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Management of differentiated thyroid carcinoma (DTC) is gradually evolving with considerations of de-escalation of treatment and/or active surveillance in a significant proportion of patients on the basis of an improved understanding of the long-term disease and functional outcomes from both surgical and non-surgical approaches. This is fueled by improved risk stratification using clinicopathologic prognostic factors as determined through high resolution ultrasound and fine needle aspiration cytology. This paper discusses general recommendations for preoperative decision-making in the management of the central compartment in DTC with particular reference to micropapillary thyroid carcinoma and encapsulated follicular variant papillary thyroid carcinoma. Given the multitude of specific factors that must be considered for each patient, therapeutic decisions should occur in a multidisciplinary setting weighing the risks of treatment morbidity against the risks of disease progression or recurrence. Recurrent/persistent disease merits special attention with regard to pre-operative planning and surgical risk, and should be managed by high-volume thyroid surgeons.

Objectives Intrathyroid metastases from extrathyroid primary tumors are rare. Clinical findings may be subtle, but detection of intrathyroid metastases has improved with sonography. The objective of this study was to evaluate the sonographic appearance of intrathyroid metastases. Methods Patients with thyroid masses with cytopathologic features matching those of an extrathyroid primary tumor were retrospectively identified. The appearances of intrathyroid metastases on sonography were reviewed for the following features: size, margin regularity, echogenicity, echotexture, vascularity on power or color Doppler ultrasonography, and the presence or absence of any associated cervical adenopathy. Results The study included 52 patients. The most frequent primary tumor sites were lung, head and neck, and breast. Intrathyroid metastases presented as a discrete nodule in 34 patients and as diffuse infiltration of the gland in 18 patients. The discrete nodules ranged in size from 1.1 to 5.6 cm (mean ± SD, 2.5 ± 1.2 cm). Thirty-three lesions (63%) had irregular margins, and 19 (37%) had well-defined margins. Most of the lesions were heterogeneously hypoechoic (n = 50, 96%). Vascularity was present in 32 of 50 measured lesions (64%) that were evaluated with Doppler sonography. Cervical adenopathy was present in 37 patients (71%). Conclusions Intrathyroid metastases have sonographic characteristics similar to those described for both benign and malignant thyroid diseases. In patients with a previous or current extrathyroid malignancy, thyroid nodules or diffuse infiltration of the thyroid gland on sonography should be viewed as a potential intrathyroid metastasis and evaluated via ultrasound-guided fine-needle aspiration regardless of the site of the primary tumor.

Background Anaplastic thyroid cancer (ATC) is a rare, aggressive, and deadly disease. Robust pre-clinical models are needed to adequately develop and study novel therapeutic agents. Patient-derived xenograft (PDX) models are thought to closely resemble patient tumors by preserving the tumor microenvironment, making them excellent pre-clinical models for drug response evaluation. We used two distinct ATC PDX models and evaluated drug response following a high-throughput screening (HTS). Methods A HTS, using NCI's Approved Oncology Set V (n=112) and a custom collection of agents (n=145), was conducted on patient-derived thyroid cancer cell lines. To identify the most effective drugs, we selected individual agents with maximal growth inhibition at each dose level relative to wells examined on the day of treatment (top 25th percentile) and subsequently used non-parametric statistics to compare effect size with other drugs and controls. This allowed us to identify classes of systemic agents which demonstrated preferential effectiveness against ATC cell lines and certain mutations. Following our prior successful work on orthotopic xenograft models, we used two established ATC PDX models, HOSC68 and HOSC199, harboring distinct genetic profiles and expanded each of them into 50 athymic mice. HOSC68 has a BRAFV600E and a TP53 mutation, while HOSC199 is wild-type for both genes, but has an HRAS mutation. Equal pieces of 4 × 4mm of tumor were transplanted subcutaneously at the level of the right flank. Following tumor growth, the mice were separated into four treatment arms. All mice received their treatment intraperitoneally following standard drug administration schedules. Tumor volume was measured on the first day of treatment and every two to three days thereafter until trial completion (14 days). Drug response was analyzed by evaluating percent tumor growth inhibition (TGI). Mouse weight was recorded over time to evaluate treatment toxicity. Following treatment completion, tumors were surgically retrieved and evaluated morphologically and histologically. Results Microtubule inhibitors, antimetabolites, and HDAC inhibitors were some of the most effective drug classes identified against ATC cell lines. Specifically, in this study, mice were treated with control (CTR), Docetaxel (DOC)-microtubule inhibitor, Pralatrexate (PRA)-antimetabolite, and LBH-589 (LBH)-HDAC inhibitor. Forty-four HOSC68 and 43 HOSC199 mice successfully grew tumor and were included in the trial. Compared to CTR, HOSC68 mice treated with DOC showed a 37% TGI (p=0.04), 88% with PRA (p&lt0.001), and 83% with LBH (p&lt0.001), while HOSC199 mice had a 2% TGI with DOC (p=0.56), 76% with PRA (p=0.005), and 83% with LBH (p=0.002). PRA and LBH were significantly more toxic than DOC and CTR (p&lt0.001) in HOSC68 mice, while all three drugs were significantly more toxic than CTR in the HOSC199 mice (p&lt0.001). Conclusion We report the first large-scale evaluation of drugs identified through a HTS analysis on ATC PDX models. This trial demonstrates the feasibility of using this platform for in vivo drug testing, while providing an avenue for future drug testing and resistance evaluation, as well as personalized therapeutics development. Citation Format: Anastasios Maniakas, Abdallah S. Mohamed, Ying C. Henderson, Hu Hei, Shaohua Peng, Diana Bell, Michelle D. Williams, Steve Scherer, David A. Wheeler, Gary L. Clayman, Mark Zafereo, Jennifer R. Wang, Maria E. Cabanillas, Clifford Stephan, Faye M. Johnson, Stephen Y. Lai. In vivo drug response evaluation in anaplastic thyroid cancer patient-derived tumor xenografts following high-throughput screening [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1662.

