Predictors of gastrostomy tube dependence in surgically managed oropharyngeal squamous cell carcinoma.

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 < 0.01) and T3/T4 tumor stage (OR 2.84; P = 0.02) were independent and significant predictors of G-tube dependence. CONCLUSION: Surgical approach, advanced tumor stage, and oral tongue resection may influence the development of nutritional dependence for surgically treated patients with OPSCC. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:415-421, 2019.

Notch1 Overexpression Correlates to Improved Survival in Cancer of the Oropharynx.

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.

High expression of myoferlin is associated with poor outcome in oropharyngeal squamous cell carcinoma patients and is inversely associated with HPV-status.

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<0.001) and these patients had 5.5 times increased hazard of death (95% Cl 3.4-8.8). Nuclear myoferlin expression was also directly associated with tumor recurrence (p<0.001), perineural invasion (p=0.008), extracapsular spread (p=0.009), higher T-stage (p=0.0015) and distant metastasis (p<0.001). In addition, nuclear MYOF expression was directly associated with IL-6 (p<0.001) and inversely with HPV status (p=0.0014). In a subgroup survival analysis, MYOF nuclear+/IL-6+ group had worst survival (84.6% mortality), whereas MYOF nuclear-/IL-6- had the best survival. Similarly, patients with HPV-negative/MYOF-positive tumors had worse survival compared to HPV-positive/MYOF-negative. Taken together, our results demonstrate for the first time that nuclear myoferlin expression independently predicts poor clinical outcome in OPSCC patients.

Surgical management of oropharyngeal squamous cell carcinoma: Survival and functional outcomes.

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.

Suppression of Proinflammatory and Prosurvival Biomarkers in Oral Cancer Patients Consuming a Black Raspberry Phytochemical-Rich Troche.

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.

Head and neck cancers, Version 2.2014. Clinical practice guidelines in oncology.

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."

Does body mass index matter while selecting the flap type for pharyngeal reconstructions?

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.

Elevated intrinsic cancer stem cell population in human papillomavirus-associated head and neck squamous cell carcinoma.

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.

Intensive care unit versus non-intensive care unit postoperative management of head and neck free flaps: comparative effectiveness and cost comparisons.

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.

Head and neck cancers, version 2.2013. Featured updates to the NCCN guidelines.

These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org).

Highly aggressive human papillomavirus-related oropharyngeal cancer: clinical, radiologic, and pathologic characteristics.

OBJECTIVE: Although the majority of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinomas have a favorable prognosis, we search for markers of poor prognosis by carefully examining a subset of highly aggressive cases. STUDY DESIGN: Seven patients with HPV-positive oropharyngeal cancer who presented with non-pulmonary distant metastasis or developed distant metastasis posttreatment were identified. Eight control cases were chosen which responded well to treatment. Pathologic and radiologic studies were reviewed and compared. RESULTS: Two cases displayed a small cell carcinoma (SmCC) component upon pathologic review. Biomarker analysis revealed lower expression of NOTCH1 in the aggressive cohort in comparison to controls (P = .04). Cases showed a predominance of clustering of lymph nodes, extracapsular spread, and central tumor necrosis. CONCLUSION: Although most HPV-related oropharyngeal cancers display a positive prognosis, it is evident that there is a subset, which behaves more aggressively. This early investigation identifies pathologic and radiologic features that may help to predict this behavior.

Transoral resection of pharyngeal cancer: summary of a National Cancer Institute Head and Neck Cancer Steering Committee Clinical Trials Planning Meeting, November 6-7, 2011, Arlington, Virginia.

Recent advances now permit resection of many pharyngeal tumors through the open mouth, an approach that can greatly reduce the morbidity of surgical exposure. These transoral techniques are being rapidly adopted by the surgical community and hold considerable promise. On November 6-7, 2011, the National Cancer Institute sponsored a Clinical Trials Planning Meeting to address how to further investigate the use of transoral surgery, both in the good prognosis human papillomavirus (HPV)-initiated oropharyngeal cancers, and in those with HPV-unrelated disease. The proceedings of this meeting are summarized.

Multiparameter analysis, including EMT markers, on negatively enriched blood samples from patients with squamous cell carcinoma of the head and neck.

