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We sought to determine whether detection of cartilage invasion (CI) by computed tomography predicts oncologic outcomes after primary total laryngectomy.Retrospective cohort study comparing oncologic outcomes between radiologic versus pathologic diagnosis.Assessment of clear CI versus gestalt CI resulted in 84% versus 48% specificity, 90.9% versus 80.3% positive predictive value (PPV), 60.6% versus 80.3% sensitivity, 44.7% versus 48% negative predictive value (NPV), respectively. Disease-free survival (DFS) was similar between cT4a and cT3/cT2 patients (p = 0.87). DFS trended towards superiority among pT3/pT2 versus pT4a patients (p = 0.18). DFS was similar among patients with CI on radiologist gestalt versus no CI (p = 0.94). Histologically confirmed CI was associated with a hazard ratio (HR) of 1.46 (p = 0.27), gestalt CI 1.13 (p = 0.70), and clear CI 1.61 (p = 0.10) for DFS.Gestalt determination of CI results in high sensitivity but low specificity, while clear determination of CI results in moderate sensitivity and high specificity.

Demographic and expression data

Supplementary Figure 1 from Gene Expression Differences Associated with Human Papillomavirus Status in Head and Neck Squamous Cell Carcinoma

Human papillomavirus (HPV) is associated with a subset of head and neck squamous cell carcinoma (HNSCC). Between 15% and 35% of HNSCCs harbor HPV DNA. Demographic and exposure differences between HPV-positive (HPV+) and negative (HPV−) HNSCCs suggest that HPV+ tumors may constitute a subclass with different biology, whereas clinical differences have also been observed. Gene expression profiles of HPV+ and HPV− tumors were compared with further exploration of the biological effect of HPV in HNSCC. Thirty-six HNSCC tumors were analyzed using Affymetrix Human 133U Plus 2.0 GeneChip and for HPV by PCR and real-time PCR. Eight of 36 (22%) tumors were positive for HPV subtype 16. Statistical analysis using Significance Analysis of Microarrays based on HPV status as a supervising variable resulted in a list of 91 genes that were differentially expressed with statistical significance. Results for a subset of these genes were verified by real-time PCR. Genes highly expressed in HPV+ samples included cell cycle regulators (p16INK4A, p18, and CDC7) and transcription factors (TAF7L, RFC4, RPA2, and TFDP2). The microarray data were also investigated by mapping genes by chromosomal location (DIGMAP). A large number of genes on chromosome 3q24-qter had high levels of expression in HPV+ tumors. Further investigation of differentially expressed genes may reveal the unique pathways in HPV+ tumors that may explain the different natural history and biological properties of these tumors. These properties may be exploited as a target of novel therapeutic agents in HNSCC treatment.

Background Over 450,000 individuals are hospitalized with burns annually and roughly 35% are scald burns. Children younger than 5 years of age are at the greatest risk of scald burn injury. Caregiver burn prevention programs have been found to reduce the prevalence of injuries in young children; however, low-income and underserved populations seldomly have access to these programs. The impact of scald burn prevention programs in underserved populations remains unexplored. The objective of the current study was to evaluate the efficacy of a scald burn prevention program at a Level One Pediatric Trauma Center in a low-income, underserved community. Methods Our hospital developed a one-hour scald burn prevention program for caregivers with children 5 years of age or younger. The program educated caregivers on ways to prevent scald burns and create safeguards in their home. Caregivers completed a pre-post survey to measure their ability to identify hot or cold objects, as well as respond to items about their perceptions of the program’s utility, their willingness to share it with others, and the likelihood that they would use the information in the future. Data was analyzed using a paired t-test. Results Two-hundred and sixty-nine (N = 269) caregivers participated in the program. Before the program, caregivers could identify potentially hot objects 83.17% of the time, and after the program, they were able to identify these items 92.31% of the time: t (268) = 12.46, p d = 1.07. Additionally, 95% of caregivers indicated that the program was helpful, 99% stated that they were likely to share this information with others, and 100% indicated that they would use the information from the program. Conclusions Education is a critical component to prevent scald burns. Results indicate that a hospital-led scald burn prevention program can positively impact a caregiver’s ability to identify possible scald-burn risks. Providing education to caregivers who typically do not receive this information could lower the prevalence of scald burns not only institutionally, but in communities that are disproportionately impacted by this mechanism of injury.

