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Supplementary Table 4 from Tumor Suppressor Activity of CCAAT/Enhancer Binding Protein α Is Epigenetically Down-regulated in Head and Neck Squamous Cell Carcinoma

Supplementary Table 1 from Tumor Suppressor Activity of CCAAT/Enhancer Binding Protein α Is Epigenetically Down-regulated in Head and Neck Squamous Cell Carcinoma

Supplementary Table 2 from Tumor Suppressor Activity of CCAAT/Enhancer Binding Protein α Is Epigenetically Down-regulated in Head and Neck Squamous Cell Carcinoma

Tumor suppressor CCAAT enhancer binding protein α (C/EBPα) is a transcription factor involved in cell cycle control and cellular differentiation. In a recent study, microarray expression profiling on head and neck squamous cell carcinoma (HNSCC) samples identified significant C/EBPα down-regulation, correlating with poor prognosis. However, the mechanisms of C/EBPα down-regulation remained elusive. C/EBPα has been previously found to provide an antiproliferative role in lung cancer, and our laboratory showed that its down-regulation involves epigenetic mechanisms. This prompted us to investigate the involvement of epigenetics in down-regulating C/EBPα in HNSCC. Here, we show that C/EBPα is down-regulated in HNSCC by loss of heterozygosity and DNA methylation, but not by gene mutation. We found a consistently methylated upstream regulatory region (−1,399 bp to −1,253 bp in relation to the transcription start site) in 68% of the HNSCC tumor samples, and DNA demethylation using 5-aza-2′-deoxycytidine treatment was able to significantly restore C/EBPα mRNA expression in the HNSCC cell lines we tested. In addition, C/EBPα overexpression in a HNSCC cell line (SCC22B) revealed its ability to provide tumor suppressor activity in HNSCC in vitro and in vivo. In conclusion, we showed for the first time not only that C/EBPα has tumor suppressor activity in HNSCC, but also that it is down-regulated by DNA promoter methylation. [Cancer Res 2007;67(10):4657–64]

Supplementary Figure Legends 1-2 from Tumor Suppressor Activity of CCAAT/Enhancer Binding Protein α Is Epigenetically Down-regulated in Head and Neck Squamous Cell Carcinoma

Supplementary Figure 1 from Tumor Suppressor Activity of CCAAT/Enhancer Binding Protein α Is Epigenetically Down-regulated in Head and Neck Squamous Cell Carcinoma

Objective To identify predictors of overall survival (OS) and to stratify patients according to significant prognostic variables. Methods A retrospective study of 274 consecutive patients with primary Oral Cavity Squamous Cell Carcinoma. Kaplan-Meier, Cox proportional hazard models, and recursive partitioning analysis (RPA) were used for analysis of OS. These results were further validated using National Cancer Database cohort of 21 895 patients. Results Median OS was 3.65 years. T-classification and N-classification, alcoholic beverages/week, age, and adjuvant treatment were significant predictors of OS. RPA identified high-risk subpopulations: N0-1 patients with CCI ≥ 4.5 and N2-3 patients ordered by those not receiving adjuvant treatment, those with T3-4 disease despite adjuvant therapy, and those having T1-2 disease with adjuvant therapy. Conclusions This study utilized significant prognostic indicators and RPA to highlight the importance of age, N-classification, T-classification, comorbidity, and adjuvant therapy in conjunction with American Joint Committee on Cancer staging to improve preoperative counseling.

OBJECTIVES To elucidate predictive factors in the perioperative period resulting in gastrostomy tube (G-tube) dependence for patients undergoing primary surgical treatment of oropharyngeal squamous cell carcinoma (OPSCC) in the modern era. METHODS Two hundred and thirty patients with known OPSCC treated with primary surgery were screened and selected from a retrospective database spanning from 2002 to 2012 at The Ohio State University Wexner Medical Center (Columbus, Ohio), with univariable and multivariable logistic regression modeling used to determine independent predictive factors resulting in G-tube dependence (defined as tube persistence/presence 1 year after surgery). RESULTS Surgical approach, baseline characteristics, tumor (T)-nodal-metastasis stage, human papillomavirus status, extent of tissue resected, surgical complications, reconstructive technique, preoperative G-tube presence, and adjuvant treatment were recorded. Patients undergoing open surgery for OPSCC without adjuvant treatment had 42.9% G-tube dependence (44.6% with adjuvant chemoradiation [CRT]) compared to 0% for those undergoing transoral nonrobotic surgery (8.1% with adjuvant CRT) and 0% for those undergoing transoral robotic surgery (10.3% with adjuvant CRT). In multivariable analysis, greater than 25% of the oral tongue resected (odds ratio [OR] 12.29; P = 0.03), an open surgical approach (OR 5.72; P

OBJECTIVES: to examine the impact of radiotherapy center volume on overall survival in patients with oral cavity and oropharyngeal squamous cell carcinoma getting adjuvant radiation therapy after receiving surgery at a high-volume center. MATERIALS AND METHODS: a retrospective study was conducted on patients with oral cavity squamous cell carcinoma or oropharyngeal squamous cell carcinoma treated surgically at a tertiary institution from 2000 to 2012 who received adjuvant radiotherapy. The outcome variable was overall survival and the independent variable was location of adjuvant radiation therapy: high-volume center (HVC) versus low-volume center (LVC). Cox proportional hazards models were used to assess associations between predictors of death. Variables that were found to be significant at the α = 0.10 were included in a multivariable model. RESULTS: 336 patients met inclusion criteria. One-hundred thirty-nine patients received adjuvant radiation therapy at HVC and 197 patients received adjuvant radiation therapy at LVC. A univariate Cox proportional hazards model identified the variables location, age, marital status, subsite, T stage, extracapsular extension, and smoking status to include in a multivariable model. Age, subsite, T stage, and extracapsular extension were independent predictors of overall survival (p < .05). Location (p=.55), marital status (p=.29), and smoking status (p=.22) were not statistically significant predictors of survival. CONCLUSION: After surgery at a HVC, the volume of adjuvant radiation therapy center was not significantly associated with overall survival. Significant predictors of survival included age, subsite, T stage, and extracapsular extension.

