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Background: We examined the effect of free tissue neurotization on speech and swallowing outcomes for patients undergoing reconstruction of hemiglossectomy defects with a radial forearm free flap (RFFF). Methods: A retrospective study was performed in patients with oral cavity squamous cell carcinoma undergoing a hemiglossectomy and reconstruction with a RFFF. Functional outcomes including nutritional mode, range of liquids and solids, and speech understandability were analyzed 1‐year post‐treatment. Results: Eighty‐four patients were included in this analysis, 41 of whom had neurotized flaps (49%). No significant differences in demographic or clinical variables were seen between the neurotized and non‐neurotized groups. On multivariate analysis controlling for BMI, flap area, and N‐classification, patients with neurotized flaps were significantly more likely to have normal range of liquids and solids and less likely to have a G‐tube. Conclusions: Neurotization of RFFF reconstructing hemiglossectomy defects results in decreased G‐tube dependence and improved range of liquids and solids. [ABSTRACT FROM AUTHOR]

Background: Single cycle induction chemotherapy (IC) with platinum and 5‐flurouracil (PF) and treatment based on clinical response predicts organ preservation in laryngeal cancer. Other agents offer intriguing alternatives with potentially increased ease of administration, reduced risk for severe toxicities, and increased platinum sensitivity. Methods: We report the results of a phase II bioselection trial in advanced resectable laryngeal cancer utilizing an IC regimen of two cycles of platinum plus docetaxel (TP) with a Bcl‐2 inhibitor. The primary endpoint was organ preservation rate at 12 weeks post chemoradiation. Results: Fifty‐four patients were enrolled. Response to IC was 72%. The organ preservation rate was 59% with a laryngectomy free survival of 46%. Induction related grade ≥3 toxicities were observed in 56% of patients with two grade 5 events. Conclusions: Two cycles of TP IC plus a Bcl‐2 inhibitor did not improve laryngeal preservation compared to a single cycle of PF. [ABSTRACT FROM AUTHOR]

Background: Tumor‐infiltrating lymphocytes (TILs) and cytokines are associated with prognosis among patients with head and neck squamous cell carcinoma (HNSCC). Statins (cholesterol‐lowering drugs) may improve HNSCC prognosis, particularly in human papillomavirus (HPV)‐positive cases, but the mechanism remains unclear. Methods: Statin use was collected from medical records for HNSCC cases (2008–2014). TILs were counted in tumor tissue, and a total weighted score (TILws) was created. Cytokines were measured in blood. The associations between statins and biomarkers were estimated using logistic (biomarker categories:

Head and neck squamous cell carcinoma (HNSCC) is a morbid cancer with poor outcomes. Statins possess anticancer properties such as immunomodulatory and antiinflammatory effects. The objective of our study is to identify the association between statin use among untreated HNSCC patients and overall death, diseasespecific death and recurrence. HNSCC patients were recruited to participate in the University of Michigan Head and Neck Cancer Specialized Program of Research Excellence (SPORE) from 2003 to 2014. Statin use data were collected through medical record review. Participants were considered a statin user if they used a statin at or after diagnosis. Outcome data were collected through medical record review, Social Security Death Index or LexisNexis. Our analytic cohort included 1638 participants. Cox proportional hazard models were used to estimate the association between ever statin use and HNSCC outcomes. Statin use was seen in 36.0% of participants. We observed a statistically significant inverse association between ever using a statin and overall death (HR = 0.75, 95% CI = 0.63-0.88) and HNSCC-specific death (HR = 0.79, 95% CI = 0.63-0.99) and a nonstatistically significant inverse association for recurrence (HR = 0.85, 95% CI = 0.70-1.04). When investigating the association between statin use and HNSCC outcomes utilizing interaction terms between statin use and human papillomavirus (HPV), statistically significant interactions for HNSCC-specific death and recurrence were identified (HNSCC-specific death: HPV-positive HR = 0.41, 95% CI = 0.21-0.84; HPV-negative HR = 1.04, 95% CI = 0.71-1.51; p-int=0.02; recurrence: HPV-positive HR = 0.49, 95% CI = 0.29-0.84; HPV-negative HR = 1.03, 95% CI = 0.74-1.43; p=int-0.02). Statin use may be protective for adverse outcomes in HNSCC patients, particularly those with HPV-positive disease. If true, these findings could have a meaningful impact on tertiary prevention for this cancer [ABSTRACT FROM AUTHOR]

