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BackgroundTo quantify pain severity in patients and the efficacy treatments, researchers and clinicians apply tools such as the traditional visual analog scale (VAS) that leads to inaccurate interpretation of the main sensory pain. ObjectiveThis study aimed to validate the pain measurements of a neuroscience-based 3D body pain mobile app called GeoPain. MethodsPatients with temporomandibular disorder (TMD) were assessed using GeoPain measures in comparison to VAS and positive and negative affect schedule (PANAS), pain and mood scales, respectively. Principal component analysis (PCA), scatter score analysis, Pearson methods, and effect size were used to determine the correlation between GeoPain and VAS measures. ResultsThe PCA resulted in two main orthogonal components: first principal component (PC1) and second principal component (PC2). PC1 comprises a combination score of all GeoPain measures, which had a high internal consistency and clustered together in TMD pain. PC2 included VAS and PANAS. All loading coefficients for GeoPain measures in PC1 were above 0.70, with low loadings for VAS and PANAS. Meanwhile, PC2 was dominated by a VAS and PANAS coefficient >0.4. Repeated measure analysis revealed a strong correlation between the VAS and mood scores from PANAS over time, which might be related to the subjectivity of the VAS measure, whereas sensory-discriminative GeoPain measures, not VAS, demonstrated an association between chronicity and TMD pain in locations spread away from the most commonly reported area or pain epicenter (P=.01). Analysis using VAS did not detect an association at baseline between TMD and chronic pain. The long-term reliability (lag >1 day) was consistently high for the pain area and intensity number summation (PAINS) with lag autocorrelations averaging between 0.7 and 0.8, and greater than the autocorrelations for VAS averaging between 0.3 and 0.6. The combination of higher reliability for PAINS and its objectivity, displayed by the lack of association with PANAS as compared with VAS, indicated that PAINS has better sensitivity and reliability for measuring treatment effect over time for sensory-discriminative pain. The effect sizes for PAINS were larger than those for VAS, consequently requiring smaller sample sizes to assess the analgesic efficacy of treatment if PAINS was used versus VAS. The PAINS effect size was 0.51 SD for both facial sides and 0.60 SD for the right side versus 0.35 SD for VAS. Therefore, the sample size required to detect such effect sizes with 80% power would be n=125 per group for VAS, but as low as n=44 per group for PAINS, which is almost a third of the sample size needed by VAS. ConclusionsGeoPain demonstrates precision and reliability as a 3D mobile interface for measuring and analyzing sensory-discriminative aspects of subregional pain in terms of its severity and response to treatment, without being influenced by mood variations from patients.

OBJECTIVES: In an evolving era of immunotherapeutic options for persistent or recurrent laryngeal squamous cell carcinoma (LSCC), there is a need for improved biomarkers of treatment response and survival to inform optimal treatment selection and prognostication. Herein, our primary objective was to explore correlations between tumor infiltrating lymphocytes (TILs) and PD-L1 Combined Positive Score (CPS). Secondarily, we sought to explore their combined association with survival outcomes in patients with persistent or recurrent LSCC treated with salvage surgery. MATERIALS AND METHODS: This was a retrospective cohort study at a single academic medical center. Immunohistochemistry staining for TILs and PD-L1 was performed on a tissue microarray of persistent or recurrent LSCC pathologic specimens. Correlations between TIL subsets and PD-L1 CPS were examined using Pearsons correlation coefficient and survival outcomes were analyzed with the Kaplan-Meier method and log-rank tests. RESULTS: Only CD103+ TILs showed a statistically significant, weakly-positive correlation with PD-L1 CPS (r2 = 0.264, p

