Search

Recent advances in molecular biology have changed the way we approach, diagnose, and treat cancers of the head and neck. Notable advances in head and neck squamous cell carcinomas (HNSCC) include the association of tumor suppressor genes with the human papilloma virus (HPV) in a subset of patients without the traditional risk factors of smoking and alcohol use. The detection of viruses in head and neck malignancies lends not only important diagnostic but also prognostic information as in the case of both HPV in oropharyngeal squamous cell carcinoma and Epstein bar virus in nasopharyngeal carcinoma. Multiple gene mutations have now been detected in various head and neck cancers, including EGFR and p16 in HNSCC and BRAF and RET gene mutations in thyroid carcinomas. Novel molecular therapies are being developed specifically targeting these genes. The future of state of the art therapy in head and neck cancer is based on further advances in molecular biology. This chapter provides an overview of the most up to date understanding of the molecular biology underlying head and neck cancer pathology. We also highlight future directions in both diagnosis and treatment of head and neck cancers based on the most recent research advances.

Despite the improvement in survival of pediatric patients with rhabdomyosarcoma, the outcome of patients with sinonasal rhabdomyosarcoma is poor and has not significantly changed. Since few institutions have extensive experience with sinonasal rhabdomyosarcoma in children and adults, our objective was to determine prognostic factors and treatment outcomes for this rare malignancy.A retrospective review was performed of consecutive patients with sinonasal rhabdomyosarcoma treated at our institution from 1992 to 2012. Kaplan-Meier estimates and the log-rank test were performed to determine factors associated with disease recurrence and disease-specific survival.Initial remission was achieved in 12 of the 16 patients. Age younger than 18 years (n = 9) was a positive prognostic factor, as there were no recurrences (p0.01) and no deaths (p0.01). The alveolar subtype was a poor prognostic factor, as 4 of the 5 patients with this histology died of disease (p0.01), and both patients with initial remission developed recurrence (p0.01). Presentation with later tumor-node-metastasis classification of malignant tumors (TNM) stage was also significant for poorer survival, as 2 of the 3 patients with stage IV died of disease (p = 0.05). Patient sex and treatment modality were not significant.Although the sinonasal region is an unfavorable site for rhabdomyosarcomas, in our series patients younger than 18 years and those with embryonal or botryoid subtypes responded very well to current multimodality treatment. However, a poor prognostic trend is evident in patients with sinonasal alveolar rhabdomyosarcomas, as they appear to present more often with regional and distant metastases, have increased recurrence, and decreased survival.

Objective: The study was carried out in order to 1) evaluate features that could identify patients having increased risks of regional recurrences, and 2) examine the prognostic and therapeutic implications of elective neck dissection among patients who presented with early-stage oral tongue squamous cell carcinoma with clinically negative neck (T1cN0).Method: A retrospective chart review of oral tongue cancer at a single tertiary institution identified 123 patients with T1cN0 oral tongue squamous cell carcinoma who underwent surgical tumor extirpation with/without adjuvant radiation treatment and/or chemotherapy from 1990 through 2009. This database was used to identify characteristics that are associated with occult lymph node metastases and measurement of patient outcomes.Results: Eighty-nine patients underwent elective neck dissection, of which 20 patient specimens (22%) were found to harbor occult metastatic disease. However, no significant differences were noted in the frequency of regional recurrenc...

Objective: Advances in tissue engineering offer potential alternatives to current mandibular reconstructive techniques. However, prior to clinical translation of this technology, a relevant animal model must be used to validate possible interventions. This study aims to establish the critical size segmental mandibular defect that does not heal spontaneously in the rat.Method: Thirty rats underwent creation of 1 of 4 segmental mandibular defects: 0 mm, 2 mm, 3 mm, and 5 mm. All mandibular wounds were internally fixated with 1-mm microplates and screws. Rats were allowed to heal for 12 weeks, and then all mandibles were analyzed with micro-computed tomography (CT).Results: One rat was exsanguinated intraoperatively, and 1 mandible was fractured by the drill and the animal was euthanized. This resulted in 7 animals per group. No 5-mm segmental defects successfully healed, whereas all 0-mm and 1-mm defects had continuous bony growth across the original defect on micro-CT. Three of the 3-mm defects had bony co...

Objective: Metformin has been associated with decreased cancer risk and mortality. However, the effects of metformin on clinical outcomes in oral cavity and oropharyngeal squamous cell carcinoma (OC/OP SCCA) have not been defined. We aimed to evaluate the association of metformin use and cancer recurrence in diabetic patients with OC/OP SCCA.Method: We performed a retrospective review of all patients with diabetes mellitus type II treated at our tertiary medical center for OC/OP SCCA from 2001 to 2011. The patients’ demographics, cancer TNM stage, treatment, and outcomes were analyzed.Results: We identified 69 patients with diabetes mellitus type 2 and OC/OP SCCA from 2001 to 2011. Twenty-three patients were taking metformin (11 early stage and 12 late stage) and 46 patients were not taking metformin (20 early stage and 26 late stage). Kaplan-Meier (KM) analysis and coproportional hazard univariate (Coph) analysis were performed. For early stage patients, the KM curve is promising, and the HR from the Com...

Segmental mandibular defects can result after the treatment of various pathologic processes, including osteoradionecrosis, tumor resection, or fracture nonunion with sequestration. The variety of etiologies and the frequency of occurrence make the reconstruction of segmental mandibular defects a topic of significant interest. Despite these incentives, a well-established small-animal model of the segmental mandibulectomy, including composite resection, does not exist. The objective of this study is the creation of a reliable animal model that can be used to study the reconstruction of en bloc mandibular defects. Surgical techniques and an array of reconstructive options are described.Description of an animal model.Animal laboratory at a quaternary care university medical center.We present an Animal Research Oversight Committee-approved prospective analysis of survival operations in the rat model. A detailed, stepwise description of surgical technique and relevant intraoperative anatomy is presented. Postoperative management, early pitfalls, surgical complications, and future applications are discussed.A total of 72 operations were performed by a single individual between July and October 2010. Two intraoperative and 9 postoperative complications were recognized. There were 6 orocutaneous fistulas, 2 abscesses, and 1 seroma. There were 4 fatalities, which were attributed to anesthetic complications (2, intraoperative), hematoma formation (1, postoperative), and foreign-body aspiration (1, postoperative).This novel animal model reliably replicates the en bloc segmental mandibular defects seen in our patient population and can be manipulated to achieve a wide variety of research objectives.

Objective: Snail positivity is predictive of poorly differentiated, invasive, and regionally metastatic HNSCC tumors. We have demonstrated the role of Snail in the inflammation-induced promotion of EMT. Here, we investigate the capacity of Snail to drive EMT in human oral epithelial cell lines, and its ability to confer drug resistance.Method: Snail was overexpressed in HOK and OKF oral epithelial cell lines. AIG assays, wound healing assays, invasion and migration assays, spheroid modeling, and drug resistance assays were performed. Differential gene expression between Snail-overexpressing and control epithelial and tumor cell lines was evaluated using gene expression microarray analysis.Results: The overexpression of Snail in human oral epithelial cell lines (HOK, OKF) drives EMT. OKF-Snail and HOK-Snail lines demonstrate growth in anchorage-independent growth assays; a decreased capacity to form tight spheroids; increased resistance to erlotinib; and a highly invasive and migratory nature. Gene express...

