Intensity-modulated radiotherapy for head and neck surgeons.

The development of intensity-modulated radiotherapy (IMRT) has played a major role in improving outcomes and decreasing morbidity in patients with head and neck cancer. This review addresses this vital modality with a focus on the important role of the head and neck surgeon. The technique as well as its benefits and points of caution are outlined, the definitions of tumor and treatment volumes are discussed, and the dose and fractionation are detailed. Following this are several sections dedicated to the role of the head and neck surgeon in the planning of both definitive and postoperative radiotherapy to the primary site and neck. There is a focus throughout on anatomic and surgical considerations; commonly encountered situations are illustrated. With a deeper understanding of this technique and their own pivotal contribution to target delineation, head and neck surgeons will be poised to expand their role and improve cancer care for their patients. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2368-E2373, 2016.

Disruption of mutated BRAF signaling modulates thyroid cancer phenotype.

BACKGROUND: Thyroid cancer is the most common endocrine-related cancer in the United States and its incidence is rising rapidly. Since among various genetic lesions identified in thyroid cancer, the BRAFV600E mutation is found in 50% of papillary thyroid cancers and 25% of anaplastic thyroid cancers, this mutation provides an opportunity for targeted drug therapy. Our laboratory evaluated cellular phenotypic effects in response to treatment with PLX4032, a BRAFV600E-specific inhibitor, in normal BRAF-wild-type thyroid cells and in BRAFV600E-positive papillary thyroid cancer cells. METHODS: Normal BRAF-wild-type thyroid cells and BRAFV600E-mutated papillary thyroid cancer cells were subjected to proliferation assays and analyzed for cell death by immunofluorescence. Cell cycle status was determined using an EdU uptake assay followed by laser scanning cytometry. In addition, expression of proteins within the MAPK signal transduction pathway was analyzed by Western blot. RESULTS: PLX4032 has potent anti-proliferative effects selectively in BRAF-mutated thyroid cancer cells. These effects appear to be mediated by the drug's activity of inhibiting phosphorylation of signaling molecules downstream of BRAF within the pro-survival MAPK pathway. Interestingly, PLX4032 promotes the phosphorylation of these signaling molecules in BRAF-wild-type thyroid cells. CONCLUSIONS: These findings support further evaluation of combinational therapy that includes BRAFV600E inhibitors in thyroid cancer patients harboring the BRAFV600E mutation.

Thyroidectomy outcomes: a national perspective.

OBJECTIVES: Describe trends and outcomes of patients undergoing thyroidectomy. STUDY DESIGN AND SETTING: Retrospective search of national inpatient database. SUBJECTS AND METHODS: The Nationwide Inpatient Sample 2009 was searched using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for thyroidectomy. Data extraction included patient demographics, hospital characteristics, and associated diagnoses. Subgroup analysis was performed on mortalities; bivariate and multivariate analysis was used to examine predictors of complications. RESULTS: In the United States, 59,478 patients were admitted and underwent thyroidectomy in 2009. Their mean (SD) age was 53.0 (16.4) years. Mean (SD) length of stay was 3.0 (6.9) days, and mean (SD) total charges was $39,236 ($73,679). Total thyroidectomy was performed in 53.6% of patients; 33.2% underwent unilateral lobectomy. Most common thyroid disorders included nontoxic nodular goiter (36.0%) and malignant neoplasm (30.3%). There were 363 (0.61%) mortalities, with a mean (SD) age of 65.5 (15.2) years, length of stay of 13.9 (15.2) days, and total charges of $218,855 ($191,977). Of all patients, 6.18% had hypocalcemia and 0.77% had hypoparathyroidism; the incidence of vocal cord paresis was 0.85% unilaterally and 0.34% bilaterally. Multivariate analysis revealed predictors of complications following thyroid surgery were female sex (P = .0001), total thyroidectomy procedure (P < .0001), hospital location and teaching status (P = .0060), hospital bed size (P = .0054), type of thyroid disorder, and underlying patient comorbidities. CONCLUSION: Reporting of normative data for thyroidectomy facilitates comparison. Hospitalizations for patients undergoing thyroidectomy require significant resource utilization. Predictors of complications include female sex, type of thyroid disorder and procedure, hospital location and teaching status, hospital bed size, and patient comorbidities.

