Abstract Background: Patients with normocalcemic primary hyperparathyroidism (PHPT) share similar risks of osteoporosis and nephrolithiasis with patients having hypercalcemic PHPT. The prevalence and natural history of normocalcemic PHPT is not well defined. Parathyroid microadenomas weighing < 100 mg may present as special clinical challenges in both the diagnosis and surgical resection. Clinical Case: A 55-year-old woman presented for an evaluation of osteoporosis following a non-traumatic L1 compression fracture at the age of 50 years. Noting an initial serum calcium of 10 mg/dL, we diagnosed her with normocalcemic PHPT based on a concurrent parathyroid hormone (PTH) level of 112 pg/mL (12-88 pg/mL) and a lack of other causes for an elevated PTH, including a normal eGFR, serum 25-hydroxyvitamin D, 24-hour urine calcium, and autoantibodies for celiac disease. Initial dual-energy x-ray absorptiometry (DXA) scan from 2015 showed normal bone mineral density (BMD) and T-scores in the L-spine, total hip, and femoral neck. Neck imagings, including ultrasound, sestamibi scan, and 4D CT, failed to localize a parathyroid adenoma. In the absence of a target and indications for parathyroidectomy other than osteoporosis, she was treated with bisphosphonates. While her serum calcium remained normal (9.6-10.2 mg/dL) despite an elevated PTH level (92-116 pg/mL) over a two-year period, subsequent DXA scans showed a significant loss in BMD on the bisphosphonates, prompting a peripheral DXA scan, which revealed severe osteoporosis at the distal third of the forearm (BMD 0.450 g/cm2, T-score -3.7), consistent with PTH-associated bone resorption. Following a 4-gland exploration with removal of 2 parathyroid microadenomas (63 and 100 mg), intra- and post-operative PTH levels normalized. She now awaits a repeat DXA scan at 1 year after a successful parathyroidectomy. Conclusion: Although many patients with normocalcemic PHPT may progress to develop hypercalcemia, some remain normocalcemic over an extended period. We report a patient who maintained normocalcemia for over 2 years. To correctly establish the diagnosis of normocalcemic PHPT, a comprehensive evaluation must be performed to exclude secondary causes of an elevated PTH (renal insufficiency, hypovitaminosis D, hypercalciuria, and malabsorption). Since significant osteoporosis may be preferentially seen in the cortical bone, BMD at the distal 1/3 of forearm should be evaluated in addition to the L-spine, hips and femoral necks. When a parathyroid adenoma cannot be localized in patients with normocalcemic PHPT, a careful 4-gland exploration for parathyroid microadenoma(s), paying special attention to the size, texture, and shape of the glands, and guided by intraoperative PTH levels, ensures the successful removal of the culprit gland(s).

This article is intended to demystify the process for those with a potential interest in acquiring ultrasound skills. It is not intended to be a comprehensive review of head and neck ultrasound but, rather, is focused on the bare minimum requirements and considerations involved in clinician-performed ultrasound. The article covers the initial diagnosis and the unparalleled usefulness of ultrasound for surgical planning just before incision. Further readings are listed at the end of the article to direct the reader to some excellent texts to help build confidence and experience.

Program DescriptionThe theme of this audience interactive miniseminar is to incorporate what is new and controversial in the management of differentiated thyroid cancer as well as to examine the level that molecular biology is incorporated into the management of thyroid neoplasms. The American Thyroid Guidelines for differentiated thyroid cancer are a widely quoted document. The level of evidence on which these recommendations are made varies extensively leaving considerable room for debate. Some aspects of surgical management such as laryngoscopy, bronchoscopy, and neuro‐monitoring are left out of the document. The moderator will provide a brief background power‐point presentation on the pertinent ATA guideline as a template. Expert panelists will debate case presentations germane to the given guideline and determine the level of agreement. Audience interactive opinion will be sought. The specific guidelines (where applicable) and case presentations will include: 1) Ultrasound indications for fine needle aspiration and the use of molecular markers from the FNA; 2) Laryngoscopy and neuro‐monitoring; 3) Extent of initial surgical therapy for low‐risk differentiated thyroid neoplasms and the potential role for molecular markers; 4) Bronchoscopy, preparation for airway management and extent of surgery for high risk patients with extra‐thyroidal spread; and 5) Surgery for recurrent differentiated thyroid cancer and the role of molecular targeted therapy. Panelists and the interactive audience will give opinions on the relevance of the ATA guidelines to their thyroid surgical practice.Educational Objectives1) Learn the benefits and limitations of the American Thyroid Association Guidelines. 2) Learn about molecular markers for diagnosis, prognostication, and molecular‐targeted therapy. 3) Learn about ultrasound‐guided FNA, management of low‐ and high‐risk patients, and recurrence.