Background: Of interest is the long‐term neck and shoulder impairment of patients treated with primary chemoradiotherapy (CRT). This is important for counseling patients regarding treatment decisions when discussing primary CRT. Methods: A cross‐sectional study to identify factors that contribute to neck and shoulder dysfunction in patients treated with primary CRT. We utilized the neck dissection impairment index (NDII). Eighty‐seven patients treated between 2003 and 2010, who were free of disease, responded; 24 of these 87 underwent post‐CRT neck dissection. Mean interval since completion of CRT was over 5 years (62.7 months). Mean age, 63.5 years, male:female 75:12. Results: Mean NDII score was 87.4 (SD 22.1, range 5–100). Multiple linear regression revealed worse NDII scores for patients with larger pre‐CRT gross tumor nodal volume (GTVnodal), controlled for age, sex, body mass index (BMI), and the presence of neck dissection (p = 0.02). There were significant associations with increasing GTVnodal and "low" scores for components of the NDII that assessed neck pain (p = 0.02), neck stiffness (p = 0.01), lifting heavy objects (p = 0.02), reaching overhead (p = 0.02), and ability to do work (p = 0.02). Physical therapy (PT) was evaluated as an "anchor" but it was prescribed "as needed." Regression revealed participation in PT was associated with higher GTVnodal, lower BMI, presence of neck dissection, and female sex (p = 0.00007). Conclusion: GTVnodal was an independent predictor of neck and shoulder impairment. High GTVnodal was associated with increased pain and stiffness, and increased difficulty lifting heavy objects, reaching overhead, overall ability to perform work‐related tasks and was associated with participation in post‐treatment PT. [ABSTRACT FROM AUTHOR]

Background: There are limited treatment options for unresectable recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Vascular endothelial growth factor is of significant interest for targeted therapy in R/M HNSCC because of its central role in tumorigenesis and immunosuppression. Axitinib is a potent inhibitor of vascular endothelial growth factor receptor (VEGFR) 1 , VEGFR2, VEGFR3, platelet‐derived growth factor receptor, as well as c‐kit and offers such an approach. Methods: This article reports the results of a phase 2 trial evaluating axitinib in R/M HNSCC according to the Choi criteria for radiographic response assessment. The primary endpoint of this trial was 6‐month overall survival. RESULTS: Twenty‐nine patients were enrolled, and 28 were evaluable for a response. Patients were heavily pretreated with 61% having had at least 1 previous systemic treatment in the metastatic setting (range, 0‐5). The median overall survival of 9.8 months and the 6‐month overall survival rate of 70% met the protocol‐defined criteria for clinical efficacy. The best overall response rate was 42%. Correlative analyses demonstrated that PI3K signaling pathway alterations were associated with an increased response to therapy (75% vs 17%). A marked response to therapy was seen in a subgroup of patients who were treated with an immune checkpoint inhibitor after progression on axitinib. Conclusions: Treatment with axitinib is associated with improved survival in patients with heavily pretreated head and neck cancer, and PI3K pathway alterations may serve as a biomarker for response. Further investigation is warranted to evaluate axitinib in biomarker‐selected populations, especially in combination with immune checkpoint inhibitor therapy. Lay Summary: Metastatic head and neck squamous cancer is an incurable disease with limited treatment options and a poor prognosis.This study is the first to demonstrate that the targeted oral drug axitinib improves survival in patients with heavily pretreated metastatic head and neck cancer.Furthermore, patients whose tumors have specific mutations derive the greatest benefit from therapy.The investigation of axitinib alone or in combination with immunotherapy in a genomic biomarker–selected population is warranted. This study demonstrates that treatment with axitinib improves survival in patients with heavily pretreated recurrent or metastatic head and neck squamous cell carcinoma, that alternative response criteria enable the identification of patients with atypical radiographic responses, and that patients with PI3K pathway alterations may derive exceptional benefit from therapy. Clinically, this study provides evidence for the evaluation of axitinib alone or in combination with immunotherapy in a genomic biomarker–selected population. [ABSTRACT FROM AUTHOR]

Background: Alternative therapeutic strategies are needed for localized oropharyngeal carcinoma. Cetuximab represents a potential option for those ineligible for cisplatin or, until recently, an agent for de‐escalation in low risk HPV+ oropharyngeal carcinoma (OPSCC). Our objective was to define the toxicity and efficacy of cetuximab‐radiotherapy. Methods: We conducted paired phase II trials evaluating cetuximab‐radiotherapy in two cohorts (a) low risk HPV+ OPSCC and (b) cisplatin ineligible. The mean follow‐up was 48 months. Results: Forty‐two patients were enrolled in cohort A with a 2‐year disease free survival (DFS) of 81%. Twenty‐one patients were enrolled in cohort B prior to closure due to adverse outcomes with a 2‐year DFS of 37%. Severe toxicities were seen in 60% of patients, 30% required enteral nutrition. Conclusion: Among cisplatin ineligible patients, cetuximab treatment engendered poor outcomes. Rates of severe toxicities were on par with platinum‐based regimens suggesting that cetuximab is not a benign treatment. [ABSTRACT FROM AUTHOR]