BackgroundRecurrent laryngeal squamous cell carcinomas (LSCCs) are associated with poor outcomes, without reliable biomarkers to identify patients who may benefit from adjuvant therapies. Given the emergence of tumor-infiltrating lymphocytes (TIL) as a biomarker in head and neck squamous cell carcinoma, we generated predictive models to understand the utility of CD4+, CD8+ and/or CD103+ TIL status in patients with advanced LSCC.MethodsTissue microarrays were constructed from salvage laryngectomy specimens of 183 patients with recurrent/persistent LSCC and independently stained for CD4+, CD8+, and CD103+ TIL content. Cox proportional hazards regression analysis was employed to assess combinations of CD4+, CD8+, and CD103+ TIL levels for prediction of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) in patients with recurrent/persistent LSCC.ResultsHigh tumor CD103+ TIL content was associated with significantly improved OS, DSS, and DFS and was a stronger predictor of survival in recurrent/persistent LSCC than either high CD8+ or CD4+ TIL content. On multivariate analysis, an "immune-rich" phenotype, in which tumors were enriched for both CD103+ and CD4+ TILs, conferred a survival benefit (OS hazard ratio: 0.28, p = 0.0014; DSS hazard ratio: 0.09, p = 0.0015; DFS hazard ratio: 0.18, p = 0.0018) in recurrent/persistent LSCC.ConclusionsAn immune profile driven by CD103+ TIL content, alone and in combination with CD4+ TIL content, is a prognostic biomarker of survival in patients with recurrent/persistent LSCC. Predictive models described herein may thus prove valuable in prognostic stratification and lead to personalized treatment paradigms for this patient population.

BACKGROUND:Patients undergoing salvage laryngectomy are predisposed to radiation-induced hypothyroidism and impaired wound healing secondary to the tissue effects of prior treatment. The impact of hypothyroidism on postoperative wound healing is not established. METHODS:A single-institution retrospective case series was performed. The inclusion criteria specified preoperatively euthyroid adults who underwent salvage laryngectomy with concurrent neck dissection between 1997 and 2015 for persistent or recurrent laryngeal squamous cell carcinoma after radiation or chemoradiation therapy (n = 182). The principal explanatory variable was postoperative hypothyroidism, defined as thyroid-stimulating hormone (TSH) higher than 5.5 mIU/L. The primary end points of the study were pharyngocutaneous fistulas and wounds requiring reoperation. Multivariate analysis was performed. RESULTS:The fistula rate was 47% among hypothyroid patients versus 23% among euthyroid patients. In the multivariate analysis, the patients who experienced hypothyroidism in the postoperative period had a 3.6-fold greater risk of fistula [95% confidence interval (CI) 1.8-7.1; p = 0.0002]. The hypothyroid patients had an 11.4-fold greater risk for a required reoperation (24.4 vs 5.4%) than the euthyroid patients (95% CI 2.6-49.9; p = 0.001). The risk for fistula (p = 0.003) and reoperation (p = 0.001) increased with increasing TSH. This corresponds to an approximate 12.5% incremental increase in the absolute risk for fistula and a 10% increase in the absolute risk for reoperation with each doubling of the TSH. CONCLUSION:Postoperative hypothyroidism independently predicts postoperative wound-healing complications. The association of hypothyroidism with fistula formation may yield opportunities to modulate wound healing with thyroid supplementation or to provide a biomarker of wound progression.

BackgroundTotal 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.MethodsA 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.ResultsFive-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).ConclusionSevere 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.

BackgroundWe 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).MethodsTissue 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.ResultsExpression 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

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.

Purpose: There is a paucity of biomarkers to predict failure in human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) following curative therapy. E6/E7 viral oncoproteins are constitutively expressed in HPV+ tumors and highly immunogenic, resulting in readily detected serum antibodies. The purpose of this study is to determine whether serum E6 and E7 antibody levels can potentially serve as a biomarker of recurrence in patients with HPV+OPSCC.Experimental Design: We evaluated E6/E7 antibody levels in patients with previously untreated, advanced stage (III, IVa-b), HPV+OPSCC receiving definitive chemoradiation under a uniform protocol from 2003 to 2010. Baseline and longitudinal serum samples were obtained from our archived repository. E6/E7 serum levels were measured using a glutathione-S-transferase capture ELISA and quantified by approximating the area under the dilution curve, and were analyzed using ANOVA and linear mixed model for longitudinal analysis.Results: We compared 22 HPV+OPSCC patients who developed recurrence with 30 patients who remained disease-free. There were no differences in T classification, N classification, disease subsite, or smoking status between the groups. In a longitudinal analysis, recurrent patients had significantly higher E6 and E7 serum antibody levels than the nonrecurrent patients over the follow-up period (P = 0.02 and P = 0.002, respectively). Patients who recurred had a lower clearance of E7 antibody than patients who remained disease-free (P = 0.0016).Conclusions: Patients with HPV+OPSCC whose disease recurs have a lower clearance of E6 and E7 antibodies than patients who do not have recurrence. The ratio of E7 antibody at disease recurrence compared with baseline is potentially a clinically significant measurement of disease status in HPV+OPSCC. Clin Cancer Res; 23(11); 2723-9. ©2016 AACR.

