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Background Well-differentiated thyroid cancer (WDTC) invading the aerodigestive tract is an uncommon entity associated with significant morbidity and reduced survival. Methods We reviewed the surgical treatment, oncologic control, and functional outcomes of 69 consecutive patients with WDTC invading the upper aerodigestive tract. Results Complete tumor excision with negative margins was achieved in 62% of patients. Tracheostomy dependence (27%) and permanent hypoparathyroidism (49%) were present or the result of surgery. Seventy-one percent of patients ate a regular diet, 59% had normal speech, and the majority (62%) reported normal activities of daily living. The local, regional, and distant recurrence was 1%, 14%, and 23%, respectively. The 5-year overall survival (OS) and disease-free survival (DFS) was 71% and 45%, respectively. Conclusion Surgical resection and appropriate adjuvant treatment can achieve excellent locoregional control while preserving function and quality of life. Long-term survival is limited by the high incidence of distant metastasis. © 2015 Wiley Periodicals, Inc. Head Neck 38: 72–78, 2016

Background Papillary thyroid carcinoma is the most common thyroid malignancy. Most papillary thyroid carcinomas contain BRAF mutations or RET/PTC rearrangements, thus providing targets for biologic therapy. Our previous studies had suggested papillary thyroid carcinomas (PTCs) with a BRAF mutation and the RET/PTC1 rearrangement have different sensitivities to MEK1/2 inhibitors, suggesting different signaling transduction pathways were involved. Methods Src signaling transduction pathway in PTC cells was examined using Src inhibitors (PP2, SU6656, or dasatinib) and si-Src RNA in vitro by Western blot analysis and proliferation analysis. An orthotopic xenograft mouse model was used for the in vivo studies using dasatinib. Results In PTC cells, Src inhibitors suppressed p-Src and p-FAK and inhibited cell growth. In addition, significant suppression and extension of the p-ERK1/2 dephosphorylation were detected in RET/PTC1-rearranged cells in combination with an MEK inhibitor (CI-1040). The Src family kinase/ABL inhibitor, dasatinib, significantly decreased tumor volume in mice inoculated with PTC cells carrying the RET/PTC1 rearrangement. In BRAF-mutated PTC cells, Src inhibitors effectively suppressed p-Src expression and dasatinib significantly decreased tumor volume with twice daily treatment. Conclusion Src inhibitors effectively inhibited the Src signaling transduction pathway in PTC cells in vitro and dasatinib suppressed tumor growth in vivo. These results suggested that Src signaling transduction pathway plays an important role in regulating growth in PTC cells. Combination of Src and MEK1/2 inhibitors extended the dephosphorylation of extracellular signal-regulated kinase (ERK)1/2 in PTCs carrying the RET/PTC1 rearrangement suggesting that combination therapy with complementary inhibitors of other signaling transduction pathways may be needed to effectively suppress growth and induce apoptosis in these cells. © 2013 Wiley Periodicals, Inc. Head Neck 36: 375–384, 2014

Aurora kinase A (AURKA) is amplified with varying incidence in multiple human cancers including head and neck squamous cell carcinoma (HNSCC). We investigated whether AURKA is a potential therapeutic target in HNSCC.We conducted an immunohistochemical analysis of AURKA expression in paired normal and tumor samples (n = 63). HNSCC cells treated with siRNA specific for AURKA were assessed for AURKA mRNA and protein expression levels by reverse transcriptase-polymerase chain reaction and Western blot analysis. Tumor cells treated with siRNA and paclitaxel were assessed for cell proliferation by MTT assay and for cell cycle distribution by flow cytometry.AURKA expression was higher in tumor than in adjacent normal in most (85%) of the samples analyzed. HNSCC cells and primary tumors revealed high expression levels of AURKA. Most primary tumors also showed high kinase activity of the enzyme. Targeted AURKA inhibition increased the sub-G1 cell fraction, with a concomitant reduction in the G1 cell population, indicating induction of apoptosis and thus markedly suppressed proliferation of HNSCC cells. Combining siRNA-induced AURKA inhibition with 5 to 10 nM paclitaxel synergistically enhanced apoptosis induction.AURKA is a potential therapeutic target for HNSCC. Further investigation of small-molecule AURKA inhibitors as therapeutic agents is warranted.