Objective: Peritonsillar abscess (PTA) is a common infectious complication of pharyngeal infection managed by otolaryngologists and emergency room physicians. Streptococcus and Fusobacterium (e.g., Fusobacterium necrophorum, FN) species are commonly isolated pathogens. The aim of this study was to determine the implication of culture results on abscess recurrence following drainage.Methods: Single-institution retrospective review of patients treated at the University of Michigan between 2000 and 2017. Demographic and clinical outcome data were analyzed, including treatment details, culture data, and recurrence.Results: One hundred fifty-six of the 990 patients in our study developed recurrence of their abscess (16%). The age ranges most susceptible to recurrence included adolescent (22.9%) and young adult groups (17.1%). Recurrent patients were more likely to have experienced acute progression of symptoms (79% vs. 71%, P = 0.03), trismus (67% vs. 55%, P = 0.006), voice changes (65% vs. 57%, P = 0.04), and dysphagia (72% vs. 61%, P = 0.01) compared to nonrecurrent patients. They were also more likely to have clinical lymphadenopathy noted on initial examination (67% vs. 56%, P = 0.009). Culture data was sent for 852 patients (86%). The presence of FN was significantly more prevalent in the recurrent group (P < 0.0001).Conclusion: There is a high observed prevalence of FN species within PTA aspirates in the recurrent PTA population. PTA aspirate should be sent for anaerobic growth to screen for Fusobacterium species. In addition, follow-up and lower threshold for subsequent tonsillectomy should be considered in this at-risk group.Level Of Evidence: 3 Laryngoscope, 129:1567-1571, 2019. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: An uncommon phenomenon in relation to the peritonsillar abscess (PTA) is the intratonsillar abscess (ITA) or formation of an abscess within tonsillar parenchyma. This study sought to characterize our experience with diagnosis and management of ITAs in the context of the PTA patient population.Study Design: Case-control series.Methods: This is a single-institution retrospective review of patients treated at the University of Michigan between 2000 and 2017.Results: Six hundred fifty-five adult patients were identified. The incidence of ITA within the PTA population was 7% (n = 43). Patients with ITA had lower mean white blood cell count (P = .03), lower proportion of trismus (P < .0001), otalgia (P = .007), vocal changes (P < .0001), and fewer incidences of acute progression of symptoms (P = .0007). On multivariable analysis, ITA patients were noted to be older, present with a longer duration of symptoms, and have greater incidence of neck pain and lymphadenopathy. Drainage was attempted in fewer ITA patients and was rarely successful (15%) in comparison to successful drainage for PTA patients (69%) (P < .0001).Conclusions: Symptomatology differs for ITA, as fewer present with the classic PTA symptoms of otalgia, trismus, and voice alterations. The lack of classic symptoms likely leads to delayed presentation. A greater number of ITA patients presented with neck pain and lymphadenopathy. In the ITA population, aspiration attempts were more infrequent and less successful in yielding purulence. Given infrequent yield of pus and low overall recurrence rate, the diagnosing clinician should consider medical management in this distinct patient population.Level Of Evidence: 4 Laryngoscope, 129:1354-1359, 2019. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to evaluate the AJCC eighth edition clinical staging system for human papillomavirus (HPV)‐associated oropharyngeal squamous cell carcinoma and to further understand how clinical stage and smoking history affect oncologic outcomes. The purpose of this study was to present the understanding of how clinical stage and smoking history affect oncologic outcomes in human papillomavirus (HPV)‐associated oropharyngeal squamous cell carcinoma (SCC) is critical for selecting patients for treatment deintensification. Methods: Kaplan‐Meier and Cox regression were used to evaluate overall survival (OS), locoregional recurrence‐free survival (LRFS), and distant recurrence‐free survival (DRFS). Concordance statistics (C‐indices) were used to compare discriminating ability. Results: The OS and DRFS but not LRFS were significantly distributed using the American Joint Committee on Cancer (AJCC) seventh and eighth editions criteria. The C‐indices for OS, LRFS, and DRFS were 0.57, 0.54, and 0.60, respectively, using the AJCC seventh edition, and 0.63, 0.53, and 0.65, respectively, using the AJCC eighth edition. On multivariate analysis, 1 + pack‐year smoking history correlated with OS (hazard ratio [HR] 1.96; 95% confidence interval [CI] 1.2‐3.1; P < .01) but not LRFS or DRFS. Conclusion: These results support implementation of the AJCC eighth edition for HPV‐associated oropharyngeal SCC. Clinical stage may be more important than smoking history in selection for deintensification. [ABSTRACT FROM AUTHOR]

Background: Accurate, individualized prognostication in patients with oropharyngeal squamous cell carcinoma (OPSCC) is vital for patient counseling and treatment decision making. With the emergence of human papillomavirus (HPV) as an important biomarker in OPSCC, calculators incorporating this variable have been developed. However, it is critical to characterize their accuracy prior to implementation.Methods: Four OPSCC calculators were identified that integrate HPV into their estimation of 5-year overall survival. Treatment outcomes for 856 patients with OPSCC who were evaluated at a single institution from 2003 through 2016 were analyzed. Predicted survival probabilities were generated for each patient using each calculator. Calculator performance was assessed and compared using Kaplan-Meier plots, receiver operating characteristic curves, concordance statistics, and calibration plots.Results: Correlation between pairs of calculators varied, with coefficients ranging from 0.63 to 0.90. Only 3 of 6 pairs of calculators yielded predictions within 10% of each other for at least 50% of patients. Kaplan-Meier curves of calculator-defined risk groups demonstrated reasonable stratification. Areas under the receiver operating characteristic curve ranged from 0.74 to 0.80, and concordance statistics ranged from 0.71 to 0.78. Each calculator demonstrated superior discriminatory ability compared with clinical staging according to the seventh and eighth editions of the American Joint Committee on Cancer staging manual. Among models, the Denmark calculator was found to be best calibrated to observed outcomes.Conclusions: Existing calculators exhibited reasonable estimation of survival in patients with OPSCC, but there was considerable variability in predictions for individual patients, which limits the clinical usefulness of these calculators. Given the increasing role of personalized treatment in patients with OPSCC, further work is needed to improve accuracy and precision, possibly through the identification and incorporation of additional biomarkers. [ABSTRACT FROM AUTHOR]