Adjuvant chemoradiation (CRT), with high-dose cisplatin remains standard treatment for oral cavity squamous cell carcinoma (OCSCC) with high-risk pathologic features. We evaluated outcomes associated with different cisplatin dosing and schedules, concurrent with radiation (RT), and the effect of cumulative dosing of cisplatin. An IRB-approved collaborative database of patients (pts) with primary OCSCC (Stage I–IVB AJCC 7th edition) treated with primary surgical resection between January 2005 and January 2015, with or without adjuvant therapy, was established from six academic institutions. Patients were categorized by cisplatin dose and schedule, and resultant groups compared for demographic data, pathologic features, and outcomes by statistical analysis to determine disease free survival (DFS) and freedom from metastatic disease (DM). From a total sample size of 1282 pts, 196 pts were identified with high-risk features who were treated with adjuvant CRT. Administration schedule of cisplatin was not significantly associated with DFS. On multivariate (MVA), DFS was significantly better in patients without perineural invasion (PNI) and in those receiving ≥200 mg/m2 cisplatin dose (p &lt, 0.001 and 0.007). Median DFS, by cisplatin dose, was 10.5 (&lt, 200 mg/m2) vs. 20.8 months (≥200 mg/m2). Our analysis demonstrated cumulative cisplatin dose ≥200 mg/m2 was associated with improved DFS in high-risk resected OCSCC pts.

BACKGROUND/AIM Head and neck cancers are often treated with extended courses of radiotherapy (RT), which may prove excessively toxic for frail patients. Split course RT (SCRT) delivers two courses of RT separated by 4-6 weeks, personalizing treatment intensity based on response. In this study, we present our updated experience using this technique. PATIENTS AND METHODS From a single institution database, we identified patients considered for SCRT. For patients undergoing a second course of RT, cumulative incidence of locoregional recurrence (LRR) and overall survival (OS) are reported. RESULTS A total of 98 patients were included, of whom seventy-five percent underwent a second course of RT. The most common fractionation was 30 Gy in 10 fractions for each course, with a median cumulative dose of 60 Gy. In those undergoing a second course of RT, median OS was 9.7 months and cumulative incidence of LRR at 6, 12, and 24 months was 17.0%, 23.1%, and 29.4%, respectively. CONCLUSION SCRT offers an attractive treatment paradigm to personalize radiation intensity based on patient tolerance, while maintaining reasonable safety and efficacy in those unfit for standard full course RT.

Significance Statement Pharyngeal fistulas to the cervical spine resulting in vertebral osteomyelitis are a rare, yet clinically important, complication of total laryngectomy performed in conjunction with chemoradiotherapy or radiation therapy. This complication is likely underdiagnosed and can have a high mortality rate. It is very important that clinicians are aware of this complication as early diagnosis and management may improve patient outcomes.

Background/aim To assess factors that predict detection of tumors and oncologic outcomes in head and neck squamous cell carcinoma of unknown primary (SCCUP). Patients and methods This was a retrospective cohort study at a single tertiary care institution. Results The primary site was detected at examination under anesthesia (EUA) in 92 (51.1%) patients. The primary site was detected by directed biopsies in 60 (65%), palatine tonsillectomy in 28 (30.4%), and lingual tonsillectomy in 4 patients (4.3%). Four of eight lingual tonsillectomies were positive (50%). Primary locations included: palatine tonsils (51, 28.3%), base of tongue (37, 20.6%), larynx (4, 2.2%), oral cavity (3, 1.67%) and nasopharynx (1, 0.6%). Human papillomavirus (HPV) positive status (HR=0.26, p=0.004) and treatment with chemoradiation (CRT) (HR=0.38, p=0.004) were associated with better disease free survival (DFS). Conclusion A primary site was located after aggressive investigation in approximately half of the patients. More research is warranted towards the use of lingual tonsillectomy. Predictors of favorable prognosis included HPV positive status and treatment with CRT.

The etiology of head and neck squamous cell carcinoma (HNSCC) is not fully understood. While risk factors such as positive human papilloma virus (HPV) status, smoking and tobacco use have been identified, they do not account for all cases of the disease. We aimed to characterize the bacteriome, mycobiome and mycobiome-bacteriome interactions of oral wash in HNSCC patients and to determine if they are distinct from those of the oral wash of matched non-HNSCC patients. Oral wash samples were collected from 46 individuals with HNSCC and 46 controls for microbiome analyses. We identified three fungal phyla and eleven bacterial phyla of which Ascomycota (fungi, 72%) and Firmicutes (bacteria, 39%) were the most dominant, respectively. A number of organisms were identified as being differentially abundant between oral wash samples from patients with HNSCC and oral wash samples from those without HNSCC. Of note, strains of Candida albicans and Rothia mucilaginosa were differentially abundant and Schizophyllum commune was depleted in those with HNSCC compared to oral wash from those without HNSCC. Our results suggest that the oral cavity of HNSCC patients harbors unique differences in the mycobiome, bacteriome, and microbiome interactions when compared to those of control patients.