// Bhavna Kumar 1, 2 , Nicole V. Brown 3 , Benjamin J. Swanson 4 , Alessandra C. Schmitt 4, 5 , Matthew Old 1, 2 , Enver Ozer 1, 2 , Amit Agrawal 1, 2 , David E. Schuller 1, 2 , Theodoros N. Teknos 1, 2 , Pawan Kumar 1, 2 1 Department of Otolaryngology-Head and Neck Surgery, The Ohio State University, Columbus, OH 43210, USA 2 Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA 3 Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA 4 Department of Pathology, The Ohio State University, Columbus, OH 43210, USA 5 Current affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30303, USA Correspondence to: Pawan Kumar, e-mail: Pawan.Kumar@osumc.edu Keywords: myoferlin, OPSCC, HPV, IL-6, nanog Received: December 22, 2015 Accepted: February 11, 2016 Published: February 23, 2016 ABSTRACT Myoferlin (MYOF) is a member of ferlin family of membrane proteins that was originally discovered as a muscle specific protein. Recent studies have shown that myoferlin is also expressed in other cell types including endothelial cells and cancer cells. However, very little is known about the expression and biological role of myoferlin in head and neck cancer. In this study, we examined expression profile of myoferlin in oropharyngeal squamous cell carcinoma (OPSCC) and assessed its correlation with disease progression and patient outcome. In univariate analyses, nuclear MYOF was associated with poor overall survival (p

Black raspberries (BRB) demonstrate potent inhibition of aerodigestive tract carcinogenesis in animal models. However, translational clinical trials evaluating the ability of BRB phytochemicals to impact molecular biomarkers in the oral mucosa remain limited. The present phase 0 study addresses a fundamental question for oral cancer food–based prevention: Do BRB phytochemicals successfully reach the targeted oral tissues and reduce proinflammatory and antiapoptotic gene expression profiles? Patients with biopsy-confirmed oral squamous cell carcinomas (OSCC) administered oral troches containing freeze-dried BRB powder from the time of enrollment to the date of curative intent surgery (13.9 ± 1.27 days). Transcriptional biomarkers were evaluated in patient-matched OSCCs and noninvolved high at-risk mucosa (HARM) for BRB-associated changes. Significant expression differences between baseline OSCC and HARM tissues were confirmed using a panel of genes commonly deregulated during oral carcinogenesis. Following BRB troche administration, the expression of prosurvival genes (AURKA, BIRC5, EGFR) and proinflammatory genes (NFKB1, PTGS2) were significantly reduced. There were no BRB-associated grade 3–4 toxicities or adverse events, and 79.2% (N = 30) of patients successfully completed the study with high levels of compliance (97.2%). The BRB phytochemicals cyanidin-3-rutinoside and cyanidin-3-xylosylrutinoside were detected in all OSCC tissues analyzed, demonstrating that bioactive components were successfully reaching targeted OSCC tissues. We confirmed that hallmark antiapoptotic and proinflammatory molecular biomarkers were overexpressed in OSCCs and that their gene expression was significantly reduced following BRB troche administration. As these molecular biomarkers are fundamental to oral carcinogenesis and are modifiable, they may represent emerging biomarkers of molecular efficacy for BRB-mediated oral cancer chemoprevention. Cancer Prev Res; 9(2); 159–71. ©2015 AACR.

Background The purpose of this study was to further define the impact of primary surgery in the management of oropharyngeal squamous cell carcinoma (SCC). Methods Two hundred ninety-six patients with oropharyngeal SCC treated with primary surgery were included. Multivariable analysis and recursive partitioning analysis (RPA) identified predictors of survival and gastrostomy tube presence. Results Multivariable analysis identified that HPV negativity (p = .0002), presence of extranodal extension (p = .0025), and advanced T classification (p = .0081) were independent predictors of survival. For HPV-positive patients, surgical approach (p = .0111) and margin status (p = .0287) were significant predictors of survival. For HPV-negative patients, extranodal extension (p = .0021) and advanced T classification (p = .0342) were significant predictors of survival. Smoking status and advanced neck disease did not impact survival, and the addition of adjuvant chemotherapy did not confer survival benefit in HPV-positive or HPV-negative subgroups. Conclusion Independent predictors of survival are unique in patients with oropharyngeal SCC treated with primary surgery. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1794–E1802, 2016

Objectives The Notch1 signaling pathway has recently been shown to be highly dysregulated in head and neck squamous cell carcinoma, but the value of Notch1 as a predictive biomarker is yet to be elucidated in oropharyngeal squamous cell carcinoma (OPSCC). The objective of this study is to evaluate Notch1 expression in surgical OPSCC specimens and determine clinicopathologic correlates. Study Design Case series with planned data collection. Setting Tertiary academic medical center. Subjects and Methods Surgical specimens from 181 patients with OPSCC were collected to create a tissue microarray (TMA). Human papillomavirus (HPV) status and Notch1 expression were determined and correlated with clinicopathologic characteristics. Results In univariate analysis, Notch1 expression correlated with improved survival as a categorical variable (hazard ratio [HR], 0.346; P < .0001) and correlated with HPV/p16 positivity as a continuous variable ( P < .0001). In multivariate analysis, Notch1 expression retained significance in HPV-positive (HR, 0.303; P = .033) and HPV-negative (HR, 0.416; P = .0055) subgroups. Similarly, Notch1 expression positively correlated with survival in p16-positive (HR, 0.469; P = .031) and p16-negative subgroups (HR, 0.310; P = .014). Conclusions In the largest OPSCC cohort to date, we found that Notch1 receptor expression positively correlates with overall survival, regardless of HPV or p16 status. Furthermore, we found higher Notch1 receptor expression in HPV/p16-positive tumors than their HPV/p16-negative counterparts.

Copyright © 2014 by the National Comprehensive Cancer Network. All rights reserved. This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers focuses on glottic laryngeal cancer, which is the most common type of laryngeal cancer and has an excellent cure rate. The lymphatic drainage of the glottis is sparse, and early stage primaries rarely spread to regional nodes. Because hoarseness is an early symptom, most glottic laryngeal cancer is early stage at diagnosis. Updates to these guidelines for 2014 include revisions to "Principles of Radiation Therapy" for each site and "Principles of Surgery," and the addition of a new section on "Principles of Dental Evaluation and Management."

