Symptom appraisal, help seeking, and lay consultancy for symptoms of head and neck cancer.

OBJECTIVE: Early diagnosis is important in head and neck cancer (HNC) patients to maximize the effectiveness of the treatments and minimize the debilitation associated with both the cancer and the invasive treatments of advanced disease. Many patients present with advanced disease, and there is little understanding as to why. This study investigated patients' symptom appraisal, help seeking, and lay consultancy up to the time they first went to see a health care professional (HCP). METHODS: We interviewed 83 patients diagnosed with HNC. The study design was cross sectional and consisted of structured telephone interviews and a medical chart review. We gathered information on the participant's personal reactions to their symptoms, characteristics of their social network, and the feedback they received. RESULTS: We found that 18% of the participants thought that their symptoms were urgent enough to warrant further investigation. Participants rarely (6%) attributed their symptoms to cancer. Eighty-nine percent reported that they were unaware of the early warning signs and symptoms of HNC. Fifty-seven percent of the participants disclosed their symptoms to at least one lay consultant before seeking help from an HCP. The lay consultants were usually their spouse (77%), and the most common advice they offered was to see a doctor (76%). Lastly, 81% of the participants report that their spouse influenced their decision to see an HCP. CONCLUSIONS: The results of this study suggest that patients frequently believe that their symptoms were nonurgent and that their lay consultants influence their decision to seek help from an HCP.

Adherence to and uptake of clinical practice guidelines: lessons learned from a clinical practice guideline on chemotherapy concomitant with radiotherapy in head-and-neck cancer.

BACKGROUND: 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. METHODS: 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 (2003-2004) was combined with a review of relevant knowledge transfer (publications and presentations at major meetings) to understand variation in adherence to a cpg. RESULTS: 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: 2-4 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 "higher" and "lower" use of ccrt, no difference in survival was observed (p = 0.64). CONCLUSIONS: 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.

The optimal organization of gynecologic oncology services: a systematic review.

BACKGROUND: A system-level organizational guideline for gynecologic oncology was identified by a provincial cancer agency as a key priority based on input from stakeholders, data showing more limited availability of multidisciplinary or specialist care in lower-volume than in higher-volume hospitals in the relevant jurisdiction, and variable rates of staging for ovarian and endometrial cancer patients. METHODS: A systematic review assessed the relationship of the organization of gynecologic oncology services with patient survival and surgical outcomes. The electronic databases medline and embase (ovid: 1996 through 9 January 2015) were searched using terms related to gynecologic malignancies combined with organization of services, patterns of care, and various facility and physician characteristics. Outcomes of interest included overall or disease-specific survival, short-term survival, adequate staging, and degree of cytoreduction or optimal cytoreduction (or both) for ovarian cancer patients by hospital or physician type, and rate of discrepancy in initial diagnoses and intraoperative consultation between non-specialist pathologists and gyne-oncology-specialist pathologists. RESULTS: One systematic review and sixteen additional primary studies met the inclusion criteria. The evidence base as a whole was judged to be of lower quality; however, a trend toward improved outcomes with centralization of gynecologic oncology was found, particularly with respect to the gynecologic oncology care of patients with advanced-stage ovarian cancer. CONCLUSIONS: Improvements in outcomes with centralization of gynecologic oncology services can be attributed to a number of factors, including access to specialist care and multidisciplinary team management. Findings of this systematic review should be used with caution because of the limitations of the evidence base; however, an expert consensus process made it possible to create recommendations for implementation.

The Potential Impact and Usability of the Eighth Edition TNM Staging Classification in Oral Cavity Cancer.