BACKGROUND Time to treatment initiation (TTI) is increasing and is associated with worsening survival. In the current study, the authors sought to identify a mechanism for this relationship by assessing the effect of TTI on clinical-to-pathologic upstaging in patients with head and neck squamous cell carcinoma (HNSCC). METHODS Using the National Cancer Data Base, the authors analyzed patients receiving definitive surgery for SCC of the oral cavity, oropharynx, larynx, and hypopharynx from 2005 through 2014. The primary outcome was T, N, or stage group upstaging, defined as higher pathologic stage than clinical stage. TTI was defined as the time between diagnosis and surgery. Multivariable logistic and Cox proportional hazards regression modeled upstaging and survival, respectively. RESULTS Cohorts of 60,194 patients, 51,380 patients, and 52,980 patients, respectively, with complete T, N, and stage group data were included. N upstaging was most common (18.6%), followed by stage group (17.4%) and T (12.1%) upstaging; all types were predicted by TTI. Compared with a TTI of 1 to 6 days, TTIs as short as 7 to 13 days (odds ratio, 1.20; P = .038) or ≥ 70 days (odds ratio, 2.04; P

Purpose/objective(s) Hypofractionated intensity modulated radiation therapy (H-IMRT) is uncommonly used in head and neck cancers due to concern for toxicity. This study reviews our experience using H-IMRT for head and neck cancers and explores its tolerability and efficacy. Materials/methods This single institution IRB approved retrospective study includes patients with head and neck cancers treated with definitive or post-operative H-IMRT from 2011-2020. Patients treated with ≥50Gy in 20 fractions to the primary tumor site and/or neck with at least 3 months of follow up were included. Patients treated to a superficial target only without proximity to mucosal surfaces or coverage of the elective neck (e.g., scalp; skin only targets) were excluded. Patients undergoing re-irradiation were excluded. Toxicity was scored using CTCAE v4.0. Acute toxicity included events occurring within 90 days of H-IMRT completion. Late toxicities occurred any time thereafter. Multiple toxicities in the same patient were scored separately. Results Fifty-nine patients with a median follow up of 10.9 months (range 3.0-111.5) were included. The majority of patients were white (93%) and male (78%) with a median age of 79.1. The most common primary tumor sites were skin (42%), major salivary glands (22%), and oral cavity (9%). The most frequent histologies included squamous cell carcinoma (66%) followed by thyroid cancer (7%), melanoma (5%), and Merkel cell carcinoma (5%). Treatment was delivered post-operatively in 80% and definitively in 20% of patients. All patients were treated with ≥50 Gy in 20 fractions, with the most common dose being 50 Gy (53%) followed by 55 Gy (44%). In 64% of patients a secondary elective dose of 45-50 Gy was used. Site treated included primary tumor site/bed with unilateral neck (54%), primary tumor site/bed with bilateral neck (19%), primary tumor site/bed alone (14%), unilateral neck (8%), and bilateral neck (5%). Five patients (8%) experienced a locoregional failure at a median time of 5.4 months (range 2.8-13.9). There were no grade 4 or 5 toxicities. Ten patients (17%) experienced acute grade 3 toxicity including mucositis (12%) and dermatitis (5%). Forty-six patients (78%) had an acute grade 2 toxicity, most commonly dermatitis (41%), pain (32%), fatigue (32%), dysgeusia (31%) and xerostomia (22%). Five patients (8%) experienced grade 2 late complications including neck fibrosis in three patients and trismus, aspiration pneumonia, and osteoradionecrosis in one patient each. No patient experienced grade 3 or higher late toxicity. No patients required the placement of a feeding tube or tracheostomy. Conclusion Hypofractionated IMRT in the definitive or post-operative treatment of head and neck cancers using ≥50Gy in 20 fractions appears safe and well tolerated with modest toxicity. Prospective studies comparing the safety and efficacy of H-IMRT to conventionally fractionated IMRT are warranted.

// Pranab K. Mukherjee 1,* , Hannah Wang 2, 3, * , Mauricio Retuerto 1 , Huan Zhang 2, 3 , Brian Burkey 4, 7 , Mahmoud A. Ghannoum 1, 7, 8 and Charis Eng 2, 3, 4, 6, 8 1 Center for Medical Mycology, Department of Dermatology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA 2 Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA 3 Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA 4 Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA 5 Section of Head and Neck Surgery and Oncology, Head and Neck Institute, Cleveland Clinic, Cleveland, OH, USA 6 Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA 7 Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA 8 Germline High Risk Cancer Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA * Contributed equally to the work and should be viewed as joint first authors Correspondence to: Charis Eng, email: engc@ccf.org Mahmoud A. Ghannoum, email: mag3@case.edu Keywords: microbiome; metagenomics; head and neck squamous cell carcinoma; lingual carcinomas Received: June 08, 2017 Accepted: September 08, 2017 Published: October 19, 2017 ABSTRACT Squamous cell carcinoma of the oral (mobile) tongue (OMTC), a non-human papilloma virus-associated oral cancer, is rapidly increasing without clear etiology. Poor oral hygiene has been associated with oral cancers, suggesting that oral bacteriome (bacterial community) and mycobiome (fungal community) could play a role. While the bacteriome is increasingly recognized as an active participant in health, the role of the mycobiome has not been studied in OMTC. Tissue DNA was extracted from 39 paired tumor and adjacent normal tissues from patients with OMTC. Microbiome profiling, principal coordinate, and dissimilarity index analyses showed bacterial diversity and richness, and fungal richness, were significantly reduced in tumor tissue (TT) compared to their matched non-tumor tissues (NTT, P

