Allergic Diseases and Chronic Adenotonsillar Diseases: A Mendelian Randomization Study.

OBJECTIVE: The existing epidemiological evidence regarding the intricate relationship between allergic diseases and chronic adenotonsillar diseases (CATD) remains inconclusive. Herein, the objective of our study is to explore the causal association using Mendelian randomization (MR). METHODS: Employing data from large genome-wide association studies, a comprehensive two-sample bidirectional MR study was conducted. The studied traits encompassed allergic rhinitis (cases n = 9707, controls n = 331173), allergic asthma (cases n = 8525, controls n = 193857), allergic conjunctivitis (cases n = 18321, controls n = 324178), atopic dermatitis (cases n = 11964, controls n = 306909), and CATD (cases n = 38983, controls n = 258553). All the patients were of European descent and participants in cohort studies. The primary analysis was executed using inverse-variance-weighted MR. Furthermore, six additional MR methods (MR-Egger, weighted median, simple mode, weighted mode, MR pleiotropy residual sum and outlier, MR robust adjusted profile score) were employed to ensure the reliability and detect potential horizontal pleiotropy within the results. The estimates obtained from the MR analysis were factored into the overall effect calculation. RESULTS: Genetically anticipated outcomes demonstrated a significant association between CATD risk and allergic rhinitis (OR = 1.141, p = 6.30E-06), allergic asthma (OR = 1.115, p = 8.31E-05), allergic conjunctivitis (OR = 1.197, p = 8.69E-07), and a suggestive association with atopic dermatitis (OR = 1.053, p = 0.040). However, no substantial correlation was observed in the reverse direction. CONCLUSIONS: Findings of our study provide evidence supporting a causal role of allergic diseases in the development of CATD, whereas the converse relationship does not appear to hold true. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Exosome-based delivery strategies for tumor therapy: an update on modification, loading, and clinical application.

Malignancy is a major public health problem and among the leading lethal diseases worldwide. Although the current tumor treatment methods have therapeutic effect to a certain extent, they still have some shortcomings such as poor water solubility, short half-life, local and systemic toxicity. Therefore, how to deliver therapeutic agent so as to realize safe and effective anti-tumor therapy become a problem urgently to be solved in this field. As a medium of information exchange and material transport between cells, exosomes are considered to be a promising drug delivery carrier due to their nano-size, good biocompatibility, natural targeting, and easy modification. In this review, we summarize recent advances in the isolation, identification, drug loading, and modification of exosomes as drug carriers for tumor therapy alongside their application in tumor therapy. Basic knowledge of exosomes, such as their biogenesis, sources, and characterization methods, is also introduced herein. In addition, challenges related to the use of exosomes as drug delivery vehicles are discussed, along with future trends. This review provides a scientific basis for the application of exosome delivery systems in oncological therapy.

Allergy History and Immunotherapy Response in Patients With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma.

OBJECTIVE: This study examines the association between patient-reported allergy history and immune checkpoint inhibition (ICI) response in patients with recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC). STUDY DESIGN: Retrospective cohort study. SETTING: Academic tertiary care hospital. METHODS: Data were collected from the electronic medical records on baseline age, sex, allergy history, human papillomavirus status, T-stage, N-stage, smoking status, and survival for patients with and without an allergy history. The primary outcome was ICI response defined as complete or partial response by the RECIST criteria. Chi-square and logistic regression analyses were conducted to compare rates and odds of ICI response. Kaplan-Meier analyses were used to compare survival between groups. RESULTS: Our study included 52 patients with an allergy history and 36 patients without an allergy history. The groups were similar in age, sex, HPV status, smoking status, and T- and N-stage. Patients with an allergy history (17/52, 32.1%) had a greater ICI response rate than patients without allergy history (4/36, 11.1%) (P = .02). After adjusting for HPV, patients with allergies had 3.93 (1.19-13.00) times increased odds of ICI response compared to patients without allergies. The median progression-free survival was 6.0 and 4.2 months for patients with and without an allergy history respectively (log-rank, P = .04). The median overall survival was 25.0 and 11.1 months for patients with and without an allergy history respectively (log-rank, P = .002). CONCLUSION: Patient-reported allergy history was associated with ICI response in patients with RMHNSCC, underscoring the potential clinical utility of allergy history in estimating ICI response.