This content presents to the neophyte ultrasonographer the essential nutshell of information needed to properly interpret ultrasound images. Basic concepts of physics related to ultrasound are supported with formulas and related to clinical use.

The approach to the thyroid nodule has been incrementally modified over the past decade. The widespread adoption of fine needle aspiration in the 1980s, coupled with increased use of serial ultrasound monitoring, arguably led to the biggest changes in recommendations for surgical intervention during the past 50 years. For the office-based practitioner, thyroid nodule presentation patterns are changing with discoveries of more thyroid "incidentalomas" and with new risk assessment challenges associated with small (<1 cm) nodules. At the same time, improved primary evaluation techniques, most notably the increasing use of small, portable ultrasound imaging units, are making many clinicians more comfortable in recommending less invasive follow-up.

OBJECTIVETo design a relational database integrating clinical and basic science data needed for multidisciplinary treatment and research in the field of vascular anomalies. Based on data points agreed on by the American Society of Pediatric Otolaryngology (ASPO) Vascular Anomalies Task Force. The database design enables sharing of data subsets in a Health Insurance Portability and Accountability Act (HIPAA)-compliant manner for multisite collaborative trials. Vascular anomalies pose diagnostic and therapeutic challenges. Our understanding of these lesions and treatment improvement is limited by nonstandard terminology, severity assessment, and measures of treatment efficacy. The rarity of these lesions places a premium on coordinated studies among multiple participant sites.DESIGNThe relational database design is conceptually centered on subjects having 1 or more lesions. Each anomaly can be tracked individually along with their treatment outcomes. This design allows for differentiation between treatment responses and untreated lesions' natural course. The relational database design eliminates data entry redundancy and results in extremely flexible search and data export functionality.SETTINGVascular anomaly programs in the United States.RESULTSA relational database correlating clinical findings and photographic, radiologic, histologic, and treatment data for vascular anomalies was created for stand-alone and multiuser networked systems. Proof of concept for independent site data gathering and HIPAA-compliant sharing of data subsets was demonstrated.CONCLUSIONSThe collaborative effort by the ASPO Vascular Anomalies Task Force to create the database helped define a common vascular anomaly data set. The resulting relational database software is a powerful tool to further the study of vascular anomalies and the development of evidence-based treatment innovation.

Purpose: Image localization of head-and-neck squamous cell carcinoma lags behind current techniques to deliver a precise radiation dose with intensity-modulated radiotherapy. This pilot study prospectively examined the use of registered 18-F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT for preradiotherapy staging of the neck.Methods and Materials: Sixty-three patients with squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx were enrolled into an institutional FDG-PET imaging protocol between September 2000 and June 2003. Of these patients, 20 went on to immediate neck dissection surgery and were studied further. Of these 20, 17 (85%) had American Joint Committee on Cancer Stage III or IV disease. All patients underwent preoperative FDG-PET and contrast-enhanced CT of the head and neck. FDG-PET/CT images were created using a nonrigid image registration algorithm developed at the University of Washington. Alternate primary and nodal gross tumor volumes were contoured with radiotherapy treatment planning software, blinded to each other and to the pathology results. One set of volumes was designed with CT guidance alone and the other with the corresponding FDG-PET/CT images. Neck dissection specimens were subdivided into surgical nodal levels intraoperatively, and the histopathologic findings were correlated with the CT and FDG-PET/CT nodal level findings.Results: FDG-PET/CT detected 17 of 17 heminecks and 26 of 27 nodal zones histologically positive by dissection (100% and 96% sensitivity, respectively). The nodal level staging sensitivity and specificity for FDG-PET/CT was 96% (26 of 27) and 98.5% (68 of 69), respectively. FDG-PET/CT correctly detected nodal disease in 2 patients considered to have node-negative disease by CT alone. Agreement between the imaging results and pathology findings was stronger for FDG-PET/CT (kappa 0.95, 95% confidence interval 0.82-0.99) than for CT alone (kappa 0.81, 95% confidence interval 0.63-0.91; p = 0.06 by two-sided McNemar's testing).Conclusion: These early findings suggest that FDG-PET/CT is superior to CT alone for geographic localization of diseased neck node levels. Confirmatory trials to substantiate the accuracy of FDG-PET/CT neck staging should be prioritized. (C) 2005 Elsevier Inc.

