis. Q-PCR demonstrated a viral load of 4 copies per cancer cell, whereas qRT-PCR for E6/E7 transcript levels were 30 copies per 1,000 human ribosomal protein large P0 (RPLP0) reference gene. The presence of HPV in non-squamous oropharyngeal carcinomas raises the possibility that HPV is also involved in the carcinogenesis of some uncommon carcinomas of the region.

Background The aim of this study was to identify new target proteins in sebaceous gland carcinoma. Methods A tissue microarray containing 115 core biopsies was constructed and stained for proteins involved in carcinogenesis, angiogenesis, inflammation, and cell-to-cell contact. Two investigators independently determined protein expression of all antibodies. Results Vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor alpha and beta (PDGFR-α/-β), epidermal growth factor receptor (EGFR), cyclooxygenase 1 and 2 (Cox-1/-2), myeloid cell leukemia sequence 1 (Mcl-1), matrix metalloproteinase 1 (MMP-1), CD9, Bmi-1, 14-3-3σ, glutathione S-transferase pi (Gstπ), and members of the sonic hedgehog (SHH), AKT, and WNT pathways were significantly overexpressed in sebaceous gland carcinomas. Conclusions We have demonstrated for the first time that proteins related to angiogenesis, inflammation, and cell proliferation are overexpressed in sebaceous gland carcinomas. These proteins may hold promise as novel therapeutic targets for the treatment of sebaceous gland carcinoma. © 2012 Wiley Periodicals, Inc. Head Neck, 2013

Background Life-threatening diseases, such as head and neck cancer (HNCa), can stimulate the emergence of a new disease-specific self-concept. We hypothesized that (i) negative cancer-stereotypes invoke distancing, which inhibits the adoption of a disease-specific self-concept and (ii) patient characteristics, disease and treatment factors, and cancer-related stressors moderate the phenomenon. Methods Head and neck cancer outpatients (N = 522) completed a semantic-differential measure of disease-specific self-concept (perceived similarity to the ‘cancer patient’) and other self-report measures in structured interviews. Negative cancer-stereotypes were represented by the number of semantic-differential dimensions (0–3) along which respondents evaluated the stereotypic ‘cancer patient’ negatively (i.e., negative valence). We tested the two-way interactions between negative valence and hypothesized moderator variables. Results We observed significant negative valence × moderator interactions for the following: (i) patient characteristics (education, employment, social networks); (ii) disease and treatment factors (cancer-symptom burden); and (iii) cancer-related stressors (uncertainty, lack of information, and existential threats). Negative cancer stereotypes were consistently associated with distancing of self from the stereotypic ‘cancer patient,’ but the effect varied across moderator variables. All significant moderators (except employment and social networks) were associated with increasing perceived similarity to the ‘cancer patient’ when respondents maintained negative stereotypes; perceived similarity decreased when people were employed or had extensive social networks. Moderator effects were less pronounced when respondents did not endorse negative cancer stereotypes. Discussion When they hold negative stereotypes, people with HNCa distance themselves from a ‘cancer patient’ identity to preserve self-esteem or social status, but exposure to cancer-related stressors and adaptive demands may attenuate these effects. Copyright © 2012 John Wiley & Sons, Ltd.

Objectives/Hypothesis: The objective of this study was to analyze the patterns of failure and to determine clinical and pathologic factors predictive of recurrence and survival of patients treated for squamous cell carcinoma of the buccal mucosa at Princess Margaret Hospital. Study Design: Retrospective chart review. Methods: A retrospective chart review of patients treated for buccal carcinoma between 1994 and 2004 was performed. Seventy patients with newly diagnosed and previously untreated squamous cell carcinoma of the buccal mucosa were included. Demographic, clinical, and pathological parameters were identified and correlated with outcomes. Results: The patient cohort consisted of 33 males and 37 females. Most patients presented with early-stage local disease (T1-T2). Surgery was the primary treatment in 61 patients. Twenty-three patients were treated with postoperative radiotherapy. Median follow-up was 3.3 years. The 5-year local, regional, and overall control rates were 57.5%, 83.5%, and 50%, respectively. The 5-year overall survival rate was 69%. The 5-year disease-specific and recurrence-free survival rates were 76.4% and 46%, respectively. The only significant predictors of survival were the nodal status and extranodal extension. Conclusions: Carcinoma of the buccal mucosa is an aggressive disease, characterized by a high rate of locoregional failure. Transoral wide excision is an adequate treatment for early-stage lesions; however, a combined approach and an elective neck dissection should be considered in advanced lesions.

Background The purpose of this study was to analyze the outcomes and treatment in patients with squamous cell carcinoma (SCC) of the oral tongue, as well as validate previously reported predictors of survival. Methods We retrospectively reviewed 259 patients treated with curative intent between 1994 and 2004. Kaplan–Meier estimates, log-rank test, and Cox regression models were used for statistical analysis. Results Two hundred fifty-nine patients were managed with surgery; 67 patients (25%) received adjuvant radiotherapy. Mean follow-up was 60 months. The 5-year local and regional control rates were 78% and 69.4%, respectively. The 5-year overall, disease-specific, and recurrence-free survival rates were 69%, 70.9%, and 53%, respectively. The only significant predictor of both overall survival (OS) and disease-free survival (DFS) on multivariable analysis was pathologic N classification. Conclusion Treatment of early tongue SCC effectively achieves local control and DFS. Nodal disease remains to be 1 of the most important prognostic factors in terms of recurrence and survival. © 2012 Wiley Periodicals, Inc. Head Neck, 2013

Background Head and neck cancer (HNCa) introduces numerous stressors. We developed the Cancer-Related Stressors Checklist (CRSC), which documents exposure to seven categories of common stressors and emotional distress. We surveyed HNCa survivors and examined associations among exposure to cancer-related stressors, illness intrusiveness (i.e., cancer-induced interference with lifestyles, activities, and interests), and distress. We also investigated whether reported exposure rates differ between self-administered and interviewer-administered measures. Methods Respondents included HNCa survivors, stratified by sex, who participated in one of two clinical studies (N1 = 162; N2 = 408) examining the psychosocial impact of illness intrusiveness. All completed the CRSC, the Center for Epidemiologic Studies Depression Scale, and the Illness Intrusiveness Ratings Scale. Study 1 respondents self-administered the instruments; an interviewer administered them in Study 2. We gathered clinical data by self-report and from medical records. Results High inter-rater reliability corroborated the 8-subscale structure of the CRSC (Krippendorff alpha = .92). Cancer-related stressor exposures differed significantly across categories (interpersonal stressors were most common). Controlling for empirically identified covariates and distress, exposure to each cancer-related stressor correlated significantly and uniquely with illness intrusiveness. All stressor categories correlated significantly with distress, but coefficients were low to moderate, substantiating incremental validity. Respondents reported fewer exposures when materials were self-administered as compared with interviewer-administered, but reported distress levels did not differ by mode of administration. Conclusions Cancer-related stressors are common and burdensome in HNCa and, therefore, merit clinical attention. Identifying specific stressors will allow more targeted and effective interventions to alleviate and prevent distress. Copyright © 2012 John Wiley & Sons, Ltd.