Estrogen activity as a preventive and therapeutic target in thyroid cancer.

Thyroid cancer is the most common endocrine-related cancer with increasing incidences during the last five years. Interestingly, according to the American Thyroid Association, the incidences of thyroid proliferative diseases occur four to five times more in women than in men with the risk of developing thyroid disorders being one in every eight females. Several epidemiological studies have suggested a possible correlation between incidences of thyroid malignancies and hormones but the precise contribution of estrogen in thyroid proliferative disease initiation, and progression is not well understood. This review is an attempt to define the phenotypic and genotypic modulatory effects of estrogen on thyroid proliferative diseases. The significance and relevance of expression of estrogen receptors, α and ß, in normal and malignant thyroid tissues and their effects on different molecular pathways involved in growth and function of the thyroid gland are discussed. These novel findings open up areas of developing alternative therapeutic treatments and preventive approaches which employ the use of antiestrogen to treat thyroid malignancies.

Second primaries after major salivary gland cancer.

OBJECTIVES: To evaluate the risk of second primary cancers in patients with major salivary gland cancer using a large population database and to examine the effects of sex, salivary gland cancer histology, and radiation therapy on the risk of second primaries. STUDY DESIGN: Population-based study using the Surveillance, Epidemiology, and End Result (SEER) cancer database. SUBJECT AND METHODS: The subjects were 15,572 men and women ages 15 and above, diagnosed with cancer of the major salivary glands from 1973 to 2006. RESULTS: There was an increased risk of oral cavity (standardized incidence ratio [SIR] = 3.48, P < .05), salivary (SIR = 9.97, P < .05), lung and bronchus (SIR = 1.60, P < .05), kidney (SIR = 1.68, P < .05), and thyroid (SIR = 2.66, P < .05) cancers. Men had an increased risk of developing kidney cancer (SIR = 1.70, P < .05) compared with women (SIR = 1.64, P > .05). Patients with mucoepidermoid carcinoma had an increased risk of a second salivary gland cancer (SIR = 8.97, P < .05) and thyroid cancer (SIR = 3.97, P < .05). Patients with adenoid cystic carcinoma had an increased risk of oral cavity (SIR = 3.76, P < .05) and nasopharyngeal (SIR = 16.88, P < .05) cancers. Patients with acinar cell carcinoma had an increased risk of salivary (SIR = 31.36, P < .05), kidney (SIR = 2.98, P < .05), and thyroid (SIR = 3.85, P < .05) cancers. Patients who received radiation therapy had a higher incidence of lung and bronchus (SIR = 2.11, P < .05), laryngeal (SIR = 3.08, P < .05), and thyroid (SIR = 2.95, P < .05) cancers compared with patients who did not receive radiation therapy (SIR = 1.18, 0.48, and 2.39, respectively; P > .05). Patients had an increased risk of developing second primaries, even 10 years after diagnosis of primary salivary gland cancer. CONCLUSIONS: Patients with major salivary gland cancers are at a risk for certain second primary cancers. This highlights the need for long-term surveillance in these patients, not only for recurrence but also for second primary cancers.

The administration of IL-12/GM-CSF and Ig-4-1BB ligand markedly decreases murine floor of mouth squamous cell cancer.

OBJECTIVE: To assess immune-based gene therapy in a murine floor of mouth (FOM) squamous cell carcinoma (SCC) model. STUDY DESIGN: In vitro and in vivo testing of immune therapy for SCC. METHODS: Multiple SCC lines were infected by using advRSV-interleukin-12 (IL-12) and advCMV-interleukin-12/granulocyte macrophage colony-stimulating factor (IL-12/GM-CSF) and monitored for production of IL-12 and GM-CSF. Intratumoral injections of viral vectors were administered with systemic Ig-4-1BB ligand in an orthotopic murine FOM SCC model and followed for tumor size and survival. RESULTS: In vitro, all cell lines produced substantial levels of IL-12 and GM-CSF. In vivo, tumors treated with advCMV-IL-12/GM-CSF and Ig-4-1BBL showed a striking reduction in tumor volume (vs control P<0.0001) and improved median survival (38 days vs 19 days for control, P<0.0001). CONCLUSION: Combination immune-based therapies effectively improve survival in mice bearing FOM SCC over single-modality therapy.