The prognosis and treatment of newly diagnosed bone metastasis of head and neck squamous cell cancer: an analysis of racial disparity.

OBJECTIVE: There is a lack of research investigating racial disparity in newly diagnosed head and neck squamous cell carcinoma with isolated bone metastases (HNSCC-BM). This study aims to investigate the clinical characteristics and prognostic factors in HNSCC-BM patients from different racial backgrounds to aid clinical decision making and management. METHODS: We retrieved data from the Surveillance, Epidemiology, and End Results (SEER) database for 345 cases of HNSCC-BM that were diagnosed between 2010 and 2017. Survival was compared using univariate and multivariate Cox proportional hazards models, Kaplan-Meier analysis, and log-rank tests. We also used propensity score matching to adjust for confounders. RESULTS: In white patients, those who were over 40 years of age had a significantly shorter survival (HR, 4.49; 95% CI 1.03-19.56; P < 0.05). Female black patients were found to survive longer compared to male patients (HR, 0.34; 95% CI 0.15-0.76; P < 0.01). Single (never married) Asians had shorter survival than married Asians (HR, 4.68; 95% CI 1.34-16.41; P < 0.05). In all three racial groups, patients who received radiotherapy in addition to chemotherapy did not survive longer than those receiving chemotherapy (P > 0.05). In Asian patients, those who underwent surgery at the primary site combined with chemoradiotherapy had significantly better survival outcomes than those who received chemoradiotherapy (HR: 0.10, 95% CI 0.01-0.88; P = 0.01). CONCLUSION: Prognostic factors differ between HNSCC-BM patients from different racial backgrounds.

Impact of comorbidities on outcomes in patients with advanced head and neck cancer undergoing immunotherapy.

OBJECTIVES: To explore the impact of pre-existing comorbidities on immunotherapy response, overall and progression-free survival, and immune-related adverse events (irAEs) of patients with advanced head and neck cancer (HNC) treated with immunotherapy. PATIENTS AND METHODS: Ninety-three patients treated with immunotherapy were identified and stratified into comorbidity absent or present (CCI < 1 and CCI ≥ 1, respectively) cohorts, and clinical outcomes were compared between these two groups. RESULTS: Patients with no comorbidities had longer overall survival (aHR = 2.74, 95% CI [1.18, 6.40], p = 0.02) and progression-free survival (aHR = 2.07, 95% CI [1.03, 4.16], p = 0.04) and a higher tumor response rate (32% in CCI < 1 vs. 14% in CC ≥ 1, p = 0.05). Risk for irAEs was higher in the comorbidity absent group (p = 0.05). CONCLUSION: Comorbidity should be considered as a significant prognostic factor in clinical decision-making for patients with advanced HNC undergoing immunotherapy.

Emerging biomaterials for tumor immunotherapy.

BACKGROUND: The immune system interacts with cancer cells in various intricate ways that can protect the individual from overproliferation of cancer cells; however, these interactions can also lead to malignancy. There has been a dramatic increase in the application of cancer immunotherapy in the last decade. However, low immunogenicity, poor specificity, weak presentation efficiency, and off-target side effects still limit its widespread application. Fortunately, advanced biomaterials effectively contribute immunotherapy and play an important role in cancer treatment, making it a research hotspot in the biomedical field. MAIN BODY: This review discusses immunotherapies and the development of related biomaterials for application in the field. The review first summarizes the various types of tumor immunotherapy applicable in clinical practice as well as their underlying mechanisms. Further, it focuses on the types of biomaterials applied in immunotherapy and related research on metal nanomaterials, silicon nanoparticles, carbon nanotubes, polymer nanoparticles, and cell membrane nanocarriers. Moreover, we introduce the preparation and processing technologies of these biomaterials (liposomes, microspheres, microneedles, and hydrogels) and summarize their mechanisms when applied to tumor immunotherapy. Finally, we discuss future advancements and shortcomings related to the application of biomaterials in tumor immunotherapy. CONCLUSION: Research on biomaterial-based tumor immunotherapy is booming; however, several challenges remain to be overcome to transition from experimental research to clinical application. Biomaterials have been optimized continuously and nanotechnology has achieved continuous progression, ensuring the development of more efficient biomaterials, thereby providing a platform and opportunity for breakthroughs in tumor immunotherapy.