AIMS: In the current eighth edition head and neck TNM staging, extranodal extension (ENE) is an adverse feature in oral cavity squamous cell cancer (OSCC). The previous seventh edition N1 with ENE is now staged as N2a. Seventh edition N2+ with ENE is staged as N3b in the eighth edition. We evaluated its potential impact on patients treated with surgery and postoperative intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: OSCC patients treated with primary surgery and adjuvant (chemo)radiotherapy between January 2005 and December 2014 were reviewed. Cohorts with pathological node-negative (pN-), pathological node-positive without ENE (pN+_pENE-) and pathological node-positive with ENE (pN+_pENE+) diseases were compared for local control, regional control, distant control and overall survival. The pN+ cohorts were further stratified into seventh edition N-staging subgroups for outcomes comparison. RESULTS: In total, 478 patients were evaluated: 173 pN-; 159 pN+_pENE-; 146 pN+_pENE+. Outcomes at 5 years were: local control was identical (78%) in all cohorts (P = 0.892), whereas regional control was 91%, 80% and 68%, respectively (P < 0.001). Distant control was 97%, 87%, 68% (P < 0.001) and overall survival was 75%, 53% and 39% (P < 0.001), respectively. Overall survival for N1 and N2a subgroups was not significantly different. In the seventh edition N2b subgroup of pENE- (n = 79) and pENE+ (n = 79) cohorts, overall survival was 67% and 37%, respectively. In the seventh edition N2c subgroups, overall survival for pENE- (n = 17) and pENE+ (n = 38) cohorts was 65% and 35% (P = 0.08), respectively. Overall, an additional 128 patients (42% pN+) were upstaged as N3b. CONCLUSIONS: When eighth edition staging was applied, stage migration across the N2-3 categories resulted in expected larger separations of overall survival by stage. Patients treated with primary radiation without surgical staging should have outcomes carefully monitored. Strategies to predict ENE preoperatively and trials to improve the outcomes of pENE+ patients should be explored.

Organizational guidance for the care of patients with head-and-neck cancer in Ontario.

Background: At the request of the Head and Neck Cancers Advisory Committee of Ontario Health (Cancer Care Ontario), a working group and expert panel of clinicians with expertise in the management of head-and-neck cancer developed the present guideline. The purpose of the guideline is to provide advice about the organization and delivery of health care services for adult patients with head-and-neck cancer. Methods: This document updates the recommendations published in the Ontario Health (Cancer Care Ontario) 2009 organizational guideline The Management of Head and Neck Cancer in Ontario. The guideline development methods included an updated literature search, internal review by content and methodology experts, and external review by relevant health care providers and potential users. Results: To ensure that all patients have access to the highest standard of care available in Ontario, the guideline establishes the minimum requirements to maintain a head-and-neck disease site program. Recommendations are made about the membership of core and extended provider teams, minimum skill sets and experience of practitioners, cancer centre-specific and practitioner-specific volumes, multidisciplinary care requirements, and unique infrastructure demands. Conclusions: The recommendations contained in this document offer guidance for clinicians and institutions providing care for patients with head-and-neck cancer in Ontario, and for policymakers and other stakeholders involved in the delivery of health care services for head-and-neck cancer.

Automatic image-to-world registration based on x-ray projections in cone-beam CT-guided interventions.

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.

Demons deformable registration for CBCT-guided procedures in the head and neck: convergence and accuracy.

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 CBCT images 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 CBCT images 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 CBCT images 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 x 1 x 2 mm3). 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 CBCT imaging 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.

Navigated non-contact fluorescence tomography.

A non-contact approach for diffuse optical tomography (DOT) has been developed for on-demand image updates using surgical navigation technology. A stereoscopic optical tracker provides real-time localization of reflective spheres mounted to a laser diode and near-infrared camera. Standard camera calibration is combined with tracking data to determine the intrinsic camera parameters (focal length, principal point and non-linear lens distortion) and the tracker-to-camera transform. Tracker-to-laser calibration is performed using images of laser beam intersection with a tracked calibration surface. Source and detector positions for a finite-element DOT implementation are projected onto the boundary elements of the tissue mesh by finding ray-triangle intersections. A multi-stage model converts camera counts to surface flux by accounting for lens aperture settings, fluorescence filter transmittance, photodetector quantum efficiency, photon energy, exposure time, readout offset and camera gain. The image-guidance framework was applied to an in-house optical tomography system configured for indocyanine green (ICG) fluorescence. Mean target registration errors for camera and laser calibration were less than 1 mm. Surface flux measurements of total reflectance and fluorescence in Intralipid-based fluorescence phantoms (0-2 µg ml-1) had mean errors of 3.1% and 4.4%, respectively, relative to diffusion theory predictions. Spatially-resolved reflectance measurements in a calibrated optical phantom agreed with theory for radial distances up to 25 mm from the laser source. Inverse fluorescence reconstructions of a sub-surface fluorescence target confirmed the localization accuracy (average target centroid error of 0.44 mm). This translational research system is under investigation for clinical applications in head and neck surgery, including oral cavity tumor resection, lymph node mapping and free-flap perforator assessment.