Objective: Evaluate the trends of use of IMRT for head and neck cancer (HNC), with emphasis on Medicare reimbursement patterns and their effect on clinical use.Method: All patients are selected from the Surveillance, Epidemiology, and End Results (SEER) database with HNC who were treated with radiation. These were then subdivided into those that were treated with IMRT. We then analyzed Medicare records for reimbursement patterns for Planning and Delivery of IMRT (CPT Codes 77301 and 77418).Results: Regression analysis was then performed on the SEER data to evaluate cancer subsites, regional differences, and outcomes. Reimbursement for IMRT for Head and Neck cancer has increased since the introduction of CPT codes for Medicare from $1579 to $2643 from 2002 to 2010. In 2000 Medicare reimbursement for IMRT was 4x that of conventional radiation. This has more recently been adjusted to 3x conventional radiation. Compensation has been cited as a major factor in the adoption of this technology. The percentage of...

Objective: Evaluate the treatment results of buccal squamous cell carcinoma at a single institution during a 40-year period.Method: A retrospective review was performed by examining the records and reviewing the pathology of 48 patients with buccal squamous cell carcinoma treated at UCLA Medical Center from 1970 to 2009. Forty-eight patients were identified that received first-time surgical therapy for squamous cell carcinoma of the buccal mucosa and had adequate follow-up.Results: Treatment entailed surgery alone in 18 out of 48 patients (37.5%) and surgery followed by radiation therapy in 30 out of 48 patients (62.5%). Composite resection of the tumor was performed in 17 out of 48 patients (35.4%) and ipsilateral neck dissections were performed in 37 out of 48 patients (77.1%). One-year observed actuarial disease-free survival rates were 60%, 46%, 0%, and 40% for T1 through T4, respectively. Univariate analysis revealed increased age as a risk factor (P = .062), and multivariate analysis demonstrated ag...

Purpose The purpose of the study was to evaluate the treatment results of adenoid cystic carcinoma (ACC) of the airway at a single institution during a 30-year period. Materials and methods All cases of ACC of the airway over a 30-year period at one tertiary care institution were reviewed retrospectively. The demographics, treatment modalities, pathologic characteristics, and outcomes were evaluated. Results Eleven patients were treated for ACC of the airway with an age range of 25 to 72 years (median, 48 years). Six patients presented with ACC in the larynx, and 5 patients had ACC of the trachea. All patients underwent surgical excision and radiation; 9 of 11 patients had postoperative external beam radiation, 1 patient had preoperative external beam radiation, and the remaining patient had postoperative neutron beam therapy. Four patients with tracheal ACC and none with laryngeal ACC had microscopic or grossly positive margins after surgery ( P = .048). Eighty percent of patients had perineural invasion on pathology. Two patients with tracheal ACC had local recurrence of disease, which occurred at 1 and 10 months postoperatively. One patient with laryngeal ACC died of distant metastatic disease at 16 months. Follow-up varied from 4 to 168 months (median, 31 months). Conclusions We report high disease-free survival rates for ACC of the airway in patients who underwent definitive surgical resection followed by postoperative radiation. There is a higher risk for local recurrence and positive surgical margins with distal tracheal location. Distant disease ultimately determines survival.

To analyze outcomes in patients with squamous cell carcinoma (SCCA) of the tonsil from the years 1998 to 2006. To assess factors that may affect disease-specific survival, such as patient characteristics and/or treatment modality.National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program.The SEER database was used to perform a population-based cohort analysis for patients diagnosed with SCCA of the tonsil from 1998 to 2006. Disease-specific survival was correlated with sex, age, ethnicity, year of diagnosis, and treatment modality in a univariate Cox proportional hazards analysis and a multiple Cox-regression model with and without interaction effect.Applied inclusion criteria resulted in 8378 patients. Of this patient cohort, 80% were male and 85% were white. The mean patient age at diagnosis was 58.1 years. On univariate and multivariate analyses, ethnicities other than white carried a significantly higher rate of disease-specific death (hazard ratio = 1.71, P.001). Each additional year of age at the time of diagnosis carried approximately a 4% increase in likelihood of disease-specific death. With each passing year of time at diagnosis, patients carried a decreased risk of disease-specific death (P.001); this value was significant in all 3 statistical models. Patients who underwent external-beam radiation had a higher likelihood of disease-specific survival with each passing year at time of diagnosis.Population analysis based on the SEER database reveals increased disease-specific survival from tonsillar SCCA in more recent years. This may be because of earlier diagnosis, an increase in less aggressive subtypes of SCCA, and more effective treatment modalities.

Objectives/Hypothesis: We systematically reviewed the published experience on the treatment outcomes of patients with head and neck cancer of unknown primary (CUP) to determine if treatment modality affects survival outcomes. Study Design: Meta-analysis. Methods: A comprehensive literature search was performed for articles reporting survival outcomes for CUP in the head and neck published within the last 12 years. Results: Eighteen studies with 1,726 patients met the inclusion criteria. All studies reported at least 5-year survival outcomes. Thirteen of the 18 studies also reported 5-year survival based on N stage, and six reported 5-year survival based on presence of extracapsular extension (EC). Overall 5-year survival in the entire group was 48.6%. Five-year survival based on N stage was as follows: N1 = 60.8%, all N2 = 51.1%, N2a = 63.6%, N2b = 42.5%, N2c = 37.5%, and N3 = 26.3%, with P < .001 on multivariate analysis. Patients who underwent surgical treatment with either postoperative radiation or chemoradiation had a 5-year survival of 52.4% compared to 46.6% for those treated with chemoradiation alone; however, this difference was not statistically significant. Patients with EC had a 5-year disease-specific survival of 56.9% compared to 81.5% for those without EC (P = .01). Conclusions: In patients with CUP, survival outcomes are most significantly influenced by clinical stage at time of diagnosis. No significant 5-year survival difference was seen between patients treated with radiation or chemoradiation alone when compared to patients who also received surgical treatment.