Combined VSV oncolytic virus and chemotherapy for squamous cell carcinoma.

OBJECTIVES: Vesicular stomatitis virus (VSV) is a negative-strand ribonucleic acid (RNA) virus that replicates specifically in tumor cells and has oncolytic effects in a variety of malignant tumors. We previously demonstrated recombinant VSV vectors incorporating viral fusion protein (rVSV-F) and interleukin 12 (rVSV-IL12) to have significant antitumor effects against squamous cell carcinoma (SCC) in a murine model. Here we evaluate the potential to combine a potent chemotherapeutic agent for SCC (cisplatin) with rVSV-F and rVSV-IL12 to improve efficacy. STUDY DESIGN: In vitro, three SCC cell lines were tested using rVSV-F and rVSV-IL12 with cisplatin, monitoring viral replication and cell survival. In an orthotopic floor of mouth murine SCC model, intratumoral injections of virus combined with systemic cisplatin were tested for tumor control and animal survival. RESULTS: In vitro, virus and cisplatin combination demonstrated rapid replication and enhanced tumor cell kill. Human keratinocytes were unaffected by virus and cisplatin. In vivo, combined rVSV-F with cisplatin reduced tumor burden and improved survival (P = .2 for both), while rVSV-IL12 monotherapy had better tumor control (P = .06) and survival (P = .024) than combination therapy. CONCLUSIONS: Addition of cisplatin did not affect the ability of either virus to replicate in or kill murine SCC cells in vitro. In vivo, combination therapy enhancedrVSV-F antitumor activity, but diminished rVSV-IL12 antitumor activity. Combination therapy may provide useful treatment for SCC with the development of more efficient viral vectors in combination with different chemotherapy agents or immunostimulatory agents.

Fusogenic vesicular stomatitis virus for the treatment of head and neck squamous carcinomas.

OBJECTIVES: This study investigates the efficacy of recombinant fusogenic VSV [rVSV-NDV/F(L289A) or rVSV-F] in the treatment of head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN AND SETTING: The in vitro replication and cytotoxicity of rVSV-F were studied in two human SCC cell lines, in one murine SCC cell line, and in human keratinocytes. The effects on tumor size and animal survival were investigated following in vivo rVSV-F treatment of floor-of-mouth tumor model C3H/HeJ mice. RESULTS: Recombinant VSV-F preferentially induced rapid syncytia formation, and replicated in (P < 0.04) and killed (P < 1 x 10(-13)) all three SCC lines tested. The virus had no observable effect on human keratinocytes. Tumor size was smaller (P < 0.03) and overall survival was better (P < 0.001) for treated animals than for control animals. CONCLUSION/SIGNIFICANCE: Recombinant VSV-F confers a modest survival benefit for HNSCC in this orthotopic murine model. This oncolytic virus holds promise as a novel cancer treatment for recurrent HNSCC.

Interleukin-12 expression enhances vesicular stomatitis virus oncolytic therapy in murine squamous cell carcinoma.