FN1 promotes prognosis and radioresistance in head and neck squamous cell carcinoma: From radioresistant HNSCC cell line to integrated bioinformatics methods.

Background: Radioresistance in head and neck squamous cell carcinoma (HNSCC) patients means response failure to current treatment. In order to screen radioresistant biomarkers and mechanisms associated with HNSCC, differentially expressed genes (DEGs) associated with radioresistance in HNSCC were investigated. Methods: The HNSCC cell line with radioresistance, Hep2-R, was established and detected the radiosensitivity using MTT, colony formation assay and flow cytometry analysis. Clariom™ D chip was applied to compare DEGs between Hep2 and Hep2-R groups and build the differential gene expression profiles associated with radioresistance in HNSCC. Bioinformatic analysis were used to find biological functions and pathways that related to radioresistance in HNSCC, including cell adhesion, cytochrome P450 and drug metabolism. Gene Expression Omnibus (GEO) datasets were selected to verify DEGs between HNSCC radioresistant cells and tissues. The representation of DEGs were validated between HNSCC patients with complete response and post-operative radiation therapy failure. In addition, we evaluated the clinical prognosis of DEGs using The Cancer Genome Atlas (TCGA) database. Results: 2,360 DEGs (|Fold Change|>1.5, p < 0.05) were identified between Hep2 and Hep2-R, including 1,144 upregulated DEGs and 1,216 downregulated DEGs. They were further verified by HNSCC radioresistant cells and tissues in GEO. 13 radioresistant DEGs showed same difference in expression level between cells and tissues. By comparing 13 DEGs with HNSCC patients, upregulations of FN1, SOX4 and ETV5 were found identical with above results. Only FN1 was a prognostic indicator of HNSCC in TCGA. Conclusion: FN1 is the potential novel biomarker for predicting poor prognosis and radioresistance in HNSCC patients. Overexpression of FN1 plays an important role in the tumorigenesis, prognosis and radioresistance of HNSCC.

Tumor Histological Grade and Immunotherapy Response in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

Importance: Tumor histological factors that predict immunotherapy response in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are not well defined. Objective: To investigate the association between tumor grade and immunotherapy response in patients with recurrent or metastatic mucosal HNSCC. Design, Setting, and Participants: In this retrospective cohort study, the medical records of 60 patients with recurrent or metastatic mucosal HNSCC treated with immune checkpoint inhibitors at Johns Hopkins Hospital between July 1, 2015, and January 22, 2020, were reviewed. Exposures: High-grade tumors (HGTs) vs low-grade tumors (LGTs) in recurrent or metastatic HNSCC. Main Outcomes and Measures: Patients were divided into 2 groups: those with LGTs (well differentiated and moderately differentiated) and those with HGTs (poorly differentiated). The main outcome was a clinically beneficial immunotherapy response, defined as complete response or partial response. Univariable and multivariable logistic regressions were conducted to calculate odds ratios for each variable's association with immunotherapy response. Survival differences were evaluated using Kaplan-Meier survival curves with multivariable Cox proportional hazards regression models. Results: The 60 patients (35 with HGTs and 25 with LGTs) had a mean (SD) age of 64.6 (8.88) years; 51 were male (85%); and 38 were current or former smokers (63%). The oropharynx was the most common primary tumor site both in patients with HGTs (22 of 35; 63%) and those with LGTs (12 of 25; 48%). Bivariate analysis showed the proportion of patients having a beneficial response to immunotherapy was greater for patients with HGTs (12 of 35; 34.3%) than those with LGTs (2 of 25, 8.0%) (difference, 26.3%; 95% CI, 7.3%-45.3%). Upon multivariable analysis, patients with HGTs had 5.35-fold increased odds (95% CI, 1.04-27.37) of having a clinically beneficial response to immunotherapy. Among patients with available tumor genomic profiling data, the mean tumor mutational burden was greater for patients with HGTs (mean [SD], 8.6 [5.4] mut/Mb; n = 8) than patients with LGTs (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference = 5.0 mut/Mb; 95% CI -1.4 to 11.4 mut/Mb; Cohen d = 1.2). Conclusions and Relevance: In this cohort study, tumor grade was independently associated with immunotherapy response in patients with recurrent or metastatic mucosal HNSCC. These findings highlight the potential role of tumor grade in predicting immunotherapy response in mucosal HNSCC.

