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Background and purpose: Programmed death-1 (PD-1) monoclonal antibody therapy plays an increasingly important role in the treatment of head and neck squamous cell carcinoma (HNSCC). However, low response rate and lack of predictive biomarkers are still the challenging problems. This study aimed to confirm that programmed death ligand-2 (PD-L2) is a predictive biomarker for the outcome of HNSCC anti-PD-1 immunotherapy. Methods: The samples and clinical data of 50 HNSCC patients undergoing PD-1 monoclonal antibody immunotherapy were collected. Immunohistochemical staining was used to analyze the level of programmed death ligand-1 (PD-L1) and PD-L2. Kaplan-Meier overall survivals were analyzed using SPSS 26.0 software, grouped by the basic clinical characteristics and the PD-L1 and PD-L2 levels. Survival curves were plotted using GraphPad Prism. Results: HNSCC had a relatively high expression rate of PD-L2 with more than 80% of cases detected as PD-L2 positive. The expression of PD-L2 significantly correlated with the clinical outcome of immunotherapy, with a mean survival of 18.8 (16.0-21.7) months for patients with high PD-L2 expression and 11.0 (9.1-12.8) months for patients with low PD-L2 expression, this difference being statistically significant. Conclusion: PD-L2 has the potential to be used as a predictive biomarker for HNSCC anti-PD-1 immunotherapy.

Background: Recent evidence suggested a potential correlation between BMI and the efficacy of immune checkpoint inhibitors in cancer patients. This study aimed to evaluate the prognostic value of the body mass index (BMI) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients treat with pembrolizumab. Methods: The current retrospective cohort study enrolled 49 R/M HNSCC patients underwent at least one cycle of pembrolizumab as second‐line treatment from June 2018 to October 2020. Survival analysis of immunotherapy prognosis and risk factor analysis of age, gender, BMI, ECOG‐PS, CPS, rT‐stage, tumor site, and tube feeding. Results: Among the 49 patients, the BMI at the time of immunotherapy ranged from 14.5 to 32.0 kg/m2. The Kaplan–Meier analysis showed that the BMI was significantly correlated with overall survival time (OS, p = 0.0007) and progression‐free survival time (PFS, p = 0.0012). BMI, gender, prior treatment, serum albumin level, ECOG‐PS, CPS and rT‐stage were analyzed in multivariate Cox regression model analysis after adjusted for potential confounding clinical variables. Patients with underweight (OS:HR = 6.862, 95% CI:1.566–30.064, p = 0.011; PFS:HR = 5.672, 95% CI:1.364–23.586, p = 0.017);ECOG≥2 (OS:HR = 0.250, 95% CI:0.086–0.731, p = 0.011;PFS:HR = 0.284, 95% CI:0.101–0.805, p = 0.018); CPS <1(OS: HR = 4.34, 95% CI:1.271–15.464, p = 0.019; PFS:HR = 3.859, 95% CI:1.180–12.618, p = 0.025) and rT4‐stage(OS:HR = 4.380, 95% CI:1.452–13.209, p = 0.009;PFS: HR = 3.799, 95% CI:1.240–11.638, p = 0.019) suffered higher risk of mortality. Conclusions: The BMI at the time of clinical diagnosis was showed to be an independent predictive factor for R/M HNSCC patients receiving pembrolizumab. Compared with normal weight patients, underweight patients have worse clinical prognosis. [ABSTRACT FROM AUTHOR]