Background: Accurate prognostication is essential to the optimal management of laryngeal cancer. Predictive models have been developed to calculate the risk of oncologic outcomes, but extensive external validation of accuracy and reliability is necessary before implementing them into clinical practice.Method: Four published prognostic calculators that predict 5-year overall survival for patients with laryngeal cancer were evaluated using patient information from a prospective epidemiology study cohort (n = 246; median follow-up, 60 months) with previously untreated, stage I through IVb laryngeal squamous cell carcinoma.Results: Different calculators yielded substantially different predictions for individual patients. The observed 5-year overall survival was significantly higher than the averaged predicted 5-year overall survival of the 4 calculators (71.9%; 95% confidence interval [CI], 65%-78%] vs 47.7%). Statistical analyses demonstrated the calculators' limited capacity to discriminate outcomes for risk-stratified patients. The area under the receiver operating characteristic curve ranged from 0.68 to 0.72. C-index values were similar for each of the 4 models (range, 0.66-0.68). There was a lower than expected hazard of death for patients who received induction (bioselective) chemotherapy (hazard ratio, 0.46; 95% CI, 0.24-0.88; P = .024) or primary surgical intervention (hazard ratio, 0.43; 95 % CI, 0.21-0.90; P = .024) compared with those who received concurrent chemoradiation.Conclusions: Suboptimal reliability and accuracy limit the integration of existing individualized prediction tools into routine clinical decision making. The calculators predicted significantly worse than observed survival among patients who received induction chemotherapy and primary surgery, suggesting a need for updated consideration of modern treatment modalities. Further development of individualized prognostic calculators may improve risk prediction, treatment planning, and counseling for patients with laryngeal cancer. Cancer 2018;124:706-16. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background We examined the prognostic value of a panel of biomarkers in patients with squamous cell carcinoma of the head and neck (SCCHN) who were human immunodeficiency virus (HIV) positive (HIV-positive head and neck cancer) and HIV negative (HIV-negative head and neck cancer). Methods Tissue microarrays (TMAs) were constructed using tumors from 41 disease site-matched and age-matched HIV-positive head and neck cancer cases and 44 HIV-negative head and neck cancer controls. Expression of tumor biomarkers was assessed by immunohistochemistry (IHC) and correlations examined with clinical variables. Results Expression levels of the studied oncogenic and inflammatory tumor biomarkers were not differentially regulated by HIV status. Among patients with HIV-positive head and neck cancer, laryngeal disease site ( P = .003) and Clavien-Dindo classification IV (CD4) counts <200 cells/μL ( P = .01) were associated with poor prognosis. Multivariate analysis showed that p16 positivity was associated with improved overall survival (OS; P < .001) whereas increased expression of transforming growth factor-beta (TGF-β) was associated with poor clinical outcome ( P = .001). Conclusion Disease site has significant effect on the expression of biomarkers. Expression of tumor TGF-β could be a valuable addition to the conventional risk stratification equation for improving head and neck cancer disease management strategies. [ABSTRACT FROM AUTHOR]

Background Total laryngectomy remains the treatment of choice for recurrent/persistent laryngeal squamous cell carcinoma (SCC) after radiotherapy (RT) or chemoradiotherapy (CRT). However, despite attempts at aggressive surgical salvage, survival in this cohort remains suboptimal. Methods A prospectively maintained single-institution database was queried for patients undergoing total laryngectomy for recurrent/persistent laryngeal SCC after initial RT/CRT between 1998 and 2015(n = 244). Demographic, clinical, and survival data were abstracted. The Kaplan-Meier survival curves and hazard ratios (HRs) were calculated. Results Five-year overall survival (OS) was 49%. Five-year disease-free survival (DFS) was 58%. Independent predictors of OS included severe comorbidity (Adult Comorbidity Evaluation-27 [ACE-27] scale; HR 3.76; 95% confidence interval [CI] 1.56-9.06), and positive recurrent clinical nodes (HR 2.91; 95% CI 1.74-4.88). Conclusion Severe comorbidity status is the strongest predictor of OS, suggesting that increased attention to mitigating competing risks to health is critical. These data may inform a risk prediction model to allow for focused shared decision making, preoperative health optimization, and patient selection for adjuvant therapies. [ABSTRACT FROM AUTHOR]