Objective The aims of this study were to define a novel classification system of tumor perineural invasion (PNI) with respect to tumor/nerve involvement such as intratumoral (IT), peripheral, or extratumoral (ET) and to determine the prognostic significance of each of these histologic subcategories in patients with noncutaneous head and neck squamous cell carcinoma (HNSCC). Study design This study is a retrospective chart review and histologic analysis of patients with HNSCC in the setting of a tertiary care medical center. Methods A clinical chart review of 142 patients with HNSCC who underwent primary surgical treatment from January 2004 through December 2007 was performed. Clinical information collected included patient age, sex, alcohol and tobacco use, tumor location, TNM stage, postoperative adjuvant chemotherapy and/or radiation treatment, and patient outcome. For each case, PNI density, the distance of each PNI focus to the tumor edge, and size of the largest nerve involved were measured. Furthermore, PNI was subcategorized as IT, peripheral, or ET. A Cox regression analysis was performed to determine if PNI was related to regional disease recurrence. Kaplan-Meier survival analysis was also performed. Results Among the 142 patients, 37 (26%) had disease progression. The maximum extent of PNI was significantly correlated with disease-free survival on multivariate analysis (P = .019) and was also significantly related to disease-free survival when T stage (P = .017), N stage (P = .021), and T and N stages (P = .02) were added to the Cox regression model. Kaplan-Meier analysis demonstrated a trend toward increased disease-free survival of PNI negative and IT/peripheral PNI compared with ET PNI. Conclusion Perineural invasion is correlated with nodal status and T stage and is related to disease-free survival. It can be subcategorized as IT, peripheral, or ET. This novel classification system has important implications with regard to clinical outcome and may help define a cohort of patients that may require more aggressive management.

To further understanding of treatment of papillary thyroid carcinoma (PTC).The Surveillance, Epidemiology, and End Results Program database was searched for patients who had undergone surgery for PTC.Areas covered by Surveillance, Epidemiology, and End Results population-based registries.Patients who had undergone PTC surgery between January 1, 1988, and December 31, 2001, were included in the study.Disease-specific survival (DSS) and overall survival (OS).Of the total 22,724 patients with PTC, 5964 patients underwent lobectomy. There were 2138 total and 471 disease-specific deaths. Controlling for tumor size, multivariate analysis revealed no survival difference between patients who had undergone total thyroidectomy and those who had undergone lobectomy. Increased tumor size, extrathyroidal extent, positive nodal status, and increased age displayed significantly worse DSS and OS (P.001). Histologically, follicular PTC subtype did not affect DSS or OS. Patients who had received radioactive iodine had poorer DSS but improved OS. Patients undergoing external beam radiation therapy had poor DSS (hazard ratio, 4.48; 95% confidence interval, 3.30-6.06; P.001) and OS (1.71; 1.42-2.07; P.001).The results of this study compel us to reinvestigate the current PTC surgical recommendations of total thyroidectomy based on tumor size because this may not affect survival across all populations. In addition, the current use of external beam radiation therapy for the treatment of PTC should be reexamined.

Objective: Human papilloma virus (HPV) and p16INKa (p16) positivity in head and neck squamous cell carcinomas (HNSCCs) is currently thought to be an encouraging prognostic indicator. However, the histopathologic changes responsible for this behavior are poorly understood. It is our objective to elucidate these histopathologic characteristics to help define the clinical utility of these markers. Design: Retrospective cohort study. Methods: 71 HNSCC tumors between July 1, 2008 and August 30, 2009 were examined for HPV, p16, and epidermal growth factor receptor (EGFR). Specified pathologic features were examined: perivascular invasion (PVI), perineural invasion (PNI), grade of squamous differentiation, basaloid classification. Results: HPV and p16 had no direct impact on perineural or perivascular invasion. However, HPV and p16 were strongly predictive of poorly differentiated tumors, as well as basaloid squamous cell carcinoma (SCCA) (P < .001). Additionally, upon multivariate analysis, HPV(+) and p16(+) tumors had an increased risk of nodal metastasis (HPV: odds ratio [OR] = 23.9 (2.2, 265.1) p = .01; p16: OR = 6.5 (1.4, 31.2) p = .02; PVI: OR = 6.0 (1.6, 22.8) p < .01). The area under the curve (AUC) of receiver operating characteristic (ROC) curves demonstrated improved predictive value for lymph node metastasis above standard H&E histopathologic features (76.7%) for both HPV (83.2%) and p16 (81.3%) individually. Conclusions: HPV(+) and p16(+) are highly predictive for poorly differentiated tumors and basaloid SCCA. Additionally, HPV and p16 positivity demonstrate superior predictive value for lymph node metastasis above standard H&E histopathologic features. Although exact recommendations should be tempered by considerations of primary tumor subsite, T-stage, and depth of invasion, head and neck multidisciplinary teams should strongly consider aggressive lymph node treatment for any HPV(+) or p16(+) tumor. Laryngoscope, 2010

Background Sensitivity and specificity data regarding positron emission tomography (PET) and PET/CT for surveillance of well-differentiated thyroid cancer does not evaluate subtypes separately. Papillary and follicular thyroid carcinoma may have different characteristics on PET/CT imaging and so should be investigated individually. Methods This is a systematic meta-analysis of studies using PET for surveillance in patients with papillary thyroid carcinoma. Results Using different statistical models, combined sensitivity of PET and PET/CT for papillary thyroid carcinoma was 77% by the fixed effect model and 82% by the random-effects model, specificity was calculated as 85% and 84%, respectively. Meta-regression was performed to evaluate whether I-131 negativity affected PET positivity; no correlation between I-131 negativity and PET sensitivity or specificity was found. Conclusion PET and PET/CT are useful modalities in surveillance of papillary thyroid carcinoma. To our knowledge, this is the first study to examine papillary thyroid carcinoma independently of other subtypes of well-differentiated thyroid carcinoma. © 2010 Wiley Periodicals, Inc. Head Neck, 2011

Previous studies have shown Snail expression integral to the epithelial-mesenchymal transition during tumor progression. However, its behavior in clinical head and neck squamous cell carcinomas (HNSCCs) is yet undefined. We therefore sought to (1) investigate clinical and histopathologic characteristics of Snail-positive HNSCC and (2) understand the link between Snail and other commonly used HNSCC tumor markers.A retrospective case-control study was conducted.This study was conducted in a large-scale academic center.Of 51 consecutive HNSCC, 42 surgical resections were included.Two separate pathologists performed standard histopathologic reviews along with immunohistochemistries (Snail, E-cadherin, p16, epidermal growth factor receptor [EGFR]) and in situ hybridization (human papilloma virus [HPV]). Medical review for all cases was performed.Twenty-two (52%) of 42 cases stained 4+ Snail (75% staining). The remaining 20 cases were considered negative. Snail was strongly inversely related to E-cadherin expression (ρ = -0.69, P.001), but statistically independent from HPV, p16, or EGFR expression. Snail(+) tumors were equally represented from each anatomic subsite. Snail(+) tumors were strongly associated with poor differentiation (P.001) and basaloid classification (P = .004). Snail(+) tumors were also strongly associated with lymphovascular invasion (P = .02), but not perineural invasion. Ultimately, 11 (50%) of 22 of Snail(+) tumors demonstrated positive nodal metastasis and 11 (79%) of 14 node-positive cases were Snail(+) (P = .02).This pilot study provides promising evidence of Snail' role as a molecular prognostic marker for HNSCC. Snail positivity is significantly predictive of poorly differentiated, lymphovascular invasive, as well as regionally metastatic tumors. Because Snail positivity appears independent of HPV, p16, and EGFR expression, Snail may prove to improve upon these markers' predictive limitations.