Hyalinizing clear cell carcinoma (HCCC) is a rare, low-grade salivary gland tumor with clear cells and hyalinized stroma. Prognosis of HCCC is excellent with few cases metastasizing to the lymph nodes and lung. We present a case of a 61-year-old male with recurrent HCCC on the base of tongue. Histologic examination revealed sheets of clear and eosinophilic cells with a background of a myxoid-like matrix. In addition, large, bizarre malignant cells, focal necrosis, and atypical mitotic figures were identified. By immunohistochemistry, the clear cells were positive for CK18, EMA and vimentin, focally positive for CK7 and CD10, but negative for p63, HMWK, SMA and calponin. A metastatic renal cell carcinoma was considered a possibility but the tumor was called “poorly-differentiated carcinoma, NOS”. The patient underwent primary radiotherapy. A recurrence was identified at 10 months follow-up. A biopsy of the recurrent tumor showed clear cell differentiation and a predominant cribriform pattern with focal cords of eosinophilic cells invading the stroma. In contrast to the original tumor, no mitotic figures, atypia or necrosis were identified. The combination of lower grade and different architectural patterns appeared markedly different than the previous biopsy and the immunohistochemical pattern was also different. The recurrent tumor showed diffuse positivity for p63 and HMWK. It was negative for CD10, vimentin, SMA and calponin. Fluorescence in situ hybridization (FISH) analysis was positive for rearrangement of the EWSR1 gene in both samples, confirming that this represented a recurrence of the same tumor. It also confirmed that the initial tumor was a HCCC with high-grade transformation.

Background The purpose of this study was to discuss the appropriate management options for parathyroid carcinomas, which is still a subject of controversy. Methods A retrospective chart review of 16 patients with parathyroid carcinoma was undertaken to determine the clinical outcome. Results All patients were initially treated with surgery, and 11 patients received adjuvant radiotherapy. The 5- and 10-year disease-specific survival rates were 100% and 80%, respectively; the 5- and 10-year disease-free survival rates were 69% and 43%, respectively. The 5- and 10-year locoregional control rates were 69% and 52%, respectively; the 5- and 10-year distant control rates were 89% and 74%, respectively. In this cohort, none of the clinicopathologic parameters could be defined as a predictor. Conclusion In patients with parathyroid carcinoma, definition of prognostic factors and the role of adjuvant radiation treatment has still to be elucidated. Nevertheless, angioinvasion and positive resection margins are critical factors regarding disease-free survival in patients with parathyroid carcinomas. © 2012 Wiley Periodicals, Inc. Head Neck, 2013

Background. Scapular tip osteomyogenous free flaps have been described for complex palate reconstruction. Minimal osteotomies are needed because of the similar shapes of the scapula and palate. We compared the bony morphology of the palate and scapular tip to determine the suitability of the scapular tip for palate reconstruction. Methods. We analyzed facial and chest CT images of 10 patients, comparing the morphology of 3 simulated palate resection specimens (total palate, subtotal palate, and hemipalate) with corresponding simulated scapular tip bone flaps from the same patient. Results. Conformance distances between palates and simulated flaps were small, indicating close shape similarity. Median conformance distances were 3.44 mm for hemipalatectomy, 3.56 mm for subtotal palatectomy, and 3.71 mm for total palatectomy. Six outlier observations accrued from 2 patients. Conclusions. Based on this analysis, there is close similarity between the shapes of the palate and the scapular tip. This similarity supports use of the scapular tip flap for selected palate defects. V C 2012 Wiley Periodicals, Inc. Head Neck 34: 1377-1382, 2012

Hypothesis: Cone-beam computed tomography (CT) is proving useful in various operative settings. We hypothesize that it has great potential as an intraoperative assessment tool for ossicular prosthesis positioning. Background: Results from prosthetic ossiculoplasty are frequently disappointing. Undetected intraoperative displacement of the prosthesis may be caused, and obscured, by placement of an overlying cartilage graft. Methods: A cadaveric right temporal bone was prepared with a tympanomeatal flap, and an extended posterior tympanotomy through a cortical mastoidectomy. Each of 3 commercially available prostheses was positioned in 3 different locations: 1) optimal, 2) grossly displaced, and 3) marginally displaced. The intended prosthetic positions were confirmed by endoscopy before and after cone-beam CT image acquisition. The primary outcome measure was the position of the prosthesis in relation to the stapes and tympanic membrane, as assessed by 5 expert reviewers blinded to the study. Secondary outcome measures included optimal dosing for adequate image resolution and radiographic scatter associated with different prosthetic materials. Results: Cone-beam CT accurately demonstrated the position of ossicular reconstruction prostheses with respect to the stapes and tympanic membrane. Prosthesis displacement, whether minimally or marked, was also accurately demonstrated. Interobserver agreement among the 5 reviewers, measured using a Fleiss κ statistic, ranged from 0.4 to 0.8 (fair to substantial agreement depending on type and position of the prosthesis). Conclusion: Cone-beam CT is a useful tool for determining the position of ossicular reconstruction prostheses in situ. We suggest it has potential for intraoperative assessment, to check positioning after the prosthesis has been covered with a cartilage graft and tympanomeatal flap.

Background Lung and head and neck cancers are widely believed to produce psychologically destructive stigma because they are linked to avoidable risk-producing behaviors and are highly visible, but little research has tested these ideas. We examined cancer-related stigma, its determinants, and its psychosocial impact in lung (n = 107) and head and neck cancer survivors (n = 99) ≤3 years post-diagnosis. We investigated cancer site, self-blame, disfigurement, and sex as determinants, benefit finding as a moderator, and illness intrusiveness as a mediator of the relation between stigma and its psychosocial impact. Methods Prospective participants received questionnaire packages 2 weeks before scheduled follow-up appointments. They self-administered widely used measures of subjective well-being, distress, stigma, self-blame, disfigurement, illness intrusiveness, and post-traumatic growth. Results As hypothesized, stigma correlated significantly and uniquely with negative psychosocial impact, but contrary to common beliefs, reported stigma was comparatively low. Reported stigma was higher in (i) men than women, (ii) lung as compared with head and neck cancer, and (iii) people who were highly disfigured by cancer and/or its treatment. Benefit finding buffered stigma's deleterious effects, and illness intrusiveness was a partial mediator of its psychosocial impact. Conclusions Stigma exerts a powerful, deleterious psychosocial impact in lung and head and neck cancers, but is less common than believed. Patients should be encouraged to remain involved in valued activities and roles and to use benefit finding to limit its negative effects. Copyright © 2011 John Wiley & Sons, Ltd.