Objective. Emerging data have demonstrated suboptimal outcomes among patients with stage II larynx cancer. Our objective is to report survival outcomes for T2N0M0 larynx cancer and to determine the cause-specific survival. Study Design. Case series with planned data collection. Setting. Tertiary academic center. Subjects. Adults with T2N0M0 squamous cell carcinoma of the larynx treated with curative intent. Methods. A head and neck cancer epidemiology database was queried for eligible subjects from 2003 to 2014. Data were extracted from the electronic medical record and research database, and survival analyses were performed. Results. Thirty-four patients with previously untreated stage II larynx cancer were identified (median follow-up 48 months). Patients included 27 males and 7 females with a mean age of 59 years. The majority of tumors arose from the glottis (59%). Of the cohort, 12% were treated with surgery, 65% radiation therapy, and 24% chemoradiation therapy. The estimated 2-year overall survival was 81%, (95% confidence interval [CI], 59%-92%), disease-specific survival was 91% (95% CI, 69%-98%), and recurrence-free survival was 84% (95% CI, 65%-93%). Four of 5 patients with persistent or recurrent disease posttreatment were successfully salvaged with total laryngectomy with 100% locoregional control. There were 11 mortalities (2 disease related, 2 due to metachronous primaries, 3 treatment related, and 4 from other/unknown causes). Conclusion. Stage II laryngeal cancer has suboptimal survival outcomes. This appears to be a reflection of medical comorbidities, propensity for metachronous primaries, and the sequelae of late treatment effects rather than poor locoregional control. [ABSTRACT FROM AUTHOR]

Objectives It is unknown if preoperative tracheostomy for persistent/recurrent laryngeal squamous cell carcinoma (LSCC) plays a role in unrecognized local disease spread and disease recurrence after salvage laryngectomy. The goals of this study were to determine the effect of preoperative tracheostomy on disease-free survival (DFS) in patients with recurrent/persistent LSCC undergoing salvage laryngectomy. Study Design Retrospective case series derived from prospectively maintained database. Setting Tertiary care academic center. Subjects Patients with recurrent/persistent LSCC after radiation/chemoradiation (RT/CRT) who underwent salvage laryngectomy at the University of Michigan from 1997 to 2015. Methods Demographic, clinical, pathologic, and survival data were collected. Kaplan-Meier survival estimates were performed. Results DFS was worse for patients with tracheostomy prior to laryngectomy than patients without a tracheostomy (5 year: 39% vs 67%; P < .001). Patients with tracheostomy prior to RT/CRT compared to patients with tracheostomy after RT/CRT or patients without a tracheostomy had worse DFS (5-year: 25%, 49%, and 67%, respectively; P < .001). In bivariable analyses controlling for T classification, N classification, or overall stage, preoperative tracheostomy was associated with worse DFS. In multivariable analysis, presence of a preoperative tracheostomy had a worse DFS (hazard ratio, 1.63; 95% confidence interval, 1.00-2.67; P = .048). Conclusion Preoperative tracheostomy is associated with disease recurrence in patients with persistent/recurrent LSCC undergoing salvage laryngectomy, particularly in patients who had tracheostomy prior to completion of initial RT/CRT. Notably, preoperative tracheostomy as a causal factor vs marker for disease recurrence is difficult to ascertain. Nevertheless, clinicians should be aware of the increased risk of locoregional recurrence in patients with preoperative tracheostomy when counseling on surgical salvage and when considering the role of additional therapy. [ABSTRACT FROM AUTHOR]

Objective: Patients with a family history of cancer may be genetically predisposed to carcinogenesis. This could affect risk of recurrence, second primary tumors, and overall outcomes after treatment of a primary cancer. We evaluated the association between family history of cancer and disease-specific survival in a cohort of patients with primary head and neck squamous carcinoma (HNSCC).Study Design: Six hundred and forty-three incident HNSCC patients recruited through the University of Michigan Specialized Program of Research Excellence were followed for up to 5 years for survival. Participants were interviewed about personal and family cancer history, demographic information, and behavioral habits.Methods: Cox proportional hazards models were used to estimate the association between family history of cancer in a first-degree relative and disease-specific survival.Results: After multivariable adjustment, we found a nonsignificant inverse association between family history and HNSCC mortality (hazard ratio [HR] = 0.88, 95% confidence interval [CI] 0.57-1.35). This association was stronger and statistically significant among patients who currently both drank alcohol and smoked cigarettes at diagnosis (HR = 0.46, 95% CI = 0.22-0.97); no association was observed among participants who did not both drink and smoke at the time of diagnosis (HR = 1.14, 95% CI = 0.68-1.91; p-interaction = 0.046).Conclusion: Results from this study suggest that having a family history of cancer may be associated with improved disease-specific survival in patients who use tobacco and alcohol. Additional large studies, particularly in populations including nonwhites and women, are needed to confirm or refute the association and to elucidate the genetic factors that may underlie this potential association.Level Of Evidence: 2b. Laryngoscope, 127:1816-1820, 2017. [ABSTRACT FROM AUTHOR]