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

Well-differentiated thyroid carcinoma (WDTC) has a high predilection for regional metastatic spread. Rates for WDTC lateral neck recurrence are reported to be as high as 24% in patients after initial thyroidectomy, lateral neck surgery, and adjuvant radioactive (RAI) iodine treatment. The objective of the study was to evaluate the efficacy, safety, and long-term outcome of comprehensive lateral neck dissection (LND) of levels II-V for recurrent or persistent WDTC in a tertiary referral center.This study retrospectively analyzed the standardized approach of LND for recurrent WDTC in the lateral neck compartment. Survival was analyzed by Cox regression analysis.Three hundred and seven patients underwent 429 LND for cytopathology-confirmed lateral neck recurrent WDTC at the University of Texas MD Anderson Cancer Center between 1994 and 2012. The vast majority (90%) of patients were originally treated elsewhere. Multilevel lateral neck dissection had been originally performed in 80% of patients, with 17% having undergone at least two previous operations. Two hundred and sixty-seven (87%) patients had previous RAI. The most common levels of recurrence were levels III and IV (33% and 33%, respectively). Postoperative complications were seen in 7% of patients. Median follow-up was 7.2 years. In-field lateral neck control was 96% at 10 years. Overall lateral neck regional control, overall survival (OS), and disease-specific survival (DSS) at 10 years was 88%, 78%, and 91%, respectively. When stratifying by age (24 years, 24-50 years, and50 years), OS and DSS was significantly better in patients50 years (OS: p 0.001; DSS: p 0.001). However, there was worse overall lateral neck control in the younger group (24 years; p = 0.04). Regional recurrence after salvage LND occurred within a median time interval of 20.0 months (2.9-121.3 months), of which 2% (8/429) developed in-field lateral neck recurrences. Of those with any lateral neck recurrence after salvage LND, 24/30 (80%) patients successfully underwent another LND, resulting in an ultimate 98% lateral neck regional control rate.Expert comprehensive LND of levels II-V is associated with few perioperative complications and results in very high in-field regional control rate and ultimate lateral neck control in recurrent/persistent WDTC.

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

Background The purpose of this retrospective analysis was to evaluate the benefits of an elective lateral neck dissection (ELND) in patients with medullary thyroid cancer (MTC) without radiographically apparent lateral neck metastases. Methods Patients with sporadic MTC without radiographic evidence of lateral neck metastasis who underwent definitive surgery were divided into 2 groups based on surgical approach: no ELND (the observation group) and ipsilateral or bilateral ELND (the ELND group). Primary outcomes were biochemical cure, locoregional recurrence, distant metastasis, and overall survival (OS). Results Sixty-six patients met inclusion criteria: 44 patients (67%) in the observation group and 22 patients (33%) in the ELND group. Two of 44 patients (5%) in the observation group developed subsequent (ipsilateral) lateral neck disease. At last follow-up, locoregional disease control rates among the observation and ELND groups were 98% and 100% (P > .999), respectively, whereas biochemical cure rates were 82% and 85% (P > .999), respectively, and 5-year OSs were 84% and 100% (P = .156), respectively. Conclusion Patients with MTC without lateral neck metastasis have similar biochemical cure rates with observation or elective dissection of lateral neck compartments.

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.

Pediatric papillary thyroid cancer (PTC) typically presents with more advanced disease as compared with adults, yet the prognosis, even in the presence of distant metastatic disease, is usually excellent. Systemic therapies other than radioactive iodine (RAI) are rarely required. Sorafenib is an orally administered multi-kinase inhibitor that has shown promise in the treatment of adults with advanced thyroid cancer, but it has not yet been studied in children with this disease.Our objective is to present an adolescent with a progressive RAI-resistant PTC who was successfully treated with sorafenib.A 14-year-old girl had progressive lung metastases from PTC despite previous therapies with almost 400 mCi (131)I. Sorafenib was initiated at a starting dose of 200 mg twice daily and decreased to a maintenance dose of 200 mg daily due to side effects that developed within 3 weeks of treatment. After 67 days on the lower dose, there was a dramatic improvement in the lung metastases. The patient was monitored while continuing thyrotropin-suppressive therapy only. Minimal regrowth of the pulmonary metastases was observed, and a second treatment course of sorafenib 200 mg every other day was equally successful in achieving a clinical response. Thyroglobulin autoantibodies declined over the course of therapy and observation.In the very rare case of the pediatric patient with progressive RAI-refractory PTC, for which no good systemic therapy exists, sorafenib may play an important role in the management of this disease.