Objectives/Hypothesis: Our group has developed an augmented image guidance system that incorporates intraoperative cone-beam computed tomography (CBCT), virtual or augmented displays, and image registration. We assessed the potential benefits of augmented endoscopy derived from this system for use during skull base navigation. Specifically, we wished to evaluate target localization accuracy and the effect on task workload and confidence. Study Design: Prospective, sequential, paired preclinical trial. Methods: A single cadaver head underwent computed tomography, and critical structures were contoured. The specimen was reimaged after endoscopic dissection and deformable registration allowed contours to be displayed on postablation CBCT imaging. A real-time virtual view including anatomical contours was provided parallel to the real endoscopic image. Twelve subjects were asked to endoscopically localize seven skull base landmarks in a conventional manner. The same exercise was then performed with augmented endoscopy. Precise three-dimensional (3D) localization was recorded with a tracked probe. The NASA task load index was completed after each exercise. A short questionnaire was also administered. Results: The real-time augmented image guidance system aided localization in 85% of responses and increased confidence in 97%. There was a significant reduction in mental demand, effort, and frustration when the technology was employed, with an increase in perceived performance (P < .05). Three dimensional navigational precision was improved for all landmarks. Conclusions: Real-time augmented image-guided surgery increases accuracy and confidence in trainee surgeons and decreases task workload during skull base navigation. This technology shows great promise in assisting in skull base surgery even for experienced surgeons.

Both maspin and glutathione S-transferase pi (GSTp) are implicated as tumor suppressors and downregulated in human prostate cancer. It is well established that GSTp downregulation is through DNA methylation–based silencing. We report here that maspin expression in prostate cancer cell line DU145 reversed GSTp DNA methylation, as measured by methylation- specific PCR, MethyLight assay, and bisulfite sequencing. The effect of maspin on GSTp expression was similar to that of the combination of a synthetic histone deacetylase (HDAC) inhibitor and DNA methylation inhibitor 5-aza-2′-deoxycytidine. Maspin expression also led to an increased level of acetylated histone 3, decreased level of methyl transferase, and methyl-CpG–binding domain proteins at the site of demethylated GSTp promoter DNA. Earlier, we have shown that maspin inhibits HDAC1. In PC3 cells, where both maspin and GSTp are expressed at a reduced level, maspin knockdown led to a significant reduction in GSTp expression, whereas dual knockdown of maspin and HDAC1 barely increased the level of GSTp expression. Thus, HDAC1 may play an essential role in cellular response to maspin-mediated GSTp desilencing. Maspin has been shown to increase tumor cell sensitivity to drug-induced apoptosis. Interestingly, GSTp reexpression in the absence of maspin expression perturbation blocked the phosphorylation of histone 2A.X, the induction of hypoxia-induced factor 1α (HIF-1α), and cell death of LNCaP cells under oxidative stress. Because DNA hypermethylation–based silencing may couple with and depend on histone deacetylation, our study suggests that endogenous HDAC inhibition by maspin may prevent pathologic gene silencing in prostate tumor progression. Mol Cancer Res; 9(6); 733–45. ©2011 AACR.

Purpose: A method of intensity-based deformable registration of CT and cone-beam CT CBCT images is described, in which intensity correction occurs simultaneously within the iterative registration process. The method preserves the speed and simplicity of the popular Demons algorithm while providing robustness and accuracy in the presence of large mismatch between CT and CBCT voxel values “intensity”. Methods: A variant of the Demons algorithm was developed in which an estimate of the relationship between CT and CBCT intensity values for specific materials in the image is computed at each iteration based on the set of currently overlapping voxels. This tissue-specific intensity correction is then used to estimate the registration output for that iteration and the process is repeated. The robustness of the method was tested in CBCT images of a cadaveric head exhibiting a broad range of simulated intensity variations associated with x-ray scatter, object truncation, and/or errors in the reconstruction algorithm. The accuracy of CT-CBCT registration was also measured in six real cases, exhibiting deformations ranging from simple to complex during surgery or radiotherapy guided by a CBCT-capable C-arm or linear accelerator, respectively. Results: The iterative intensity matching approach was robust against all levels of intensity variation examined, including spatially varying errors in voxel value of a factor of 2 or more, as can be encountered in cases of high x-ray scatter. Registration accuracy without intensity matching degraded severely with increasing magnitude of intensity error and introduced image distortion. A single histogram match performed prior to registration alleviated some of these effects but was also prone to image distortion and was quantifiably less robust and accurate than the iterative approach. Within the six case registration accuracy study, iterative intensity matching Demons reduced mean TRE to 2.5 2.8 mm compared to 3.5 3.0 mm with rigid registration. Conclusions: A method was developed to iteratively correct CT-CBCT intensity disparity during Demons registration, enabling fast, intensity-based registration in CBCT-guided procedures such as surgery and radiotherapy, in which CBCT voxel values may be inaccurate. Accurate CT-CBCT registration in turn facilitates registration of multimodality preoperative image and planning data to intraoperative CBCT by way of the preoperative CT, thereby linking the intraoperative frame of reference to a wealth of preoperative information that could improve interventional guidance. © 2011 American Association of Physicists in Medicine. DOI: 10.1118/1.3555037

Jonathan C. Irish, President of the American Head and Neck Society (AHNS) for 2017 to 2018, in his Presidential Address highlights the challenges and opportunities of the Society's reorganization in the rapidly changing field of head and neck surgery and details how AHNS members can harness this change to direct the future of their field. Specifically, AHNS members' vital roles as technically proficient surgeons, surgical team members, researchers, teachers, and leaders within an evolving medical system are explored.

Due to recent scientific advances, there is a growing demand for new indices with high fidelity to eliminate errors associated with certain index combinations and sequencing chemistries. These errors are due to insufficient edit distances (the minimum number of changes required to transform one index sequence to the other) between index sequences or index hopping. Recent publications have highlighted how sequencing reads are misassigned due to "index hopping" on Illumina patterned flow cells, such as the recently launched Illumina Novaseq which can generate billions of reads (>100 exomes) in a single run. This misassignment canlead to false positives in ultra-sensitive assays where low frequency variants or nucleic acid species are monitored. We have observed misassignment due to insufficient edit distance among Illumina TruSeq HT i7 indices at a frequency up to 1.5%. Therefore, we developed 968nt i7 indices that can be paired with the existing TruSeq HT i5 indices to achieve 768 high throughput dual combinations, which were validated using a novel method on both Illumina's 2- and 4-channel technologies as both single and dual indices. This method involved thepreparation of 96 libraries with unique, non-overlapping inserts to facilitate tracking of index misassignment. This allowed us to assess not only which index has misassigned library molecules, but also pinpoint the origin and rate of misassignment within a single run. With our 96 i7 indices, misassignment was observed at rates Citation Format: Jonathan C. Irish, Jordan RoseFigura, Sukhinder K. Sandhu, Bita Carrion, Laurie Kurihara, Vladimir Makarov. Improved sample indexing for high fidelity demultiplexing to increase confidence in low frequency variant calling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1430.