BACKGROUND Human papillomavirus 16 (HPV16) is a major risk factor for the development of head and neck squamous cell carcinoma (HNSCC), particularly the development of oropharyngeal squamous cell carcinoma (OPSCC). Cancer stem cells (CSCs) are resistant to conventional therapies, and it is postulated that they are responsible for disease recurrence and/or progression. Because the prognoses of patients with HPV16-positive and HPV-negative HNSCC are distinct, the authors sought to determine whether differences in the number of CSCs could account for this clinical observation. METHODS CSC populations in HPV16-positive and HPV-negative HNSCC were assessed using a proprietary assay based on expression of the enzyme aldehyde dehydrogenase (ALDH), an in vitro tumorsphere formation assay, and an in vivo limiting cell dilution in nonobese diabetic/severe combined immunodeficiency mice. A high-density tissue microarray was stained with ALDH1, a CSC marker, to determine the association between CSCs and HPV16-positive/HPV-negative OPSCC. RESULTS HPV16-positive HNSCC had a greater intrinsic CSC pool than HPV-negative HNSCC. Inactivation of p53 has been identified as a major mechanism for the elevated CSC population in HPV16-positive HNSCC. In vivo limiting cell dilution experiments using tumors from patients with HPV16-positive and HPV-negative OPSCC indicated that the CSC frequency was 62.5-fold greater in an HPV16-positive OPSCC tumor than in an HPV-negative OPSCC tumor. Primary tumors from patients with HPV16-positive OPSCC were associated with elevated tumor ALDH1 staining, further extending the association between HPV16 and CSCs. CONCLUSIONS The current data and the clinical observation that patients with HPV16-positive HNSCC respond more favorably to current treatment paradigms than patients with HPV-negative HNSCC support the suggestion that CSC phenotype is not homogeneous. Therefore, the reliance on the CSC number may be insufficient to accurately assess the potential of a particular tumor for disease recurrence and/or progression. Cancer 2014;120:992–1001. © 2014 American Cancer Society.

Background:Although positron emission tomography computed tomography has proven diagnostic and staging value in head and neck carcinoma, it does not have optimal sensitivity or specificity. The positron emission tomography computed tomography fluorodeoxyglucose standardised uptake value has been shown to be associated with carcinoma stage. This study evaluated the impact of major clinicopathological factors on the standardised uptake value at the primary site and at neck lymph node metastases.Subjects and methods:Two hundred and forty-three oral cavity and laryngopharyngeal carcinoma patients who underwent positron emission tomography computed tomography were included. Correlation between the positron emission tomography computed tomography standardised uptake value and various clinicopathological factors was analysed.Results:A positive correlation was found between the standardised uptake value and the size and depth of tumour infiltration, and lymph node positivity. Higher standardised uptake values were seen for more advanced tumour stages. The presence of perineural invasion, lymphatic invasion and extracapsular spread were all associated with increased standardised uptake values.Conclusion:Most of the clinicopathological features of head and neck carcinoma which are well known to be poor prognostic factors have a significant impact on positron emission tomography computed tomography fluorodeoxyglucose standardised uptake value.

Background Despite its widespread use, there is no consensus on the postoperative management in patients undergoing free flap reconstructions. We report the largest study comparing flap outcomes, morbidity, and cost in patients with head and neck cancer free flaps who recovered in the intensive care unit (ICU) versus a “specialty floor” setting. Methods This was a retrospective review of patients undergoing free flap surgery for head and neck defects over a 4-year period. Patients before a certain date went to the ICU for immediate postoperative care and after to a non-ICU setting. Postoperative medical and surgical complications and hospital charges were analyzed. Results Patients in the ICU group had a longer length of stay (LOS) and incurred greater hospital costs than the patients in the non-ICU setting. There was no difference in the flap failure rate between the 2 groups. Conclusion Consideration should be given to a floor-based postoperative management regimen for this patient population. © 2013 Wiley Periodicals, Inc. Head Neck 36: 536–539, 2014

The aim was to evaluate the efficacy of [(18)F]-2-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in evaluating metastasis of head and neck squamous cell carcinoma (HNSCC) to the cervical lymph nodes, with specific attention to the efficacy in regard to clinically negative necks. This was a retrospective review of 243 patients with HNSCC between years 2005 and 2007 treated at a comprehensive cancer care institution who underwent pre-operative PET/CT and neck dissection with either an N0 (112 patients) or N+ (131 patients) clinical nodal status. PET/CT findings were correlated with histopathological results of surgical specimens. A majority of the primary sites were oral cavity and oropharynx (70%), followed by larynx, unknown primary and hypopharynx. In the group of 112 patients who underwent 144 neck dissections with N0 nodal status, sensitivity, specificity, positive predictive value (PPV) and negative predictive (NPV) and accuracy were 57, 82, 59, 80 and 74%, respectively. In the group of 131 patients who underwent 169 neck dissections with N+ nodal status, sensitivity, specificity, PPV, NPV and accuracy were 93, 70, 96, 58 and 91%, respectively. PET/CT has a much reduced rate of efficacy for the clinically negative neck compared to the clinically positive neck. PET/CT in its current stage does not appear to offer an advantage in staging the clinically N0 neck due to high rates of false positives and negatives.

The aim of our study was to investigate the effect of patient-related factors, such as the body mass index (BMI) and tumor size, in selecting the flap type for the reconstruction of pharyngeal defects. This retrospective review included 182 patients with pharyngeal defect reconstructions with free and pedicled flaps at the Ohio State University from January 2005 to December 2008. We conducted a retrospective comparison of variety of different flap reconstruction techniques. We compared different flap reconstruction with BMI and tumor size without functional outcome such as swallowing and speech data. Although there was no statistically significant correlation (P > 0.05) when comparing the free flaps with pedicled flaps according to the BMI and tumor size, there was an obvious tendency to prefer radial forearm free flap over anterolateral thigh free flap in patients who are overweight and those with obesity with a ratio of 32:3. In the same group of patients, a similar tendency was observed to prefer fibular free flap over iliac crest free flap with a ratio of 14:5, whereas the ratio was becoming 3:5 in favor of iliac crest free flap over fibular free flap in patients with BMI of 24 or lower. Despite the fact that surgeons' experience with a certain flap type is one of the most important factors while determining which flap to reconstruct, BMI might have a significant impact while selecting the free flap types for the reconstruction of pharyngeal defects.

Objective To analyze the long-term results and the complications related to an expanded series of maxillary removal and reinsertion (MRRI) with 18-year surgical experience. Study Design Case series with chart review of the MRRI patients in the last 18 years. Setting The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute. Subjects and Methods Seventy-eight patients who underwent MRRI from February 1990 through February 2007. The median age was 51 years (range 11-77 yrs). Sixty-two (80%) patients had malignant lesions. Results MRRI has been successfully completed in all 78 patients, with no intraoperative mortality. The most commonly encountered malignant neoplasm was squamous cell cancer (40.3%), followed by esthesioneuroblastoma (24.1%), adenoid cystic cancer (8%), and other neoplasms (27.4%). The most commonly encountered postoperative complication was diplopia, which has persisted in five (6.4%) patients in the short-term and in three (4%) patients in the long-term follow-up. Nasal asymmetry was the most common long-term complication (17.9%), followed by plate-associated problems (10.2%) and midface asymmetry (10.2%). Overall five-year survival for the patients with squamous cell carcinoma was 62 percent. Conclusion MRRI is a favorable surgical technique for the treatment of anterior cranial base (ACB) tumors in adults and even in children. It improves operative morbidity by preserving both function and form of the maxillary region and gives excellent exposure to ACB.