ObjectiveTo determine biomarkers of recurrence and survival in patients with spindle cell variant squamous cell carcinoma (SpSCC) of the head and neck.Study designRetrospective case control study.SettingTertiary academic center.Subjects and methodsThirty-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).ResultsIn 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.ConclusioncMet, cyclin D1, and p16 are predictive tumor biomarkers for risk of recurrence and worse DSS in patients with SpSCC.

The incidence of human papillomavirus-positive (HPV*) head and neck squamous cell carcinoma (HNSCC) has surpassed that of cervical cancer and is projected to increase rapidly until 2060. The coevolution of HPV with transforming epithelial cells leads to the shutdown of host immune detection. Targeting proximal viral nucleic acid-sensing machinery is an evolutionarily conserved strategy among viruses to enable immune evasion. However, E7 from the dominant HPV subtype 16 in HNSCC shares low homology with HPV18 E7, which was shown to inhibit the STING DNA-sensing pathway. The mechanisms by which HPV16 suppresses STING remain unknown. Recently, we characterized the role of the STING/ type I interferon (IFN-I) pathway in maintaining immunogenicity of HNSCC in mouse models. Here we extended those findings into the clinical domain using tissue microarrays and machine learning-enhanced profiling of STING signatures with immune subsets. We additionally showed that HPV16 E7 uses mechanisms distinct from those used by HPV18 E7 to antagonize the STING pathway. We identified NLRX1 as a critical intermediary partner to facilitate HPV16 E7-potentiated STING turnover. The depletion of NLRX1 resulted in significantly improved IFN-I-dependent T cell infiltration profiles and tumor control. Overall, we discovered a unique HPV16 viral strategy to thwart host innate immune detection that can be further exploited to restore cancer immunogenicity., Introduction The coevolution of oncogenic viruses with transforming epithelial cells encourages pathogens to develop unique mechanisms that enable immune evasion. The type I interferon (IFN-I) system is an ancient and [...]

Introduction Radiation-induced hypopituitarism (RIH) has long been recognized as one of the deleterious side effects of skull base radiation. This study aims to assess the quality of life (QoL) among patients with RIH compared with radiated patients who did not develop hypopituitarism using the validated Anterior Skull Base Questionnaire (ASBQ). Methods This was a single-institution retrospective cohort study. Included patients had a history of anterior skull base tumor, underwent at least one round of radiation to the skull base, and had filled out at least one ASBQ survey after their radiation treatment. Three statistical models were used to determine the effect of hypopituitarism and treatment on QoL scores. Results A total of 145 patients met inclusion criteria, and 330 ASBQ surveys were analyzed. Thirty-five percent (51/145) had evidence of RIH at some point after their radiation treatment. Those with hypopituitarism had significantly lower overall ASBQ scores across all three models even after adjusting for potential confounders and intraperson correlation (average decrease of 0.24–0.45 on a 5-point Likert scale; p -values ranging from 0.0004 to 0.018). The increase in QoL with hormonal replacement was modulated by time out from radiation, with long-term survivors (5+ years out from radiation) gaining the most benefit from treatment (increase of 0.89 on a 5-point Likert scale, p 0.0412), especially in the vitality domain. Conclusion This data demonstrates that hypopituitarism is an independent predictor of lower QoL. Early detection and appropriate treatment are essential to avoid the negative impact of hypopituitarism on QoL. [ABSTRACT FROM AUTHOR]