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

Purpose To conduct a phase III trial of adjuvant 13-cis-retinoic acid (13cRA) plus interferon alfa (IFN-α) for preventing tumor recurrence and second primary tumors (SPTs) of skin squamous cell carcinoma (SCC) among patients with aggressive skin SCC. Patients and Methods Sixty-six patients with aggressive skin SCC were randomly assigned to receive either 6 months of combined 13cRA (1 mg/kg/d orally) and IFN-α (3 × 106 U subcutaneously three times per week) or no adjuvant therapy (control group) after SCC surgery and/or radiation. Results At 21.5 months median follow-up, treatment did not improve the time to tumor recurrence and SPT versus control (hazard ratio [HR], 1.13; 95% CI, 0.53 to 2.41), time to tumor recurrence (HR, 1.08; 95% CI, 0.43 to 2.72), or time to SPT (HR, 0.89; 95% CI, 0.27 to 2.93). Adjuvant 13cRA and IFN-α was moderately tolerable; 29% of patients in the treatment arm required dose reductions for grade 3 or 4 toxicities. Conclusion Results of this phase III trial do not support 13cRA plus IFN-α for adjuvant therapy of aggressive skin SCC. With high rates of tumor recurrence and SPTs, patients with aggressive skin SCC continue to have an unmet medical need, with devastating mortality, morbidity, and financial consequences. Promising agents with preclinical and early clinical results relevant to aggressive skin SCC deserve a high priority for future clinical drug development.

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

The UV radiation-mimetic chemical 4-nitroquinoline-1-oxide (4-NQO) is thought to induce squamous cell carcinoma (SCC) similar to those induced by UV radiation in animals. Therefore, we tested the hypothesis that cellular sensitivity to 4-NQO is associated with risk of developing skin cancer in a case-control study of 191 patients with nonmelanoma skin cancer (NMSC; 81 SCC and 110 basal cell carcinoma (BCC)) and 176 cancer-free controls. Short-term blood cultures were treated with 4-NQO at a final concentration of 10 microM for 24 hours and scored for chromatid breaks in 50 well-spread metaphases. We found that the mean frequency of chromatid breaks per cell (b/c) was significantly higher in the cases (mean+/-SD, 0.46+/-0.43 for SCC and 0.43+/-0.38 for BCC) than in the controls (0.25+/-0.25; P0.001 for both comparisons) and were associated with more-than-twofold increased risk for both SCC and BCC after adjustment for known risk factors. Therefore, our findings support the notion that sensitivity to 4-NQO reflects susceptibility to UV-induced NMSC. However, there is a lack of correlation between UVB-induced b/c and 4-NQO-induced b/c in this study population. Therefore, these findings need to be verified by additional studies.

Purpose To investigate the feasibility of combining concomitant boost accelerated radiation with docetaxel and cisplatin and assess the regimen's toxicity, locoregional control rate, and survival in patients with locally advanced head and neck cancer (HNSCC). Patients and Methods Patients with stage III-IV HNSCC were eligible. Phase I included two schedules of docetaxel and cisplatin: arm 1, once per week during weeks 1 to 4; arm 2, every 21 days for weeks 1 and 4. Radiation consisted of 72 Gy in 42 fractions over 6 weeks (concomitant boost). Results Twenty patients were enrolled in phase I. The arm 1 maximum-tolerated dose (MTD) was defined at docetaxel 15 mg/m2 and cisplatin 20 mg/m2 based on prolonged mucositis in 29% of patients. The initial dose level in arm 2 was above the MTD. In total, 52 patients were treated using the arm 1 regimen in phase II. Acute toxicity included grade 3 mucositis and dermatitis in 81% and 44% of patients. The 2-year locoregional control rate was 71%. The 2-year progression-free and overall survival rates were 61% and 65%. Median survival was 37.8 months. Late effects included feeding tube dependence in 17% of patients alive and free of disease. Conclusion Locoregional control, survival, and acute toxicity with this regimen were comparable with other trials utilizing taxanes and/or platins and concomitant conventional or altered fractionation radiation. Our data suggest that chemotherapy added to concomitant boost fractionation may increase rates of long-term feeding tube dependence. Phase III trials are needed to assess the contribution of concomitant boost fractionation to chemoradiotherapy.

Sarcomas of the head and neck are rare tumors derived from cells of mesenchymal origin. This article briefly discusses the epidemiology, etiology, and classification of head and neck sarcomas. Emphasis is placed on myofibrosarcoma, a malignant tumor of the myofibroblasts. Histologic criteria, prognostic factors, and the multidisciplinary management of these tumors are reviewed. A situation of a surgically excised myofibrosarcoma of the buccal mucosa is reported. In this patient, a stent was fabricated to stabilize a split-thickness skin graft used for the buccal mucosa reconstruction.

For patients with squamous cell carcinoma of the upper aerodigestive tract, appropriate management of the regional lymph nodes is an important and often controversial issue that has significant influence on survival. Over the years radical treatment either by surgery or radiotherapy contributed to improvement in prognosis. Recently, a more conservative approach has achieved a similar level of cancer control with less morbidity. This review considers the issues of selection of patients for treatment of the neck, choice of modality and extent of therapy, treatment of the contralateral neck, management of recurrence and influence of the site and status of the primary lesion.

Selective neck dissection is a modification of the more comprehensive modified radical or radical neck dissection that is designed to remove only those nodal levels considered to be at risk for harboring nodal metastases. The role of selective neck dissection continues to evolve: while initially designed as a staging and diagnostic procedure for patients without clinical evidence of nodal disease, a growing body of literature suggests that selective neck dissection has a therapeutic role in patients with clinical and histologic evidence of nodal metastases. The rationale behind selective neck dissection, its application in the clinically negative but histologically node-positive neck and the extended application of selective neck dissection in patients with clinical evidence of nodal disease are discussed.