Epithelial to mesenchymal transition (EMT) has been hypothesized as a mechanism by which cells change phenotype during carcinogenesis, as well as tumor metastasis. Whether EMT is involved in cancer metastasis has a specific, practical impact on the field of circulating tumor cells (CTCs). Since the generally accepted definition of a CTC includes the expression of epithelial surface markers, such as EpCAM, if a cancer cell loses its epithelial surface markers (which is suggested in EMT), it will not be separated and/or identified as a CTC. We have developed, and previously reported on the use of, a purely negative enrichment technology enriching for CTCs in the blood of squamous cell carcinoma of the head and neck (SCCHN). This methodology does not depend on the expression of surface epithelial markers. Using this technology, our initial data on SCCHN patient blood indicates that the presence of CTCs correlates with worse disease-free survival. Since our enrichment is not dependent on epithelial markers, we have initiated investigation of the presence of mesenchymal markers in these CTC cells to include analysis of: vimentin, epidermal growth factor receptor, N-cadherin, and CD44. With the aid of confocal microscopy, we have demonstrated not only presumed CTCs that express and/or contain: a nucleus, cytokeratins, vimentin, and either EGFR, CD44, or N-cadherin, but also cells that contain all of the aforementioned proteins except cytokeratins, suggesting that the cells have undergone the EMT process. We suggest that our negative depletion enrichment methodology provides a more objective approach in identifying and evaluating CTCs, as opposed to positive selection approaches, as it is not subjective to a selection bias and can be tailored to accommodate a variety of cytoplasmic and surface markers which can be evaluated to identify a multitude of phenotypic patterns within CTCs from individual patients, including so-called EMT as presented here.

Alcohol-related predictors of delirium after major head and neck cancer surgery.

OBJECTIVE: To identify specific alcohol-related predictors of postoperative delirium. DESIGN: Inception cohort, logistic regression with step-wise selection. SETTING: Ohio State University Comprehensive Cancer Center, Columbus. PATIENTS: A total of 774 patients undergoing major resection of head and neck squamous cell carcinoma. MAIN OUTCOME MEASURES: The correlation of 19 variables with postoperative delirium. One variable was an alcohol-related blood test: mean red blood cell volume (MCV). Eight variables were patient responses to alcohol-related questions. RESULTS: Eighty-nine of 774 surgical procedures (11.5%) were complicated by delirium. Six variables were significantly associated with delirium: age older than 69 years (odds ratio [OR], 2.43; P < .01), preexisting cognitive impairment (OR, 3.83; P < .01), surgery duration greater than 6 hours (OR, 2.40; P < .01), MCV greater than 95.0 femtoliters (OR, 2.23; P < .01), ever being advised to cut back on alcohol (OR, 2.25; P = .01), and not abstaining from alcohol for at least 1 continuous week in the preceding year (OR, 2.16; P = .02). The number of variables stratified delirium risk (0 variables: 198 patients, 2.5% incidence of delirium; 1 variable: 278 patients, 6% incidence of delirium; 2 variables: 206 patients, 18% incidence of delirium; and >2 variables: 92 patients, 34% incidence of delirium). CONCLUSIONS: Three clinical variables not related to alcohol drinking (age, preexisting cognitive impairment, and surgery duration), an alcohol-related laboratory test (MCV), and 2 alcohol-related questions ("At any time in your life, has anyone ever suggested that you should cut back on your drinking?" and "What is the greatest number of days in a row you have gone without an alcoholic drink in the past year?") may help in estimating a patient's risk for postoperative delirium.

The value of PET/CT to assess clinically negative necks.

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.

Gankyrin, a biomarker for epithelial carcinogenesis, is overexpressed in human oral cancer.

UNLABELLED: Little is known about the potential involvement of the oncoprotein gankyrin in human oral cancer progression. In this study, the levels of gankyrin mRNA and protein expression were assessed in human oral epithelial cell lines, at-risk normal oral tissues, premalignant oral lesions, and primary oral squamous cell carcinomas (OSCCs). MATERIALS AND METHODS: Biopsies included 6 oral epithelial cell lines, 32 OSCC specimens for qRT-PCR analysis, 27 OSCC specimens and 12 premalignant oral lesions for immunohistochemical analysis. RESULTS: Gankyrin was overexpressed in all tested oral epithelial cell lines and the majority of OSCC specimens (32/32 (100%) and 21/27 (71%) at the mRNA and protein levels, respectively). Moreover, 6/12 of premalignant oral lesions overexpressed gankyrin protein. CONCLUSION: Gankyrin overexpression is a prevalent event in human oral cancer and occurs during the early stages of oral carcinogenesis, thus being a viable therapeutic or chemopreventive target in oral cancer.

When to manage level V in head and neck carcinoma?

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 <20% (13 of 86, 15.1%). CONCLUSIONS: Because level V was not involved in any patient when the other levels were not involved, it might be reasonable to preserve level V especially in clinically and intraoperatively N0 patients.