Background. Cervical lymphadenectomy is fre- quently performed in patients with lateral cervical lymph node metastases to improve regional control of disease. However, there is no consensus regarding the appropriate levels of the neck that need to be dissected. Treatment options that have been advocated include the modified radical neck dissection, limited neck dissections, and selective nodal excisions. In par- ticular, the routine dissection of level V remains controversial due to the attendant morbidity to the spinal accessory nerve. To iden- tify clinical and pathological predictors of cervical node metasta- ses to level V in differentiated thyroid carcinoma, we reviewed our experience at The University of Texas M. D. Anderson Cancer Center for the management of metastatic well-differentiated thy- roid cancer. Methods. We retrospectively analyzed 70 patients who underwent thyroidectomy and neck dissection for well-differenti- ated thyroid cancer at M. D. Anderson Cancer Center. Results. In our series, 53% of neck specimens harbored metastatic thyroid carcinoma at level V. Additionally, 13 level V contralateral neck dissections were performed, and 57% were found positive for metastases. The presence of ipsilat- eral level V metastases was significantly associated with multifocal disease (p

Background. c-Met is upregulated in papillary thy- roid carcinoma (PTC) and can be an attractive therapeutic tar- get. We tested the effects of the small molecule c-met inhibitor PHA665752 in blocking c-met-dependent phenotypic effects in PTC cell lines. Methods. PTC patient tissues and cell lines were evaluated for c-met expression. The effect of PHA665752 on c-met phos- phorylation, downstream signaling, hepatocyte growth factor (HGF)-dependent cell growth, and induction of apoptosis was studied. The IC50 of PHA665752 in c-met-expressing PTC cells was determined, and growth curves at 0.13 ,1 3, and 103 IC50 concentrations were obtained. Poly(ADP-ribose) polymerase (PARP) and caspase-9-processing post-PHA665752 treatment were studied as markers of apoptosis, and assays analyzing HGF-dependent cell invasion and migration in the presence and absence of PHA665752 were done. Results. c-Met was upregulated in most of the patient tissues with PTC and in many PTC cell lines. PHA665752 specifically inhibited c-met phosphorylation, c-met-dependent cell growth, signal transduction, cell survival, cell invasion, and migration in PTC cells with high c-met. Conclusions. PHA665752 is an effective and specific inhibi- tor of c-met in PTC cells with high levels of c-met expression. V V C 2008 Wiley Periodicals, Inc. Head Neck 30: 991-1000, 2008

Background The purpose of this study is to catalog modern-era postoperative radiotherapy (external beam radiotherapy [EBRT]) outcomes for advanced medullary thyroid cancer. Methods Thirty-four consecutive patients with stage IVa–c disease were evaluated. Ten patients had recurrent disease, 16 had mediastinal involvement, and 10 had distant metastasis. Positive surgical margins were present in 12 cases. Median pre-EBRT serum calcitonin was 556. All patients received conformal EBRT or intensity-modulated radiotherapy. Median EBRT dose was 60 Gy and median follow-up was 46.5 months. Results Kaplan–Meier estimates of locoregional relapse–free survival, disease-specific survival, and overall survival at 5 years were 87%, 62%, and 56%, respectively. Disease in 3 patients with gross residual disease was controlled locoregionally. Distant disease at the time of EBRT did not predict survival. Two (9%) patients reported symptomatic chronic morbidity. Conclusion Surgery followed by EBRT provided durable locoregional disease control with limited morbidity. Postoperative EBRT merits consideration in cases of advanced disease at high risk for locoregional recurrence. © 2008 Wiley Periodicals, Inc. Head Neck, 2008