BACKGROUND: Mutagen sensitivity, measured as mutagen-induced chromatid breaks per cell in primary lymphocytes in vitro, has been used to study susceptibility to various epithelial cancers. Patients with xeroderma pigmentosum are highly sensitive to ultraviolet (UV) light due to inherited defects in DNA repair and have a 1000-fold higher risk of UV-induced skin cancer than the general population. However, an association between UV-induced chromosomal aberrations and risk of skin cancer in the general population has not been established. METHODS: We assessed in vitro UVB-induced chromatid breaks in a hospital-based case-control study. The study included 469 patients with skin cancer (231 with nonmelanoma skin cancer [NMSC] and 238 with cutaneous malignant melanoma [CMM]) and 329 cancer-free control subjects. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: Compared with the frequency of UVB-induced chromatid breaks per cell in control subjects (mean = 0.28 breaks per cell, 95% CI = 0.27 to 0.30), that in NMSC patients (basal cell carcinoma [BCC], n = 143, mean = 0.36 breaks per cell, 95% CI = 0.33 to 0.39 and squamous cell carcinoma [SCC], n = 88, mean = 0.35 breaks per cell, 95% CI = 0.32 to 0.38) was higher (P = .001 and P < .001, respectively), but that in CMM case patients (mean = 0.30 breaks per cell, 95% CI = 0.28 to 0.33) was not (P = .22). A frequency of chromatid breaks per cell above the median of control subjects was associated with nearly threefold increased risks for BCC (OR = 2.78, 95% CI = 1.79 to 4.30) and SCC (OR = 2.62, 95% CI = 1.50 to 4.60), but not with an increased risk of CMM. A dose-response relationship was evident between mutagen sensitivity and risk for both BCC (Ptrend < .001) and SCC (Ptrend < .001). Multiplicative interactions between mutagen sensitivity and sun exposure variables on risk, particularly for sunburn in BCC and hair color, tanning ability, and family history of skin cancer in SCC, were seen for NMSC but not CMM. CONCLUSIONS: UVB-induced mutagen sensitivity may play a role in susceptibility to NMSC but not to CMM.

BACKGROUND Sinonasal neuroendocrine tumors are rare malignancies that are represented by a spectrum of histologies, including esthesioneuroblastoma (ENB), sinonasal undifferentiated carcinoma (SNUC), neuroendocrine carcinoma (NEC), and small cell carcinoma (SmCC). The authors reviewed their institutional experience to determine whether sinonasal neuroendocrine tumors of different histologies have distinct clinical characteristics that warrant individualized treatment approaches. METHODS The authors treated 72 adults with pathologically proven, nonmetastatic, primary sinonasal neuroendocrine tumors from 1982 to 2002. There were 31 patients with ENB, 16 patients with SNUC, 18 patients with NEC, and 7 patients with SmCC. Patients with ENB usually were treated with local therapy alone (surgery and/or radiotherapy); only 3 of 31 patients (9.7%) received treatment (radiation) to regional lymphatics, and only 5 of 31 patients (16.1%) received chemotherapy. In contrast, patients with non-ENB histologies usually received chemotherapy (10 of 16 patients with SNUC, 12 of 18 patients with NEC, and 5 of 7 patients with SmCC), and nonsurgical locoregional therapy was used more frequently (6 of 16 patients with SNUC, 4 of 18 patients with NEC, and 5 of 7 patients with SmCC). RESULTS The median follow-up for surviving patients was 81.5 months (range, 6–266 months). The Kaplan–Meier estimate of overall survival at 5 years was 93.1% for patients with ENB, 62.5% for patients with SNUC, 64.2% for patients with NEC, and 28.6% for patients with SmCC (P = 0.0029; log-rank test). The local control rate at 5 years also was superior for patients who had ENB (96.2%) compared with patients who had SNUC (78.6%), NEC (72.6%), or SmCC (66.7%) (P = 0.04). The regional failure (RF) rate at 5 years was 8.7% for patients with ENB, 15.6% for patients with SNUC, 12.9% for patients with NEC, and 44.4% for patients with SmCC. Additional late events increased the RF rate for patients with ENB to 31.9% at 10 years. The distant metastasis rate at 5 years was 0.0% for patients with ENB, 25.4% for patients with SNUC, 14.1% for patients with NEC, and 75.0% for patients with SmCC. CONCLUSIONS This spectrum of malignancies with neuroendocrine features shares a common site of origin within the head and neck, but their natural histories appear to diverge into two main groups: ENB and non-ENB. Patients with ENB had excellent local and distant control rates with local therapy alone. Given the higher rates of systemic failure for patients with SNUC, NEC, and SmCC, the authors favor the use of combined-modality therapy for these patients. Cancer 2004. © 2004 American Cancer Society.