Background. 2-deoxy-2[F-18]fluoro-D-glucose-positron emission tomography (FDG-PET) imaging can be registered with CT images and can potentially improve neck staging sensitivity and specificity in patients with head and neck squamous cell cancer. The intent of this study was to examine the use of registered FDG-PET/CT imaging to guide head and neck intensity modulated radiotherapy (IMRT) planning.Methods. Twenty patients with squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx underwent FDG-PET and contrast-enhanced CT imaging of the head and neck before neck dissection surgery, Combined FDG-PET/CT images were created by use of a nonrigid image registration algorithm. All IMRT plans were theoretical and were not used for treatment. We prescribed 66 Gy in 30 fractions to FDG-avid CT abnormalities and nodal zones directly involved with disease, without prophylactic coverage of uninvolved neck levels. Matched CT-guided IMRT plans designed according to the specifications of Radiation Therapy Oncology Group (RTOG) H-0022 were available for comparison. We investigated the feasibility of FDG-PET/CT-directed IMRT dose escalation in five patients with FDG-avid disease located away from critical normal structures. After 66 Gy, FDG-avid disease with 0.5-cm margins was boosted in 220 cGy increments until dose-limiting criteria were reached.Results. Elimination of prophylactic coverage to FDG-PET/CT-negative neck levels markedly reduced mean dose (Dmean) to the contralateral parotid gland (p < .001) and Dmean to the laryngeal cartilage (p = .001). No FDG-PET/CT-directed plan missed pathologically verified nodal disease. During the dose escalation exercise, we successfully increased the dose to 95% of the planning target volume (PTV95%) to a mean of 7490 cGy (range, 7153-8098 cGy).Conclusions. We demonstrate early proof of the principle that FDG-PET/CT-guided IMRT planning can selectively target and intensify treatment of head and neck disease while reducing critical normal tissue doses. Routine clinical use of such planning should not be engaged until the accuracy of FDG-PET/CT is fully validated. Future directions, including refinement of treatment to gross disease and radiologically uninvolved neck nodal levels, are discussed. (c) 2005 Wiley Periodicals, Inc.

It is important to develop an inner ear damage protocol for mice that avoids systemic toxicity and produces damage in a relatively rapid fashion, allowing for study of early cellular and molecular mechanisms responsible for hair cell death and those that underlie the lack of hair cell regeneration in mammals. Ideally, this damage protocol would reliably produce both partial and complete lesions of the sensory epithelium. We present a method for in vivo induction of hair cell damage in the mouse via placement of gentamicin-soaked Gelfoam in the round window niche of the inner ear, an adaptation of a method developed to study hair cell regeneration in chicks. A total of 82 subjects underwent the procedure. Variable doses of gentamicin were used (25, 50, 100 and 200 μg). Saline-soaked Gelfoam, sham-operations and the contralateral, non-operated cochlea were used as controls. Survival periods were 1, 3 and 14 days. Damage was assessed on scanning electron microscopy. We found that this method produces relatively rapid hair cell damage that varies with dose and can extend the entire length of the sensory epithelium. In addition, this protocol produces no systemic toxicity and preserves the contralateral ear as a control.

OBJECTIVE To confirm that high pretreatment uptake of 2-deoxy-2[(18)F]fluoro-d-glucose (FDG) detected by positron emission tomography (PET) measured at the primary head and neck squamous cell carcinoma (HNSCC) and at metastatic nodal disease predicts poor outcomes for HNSCC. DESIGN AND PATIENTS We enrolled 63 consecutive patients with a histological diagnosis of HNSCC (including tumors of the oral cavity, oropharynx, larynx, and hypopharynx) from September 2000 through June 2003, into a prospective institutional imaging trial. Fifty-four patients (86%) underwent a baseline FDG-PET scan before curative treatment and were eligible for analysis. RESULTS A primary tumor standardized uptake value (SUV) of greater than 9.0 predicted inferior local recurrence-free survival (P = .02) and disease-free survival (P = .03). Nodal SUV dichotomized according to the cohort median of 6.1 did not predict for either disease outcome (P = .71 and P = .98, respectively). On proportional hazards analysis, local recurrence and disease event hazard ratios for a primary tumor SUV of 9.0 or greater remained significant or at borderline significance when adjusted for nodal SUV or other clinical covariates. CONCLUSIONS Our findings support an association between baseline primary tumor FDG SUV and HNSCC outcomes. In contrast, nodal FDG SUV was not predictive. Primary tumor FDG SUV is a promising prognostic factor and may establish the need for intensified locoregional therapy in individual patients. Multi-institutional imaging trials and further characterization of the biology responsible for elevated FDG uptake in HNSCC will be necessary to confirm the prognostic utility of FDG-labeled PET.