The goal of this study was to quantitatively describe aspects of coronal tongue movement in different anatomical regions of the tongue. Four normal speakers and a speaker with partial glossectomy read four repetitions of a metronome-paced poem. Their tongue movement was recorded in four coronal planes using two-dimensional B-mode ultrasound imaging. Quantitative indicators of tongue function (total distance travelled and concavity) were calculated. In all participants, it was observed that the centre of the tongue travelled greater distances than the lateral free margins. The tongues of the female speakers F1 and F2 travelled greater distances than those of the males M1 and M2. The greatest distances travelled were observed in the speaker with partial glossectomy G. In three of the participants, the greatest cumulative distances were recorded for the anterior tongue (F1, M1, and G) and in the other two (F2 and M2) in the posterior tongue. The concavity measure illustrated that the posterior tongue showed consistent grooving during connected speech, in all speakers. Flatness or convexity of the tongue was mainly observed in the anterior tongue. The study provides the first quantitative description of coronal tongue movement in a complex speech passage. Future research will have to further examine the effects of gender and orofacial morphology on the coronal shape and movement of the tongue.

The objective of this study was to assess the accuracy and reproducibility of a novel cone-beam computed tomography (CBCT)-guided navigation system designed for osteotomies with joint-sparing bone cuts.Eighteen surgeons participated in this study. First, 3 expert tumor surgeons resected bone tumors in 3 Sawbones tumor models identical to actual patient scenarios. They first performed these osteotomies without navigation and then performed them using a navigation system and 3-dimensional (3D) planning tools based on CBCT imaging. The 2 sets of measurements were compared using image-based measurements from post-resection CBCT. Next, 15 residents, fellows, and orthopaedic staff surgeons were instructed on the use of the system, and their navigated resections were compared with navigated resections performed by the 3 expert tumor surgeons.One hundred and twenty-six navigated cuts done by the orthopaedic oncologists were compared with 126 non-navigated cuts by the same surgeons. The cuts violated the tumor in 22% (6) of the 27 non-navigated resections compared with none of the 27 navigated resections. The navigated cuts were significantly more accurate in terms of entry point, pitch, and roll (p0.001). The variation among the 3 surgeons when they used navigation was0.6 mm for the entry cut and, on average, 1.5° for pitch and roll. All 18 surgeons then completed a total of 144 navigated cuts. The level of experience did not result in a significant difference among groups with regard to cut accuracy. Two cuts went into the tumor. The mean distance from the planned bone cuts to the actual entry points into bone was 1.5 mm (standard deviation [SD] = 1.4 mm) for all users. The mean difference in pitch and roll between the planned and actual cuts was 3.5° (SD = 2.8°) and 3.7° (SD = 3.2°) for all users.Even in expert hands, navigated cuts were significantly more accurate than non-navigated cuts. When the osteotomies were aided by navigation, their accuracy did not differ according to the level of professional experience. CBCT-based metrics enable intraoperative assessments of cut accuracy and reconstruction planning.CBCT-guided navigated osteotomies can improve accuracy regardless of surgeon experience and decrease the variability among different surgeons.

Background The objective of the study was to evaluate the prognostic and therapeutic implications of an initial positive frozen section margin that was revised until negative (microscopic tumor cut-through), and to analyze the influence of microscopic margin status on oral carcinoma control. Methods The approach in our investigation was through a retrospective review of patients treated with primary surgery, with frozen section margin control in oral carcinoma. Inclusion criteria included availability of frozen and permanent section histology reports of resection margins and negative final resection margins. Results Of 547 patients studied, 175 received adjuvant radiation. Local and regional control and disease-specific survival rates were 81.6%, 78.4%, and 76.3%, respectively. Tumor cut-through and pathologic nodal (pN) stage had an independently adverse effect on local control. Tumor cut-through adversely affected cancer control and survival, but this effect diminished significantly in the absence of regional disease. Conclusions Microscopic tumor cut-through revised to negative margins is a powerful prognosticator that is observed only when regional disease is also present. The value of adjuvant therapeutic regimens is questionable in patients with microscopic tumor cut-through, revised to negative margins, and with no regional disease. © 2010 Wiley Periodicals, Inc. Head Neck, 2010

Background. We aimed to determine predictors of morbidity in patients undergoing microvascular free flap reconstruction of the head and neck. Methods. We prospectively evaluated 796 cases between 1999 and 2007 using univariate and multivariate analysis to determine predictors of morbidity and prolonged hospital stay. Results. Two hundred thirty-nine patients (30%) developed major complications. Age, body mass index (BMI), American Society of Anesthesiology (ASA) score, Kaplan Feinstein comorbidity index (KFI) score, preoperative hemoglobin, and tracheostomy were independent predictors of major complica- tion. Predictors of prolonged hospital stay included age, recent weight loss, alcohol excess, ASA, KFI, preoperative hemoglo- bin, mucosal surgery, anesthesia duration, and crystalloid replacement volume. Conclusion. Several variables are associated with an increased risk of development of major complications following free flap recon- struction of the head and neck. Although many of these variables are irreversible, they aid risk stratification of patients undergoing free flap reconstruction, and assist clinicians in making treatment decisions, consenting, and providing patients with realistic expectations regarding their perioperative course. V C 2010 Wiley Periodicals, Inc. Head Neck 32: 1345-1353, 2010

The expression of matrix metalloproteinases (MMPs) in epithelial-myoepithelial salivary gland carcinoma has not been studied previously.Immunohistochemistry for MMP-1, -7, -9, -13, Ki-67, and HER-2, as well as HER-2 gene amplification by silver enhanced in situ hybridization was performed in a series of 12 paraffin-embedded histopathologic samples of patients from Canada and Finland.A positive MMP-13 (p = .0022), higher MMP-13 (p = .0274), and higher MMP-9 (p = .0274) index (multiplication of staining intensity by percentage of the positive cells) predicted better overall survival. In disease-specific analysis, higher MMP-9 index (p = .0327) predicted better survival. A higher volume corrected index (VCI) of Ki-67 (p = .0339) predicted worse disease-specific survival. In 1 patient, HER-2 oncogene amplification was observed.MMPs and Ki-67 may have prognostic impact in epithelial-myoepithelial carcinoma.

