Metastatic Disease of the Temporal Bone: A Contemporary Review.

OBJECTIVES: To identify the frequency and primary site of metastatic pathologies to the temporal bone and characterize the associated symptomatology. METHODS: The MEDLINE, Embase, and Web of Science databases were systematically reviewed according to the PRISMA guidelines to identify all cases of pathologically confirmed distant temporal bone metastases published with English translation until October 2019. Descriptive statistics were performed. RESULTS: Out of 576 full-length articles included for review, 109 met final criteria for data extraction providing 255 individual cases of distant temporal bone metastases. There was a male predominance (54.9%) with median age of 59.0 years (range 2-90). The most common locations of primary malignancy included the breasts (19.6%), lungs (16.1%), and prostate (8.6%). Most tumors were carcinomas of epithelial origin (75.3%) and predominantly adenocarcinoma (49.4%). The commonest metastatic sites encountered within the temporal bone were the petrous (72.0%) and mastoid (49.0%) portions. Bilateral temporal bone metastases occurred in 39.8% of patients. Patients were asymptomatic in 32.0% of cases. Symptomatic patients primarily reported hearing loss (44.3%), facial palsy (31.2%), and otalgia (16.6%) for a median duration of 1 month. Petrous lesions were associated with asymptomatic cases (P = .001) while mastoid lesions more often exhibited facial palsy (P = .026), otalgia (P < .001), and otorrhea (P < .001). Non-carcinomatous tumors were associated with petrosal metastasis (P = .025) and asymptomatic cases (P = .109). Carcinomatous metastases more often presented with otalgia (P = .003). CONCLUSIONS: Temporal bone metastasis is uncommon but should be considered in patients with subacute otologic symptoms or facial palsy and history of distant malignancy. Laryngoscope, 131:1101-1109, 2021.

Rapid mandible margins for intraoperative assessment.

OBJECTIVES: To determine the feasibility of a rapid method of processing mandible bone margins for intraoperative histopathologic examination and to assess the relative value of fine, coarse, and core specimens in assessing bone margins. STUDY DESIGN: Prospective histologic controlled study. SETTING: A tertiary level academic medical center histopathology laboratory. SUBJECTS AND METHODS: Multiple bone samples were collected from fresh (<12 hours post-mortem) human cadaveric mandible using a 1) standard 4mm otolaryngologic cutting drill bit 2) diamond drill bit and 3) cutting core biopsy trocar. The specimens were placed in one of three decalcifying solutions (Decal A, Calex, EDTA Decal) from 15 to 75 minutes or control (fixation in 10% formalin). After each designated decalcification time period, specimens were cryosectioned or paraffin embedded and subsequently reviewed by a head and neck surgical pathologist. The specimens were assessed for overall quality, adequacy of decalcification, soft tissue quality, marrow quality, and presence of artifact. RESULTS: Bone margin specimens collected with a 4mm burr and processed with EDTA Decal for 30 minutes yielded the highest quality histopathologic slides compared to the other methods in a similar time frame. The adequacy of decalcification directly impacted the quality of histopathologic assessment. CONCLUSIONS: Mandible bone margins can be rapidly and safely prepared and adequately evaluated with only 30 minutes of decalcification. This method may provide acceptable intraoperative assessment of bone margins in patients with tumors which involve or approximate bone. We plan to examine this model in a prospective clinical study of patients with cancer invading mandibular bone.

HRAS mutations and resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in head and neck squamous cell carcinoma cells.

BACKGROUND: The purpose of this study was to identify mechanisms of innate resistance to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Specifically, we analyzed the role of HRAS mutations in erlotinib resistance. METHODS: Erlotinib sensitivity was determined by methyl thiazolyl-tetrazolium (MTT) assays. Molecular signaling pathways and somatic mutations were examined. Changes in sensitivity after modulation of HRAS expression were evaluated. RESULTS: All 7 cell lines were wild-type for EGFR and KRAS regardless of erlotinib sensitivity; however, 1 erlotinib-resistant cell line (HN31) harbored an HRAS G12D mutation. Downregulation of HRAS expression by small interfering RNA (siRNA) or short hairpin RNA (shRNA) in HN31 led to increased erlotinib sensitivity in vitro and in vivo. Transfection of activating HRAS-mutant (G12D and G12V) constructs into erlotinib-sensitive cell lines made them more resistant to erlotinib. CONCLUSION: Activating HRAS mutations can confer erlotinib resistance in an HRAS mutant HNSCC cell line.

