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Background: An emerging subset of oropharyngeal squamous cell carcinomas (OPSCC) is caused by HPV. HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC, but other prognostic markers for these two different diseases are scarce. Our aim was to evaluate serum levels and tumor expression of matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and to assess their prognostic role in HPV-positive and HPV-negative OPSCC. Materials and methods: A total of 90 consecutive OPSCC patients diagnosed and treated with curative intent at the Helsinki University Hospital between 2012 and 2016 were included. Serum samples were prospectively collected. An immunofluorometric assay and an enzyme-linked immunosorbent assay were used to determine MMP-8 and TIMP-1 serum concentrations, respectively. HPV status of the tumors was determined using a combination of HPV-DNA genotyping and p16-INK4a immunohistochemistry. The endpoints were overall survival (OS) and disease-free survival (DFS). Results: High TIMP-1 serum levels were strongly and independently associated with poorer OS (adjusted HR 14.7, 95% CI 1.8–117.4, p = 0.011) and DFS (adjusted HR 8.7, 95% CI 1.3–57.1, p = 0.024) among HPV-negative patients; this association was not observed in HPV-positive OPSCC. Although TIMP-1 was immunoexpressed in the majority of the tumor tissue samples, the level of immunoexpression was not associated with prognosis, nor did MMP-8 serum levels. Conclusion: Our results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients. [ABSTRACT FROM AUTHOR]

Conclusion: Transforming growth factor β1 gene ( TGFβ1) genotype is a potential p16 independent prognostic factor predicting response to chemoradiotherapy in head and neck squamous cell carcinoma (HNSCC). Objectives: Expression of p16 and epidermal growth factor receptor (EGFR) has been reported to be associated with survival in HNSCC. We have previously reported that genetic polymorphism of TGFβ1 is linked with survival in HNSCC patients who have undergone chemoradiotherapy. We evaluate here whether TGFB1 genotype can serve as a prognostic factor independent of tumor p16 and EGFR expression. Methods: Expression of p16 and EGFR was studied by immunohistochemistry in tumors from 130 HNSCC patients. Peripheral blood DNA was used to genotype 95 patients for single nucleotide polymorphism rs1800470 within the TGFβ1 gene. The minimum follow-up time was 31 months. Results: p16 overexpression was associated with an improved disease-free survival (hazard ratio (HR) = 0.39, 95% CI 0.19-0.78), whereas no evident association was observed between EGFR expression and disease-free survival (HR = 0.90, 95% CI 0.68-1.19). Among the 37 patients who had received chemoradiotherapy, TGFβ1 genotype was associated with disease-free (HR = 0.44, 95% CI 0.19-1.02) and overall survival (HR = 0.31, 95% CI 0.12-0.80) independent of tumor p16 expression. [ABSTRACT FROM AUTHOR]

Summary: Cancer invasion induces extracellular matrix remodeling and collagen degradation. The aim of this study was to assess whether serum levels of type I and III collagen degradation products were associated with patient survival in head and neck squamous cell carcinoma (HNSCC). A novel enzyme immunoassay was developed for measuring type III collagen N-terminal telopeptide (IIINTP) in human serum samples. In addition, type I collagen C-terminal telopeptide (ICTP), matrix metalloprotease-8 (MMP-8) and tissue inhibitor of metalloproteases-1 (TIMP-1) were assessed in 205 blood samples from HNSCC patients. High levels of serum ICTP and IIINTP and plasma TIMP-1 were associated with poor survival. The concentration of ICTP was associated with levels of IIINTP and TIMP-1. The plasma concentration of MMP-8 was associated with tumor stage, but not with survival or levels of ICTP, IIINTP or TIMP-1 suggesting that other collagenases/proteases are responsible for the cleavage of type I and type III collagens. The rate of type I and type III collagen degradation is associated with patient survival and can be used as a prognostic marker in HNSCC. [ABSTRACT FROM AUTHOR]