Background. Significant morbidity is associated with management of anterior skull base neoplasms. The aim of this study was to evaluate the posttreatment patient's quality of life (QOL). Methods. A retrospective chart review identified 27 patients. QOL tools included the Functional Assessment of Cancer Therapy–Head & Neck, Centre for Epidemiologic Studies Depression Scale (CES-D), Atkinson Life Happiness Rating (ALHR), and Midface Dysfunction Scale (MDS). Results. Postoperative radiotherapy and chemotherapy was required in 16 and 2 patients, respectively. The median FACT, ALHR, and CES-D scores were 118 ± 21, 9 ± 2, and 17 ± 8, respectively. Smell and nasal crusting disturbance was reported by 69% and 61%, respectively. CES-D > 16 and patients with recurrent disease correlated with a lower Total-FACT score. Adjuvant radiotherapy correlated with a lower FACT-H&N score. Patient sex, marital-status, pathology, surgical technique, or complication rate did not correlate with worse QOL. Conclusion. Anterior skull base neoplasms survivors have an overall acceptable QOL. Most complaints relate to MDS. Recurrence, adjuvant radiotherapy, and MDS had lower QOL scores. © 2009 Wiley Periodicals, Inc. Head Neck, 2009

MicroRNAs (miRs) are non-coding RNA molecules involved in cancer initiation and progression. Deregulated miR expression has been implicated in cancer; however, there are no studies implicating an miR signature associated with progression in oral squamous cell carcinoma (OSCC). Although OSCC may develop from oral leukoplakia, clinical and histological assessments have limited prognostic value in predicting which leukoplakic lesions will progress. Our aim was to quantify miR expression changes in leukoplakia and same-site OSCC and to identify an miR signature associated with progression. We examined miR expression changes in 43 sequential progressive samples from 12 patients and four non-progressive leukoplakias from four different patients, using TaqMan Low Density Arrays. The findings were validated using quantitative RT-PCR in an independent cohort of 52 progressive dysplasias and OSCCs, and five non-progressive dysplasias. Global miR expression profiles distinguished progressive leukoplakia/OSCC from non-progressive leukoplakias/normal tissues. One hundred and nine miRs were highly expressed exclusively in progressive leukoplakia and invasive OSCC. miR-21, miR-181b and miR-345 expressions were consistently increased and associated with increases in lesion severity during progression. Over-expression of miR-21, miR-181b and miR-345 may play an important role in malignant transformation. Our study provides the first evidence of an miR signature potentially useful for identifying leukoplakias at risk of malignant transformation.

Purpose: The accuracy and convergence behavior of a variant of the Demons deformable registration algorithm were investigated for use in cone-beam CT (CBCT)-guided procedures of the head and neck. Online use of deformable registration for guidance of therapeutic procedures such as image-guided surgery or radiation therapy places trade-offs on accuracy and computational expense. This work describes a convergence criterion for Demons registration developed to balance these demands; the accuracy of a multiscale Demons implementation using this convergence criterion is quantified in CBCTimages of the head and neck. Methods: Using an open-source “symmetric” Demons registration algorithm, a convergence criterion based on the change in the deformation field between iterations was developed to advance among multiple levels of a multiscale image pyramid in a manner that optimized accuracy and computation time. The convergence criterion was optimized in cadaver studies involving CBCTimages acquired using a surgical C-arm prototype modified for 3D intraoperative imaging. CBCT-to-CBCT registration was performed and accuracy was quantified in terms of the normalized cross-correlation (NCC) and target registration error (TRE). The accuracy and robustness of the algorithm were then tested in clinical CBCTimages of ten patients undergoing radiation therapy of the head and neck. Results: The cadaver model allowed optimization of the convergence factor and initial measurements of registration accuracy: Demons registration exhibited TRE = ( 0.8 ± 0.3 ) mm and NCC = 0.99 in the cadaveric head compared to TRE = ( 2.6 ± 1.0 ) mm and NCC = 0.93 with rigid registration. Similarly for the patient data, Demons registration gave mean TRE = ( 1.6 ± 0.9 ) mm compared to rigid registration TRE = ( 3.6 ± 1.9 ) mm , suggesting registration accuracy at or near the voxel size of the patient images ( 1 × 1 × 2 mm 3 ) . The multiscale implementation based on optimal convergence criteria completed registration in 52 s for the cadaveric head and in an average time of 270 s for the larger FOV patient images. Conclusions: Appropriate selection of convergence and multiscale parameters in Demons registration was shown to reduce computational expense without sacrificing registration performance. For intraoperative CBCTimaging with deformable registration, the ability to perform accurate registration within the stringent time requirements of the operating environment could offer a useful clinical tool allowing integration of preoperative information while accurately reflecting changes in the patient anatomy. Similarly for CBCT-guided radiation therapy, fast accurate deformable registration could further augment high-precision treatment strategies.

The objective of this study is to report the long-term outcomes of salvage surgery following local and/or regional failure of tonsillar carcinoma treated with standard fractionation radiotherapy. All cases of carcinoma of the tonsil treated by radical radiotherapy at the Princess Margaret Hospital between January 1970 and December 1990 were reviewed retrospectively. Patients who underwent salvage surgery for local and/or regional recurrent squamous cell carcinoma of the tonsil following radiation therapy were included for analysis. 239 out of 640 patients with tonsillar carcinoma recurred post radiotherapy. 175 patients were deemed candidates for surgical salvage. At the time of the last follow-up, only 13 patients were alive and 162 patients had died. The majority of patients (n = 96, 59%) died with disease. The median time to death was approximately 1.3 years following salvage surgery. The 5-year overall survival rate was 23%. The 5-year cause-specific survival was 40%. The probability of death due to disease was higher than the probability of death due to other causes. Both N-classification and T-classification were found to be significant predictors of time to death. In conclusion, in spite of the fact that the patients in this study had been treated prior to the widespread introduction of altered fractionation and concurrent chemoradiation for advanced tonsil carcinoma, it demonstrates the poor prognosis of recurrent disease. Despite the poor prognosis, 20% of patients will be alive at 5 years and therefore salvage surgery should be considered when possible.

Background. The association between nodal ratio and survival has not been assessed in squamous cell carcino- mas of the head and neck. Methods. This is a population-based analysis, using the Surveillance, Epidemiology, and End-Results database, to determine whether nodal ratio impacts survival in patients with oral cavity squamous cell carcinoma. Results. Between 1988 and 2005, 2955 new diagnoses of N1 or N2 squamous cell carcinoma of the oral cavity were iden- tified. The mean nodal ratio was 16.9%. Nodal ratio was found to be strongly statistically associated with overall survival in both univariate and multivariate analyses. Patients could be stratified into low- (0% to 6%), moderate- (6% to 12.5%), and high-risk (>12.5%) groups based on nodal ratio. Conclusions. In patients with squamous cell carcinoma of the oral cavity, an increased nodal ratio is a strong predictor of decreased survival. Risk of death can be stratified based on nodal ratio. V C 2009 Wiley Periodicals, Inc. Head Neck 31: 1129-1136, 2009