Intraoperative cone-beam CT spatial priors for diffuse optical fluorescence tomography.

A hybrid system for intraoperative cone-beam CT (CBCT) imaging and continuous-wave fluorescence tomography (FT) has been developed using an image-guidance framework. Intraoperative CBCT images with sub-millimeter spatial resolution are acquired with a flat-panel C-Arm. Tetrahedral meshes are generated from CBCT for finite element method implementation of diffuse optical tomography (NIRFAST). Structural data from CBCT is incorporated directly into the optical reconstruction process using Laplacian-type regularization ('soft spatial priors'). Experiments were performed using an in-house optical system designed for indocyanine green (ICG) fluorescence. A dynamic non-contact geometry was achieved using a stereoscopic optical tracker for real-time localization of a laser diode and CCD camera. Source and detector positions were projected onto the boundary elements of the tissue mesh using algorithms for ray-triangle intersection and camera lens calibration. Simulation studies showed the capabilities of a soft-prior approach, even in the presence of segmentation uncertainties. Experiments with ICG targets embedded in liquid phantoms determined the improvements in the quantification of the fluorophore yield, with errors of 85% and <20% for no priors and spatial priors, respectively. Similar results were observed with the ICG target embedded in ex vivo porcine loin, with errors of 52% and 12%, respectively. A proof-of-principal animal study was performed in a VX2-tumor in vivo rabbit model using liposomal nanoparticles co-encapsulating contrast for CT (iohexol) and fluorescence (ICG) imaging. Fusion of CBCT and FT reconstructions demonstrated concurrent anatomical and functional delineations of contrast enhancement around the periphery of the buccal tumor. These developments motivate future clinical translation of the FT system into an ongoing CBCT-guided head and neck surgery trial.

Geometric calibration of a mobile C-arm for intraoperative cone-beam CT.

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.

Emergency department visits and unplanned hospitalizations in the treatment period for head and neck cancer patients treated with curative intent: A population-based analysis.

BACKGROUND: Mucosal head and neck squamous cell cancers are often managed with multimodality treatment which can be associated with significant toxicity. The objective of this study was to assess emergency department visits and unplanned hospitalizations for these patients during and immediately after their treatment. METHODS: A cohort of patients treated for head and neck squamous cell carcinoma was developed using administrative data. Emergency department visits and hospitalizations in the 90-day post-treatment period was determined. If a second treatment was initiated prior to the completion of 90 days, the attributable risk period was changed to the second treatment. RESULTS: Cohort of 3898 patients (1312 larynx/hypopharynx; 2586 oral cavity/oropharynx) from 2008 to 2012. The number of unplanned hospitalizations or ED visits (per 100 patient days) were 0.69 for surgery, 0.78 for surgery followed by concurrent chemoradiotherapy (CCRT), 0.55 for surgery followed by radiotherapy, 0.86 for CCRT, and 0.50 for radiation. Patients receiving CCRT had a statistically higher likelihood of treatment period events. The larynx/hypopharynx cancer subsite, higher comorbidity and more advanced stage of disease were all independent predictors of events. CONCLUSIONS: Patients undergoing treatment for head and neck cancer have significant unplanned hospitalizations and visits to the emergency department in the treatment period. Rates are higher in patients receiving CCRT. Quality improvement interventions should be used to improve these rates.

Radiologic-Pathologic Correlation of Tumor Thickness and Its Prognostic Importance in Squamous Cell Carcinoma of the Oral Cavity: Implications for the Eighth Edition Tumor, Node, Metastasis Classification.