Coordinated targeting of the EGFR signaling axis by microRNA-27a*.

Epidermal growth factor receptor (EGFR) has been characterized as a critical factor in the development and progression of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC). However, monotherapy with EGFR-specific agents has not been as dramatic as preclinical studies have suggested. Since complex regulation of the EGFR signaling axis might confound current attempts to inhibit EGFR directly, we searched for microRNAs (miRNAs) that may target the EGFR signaling axis. We identified miR-27a (miR-27a-3p) and its complementary or star (*) strand, miR-27a* (miR-27a-5p), as novel miRNAs targeting EGFR, which were significantly downregulated in multiple HNSCC cell lines. Analysis of human specimens demonstrated that miR-27a* is significantly underexpressed in HNSCC as compared to normal mucosa. Increased expression of miR-27a* in HNSCC produced a profound cytotoxic effect not seen with miR-27a. Analysis for potential targets of miR-27a* led to the identification of AKT1 (protein kinase B) and mTOR (mammalian target of rapamycin) within the EGFR signaling axis. Treatment with miR-27a* led to coordinated downregulation of EGFR, AKT1 and mTOR. Overexpression of EGFR signaling pathway components decreased the overall effect of miR-27a* on HNSCC cell viability. Constitutive and inducible expression of miR-27a* in a murine orthotopic xenograft model of oral cavity cancer led to decreased tumor growth. Direct intratumoral injection of miR-27a* inhibited tumor growth in vivo. These findings identify miR-27a* as a functional star sequence that exhibits novel coordinated regulation of the EGFR pathway in solid tumors and potentially represents a novel therapeutic option.

Minor salivary gland malignancies in the pediatric population.

BACKGROUND: Minor salivary gland malignancies in children are rare and data on treatment and outcomes are limited. METHODS: A retrospective chart review of all pediatric patients with the pathologic diagnosis of minor salivary gland malignancy at a tertiary care cancer hospital was used to conduct this review. RESULTS: From 1952 to 2006, 35 children with minor salivary gland cancers were treated at The University of Texas MD Anderson Cancer Center. Mean age was 15.2 +/- 2.9 years with a slight female predominance. Recurrence occurred in 4 patients and was significantly associated with positive margins, advanced stage, and high histologic grade. Overall survival (OS) and disease-specific survival (DSS) were 89.3% and 88.4%, respectively, at 5 years. Advanced stage, positive margins, and high grade were associated with adverse survival. CONCLUSION: Minor salivary gland malignancies in children are rare. Surgical resection with clear margins yields excellent outcomes in patients with low-intermediate grade and early stage tumors. Patients with high-grade malignancies do poorly despite multimodality therapy.

Hyaluronic acid-paclitaxel conjugate inhibits growth of human squamous cell carcinomas of the head and neck via a hyaluronic acid-mediated mechanism.

Chemotherapeutic regimens incorporating taxanes significantly improve outcomes for patients with squamous cell carcinomas of the head and neck (SCCHN). However, treatment with taxanes is limited by toxicities, including bone marrow suppression and peripheral neuropathies. We proposed that conjugating taxanes to targeting carrier molecules would increase antitumor efficacy and decrease toxicity. The cell surface proteoglycan, CD44, is expressed on most SCCHNs, and we hypothesized that it is an attractive candidate for targeted therapy via its natural ligand, hyaluronic acid (HA). We determined whether HA-paclitaxel conjugates were able to decrease tumor growth and improve survival in orthotopic nude mouse human SCCHN xenograft models. HA-paclitaxel concentration-dependent growth inhibition of human SCCHN cell lines OSC-19 and HN5 in vitro, very similarly to free paclitaxel treatment. Tumor cell uptake of FITC-labeled HA-paclitaxel was significantly blocked with free HA, indicating the dependence of uptake on CD44. HA-paclitaxel administered intravenously once per week for three weeks at 120 mg/kg paclitaxel equivalents, far above the paclitaxel maximum tolerated dose, exerted superior tumor growth control to that of paclitaxel in both orthotopic OSC-19-luciferase and HN5 xenograft models in vivo. Mouse survival following HA-paclitaxel administration was prolonged compared with that of controls in mice implanted with either of these xenografts. Mice treated with HA-paclitaxel displayed increased TUNEL(+) cells in tumor tissue, as well as markedly reduced microvessel density compared to those treated with free paclitaxel. No acute histopathological changes were observed in mice treated with HA-paclitaxel. Thus, we conclude that HA-paclitaxel effectively inhibits tumor growth in human SCCHN xenografts via an HA-mediated mechanism and this conjugate should be considered for further preclinical development for this disease.

Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model.

PURPOSE: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear. EXPERIMENTAL DESIGN: Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature. RESULTS: Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3% (P < 0.001) and 66.6% (P < 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P < 0.01) and vascular volume fraction (P < 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control. CONCLUSION: The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo.

Dual inhibition of epidermal growth factor receptor and insulin-like growth factor receptor I: reduction of angiogenesis and tumor growth in cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most common nonmelanoma skin cancer. Most of the approximately 250,000 cases occurring annually in the United States are small, nonaggressive, and cured by excision alone. However, a subset of these tumors which are defined by poorly differentiated histology, large tumor size, invasion of adjacent structures, and/or regional metastases can prove resistant to treatment despite adjuvant radiotherapy and can have an increased risk of recurrence and nodal metastasis. Novel therapeutic approaches are necessary to improve the outcomes for patients with aggressive CSCC. METHODS: We analyzed the effect of targeted therapy on the growth and survival of CSCC cell lines using an anti-insulin-like growth factor-I receptor (IGF-IR) antibody, A12, alone or in combination with an anti-epidermal growth factor receptor (EGFR) antibody, cetuximab, both in vitro and in vivo in an athymic nude mouse model of CSCC. RESULTS: Treatment with A12 and cetuximab inhibited the signaling pathways of IGF-IR and EGFR and inhibited proliferation and induced apoptosis of squamous cell carcinoma (SCC) cell lines in vitro. Immunohistochemical staining revealed decreased proliferating cell nuclear antigen (PCNA), microvessel density, and increased apoptosis within the treated tumor xenografts. In addition, the administration of A12, alone or in combination with cetuximab inhibited the growth of tumors by 51% and 92%, respectively, and significantly enhanced survival in the nude mouse model of CSCC (p = .044 and p < .001, respectively). CONCLUSION: These data suggest that dual treatment with monoclonal antibodies to the EGFR and IGF-IR may be therapeutically useful in the treatment of CSCC.

Targeted molecular therapy of head and neck squamous cell carcinoma with the tyrosine kinase inhibitor vandetanib in a mouse model.

BACKGROUND: We investigated the effects of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2) and epidermal growth factor receptor (EGFR), alone and in combination with paclitaxel in an orthotopic mouse model of human head and neck squamous cell carcinoma (HNSCC). METHODS: The in vitro effects of vandetanib (ZACTIMA) were assessed in 2 HNSCC cell lines on cell growth, apoptosis, receptor and downstream signaling molecule expression, and phosphorylation levels. We assessed in vivo effects of vandetanib and/or paclitaxel by measuring tumor cell apoptosis, endothelial cell apoptosis, microvessel density, tumor size, and animal survival. RESULTS: In vitro, vandetanib inhibited the phosphorylation of EGFR and its downstream targets in HNSCC cells and inhibited proliferation and induced apoptosis of HNSCC cells and extended survival and inhibited tumor growth in nude mice orthotopically injected with human HNSCC. CONCLUSION: Vandetanib has the potential to be a novel molecular targeted therapy for HNSCC.

The effect of combination anti-endothelial growth factor receptor and anti-vascular endothelial growth factor receptor 2 targeted therapy on lymph node metastasis: a study in an orthotopic nude mouse model of squamous cell carcinoma of the oral tongue.