Objective To investigate the involvement of level I neck lymph node groups in head and neck carcinoma and compare the effect of primary tumor sites, such as oral cavity (OC), oropharynx (OP), hypopharynx (HP), and larynx (Lx), on level I lymph node metastasis. Study Design Case series with chart review. Setting Comprehensive Cancer Center. Subjects and Methods A total of 243 patients with OC and laryngopharyngeal carcinoma who underwent neck dissections in the last three years were included in the study. The primary tumor site was OC, followed by OP, Lx, HP, and carcinoma of unknown primary (CUP). Results Level I was involved in 29 of 243 (11.9%) patients. The other levels were also positive in all but five (17.2%) level I–involved patients. The primary tumor site with level I lymph node metastasis was OC (19.1%), followed by CUP (11.1%), OP (9.8%), Lx (4.4%), and HP (0%). The Lx primary site involved level I only if there were multiple other adverse prognostic features, such as N3 neck, extracapsular spread, pathologic involvement of all resected lymph nodes, involvement of all levels I-V, and invasion of the submandibular gland. Conclusion Although the submandibular content is resected as part of radical and modified radical neck dissections, level I–sparing selective neck dissections could be a safe and effective surgical neck management strategy in appropriately selected patients with OP, Lx, and HP carcinoma.

Objectives/Hypothesis: Assess impact of clinical variables upon survival in patients diagnosed with recurrent head and neck carcinoma and better delineate role of post-treatment surveillance. Methods: Variables including previous tumor site, stage, prior therapy, location of recurrence, patient-identified symptoms, compliance with recommended surveillance, definitive salvage therapy, and clinical outcome were recorded for patients diagnosed with recurrent head and neck cancer from which estimates of survival were generated and compared. Results: One hundred five patients were identified as having been diagnosed with recurrent disease. The majority (81%) were deemed compliant with recommended surveillance. Eighty-nine patients (85%) identified new symptoms/findings prior to diagnosis. Survival was not significantly different between compliant and noncompliant patients (P = .20). For patients who underwent salvage therapy, no significant differences in survival were seen according to original primary site or mode of treatment for recurrence. Better survival was seen in patients with original prior early stage disease (P = .0001) and in patients with local-only site of disease recurrence (P = .0001). Conclusions: In patients with recurrent disease, survival may relate more to variables associated with prior disease or recurrence location than those associated with follow-up surveillance. Surveillance and salvage therapy for recurrent disease may, however, preferentially benefit certain subgroups: 1) patients with prior early stage disease, and 2) those in whom site of recurrence is local-only. Despite high compliance with recommended surveillance, survival remains extremely poor for patients with recurrent disease previously treated for advanced stage disease or with those with regional recurrence. As such, the impact of routine surveillance upon survival in these patients remains unclear. Laryngoscope, 2009

Objectives/Hypothesis: To determine factors impacting recurrence and long-term survival of adenoid cystic carcinoma (ACC) of the head and neck after definitive resection. Study Design: Retrospective cohort study at an academic tertiary care hospital. Methods: Patients with ACC of the head and neck treated at our institution were reviewed. Those not receiving surgery, or with metastatic disease were excluded. Clinicopathological data on each patient was collected. Results: Of 113 patients identified with ACC, 99 were studied. The overall median survival for the cohort was 71 months (mean ± standard deviation, 94 ± 79 months). American Joint Committee on Cancer (AJCC) tumor stage and N stage were independent predictors of survival on multivariate analysis. Mean overall survival (P = .001) and time to recurrence (P = .006) were lower for patients with cervical lymph node positive disease (N+). Tumors in major salivary glands were associated with longer survival (P = .027). The overall recurrence rate was 53%, with a mean time to recurrence of 63 ± 64 months. The presence of lymphovascular invasion predicted recurrence on multivariate analysis (P = .002), with advanced tumor stage predicting early (≤36 months) recurrence (P = .013). Among the 57 patients who received adjuvant radiation therapy, there was no difference in survival, rate of recurrence, or time to recurrence, when compared to patients treated with surgery alone. Conclusions: Clinicopathological variables including AJCC tumor stage, tumor site, presence of N+ disease, and lymphovascular invasion may be used as prognostic factors in predicting survival and recurrence after a definitive resection of ACC of the head and neck. Laryngoscope, 2010

A completely negative enrichment technology was used to detect circulating tumor cells, CTCs, in the peripheral blood of head and neck cancer patients. Of 32 blood samples, 63 percent contained CTCs and the number of CTCs identified per ml of blood collected ranged from 0 to 214. The final purity ranged from 1 CTC in 9 total cells to 1 CTC in 20,000 total cells, the final purity being both a function of the number of CTCs and the performance of the specific enrichment. Consistent with previous reports, CTC were positively identified if: 1) they contained a nucleus based on DAPI stain, 2) stained positive for cytokeratins, and 3) have a high nuclei to cytoplasmic ratio. In addition, for a blood sample to be considered positive for CTCs, the enriched sample must be positive for Epithelial Growth Factor Receptor, EGFR, as measured by RT-PCR. While most of the blood samples were obtained during surgery, a number were taken prior to, and during surgery. In all of the pre- and post- surgery paired samples, significant numbers of CTCs were detected. A number of these enriched samples were observed under confocal microscope in addition to the microscopic observations under traditional wide-field fluorescent microscope. As expected, the FITC stained cytokeratins appeared in the cytoplasm and the average size of these positively stained cells, on the cytospin, was in the range of 8-12 microns. Future studies will involve the investigation if cancer stem cell and mesenchymal markers are present on these CTCs and correlations of patient outcome to the number and type of CTC present.