BACKGROUND AND PURPOSE: Addressing the performance of an imaging-based parameter compared to a "gold standard" pathologic measurement is essential to achieve accurate clinical T-classification. Our aim was to determine the radiologic-pathologic tumor thickness correlation and its prognostic value in oral squamous cell carcinoma. MATERIALS AND METHODS: All pathologic T1-T3 (seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer) oral squamous cell carcinomas diagnosed between 2010 and 2015 were reviewed. Radiologic tumor thickness was measured on preoperative CT or MR imaging blinded to pathology. The radiologic-pathologic tumor thickness correlation was calculated. The impact of the imaging-to-surgery time interval and imaging technique on the correlation was explored. Intra-/interrater reliability on radiologic tumor thickness was calculated. The correlation of radiologic-versus-pathologic tumor thickness and its performance as the seventh edition T-category modifier was evaluated. Multivariable analysis assessed the prognostic value of the radiologic tumor thickness for overall survival adjusted for age, seventh edition T-category, and performance status. RESULTS: For 354 consecutive patients, the radiologic-pathologic tumor thickness correlation was similar for the image-to-surgery interval of ≤4.0 weeks (ρ = 0.76) versus 4-8 weeks (ρ = 0.80) but lower in those with more than an 8-week interval (ρ = 0.62). CT and MR imaging had similar correlations (0.76 and 0.80). Intrarater and interrater reliability was excellent (0.88 and 0.84). Excluding 19 cases with an imaging-to-surgery interval of >8 weeks, 335 patients were eligible for further analysis. The radiologic-pathologic tumor thickness correlation was 0.78. The accuracy for upstaging the T-classification based on radiologic tumor thickness was 83% for pathologic T1 and 74% for pathologic T2 tumors. Multivariable analysis confirmed the prognostic value of radiologic tumor thickness (hazard ratio = 1.5, P = .02) for overall survival. CONCLUSIONS: This study demonstrates a good radiologic-pathologic tumor thickness correlation. Intrarater and interrater reliability for radiologic tumor thickness was excellent. Radiologically thicker tumor was predictive of inferior survival.

Image quality and localization accuracy in C-arm tomosynthesis-guided head and neck surgery.

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 (theta(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 theta(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 theta(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 theta(tot) approximately 30 degrees, whereas sagittal and axial localization degraded rapidly below theta(tot) approximately 60 degrees. Similarly, localization precision was better than approximately 1 mm within the coronal plane, compared to approximately 2-3 mm out-of-plane for tomosynthesis angles below theta(tot) approximately 45 degrees. An overall 3D localization accuracy of approximately 2.5 mm was achieved with theta(tot) approximately 90 degrees 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.

Fluctuating asymmetry in dental and mandibular nonmetric traits as evidence for childcare sex bias in 19th/20th century Portugal.

Fluctuating asymmetry, often considered a measure of developmental instability, was studied in the dental morphological traits of 600 individuals from among the poorest sectors of society in 19th-20th century Portugal. The aims are to identify and interpret any differences between: (1) males and females, and (2) patterns of distribution among teeth with different odontogenic timings, to assess if any sex bias existed in childcare. Dental and mandibular morphological traits were recorded using the Arizona State University Dental Anthropology System. z-Ratios were used to compare summed absolute fluctuating asymmetry frequencies between sexes and age groups. Results from rank correlation coefficients ruled out directional asymmetry and antisymmetry, based on positive (>0.2) bilateral association of traits in larger samples. Sex differences were significant (z-ratio=3.128; p=0.0018), while age differences were not (z-ratio=-0.644; p=0.5196). Teeth forming after infancy tended to be more asymmetric in females. Potential reasons for the sex difference include: (1) greater female susceptibility to developmental instability, (2) greater male childhood mortality that yields lower fluctuating asymmetry in surviving males, and/or (3) cultural bias favoring male access to resources. Results suggest the latter hypothesis is most likely, as fluctuating asymmetry is enhanced during childhood, perhaps coinciding with gender role definitions. There seems to be no association between asymmetry and early mortality in males. A lack of parallels in prior research renders differential sex reaction to environmental stress dubious. This population may have favored male children in their access to appropriate conditions for development.

Intraoperative cone-beam CT for guidance of head and neck surgery: Assessment of dose and image quality using a C-arm prototype.