Purpose Using a transnasal, transfacial, anterior skull base approach, we have removed olfactory neuroblastomas (OFN) obviating the need for a frontal craniotomy. The objectives were to present our surgical approach in achieving clear margins, to assess patient survival, and to recommend eligibility criteria. Materials and methods A retrospective chart review was done to identify patients diagnosed with OFN who underwent this surgical approach. Thirteen patients were identified who underwent our pictorially described approach. Postoperative assessment of pathologic margins, patient survival, and limitations of surgical approach was determined. Results Of the 13 patients, 12 (92%) had clear postsurgical margins. One patient had residual intracranial disease due to coagulopathy preventing further resection. Twelve patients remain alive with 10 patients remaining disease-free (follow-up ranging from 11 to 64 months). Three patients presented with recurrent disease initially, with 2 having had subsequent repeat local and regional recurrences, respectively; one of whom died recently of the rerecurrent disease. One patient had a postoperative cerebrospinal fluid leak repaired via the original surgical approach. Conclusions Although craniofacial resection remains an accepted approach for surgical treatment of OFN, we have adopted a transnasal, transfacial approach eliminating the need for a frontal craniotomy. This approach allows for adequate exposure of the cribriform plate, dura, and anterior skull base. Our technique minimizes dural defects and prevents many craniotomy-associated complications, including frontal lobe retraction. Long-term follow-up is needed to compare survival using this approach; however, our results to date are quite promising.

Purpose: As a transcriptional repressor of E-cadherin, Snail has predominantly been associated with epithelial-mesenchymal transition, invasion, and metastasis. However, other important Snail-dependent malignant phenotypes have not been fully explored. Here, we investigate the contributions of Snail to the progression of nonsmall cell lung cancer (NSCLC). Experimental Design: Immunohistochemistry was done to quantify and localize Snail in human lung cancer tissues, and tissue microarray analysis was used to correlate these findings with survival. NSCLC cell lines gene-modified to stably overexpress Snail were evaluated in vivo in two severe combined immunodeficiency murine tumor models. Differential gene expression between Snail-overexpressing and control cell lines was evaluated using gene expression microarray analysis. Results: Snail is upregulated in human NSCLC tissue, and high levels of Snail expression correlate with decreased survival (P < 0.026). In a heterotopic model, mice bearing Snail-overexpressing tumors developed increased primary tumor burden (P = 0.008). In an orthotopic model, mice bearing Snail-overexpressing tumors also showed a trend toward increased metastases. In addition, Snail overexpression led to increased angiogenesis in primary tumors as measured by MECA-32 (P < 0.05) positivity and CXCL8 (P = 0.002) and CXCL5 (P = 0.0003) concentrations in tumor homogenates. Demonstrating the importance of these proangiogenic chemokines, the Snail-mediated increase in tumor burden was abrogated with CXCR2 blockade. Gene expression analysis also revealed Snail-associated differential gene expression with the potential to affect angiogenesis and diverse aspects of lung cancer progression. Conclusion: Snail upregulation plays a role in human NSCLC by promoting tumor progression mediated by CXCR2 ligands. (Clin Cancer Res 2009;15(22):68209)

To evaluate the treatment results of pleomorphic adenoma (PA) of the parapharyngeal space at a single institution during a 30-year period.A retrospective review.This study was performed by examining the records and reviewing the pathology of 44 patients with PA of the parapharyngeal space treated at a single medical center from January 1975 to November 2005.Of the 44 patients with PA, 35 patients underwent 38 excisions. Eleven men and 27 women were treated surgically. Follow-up varied from 24 months to 180 months. There were three recurrences in two patients. Recurrence rates at 5 and 10 years were equal at 7.9%. Gender, age, tumor volume, surgical approach, pathologic surgical margin status, and prior resections were evaluated for significant prognostic factors. Advanced age proved a poor prognostic indicator (P.05). History of prior resection (P.01) was significant for recurrence. Positive surgical margins (P = .69) proved a negative association.We report low recurrence rates in this patient population with two important prognostic indicators. History of prior resection is significant to predict recurrence. Interestingly, positive surgical margins are actually shown not to effect risk of recurrence. Local recurrence of the tumor is associated with further recurrence and less favorable prognosis.

Objectives To determine the role of ZEB1 in the inflammation-induced promotion of the epithelial-mesenchymal transition (EMT) in head and neck squamous cell carcinoma (HNSCC). Study Design A molecular biology study. Real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), Western blot analysis, and immunohistochemical staining of human HNSCC tissue sections were used to determine how inflammation affects the transcriptional repressor, ZEB1. Setting An academic hospital laboratory. Subjects and Methods Relative ZEB1 RNA levels were determined by RT-PCR, and protein expression was evaluated in situ by immunohistochemical staining of human HNSCC tissue sections. Results IL-1β-treated HNSCC cell lines demonstrated a significant decrease in E-cadherin mRNA and an increase in the mRNA expression of the transcriptional repressor ZEB1. IL-1β exposure led to enhanced ZEB1 binding at the chromatin level, as determined by chromatin immunoprecipitation assays (ChIP). An inverse relationship between ZEB1 and E-cadherin was demonstrated in situ by immunohistochemical staining of human HNSCC tissue sections. Conclusions Our recent investigations indicate that inflammatory mediators are potent regulators of EMT in HNSCC. This is the first report indicating the role of ZEB1 in the inflammation-induced promotion of EMT in HNSCC. This newly defined pathway for transcriptional regulation of E-cadherin in HNSCC has important implications for targeted chemoprevention and therapy.

Purpose: Inflammatory cytokines have been implicated in the progression of head and neck squamous cell carcinoma (HNSCC). Herein we investigate the mechanisms by which interleukin-1β (IL-1β) might contribute to Epithelial-Mesenchymal Transition (EMT) in HNSCC. Experimental Design: We evaluated the effect of IL-1β on the molecular events of EMT in surgical specimens and HNSCC cell lines. We examined the correlation with tumor histologic features, and a SCID xenograft model was used to assess the effects of Snail overexpression. Results: Cyclooxygenase-2 (COX-2)-dependent pathways contribute to the modulation of E-cadherin expression in HNSCC. An inverse relationship between COX-2 and E-cadherin was shown in situ by double immunohistochemical staining of human HNSCC tissue sections. Treatment of HNSCC cells with IL-1β caused the downregulation of E-cadherin expression and upregulation of COX-2 expression. This effect was blocked in the presence of COX-2 small hairpin RNA. IL-1β–treated HNSCC cell lines showed a significant decrease in E-cadherin mRNA and an increase in the mRNA expression of the transcriptional repressor Snail. IL-1β exposure led to enhanced Snail binding at the chromatin level. Small hairpin RNA–mediated knockdown of Snail interrupted the capacity of IL-1β to downregulate E-cadherin. In a SCID xenograft model, HNSCC Snail-overexpressing cells showed significantly increased primary and metastatic tumor burdens. Conclusions: IL-1β modulates Snail and thereby regulates COX-2–dependent E-cadherin expression in HNSCC. This is the first report indicating the role of Snail in the inflammation-induced promotion of EMT in HNSCC. This newly defined pathway for transcriptional regulation of E-cadherin in HNSCC has important implications for targeted chemoprevention and therapy. (Clin Cancer Res 2009;15(19):6018–27)

Inflammation is an important contributor to lung tumor development and progression. In addition, inflammatory signaling may promote epithelial to mesenchymal transition, development of aggressive metastatic tumor phenotypes, and play a role in resistance to targeted therapies. New insights in inflammatory signaling have led to the evaluation of combination therapies that target these specific pathways. In addition to developing the optimal combination of targeted agents, biomarker-based selection of patients who will likely benefit will be critical to the success of this strategy. Here we focus on the potential contribution of inflammatory mediator-induced resistance to epidermal growth factor receptor tyrosine kinase inhibitors.