ABSTRACT Background To better understand the associations between a history of tobacco use and survival outcomes, cigarette use was prospectively surveyed in 687 previously untreated patients with cancer of the oral cavity ( n = 271), oropharynx ( n = 257), larynx ( n = 135), or hypopharynx ( n = 24). Methods Kaplan-Meier and Cox models explored the associations of tobacco use intensity (packs/day), duration (years of use), and timing before diagnosis with overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS). Results Cigarette use duration, timing, and intensity were significant predictors for all outcomes in univariate analysis. Never smoking and pack-years were not significantly associated with outcomes after adjustment for prognostic factors, such as stage, comorbidities, and human papillomavirus (HPV) status, which were strongly associated with clinical outcomes. Conclusion The findings confirm the association between smoking history and survival and the importance of clinical variables in evaluating smoking as a prognostic factor. Timing, intensity, and duration of cigarette use should be considered with other prognostic factors when considering risk stratification for treatment planning. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1810-1820, 2016 [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Assess tumor suppressor p53 (TP53) functional mutations in the context of other biomarkers in advanced larynx cancer.Study Design: Prospective analysis of pretreatment tumor TP53, human papillomavirus (HPV), Bcl-xL, and cyclin D1 status in stage III and IV larynx cancer patients in a clinical trial.Methods: TP53 exons 4 through 9 from 58 tumors were sequenced. Mutations were grouped using three classifications based on their expected function. Each functional group was analyzed for response to induction chemotherapy, time to surgery, survival, HPV status, p16INK4a, Bcl-xl, and cyclin D1 expression.Results: TP53 mutations were found in 22 of 58 (37.9%) patients with advanced larynx cancer, including missense mutations in 13 of 58 (22.4%) patients, nonsense mutations in four of 58 (6.9%), and deletions in five of 58 (8.6%). High-risk HPV was found in 20 of 52 (38.5%) tumors. A classification based on Evolutionary Action score of p53 (EAp53) distinguished missense mutations with high risk for decreased survival from low-risk mutations (P = 0.0315). A model including this TP53 classification, HPV status, cyclin D1, and Bcl-xL staining significantly predicts survival (P = 0.0017).Conclusion: EAp53 functional classification of TP53 mutants and biomarkers predict survival in advanced larynx cancer.Level Of Evidence: NA. Laryngoscope, 126:E292-E299, 2016. [ABSTRACT FROM AUTHOR]

Background Because immune responses within the tumor microenvironment are important predictors of tumor biology, correlations of types of tumor infiltrating lymphocytes (TILs) with clinical outcomes were determined in 278 patients with head and neck squamous cell carcinoma (HNSCC). Methods Infiltrating levels of CD4 (helper T cells), CD8 (cytotoxic/suppressor T cells), FoxP3 (regulatory T cells), CD68 (myeloid-derived suppressor cells,) and CD1a (Langerhans) cells were measured in tissue microarrays (TMAs). Cox models tested associations with patient outcomes after adjusting for all known prognostic factors. Median follow-up was 36.6 months. Results Higher CD4 and CD8 TIL levels were associated with improved overall survival (OS; hazard ratio [HR] = 0.77; 95% confidence interval [CI] = 0.65-0.93; p = .005 and HR = 0.77; 95% CI = 0.64-0.94; p = .008, respectively), and relapse-free survival (RFS; p = .03 and .05, respectively). After controlling for prognostic factors, higher CD4 levels predicted improved OS and disease-specific survival (DSS; p = .003 and p = .004, respectively). Conclusion The findings suggest that TILs are a significant independent prognostic factor for HNSCC that differ by treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1074-1084, 2016 [ABSTRACT FROM AUTHOR]

Objective: To determine biomarkers of recurrence and survival in patients with spindle cell variant squamous cell carcinoma (SpSCC) of the head and neck.Study Design: Retrospective case control study.Setting: Tertiary academic center.Subjects and Methods: Thirty-two SpSCC patients (mean age, 68.8) between 1987 and 2009 were identified and reviewed. A tissue microarray (TMA) was constructed from tumor specimens. Tumor biomarkers under study included p16, epidermal growth factor receptor (EGFR), p53, EZH2, cyclin D1, CD104, HGFa, p21, and cMET. An additional TMA was constructed from patients with non-SpSCC oral cavity squamous cell carcinoma for comparative purposes. The main outcomes were overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS).Results: In the SpSCC cohort, tumors positive for cMet had worse OS (P < .001). Patients positive for cMet (P = .007), cyclin D1 (P = .019), and p16 (P = .004) had worse DSS. Recurrence-free survival was also worse in patients with tumors positive for cMet (P = .037), cyclin D1 (P = .012), and p16 (P < .001). Compared with the oral cavity cohort, there was a significantly larger proportion of patients in the SpSCC group with tumors staining positive for cMet and a lower proportion of tumors positive for cyclin D1.Conclusion: cMet, cyclin D1, and p16 are predictive tumor biomarkers for risk of recurrence and worse DSS in patients with SpSCC. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to examine associations of pretreatment serum carotenoids, tocopherols, and quercetin with prognosis in 154 patients newly diagnosed with head and neck cancer. Methods Pretreatment blood and health surveys were collected. Serum micronutrients were measured by high performance liquid chromatography. Data on recurrence and death were collected annually. Cox proportional hazards models measured associations of serum nutrient concentrations with recurrence and overall survival. Results During a median follow-up time of 37 months, there were 32 recurrences and 27 deaths. After controlling for covariates, subjects with high versus low serum xanthophyll and total carotenoid concentrations had significantly longer recurrence-free time ( p = .002 and p = .02, respectively). Overall survival time was significantly longer in patients with high versus low serum xanthophyll concentrations ( p = .02). Conclusion Future research should evaluate the possible benefits of interventions to increase intakes of rich food sources of xanthophylls in this patient population. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1591-E1597, 2016 [ABSTRACT FROM AUTHOR]