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 <0.5 mR (<0.005 mSv) at 2 m from isocenter. Three-dimensional (3D) image quality was assessed in CBCT reconstructions of an anthropomorphic head phantom containing contrast-detail spheres (11-103 HU; 1.6-12.7 mm) and a natural human skeleton. The contrast-to-noise ratio (CNR) was evaluated across a broad range of dose (0.6-23.3 mGy). CNR increased as the square root of dose, with excellent visualization of bony and soft-tissue structures achieved at approximately 3 mGy (0.10 mSv) and approximately 10 mGy (0.35 mSv), respectively. The prototype C-arm demonstrates CBCT image quality sufficient for guidance of head and neck procedures based on soft-tissue and bony anatomy at dose levels low enough for repeat intraoperative imaging, with total dose over the course of the procedure comparable to or less than the effective dose of a typical (2 mSv) diagnostic CT of the head.

Explaining socioeconomic status effects in laryngeal cancer.

INTRODUCTION: People with lower socioeconomic status (SES) experience shorter survival times after a cancer diagnosis for many disease sites. We determined whether area-level SES was associated with the outcomes: cause-specific survival and local-regional failure in laryngeal cancer in Ontario, Canada. When we found an association we sought explanations that might be related to access to care including age, sex, rural residence, tumor stage, lymph node status, use of diagnostic imaging, treatment type, percentage of prescribed radiotherapy delivered, number of radiotherapy interruption days, treatment waiting time, and treating cancer center. MATERIALS AND METHODS: The study population consisted of 661 glottic and 495 supraglottic stage-stratified randomly-sampled patients identified using the Ontario Cancer Registry. Area-level SES quintiles were assigned using adjusted median household income from the Canadian Census. Other data were collected from patient charts. Explanations for SES effects were determined by measuring whether the effect moved toward the null value by at least 10% when an access indicator was added to a the model. RESULTS: Socioeconomic status was not related to either outcome for those with supraglottic cancer, but an association was present in glottic cancer. With the highest socioeconomic status quintile as the referent group, the relative risks for patients in the lowest socioeconomic quintile were 2.75 (95% CI 1.48, 5.12) for cause-specific survival and 1.90 (95% CI 1.24, 2.93) for local-regional failure. Disease stage as measured by T-category explained between 3% and 23% of these socioeconomic effects. None of the other access indicators met our 10% change criterion. CONCLUSION: We question why people in lower socioeconomic quintiles were not diagnosed earlier in the disease progression. Having ruled out several variables that may be related to access to care, additional biologic and social variables should be examined to further understand socioeconomic status effects.

Nasopharyngeal brush biopsies and detection of nasopharyngeal cancer in a high-risk population.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an important tumor in many countries. Ethnic and regional factors strongly influence disease risk. NPC is usually diagnosed late in disease development, and 10-year survival rates are as low as 10%. Epstein-Barr virus (EBV), a possibly causative agent, is present in all cells of essentially all undifferentiated NPCs. We wished to determine the following: 1) whether an ambulatory nasopharyngeal brush biopsy could provide sufficient tumor cell DNA for the detection of EBV and 2) whether the detection of EBV in this locale reflects the presence of tumor cells or simply EBV carrier status. METHODS: We collected nasopharyngeal tissue via ambulatory brush biopsies from 21 patients with newly diagnosed NPC and from 157 subjects with other otolaryngologic complaints. The majority of study subjects were from high-risk populations. Sample DNA was analyzed for the presence of EBV genomic sequences by use of the polymerase chain reaction (PCR). RESULTS: Ninety-six percent of samples yielded sufficient DNA for PCR amplification. Nineteen of 21 patients with NPC brushed positive for EBV DNA, while all but two (1.3%) of 149 informative control subjects were negative for EBV (two-sided P<.0001). One of the EBV-positive control subjects had an EBV-positive inverted sinonasal papilloma; the other EBV-positive control subject exhibited no overt clinical disease. CONCLUSION: Demonstration of EBV DNA in nasopharyngeal brush biopsy specimens detects NPC with a sensitivity of at least 90% (95% confidence interval = 89.63%-91.32%) and a specificity of approximately 99% (95% confidence interval = 98.64%-98.68%). This technique merits further testing as a possible ambulatory screening strategy in high-risk populations.

Clinicopathological characteristics and cell cycle proteins as potential prognostic factors in myoepithelial carcinoma of salivary glands.