Background Metabolomics represents a promising approach for discovering novel targets and biomarkers in head and neck squamous cell carcinoma (HNSCC). Here we used metabolomics to identify oral metabolites associated with HNSCC. Methods Tumor and adjacent normal tissue from surgical resections and presurgical oral washes as well as oral washes were collected from healthy participants. Metabolites extractions of these samples were analyzed by liquid chromatography-mass spectroscopy (LC/MS), LC/MS/MS and gas chromatography-MS (GC/MS). Results Among 28 samples obtained from 7 HNSCC cases and 7 controls, 422 metabolites were detected (269 identified and 153 unidentified). Oral washes contained 12 and 23 metabolites in healthy controls and HNSCC patients, respectively, with phosphate and lactate being the most abundant. Small molecules related to energy metabolism were significantly elevated in HNSCC patients compared to controls. Levels of beta-alanine, alpha-hydroxyisovalerate, tryptophan, and hexanoylcarnitine were elevated in HNSCC oral washes compared to healthy controls (range 7.8-12.2-fold). Resection tissues contained 22 metabolites, of which eight were overproduced in tumor by 1.9- to 12-fold compared to controls. TCA cycle analogs 2-hydroxyglutarate (2-HG) and 3-GMP were detected exclusively in tumor tissues. Targeted quantification of 2-HG in a representative HNSCC patient showed increase in tumor tissue (14.7 μg/mL), but undetectable in normal tissue. Moreover, high levels of 2-HG were detected in HNSCC cell lines but not in healthy primary oral keratinocyte cultures. Conclusions Oral metabolites related to energy metabolism were elevated in HNSCC, and acylcarnitine and 2HG may have potential as non-invasive biomarkers. Further validation in clinical studies is warranted., Highlights • Metabolomics identified HNSCC-associated oral metabolites in tissues and oral wash. • Oral metabolites related to energy metabolism were elevated in HNSCC. • 2-hydroxyglutarate was detected in HNSCC tumor but not in adjacent normal tissues. • 2-hydroxyglutarate and acylcarnitine may have potential as non-invasive biomarkers.

Background Using the frameworks of transformational learning and situated learning theory, we developed a technology-enhanced professionalism curricular model to build a learning community aimed at promoting residents' self-reflection and self-awareness. The RAPR model had 4 components: (1) Recognize: elicit awareness; (2) Appreciate: question assumptions and take multiple perspectives; (3) Practice: try new/changed perspectives; and (4) Reflect: articulate implications of transformed views on future actions. Objective The authors explored the acceptability and practicality of the RAPR model in teaching professionalism in a residency setting, including how residents and faculty perceive the model, how well residents carry out the curricular activities, and whether these activities support transformational learning. Methods A convenience sample of 52 postgraduate years 1 through 3 internal medicine residents participated in the 10-hour curriculum over 4 weeks. A constructivist approach guided the thematic analysis of residents' written reflections, which were a required curricular task. Results A total of 94% (49 of 52) of residents participated in 2 implementation periods (January and March 2015). Findings suggested that RAPR has the potential to foster professionalism transformation in 3 domains: (1) attitudinal, with participants reporting they viewed professionalism in a more positive light and felt more empathetic toward patients; (2) behavioral, with residents indicating their ability to listen to patients increased; and (3) cognitive, with residents indicating the discussions improved their ability to reflect, and this helped them create meaning from experiences. Conclusions Our findings suggest that RAPR offers an acceptable and practical strategy to teach professionalism to residents.

Background The eighth edition of the American Joint Committee on Cancer staging manual (AJCC8) added depth of invasion to the definition of pathologic T stage (pT). In the current study, the authors assess pT stage migration and the prognostic performance of the updated pT stage and compare it with other clinicopathologic variables in patients with early squamous cell carcinoma of the oral tongue (OTSCC; tumors measuring ≤4 cm) with histologically benign lymph nodes (pN0). Methods A multi-institutional cohort of patients with early OTSCC was restaged as per AJCC8. Primary endpoints were local recurrence (LR) and locoregional recurrence (LRR). Influential variables were identified and an LR/LRR prediction model was developed. Results There were a total of 494 patients, with 49 LR and 73 LRR. AJCC8 pT criteria resulted in upstaging of 37.9% of patients (187 of 494 patients), including 34.5% (64 of 185 patients) from pT2 to pT3, without improving the prognostication for LR or LRR. Both LR and LRR were found to be similar for patients with AJCC8 pT2 and pT3 disease. On multivariate analysis, LR was only found to be associated with distance to the closest margin (hazard ratio, 0.36; 95% CI, 0.20-0.64 [P = .0007]) and perineural invasion (hazard ratio, 1.92; 95% CI, 1.10-0.64 [P = .046]). Based on these 2 predictors, a final proportional hazards regression model (which may be used similar to a nomogram) was developed. The proposed model appeared to be superior to AJCC pT stage for estimating the probability of LR and LRR for individual patients with early OTSCC. Conclusions AJCC8 pT criteria resulted in pT upstaging of patients with pN0 disease without improved LR or LRR prognostication. The proposed model based on distance to the closest margin and perineural invasion, status outperformed pT as a predictor of LR and LRR in patients with early OTSCC.