Objectives: To compare the yield of detecting occult tumors by performing tonsillectomy and deep tonsil biopsies in patients with metastatic carcinoma to the neck in whom a primary tumor was not evident on physical examination, radiography, or panendoscopy. Study Design: Retrospective study. Methods: Over a 10-year period, the charts of all patients diagnosed with metastatic carcinoma to the neck in whom a primary tumor was not evident on examination, imaging, and panendoscopy were reviewed. Specifically, we compared groups of patients who had undergone diagnostic tonsillectomy with those who had undergone deep tonsil biopsies in search of an occult primary tumor. Results: One hundred twenty-two patients were identified as meeting study criteria. All underwent directed biopsies of the tongue base, hypopharynx, and nasopharynx as well as either deep tonsil biopsies or diagnostic tonsillectomy. Deep tonsil biopsies were performed in 95 patients. In this group, 11 primary tumors were subsequently identified (11.6%): three in the tonsil, six in the tongue base, one in the hypopharynx, and one in the nasopharynx. Tonsillectomy was performed in 27 patients. Eleven primary tumors were identified (40.7%): eight in the tonsils, two in the tongue base, and one in the hypopharynx. All tonsil primary tumors identified were ipsilateral to the presenting neck mass. The overall yield of finding an occult primary carcinoma in the tonsil was 3.2% for deep tonsil biopsies vs. 29.6% for tonsillectomies (P < .0002). Conclusions: Tonsillectomy offers a significantly higher likelihood of finding occult tonsillar tumors than deep tonsil biopsy. Laryngoscope, 119:102–106, 2009

For most solid tumors, tumorigenesis occurs as a multistep process including both genetic and epi-genetic alterations, which together provide cancer cells with a selective growth advantage. Transformation of normal cells into malignant cells is characterized by a limited set of acquired capabilities, which are likely shared among different tumor types.1 However, metastases to distant organ sites are ultimately responsible for most cancer deaths.2 Despite much progress, important questions about metastatic progression remain to be answered.2–4 With respect to metastatic origins, 2 conflicting views have been proposed. The “rare metastatic variants” model holds that rare metastatic cells preexist within the primary tumor and subsequently progress to metastases by the process of selection.5,6 This model has recently been challenged by the results of global gene expression profiling in various cancer types. These studies have provided evidence for the independent evolution of 2 classes of primary tumors, those that are predisposed to metastasize and those that are not (“primary tumor predisposition” model).7–11 We have attempted to address the mechanism(s) of metastasis using expression profiling of genetically matched primary tumors, lymph node metastases, and adjacent normal tissue. In this study, we focused on squamous cell carcinoma (SCC) of the head and neck (HNSCC) as a prototypic epithelial solid tumor.12–14 Several molecular alterations associated with HNSCC have been identified, but a complete understanding of the complex molecular events underlying tumori-genesis and metastasis is still lacking.13,15,16 Cervical lymph node metastases are the single most adverse independent prognostic indicator for local recurrence and/or distant metastasis.17 A reliable method to identify those tumors most likely to recur or to produce distant metastases would significantly enhance the choice of effective treatment options and, therefore, outcomes for the patients. Several groups have attempted to predict lymph node metastases retrospectively by identifying a metastatic signature in primary tumor tissues. However, in the majority of these studies, the predictive signatures have not been compared with the expression signature that is actually present in the metastases themselves. To identify the genetic changes underlying HNSCC tumor initiation, progression, and metastasis directly, we generated comprehensive expression profiles for 70 samples, including primary tumors, genetically matched normal adjacent mucosae and genetically matched cervical lymph node metastases. Rigorous statistical analysis revealed unique expression profiles differentiating normal mucosae from primary tumor and metastatic lesions. Genetically matched primary tumor/metastasis samples (ie, from the same patients) showed highly correlated individual profiles, consistent with the notion that the metastatic potential is already encoded in the primary tumor. However, we also identified 46 genes whose dysregulated expression was specific for head and neck cancer metastasis, suggesting that the acquisition of an additional limited number of clonal changes results in the final metastatic cell(s). Findings are compared with those of other published studies, and the implications for the metastatic process in solid tumors and the utility for clinical prognostication based on gene expression in primary tumors are discussed.

Objectives/Hypothesis: To demonstrate the feasibility of the carotid artery dissection and/or resection and reanastomosis, and to show its positive impact on survival and disease control rates for the head and neck carcinomas involving the carotid artery. Study Design: Tertiary center (Comprehensive Cancer Center). Case series review. Methods: The data of 90 patients with head and neck malignancies involving the carotid artery were operated for the carotid artery dissection and/or resection, and reanastomosis in the last 10 years were retrospectively reviewed and analyzed. Results: Eighty (89%) of the 90 patients' head and neck malignancies were squamous cell carcinoma. Fifty-two (65%) and 28 (35%) of 80 patients were recurrent and stage IV disease, respectively. There was no stage I to III disease. Carotid artery was dissected and preserved in 64 (71.1%) of the 90 patients. Eighteen (20%) of 90 patients needed carotid artery dissection with resection and reanastomosis. Eight (8.9%) patients were unresectable. Sixty (75%) of 80 patients needed reconstruction with regional or free flaps and grafts. Overall 2- and 5-year estimated survivals were 32.4% and 27.8% for all; 14.3% and 10.7% for recurrent; 64.3% and 57.8% for stage IV previously untreated; and 22.0% and 22.0% for carotid artery resected-reanastomosed patients, respectively. Conclusions: The carotid artery dissection without resection is an achievable goal in majority of patients with the advanced stage head and neck carcinoma involving the carotid artery. Resection and reanastomosis of carotid artery, especially in the previously untreated carotid involved patients, is a feasible surgery and achieves better survival and disease control rates when compared with the unresected or recurrent disease patients.

Tumor suppressor CCAAT enhancer binding protein α (C/EBPα) is a transcription factor involved in cell cycle control and cellular differentiation. In a recent study, microarray expression profiling on head and neck squamous cell carcinoma (HNSCC) samples identified significant C/EBPα down-regulation, correlating with poor prognosis. However, the mechanisms of C/EBPα down-regulation remained elusive. C/EBPα has been previously found to provide an antiproliferative role in lung cancer, and our laboratory showed that its down-regulation involves epigenetic mechanisms. This prompted us to investigate the involvement of epigenetics in down-regulating C/EBPα in HNSCC. Here, we show that C/EBPα is down-regulated in HNSCC by loss of heterozygosity and DNA methylation, but not by gene mutation. We found a consistently methylated upstream regulatory region (−1,399 bp to −1,253 bp in relation to the transcription start site) in 68% of the HNSCC tumor samples, and DNA demethylation using 5-aza-2′-deoxycytidine treatment was able to significantly restore C/EBPα mRNA expression in the HNSCC cell lines we tested. In addition, C/EBPα overexpression in a HNSCC cell line (SCC22B) revealed its ability to provide tumor suppressor activity in HNSCC in vitro and in vivo. In conclusion, we showed for the first time not only that C/EBPα has tumor suppressor activity in HNSCC, but also that it is down-regulated by DNA promoter methylation. [Cancer Res 2007;67(10):4657–64]