An immune tolerant tumor microenvironment promotes immune evasion of lung cancer. Agents that antagonize immune tolerance will thus aid the fight against this devastating disease. Members of the tumor necrosis factor receptor (TNFR) family modulate the magnitude, duration and phenotype of immune responsiveness to antigens. Among these, GITR expressed on immune cells functions as a key regulator in inflammatory and immune responses. Here, we evaluate the GITR agonistic antibody (DTA-1) as a mono-therapy and in combination with therapeutic vaccination in murine lung cancer models. We found that DTA-1 treatment of tumor-bearing mice increased: (i) the frequency and activation of intratumoral natural killer (NK) cells and T lymphocytes, (ii) the antigen presenting cell (APC) activity in the tumor, and (iii) systemic T-cell specific tumor cell cytolysis. DTA-1 treatment enhanced tumor cell apoptosis as quantified by cleaved caspase-3 staining in the tumors. DTA-1 treatment increased expression of IFNγ, TNFα and IL-12 but reduced IL-10 levels in tumors. Furthermore, increased anti-angiogenic chemokines corresponding with decreased pro-angiogenic chemokine levels correlated with reduced expression of the endothelial cell marker Meca 32 in the tumors of DTA-1 treated mice. In accordance, there was reduced tumor growth (8-fold by weight) in the DTA-1 treatment group. NK cell depletion markedly inhibited the antitumor response elicited by DTA-1. DTA-1 combined with therapeutic vaccination caused tumor rejection in 38% of mice and a 20-fold reduction in tumor burden in the remaining mice relative to control. Mice that rejected tumors following therapy developed immunological memory against subsequent re-challenge. Our data demonstrates GITR agonist antibody activated NK cell and T lymphocyte activity, and enhanced therapeutic vaccination responses against lung cancer.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world and affects 50,000 Americans annually. During the past 20 years, treatments for HNSCC have changed dramatically due largely to the advent of novel approaches such as combined modality therapy, as well as improvements in surgical and radiotherapeutic techniques. Ongoing advances in the multidisciplinary management of this complex and multivariate disease process are resulting in improved function, quality of life and survival. Here, we review state-of-the-art therapy and presents selected advances in the treatment of head and neck cancer.

Purpose The purpose of this study is to explore the presence of informative RNA biomarkers from human serum transcriptome, and evaluate the serum transcriptome diagnostics for disease detection. Oral squamous cell carcinoma (OSCC) was selected as the proof-of-concept disease. Patients and Methods Blood samples were collected from patients (n = 32) with primary T1/T2 OSCC and matched healthy patients (n = 35). Circulating RNA was isolated from serum and linearly amplified using T7 polymerase. Microarrays were applied for profiling transcriptome in serum from 10 cancer patients and controls. The differential gene expression was analyzed by combining the present calls, t tests, and fold-change statistics. Quantitative polymerase chain reaction (PCR) was used to validate the selected candidate RNA markers identified by microarray. Receiver operating characteristic curve and classification models were exploited to evaluate the diagnostic power of these markers for OSCC. Results Human serum circulating mRNAs were presented by reverse transcriptase PCR. Microarray identified 2,623 ± 868 probes assigned present calls in OSCC (n = 10) versus 1,792 ± 165 in healthy patients (n = 10), indicating a higher complexity of serum transciptome in OSCC patients (P = .002, Wilcoxon test). Three hundred thirty-five serum RNAs exhibited significantly differential expression level between the two groups (P < .05, t test; fold ≥ 2). Five cancer-related gene transcripts were consistently validated by quantitative PCR on serum from OSCC patients (n = 32) and controls (n = 35). The best combination of biomarkers yielded a receiver operating characteristic curve value of 88%, sensitivity (91%), and specificity (71%) in distinguishing OSCC. Conclusion The utility of serum transcriptome diagnostics is successfully demonstrated for OSCC detection. This novel concept could be developed as an adjunctive tool for disease diagnosis.

Importance There is a need for larger studies characterizing the effect of tumor grade on survival for patients with esthesioneuroblastoma. Objective To investigate prognostic factors for survival in patients diagnosed with esthesioneuroblastoma, including emphasis on tumor grade. Design, Setting, and Participants Retrospective, population-based cohort study of patients in the Surveillance, Epidemiology, and End Results (SEER) tumor registry who were diagnosed with esthesioneuroblastoma from January 1, 1973, to January 1, 2010. The last date of survival follow-up was 2013. Main Outcomes and Measures Overall and disease-specific survival. Results The cohort included 281 patients with a mean age of 52 years. There were 154 males (54.8%) and 127 females (45.2%). Kaplan-Meier analysis demonstrated an overall and disease-specific survival rate of 61% and 70% at 5 years and 50% and 64% at 10 years, respectively. Multivariable Cox regression analysis showed that advanced tumor grade and modified Kadish stage (hazard ratio, 4.930; 95% CI, 2.635-9.223; P = .001) portended worse disease-specific survival, and radiation therapy (hazard ratio, 0.499; 95% CI, 0.272-0.916; P = .03) improved disease-specific survival. Patients with low-grade tumors (grades I and II) demonstrated an overall and disease-specific survival rate of 84% and 92% at 5 years and 67% and 87% at 10 years, respectively. Multivariable analysis of low-grade tumors only revealed receiving surgery ( P = .004) as an independent positive predictor of disease-specific survival. High-grade tumors (grades III and IV) demonstrated overall and disease-specific survival of 40% and 50% at 5 years and 34% and 43% at 10 years, respectively. Multivariable analysis of high-grade tumors showed modified Kadish stage (hazard ratio, 2.025; 95% CI, 1.430-2.866; P P = .02) independently predicted improved disease-specific survival. Conclusions and Relevance Here, to our knowledge, we report the largest study investigating prognostic factors for survival, with the inclusion of tumor grade, in patients diagnosed with esthesioneuroblastoma. Patients with high-grade tumors had substantially worse survival rates than patients with low-grade tumors. Multivariable analysis revealed only receiving surgery as an independent predictor of disease-specific survival for patients with low-grade tumors, while modified Kadish stage and postoperative radiation therapy were significant factors in predicting disease-specific survival in patients with high-grade tumors. This study highlights the growing evidence that tumor grade should be a key factor in predicting survival in patients with esthesioneuroblastoma, and that adjuvant radiation therapy improves survival rates among patients with high-grade, but not low-grade, tumors.