Background We recently described the imaging characteristics of multiple confluent regional metastases (matted nodes) and found that this characteristic was associated with distant metastasis in patients with oropharyngeal squamous cell carcinoma (SCC). The purpose of this study was to determine if matted nodes are a predictive marker for distant metastasis. Methods Radiologic lymph node characteristics on 205 patients with untreated stage III/IV with oropharyngeal SCC of whom 192 had known human papillomavirus (HPV) status underwent weekly carboplatin and paclitaxel with concomitant intensity-modulated radiation therapy (IMRT) between 2003 and 2010 with a minimum of 2-year of follow-up. Results The 3-year disease-specific survival (DSS) for patients with matted nodes was 58% versus 97% with nonmatted nodes ( p = .0001). The prevalence of matted nodes in the population was 20%. The positive predictive value of matted nodes for distant metastasis was 66%, and the negative predictive value was 99%. Conclusion Matted nodes are a predictive marker for distant disease and can be used for planning new clinical interventions. © 2014 Wiley Periodicals, Inc. Head Neck 38: 184-190, 2016 [ABSTRACT FROM AUTHOR]

Due to the high incidence of recurrent squamous cell carcinoma of the head and neck and the toxicity profile of current salvage regimens, there is a need for tolerable and effective treatment options. We performed a retrospective matched case series to report our experience with recurrent high-risk patients who received capecitabine (CAP) therapy in the adjuvant setting after salvage therapy. The 5-year recurrence-free survival rates for the CAP and control cohorts were 54% (95% CI, 0.27%-0.75%) and 27% (95% CI, 0.09%-0.50%), respectively. Multivariable Cox modeling showed a significant improvement in recurrence-free survival in the CAP cohort (hazard ratio, 0.19; 95% CI, 0.04-0.92; P = .0392). While this was a respective analysis that could not control for all variables, these exploratory findings offer insights that may inform a prospective study to determine CAP efficacy. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are the 2 most common cutaneous carcinomas. Molecular profiles predicting metastasis of these cancers have not been identified. Methods Epigenetic profiles of 37 primary cases of cutaneous SCC and BCC were quantified via the Illumina Goldengate Cancer Panel. Differential protein expression by metastatic potential was analyzed in 110 total cases by immunohistochemical (IHC) staining. Results Unsupervised hierarchical clustering analysis revealed that metastatic BCCs had a methylation profile resembling cutaneous SCCs. Metastatic cutaneous SCCs were found to be hypermethylated at FRZB (median methylation: 46.7% vs 4.7%; p = 4 × 10−5). Metastatic BCCs were found to be hypomethylated at MYCL2 (median methylation: 3.8% vs 83.4%; p = 1.9 × 10−6). Immunohistochemical staining revealed few differences between metastatic and nonmetastatic cancers. Conclusion Metastatic primary BCCs and cutaneous SCCs had distinct epigenetic profiles when compared to their nonmetastatic counterparts. Epigenetic profiling may prove useful in future diagnosis and prevention of advanced nonmelanoma skin cancers. © 2014 Wiley Periodicals, Inc. Head Neck 37: 994-1001, 2015 [ABSTRACT FROM AUTHOR]

ABSTRACT Background Cancer stem cells (CSCs) represent a subpopulation of cells responsible for tumor growth. Their role in head and neck squamous cell carcinoma (HNSCC) tumorigenesis and metastasis remains uncertain. Methods Wound healing and an orthotopic animal model were used to study cells expressing the CSC phenotype (CD44high and aldehyde dehydrogenase [ALDH]+) and assess mobility, tumorigenesis, and metastasis. A prospective collection of 40 patient-derived primary HNSCC specimens were analyzed for CSC-proportion compared to clinical variables. Results CSCs exhibited significantly faster wound closure and greater tumorigenesis and regional metastasis in vivo than non-CSCs. In primary patient tumors, size and advanced stage were correlated with elevated proportion of CSCs, however, not with survival. Conclusion HNSCC stem cells mediate tumorigenesis and regional metastasis in vivo. In primary patient tumors, CSC-proportion was associated with tumor size and stage, but not with metastatic spread or survival. CSC burden alone may only represent a minor variable in understanding CSCs and metastasis. © 2014 Wiley Periodicals, Inc. Head Neck 37: 317-326, 2015 [ABSTRACT FROM AUTHOR]

Background The current American Joint Committee on Cancer (AJCC) staging system may not accurately reflect survival in patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC). The purpose of this study was to develop a system that more precisely predicts survival. Methods CT scans from 156 patients who underwent chemoradiation for advanced-stage oropharyngeal SCC with >2 years follow-up were reviewed. We modeled patterns of nodal metastasis associated with different survival rates. We defined HPV+N1 as a single node <6 cm, ipsilaterally, contralaterally, or bilaterally. HPV+N2 was defined as a single node ≥6 cm or ≥2 nodes ipsilaterally/contralaterally or ≥3 nodes bilaterally. HPV+N3 was defined as matted nodes. Results There was no significant difference in disease-specific survival (DSS; p = .14) or overall survival (OS; p = .16) by AJCC classification. In patients grouped by HPV+N1, HPV+N2, and HPV+N3 nodal classification, significant differences in DSS (100%, 92%, and 55%, respectively; p = .0001) and OS (100%, 96%, and 55%, respectively; p = .0001) were found. Conclusion A staging system with reclassification of size, bilaterality, and matted nodes more accurately reflects survival differences in this cohort of patients. Review of the AJCC staging system with these criteria should be considered for HPV-positive oropharyngeal SCC. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1233-1240, 2014 [ABSTRACT FROM AUTHOR]