Background. This cross-sectional study sought to determine patient quality of life and function after prosthetic rehabilitation for maxillary and palate defects following cancer resection. Methods. Sixty-nine patients were identified, 42 participated in the study (61%). The Obturator Functioning Scale (OFS) and 4 general quality of life measures (Mental Health Inventory (MHI), Impact of Events Scale (IES), Illness Intrusiveness Rat- ings Scale (IIRS), and Centre for Epidemiologic Studies Depres- sion Scale (CES-D)) were correlated with clinical parameters. Results. Leakage when swallowing foods was the most fre- quently reported problem with the obturator (29%). Positive correlation was noted between the OFS and both the IES sub- scales (p < .01) and CES-D (p < .001). Difficulty with speech and eating was associated with increased avoidance of social situations. The surgical approach had a significant effect on the OFS, IES, and MHI subscales (p < .01). Conclusion. These results support the findings that good ob- turator function is associated with a better quality of life. V

Background. In patients with extensive soft tissue fibrosis requiring circumferential pharyngeal reconstruction fol- lowing definitive radiotherapy and/or chemotherapy, we take advantage of abundant omental progenitor factors in the tubed gastro-omental free flap. This study reviews our experience with this flap. Methods. Review of 11 patients (median follow-up, 2.8 years) undergoing total pharyngolaryngectomy following organ preservation protocols for recurrent squamous cell carcinoma (n ¼ 9) and stricture (n ¼ 2). Results. Operative morbidity and mortality rates were 54% and 9%, respectively. One patient died following carotid rup- ture. Complications included: chyle leak (18%), pharyngocuta- neous fistula (9%), and late stricture (27%). Ten patients (91%) achieved oral diet, and all 7 patients (100%) considered suita- ble for tracheoesophageal speech rehabilitation achieved func- tional speech. Seven patients remain alive without disease at a median of 41 months following surgery. Conclusions. The gastro-omental flap provides a viable option in high-risk patients undergoing circumferential pharyn- geal reconstruction. V C 2009 Wiley Periodicals, Inc. Head Neck 31: 655-663, 2009

Intraoperative imaging offers a means to account for morphological changes occurring during the procedure and resolve geometric uncertainties via integration with a surgical navigation system. Such integration requires registration of the image and world reference frames, conventionally a time consuming, error-prone manual process. This work presents a method of automatic image-to-world registration of intraoperative cone-beam computed tomography (CBCT) and an optical tracking system. Multimodality (MM) markers consisting of an infrared (IR) reflective sphere with a 2 mm tungsten sphere (BB) placed precisely at the center were designed to permit automatic detection in both the image and tracking (world) reference frames. Image localization is performed by intensity thresholding and pattern matching directly in 2D projections acquired in each CBCT scan, with 3D image coordinates computed using backprojection and accounting for C-arm geometric calibration. The IR tracking system localized MM markers in the world reference frame, and the image-to-world registration was computed by rigid point matching of image and tracker point sets. The accuracy and reproducibility of the automatic registration technique were compared to conventional (manual) registration using a variety of marker configurations suitable to neurosurgery (markers fixed to cranium) and head and neck surgery (markers suspended on a subcranial frame). The automatic technique exhibited subvoxel marker localization accuracy (< 0.8 mm) for all marker configurations. The fiducial registration error of the automatic technique was (0.35 +/-0.01) mm, compared to (0.64 +/- 0.07 mm) for the manual technique, indicating improved accuracy and reproducibility. The target registration error (TRE) averaged over all configurations was 1.14 mm for the automatic technique, compared to 1.29 mm for the manual in accuracy, although the difference was not statistically significant (p = 0.3). A statistically significant improvement in precision was observed-specifically, the standard deviation in TRE was 0.2 mm for the automatic technique versus 0.34 mm for the manual technique (p = 0.001). The projection-based automatic registration technique demonstrates accuracy and reproducibility equivalent or superior to the conventional manual technique for both neurosurgical and head and neck marker configurations. Use of this method with C-arm CBCT eliminates the burden of manual registration on surgical workflow by providing automatic registration of surgical tracking in 3D images within approximately 20 s of acquisition, with registration automatically updated with each CBCT scan. The automatic registration method is undergoing integration in ongoing clinical trials of intraoperative CBCT-guided head and neck surgery.

Objectives: Knowledge of prognostic factors is essential for patient care and research. The objectives of this study were to demonstrate that prognostic factors and their impact can vary depending on study design and to examine the relationships between select prognostic factors. Methods: Retrospective population-based study of patients with cancer of the hypopharynx in Ontario, Canada, from January 1990 to December 1999 identifying and comparing prognostic factors for different survival outcomes and different subpopulations using Kaplan Meier analysis and Cox Proportional Hazards models. Results: The impact of prognostic factors varies within subgroups of a study population, varies with treatment decisions, and varies with the outcome of interest. Conclusions: N and T category were the dominant prognostic factors in hypopharyngeal cancer. Performance status was an independent predictor of survival. Laryngoscope, 2009

Objectives: to describe three-dimension (3-D) tomosynthesis and cone beam computed tomography (CBCT) as an intraoperative imaging system to guide both sinus and skull-base surgery in a cadaveric model. Methods: five cadaveric heads underwent baseline CBCT imaging. Surgical targets were resected from each head (uncinectomy, ethmoidectomy, medial maxillectomy, pituitary gland resection, and clivus ablation). Intraoperative imaging was provided so that for a given task, the acquisition arc (theta(tot) = 20 degrees, 45 degrees, 60 degrees, 90 degrees, 178 degrees) of the tomosynthesis scan was fixed. Different heads and tasks were allocated different acquisition angles. There was no limit to the number of scans that could be requested. Residual target was highlighted with 3-D visualization software. Result: the larger the image acquisition angle, the better the image. Only CBCT (theta(tot) approximately 178 degrees) provided nearly isotropic 3-D spatial resolution and soft-tissue visibility in all three views. The volume of residual tissue remaining and the volume of adjacent-normal tissue that was resected were calculated as a function of tomosynthesis angle. For the easier surgical tasks (uncinectomy, ethmoidectomy) the residual tissue was not related to the tomosynthesis angle. However, for the difficult ablative tasks, the image quality became more important and tomosynthesis angle was related to the residual tissue. Conclusions: we describe an intraoperative imaging platform that can deliver near-real-time images of the target and related structures with low radiation dose. Tomosynthesis scanning angles higher than 60 degrees provided quantifiable benefits to the surgeon and facilitated total target ablation while helping to spare surrounding structures.