Background. Lymph node metastasis from differentiated thyroid carcinoma may occur outside of the basins at greatest risk of spread, such as the lateral retropharyngeal lymph nodes. The extensive surgery of traditional approaches to the retropharyngeal space are rarely justified in the treatment of metastatic differentiated thyroid cancer. Therefore, a less invasive surgical approach is advantageous in resection of metastatic lateral retropharyngeal nodes. Methods. To assess feasibility and safety, we report transoral excision guided by preoperative ultrasonography in a series of 3 consecutive patients with differentiated thyroid cancer metastatic to the retropharyngeal space. Results. In all cases, the metastatic lateral retropharyngeal lymph node was successfully removed by transoral retropharyngotomy without complications. Conclusions. We advocate a transoral approach guided by preoperative ultrasonography for resection of differentiated thyroid cancer metastatic to the retropharyngeal lymph nodes. The approach is feasible, minimally invasive, and safe in achieving the goals in management of regionally metastatic disease. © 2006 Wiley Periodicals, Inc. Head Neck, 2007

Background Telomerase (reverse transcriptase) has been shown to play a role in the process of cellular immortalization. Methods Telomerase activity was determined in 11 head and neck squamous cell carcinoma (SCCHN) cell lines. The effects of wild-type p16, p21, E2F-1, and p53 genes on telomerase activity were examined by introducing the wild-type genes into two SCCHN cell lines by means of a recombinant adenovirus. Results We found elevated telomerase activity in 10 of the 11 SCCHN cell lines tested. When we infected Tu-138 and Tu-167 cell lines with wild-type p16, p21, E2F-1, and p53 genes, we found that p16 had little effect on telomerase activity. Both E2F-1 and p53 were known to induce apoptosis in SCCHN cell lines. Significantly reduced telomerase activity by p53 in both cell lines and E2F-1 in Tu-167 cells was in agreement with suppression of cell growth. Overexpression of p21 also exhibited reduction in telomerase activity. Conclusions We conclude from this study that overexpression of E2F-1 and p53 can reverse telomerase activity in SCCHN cell lines and that telomerase activity may be involved in cancer cell immortalization. © 2000 John Wiley & Sons, Inc. Head Neck 22: 347–354, 2000.

Background Vascular endothelial growth factor (VEGF) is a potent paracrine angiogenic factor involved in angiogenesis. We determined whether antisense VEGF transfection can suppress angiogenic activity of a human squamous cell carcinoma of the head and neck (SCCHN) cell line. Methods Human SCCHN cell lines were screened for VEGF secretion by ELISA. The highest VEGF secreting cell line was transfected with an antisense VEGF vector. Endothelial cell migration assays were performed using the conditioned medium from the transfected clones. Tumorigenicity assays of the transfectants in nude mice were also performed. Results Antisense VEGF expression exhibited a 20-fold inhibition of VEGF secretion. The addition of conditioned medium from the antisense clones resulted in 50% reduction of endothelial migration. There was no effect on in vivo tumorigenicity. Conclusions Antisense VEGF transfection effectively down-regulated VEGF secretion from SCCHN cells that had high VEGF secretion. Targeting VEGF expression may be useful for suppressing angiogenesis in head and neck cancer. © 2000 John Wiley & Sons, Inc. Head Neck 22: 483-488, 2000.