BACKGROUND Proinflammatory cytokine levels may be associated with cancer stage, recurrence, and survival. The objective of this study was to determine whether cytokine levels were associated with dietary patterns and fat-soluble micronutrients in patients with previously untreated head and neck squamous cell carcinoma (HNSCC). METHODS This was a cross-sectional study of 160 patients with newly diagnosed HNSCC who completed pretreatment food frequency questionnaires (FFQs) and health surveys. Dietary patterns were derived from FFQs using principal component analysis. Pretreatment serum levels of the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) were measured using an enzyme-linked immunosorbent assay, and serum carotenoid and tocopherol levels were measured by high-performance liquid chromatography. Multivariable ordinal logistic regression models examined associations between cytokines and quartiles of reported and serum dietary variables. RESULTS Three dietary patterns emerged: whole foods, Western, and convenience foods. In multivariable analyses, higher whole foods pattern scores were significantly associated with lower levels of IL-6, TNF-α, and IFN-γ ( P ≤ .001, P = .008, and P = .03, respectively). Significant inverse associations were reported between IL-6, TNF-α, and IFN-γ levels and quartiles of total reported carotenoid intake ( P = .006, P = .04, and P = .04, respectively). There was an inverse association between IFN-γ levels and serum α-tocopherol levels ( P = .03). CONCLUSIONS Consuming a pretreatment diet rich in vegetables, fruit, fish, poultry, and whole grains may be associated with lower proinflammatory cytokine levels in patients with HNSCC. Cancer 2014;120:2704-2712. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background Optimal treatment for locally advanced squamous cell carcinoma of the oropharynx (SCCOP) is not well defined. Here we retrospectively compare survival and toxicities from 2 different organ preservation protocols. Methods The matched dataset consisted of 35 patients from each trial matched for age, stage, smoking, and tumor human papillomavirus (HPV) status. Patients in the University of Michigan Cancer Center (UMCC) trial 9921 were treated with induction chemotherapy (IC) followed by high-dose cisplatin and radiation in responders or surgery in nonresponders. Patients in the UMCC trial 0221 were treated with weekly carboplatin and paclitaxel and radiation. Results Survival was comparable for both studies and did not differ significantly across each trial after stratifying by HPV status. Grade 3 and 4 toxicities were more frequent in UMCC 9921. At 6 months posttreatment, gastrostomy tube (G-tube) dependence was not statistically different. Conclusion These data suggest that survival outcomes in patients with locally advanced SCCOP are not compromised with weekly chemotherapy and radiation therapy, and such treatment is generally more tolerable. © 2013 Wiley Periodicals, Inc. Head Neck 36: 617-623, 2014 [ABSTRACT FROM AUTHOR]

In this paper, we develop a Bayesian approach to estimate a Cox proportional hazards model that allows a threshold in the regression coefficient, when some fraction of subjects are not susceptible to the event of interest. A data augmentation scheme with latent binary cure indicators is adopted to simplify the Markov chain Monte Carlo implementation. Given the binary cure indicators, the Cox cure model reduces to a standard Cox model and a logistic regression model. Furthermore, the threshold detection problem reverts to a threshold problem in a regular Cox model. The baseline cumulative hazard for the Cox model is formulated non-parametrically using counting processes with a gamma process prior. Simulation studies demonstrate that the method provides accurate point and interval estimates. Application to a data set of oropharynx cancer patients suggests a significant threshold in age at diagnosis such that the effect of gender on disease-specific survival changes after the threshold. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis To determine if tumor biomarkers were predictive of outcome in a prospective cohort of patients with advanced larynx cancer treated in a phase II clinical trial. Study Design Prospectively collected biopsy specimens from 58 patients entered into a Phase II trial of organ preservation in advanced laryngeal cancer were evaluated for expression of a large panel of biomarkers, and correlations with outcome were determined. Methods Tissue microarrays were constructed from pretreatment biopsies and stained for cyclin D1, CD24, EGFR, MDM2, PCNA, p53, survivin, Bcl-xL, Bcl-2, BAK, rhoC, and NFκB. Pattern of invasion and p53 mutations were assessed. Correlations with overall survival (OS), disease-specific survival (DSS), time free from indication of surgery, induction chemotherapy response, and chemoradiation response were determined. Cox models were used to assess combinations of these biomarkers. Results Low expression of BAK was associated with response to induction chemotherapy. Low expression of BAK and cytoplasmic NFκB was associated with chemoradiation response. Aggressive histologic growth pattern was associated with response induction chemotherapy. Expression of cyclin D1 was predictive of overall and disease-specific survival. Overexpression of EGFR was also associated with an increased risk of death from disease. Bcl-xL expression increased significantly in persistent/recurrent tumors specimens when compared to pretreatment specimens derived from the same patient ( P = 0.0003). Conclusions Evaluation of biomarker expression in pretreatment biopsy specimens can lend important predictive and prognostic information for patients with advanced larynx cancer. Level of Evidence N/A. Laryngoscope, 124:179-187, 2014 [ABSTRACT FROM AUTHOR]