Association of Tumor Site With the Prognosis and Immunogenomic Landscape of Human Papillomavirus-Related Head and Neck and Cervical Cancers.

Importance: Human papillomavirus (HPV)-positive status in patients with oropharyngeal squamous cell carcinoma (OPSCC) is associated with improved survival compared with HPV-negative status. However, it remains controversial whether HPV is associated with improved survival among patients with nonoropharyngeal and cervical squamous cell tumors. Objective: To investigate differences in the immunogenomic landscapes of HPV-associated tumors across anatomical sites (the head and neck and the cervix) and their association with survival. Design, Setting, and Participants: This cohort study used genomic and transcriptomic data from the Cancer Genome Atlas (TCGA) for 79 patients with OPSCC, 435 with nonoropharyngeal head and neck squamous cell carcinoma (non-OP HNSCC), and 254 with cervical squamous cell carcinoma and/or endocervical adenocarcinoma (CESC) along with matched clinical data from TCGA. The data were analyzed from November 2020 to March 2021. Main Outcomes and Measures: Positivity for HPV was classified by RNA-sequencing reads aligned with the HPV reference genome. Gene expression profiles, immune cell phenotypes, cytolytic activity scores, and overall survival were compared by HPV tumor status across multiple anatomical sites. Results: The study comprised 768 patients, including 514 (66.9%) with HNSCC (380 male [73.9%]; mean [SD] age, 59.5 [10.8] years) and 254 (33.1%) with CESC (mean [SD] age, 48.7 [14.1] years). Human papillomavirus positivity was associated with a statistically significant improvement in overall survival for patients with OPSCC (adjusted hazard ratio [aHR], 0.06; 95% CI, 0.02-0.17; P < .001) but not for those with non-OP HNSCC (aHR, 0.64; 95% CI, 0.31-1.27; P = .20) or CESC (aHR, 0.50; 95% CI, 0.15-1.67; P = .30). The HPV-positive OPSCCs had increased tumor immune infiltration and immunomodulatory receptor expression compared with HPV-negative OPSCCs. Compared with HPV-positive non-OP HNSCCs, HPV-positive OPSCCs showed greater expression of immune-related metrics including B cells, T cells, CD8+ T cells, T-cell receptor diversity, B-cell receptor diversity, and cytolytic activity scores, independent of tumor variant burden. The immune-related metrics were similar when comparing HPV-positive non-OP HNSCCs and HPV-positive CESCs with their HPV-negative counterparts. The 2-year overall survival rate was significantly higher for patients with HPV-positive OPSCC compared with patients with HPV-negative OPSCC (92.0% [95% CI, 84.8%-99.9%] vs 45.8% [95% CI, 28.3%-74.1%]; HR, 0.10 [95% CI, 0.03-0.30]; P = .009). Conclusions and Relevance: In this cohort study, tumor site was associated with the immune landscape and survival among patients with HPV-related tumors despite presumed similar biologic characteristics. These tumor site-related findings provide insight on possible outcomes of HPV positivity for tumors in oropharyngeal and nonoropharyngeal sites and a rationale for the stratification of HPV-associated tumors by site and the subsequent development of strategies targeting immune exclusion in HPV-positive nonoropharyngeal cancer.

Neoadjuvant immunotherapy prior to surgery for mucosal head and neck squamous cell carcinoma: Systematic review.

Given the recent successes of anti-PD-1 immunotherapy, many clinical trials have sought to assess the safety and efficacy of this treatment modality in the neoadjuvant setting. This systematic review provides a comprehensive summary of findings from neoadjuvant head and neck cancer immunotherapy clinical trials with a focus on PD-1/PD-L1 axis blockade. Pubmed, Embase, Cochrane Library, Web of Science, Google Scholar, and clinicaltrials.gov were systematically searched for all eligible neoadjuvant head and neck cancer immunotherapy clinical trials. Eight clinical trials met the inclusion criteria comprising a total of 260 patients. Study drugs included nivolumab, pembrolizumab, ipilimumab, durvalumab, and tremelimumab. The overall mean objective response rate (ORR) was 45.9 ± 5.7% with a 41.5 ± 5.6% single agent mean ORR. There were no deaths due to immune-related toxicities. Neoadjuvant immunotherapy for mucosal head and neck squamous cell cancer has demonstrated favorable response rates with no unexpected immune-related toxicities in phase I/II clinical trials.