Summary: Expression of matrix metalloproteinase-8 (MMP-8) in tongue cancer cells has been associated with an improved prognosis. MMP-8 is inhibited by tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and elevated levels of TIMP-1 in blood have been associated with poor prognosis in many cancers. We wished to evaluate the usefulness of peripheral blood MMP-8 and TIMP-1 levels as well as the genotypes of MMP8 and TIMP1 in predicting prognosis in head and neck squamous cell carcinoma (HNSCC). Plasma concentrations of MMP-8 and TIMP-1 were analyzed in 136 HNSCC patients. MMP8 and TIMP1 genotypes were determined by analysis of single nucleotide polymorphisms (SNP) in peripheral blood DNA. The mean follow-up time was 3.3years. We found that plasma MMP-8 level did not predict survival but that TIMP-1 level was associated with survival. The adjusted hazard ratio of death scored as a continuous variable on the log10 scale was 23.2 (95% CI 1.88–286, P =0.01) and that of MMP-8 1.24 (95% CI 0.54–2.84, P =0.61). Immunohistochemical staining showed that TIMP-1 was expressed in vascular endothelium of tumor. TIMP-1 levels were associated with TIMP1 genotype in women but not in men. MMP8 genotype did not correlate with survival or MMP-8 level. Plasma TIMP-1 levels predict survival in HNSCC. TIMP-1 expression is genetically controlled in women. As TIMP-1 inhibits the activity of MMP-8 and it also functions as a growth factor, it may directly influence HNSCC progression. [Copyright &y& Elsevier]

Summary: Chemoradiotherapy (CRT) of head and neck squamous cell carcinoma (HNSCC) is often accompanied by severe mucosal reactions. We have recently shown that the single nucleotide polymorphism (SNP) rs1982073 of the TGFβ1 gene (TGFB1) is associated with the survival of HNSCC patients who have undergone CRT. In order to evaluate possible mechanisms mediating this, we investigated if the TGFB1 polymorphism was associated with the severity of mucositis induced by CRT. Peripheral blood DNA of 34 HNSCC patients who had undergone CRT was genotyped for the SNP rs1982073 of the TGFB1. Mucositis was graded according to acute toxicity criteria of radiation therapy oncology group (RTOG). The mean follow-up time was 48months (range, 4–115months). We did not find a significant association between the TGFB1 polymorphism and the degree of acute mucositis (OD=2.65; 95% CI 0.50–13.89; p =0.25). The degree of acute mucositis was not connected to disease-free survival (p =0.35). However, the TGFB1 polymorphism was associated with survival irrespective of the degree of mucositis (HR=3.23; 95% CI 1.19–8.77; p =0.02). [Copyright &y& Elsevier]

In oropharyngeal squamous cell carcinoma (OPSCC), the expression pattern of toll-like receptors (TLRs), in comparison between human papillomavirus (HPV)-positive and -negative tumors differs. TLRs control innate immune responses by activating, among others, the nuclear factor-κΒ (NF-κΒ) signaling pathway. Elevated NF-κΒ activity is detectable in several cancers and regulates cancer development and progression. We studied TLR5 expression in 143 unselected consecutive OPSCC tumors, and its relation to HPV-DNA and p16 status, clinicopathological parameters, and patient outcome, and studied TLR5 stimulation and consecutive NF-κB cascade activation in vitro in two human OPSCC cell lines and immortalized human keratinocytes (HaCat). Clinicopathological data came from hospital registries, and TLR5 immunoexpression was evaluated by immunohistochemistry. Flagellin served to stimulate TLR5 in cultured cells, followed by analysis of the activity of the NF-κB signaling cascade with In-Cell Western for IκΒ and p-IκΒ. High TLR5 expression was associated with poor disease-specific survival in HPV-positive OPSCC, which typically shows low TLR5 immunoexpression. High TLR5 immunoexpression was more common in HPV-negative OPSCC, known for its less-favorable prognosis. In vitro , we detected NF-κΒ cascade activation in the HPV-positive OPSCC cell line and in HaCat cells, but not in the HPV-negative OPSCC cell line. Our results suggest that elevated TLR5 immunoexpression may be related to reduced NF-κΒ activity in HPV-negative OPSCC. The possible prognosis-worsening mechanisms among these high-risk OPSCC patients however, require further evaluation. • High TLR5 expression was associated with poor DSS in HPV-positive OPSCC, typically showing low TLR5 immunoexpression. • High TLR5 immunoexpression was more common in HPV-negative OPSCC, known for its less-favorable prognosis. • In vitro stimulation of TLR5 with flagellin activated the NF-kB cascade in HPV-positive OPSCC cells and in HaCat cells. • No activation of the NF-kB cascade by TLR5 stimulation in HPV-negative OPSCC cells occurred. • Elevated TLR5 immunoexpression may be related to reduced NF-kB activity in HPV-negative OPSCC. [ABSTRACT FROM AUTHOR]