The purpose of this study was to further define the impact of primary surgery in the management of oropharyngeal squamous cell carcinoma (SCC).Two hundred ninety-six patients with oropharyngeal SCC treated with primary surgery were included. Multivariable analysis and recursive partitioning analysis (RPA) identified predictors of survival and gastrostomy tube presence.Multivariable analysis identified that HPV negativity (p = .0002), presence of extranodal extension (p = .0025), and advanced T classification (p = .0081) were independent predictors of survival. For HPV-positive patients, surgical approach (p = .0111) and margin status (p = .0287) were significant predictors of survival. For HPV-negative patients, extranodal extension (p = .0021) and advanced T classification (p = .0342) were significant predictors of survival. Smoking status and advanced neck disease did not impact survival, and the addition of adjuvant chemotherapy did not confer survival benefit in HPV-positive or HPV-negative subgroups.Independent predictors of survival are unique in patients with oropharyngeal SCC treated with primary surgery. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1794-E1802, 2016.

Jennifer R. Grandis, MD, James F. Battey, MD, Robert M. Califf, MD, Richard A. Chole, MD, Bruce J. Gantz, MD, George A. Gates, MD, Lester Gorelic, PhD, Maureen T. Hannley, PhD, Kevin S. Hardwick, DDS, Jeffrey P. Harris, MD, Wishwa N. Kapoor, MD, Stephen Y. Lai, MD, PhD, Anil K. Lalwani, MD, Lloyd B. Minor, MD, Joseph P. Nadol, MD, J. Christopher Post, MD, PhD, Peter S. Roland, MD, Alan M. Schechter, MD, David E. Schuller, MD, Daniel A. Sklare, PhD, P. Ashley Wackym, MD, Randal S. Weber, MD, Ernest A. Weymuller Jr, MD, Gregory T. Wolf, MD, and Gayle E. Woodson, MD, Pittsburgh, Pennsylvania; Bethesda, Baltimore, Maryland; Durham, North Carolina; St Louis, Missouri; Iowa City, Iowa; Alexandria, Virginia; San Diego, California; New York, New York; Boston, Massachusetts; Dallas, Houston, Texas; Columbus, Ohio; Milwaukee, Wisconsin; Springfield, IL

Purpose The Southwest Oncology Group designed a phase II trial for patients with base of tongue or hypopharyngeal cancer to evaluate the complete histologic response rate at the primary site after induction chemotherapy followed by chemoradiotherapy for responders. Secondary end points were the rate of organ preservation and the need for salvage surgery. Patients and Methods Fifty-nine eligible patients were enrolled; 37 had base of tongue cancer, and 22 had hypopharynx cancer. Forty-two percent had stage III disease, and 58% had stage IV disease. Induction chemotherapy was two cycles of cisplatin 100 mg/m2 and fluorouracil 1,000 mg/m2/d for 5 days. Patients who had a greater than 50% response at the primary site were treated with radiation 72Gy and concurrent cisplatin 100 mg/m2 for three cycles. Patients with less than partial response at the primary had immediate salvage surgery. Results Forty-five patients (76%) had a greater than 50% response at the primary after induction chemotherapy; 43 went on to receive definitive chemoradiotherapy. Thirty-two patients (54%) achieved a histologic complete response at the primary site, and an additional nine patients had a complete clinical response, but biopsy was not done. Seventy-five percent of patients did not require surgery at the primary tumor site. The 3-year overall survival was 64%. The 3-year progression-free survival with organ preservation was 52%. Conclusion Patients with base of tongue or hypopharyngeal cancer treated with this regimen of induction chemotherapy followed by definitive chemoradiotherapy have a good rate of organ preservation without compromise of survival.

Purpose: The Head and Neck Intergroup conducted a phase III randomized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer. Patients and Methods: Eligible patients were randomly assigned between arm A (the control), single daily fractionated radiation (70 Gy at 2 Gy/d); arm B, identical radiation therapy with concurrent bolus cisplatin, given on days 1, 22, and 43; and arm C, a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy, 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle. Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and, if necessary, as salvage therapy on all three treatment arms. Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test. Results: Between 1992 and 1999, 295 patients were entered on this trial. This did not meet the accrual goal of 362 patients and resulted in premature study closure. Grade 3 or worse toxicity occurred in 52% of patients enrolled in arm A, compared with 89% enrolled in arm B (P < .0001) and 77% enrolled in arm C (P < .001). With a median follow-up of 41 months, the 3-year projected overall survival for patients enrolled in arm A is 23%, compared with 37% for arm B (P = .014) and 27% for arm C (P = not significant). Conclusion: The addition of concurrent high-dose, single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival, although it also increases toxicity. The loss of efficacy resulting from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery.

As it becomes common for hyperparathyroidism to be detected earlier in the course of the disease, the bony manifestations of the disease are rarely seen. Presented here is a rare case of brown tumor of the maxilla as the presenting symptom of primary hyperparathyroidism.

Objectives/Hypothesis: As superselective neck dissection strategy is gaining popularity to minimize postoperative morbidity and better life quality, we investigated the metastatic nodal status of level V neck lymph node group for head and neck squamous cell carcinoma in various primary sites. We have also aimed to display the impact of involvement of other nodal groups on level V. Study Design: Retrospective review of histopathologic examination of case series at a comprehensive cancer center. Methods: The study group was composed of 107 patients who underwent a type of neck dissection including level V among 243 patients. The impact of primary site and metastatic nodal status of other levels on metastasis to level V involvement were evaluated. Results: The most common primary tumor site was oropharynx (n = 43), followed by oral cavity (n = 32), larynx (n = 16), carcinoma of unknown primary (n = 10), and hypopharynx (n = 6). General pathologic N positivity for all levels was 78.3% (76 of 97) when 10 carcinoma of unknown primary patients were excluded. Level V was involved in 13 of 107 (12.1%) patients. Level V was not involved in any patient when the other levels were not involved (0 of 21). Even when considering only N+ patients, the ratio of N positivity for level V is still

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers focuses on glottic laryngeal cancer, which is the most common type of laryngeal cancer and has an excellent cure rate. The lymphatic drainage of the glottis is sparse, and early stage primaries rarely spread to regional nodes. Because hoarseness is an early symptom, most glottic laryngeal cancer is early stage at diagnosis. Updates to these guidelines for 2014 include revisions to "Principles of Radiation Therapy" for each site and "Principles of Surgery," and the addition of a new section on "Principles of Dental Evaluation and Management."