BACKGROUND The objectives of this study were to determine the efficacy, organ-preservation rate, and safety of intraarterial (IA) cisplatin in combination with intravenous paclitaxel and ifosfamide in patients with locally advanced carcinoma of the paranasal sinuses who required orbital exenteration or major craniofacial resection for complete tumor resection. METHODS Patients were treated with intravenous paclitaxel (135 mg/m2) on Day 1, ifosfamide (1000 mg/m2) on Days 1–3, sodium mercaptoethanesulfonate (600 mg/m2) on Days 1–3, and IA cisplatin (100 mg/m2) on Day 1 every 21 days. RESULTS Of 24 study participants, 20 patients received at least 1 course of IA cisplatin, 1 patient had an early death, and 19 patients were evaluable for response. Five of those 19 patients (26%) achieved a complete response (CR), 6 patients (32%) achieved a partial response, and 8 patients (42%) had stable disease or developed progressive disease. Eye-sparing surgery followed by radiotherapy (RT) was feasible in 7 of 24 patients, RT was offered to only 7 patients, whereas 3 patients received chemotherapy and RT, 2 patients refused further therapy, 3 patients underwent craniofacial resection with orbitectomy, and 1 patient was treated systemically for metastatic disease. At the completion of treatment, 14 of 23 patients (61%) with locally advanced disease were disease free, and the orbit was preserved in 21 of 24 patients (88%). The overall survival, progression-free survival, and disease-free survival rates at 2 years were 60%, 50%, and 84%, respectively. Toxicity was substantial, with two patients experiencing cerebrovascular ischemia (one transient and one cerebrovascular accident) and three patients experiencing cranial neuropathy, which was reversible in two patients. CONCLUSIONS Despite the encouraging organ-preservation rate, the approach studied resulted in substantial toxicity, and more effective adjunctive therapy is needed. Alternative approaches, including the integration of targeted therapy agents in induction chemotherapy regimens followed by concomitant chemotherapy and RT or eye-sparing surgery, need further exploration. Cancer 2003. © 2003 American Cancer Society.

The primary goals of this interdisciplinary consensus statement are to define the eligibility criteria for management of recurrent and persistent cervical nodal disease in patients with differentiated thyroid cancer (DTC) and to review the risks and benefits of surgical intervention versus active surveillance.A writing group was convened by the Surgical Affairs Committee of the American Thyroid Association and was tasked with identifying the important clinical elements to consider when managing recurrent/persistent nodal disease in patients with DTC based on the available evidence in the literature and the group's collective experience.The decision on how best to manage individual patients with suspected recurrent/persistent nodal disease is challenging and requires the consideration of a significant number of variables outlined by the members of the interdisciplinary team. Here we report on the consensus opinions that were reached by the writing group regarding the technical and clinical issues encountered in this patient population.Identification of recurrent/persistent disease requires a team decision-making process that includes the patient and physicians as to what, if any, intervention should be performed to best control the disease while minimizing morbidity. Several management principles and variables involved in the decision making for surgery versus active surveillance were developed that should be taken into account when deciding how best to manage a patient with DTC and suspected recurrent or persistent cervical nodal disease.

The purpose of this article is to describe the use of transoral sonography in the diagnosis, fine-needle aspiration (FNA) biopsy, and intraoperative localization of retropharyngeal masses.We reviewed images and data for eight patients with a retropharyngeal mass identified on CT, MRI, or PET/CT as being suspicious for a metastatic Rouviere node. Transoral ultrasound was performed using a commercially available endorectal or endovaginal transducer. Transoral ultrasound-guided FNA biopsy was performed using a needle guide attached to the transducer shaft. Color and power Doppler imaging were used to identify the internal carotid artery and jugular vein and to plan the safest path to the targeted mass. The mass was intraoperatively localized by marking the mucosa with a permanent marker or by injecting methylene blue.There were six patients with a history of thyroid cancer (five papillary cancers and one medullary cancer), one patient with a history of esthesioneuroblastoma, and one patient with no history of cancer. Transoral ultrasound imaging was successful in all eight patients. Transoral ultrasound-guided FNA biopsy was performed in four patients, and a satisfactory cytologic diagnosis was obtained in all cases, although in one of those four cases, an additional core biopsy with an 18-gauge needle was performed to completely rule out lymphoma. Six patients underwent a transoral resection of the lesion. In three of them, the lesion was localized intraoperatively by making a mark on the mucosa and in one case by adding transoral ultrasound-guided injection of methylene blue.Transoral ultrasound can be used to visualize, sample, and localize abnormal masses in the retropharyngeal space, such as metastatic Rouviere nodes in patients with a history of head and neck cancer.

Importance Despite performing total thyroidectomy (TT), postoperative radioactive iodine (RAI) imaging often demonstrates the presence of residual thyroid tissue within the operative bed. Objective To measure the extent of TT using postoperative RAI imaging and assessing serum thyroglobulin (Tg) level for patients with differentiated thyroid carcinoma (DTC). Design, Setting, and Participants We evaluated 245 patients undergoing TT for clinically staged cT1-3N0M0 DTC, who underwent diagnostic postoperative RAI imaging. Interventions Total thyroidectomy. Main Outcomes and Measures On the basis of quantitative measurements, RAI uptake (RAIU) in the thyroid bed of 0.2% of administered activity was selected as the cutpoint to determine the presence or absence of thyroid remnant. Results By postoperative RAI imaging, TT in 106 patients (43%) resulted in RAIU of less than 0.2%. In the remaining 139 patients (57%), there was measurable iodine-avid thyroid tissue and/or tumor in the thyroid bed (n = 117 [84%]), the neck (n = 4 [3%]), or both (n = 18 [13%]). For the entire study population, mean 24-hour RAIU was 0.62%. Stimulated serum Tg levels were obtained in 232 of 245 patients (95%). Measurable stimulated Tg level (≥1 ng/mL) (to convert to micrograms per liter, multiply by 1) was found in 26 of 102 patients (25%) without thyroid remnant and in 87of 133 patients (65%) with thyroid remnant ( P Conclusions and Relevance A goal of postthyroidectomy RAIU of less than 0.2% helps maximize the likelihood of an unmeasurable postoperative Tg level, potentially simplifying follow-up evaluation and reducing the use of postoperative RAI in order to facilitate surveillance.