The prognosis of HPV-associated metastatic pharyngeal patients by primary and distant site.

OBJECTIVES: Human papillomavirus (HPV) positivity is a favorable prognostic factor in the general population of head and neck squamous cell carcinoma (HNSCC) patients. However, its impact on the survival of metastatic HNSCC of pharynx (mHNSC-P) patients is unclear. This study aims to investigate the associations between HPV status and survival in mHNSC-P patients. METHODS: 735 mHNSC-P patients diagnosed at first presentation from 2010 to 2016 were retrieved from the Surveillance, Epidemiology and End Result database (SEER). Chi-Squared test, univariate and multivariate cox proportional hazards model, Kaplan-Meier analysis, and log-rank test were applied to compare HPV-positive and -negative mHNSC-P patients. RESULT: Using univariate cox proportional hazards analysis, HPV status, primary site, T stage, treatment and distant metastatic site correlate with the overall survival (OS) and disease-specific survival (DSS) in mHNSC-P patients. Multivariate cox regression analysis shows that HPV-positive mHNSC-P patients experienced significantly better OS (HR: 0.62 CI: 0.51-0.76, p < 0.001) and DSS (HR: 0.73 CI: 0.58-0.91, p < 0.01) as compared to HPV-negative mHNSC-P patients. Subgroup analysis indicates that HPV-associated OS and DSS benefits exist in patients with metastatic HNSCC of oropharynx (mHNSC-OP) but not in patients with metastatic HNSCC of non-oropharynx (mHNSC-non-OP). Among mHNSC-OP patients, HPV positivity confers disease-specific survival benefit in patients with oligometastatic rather than polymetastatic patients. Furthermore, HPV associated OS and DSS advantages in mHNSC-OP with lung metastasis was observed. CONCLUSION: HPV-positive mHNSC-OP patients with lung metastasis show better survival than HPV-negative mHNSC-OP patients, providing key information to guide patient treatment approaches.

Nutritional Status as a Predictive Biomarker for Immunotherapy Outcomes in Advanced Head and Neck Cancer.

The association between pretreatment nutritional status and immunotherapy response in patients with advanced head and neck cancer is unclear. We retrospectively analyzed a cohort of 99 patients who underwent treatment with anti-PD-1 or anti-CTLA-4 antibodies (or both) for stage IV HNSCC between 2014 and 2020 at the Johns Hopkins Hospital. Patient demographics and clinical characteristics were retrieved from electronic medical records. Baseline prognostic nutritional index (PNI) scores and pretreatment body mass index (BMI) trends were calculated. Associations between PNI and BMI were correlated with overall survival (OS), progression-free survival (PFS), and immunotherapy response. In univariate analysis, there was a significant correlation between OS and PFS with baseline PNI (OS: HR: 0.464; 95% CI: 0.265-0.814; PFS: p = 0.007 and HR: 0.525; 95% CI: 0.341-0.808; p = 0.003). Poor OS was also associated with a greater decrease in pretreatment BMI trend (HR: 0.42; 95% CI: 0.229-0.77; p = 0.005). In multivariate analysis, baseline PNI but not BMI trend was significantly associated with OS and PFS (OS: log (HR) = -0.79, CI: -1.6, -0.03, p = 0.041; PFS: log (HR) = -0.78, CI: -1.4, -0.18, p = 0.011). In conclusion, poor pretreatment nutritional status is associated with negative post-immunotherapy outcomes.

MTDH associates with m6A RNA methylation and predicts cancer response for immune checkpoint treatment.

Immune checkpoint blockade (ICB) persistently provides a prognosis improvement but only in a small fraction of patients with cancer due to immunotherapy resistance induced by the consecutive activated oncogenic pathways, including MAPK, Akt, and WNT pathway partially driven by Metadherin (MTDH). However, there is no study to investigate the potential role and mechanisms of MTDH in ICB-treated cancers. Here, we systematically explored the cohorts from The Cancer Genome Atlas (TCGA) and independent cancer cohorts. Elevated MTDH expression was founded to associate with a worse overall survival and poorer immune response in patients with cancer. Dysregulated tumor-infiltrating immune cells and inhibitory immune checkpoint expression were correlated with MTDH expression. Furthermore, the mutual interactions between epithelial-to-mesenchymal-transition, m6A-RNA-methylation, and MTDH may illustrate the potential mechanisms of MTDH resistant to ICB treatment. Although more designed experiments and trials are needed in the future, targeting MTDH may help to overcome immunotherapy resistance in a wide range of cancers.

Metabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the nasopharynx mainly characterized by geographic distribution and EBV infection. Metabolic reprogramming, one of the cancer hallmarks, has been frequently reported in NPCs to adapt to internal energy demands and external environmental pressures. Inevitably, the metabolic reprogramming within the tumor cell will lead to a decreased pH value and diverse nutritional supplements in the tumor-infiltrating micro-environment incorporating immune cells, fibroblasts, and endothelial cells. Accumulated evidence indicates that metabolic reprogramming derived from NPC cells may facilitate cancer progression and immunosuppression by cell-cell communications with their surrounding immune cells. This review presents the dysregulated metabolism processes, including glucose, fatty acid, amino acid, nucleotide metabolism, and their mutual interactions in NPC. Moreover, the potential connections between reprogrammed metabolism, tumor immunity, and associated therapy would be discussed in this review. Accordingly, the development of targets on the interactions between metabolic reprogramming and immune cells may provide assistances to overcome the current treatment resistance in NPC patients.

Establishment and validation of immune microenvironmental gene signatures for predicting prognosis in patients with head and neck squamous cell carcinoma.

Tumor cells influencing the microenvironment are essential for restrained immunity in head and neck squamous cell carcinoma (HNSCC). There has been considerable progress in the research on monoclonal antibodies for antigen-specific immunotherapy that overcome immunosuppressive checkpoint receptor/ligand signaling in patients with HNSCC. However, alteration of immunogenicity and formation of neoantigens that lead to dysregulation and immunosuppression in the HNSCC microenvironment is not well-defined. The aim of this study was to quantify the Immune, Stromal, and ESTIMATE scores based on the gene matrix of patients with HNSCC reported in The Cancer Genome Atlas (TCGA). We examined the association of the Immune, Stromal, and ESTIMATE scores with the pathologic characteristics of patients with HNSCC, using weighted gene co-expression network (WGCNA) and protein-protein interaction (PPI) analyses, and selected 17 hub gene signatures from the key gene module that was mostly correlated to immunocyte infiltration. Gene functional enrichment showed that this key gene module was closely related to the regulation of immune cell activation and its relevant pathways. In the prognostic analysis, high expression of CD3E, SASH3, CD2, SIRPG, UBASH3A, IKZF1, SPN, IL10RA, SLA, and CD3G was significantly associated with a good prognosis. Consequently, these prognosis-related genes were validated via analysis of mRNA expression in tumor-infiltrating lymphocytes (TILs) and matched peripheral blood lymphocytes (PBLs) in ten patients with HNSCC, and the expression of these genes was significantly higher in TILs compared to that in PBLs. These findings provide a novel understanding of the tumor immune targets for improved therapeutic regimes in patients with HNSCC.

A characterization and prognosis prediction model for primary squamous cell carcinoma of the thyroid.

BACKGROUND: Primary squamous cell carcinoma of the thyroid (PSCCTh) is a sporadic malignancy arising from the thyroid gland. The factors that affect treatment and survival in patients with PSCCTh remain unclear. Our study aims to characterize PSCCTh and establish a prognosis prediction model for patients with PSCCTh. METHODS: Clinical data and follow-up information for 277 patients from 1973 to 2016 were collected from the Surveillance, Epidemiology, and End Results Program (SEER) 18-registry database (RRID:SCR_003293). Univariate and multivariate Cox proportional hazards analyses and nomogram modeling of potential prognostic factors were conducted. RESULTS: Among the collected patient cases, 57% were female and 43% were male. The median survival of all cases was 6 months; by gender, median survival was 5 and 8 months in the female and male groups, respectively. Univariate and multivariate Cox proportional hazards analyses revealed that age, extent of disease (EOD), T stage, N stage, and treatment were independent prognostic indicators for overall survival (OS) and disease-specific survival (DSS) in patients with PSCCTh. In addition, it was confirmed that the established nomogram model had good consistency and discrimination for PSCCTh prognosis as measured by the concordance index (C-index), area under the receiver operating characteristic (ROC) curve (AUC), and calibration curves. CONCLUSIONS: Our study indicates that age, EOD, T stage, N stage, and treatment may correlate with OS and DSS in patients with PSCCTh. Importantly, our nomogram prediction model, constructed using parameters including age, T stage, N stage, and treatment, may assist physicians in evaluating patients' prognoses and providing precise therapy for PSCCTh.