OBJECTIVE: To evaluate the therapeutic effect of treatment with a combination of the monoclonal antibodies to the vascular endothelial growth factor receptor (DC101) and the epidermal growth factor receptor (cetuximab) in an orthotopic nude mouse model of metastatic squamous cell carcinoma of the oral tongue (SCCOT). DESIGN: In vivo study. SETTING: A translational research laboratory at a comprehensive cancer center. SUBJECTS: Male athymic nude mice aged 8 to 12 weeks. INTERVENTION: To develop orthotopic nude mouse models of SCCOT, OSC-19 cells or luciferase (Luc)-expressing OSC-19-Luc and JMAR-Luc cells were injected into the tongues of nude mice. Animals were randomly divided into 4 groups: DC101 alone, cetuximab alone, DC101 plus cetuximab, or placebo, and all treatments were administered twice per week for 4 weeks. The in vivo antitumor activity was monitored noninvasively by bioluminescence imaging. Tumors were resected at necropsy, and immunohistochemical and immunofluorescent staining were performed. MAIN OUTCOME MEASURES: Tumor size, bioluminescence, animal survival, and percentage of animals with lymph node metastasis. RESULTS: At the conclusion of the treatment period, the mean tumor volumes in the cetuximab alone and the DC101 plus cetuximab groups had decreased significantly compared with those that received the placebo control (68% [P = .002] and 84% [P < .001], respectively). Significant effects of the treatment were also observed in bioluminescence imaging. Mice treated with DC101 plus cetuximab also lived longer and had a lower incidence of neck lymph node metastases compared with the control group (P = .003). CONCLUSIONS: Treatment with DC101 plus cetuximab inhibited the growth of SCCOT and decreased the incidence of the neck lymph node metastases in vivo. These results suggest that this combination treatment may be an effective strategy against metastatic SCCOT and warrants further preclinical trials.

Phosphorylated insulin like growth factor-I receptor expression and its clinico-pathological significance in histologic subtypes of human thyroid cancer.

Overexpression of insulin-like growth factor-I receptor (IGF-IR) is seen in a multitude of human thyroid cancers and correlates with poor prognosis. However, recent studies suggest that low phospho-IGF-IR (pIGF-IR) expression rather than its overexpression may be an indicator of poorly differentiated disease. No previous study has evaluated the expression of pIGF-IR to determine if activation or loss of expression of this receptor is associated with thyroid tumor progression. Accordingly, a quantitative immunohistochemical (IHC) method was used to evaluate the clinico-pathological significance of pIGF-IR expression in archival samples of human thyroid carcinomas. Quantitative analysis of pIGF-IR levels revealed a significant difference in the median index of pIGF-IR between different histological subtypes of thyroid cancer (P < 0.001). Specifically, the median pIGF-IR index of differentiated thyroid cancers was significantly higher than the median index of other poorly differentiated thyroid cancer (P < 0.001). This was further confirmed in individual tumor sections of thyroid carcinoma where anaplastic and differentiated components co-existed. No significant difference was noted in the pIGF-IR index of tumors grouped by size or stage but a trend towards lower mean pIGF-IR index was noted in older patients. Our data indicates that pIGF-IR is upregulated in a majority of follicular thyroid carcinomas, suggesting it may be a potential target for therapy for patients with this disease. In addition, since low pIGF-IR expression was found to correlate with aggressive human thyroid carcinoma, it also suggests that IGF-IR may not be needed for progression of anaplastic thyroid carcinoma possibly because other cell signaling pathways are activated, obviating the need for IGF-IR signaling. However, more mechanistic studies would be necessary to substantiate the possibility that pIGF-IR may be important for differentiation of thyroid tissues and is lost with disease progression.

Evaluation and management of the unknown primary carcinoma of the head and neck.

Squamous cell carcinoma of unknown primary origin in the head and neck is encountered as a recurring clinical problem in head and neck cancer clinics, affecting 3% to 25% of patients. This article describes the clinical presentation, appropriate evaluation, and treatment strategies for this important subgroup. Treatment--best carried out with multidisciplinary teams of specialists experienced in the care of head and neck cancer patients--is curative for most of these patients.

Clinical significance of SNAP somnography test acoustic recording.