Background. A previous study at our institution noted that only 15% of newly diagnosed patients with oral cancer could identify smoking or alcohol abuse as major risk factors for the development of their cancer. The objective of this study was to determine the effectiveness of a simple educational intervention in 189 consecutively identified patients with head and neck malignancy. Methods. Patients were interviewed prior to and immediately following reading a written educational pamphlet. The patients were then interviewed 5 weeks later to determine longer-term recall. Recall success was correlated to patient demographic parameters including level of education, occupation, sex, age, and place of residence. Results. Immediate recall success increased, on average, 27% from preintervention knowledge, with the largest increase for the risk factor of alcohol abuse. Five-week postintervention recall success decreased on average 10.5% for all risk factors with the largest decrease being seen for smokeless tobacco use (12%). The immediate and 5-week recall success increases were both statistically significant when compared to the preintervention recall success (p < .05). Patient education level had the greatest impact on recall success at all time points (ANOVA, p < .001). Long-term recall for patients over the age of 60 was also statistically poorer. Conclusions. An educational intervention can have significant impact on patient knowledge of cancer risk. More effective educational interventions for poorly educated patients and the elderly may have to be devised to increase intervention success. Whether this knowledge translates into behavior change still needs to be studied. © 2008 Wiley Periodicals, Inc. Head Neck, 2009

Purpose The role of primary radiotherapy (RT) for laryngeal verrucous carcinoma (LVC) is controversial because of concerns about anaplastic transformation, an increased incidence of metastases, and poorer local control after RT. To address these concerns, we report our experience. Methods and Materials All patients with pathologically diagnosed LVC treated with primary RT at our institution between 1961 and 2004 were reviewed. The local control, overall survival, and disease-specific survival rate were established. The outcome after salvage treatment and the incidence of metastases and anaplastic transformation were determined. Results Of 62 LVC patients with a minimal follow-up of 2 years, 20 local and 1 nodal recurrence were identified. Salvage surgery was undertaken in 18 of the 21 patients, and disease control was achieved in 17; the eighteenth patient died of a complication after surgery. Ultimate laryngeal preservation was achieved in 50 patients (81%), including 42 after initial RT and an additional 8 after salvage surgery. Distant failure and anaplastic transformation were not observed. Second cancers after RT were identified in 4 patients, only 1 of which was a head-and-neck cancer detected 11 years later. Of the 39 deceased patients, only 3 died of LVC. The local control, overall survival, and disease-specific survival rate at 5 years was 66% (95% confidence interval, 52–77%), 87% (95% confidence interval, 75–93%), and 97% (95% confidence interval, 87–99%), respectively. Conclusion The results of our study have shown that the initial control of LVC with RT is less reliable compared with reports from surgical series; however, local recurrence was almost always salvaged successfully, resulting in disease-specific survival rates equivalent to those of surgical series. Neither anaplastic transformation nor unusual metastasis development was observed in this series.

Background. Esthesioneuroblastoma is rare. The aim of the study was to review our experience and to evaluate the staging system and treatment that best correlates with the patient outcome. Methods. Thirty-nine patients were identified between 1972 and 2006. Results. At presentation 10% had cervical metastases. None had distant metastasis. Five were treated with surgery, 2 with chemotherapy, 1 with radiotherapy, and 30 with surgery and radiation. Local disease control was 82.6% at 5 years. Recur- rence was seen in 33% with local and regional disease recur- rence at 15% and 18%, respectively. The 5- and 10-year overall survival rates were 87.9% and 69.2%, respectively. Dulguerov classification correlated most closely to survival and recurrence. Conclusions. Dulguerov classification best correlates with the patient's outcome. A combined approach is the preferred treat- ment. It makes no difference whether radiotherapy is given pre or postsurgical resection. Recurrence can occur even 15 years after treatment. Therefore, long-term follow-up is essential. V C 2008

BACKGROUND. The authors have previously shown that overexpression of claudin 1 (CLDN1) is associated with advanced disease stage in oral squamous cell carcinomas (OSCCs). Their goal was to examine CLDN1 expression in a large series of primary OSCCs and to further investigate whether CLDN1 overexpression plays a role in invasion in OSCC. METHODS. CLDN1 gene expression levels were determined by quantitative real-time reverse transcription polymerase chain reaction (QRT-PCR) in 100 primary OSCCs. CLDN1 protein expression was examined by immunohistochemistry in 70 of 100 OSCCs. E-Cadherin protein levels were also assessed in 58 OSCCs. The authors performed a transwell Matrigel invasion assay for assessment of the invasive potential of CLDN1 overexpressing oral carcinoma cells. Western blotting and QRT-PCR were used to assess CLDN1 expression in transfected cells and controls. RESULTS. CLDN1 mRNA was increased (median = 18.5) in 79 of 100 OSCCs, compared with normal oral mucosa (expression = 1.0). CLDN1 overexpression was associated with angiolymphatic (P = .037) and perineural invasion (P = .051). CLDN1 was highly expressed in 48 of 70 (68%) OSCCs. E-Cadherin was lost or underexpressed in 49 of 58 (84%) OSCCs. The invasion assay showed that cells overexpressing CLDN1 have increased invasive potential, whereas small interfering RNA–mediated depletion of CLDN1 decreased the invasive potential of cells. CONCLUSIONS. CLDN1 overexpression is associated with angiolymphatic and perineural invasion, consistent with aggressive tumor behavior. Overexpression of CLDN1 protein is associated with increased invasiveness of oral carcinoma cells. Cancer 2008. © 2008 American Cancer Society.

A geometric calibration method that determines a complete description of source-detector geometry was adapted to a mobile C-arm for cone-beam computed tomography (CBCT). The non-iterative calibration algorithm calculates a unique solution for the positions of the source (X(s), Y(s), Z(s)), detector (X(d), Y(d), Z(d)), piercing point (U(o), V(o)), and detector rotation angles (phi, theta, eta) based on projections of a phantom consisting of two plane-parallel circles of ball bearings encased in a cylindrical acrylic tube. The prototype C-arm system was based on a Siemens PowerMobil modified to provide flat-panel CBCT for image-guided interventions. The magnitude of geometric nonidealities in the source-detector orbit was measured, and the short-term (approximately 4 h) and long-term (approximately 6 months) reproducibility of the calibration was evaluated. The C-arm exhibits large geometric nonidealities due to mechanical flex, with maximum departures from the average semicircular orbit of deltaU(o) = 15.8 mm and deltaV(o) = 9.8 mm (for the piercing point), deltaX and deltaY = 6-8 mm and deltaZ = 1 mm (for the source and detector), and deltaphi approximately 2.9 degrees, deltatheta approximately 1.9 degrees, and delta eta approximately 0.8 degrees (for the detector tilt/rotation). Despite such significant departures from a semicircular orbit, these system parameters were found to be reproducible, and therefore correctable by geometric calibration. Short-term reproducibility was < 0.16 mm (subpixel) for the piercing point coordinates, < 0.25 mm for the source-detector X and Y, < 0.035 mm for the source-detector Z, and < 0.02 degrees for the detector angles. Long-term reproducibility was similarly high, demonstrated by image quality and spatial resolution measurements over a period of 6 months. For example, the full-width at half-maximum (FWHM) in axial images of a thin steel wire increased slightly as a function of the time (delta) between calibration and image acquisition: FWHM=0.62, 0.63, 0.66, 0.71, and 0.72 mm at delta = 0 s, 1 h, 1 day, 1 month, and 6 months, respectively. For ongoing clinical trials in CBCT-guided surgery at our institution, geometric calibration is conducted monthly to provide sufficient three-dimensional (3D) image quality while managing time and workflow considerations of the calibration and quality assurance process. The sensitivity of 3D image quality to each of the system parameters was investigated, as was the tolerance to systematic and random errors in the geometric parameters, showing the most sensitive parameters to be the piercing point coordinates (U(o), V(o)) and in-plane positions of the source (X(s), Y(s)) and detector (X(d), Y(d)). Errors in the out-of-plane position of the source (Z(s)) and detector (Z(d)) and the detector angles (phi, theta, eta) were shown to have subtler effects on 3D image quality.