Background Surgeons have been using selective neck dissections in the treatment of squamous carcinoma of the upper aerodigestive tract for over 20 years. To date, no data is available that can answer the question “What are the patterns of failure in the neck following a selective neck dissection and is a selective neck dissection a reliable procedure for metastatic disease?” Methods To answer this question, the medical records of all patients with squamous carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx treated at The University of Texas M. D. Anderson Cancer Center from January 1, 1985–December 31, 1990, with a selective neck dissection were reviewed. Five hundred seventeen neck dissections were analyzed: suprahyoid (41), supraomohyoid (284), and anterolateral (192). The end point of the study was regional failure and survival. Results Regional recurrence in patients treated with a suprahyoid dissection was 43% with pathologically positive nodes. The regional recurrence in the patients treated with a supraomohyoid neck dissection was 1.9% with pathologically negative nodes, 35.7% with path N1 without postoperative radiation therapy, and 5.6% with postoperative radiation therapy. The neck staged pathologically N2B failed with and without postoperative radiation, 8.3% and 14%, respectively. Thirteen percent of the anterior/lateral neck dissections failed regionally. If multiple pathologically positive nodes (N2B) were present, the regional failure with postoperative radiation was 30% and 33.3% without postoperative radiation. Conclusion The results of this retrospective study suggest that a selective neck dissection is a satisfactory staging procedure and is a definitive operation if all the nodes are pathologically negative. However, if a node is found to be invaded with cancer, the use of postoperative radiation is advisable. © 1999 John Wiley & Sons, Inc. Head Neck 21: 499–505, 1999.

Background Over-expression of human epidermal growth factor receptor (EGFR) is associated with a variety of human malignancies, including head and neck cancer. It has also been studied for its effect on cancer cell responses to chemotherapy. To accurately measure changes in EGFR expression that might be of diagnostic or prognostic importance in head and neck cancers, a quantitative assay for the direct detection of EGFR messenger ribonucleic acid (mRNA) was developed. Methods Our method was based on competitive reverse transcriptase-polymerase chain reaction (RT-PCR) that was able to measure EGFR mRNA levels undetectable by northern-blot analysis. We measured EGFR mRNA by RT-PCR in human head and neck cancers and their corresponding adjacent, histologically normal tissues and in cisplatin-treated and untreated oral epithelial cell lines. Results All the tumor samples had higher EGFR mRNA levels than their corresponding adjacent normal tissues. It is also shown that EGFR mRNA levels in normal oral epithelial cells were elevated after exposure to cisplatin. In contrast, EGFR mRNA levels in oral cancer cells were decreased after the exposure, suggesting that increased EGFR expression may have different functions in cancer cells and in normal cells under stress. Conclusions Accurate monitoring of EGFR expression may be a useful marker for diagnosis, treatment, and prognosis of head and neck cancer. © 1998 John Wiley & Sons, Inc. Head Neck 20:320–327, 1998.

Background. Elderly patients over 80 years of age represent a growing population, some of whom have complex medical problems that are compounded by the presence of upper aerodigestive tract cancer. Methods. Forty-three patients, aged 80 years and older, who were initially seen with head and neck squamous cell carcinoma from 1986 to 1992 at a tertiary-care center were compared with 79 similar patients, aged 65 years or younger, in a retrospective, case-control study. Results. Median overall survival for the patients over 80 years of age was significantly lower than that for the controls (ρ = .001). However, their overall survival was similar to the actuarial survival for the general octogenarian population. Advanced age also adversely affected local control (ρ

Background Galectins are carbohydrate-binding proteins thought to be important for cell growth and differentiation, whose expression is altered in some tumors with aggressive phenotype. Our objective was to evaluate the expression of galectins in head and neck squamous cell carcinoma (HNSCC). Methods Fourteen HNSCC cell lines and four primary tumor specimens were evaluated using immunoblotting, and immunohistochemical analysis was performed on 35 primary HNSCCs. Results Galectin-1 and galectin-3 were expressed in most HNSCC cell lines and primary tumor specimens. Galectin-1 was detected in the basal layer of normal adjacent mucosa, in connective tissue stroma, and at the periphery of invasive tumor islands. Galectin-3 localized to superficial mucosal layers, and adjacent to keratin pearls is in invasive carcinoma. Conclusions Galectins are manifested in HNSCC tumors and are localized to the cell surface, where they may participate in cellular interactions. The expression pattern of galectins appears to be associated with degree of squamous differentiation, suggesting a potential role for galectins as biologic and differentiation markers in HNSCC. HEAD & NECK 1996;18:422–432 © 1996 John Wiley & Sons, Inc.