OBJECTIVE: To examine the clinical significance of acoustic data recorded by the SNAP home polysomnography system (SNAP Laboratories, Glenview, IL). STUDY DESIGN AND SETTING: Retrospective analysis of SNAP data from 59 patients undergoing evaluation for sleep apnea at the University of Nebraska Medical Center and an associated private practice in Omaha, NE. RESULTS: Snoring did not correlate with anthropometric variables such as body mass index and neck circumference. Statistical analysis showed no correlation between respiratory disturbance index and the maximum or average loudness of snoring. Average loudness was predictive of the presence of sleep apnea. Spectral analysis of snoring sonography found that the proportion of snoring events associated with a palatal source correlated strongly with the loudness of snoring. CONCLUSION: These data suggest that analysis of snoring has limited utility in the evaluation of the patient with sleep apnea but may be able to select patients who would benefit from palatal procedures to reduce snoring.

Canine adenovirus vectors for lung-directed gene transfer: efficacy, immune response, and duration of transgene expression using helper-dependent vectors.

A major hurdle to the successful clinical use of some viral vectors relates to the innate, adaptive, and memory immune responses that limit the efficiency and duration of transgene expression. Some of these drawbacks may be circumvented by using vectors derived from nonhuman viruses such as canine adenovirus type 2 (CAV-2). Here, we evaluated the potential of CAV-2 vectors for gene transfer to the respiratory tract. We found that CAV-2 transduction was efficient in vivo in the mouse respiratory tract, and ex vivo in well-differentiated human pulmonary epithelia. Notably, the in vivo and ex vivo efficiency was poorly inhibited by sera from mice immunized with a human adenovirus type 5 (HAd5, a ubiquitous human pathogen) vector or by human sera containing HAd5 neutralizing antibodies. Following intranasal instillation in mice, CAV-2 vectors also led to a lower level of inflammatory cytokine secretion and cellular infiltration compared to HAd5 vectors. Moreover, CAV-2 transduction efficiency was increased in vitro in human pulmonary cells and in vivo in the mouse respiratory tract by FK228, a histone deacetylase inhibitor. Finally, by using a helper-dependent CAV-2 vector, we increased the in vivo duration of transgene expression to at least 3 months in immunocompetent mice without immunosuppression. Our data suggest that CAV-2 vectors may be efficient and safe tools for long-term clinical gene transfer to the respiratory tract.

Grisel's syndrome: a case report and review of the literature.

Grisel's syndrome is non-traumatic atlantoaxial subluxation (AAS) secondary to an inflammatory process in the upper neck. It is a rare condition that occurs almost exclusively in children and has been associated with upper cervical infections and otolaryngologic procedures. A case of AAS secondary to an upper cervical infection is presented. Potential sequelae can be severe; early diagnosis and treatment of Grisel's syndrome can prevent tragic outcome.

Surgical anatomy of the parotid duct with emphasis on the major tributaries forming the duct and the relationship of the facial nerve to the duct.

Although there is a great amount in the literature to describe the anatomy of the parotid gland as a whole, little attention is given to the parotid duct. The purpose of this study is to examine the surgical anatomy of the parotid duct with special emphasis placed on the major tributaries forming the parotid duct and the relationship of the facial nerve to the duct. Twenty-nine fresh cadaver halves were dissected and the branching pattern of the ducts, position within the parotid, and their relationship to the facial nerve were studied. Of the complete heads studied, the parotid duct had the same pattern in 78.6% on the right and left sides. The parotid ducts in 31.0% of the half heads presented as a single discernible duct from parotid papilla to within the gland. In 62.1% of the half heads, the ducts were formed by a branching pattern within the gland. In the ducts with a branching pattern, 48.3% displayed a bifurcated pattern, 6.9% were trifurcated, and 6.9% had multiple branches. In 6.9% of the half heads studied, the parotid ducts bifurcated distal to the parotid gland. In all cases, the deep lobe of the parotid enveloped the parotid duct; only small ductules connected the superficial lobe with the duct. The facial nerve and its branches were always observed lateral to the parotid duct. Because one dissects lateral to the facial nerve during a superficial parotidectomy, generally the parotid duct remains intact and potential complications such as facial paralysis, sialoceles, and fistulizations are thereby minimized.