BACKGROUND Inverted papilloma (IP) is a frequent benign sinonasal tumor that is characterized histologically by squamous metaplasia, epithelial acanthosis, and hyperplasia of the nasal epithelium. Because of its high recurrence rate and malignant transformation potential, careful long-term follow up is necessary. METHODS The purpose of the current report was to study the expression of squamous cell carcinoma (SCC) antigen in sinonasal IPs and to evaluate the usefulness of SCC antigen as a biologic marker for the follow-up of patients with sinonasal IP. The expression of SCCA1 in three sinonasal IP cases, three sinonasal SCC cases, and cases of normal nasal epithelium were examined by Western blot analysis, and the SCCA1 expression pattern in 31 IP specimens and 4 carcinoma in IP specimens were evaluated immunohistochemically. The serum levels of SCC antigen in 11 patients with sinonasal IP also were analyzed. RESULTS SCCA1 was overexpressed in all three sinonasal IP tissues compared with sinonasal SCC tissues or normal nasal epithelium. SCCA1 cytoplasmic immunoreactivity was detected in the suprabasal epidermal keratinocytes of all 31 sinonasal IP cases. In the four carcinoma in IP specimens, SCCA1 expression in the papillomatous lesion was more intense than in the cancerous lesion. The serum SCC antigen level was high in 10 of 11 patients with IP (91%) and significantly decreased after surgical resection of the tumors. CONCLUSIONS The results of the current study indicate that SCCA1 frequently is overexpressed and may play a biologic role in the development of sinonasal IPs. Serum SCC antigen may be a useful biologic marker in patients with sinonasal IP. Cancer 2002;94:152–8. © 2002 American Cancer Society.

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.

Patients with head and neck cancers are excellent candidates for gene therapy. With few effective alternatives for patients with recurrent or locally metastatic disease, gene therapy offers a new approach for local control and the possibility to enhance other treatment modalities as well. Different therapeutic genes, including tumor suppressor genes, prodrug or suicide genes, and genes whose products enhance immunocompetence, can be delivered using specifically designed vectors with little toxicity or threat of undesirable viral spread. Two of these gene therapy agents, RPR/INGN 201 and HLA-B7 + beta2 microglobulin, have shown clinical activity, according to reports from phase I trials.

New approaches to the treatment of head and neck cancer involve delivery of the therapeutic agent by direct injection into the tumor lesions. This locoregional therapy allows adaptation of conventional chemotherapy agents, such as bleomycin and cisplatin, to achieve higher drug concentrations in the tumor while avoiding severe systemic toxicities. Novel therapies administered through tumor injection, such as gene transfer, photosensitization, and biologic response modification, have been investigated in preclinical studies and are currently in different phases of clinical trial.

Few situations present greater potential for airway management challenges than head and neck oncologic surgery. Such patients often present to the operating room with conditions that make mask ventilation and tracheal intubation potentially or obviously difficult following the induction of general anesthesia. 21 Frequently, the surgical procedures are lengthy, especially those involving plastic reconstruction of a large defect. The surgical team usually requires complete and easy access to the operative site, which is either the airway itself or an area near it. 20 The anesthesiologist may not be able to position him or herself near the patient's head, 30 yet, the surgical team expects the timely establishment of general anesthesia in the patient, a quiet operative field free of bulky equipment, and the patient's smooth emergence from anesthesia at the end of the operation. 20 This article describes a concise and safe approach for securing and managing the airways of patients undergoing surgical therapy for head and neck cancer. The approach is based on current airway management principles and techniques and emphasizes the prevention of airway problems associated with this type of surgery. 58

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 The clinical course of laryngeal squamous cell carcinoma (LSCC) varies considerably among patients. New biologic markers are needed to facilitate the stratification of individual patients within the conventional clinicopathologic stages of LSCC. METHODS Eighty-three LSCCs from an equal number of patients who received at least 10 years of follow-up were investigated for p53, p21WAF1/CIP1, and bcl-2 protein expression by immunohistochemical techniques. The results were correlated with various clinicopathologic parameters, DNA content, and patient outcome by univariate and multivariate statistical analyses. RESULTS Stage IV disease, large tumor size (>3 cm), positive lymph node status, extranodal extension, and p53 overexpression (in > 75% of cells) correlated significantly with prognosis in univariate analysis. There was no correlation between patient outcome and age, gender, race, histologic differentiation, or expression of bcl-2 or p21WAF1/CIP1. In multivariate analysis, lymph node status and p53 overexpression were the only factors significantly associated with survival. CONCLUSIONS High p53 expression and positive lymph node status were independent predictors of the outcomes of patients with LSCC. These factors may assist in prognostication and better classification of patients for treatment. Cancer 1998;82:2159-2165. © 1998 American Cancer Society.