Purpose: Oral fluid (saliva) meets the demand for noninvasive, accessible, and highly efficient diagnostic medium. Recent discovery that a large panel of human RNA can be reliably detected in saliva gives rise to a novel clinical approach, salivary transcriptome diagnostics. The purpose of this study is to evaluate the diagnostic value of this new approach by using oral squamous cell carcinoma (OSCC) as the proof-of-principle disease. Experimental Design: Unstimulated saliva was collected from patients (n = 32) with primary T1/T2 OSCC and normal subjects (n = 32) with matched age, gender, and smoking history. RNA isolation was done from the saliva supernatant, followed by two-round linear amplification with T7 RNA polymerase. Human Genome U133A microarrays were applied for profiling human salivary transcriptome. The different gene expression patterns were analyzed by combining a t test comparison and a fold-change analysis on 10 matched cancer patients and controls. Quantitative polymerase chain reaction (qPCR) was used to validate the selected genes that showed significant difference (P < 0.01) by microarray. The predictive power of these salivary mRNA biomarkers was analyzed by receiver operating characteristic curve and classification models. Results: Microarray analysis showed there are 1,679 genes exhibited significantly different expression level in saliva between cancer patients and controls (P < 0.05). Seven cancer-related mRNA biomarkers that exhibited at least a 3.5-fold elevation in OSCC saliva (P < 0.01) were consistently validated by qPCR on saliva samples from OSCC patients (n = 32) and controls (n = 32). These potential salivary RNA biomarkers are transcripts of IL8, IL1B, DUSP1, HA3, OAZ1, S100P, and SAT. The combinations of these biomarkers yielded sensitivity (91%) and specificity (91%) in distinguishing OSCC from the controls. Conclusions: The utility of salivary transcriptome diagnostics is successfully demonstrated in this study for oral cancer detection. This novel clinical approach could be exploited to a robust, high-throughput, and reproducible tool for early cancer detection. Salivary transcriptome profiling can be applied to evaluate its usefulness for other major disease applications as well as for normal health surveillance.

Since morbidity and mortality rates due to oral cavity and oropharyngeal squamous cell carcinoma (OSCC) have improved little in the past 30 years, early detection or prevention of this disease is likely to be most effective. Using laser-capture microdissection, we have identified the expression of 2 cellular genes that are uniquely associated with OSCC: interleukin (IL) 6 and IL-8. These cytokines may contribute to the pathogenesis of this disease, and have been linked with increased tumor growth and metastasis.To investigate whether IL-6 and/or IL-8 could serve as informative biomarkers for OSCC in saliva and/or serum and to determine if there is a role for saliva as a diagnostic medium for OSCC.Patients with newly diagnosed T1 or T2 oral cavity or oropharyngeal histologically confirmed squamous cell carcinoma were recruited for the study. Age and sex-matched disease-free subjects were used as controls. Using quantitative real-time polymerase chain reaction analysis and enzyme-linked immunosorbent assay, we respectively assessed the expression of IL-6 and IL-8 in serum (controls, n = 32; patients with OSCC, n = 19) and saliva (controls, n = 32; patients with OSCC, n = 32) at the messenger RNA (mRNA) and protein levels.Specificity and sensitivity of these biomarkers for OSCC and their predictive value.Interleukin 8 was detected at higher concentrations in saliva (P.01) and IL-6 was detected at higher concentrations in serum of patients with OSCC (P.01). We confirmed these results at both the mRNA and the protein levels, and the results were concordant. The concentration of IL-8 in saliva and IL-6 in serum did not appear to be associated with sex, age, or alcohol or tobacco use (P.75). Using statistical analysis, we were able to determine the threshold value, sensitivity, and specificity of each biomarker, as well as a combination of biomarkers, for detecting OSCC.Our findings indicate that IL-8 in saliva and IL-6 in serum hold promise as biomarkers for OSCC. A saliva-based test could be a cost-effective adjunctive tool in the diagnosis and follow-up of patients with OSCC.

Problem: Since morbidity and mortality rates due to oral cavity and oropharyngeal squamous cell carcinoma (OSCC) have improved little in the past 30 years, early detection or prevention of this disease is likely to be most effective. Using laser-capture microdissection, we identified the expression of 2 cellular genes that are uniquely associated with OSCC: IL-6 and IL-8. We then set out to investigate whether IL-6 and/or IL-8 could serve as informative biomarkers for OSCC in patient saliva and/or serum and to determine if there is a role for saliva as a diagnostic medium for OSCC. Methods: Patients with newly diagnosed T1 or T2 oral cavity (OC) or oropharyngeal (OP) histologically confirmed SCCA were recruited for the study. Age and sex-matched disease-free subjects were used as controls. Using quantitative real-time PCR and ELISA, we respectively assessed the expression of IL-6 and IL-8 in serum (controls, n = 32; cancer patients, n = 19) and saliva (controls, n = 32; cancer patients, n = 32) at the messenger RNA (mRNA) and protein levels. Results: IL-8 was detected at higher concentrations in saliva ( P P P > 0.75). Using statistical analysis, we were able to determine the threshold value, sensitivity, and specificity of each biomarker, as well as a combination of biomarkers, Conclusion: Our findings indicate that IL-8 in saliva, and IL-6 in serum hold promise as biomarkers for OSCC. Significance: A saliva-based test could be a cost-effective adjunct tool in the diagnosis and follow-up of patients with OSCC. Support: This study was supported by NIH grant UO1-DE15018 and an Interdisciplinary Cancer Research Grant from the UCLA Jonsson Cancer Center.

Introduction : Parotid gland injuries occur infrequently following blunt trauma, which typically involves significant force resulting in complicated gland injury. Case report : We present a case of uncomplicated parotid gland injury that resolved with conservative management. Discussion : Injury to the parotid gland can result in complicated gland injury involving facial nerve neuropathy, hematoma or pseudocyst formation. Patients with blunt trauma to the parotid gland should be evaluated for any associated injury and be managed conservatively for uncomplicated injury.