PURPOSE: To determine which factors influence cost in head and neck cancer (HNC) to inform the development of a bundled payment model (BPM). METHODS: Patients with stages 0 to IVB (by American Joint Commission on Cancer, 7th edition) HNC of various sites and histology treated definitively at a single tertiary care center during 2013 were included. Clinical variables and direct cost data were obtained, and their associations were investigated using χ2, t, Wilcoxon rank sum, and analysis of variance testing. Results were used to develop a BPM. RESULTS: One hundred fifty patients were included; 87% were white, 74% were men, 48% had oropharyngeal cancer, and 58% had stage IVA disease. Treatment consisted of surgery alone (17%), radiation alone (11%), surgery plus radiation (14%), chemoradiation (45%), and surgery plus chemoradiation (13%). On multivariable analysis, both increasing group stage and number of treatment modalities used were significantly associated with higher cost. Given that stage often dictates treatment, we developed three cost tiers that were based on overall treatment modality. Tier A, the least costly, consisted of single-modality therapy with either surgery alone or radiation alone (median cost divided by the median overall cost of treatment, 0.54; 25th to 75th percentile range, 0.29 to 1.02), followed by tier B, which consisted of bimodality therapy with either chemoradiation or surgery plus radiation (1.03; range, 0.81 to 1.35), followed by tier C, which consisted of trimodality therapy with surgery plus chemoradiation (1.43; range, 1.10 to 1.96). CONCLUSION: The number of treatment modalities required is the primary driver of cost in HNC. These data can simplify development of a comprehensive HNC BPM.

BACKGROUND/AIM There are limited data regarding survival, failure patterns, and factors associated with disease recurrence in patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) with nodal metastases. PATIENTS AND METHODS A retrospective analysis of patients with cSCC-HN metastatic to cervical and/or parotid lymph nodes treated with surgery and post-operative radiation therapy was performed. RESULTS This study included 76 patients (57 immunocompetent and 18 immunosuppressed) with a median follow-up of 18 months. Overall survival, disease-free survival (DFS), and disease recurrence (DR) at 2 years was 60%, 49%, and 40%, respectively. Immunosuppressed patients had significantly lower 2-year DFS (28% vs. 55%; p=0.003) and higher DR (61% vs. 34%; p=0.04) compared to immunocompetent patients. Analysis of immunocompetent patients demonstrated extracapsular extension (ECE) as the only factor associated with DR (p

Background While the role of the gut microbiome in inflammation and colorectal cancers has received much recent attention, there are few data to support an association between the oral microbiome and head and neck squamous cell carcinomas. Prior investigations have been limited to comparisons of microbiota obtained from surface swabs of the oral cavity. This study aims to identify microbiomic differences in paired tumor and non-tumor tissue samples in a large group of 121 patients with head and neck squamous cell carcinomas and correlate these differences with clinical-pathologic features. Methods Total DNA was extracted from paired normal and tumor resection specimens from 169 patients; 242 samples from 121 patients were included in the final analysis. Microbiomic content of each sample was determined using 16S rDNA amplicon sequencing. Bioinformatic analysis was performed using QIIME algorithms. F-testing on cluster strength, Wilcoxon signed-rank testing on differential relative abundances of paired tumor-normal samples, and Wilcoxon rank-sum testing on the association of T-stage with relative abundances were conducted in R. Results We observed no significant difference in measures of alpha diversity between tumor and normal tissue (Shannon index: p = 0.13, phylogenetic diversity: p = 0.42). Similarly, although we observed statistically significantly differences in both weighted (p = 0.01) and unweighted (p = 0.04) Unifrac distances between tissue types, the tumor/normal grouping explained only a small proportion of the overall variation in the samples (weighted R2 = 0.01, unweighted R2

Mammary analogue secretory carcinoma (MASC) is a recently identified salivary tumor that shares morphological features of secretory carcinoma of the breast, salivary acinic cell carcinoma, low grade cystadenocarcinoma and mucoepidermoid carcinoma. To date, a majority of cases have been reported in the major salivary glands with very few seen in the palate. We present 2 single institution cases of MASC of the soft palate to help further characterize this novel tumor.

Achieving locoregional control in high-risk patients with head and neck cancer who are poor candidates for standard continuous-course (chemo) radiotherapy due to advanced age, comorbidities, or very advanced disease is challenging. At our Institution, we have significant experience with a regimen of split-course, accelerated, hypofractionated radiotherapy (SCAHRT) for these patients.The SCAHRT regimen consisted of 60-72 Gy in 20-24 fractions separated by several weeks mid-course to allow for toxicity recovery and disease reassessment. It was used for patients with advanced age, significant co-morbidities, anticipated intolerance to definitive (chemo)radiation, and those with oligometastatic disease. Disease-free and overall survival rates were calculated using Kaplan-Meier analysis.Fifty-eight out of 65 patients (89%) completed both courses of treatment. Patients without metastatic or recurrent disease were evaluated for treatment response and survival (n=39). Among this group, total tumor response was 91%, and median locoregional failure-free survival and overall survival were 25.7 and 8.9 months, respectively.In high-risk patients unable to tolerate continuous-course definitive (chemo)radiation, SCAHRT is a safe, well-tolerated and effective method of achieving durable locoregional disease control. In properly selected patients, this regimen is preferable to purely palliative approaches.