Myoepithelial carcinoma (MCA) is a rare malignancy of salivary glands that was included in the WHO Classification of Head and Neck Tumors in 1991. MCA has shown a broad spectrum of clinical outcomes, but attempts to identify prognostic markers for this malignancy have not resulted in significant progress. Conventional histopathological characteristics such as tumour grade, nuclear atypia, mitotic index and cell proliferation have failed to predict the outcome of MCA. In this study, we reviewed the histopathology of 19 cases of MCA focusing on nuclear atypia, mitotic count, tumour necrosis, nerve and vascular invasion and occurrence of a pre-existing pleomorphic adenoma in connection to the MCA. Histopathological characteristics and clinical information were correlated with the immunohistochemical expression of cell cycle proteins including c-Myc, p21, Cdk4 and Cyclin D3. The proportion of tumour cells immunoreactive for these markers and their intensity of staining were correlated with clinical information using logistic regression, Kaplan-Meier and Cox regression. Using logistic regression analysis, cytoplasmic c-Myc expression was associated with the occurrence of metastases (P = 0.019), but limitations of semi-quantitation of immunostaining and the limited number of cases preclude definitive conclusions. Our data show that the occurrence of tumour necrosis predicts poor disease-free survival in MCA (P = 0.035).

Correlation between clinical and MRI assessment of depth of invasion in oral tongue squamous cell carcinoma.

BACKGROUND: Neck metastasis is the most important prognostic factor in oral cavity squamous cell carcinomas (SCC). Apart from the T- stage, depth of invasion has been used as a highly predictable factor for microscopic neck metastasis, despite the controversy on the exact depth cut off point. Depth of invasion can be determined clinically and radio logically. However, there is no standard tool to determine depth of invasion preoperatively. Although MRI is used widely to stage the head and neck disease, its utility in depth evaluation has not formally been assessed. OBJECTIVE: To compare preoperative clinical and radiological depth evaluation in oral tongue SCC using the standard pathological depth. To compare clinical and radiological accuracy between superficial (<5 mm) vs. deep invaded tumor (≥5 mm) METHODS: This prospective study used consecutive biopsy-proven oral tongue invasive SCC that presented to the University health network (UHN), Toronto. Clinical examination, radiological scan and appropriate staging were determined preoperatively. Standard pathology reports postoperatively were reviewed to determine the depth of invasion from the tumor specimen. RESULTS: 72 tumour samples were available for analysis and 53 patients were included. For all tumors, both clinical depth (r = 0.779; p < 0.001) and radiographic depth (r =0.907; p <0.001) correlated well with pathological depth, with radiographic depth correlating slightly better. Clinical depth also correlated well with radiographic depth (r = 0.731; p < 0.001). By contrast, for superficial tumors (less than 5 mm on pathological measurement) neither clinical (r = 0.333, p = 0.34) nor radiographic examination (r = - 0.211; p = 0.56) correlated with pathological depth of invasion. CONCLUSION: This is the first study evaluating the clinical assessment of tumor thickness in comparison to radiographic interpretation in oral cavity cancer. There are strong correlations between pathological, radiological, and clinical measurements in deep tumors (≥5 mm). In superficial tumors (<5 mm), clinical and radiological examination had low correlation with pathological thickness.

Abnormalities of the ARF-p53 pathway in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is associated with heavy smoking and drinking, but the molecular pathway of tumorigenesis is not understood. Inactivation of the p53 tumor suppressor gene is likely to play an important role since p53 mutation is frequently found. The p14ARF tumor suppressor gene is functionally linked to p53, because it is activated by oncogenes and causes p53-dependent growth arrest and apoptosis. The relationship between p14ARF and p53 inactivation has not been described for OSCC. We studied 25 cases of OSCC to determine if there is an inverse correlation between p53 mutation and p14ARF inactivation by homozygous deletion or mutation. p53 mutation was found in 16 of 25 cases (64%), including nine missense and seven truncating mutations. While all cases with missense mutations showed abnormal accumulation of p53 protein, there were also five carcinomas which showed increased p53 staining in the absence of mutation. p14ARF deletion or mutation was found in eight cases (32%), six of which also demonstrated p53 mutation. Our findings indicate that OSCC often involves loss of both p14ARF and p53 function and suggest that inactivation of these two tumor suppressor genes are not functionally equivalent during tumorigenesis.