BACKGROUND Accurate baseline staging is necessary to appropriately treat head and neck squamous cell carcinoma. [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) is valuable for locoregional staging of primary head and neck disease. The effectiveness of FDG-PET for the detection of distant metastatic or synchronous disease remains unproven. OBJECTIVE To investigate the utility of FDG-PET extended into the abdomen (extended-field FDG-PET) for wide-field staging of head and neck tumors. METHODS This is a prospective institutional study of 35 consecutive patients diagnosed with American Joint Committee on Cancer (AJCC)-defined stage II-IV squamous cell carcinoma of the oral cavity, oropharynx, or larynx between September 2000 and June 2002. Thirty-three patients (94%) were eligible for analysis. All patients were routinely staged with chest radiography, liver function tests, and extended-field FDG-PET. Chest or abdominal computed tomographic scans were used as corroborative studies and were obtained only when one of the above tests indicated distant disease. RESULTS Of 33 patients, 7 (21%) had evidence of distant disease by extend-field FDG-PET-4 with metastases and 3 with synchronous primary cancers of the aerodigestive tract. [F-18]-fluorodeoxyglucose PET detected hepatic, bone, gastrointestinal, and mediastinal disease not identified by chest radiography or liver function tests. Two of the 7 patients with FDG-avid distant disease had false-negative staging by all other tests, including computed tomography. CONCLUSIONS Extended-field FDG-PET is feasible and may improve staging of primary head and neck squamous cell carcinoma. Use of staging FDG-PET must be explicitly described in reports from centers engaged in prospective research to facilitate comparison with historical results.

For most patients, a total laryngectomy should not be used as the initial treatment for any stage laryngeal tumor. The goal in treating a patient with laryngeal cancer must be not only to cure but also to provide the best functional outcome for the patient. In the United States, the treatment of laryngeal cancer has moved from radical surgery toward a more conservative approach involving definitive radiotherapy and chemotherapy, with extirpative surgery held in reserve for salvage. In Europe, there has been increasing reliance on limited endoscopic cordectomy procedures for early tumors and the use of function-preserving surgical approaches for more advanced lesions. Careful monitoring of the conservatively treated patient is mandatory to allow for early salvage of failures to the original therapy. Because of the high costs of hospitalization, the direct medical costs attributable to conservative approaches are equal to or less than the costs for more radical surgical resections. Even if survivals are only equivalent, organ preservation approaches should be the treatment of choice for most patients.

Evidence-based medicine has always relied on databases. Anyone who needs to know anything about the outcome of a treatment needs a database, but individual practitioners may feel that database design is beyond them for various reasons. Effective database design does not require complexity. This article seeks to be a practical guide for those who are contemplating development of their own database.

OBJECTIVETo investigate the safety and efficacy of alloantigen plasmid DNA therapy in patients with advanced head and neck squamous cell carcinoma using Allovectin-7 (Vical Inc, San Diego, Calif), a DNA/lipid complex designed to express the class I major histocompatibility complex antigen HLA-B7.DESIGNMulti-institutional prospective trial.SETTINGAcademic medical setting.PATIENTSA total of 69 patients were enrolled in 3 sequential clinical trials: a single-center phase 1 trial and 2 multicenter phase 2 trials. Eligibility criteria included unresectable squamous cell carcinoma that failed conventional therapy, Karnofsky performance status score of 70 or greater, and no concurrent anticancer or immunosuppressive therapies.INTERVENTIONPatients received 2 biweekly intratumoral injections of 10 microg (phase 1 and first phase 2 trials) or 100 microg (second phase 2 trial) of Allovectin-7 followed by 4 weeks of observation. Patients with stable or responding disease after the observation period were given a second treatment cycle identical to the first.MAIN OUTCOME MEASURESPatients were assessed for toxic effects, and tumor size was measured after cycles 1 (at 6 weeks) and 2 (at 16 weeks).RESULTSAllovectin-7 treatment was well tolerated, with no grade 3 or 4 drug-related toxic effects. Of 69 patients treated, 23 (33%) had stable disease or a partial response after the first cycle of treatment and proceeded to the second cycle. After the second cycle, 6 patients had stable disease, 4 had a partial response, and 1 had a complete response. Responses persisted for 21 to 106 weeks.CONCLUSIONSIntratumoral plasmid DNA immunotherapy for head and neck cancer with Allovectin-7 is safe, and further investigations are planned in patients with less advanced disease, where it could potentially improve patient survival and reduce the need for radical high-morbidity treatments.