PURPOSE Standard therapies of head and neck squamous cell carcinoma (HNSCC) often cause profound morbidity and have not significantly improved survival over the last 30 years. Preclinical studies showed that adenoviral vector delivery of the wild-type p53 gene reduced tumor growth in mouse xenograft models. Our purpose was to ascertain the safety and therapeutic potential of adenoviral (Ad)-p53 in advanced HNSCC. PATIENTS AND METHODS Patients with incurable recurrent local or regionally metastatic HNSCC received multiple intratumoral injections of Ad-p53, either with or without tumor resection. Patients were monitored for adverse events and antiadenoviral antibodies, tumors were monitored for response and p53 expression, and body fluids were analyzed for Ad-p53. RESULTS Tumors of 33 patients were injected with doses of up to 1 x 10(11) plaque-forming units (pfu). No dose-limiting toxicity or serious adverse events were noted. p53 expression was detected in tumor biopsies despite antibody responses after Ad-p53 injections. Clinical efficacy could be evaluated in 17 patients with nonresectable tumors: two patients showed objective tumor regressions of greater than 50%, six patients showed stable disease for up to 3.5 months, and nine patients showed progressive disease. One resectable patient was considered a complete pathologic response. Ad-p53 was detected in blood and urine in a dose-dependent fashion, and in sputum. CONCLUSION Patients were safely injected intratumorally with Ad-p53. Objective antitumor activity was detected in several patients. The infectious Ad-p53 in body fluids was asymptomatic, and suggests that systemic or regional treatment may be tolerable. These results suggest the further investigation of Ad-p53 as a therapeutic agent for patients with HNSCC.

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 Prospective randomized and retrospective studies on adjunctive chemotherapy in patients with advanced locoregional nasopharyngeal carcinoma have yielded conflicting results and the role of chemotherapy in this disease had not been clearly defined. The authors report the results of a single institution, matched cohort study comparing a group of 61 patients with advanced stage nasopharyngeal carcinoma treated with induction chemotherapy followed by radiation therapy with a matched group treated with radiotherapy alone. METHODS Between 1985 and 1992, 61 patients with advanced locoregional nasopharyngeal carcinoma received induction chemotherapy (cisplatin, 100 mg/m2 on Day 1 and 5-fluorouracil [5-FU], 1000 mg/m2, on Days 1-5) for 3 cycles followed by definitive radiation therapy (CT/RT group). This group was matched with a group of 61 patients from a population of 378 patients who received radiation therapy alone (RT group). Matching characteristics were T classification, N classification, histology, and level of cervical lymph node metastases. These characteristics were found to be significant determinants of distant metastasis (DM) and/or survival in a multivariate analysis that was performed in the entire radiotherapy group. Radiation therapy consisted of 66-72 gray in 6.5 to 7 weeks in both groups. Fifty-nine patients (97%) in both groups had Stage IV disease. Fifteen patients (25%) in both groups had lower cervical lymph node metastases. The tumor histologic types also had similar distribution in both groups. Median follow-up time among surviving patients of the CT/RT group was 4.9 years (range, 1.3-9.8 years). RESULTS The 5-year cumulative incidence of DM was 19 ± 5% for the CT/RT group and 34 ± 6% for the RT alone group (P = 0.019; log rank test). This reduction in distant failure was more prominent in patients with intermediate (N2-N3 disease; upper or midcervical lymph nodes), or high risk (N2-N3 disease; lower cervical lymph nodes) of DM. This reduction in DM translated into improvement in disease free survival (DFS) and overall survival (OS). The 5-year actuarial DFS rates were 64 ± 6% for the CT/RT group compared with 42 ± 7% for the RT group (P = 0.015). The 5-year actuarial OS rates were 69 ± 6% (CT/RT group) and 48 ± 7% (RT group), respectively (P = 0.012). The incidence of locoregional failure was slightly lower in the CT/RT group, but this difference did not reach statistical significance. There was no significant difference in the incidence and severity of acute mucositis between the two groups during radiotherapy. The 5-year cumulative incidence of Grade 3 or higher late complications was also similar in both groups (5 ± 3% in the CT/RT group and 8 ± 3% in the RT group; P = 0.721). CONCLUSIONS This matched cohort study provides additional evidence that induction cisplatin-5-FU chemotherapy prior to definitive radiation improves freedom from distant metastasis, DFS, and OS for patients with locoregional Stage IV nasopharyngeal carcinoma without increasing treatment-related morbidity. Cancer 1997; 79:1279-86. © 1997 American Cancer Society.

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.

Head and neck cancer continues to present a major therapeutic challenge to physicians. Recent advances in molecular or gene therapy have allowed us to reassess these malignancies and consider novel strategies for their management. Since the first clinical trial 5 years ago, it has become apparent that gene transfer is no longer a speculative approach for treating malignancies. Gene therapy involves the introduction of genetic material (DNA) into host cells to induce the expression of the therapeutic product of that gene. This review summarizes the most recent data concerning the use of gene therapy as a treatment strategy for head and neck solid malignancies. A brief overview of the basic concepts of gene therapy as well as future potential applications is also discussed.