Programmed Death-1/Programmed Death-Ligand 1-Axis Blockade in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Stratified by Human Papillomavirus Status: A Systematic Review and Meta-Analysis.

Background: Programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors have provided clinical benefit to head and neck squamous cell carcinoma (HNSCC) patients in recent clinical trials. However, it remains unclear as to whether human papillomavirus (HPV) status is associated with improved clinical outcome of anti-PD-1 or anti-PD-L1 immunotherapy in HNSCC. Methods: PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched up to February 28, 2021. Published clinical trials of HNSCC patients treated with only PD-1 or PD-L1 inhibitors were selected. The primary or secondary outcome of these studies included objective response rate (ORR) stratified by HPV status. The pooled odds ratio (OR) and hazard ratio (HR) were estimated using a fixed-effect model. Results: A total of seven eligible studies comprising 814 patients were included. The ORR of HPV positive HNSCC patients was significantly higher than that of HPV negative HNSCC patients (OR = 1.77; 95%CI = 1.14-2.74; P = 0.01), and this favorable effect occurred in pooled anti-PD-L1 trials (OR = 2.66; 95%CI = 1.16-6.11; P = 0.02). In comparison, the pooled OR was 1.51 in anti-PD-1 trials (95%CI = 0.90-2.54; P = 0.12). Survival analysis indicated that HPV positive HNSCC patients had a lower risk of overall death as compared to HPV negative HNSCC patients (HR = 0.77; 95%CI = 0.60-0.99; P = 0.04). Conclusions: HPV positive HNSCC patients display improved outcomes with PD-1/PD-L1 axis blockade as compared to HPV negative HNSCC patients. These improved outcomes are likely driven to a greater extent by anti-PD-L1 inhibitors. However, randomized controlled trials with greater numbers of patients are needed for validation of these early findings.

Association Between Vitamin D Exposure and Head and Neck Cancer: A Systematic Review With Meta-Analysis.

Background: Vitamin D deficiency is a well-described preventable cause of many cancers; the association of vitamin D use with the development of head and neck cancer (HNC) is not clear. We aim to conduct a systematic review of the studies assessing the relation between vitamin D exposure and the prevention and prognosis of the HNC using meta-analysis. Methods: PubMed, EMBASE, Cochrane Library, Web of Science up to 1 January 2021, and reference lists of related studies were searched. We extracted observational studies reporting the association between vitamin D (vitamin D receptor gene polymorphisms, 25-hydroxyvitamin D concentrations, and vitamin D intake) and the outcomes of interest (HNC incidence and HNC mortality) in HNC patients aged 18 or older. Fixed effects models were used to calculate pooled effect sizes and 95% confidence intervals (CIs) by RevMan (version 5.3). Results: Sixteen studies with a total of 81,908 participants were enrolled in our meta-analysis. Based on the pooled genomic analysis, comparing with participants with the genotypes of Ff + FF or FF, the pooled odds ratio (OR) of participants with the genotype of ff was 0.77 (95% CI: 0.61 to 0.97) and 0.75 (0.58 to 0.97), respectively. A similar trend was noted when comparing tt with Tt + TT or TT, in which OR (95% CI) was 0.70 (0.55 to 0.90) and 0.72 (0.55 to 0.95). No significant association was identified between BsmI polymorphism and HNC. Furthermore, the OR of HNC incidence was 0.77 (0.65 to 0.92) for participants with vitamin D intake over the ones with a regular diet. High concentrations of circulated 25-hydroxyvitamin D (25-OHD) significantly decreased by 32% of HNC incidence (OR (95% CI): 0.68 (0.59 to 0.78)) and increased HNC survival (pooled hazard ratio 1.13, 1.05 to 1.22) during a 4-5 years follow-up. High concentrations of circulating 25-OHD in patients with HNC led to a decreased risk of mortality to 0.75 (0.60 to 0.94) as the follow-up extends to 8-12 years. Conclusions: Elevated activities of vitamin D by diet intake, genomic polymorphisms, or circulated 25-OHD may protect people from HNC and improve the prognosis of patients with HNC. Systematic Review Registration: PROSPERO, identifier CRD42020176002 (https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=176002).