Background Laryngeal adenoid cystic carcinoma (ACC) is a rare disease. We reviewed our experience at the Princess Margaret Hospital (PMH) with its treatment. Methods This is a retrospective chart review of 15 cases treated at PMH between 1963 and 2005. Results The mean age was 48.6 years. There was no sex predilection. The subglottis was the most common subsite involved. Only 2 patients had regional metastasis. Local or regional recurrence was noted in 5 patients (33.3%). The distant metastasis rate was 66.7% and involved the lungs. The median follow-up time was 6.9 years. The 5- and 10-year overall and disease-specific survival rates were 64% and 46%, and 69% and 49%, respectively. Conclusion Laryngeal ACC is a rare disease with a high rate of distant recurrence. Its management should emphasize maximizing local and regional disease control by surgery followed by radiotherapy with distant disease failure eventually dictating survival. © 2008 Wiley Periodicals, Inc. Head Neck, 2008

// Stephen T. Guest 1 , Zachary R. Kratche 1 , Jonathan C. Irish 1 , Robert C. Wilson 1 , Ramsi Haddad 1 , Joe W. Gray 3, 4 , Elizabeth Garrett-Mayer 2 , Stephen P. Ethier 1 1 Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA 2 Department of Public Health Science, Medical University of South Carolina, Charleston, South Carolina, USA 3 Department of Biomedical Engineering, Oregon Health and Sciences University, Portland, Oregon, USA 4 Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon, USA Correspondence to: Stephen T. Guest, email: guests@musc.edu Keywords: breast cancer, functional genomics, BCL2L1, FGFR, AKT Received: January 28, 2016 Accepted: April 10, 2016 Published: May 02, 2016 ABSTRACT A critical first step in the personalized approach to cancer treatment is the identification of activated oncogenes that drive each tumor. The Identification of driver oncogenes on a patient-by-patient basis is complicated by the complexity of the cancer genome and the fact that a particular genetic alteration may serve as a driver event only in a subset of tumors that harbor it. In this study, we set out to identify the complete set of functional oncogenes in a small panel of breast cancer cell lines. The cell lines in this panel were chosen because they each contain a known receptor tyrosine kinase (RTK) oncogene. To identify additional drivers, we integrated functional genetic screens with copy number and mutation analysis, and cancer genome knowledge databases. The resulting functional oncogene signatures were able to predict responsiveness of cell lines to targeted inhibitors. However, as single agents, these drugs had little effect on clonogenic potential. By contrast, treatment with drug combinations that targeted multiple oncogenes in the signatures, even at very low doses, resulted in the induction of apoptosis and striking synergistic effects on clonogenicity. In particular, targeting a driver oncogene that mediates AKT phosphorylation in combination with targeting the anti-apoptotic BCL2L1 protein had profound effects on cell viability. Importantly, because the synergistic induction of cell death was achieved using low levels of each individual drug, it suggests that a therapeutic strategy based on this approach could avoid the toxicities that have been associated with the combined use of multiple-targeted agents.

The image quality and localization accuracy for C-arm tomosynthesis and cone-beam computed tomography(CBCT) guidance of head and neck surgery were investigated. A continuum in image acquisition was explored, ranging from a single exposure (radiograph) to multiple projections acquired over a limited arc (tomosynthesis) to a full semicircular trajectory (CBCT). Experiments were performed using a prototype mobile C-arm modified to perform 3D image acquisition (a modified Siemens PowerMobil). The tradeoffs in image quality associated with the extent of the source-detector arc ( θ tot ) , the number of projection views, and the total imaging dose were evaluated in phantom and cadaver studies. Surgical localization performance was evaluated using three cadaver heads imaged as a function of θ tot . Six localization tasks were considered, ranging from high-contrast feature identification (e.g., tip of a K-wire pointer) to more challenging soft-tissue delineation (e.g., junction of the hard and soft palate). Five head and neck surgeons and one radiologist participated as observers. For each localization task, the 3D coordinates of landmarks pinpointed by each observer were analyzed as a function of θ tot . For all tomosynthesis angles, image quality was highest in the coronal plane, whereas sagittal and axial planes exhibited a substantial decrease in spatial resolution associated with out-of-plane blur and distortion. Tasks involving complex, lower-contrast features demonstrated steeper degradation with smaller tomosynthetic arc. Localization accuracy in the coronal plane was correspondingly high, maintained to < 3 mm down to θ tot ∼ 30 ° , whereas sagittal and axial localization degraded rapidly below θ tot ∼ 60 ° . Similarly, localization precision was better than ∼ 1 mm within the coronal plane, compared to ∼ 2 – 3 mm out-of-plane for tomosynthesis angles below θ tot ∼ 45 ° . An overall 3D localization accuracy of ∼ 2.5 mm was achieved with θ tot ∼ 90 ° for most tasks. The high in-plane spatial resolution, short scanning time, and low radiation dose characteristic of tomosynthesis may enable the surgeon to collect near real-time images throughout the procedure with minimal interference to surgical workflow. Therefore, tomosynthesis could provide a useful addition to the image-guided surgery arsenal, providing on-demand, high quality image updates, complemented by CBCT at critical milestones in the surgical procedure.

Background This study compared our experience with completion thyroidectomy (CT) and total thyroidectomy (TT) in the management of well-differentiated thyroid cancer (WDTC). We compared complication rates and analyzed the implications of the intraoperative management of the parathyroid glands. Study Design We performed a retrospective cohort study comparing outcomes between patients undergoing CT and TT between January 1994 and December 2004. All patients had surgery for either suspected or confirmed WDTC on fine-needle aspiration. Results There were 201 CTs and 149 TTs. Mean hospital stays were 4.5 and 3.5 days for the CT and TT groups, respectively (p=0.001). Temporary recurrent laryngeal nerve paresis occurred in 2.0% (4 of 201) and 3.3% (5 of 149) of patients in the CT and TT groups, respectively. There was one (0.5%) case of permanent recurrent laryngeal nerve paralysis in the CT group. Permanent hypoparathyroidism rates were 2.5% and 3.3% in the CT and TT groups, respectively. There was no difference between the two groups in terms of total numbers of parathyroid glands autotransplanted (p=0.63) or present in the specimen (p=0.26). Conclusions Completion thyroidectomy is a safe and appropriate option in the management of select cases of WDTC in which a definitive preoperative or intraoperative diagnosis is not available. But it requires a longer hospitalization, so it has implications for both hospital resources and the patients involved.