To determine the complications of extensive cranial-base resection requiring free-tissue transfer (FTT) and the effect of these resections on local control and survival among patients with malignant neoplasms of the skull base.Before the advent of FTT, cranial-base surgery was often limited by our inability to adequately repair defects comprising communication between the central nervous system and upper aerodigestive tract. The use of FTT in cranial-base resections was therefore assessed to determine whether the improved procedure (ie, extensive resections) would improve local control and prolong survival.A retrospective review of 39 consecutive craniofacial resections with FTT reconstruction in patients with malignant neoplasms involving the cranial base.All 39 patients had malignant neoplasms, including 20 squamous cell carcinomas, eight basal cell carcinomas, two melanomas, two neuroendocrine carcinomas, two adenoid cystic carcinomas, and various other malignant neoplasms. Resections involved the anterior, middle, or posterior cranial fossa in 19 patients (49%), 10 patients (26%), and three patients (8%) of cases, respectively. The remaining seven surgeries (18%) involved resection of more than one of these cranial base sites.Early (14 days after surgery) complications occurred in 14 (36%) of 39 patients. Major complications included failure of microvascular anastomosis (n = 1), pneumonitis (n = 3), perioperative myocardial infarction (n = 1), and cerebrovascular accident (n = 1). The microvascular anastomosis failure was promptly treated with surgical intervention. Two patients (5%) experienced late postoperative complications; one had cellulitis at the donor site, and the other had pneumonitis. No perioperative deaths or complications such as meningitis, epidural abscess, or tension pneumocephalus occurred. The 2-year disease-specific survival rate was 55%, and the 2-year local control rate, 49%; both were determined by the Kaplan-Meier method. The nine patients who died of their disease had a median survival of 9 months. Log-rank testing showed that pathologically positive margins and transdural pathology were the most significant predictors of local recurrence and death of disease.Contemporary surgical approaches provide an opportunity for wide surgical excision of dura and skull-base structures that normally separate the intracranial and extracranial cavities. These major skull-base resections can be reconstructed safely and effectively with FTT. Patients with malignant neoplasms of the dura and skull base should be approached with the understanding that transdural disease portends an increased risk of local recurrence and death of disease.

The optimal management of structurally identified neck disease after initial surgery for thyroid carcinoma is nuanced and must be individually tailored to thepatient andhis or her disease. As such, it is ideally evaluated and managed with the patient from an experienced interdisciplinary program perspective. Proficiency and focused expertise in diagnostic imaging (ultrasound, cross-sectional, and nuclear), pathology, surgery, endocrinology, radiation oncology, and systemic therapy are integral components of such a program.Athoroughunderstandingof the risksof thediseaseandtreatmentoptions, includingmanagementof complications, is required. While no single algorithm is available, several large series, systematic reviews, andguidelineshavebeenpublished, fromwhich some generalities can be gleaned.1-8 The likelihood of persistent or recurrent structural disease can be predicted by tumor type, TNM stage, and American Thyroid Association (ATA) risk of recurrence. A structurally incomplete response to initial therapy implies disease that can be identified with imaging and is biopsy proven or highly likely to be malignant. For well-differentiated papillary and follicular thyroid carcinoma, this occurrence is observed in approximately 5% of ATA low-risk patients, 25% of ATA intermediate-risk patients, and 70% of ATA high-risk patients. The disease-specific mortality rate of patients with biochemically incomplete response but without structurally identifiable disease is essentially zero but increases to approximately 10% in patients with locoregional structural disease and approximately 60% in patients with distant disease. The histologic type of thyroid carcinoma significantly affects both prognosis and local, regional, or distant disease. Classic papillary thyroid carcinomahas a highpredilection for nodalmetastasis, whereas follicular carcinomas, including Hurthle and insular variants, have a higher likelihood of hematogenous and lymphatic spread, especially when vascular invasion is present, which in the neck often manifests as soft-tissue and local recurrence. Local invasion ismuchmorecommon insoft-tissue recurrence, althoughextranodal extension of regional metastatic disease can also be invasive. The morbidity of untreated invasive disease is inherently greater, arguing formore aggressivemanagement, but the surgical morbidity is also greater. The likelihood of surgical cure of persistent structural disease isolated to the neck is greatest for initially understaged and undertreated nodal disease, for which a compartment-oriented neck dissection has a 70% to 90% chance of complete eradication of structurally detectable disease.3 Biochemical resolution of disease is less likely, approximately 25% to 50% based on stimulated thyroglobulin levels.3 The structural burden of disease inversely correlates with the likelihood of surgical cure, with patients having multiple detectable lesions in multiple levels less likely curable than those with one or a few isolated lesions. The biochemical burden of disease also inversely correlates, such that patients with higher biochemical markers are much less likely to be cured surgically. The small subset of patients with radioiodine-avid, low-volume structural disease have the highest likelihood of biochemical cure (80%) with revision surgery and repeat radioiodine therapy.3 The goal of revision neck surgery is generally resolution of all structurally detectable disease, as well as associated occult microscopic disease, while minimizing the surgical morbidity. However, patients with known distant metastasis may occasionally benefit from revision neck surgery to prevent complications of locally invasive disease, especially involving the aerodigestive tract. A lateral neck dissection for differentiated thyroid cancer is a frequently performed surgery; however, the dissection is not the same as that for aerodigestive tract cancers, and nuances are worth elucidating. Surgery for lateral neck disease should include levels IIa to Vb to minimize risk to the marginal and spinal accessory nerves unless there is disease beyond these levels or bulky disease at the borders. The spinal accessory nerve should be identified and preserved in all lateral neck dissections for thyroid malignancies. The transverse cervical lymphatics, including the infraclavicular nodes, extending into level Vb and lymphatic contents posterior to the carotid artery in levels III and IV are the primary echelon of lateral neck nodal metastases due to the thyroid vasculature originating from the thyrocervical trunk inferiorly and external carotid superiorly. Meticulous dissection in the carotid and vertebral area is required, and control of chylous and lymphatic vessels is a necessary component of the dissection. Last, the lateral neck dissection must fully dissect level IIa anterior to the internal jugular vein in the subdigastric area, identify the hypoglossal nerve, and remove the nodal basins through to the transition to level VI superiorly. In the event of prior lateral neck surgery, more selective revision compartmental surgery may be appropriate to minimize the surgical morbidity.