Objectives:(1) Analyze the prognostic factors implicated in survival of patients with recurrent oral cavity squamous cell carcinoma (SCC). (2) Highlight the poor salvage and overall survival rates in this patient population.Methods:Between 1997 and 2006, 235 patients with oral cavity SCC were identified, of which 85 experienced recurrences. Overall survival and prognostic factors were analyzed, including epidemiologic, tumor-specific factors, and surgical outcomes.Results:Eighty-five of 235 patients experienced recurrence of their primary oral cavity SCC. Only 8 (9.4%) patients have survived, with follow-up ranging from 8 to 14 years. Six of the surviving patients had tongue primaries, while the other 2 had buccal mucosa and hard palate primaries. All 8 surviving patients were staged T1 (1) or T2 (7) and were N0 (6), N1 (1), or N2b (1). Among deceased patients, 9 (11.7%) were staged T3 and 16 (20.1%) T4. Tumor volume (cm3) also varied greatly between surviving (3.97) and deceased (22.14) patients.Conclusi...

Objectives Objectives of the study were 1) to analyze the complication incidence and resource utilization of two methods of bedside tracheostomy and 2) to define selection criteria for bedside tracheostomy. Study Design Prospective randomized trial in the setting of a tertiary care center at a university hospital. Methods One hundred sixty-four consecutive intubated patients selected for elective tracheostomy were enrolled. One hundred patients met selection criteria for bedside tracheostomy and were randomly assigned to either open surgical tracheostomy (50) or endoscopically guided percutaneous dilational tracheotomy(50). The remaining 64 patients received open surgical tracheostomies in the operating room. Main outcome measures were 1) perioperative and postoperative complication incidence and 2) resource utilization. Results Patients meeting our selection criteria for bedside tracheostomy had a significantly reduced perioperative complication rate compared with those who failed to meet these criteria, and subsequently underwent tracheostomy placement in the operating room (5% vs. 20%, P less than or equal to .01). No statistically significant difference was found in the perioperative complication incidence between the two methods of bedside tracheostomy. However, percutaneous tracheostomy placement at the bedside resulted in a significant increase in postoperative complication incidence (16% vs. 2%, P

From February 1993 through July 1994, 37 patients with stage III-IV squamous cell carcinomas of the oral cavity, oropharynx, or hypopharynx (stage II-IV) were registered to a treatment regimen consisting of preoperative continuous infusion cisplatin (80 mg/m2/80 hours) with hyperfractionated external beam radiotherapy (9.1 Gy/7 fractions of 1.3 Gy BID), surgical resection, intraoperative radiotherapy (7.5 Gy), and postoperative radiotherapy (40 Gy) with concurrent cisplatin (100 mg/m2 x 2 courses). The objectives of the regimen were to improve patient compliance while also increasing treatment intensity. The purpose of this article is to report the local, regional (nodal), and distant disease control of these patients after an extended time at risk (median 40 months). Overall compliance (73%), local control at primary site (97%), and regional nodal control (95%) were excellent. The rate of distant metastasis was 19%. Absolute survival at 48 months was 45.9%.

The INK4a-ARF locus is located on human chromosome 9p21 and is known to encode two functionally distinct tumor-suppressor genes. The p16(INK4a) (p16) tumor-suppressor gene product is a negative regulator of cyclin-dependent kinases 4 and 6, which in turn positively regulate progression of mammalian cells through the cell cycle. The p14(ARF) tumor-suppressor gene product specifically interacts with human double minute 2, leading to the subsequent stabilization of p53 and G(1) arrest. Previous investigations analyzing the p16 gene in squamous cell carcinomas of the head and neck (SCCHNs) have suggested the predominate inactivating events to be homozygous gene deletions and hypermethylation of the p16 promoter. Somatic mutational inactivation of p16 has been reported to be low (0-10%, with a combined incidence of 25 of 279, or 9%) and to play only a minor role in the development of SCCHN. The present study examined whether this particular mechanism of INK4a/ARF inactivation, specifically somatic mutation, has been underestimated in SCCHN by determining the mutational status of the p16 and p14(ARF) genes in 100 primary SCCHNs with the use of polymerase chain reaction technology and a highly sensitive, nonradioactive modification of single-stranded conformational polymorphism (SSCP) analysis termed "cold" SSCP. Exons 1alpha, 1beta, and 2 of INK4a/ARF were amplified using intron-based primers or a combination of intron- and exon-based primers. A total of 27 SCCHNs (27%) exhibited sequence alterations in this locus, 22 (22%) of which were somatic sequence alterations and five (5%) of which were a single polymorphism in codon 148. Of the 22 somatic alterations, 20 (91%) directly or indirectly involved exon 2, and two (9%) were located within exon 1alpha. No mutations were found in exon 1beta. All 22 somatic mutations would be expected to yield altered p16 proteins, but only 15 of them should affect p14(ARF) proteins. Specific somatic alterations included microdeletions or insertions (nine of 22, 41%), a microrearrangement (one of 22, 5%), and single nucleotide substitutions (12 of 22, 56%). In addition, we analyzed the functional characteristics of seven unique mutant p16 proteins identified in this study by assessing their ability to inhibit cyclin-dependent kinase 4 activity. Six of the seven mutant proteins tested exhibited reduced function compared with wild-type p16, ranging from minor decreases of function (twofold to eightfold) in four samples to total loss of function (29- to 38-fold decrease) in two other samples. Overall, somatic mutation of the INK4a/ARF tumor suppressor locus, resulting in functionally deficient p16 and possibly p14(ARF) proteins, seems to be a prevalent event in the development of SCCHN. Mol. Carcinog. 30:26-36, 2001.

Purpose. Telomerase is a ribonucleoprotein that extends telomeres at the ends of chromosome. Increased telomerase activity is associated with cellular immortality. The currently available assay for telomerase, i.e., telomeric repeat amplification protocol (TRAP), consists of 2 steps: (a) telomerase-mediated extension of an oligonucleotide primer by the enzyme-containing extracts of cells and tissues, and (b) amplification of the telomerase-extended primer products by polymerase chain reaction (PCR) and detection of the PCR products. It is generally accepted that the current TRAP assay lacks quantitative precision. The present study was to develop a quantitative telomerase assay with greater precision and sensitivity.