Objective: Head and neck Squamous cell carcinoma (HNSCC) is difficult to resect completely by surgery due to complicated context and therefore exhibits high recurrence rate in the patient. To reduce tumor recurrence after surgery, we developed a biodegradable polymer to deliver CCL21 cytokine and cisplatin, and evaluate its efficacy in a partially resected xenograft animal model of HNSCC. Study Design: in vivo study. Setting: Academic research laboratory. Subjects and Methods: After xenograft HNSCC tumors were established by subcutaneous injection, C3H/HeJ mice underwent surgery to debulk their tumors to a size of 0.5x0.5x0.5 cm3 and received different polymer implantation. For cytokine studies, mice were grouped into: (1) no polymer; (2) plain polymer; (3) plain polymer with intratumoral injection of recombinant CCL21 twice a week; (4) polymer containing parental dendritic cells; (5) polymer containing dendritic cells secreting CCL21 (DC-CCL21). For cisplatin studies, mice were randomized to receive implantation of (1) no polymer; (2) plain polymer; (3) plain polymer with local cisplatin injection; (4) cisplatin polymer. The two groups of mice implanted with cisplatin polymer or no polymer were further randomized to receive (1) 4 Grays external beam radiation for 4 days; (2) no radiation. Tumor size was measured until the mice were euthanized. At necropsy, the tumors were excised and weighed. Results: Our results using this novel polymer platform demonstrate a significant reduction in tumor growth. The DC-CCL21 polymer reduced SCCVII/SF tumors in the C3H/HeJ mice by over 41% compared to the control groups (p Conclusion: Herein we demonstrate the efficacy of a novel polymer platform in delivering cisplatin and cytokines to a partially resected SCC in a murine model. We also demonstrate that we can effectively grow dendritic cells in the polymer that can actively secrete CCL21. Our results indicate that this polymer may represent a new therapeutic modality for patients with HNSCC. Once this polymer platform is optimized we will plan for validation in the context of a prospective trial in patients with unresectable advanced or recurrent HNSCC. Citation Format: Yuan Lin, Sherven Sharma, Steven M. Dubinett, Ben Wu, Maie St. John. A novel modular polymer platform for the treatment of oral and head and neck carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4581. doi:10.1158/1538-7445.AM2014-4581

PURPOSE: In head and neck squamous cell carcinoma (HNSCC), mutations of p53 usually coexist with aberrant activation of NF-kappaB (NF-κB) and other transcription factors which promote tumor pathogenesis. However, how these factors mediate oncogenesis and metastasis is not fully understood. Herein we investigate the mechanisms by which p53 and NF-κB contribute to Epithelial-Mesenchymal Transition (EMT) in HNSCC. EXPERIMENTAL DESIGN: We evaluated the effects of p65 mutation on the molecular events of EMT in surgical specimens and HNSCC cell lines. We examined the correlation with tumor histologic features. RESULTS: In HNSCC cell lines with mutant p53, p65 knockdown promotes EMT. In contrast, in normal oral epithelial cells or HNSCC cells with WT p53, p65 over-expression, instead of knockdown, promotes EMT. Ablation of p53 in normal oral epithelial cells blocks p65 induced EMT. These findings are functionally corroborated herein in three-dimensional cell culture, anchorage-independent growth assays, and tumor cell migration assays. CONCLUSIONS: This is the first report indicating the role of p53 status in the NF-κB -induced promotion of EMT in HNSCC. Bortezomib-based regimens have been shown to have minimal activity in recurrent or metastatic head and neck cancer. Our new findings are important in understanding a possible basis for these clinical findings as well as defining important implications for targeted chemoprevention and therapy. Citation Format: Yuan Lin, Jie Luo, Elliot Abemayor, Sherven Sharma, Steven Dubinett, Maie St John. p53-dependent regulation of epithelial-to-mescenchymal transition by nf-κb in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1141. doi:10.1158/1538-7445.AM2014-1141

We have previously used mosaic flies to screen for tumour suppressors or negative regulators of cell proliferation1. The cellular composition of these flies resembles that of cancer patients who are chimaeric individuals carrying a small number of mutated somatic cells. One of the genes we identified is the large tumour suppressor gene, lats (also known as wts), which encodes a putative serine/threonine kinase1,2. Somatic cells mutant for lats undergo extensive proliferation and form large tumours in many tissues in mosaic adults. Homozygous mutants for various lats alleles display a range of developmental defects including embryonic lethality1. Although many tumour suppressors have been identified in Drosophila melanogaster3,4,5,6,7, it is not clear whether these fly genes are directly relevant to tumorigenesis in mammals. Here, we have isolated mammalian homologues of Drosophila lats. Human LATS1 suppresses tumour growth and rescues all developmental defects, including embryonic lethality in flies. In mammalian cells, LATS1 is phosphorylated in a cell–cycle–dependent manner and complexes with CDC2 in early mitosis. LATS1–associated CDC2 has no mitotic cyclin partner and no kinase activity for histone H1. Furthermore, lats mutant cells in Drosophila abnormally accumulate cyclin A. These biochemical observations indicate that LATS is a novel negative regulator of CDC2/cyclin A, a finding supported by genetic data in Drosophila demonstrating that lats specifically interacts with cdc2 and cyclin A.

Objectives: Understanding the molecular mechanisms that mediate HNSCC metastasis may enable identification of novel therapeutic targets. We have reported the role of the E-cadherin transcriptional repressor, Snail, in the inflammation-induced promotion of EMT in HNSCC. Herein we demonstrate that inflammatory mediators also upregulate p38 and p38 interacting protein (p38IP), thus further defining the cycle by which inflammation promotes tumor progression. Methods: A molecular biology study. Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot analysis, and 3-D spheroid culture were used to determine how inflammation affects p38, p38IP and EMT. Results: p38 kinase inhibitor treated, and p38 shRNA HNSCC cell lines demonstrated a significant upregulation in E-cadherin mRNA and a decrease in the mRNA expression of the transcriptional repressor Snail. p38 shRNA HNSCC cell lines show a less invasive phenotype in a spheroid model, and demonstrate decreased tumor growth in a SCID mouse model. An inverse relationship between p-p38 and E-cadherin was demonstrated in situ by immunohistochemical staining of human HNSCC tissue sections. Activation of p38 is required for the robust IL-1β induced E-cadherin downregulation and Snail upregulation. IL-1β increases p-p38 and has a more rapid and robust effect on p38. Snail overexpression also enhanced p-p38 in vitro. Inhibition of p38 blocked HNSCC tumor growth in vivo. p38 activates p38IP, a p38 downstream component in STAGA transcriptional activator complex, in HNSCC cell lines. p38 bound to and stabilized p38IP, a subunit of histone acetyltransferase STAGA, resulting in enhanced transcription of Snail. Inhibition of p38IP blocked HNSCC migration and invasion both in vitro and in vivo. In HNSCC patient samples, p38IP expression was increased compared to adjacent normal tissue. Conclusions: In gastrulation, a Snail-independent P38/P38IP pathway is required in the primitive streak to downregulate E-cadherin expression at the posttranscriptional level. Herein we provide the first report that in HNSCC a snail-dependent p38/p38IP pathway is essential for E-cadherin down-regulation and cell invasion. Our work herein demonstrates for the first time that a snail-p38/p38IP feedback loop jointly down regulates E-cadherin and drives a potent EMT in HNSCC. This newly defined pathway has important implications for targeted chemoprevention and therapy. Citation Format: Yuan Lin, Guangyu Wang, Jie Luo, Chi Lai, Elliot Abemayor, David Elashoff, Steve Dubinett, Maie A. St. John. p38 MAPK mediates epithelial-mesenchymal transition by regulating p38IP and snail in head and neck squamous cell carcinoma (HNSCC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1490. doi:10.1158/1538-7445.AM2013-1490

Lung cancer evades host immune surveillance by dysregulating inflammation. Tumors and their surrounding stromata produce growth factors, cytokines, and chemokines that recruit, expand, and/or activate myeloid-derived suppressor cells (MDSCs). MDSCs regulate immune responses and are frequently found in malignancy. In this review the authors discuss tumor-MDSC interactions that suppress host antitumor activities and the authors' recent findings regarding MDSC depletion that led to improved therapeutic vaccination responses against lung cancer. Despite the identification of a repertoire of tumor antigens, hurdles persist for immune-based anticancer therapies. It is likely that combined therapies that address the multiple immune deficits in cancer patients will be required for effective therapy. MDSCs play a major role in the suppression of T-cell activation and they sustain tumor growth, proliferation, and metastases. Regulation of MDSC recruitment, differentiation or expansion, and inhibition of the MDSC suppressive function with pharmacologic agents will be useful in the control of cancer growth and progression. Pharmacologic agents that regulate MDSCs may be more effective when combined with immunotherapies. Optimization of combined approaches that simultaneously downregulate MDSC suppressor pathways, restore APC immune-stimulating activity, and expand tumor-reactive T cells will be useful in improving therapy.