Overexpressed PLAU and its potential prognostic value in head and neck squamous cell carcinoma.

BACKGROUND: Metastasis is a major event for survival and prognosis in patients with head and neck squamous cell carcinomas (HNSCC). A primary cause of metastasis is the proteolytic degradation of the extracellular matrix (ECM). The plasminogen activator urokinase (PLAU) is involved in the transformation of plasminogen to plasmin leading to hydrolyzation of ECM-related proteins. However, the role of PLAU expression in HNSCC is unclear and the worth being investigated. METHODS: PLAU expression profiles and clinical parameters from multiple HNSCC datasets were used to investigate the relationship of PLAU expression and HNSCC survival. GO and PPI network were established on PLAU-related downstream molecular. The stroma score was deconvoluted for analysis of PLAU's association with the immune environment. ROC analysis was applied to show the performance of PLAU in predicting HNSCC prognosis. RESULTS: PLAU mRNA was significantly elevated, as opposed to its methylation, in HNSCC tumor samples over normal specimens (all p < 0.01). Univariate and multivariate cox analysis showed PLAU could be an independent indicator for HNSCC prognosis. Combining with neck lymph node status, the AUC of PLAU in predicting 5-years overall survival reached to 0.862. GO enrichment analysis showed the major biological process (extracellular matrix organization and the P13K-Akt signaling pathway) may involve to the possible mechanism of PLAU's function on HNSCC prognosis. Furthermore, PLAU expression was positively correlated with stroma cell score, M1 type macrophages, and negatively associated with CD4 + T cell, Tregs cell, and follicular helper T cell. CONCLUSIONS: PLAU might be an independent biomarker for predicting outcomes of HNSCC patients. The elevated expression of PLAU was associated with HPV positivity and neck node status. The PI3K-Akt pathway and aberrant proportions of immune cells might underly the mechanism of PLAU's oncogene role in HNSCC.

Hepatitis C Virus RNA Transcript Associates with Prognosis in Non-human Papillomavirus Associated Head and Neck Squamous Cell Carcinoma.

OBJECTIVE/HYPOTHESIS: Hepatitis C virus (HCV) was reported to associate with head and neck squamous cell carcinoma (HNSCC) in many studies. However, its correlation with prognosis of non-human papillomavirus (HPV) associated HNSCC remains unknown. Here, we sought to investigate clinical significance of HCV RNA transcript in non-HPV associated HNSCC by analyzing corresponding RNA-seq data. STUDY DESIGN: A retrospective cohort study. METHODS: Four hundred and forty-eight non-HPV associated HNSCC patients with aligned RNA-seq and clinical follow-up data were included and divided into two groups: low-HCV and high-HCV. Means of continuous variables and proportions of categorical variables were compared using independent sample t-test and chi-square test, respectively. Survival data were compared using Cox regression analysis, Kaplan-Meier curves, and log-rank test. Expression of genome-wide mRNAs and abundance of immune cells were compared using volcano plot and cell signature estimated score analysis. RESULTS: HCV RNA transcript negatively correlates with pathologic (P = .028) and clinical-stage (P = .023), clinical N stage (P = .025), and nodal extracapsular spread (P = .042) and is an independent prognosis factor in non-HPV associated HNSCC (HR = 1.488; 95% CI: 1.004-2.206; P = .048). Elevated expression of HCV improved 5-year overall survival (43.6% vs. 53.2%; P = .035) in all non-HPV associated HNSCC patients, the same as in male (46.6% vs. 58.7%; P = .049), clinical M0 stage (42.8% vs. 52.9%; P = .036), white (42.9% vs. 55.9%; P = .010), and histologic grade 1 to 2 subgroups (42.1% vs. 57.2%; P = .043). The expression of several immune-related genes and abundance of some immune cells significantly changed with the increase of HCV RNA transcript, while HCV-related oncogenes and tumor suppressor gene did not. CONCLUSIONS: HCV RNA transcript is an independent favorable factor for prognosis of non-HPV associated HNSCC. LEVELS OF EVIDENCE: 4 Laryngoscope, 131:1774-1781, 2021.