The purpose of the present study was to identify variables associated with high risk of failure in patients with locally advanced squamous cell carcinoma of the oral cavity (SCC-OC).This retrospective study included 191 patients with stage III-IVb SCC-OC treated with post-operative radiotherapy (RT) or chemoradiotherapy (CRT) between 1995 and 2013. Disease-free (DFS) and overall survival (OS) were analyzed; variables associated with inferior DFS were identified.Seventy-five patients (39%) recurred. DFS and five-year OS were 52% and 54%, respectively. Poorly differentiated tumors (p=0.03), recurrent tumors (p=0.02) and high nodal ratio (p=0.02) were associated with an increased risk of recurrence. CRT was associated with improved DFS in patients with positive margins and/or extracapsular extension (p=0.021).Tumors that are recurrent, high grade, or have high nodal ratio are at risk of recurrence. Presence of these disease features should be taken into consideration for better risk stratification.

Clinical observations and epidemiologic studies suggest that the incidence of head and neck squamous cell carcinoma (HNSCC) correlates with dental hygiene, implying a role for bacteria-induced inflammation in its pathogenesis. Here we begin to explore the pilot hypothesis that specific microbial populations may contribute to HNSCC pathogenesis via epigenetic modifications in inflammatory- and HNSCC-associated genes. Microbiomic profiling by 16S rRNA sequencing of matched tumor and adjacent normal tissue specimens in 42 individuals with HNSCC demonstrate a significant association of specific bacterial subpopulations with HNSCC over normal tissue (P < 0.01). Furthermore, microbial populations can separate tumors by tobacco status (P < 0.008), but not by alcohol status (P = 0.41). If our subhypothesis regarding a mechanistic link from microorganism to carcinogenesis via inflammation and consequent aberrant DNA methylation is correct, then we should see hypermethylation of relevant genes associate with specific microbiomic profiles. Methylation analysis in four genes (MDR1, IL8, RARB, TGFBR2) previously linked to HNSCC or inflammation shows significantly increased methylation in tumor samples compared with normal oral mucosa. Of these, MDR1 promoter methylation associates with specific microbiomic profiles in tumor over normal mucosa. Additionally, we report that MDR1 methylation correlates with regional nodal metastases in the context of two specific bacterial subpopulations, Enterobacteriaceae and Tenericutes (P < 0.001 for each). These associations may lead to a different, and potentially more comprehensive, perspective on the pathogenesis of HNSCC, and support further exploration of mechanistic linkage and, if so, novel therapeutic strategies such as demethylating agents and probiotic adjuncts, particularly for patients with advanced or refractory disease.

BACKGROUND: The standard treatment for patients with oral cavity cancer (OCC) with intermediate risk pathologic variables after surgery is adjuvant radiotherapy. Despite this, one-third of patients experience locoregional failure (LRF). Clinicopathologic prognostic models have not been able to identify subsets of patients at higher risk of failure in whom treatment intensification with the addition of systemic chemotherapy should be considered. We posited that gene expression-derived tumor taxonomies can predict treatment failures and therefore guide more nuanced clinical decision making. Herein, we report on a score model based on OCC gene expression characteristics that can be incorporated into risk stratification and treatment decisions. METHODS: Formalin-fixed paraffin-embedded (FFPE) tissue samples from patients with intermediate risk OCC treated with surgery followed by radiation alone were subjected to quantitative nuclease protection and next-generation sequencing to measure gene expression (HTG Molecular EdgeSeq™). A subset of samples that had corresponding frozen tumor samples were profiled by RNAseq to validate the FFPE results. Patients were divided into two groups based on LRF. Differentially expressed genes were identified using the R limma package. 98 genes were selected on the basis of unadjusted P values and predicted biological impact, as measured by gene set enrichment results (GSEA) and resultant biological pathway scores. The Cancer Genome Atlas (TCGA) HNSCC dataset (n=521) was used to validate the prognostic performance of our gene set. RESULTS: Of the 78 patients included in the study, 35% of patients had LRF. GSEA of the 98 genes demonstrated a role for DNA repair, oxidative phosphorylation, hypoxia and p53 pathways, indicating radiobiologic plausibility for a significant subset of the genes that constitute the score. The mean composite score was 0.42 for patients with LRF, and -0.19 for patients without LRF (P = 0.0002). The Kaplan-Meier estimates of progression free survival at 3 years for the 1st (high risk) and 4th quartile (low risk) groups were 0.65 (0.47 to 0.89; 95% CI) and 0.93 (0.82 to 1; 95% CI), respectively. On multivariate analysis, the composite score was the strongest predictor of LRF (P = 0.0073). Composite scores also strongly predicted for overall survival in the TCGA HNSCC dataset (P < 0.01) and the Kaplan-Meier estimates of overall survival at 2 years for the 1st and 4th quartile groups were 0.55 (0.45 to 0.68; 95% CI) and 0.73 (0.63 to 1; 84% CI), respectively. Composite scores performed the best in patients with OCC (P = 0.033). CONCLUSIONS: We developed a gene signature that predicts LRF in patients with intermediate risk OCC treated with surgery and adjuvant radiotherapy. Further validation on larger datasets are needed. This biomarker can potentially identify higher risk patients who should be considered for intensification strategies with the addition of systemic therapy. Citation Format: Elif I. Sarihan, Brian B. Burkey, Joseph Scharpf, Robert Lorenz, Eric D. Lamarre, Brandon Prendes, Jessica L. Geiger, David J. Adelstein, Shlomo A. Koyfman, Mohamed E. Abazeed. A biologic basis for locoregional failure in patients with oral cavity cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3681.