Objective To evaluate the therapeutic efficacy of a novel modular polymer platform in the treatment of head and neck squamous cell carcinoma (HNSCC). Design In vivo study. Setting Academic research laboratory. Subjects and Methods C3H/HeJ mice and SCID/beige mice were randomized to receive implantation of no polymer, plain polymer, plain polymer with local cisplatin injection, or cisplatin polymer. The 2 groups of mice implanted with cisplatin polymer or no polymer were further randomized to receive 4 Gy of external beam radiation for 4 days or no radiation. Tumor size was measured until the mice were humanely killed. At necropsy, the tumors were excised and weighed. Results There was a significant reduction in tumor growth using this novel polymer platform. The cisplatin-secreting polymer effectively reduced human head and neck tumor growth in SCID mice by 17-fold and SCC VII/SF tumors in C3H/HeJ mice by more than 16-fold compared with the control, plain polymer, and plain polymer + intratumoral cisplatin injection groups (P = .01 for both). We also observed a statistically significant lower tumor weight in mice treated with cisplatin polymer and concomitant radiation compared with the radiation alone and control groups. Conclusions We demonstrate the efficacy of a novel polymer platform in delivering cisplatin to a partially resected SCC in a murine model. This polymer may represent a new therapeutic modality for patients with HNSCC. Once this polymer platform is optimized, we will plan for validation in the context of a prospective trial in patients with unresectable advanced or recurrent HNSCC.

Educational objective: At the conclusion of this presentation, the participants should be able to discuss the benefits of a modular polymer platform, which will improve the outcome for patients with advanced HNSCC. Objective: To evaluate the therapeutic efficacy of an immunomodulator secreting polymer platform in the treatment of HNSCC. Study Design: in vivo animal study. Setting: Academic research laboratory. Subjects and Methods: C3H/HeJ mice were injected with SCCVII/SF cells. After tumors reached 1 cm in size, animals then underwent surgery and were randomized to receive implantation of (1) no polymer; (2) plain polymer; (3) plain polymer with dendritic cells (DC) secreting the chemokine CCL21; (4) plain polymer with DC alone; and 5) plain polymer + daily CCL21 injection. Tumor size was measured until the mice were euthanized. At necropsy, the tumors were excised and weighed. Results: We were able to demonstrate that DC are viable and functionally secrete CCL21 up to 14 days in the polymer. DC-CCL21 secreting polymer effectively reduced tumor growth mice by over 16-fold (P < 0.01) as compared to control, plain polymer, and plain polymer + intratumoral CCL21 injection groups. Flow cytometry analysis revealed that there was a significant increase in CD4+ T cells, as well as a significant decrease in CD4+/CD25+ regulatory T cells in the tumor site, underlying the significant tumor regression observed. Conclusion: The major limitation for the clinical use of cytokines is the lack of an effective protocol for the sustained delivery of cytokines to the tumor milieu. We demonstrate the efficacy of a novel polymer platform in delivering DC-CCL21 to SCCA in a murine model. Our results indicate that this polymer may represent a new therapeutic modality for patients with HNSCC. Once this polymer platform is optimized we will plan for validation in the context of a prospective trial in patients with unresectable advanced or recurrent HNSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4409. doi:1538-7445.AM2012-4409

Objectives: To determine the roles of Snail and p38 in the inflammation-induced promotion of EMT in HNSCC. Study Design: A molecular biology study. Real-time quantitative RT-PCR, Western blot analysis, spheroid modeling, and immunohistochemical staining of human HNSCC tissue sections were used to determine how inflammation affects Snail and p38. Setting: An academic hospital laboratory. Subjects and Methods: Relative RNA levels were determined by RT-PCR, and protein expression was evaluated by immunofluorescence (IF) and in situ by immunohistochemical staining of human HNSCC tissue sections. Results: p38 kinase inhibitor treated, and p38 shRNA HNSCC cell lines demonstrated a significant upregulation in E-cadherin mRNA and a decrease in the mRNA expression of the transcriptional repressor Snail. p38 shRNA HNSCC cell lines show a less invasive phenotype in a spheroid model. An inverse relationship between p38 and E-cadherin was demonstrated in situ by immunohistochemical staining of human HNSCC tissue sections. p38 is required for the robust IL-1β induced E-cadherin downregulation and Snail upregulation. IL-1β increases p-p38 and has a more rapid and robust effect on p38 in Snail overexpressing cell lines. Conclusions: In gastrulation, it is a Snail-independent pathway in which p38 is required in the primitive streak to downregulate E-cadherin expression at the posttranscriptional level. Herein we provide the first report that p38 is required for the Snail-induced E-cadherin down-regulation and cell invasion in HNSCC. A Snail-p38 feedback loop jointly down regulates E-cadherin and drives a potent EMT in HNSCC. This newly defined pathway has important implications for targeted chemoprevention and therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3432. doi:10.1158/1538-7445.AM2011-3432

Figure 7. Knocking down NFkB leads to diminished IMP-3 expression. HNSCCs are notably aggressive cancers which cause death primarily due to metastases2. Metastasis involves a complex change in epithelial cell behavior wherein the cell locally invades through the epithelial basement membrane, enters blood or lymph vessels, travels through the circulation, exits the vessel, and replicates at a distant organ. Growing evidence suggests such enhanced mobility requires the cell undergo an epithelial-mesenchymal transition. EMT is a normal part of embryonic development. Therefore, it has been hypothesized that in adults the reactivation of genes involved in embryonic EMT underlies the mechanism of cancer metastasis3.

4. Wide local excision should be performed if tolerated. The role of radiation therapy is unclear because of limited experience with treatment. A 60 year-old male presented with a history of a prior excision of a right temporal/pre-auricular pilomatrixoma. A 2x2 cm lesion recurred at the original site, and he was scheduled for elective re-resection 1 month later. When the patient presented to surgery, the lesion had tripled in size. Because of this rapid growth, the excision was deferred and repeat biopsy and further work-up with repeat imaging was performed. Biopsy was again consistent with pilomatrixoma.