Background This retrospective study analyzes the outcome of treatment of a cohort of patients with hypopharyngeal tumors staged T1 or T2 treated with curative radiation alone to the primary tumor. The potential influence of advances in technology and radiobiology are studied. Methods Eighty-two patients with early-stage (T1, 19 patients; T2, 63 patients) hypopharyngeal squamous cell carcinomas treated between 1976 and 1992 at the University of Texas M. D. Anderson Cancer Center completed a course of definitive radiotherapy to their primary tumors. Forty-three patients (52%) were node positive, of which 23 (28%) had surgery to their involved necks in addition to radiation. Thirty-six patients (44%) had computerized tomography (CT) as part of the staging workup. Doses to the primary ranged from 60 to 79 Gy. Forty-four patients (54%) in this study were treated with twice-daily radiation (BID). Boosts to gross disease using off spinal cord fields were treated with Co60 gamma rays in 40 patients (49%); 34 (41%) with 6–25 MV x-rays (X), and 8 (10%) with an ipsilateral electron beam field. Results The 2-year actuarial local control rates for patients with T1 and T2 disease were 89% and 77%, respectively. Subgroup analysis of T2 patients showed the following differences in actuarial local control rates at 2 years: BID, 86%; no BID, 60% (p, .004%); CT, 83%; no CT, 71% (p, .1); X boost, 88%; no X boost, 67% (p, .04). The actuarial 2- and 5-year survival rates for all patients were 72% and 52%, respectively. Conclusions A majority of patients with early hypopharyngeal lesions are radiocurable. Patients treated with hyperfractionated radiotherapy and off spinal cord fields with 6 MV (or higher energy) x-ray beams had improved local control rates. CT scans assisted in appropriate patient selection for definitive treatment with radiation. HEAD & NECK 1996;18:317–322 © 1996 John Wiley & Sons, Inc.

Wound infections resulting from contamination during major head and neck surgery continue to be a critical issue. In this study, specimens of pus or draining fluids from the wounds of 43 surgical patients who received perioperative administration of ampicillin/sulbactam or clindamycin were cultured for aerobic and anaerobic isolates to species level. Polymicrobial infections were identified in 13 of 43 patients (30%); 82% of isolates were aerobic organisms (45 of 55), and 18% were anaerobic or facultative species (10 of 55). Nine of 43 patients (21%) showed no bacterial isolates from cultured material. Independent of the primary site of malignancy or antibiotics used, nine of 25 isolates (36%) obtained from patients who underwent concomitant dental extractions, but only one of 24 (4%) who did not, developed anaerobic infections, (p < 0.001). The minimum inhibitory concentration of anaerobic isolates suggested sensitivity to the antibiotics used, and minimum bactericidal concentration data suggested that further postoperative doses may be required to adequately treat the heavily contaminated wounds. These data suggest that wound colonization following dental extraction procedures in clean contaminated head and neck surgery increases the risk of anaerobic infections. The use of a therapeutic dose and longer duration of perioperative antibiotics may be warranted.

Background. The aim of this study was to review institutional outcomes for anaplastic thyroid cancer treated with conformal 3-dimensional radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT). Methods. In all, 53 consecutive patients were analyzed. Thirty-one (58%) patients were irradiated with curative intent. Median radiation dose was 55 Gray (Gy; range, 4–70 Gy). Thirteen (25%) patients received IMRT to a median 60 Gy (range, 39.9–69.0 Gy). Thirty-nine (74%) patients received chemotherapy with radiation. Results. The Kaplan–Meier estimate of overall survival (OS) at 1 year for definitively irradiated patients was 29%. Patients without distant metastases receiving ≥50 Gy had superior survival outcomes; 5 such patients had no evidence of disease at last follow-up. Use of IMRT versus 3DRT did not influence toxicity. Conclusions. Outcomes for anaplastic thyroid cancer treated with 3DRT or IMRT remain equivalent to historical results. Healthy patients with localized disease who tolerate full dose irradiation can potentially enjoy prolonged survival. Biologically targeted radiosensitization merits prioritized investigation. © 2009 Wiley Periodicals, Inc. Head Neck, 2009