Synovial sarcoma is typically an aggressive malignant tumor of the soft tissues, usually in the extremities, that affects young adults. Tumors of the head and neck are rare. Reported head and neck sites have included the hypopharynx (the most common site), the oropharynx, the larynx, and the soft tissues of the neck; only 4 cases of orbital involvement have been previously reported. We describe a case of synovial sarcoma of the medial canthus, which we discovered during a review of a tumor registry. The patient, an 18-year-old woman, underwent conservative excision and postoperative radiation therapy. Long-term follow-up detected no evidence of recurrence. Because there is no established, consistent approach to the treatment of synovial sarcoma of the head and neck, we also present a consensus management plan based on our review of the literature.

BACKGROUND. Patients with recurrent or metastatic HNC have a poor response and survival with currently available chemotherapy agents. Thus, new agents are needed. The authors report the results of a phase II trial of irinotecan and cisplatin in patients with metastatic or recurrent HNC. METHODS. Patients were treated with irinotecan 65 mg/m2 IV over 90 minutes and cisplatin 30 mg/m2 were administered intravenously weekly for four weeks, followed by a two week rest. However, after 17 patients were treated with weekly irinotecan at a dose of 65 mg/m2, toxicity analysis demonstrated the poor tolerance of that dose in this patient population. Thus, the protocol was amended, and irinotecan was dose reduced to a starting dose of 50 mg/m2. Twenty-three additional patients were treated with this dose. RESULTS. Forty patients were enrolled on study between February 2002 and April 2006, 17 patients at the first dose level and 23 patients at the amended dose level. Overall, 12 of 17 patients (71%) treated with irinotecan 65 mg/m2 experienced clinically significant grade 3 or 4 toxicity. Twelve patients required dose reductions. Toxicity was reduced but 17% of patients still experienced grade 3 or 4 toxicity on the lower irinotecan dose. The response rate was 35% for patients treated at irinotecan 65 mg/m2 and 22% for patients treated at 50 mg/m2. No complete responses were noted. CONCLUSIONS. The combination of irinotecan and cisplatin is efficacious in a poor prognosis group of patients but toxicity is substantial. Cancer 2008. © 2008 American Cancer Society.

Carcinogen exposure from tobacco smoking is the major cause of upper aerodigestive tract cancer, yet heavy smokers only have about a 10% life-time risk of developing one of these cancers. Current technologies allow only limited prediction of cancer risk and there are no approved screening methods applicable to the general population. We developed a method to assess somatic mutational load using small-pool PCR (SP-PCR) and analysed mutations in DNA isolated from cells obtained by mouth rinse. Mutation levels in the hypermutable tetranucleotide marker D7S1482 were analysed in specimens from 25 head and neck squamous carcinoma (HNSCC) cases and 31 controls and tested for associations with age, smoking history and cancer status. We found a significant association between mutation frequency and age (P=0.021, Generalized Linear Model (GLM), N=56), but no influence of smoking history. Cases had higher mutation frequencies than controls when corrected for the effects of age, a difference that was statistically significant in the subgroup of 10 HNSCC patients who were treated with surgery only (P=0.017, GLM, N=41). We also present evidence that cancer status is linked to levels of nonunique, and presumably clonally derived, mutations in D7S1482. Insertion mutations were observed in 833 (79%) of 1058 alleles, of which 457 (43%) could be explained by insertion of a single repeat unit; deletion mutations were found in 225 (21%) of tested alleles. In conclusion, we demonstrate that the sensitive detection of single molecule mutations in clinical specimens is feasible by SP-PCR. Our study confirms an earlier report that microsatellite mutations increase with age and is the first to provide evidence that these mutations may be associated with cancer status in individual subjects.