BACKGROUND Previous Phase II trials evaluating paclitaxel as a single agent have produced objective response rates of 38–40%. However, in these studies patients had recurrent disease and had received previous treatment with chemotherapy, radiation, surgery, or some combination of the same. To the authors' knowledge, the study reported here is the first to examine the role of paclitaxel in affecting objective antitumor response, as a single agent, in a previously untreated patient population. METHODS Patients with untreated, resectable, advanced squamous cell carcinoma of the head and neck were eligible for this Phase II trial. The treatment plan included paclitaxel 250 mg/m2 administered by 24-hour intravenous infusion every 21 days for a total of 3 courses and primary prophylaxis with colony stimulating factor during each course of chemotherapy. Surgical resection was performed after recovery from the final course of chemotherapy. After adequate wound healing, patients received external beam radiotherapy (median dose to primary site, 55.8 Gray [Gy]; median dose to neck sites, 50.4 Gy). RESULTS Forty-five patients were registered. Thirty-eight patients completed the planned chemotherapy, 41 patients underwent surgical resection, and 37 patients completed the intended radiotherapy. The objective response rate was 50% (10% complete response; 40% partial response). Severe or life-threatening (Grade 3 or higher) granulocytopenia or thrombocytopenia occurred in 78% and 27% of patients, respectively. Two patients died of sepsis. Seventy-one percent, 67%, and 91% of patients were free of local, lymph node, and distant recurrence, respectively, with a median follow-up of 37 months. The 4-year overall survival and disease-related survival rates were 44.4% and 52.9%, respectively. CONCLUSION The authors conclude that paclitaxel is an active agent in patients with advanced head and neck carcinoma. However, the overall disease control, achieved by using paclitaxel as induction therapy, did not appear to be better than that achieved with standard treatment methods. Combined modality regimens with concurrent chemotherapy and radiotherapy have demonstrated more promise. Cancer 2000;89:2587–96. © 2000 American Cancer Society.

Surgery for cervical esophageal malignancy frequently involves comcomitant total laryngectomy carried out because of either oncologic or functional concerns. Though uncommon, preservation of the larynx has, in recent years, been described in patients undergoing cervical esophagectomy with reconstruction of the resulting circumferential esophageal defect achieved using either free jejunal flaps or gastric pullup procedures. The use of tubed-free cutaneous flaps for circumferential cervical esophageal reconstruction, however, has been rarely described in situations where the larynx has been preserved. We describe successful use of a tubed radial forearm-free flap for reconstruction of a circumferential cervical esophageal defect with preservation of the larynx. Use of the radial forearm flap in this situation resulted in minimal donor site-related morbidity, avoided the need for laparotomy and excellent voice and swallowing function were maintained. As such, use of tubed cutaneous free flaps can be considered an option for cervical esophageal reconstruction when the larynx has been preserved.

Purpose: This is a retrospective review to evaluate the role of surgery and intraoperative electron beam radiotherapy (IOERT) in the treatment of patients with previously irradiated advanced head and neck cancers. Methods and Materials: Between January 1992 and March 1997, 38 patients (31 males, 7 females; median age of 62 years) with recurrent head and neck cancer were treated with maximal resection and IOERT at the Ohio State University (OSU). All had been previously treated with full-course radiotherapy (median 65.1 Gy, range 50–74.4 Gy). Twenty-nine patients (76%) had previously undergone one or more surgical procedures. After maximal surgery the tumor bed was treated with IOERT (single field in 36 patients and 2 fields in 2 patients), most commonly with 6 MeV electrons (87%). The dose administered (at 90% isodose line) was 15 Gy for close or microscopically positive margins in 34 patients and 20 Gy for gross disease in 1 patient. Further external beam radiation therapy (EBRT) was not given. Results: After a median follow-up of 30 months (range 8–39 months), 24 of the 38 patients (66%) recurred within the IOERT field. Median time to IOERT failure was 6 months (95% CI: 4.3–7.7). The 6-month, 1-, and 2-year control rates within the IOERT volume were 41%, 19%, and 13 %, respectively. Thirty of the 38 patients (79%) recurred in locoregional areas. Median time to locoregional failure was 4 months (95% CI: 3.3–4.7). The 6-month, 1-, and 2-year locoregional control rates were 33%, 11%, and 4%, respectively. Distant metastases ocurred in 7 patients, 5 in association with IOERT failure and 2 with locoregional failure. Median overall survival was 7 months (95% CI: 4.7–9.3). The 6-month, 1-, 2-, and 3-year actuarial survival rates were 51%, 21%, 21%, and 8%, respectively. Major treatment-related complications occurred in 6 patients (16%). Conclusion: IOERT alone, at the dose used, is not sufficient for control of recurrent, previously irradiated head and neck cancers. Since higher IOERT doses are associated with high morbidity, we are currently evaluating the addition of limited EBRT dose and/or brachytherapy to improve the local control of these poor prognostic recurrent tumors, with acceptable morbidity.

Objectives: To describe an approach based on initial tissue-conserving surgery used to obtain histologically determined prognostic information that has therapeutic implications and the potential to enhance preservation of function. Study Design: Analysis of a group of patients with head and neck cancer treated initially with tissue-conserving surgery based on Mohs' histographic sectioning and selected neck dissection to derive histologically determined prognostic information with therapeutic implications and preservation in function. Methods: This study is primarily based on an analysis of patients from January 1, 1989, through June 4, 1996 assigned to a protocol evaluating resection of oral cavity squamous cell cancer with margin control using Mohs' histographic technique and/or a group of patients with neck assessment of NO on clinical examination who are undergoing supraomohyoid neck dissections. Results: Thirty-three primary tumor resections were performed using the Mohs' technique, and 54% required two or more Mohs' sections before clear histologic margins were obtained following resection based on clinically determined negative margins. There were 44 patients who underwent unilateral or bilateral supraomohyoid neck dissections, and 33% had occult, histologically positive nodes. When compared with the disease of the neck specimens, a preoperative computed tomography scan had a sensitivity of 25%, a specificity of 77%, and an accuracy of 63%. Conclusions : This report describes the effectiveness of Mohs' histographic sectioning and selective neck dissection as a means of determining prognostic information that can be used to develop a focused and cost-effective treatment program that, along with contemporary reconstructive techniques, provides a potential enhancement of function preservation.

PURPOSE The Southwest Oncology Group (SWOG) coordinated an Intergroup study with the participation of Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. MATERIALS AND METHODS Radiotherapy was administered in both arms: 1.8- to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total dose of 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P < .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P < .001). CONCLUSION We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.