Background: Extranodal marginal zone B‐cell lymphoma of mucosa‐associated lymphoid tissue (MALT lymphoma) in the oromaxillofacial head and neck region is rare, with limited data available. This retrospective study explored the clinical features, stage, treatment, and prognosis of this disease. Methods: Overall, 105 patients with MALT lymphomas in the oromaxillofacial head and neck region were included in this retrospective analysis. SPSS 22.0 software package was used for data analysis and a two‐tailed P value of ≤.05 was considered statistically significant. Primary endpoints of the study were the complete response (CR) rate, overall survival (OS), and progression‐free survival (PFS). Results: About 52% of the patients had long‐term xerostomia, autoimmune diseases, or chronic parotitis and 81% had diseases involving the large salivary glands. Ann Arbor staging of the patients was as follows: stages I/II, 73 patients and stages III/IV, 32 patients. In the 97 patients followed up, CR rate after initial treatment was 80%. Tumor progression was observed in 12 patients and 14 patients died. There was a significant difference between the rate of CR in localized (87%) and disseminated (67%) lymphoma patients (P =.02). The 5‐ and 10‐year PFS of the localized lymphoma patients were both 91%, whereas those of the disseminated lymphoma patients were 83% and 65%, respectively (P =.03). The 5‐year PFS rates of the chemotherapy and non‐chemotherapy groups in the disseminated lymphoma patients were 85% and 73% (P =.04). Meanwhile, the 5‐year PFS rates of the rituximab and non‐rituximab groups in the disseminated lymphoma patients were 100% and 70% (P =.03). In multivariate analysis, MALT Lymphoma International Prognostic Index (MALT‐IPI) was an independent prognostic factor affecting OS, whereas Ann Arbor staging affected PFS. Conclusions: This study suggests that the outcome after initial treatment of MALT lymphomas in the oromaxillofacial head and neck region is satisfactory and that this disease progresses slowly. The CR rate and PFS of localized lymphoma patients are better than those of disseminated lymphoma patients. Systemic treatment (chemotherapy or rituximab) may improve PFS in disseminated disease patients. MALT‐IPI and Ann Arbor staging are independent prognostic factors. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) is highly expressed in head and neck squamous cell carcinoma (HNSCC) and related to cancer progression. The resistance to anti-EGFR therapy remains a major clinical problem in HNSCC. In this study, we found that TOLL-like receptor 4 (TLR4) was highly expressed in 50% of EGFR overexpressed HNSCC biopsies, which correlated to worse prognosis in patients. In HNSCC cell lines, activation of TLR4 reversed cetuximab-induced the inhibition of proliferation, migration and invasion. LPS induced of TLR4 signaling was potentiated under cetuximab treatment, showing increased activation of downstream NF-κB and MAPK pathways. Accordingly, cetuximab treatment also increased expression of TNF-α, COX2, and other molecules involved in TLR4 induced tumor inflammation. Mechanistically, we found inhibition of EGFR by cetuximab led to decreased phosphorylation of Src and sequentially Src-medicated activation of Cbl-b. This inhibited Cbl-b-mediated degradation of the key TLR4 adaptor protein MyD88 and activated TLR4 signaling. TLR4 or MyD88 overexpressed CAL27 and SCC4 cells grew faster and were more resistant to cetuximab and gefitinib both in vitro and in vivo . Out study delineates a crosstalk between EGFR and TLR4 pathways and identified TLR4 as a potential biomarker as well as a therapeutic target in overcoming the resistance to anti-EGFR therapy of HNSCC., Competing Interests: None., (AJCR Copyright © 2020.)

Circular RNAs (circRNAs) are known to be associated with carcinogenesis, and can serve as potential biomarkers for cancer diagnosis and therapeutic implications. However, little is known about their expression patterns in oral mucosal melanoma (OMM), an extremely rare cancer that is distinct from cutaneous melanoma for its clinical course and prognosis. To investigate circRNAs expression profile in OMM, we performed a circRNAs microarray to analyze 6 primary OMM samples with lymph nodes dissemination, and constructed a genome-wide circRNA profile. Our results revealed that 90 circRNAs were significantly dysregulated in the metastatic OMM tissues when compared to the paired adjacent tissues. Among them, hsa&#95;circ&#95;0005320, hsa&#95;circ&#95;0067531, hsa&#95;circ&#95;0008042 were significantly upregulated in primary tumor and metastatic lymph nodes compared to paired adjacent normal tissues and non-metastatic lymph nodes, whereas the expression of hsa&#95;circ&#95;0000869 and hsa&#95;circ&#95;0000853 were downregulated relatively. Gene Ontology (GO) and pathway analyses of differentially expressed circRNAs indicated that these identified circRNAs might play important roles in protein modification, protein binding and cellular metabolism in metastatic OMM. Functions of several selected circRNA were also identified. In addition, by using bioinformatics predictions, we further demonstrated that hsa&#95;circ&#95;0005320, hsa&#95;circ&#95;0067531 and hsa&#95;circ&#95;0000869 could serve as competing endogenous RNA (ceRNA), which might regulate tumorigenesis and metastatic of OMM by binding to specific microRNAs. Our results not only suggested that circRNAs might play critical roles in metastasis of OMM, but also provided critical information of circRNAs in regulating OMM progression. The findings would help us to develop potential biomarkers for clinical diagnosis and design therapeutic strategies for OMM., Competing Interests: None.

Oral cancer is a serious disease caused by environmental factors and/or susceptible genes. In the present study, in order to identify useful genetic biomarkers for cancer prediction and prevention, and for personalized treatment, we detected somatic mutations in 5 pairs of oral cancer tissues and blood samples using whole exome sequencing (WES). Finally, we confirmed a novel nonsense single-nucleotide polymorphism (SNP; chr19:15288426A>C) in the NOTCH3 gene with sanger sequencing, which resulted in a N1438T mutation in the protein sequence. Using multiple in silico analyses, this variant was found to mildly damaging effects on the NOTCH3 gene, which was supported by the results from analyses using PANTHER, SNAP and SNPs&GO. However, further analysis using Mutation Taster revealed that this SNP had a probability of 0.9997 to be 'disease causing'. In addition, we performed 3D structure simulation analysis and the results suggested that this variant had little effect on the solubility and hydrophobicity of the protein and thus on its function; however, it decreased the stability of the protein by increasing the total energy following minimization (-1,051.39 kcal/mol for the mutant and -1,229.84 kcal/mol for the native) and decreasing one stabilizing residue of the protein. Less stability of the N1438T mutant was also supported by analysis using I-Mutant with a DDG value of -1.67. Overall, the present study identified and confirmed a novel mutation in the NOTCH3 gene, which may decrease the stability of NOTCH3, and may thus prove to be helpful in cancer prognosis.