Nonsurgical treatment of advanced supraglottic laryngeal cancer is widely used as part of a larynx preservation protocol. However, recent studies have suggested that nonsurgical treatment may be associated with inferior survival. Furthermore, it is not clear whether preservation of the larynx provides superior voice or swallowing function in the long term.To test the hypothesis that surgical treatment of advanced-stage squamous cell carcinoma of the supraglottic larynx is associated with superior overall survival (OS), freedom from recurrence (FFR), and noninferior voice and swallowing function.Retrospective medical record review of patients treated for stage III or IV squamous cell carcinoma of the supraglottic larynx between January 1990 and June 2013 at a tertiary referral center: 97 patients underwent surgical treatment and 138, nonsurgical treatment. Exclusion criteria included prior definitive treatment for laryngeal cancer or evidence of distant metastatic disease at presentation. The median follow-up for all 235 patients was 63 months.Surgical or nonsurgical therapy.Freedom from recurrence (FFR), OS, larynx preservation, voice graded from 1 to 5, and swallowing graded from 1 to 6 using our voice and swallowing function scales.Surgical treatment was associated with superior FFR (5-year FFR: 75% vs 55%; P = .006) but not OS (5-year OS: 52% vs 52%; P = .61). The larynx was preserved in 83% of patients in the nonsurgical group vs 42% of patients in the surgical group (P .001). Voice function was superior in the nonsurgical group at all time points through 5 years after treatment (mean voice score, 3.8 vs 2.6; P .001). Swallowing function was comparable between surgical and nonsurgical groups. Multivariable analysis revealed that advanced age (hazard ratio [HR], 1.43 per 10-year increment; 95% CI, 1.19-1.72) and clinical N stage (HR, 1.17 per 1-level increment; 95% CI, 1.05-1.30) were associated with worse OS, while treatment with chemotherapy was associated with superior OS (HR, 0.61; 95% CI, 0.41-0.92).Compared with surgical treatment, nonsurgical treatment as part of a larynx preservation protocol is associated with a higher likelihood of recurrence but has similar OS and should continue to be viewed as a viable alternative for the treatment of advanced supraglottic laryngeal cancer.

Fewer than five case reports of primary large cell neuroendocrine carcinoma of the nasopharynx are known to the authors. No previous reports have included examples of cytomorphology or have proven association with Epstein-Barr virus. We herein illustrate MRI findings, histopathologic features, immunohistochemical characterization, cytologic details, and in situ hybridization studies from a unique case of primary large cell neuroendocrine carcinoma of the nasopharynx in a 38-year-old Caucasian male patient. Recognition of rare tumor types of the nasopharynx allows for refinements in disease management and prognostication.

Importance Important differences exist in the pattern and timing of distant metastases between human papillomavirus–initiated (HPV+) and HPV− oropharyngeal squamous cell carcinoma (OPSCC). However, our understanding of the natural history of distant metastases in HPV+ OPSCC and its implications for surveillance is limited. Objective To investigate the rate, pattern, and timing of distant metastases in advanced-stage OPSCC treated definitively with concomitant chemoradiotherapy. Design, Setting, and Participants In a retrospective review, we identified 291 patients with pathologically diagnosed stages III to IVB OPSCC and known HPV status from a tumor registry at the Cleveland Clinic. Patients were treated from January 1, 1996, through December 31, 2013. Details of treatment failure and the natural history of the disease were retrieved from the electronic medical records. Interventions All patients were treated with definitive concomitant chemoradiotherapy. Main Outcomes and Measures The primary outcome was the rate and timing of distant metastases. Secondary outcomes included the pattern of distant failure and survival after distant metastases. Results Thirty-seven patients developed distant metastatic disease after definitive treatment, including 28 of 252 patients with HPV+ disease and 9 of 39 patients with HPV− disease. The 3-year projected distant control rate was higher in the HPV+ group (88% vs 74%; P = .01). The median time to develop distant metastases was also longer after the completion of treatment for HPV+ disease compared with HPV− disease (16.4 vs 7.2 months; P = .008). We detected a trend in patients with HPV+ disease for more distant metastatic sites involved than in those with HPV− disease (2.04 vs 1.33 sites; P = .09). Although the lung was the most common distant site involved in HPV+ and HPV− disease (HPV+ group, 23 of 28 patients [82%]; HPV− group, 7 of 9 patients [78%]), the HPV+ group had metastases to several subsets atypical for head and neck squamous cell carcinoma, including the brain, kidney, skin, skeletal muscle, and axillary lymph nodes in 2 patients each and in the intra-abdominal lymph nodes in 3 patients. The rate of 3-year overall survival was higher in the HPV+ group (89.9% vs 62.0%; P P Conclusions and Relevance This retrospective review suggests that distant metastases in patients with HPV+ OPSCC occurs significantly later after completion of chemoradiotherapy than in patients with HPV− disease. Human papillomavirus–initiated OPSCC also appears to involve a greater number of subsites and metastatic sites infrequently seen in head and neck squamous cell carcinoma. Distant metastatic disease in HPV+ OPSCC has unique characteristics and a natural history that may require alternative surveillance strategies.