BACKGROUNDDuring a 5-year period, we analyzed 3 patient subsets from the University of Washington Quality of Life (UW-QOL) Registry and published the results. In each instance, editorial review has raised legitimate concerns regarding the UW-QOL instrument that deserve public comment. We present our response to these criticisms. Since our original publication (1993), we have added domains to the original UW-QOL instrument. These additions reflected our concern that we might be missing important elements in the spectrum of disease-specific response to treatment. Using the data we have accumulated in the last 5 years, we present an analysis of the internal consistency of the UW-QOL. We have identified those domains that are responsive (or not responsive) to treatment effect and have revised the UW-QOL accordingly to create the UW-QOL-R, which is recommended for future use.DESIGNThe project began January 1, 1993, after approval by the UW Human Subjects Committee. Critical comments offered by external review were collated and responded to. Internal consistency was evaluated by interitem correlation matrix (Cronbach alpha) testing.SUBJECTSAll new patients presenting to the UW Medical Center (Seattle) with a diagnosis of head and neck cancer were asked to participate in a prospective analysis of QOL changes during and after treatment.INTERVENTIONPatients completed the pretreatment QOL questionnaire on the day of their initial workup. The format for the pretreatment test was an interviewer-supervised self-administered test; the subsequent tests were self-administered and were completed at 3, 6, 12, 24, and 36 months. Other data entered for each patient included site, stage, treatment, histologic classification, reconstruction, and current status. A QOL registrar was responsible for patient follow-up, data collection, and collation. All data were entered into the departmental relational database.RESULTSCriticisms by external review included the following: "it is improper to call it [UW-QOL] a measure of quality of life"; "the summary scale is problematic because it implies that each of the subscales are weighted or 'valued' equally"; "some domain questions relate to surgery specific issues. while others are specific to radiation"; "we were confused by the scoring"; and "the UW-QOL index does not specifically address the psychological impact of the disease and its treatment." After evaluation of internal consistency, the UW-QOL was modified by removing 2 domains that correlated poorly with the others. This resulted in a 10-item instrument (UW-QOL-R) with an overall internal consistency score of 0.85.CONCLUSIONSThe UW-QOL can be effectively and accurately used to compare treatment effects in the management of head and neck cancer. With this revised instrument, the 10 items appear to measure the domains of overall QOL in a highly consistent and reliable fashion over time.

Exogenous expression of hTERT, the catalytic component of telomerase, is sufficient for the immortalization of human fibroblasts but insufficient for the immortalization of human foreskin keratinocytes (HFKs) and human mammary epithelial cells (HMECs). These latter cell types can overcome senescence by coexpression of hTERT and human papillomavirus (HPV) E7 or by expression of hTERT and loss of p16(INK4a) expression, indicating that the retinoblastoma (Rb) pathway, along with a telomere maintenance pathway, plays a role in determining the life span of epithelial cells. In this study, we further characterize hTERT-immortalized HFKs and human adenoid epithelial cells (HAKs) for genotypic and phenotypic alterations that are associated with immortalization. Of five hTERT-immortalized HFK and HAK cell lines examined, four exhibited repression of p16(INK4a) expression by promoter methylation or specific large-scale deletion of chromosome 9p, the location of p16(INK4a). Interestingly, one cell line exhibited complete down-regulation of expression of p14(ARF), with only slight down-regulation of expression of p16(INK4a). Yet, all of the immortal cells lines exhibited hyperphosphorylated Rb. Cytogenetic analysis revealed clonal chromosome aberrations in three of the five cell lines. All of the cell lines retained a growth block response with the expression of mutant ras. When grown on organotypic raft cultures, however, the hTERT-immortalized cells exhibited a maturation delay on terminal differentiation. Our results indicate that immortalization of epithelial cells may require both activation of telomerase and other genetic and/or epigenetic alterations that abrogate normal differentiation.