OBJECTIVES: Replication-competent, vesicular stomatitis virus (VSV) has been demonstrated to be an effective oncolytic agent in a variety of malignant tumors. Cytokine gene transfer has also been used as immunomodulatory therapy for cancer. To test the use of combining these two approaches, an oncolytic VSV vector (rVSV-IL12) was designed to express the murine interleukin 12 (IL12) gene. This cytokine-carrying oncolytic virus was compared with an analogous noncytokine-carrying fusogenic virus (rVSV-F) in the treatment of murine SCC VII squamous cell carcinoma (SCC). STUDY DESIGN AND SETTING: The authors performed in vitro testing of recombinant VSV-F and recombinant VSV-IL12 in SCC cell lines. In vivo testing of multiple direct intratumoral injections of rVSV-F or rVSV-IL12 in an orthotopic floor of mouth murine model was performed. Each cell line was tested using rVSV-F or rVSV-IL12 at multiplicity of infection of 0.01. The ability of each virus to replicate was tested by real-time reverse transcriptase-polymerase chain reaction over 48 hours to determine viral copies of RNA. Cell survival was determined by MTT assay over 72 hours. IL12 expression by rVSV-IL12-treated cells was determined by enzyme-linked immunosorbent assay. RESULTS: Both viruses demonstrated similar infection efficiency, viral replication, and cytotoxicity in vitro. In an SCC VII orthotopic floor of mouth model in immunocompetent C3H/HeJ mice, multiple intratumoral injections with each virus caused a significant reduction in tumor volume when compared with saline injections alone. The rVSV-IL12-treated tumors showed a striking reduction in tumor volume when compared with rVSV-F and saline-treated tumors (P < .005). This striking reduction in tumor volume translated into a substantial survival benefit in rVSV-IL12-treated animals. No treatment-related toxicity was observed in either group. CONCLUSION/SIGNIFICANCE: rVSV-IL12 is a novel oncolytic vesicular stomatitis virus that effectively expresses IL12 and significantly enhances the treatment of head and neck murine carcinoma. Such combined oncolytic and immunomodulatory strategies hold promise in the treatment of head and neck cancers.

Screening of middle ear effusion for the common sinus pathogen Bipolaris.

Recently, a third of middle ear effusions have been shown to harbor fungal DNA by polymerase chain reaction (PCR). This suggests that fungi, in addition to being an important sinus pathogen, may also play an important role in acute and serous otitis media. Bipolaris is an important sinus pathogen whose role in infections of the ear is unknown. In this study, we assessed if Bipolaris DNA was present in 19 middle ear effusions that were PCR positive for the presence of fungi. Primer pair specific for Bipolaris spicifera was tested against DNA from various bacterial and fungal species to demonstrate its specificity and was subsequently used on DNA isolated from effusions to determine if Bipolaris-specific DNA was present. None of the nineteen specimens tested positive for Bipolaris by PCR or standard culture technique. This suggests that while fungi may play an important role in otitis media, this study does not support a role for Bipolaris as a middle ear pathogen and may reflect regional differences in its prevalence.

Use of laboratory evaluation and radiologic imaging in the diagnostic evaluation of children with sensorineural hearing loss.

OBJECTIVE: Laboratory testing and radiologic imaging are commonly used to delineate syndromic from nonsyndromic sensorineural HL (SNHL). The aim of this study was to examine the yield of laboratory tests and radiologic imaging commonly used in the diagnostic evaluation of SNHL in children. STUDY DESIGN: Retrospective analysis of 114 (54 female, 60 male) consecutively investigated children with SNHL between 1998 and 2000 at a tertiary-care university hospital. METHODS: Results of routine laboratory testing to assess autoimmunity, blood dyscrasias, endocrine abnormalities, renal function, infection, and cardiac testing were reviewed. Results of radiologic evaluation were also reviewed. In general, computed tomography (CT) was obtained in patients with symmetric SNHL, whereas magnetic resonance imaging (MRI) with or without CT was obtained in asymmetric SNHL. RESULTS: Laboratory evaluation of the blood did not yield the etiology of SNHL in any patient. Blood tests for autoimmune disease were often positive but did not correlate with clinical disease. Nonspecific elevation of erythrocyte sedimentation rate (ESR) and antinuclear antibody (ANA) was present in 22% of cases. An abnormal electrocardiogram with a prolonged QT interval resulted in the diagnosis of Jervall and Lange-Nielsen syndrome. In the 97 patients who underwent radiologic studies, abnormalities were present in 38 of 97 studies (39%). Isolated inner ear malformations were twice as common as multiple abnormalities with large vestibular aqueducts as the most common isolated finding. CONCLUSION: In the evaluation of children with unexplained SNHL, routine laboratory evaluation should be reconsidered given its low diagnostic yield. However, radiologic abnormalities of the inner ear are common. Identification of inner ear malformations has direct impact on management of these children, suggesting that all children should undergo radiologic imaging as an integral component of evaluation of SNHL.