Differential Impact of IL-10 Expression on Survival and Relapse between HPV16-Positive and -Negative Oral Squamous Cell Carcinomas

<div><p>Human papillomavirus (HPV) is a risk factor in a subset of oropharyngeal cancer; however, the contribution of HPV in the malignancy of oral squamous cell carcinomas (OSCC) is not fully understood in Taiwanese. Herein, 61 patients with no risk factors and 117 patients with one or more risk factors were enrolled in this study. HPV16/18 infection rate in non-smokers, non-drinkers and non-betel quid chewers was higher than their counterparts. The development of HPV-infected cancer has been shown to be associated with interleukin-10 (IL-10) expression. To this end, IL-10 mRNA expression in OSCC tumors was evaluated by real-time RT-PCR. Data showed that HPV-positive patients had higher IL-10 mRNA levels than in HPV-negative patients. Kaplan-Meier and Cox-regression analysis indicated that the prognostic significance of IL-10 mRNA on overall survival and relapse free survival was only observed in HPV-positive OSCC, but not in HPV-negative OSCC. Mechanistically, the elevation of IL-10 by E6 was responsible for increased colony formation and migration capability in OSCC cells. Therefore, we suggest that IL-10 induced by E6 promotes cell growth and migration capability and consequent poor survival and relapse in HPV-positive OSCC.</p> </div

Relationships between HPV16, HPV18 and HPV16/18 infection and clinical parameters in OSCC patients.

1<p>Other tumor sites includes plate (n = 1), gingival (n = 8), and lip (n = 9).</p>*<p>p<0.05;</p>#<p>p = 0.05.</p

Multivariate analysis of the influence of various parameters on overall survival (OS) and relapse free survival (RFS) in oral cancer patients according to gender.

<p>Multivariate analysis of the influence of various parameters on overall survival (OS) and relapse free survival (RFS) in oral cancer patients according to gender.</p

Kaplan-Meier analysis was used to assess the influence of IL-10 on OS and RFS.

<p>(A) in all study population, (B) in patients with HPV 16/18 infection compared to those without HPV 16/18 infection, (C) in patients with HPV 16/18 non-infection, and (D) in patients with HPV16/18 infection.</p

Comparison of IL-10 mRNA expression levels between HPV-positive and HPV–negative OSCC patients.

<p>Fourteen of 178 patients had both HPV16 and 18 infections.</p><p>IL-10 low: 0.6±0.8 (0.0–2.38); IL-10 high: 237.0±413.5 (2.39–1402.2).</p

IL-10 expression increases associated with HPV16/18 E6 is responsible for the migration capability of OSCC cell lines.

<p>(A) IL-10 expression in a panel of OSCC cell lines was evaluated by Western blotting; (B) GNM cells were knocked down by transfection of shHPV18 E6 and Tw2.6 cells were transiently transfected with HPV16 E6 cDNA plasmid for 48 hrs. β-actin was used as a protein loading control; (C) GNM cells were knocked down by transfection of shIL-10. Tw2.6 and SCC25 cells were co-transfected with HPV16 E6 cDNA plasmid, and then E6 and IL-10 expression were determined by Western blotting. β-actin was used as a protein loading control; (D) The migration and colony formation capability of GNM cells with or without transfection of shIL-10 was evaluated by transwell migration assay; and (E) E6 transfected-Tw2.6 and -SCC25 cells were co-transfected with two doses of shIL-10, and then the migration and colony formation capability of both cells was evaluated by transwell migration assay.</p

Baseline and Trend of Lymphocyte-to-Monocyte Ratio as Prognostic Factors in Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer Patients Treated with First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

<div><p>Background</p><p>Patients with early-stage lung cancer who have a high baseline lymphocyte-to-monocyte ratio (LMR) have a favorable prognosis. However, the prognostic significance of LMR in patients with advanced-stage <i>EGFR</i>-mutant non-small cell lung cancer (NSCLC) receiving first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has not been established. We conducted a retrospective analysis to investigate the influence of LMR on clinical outcomes including progression-free survival (PFS) and overall survival (OS) in <i>EGFR</i>-mutant patients with NSCLC.</p><p>Materials and Methods</p><p>Of 1310 lung cancer patients diagnosed between January 2011 and October 2013, 253 patients receiving first-line EGFR-TKIs for <i>EGFR</i>-mutant NSCLC were included. The cut-off values for baseline and the 1-month-to-baseline ratio of LMR (MBR), determined by using receiver operating characteristic curves, were 3.29 and 0.63, respectively. Patients were divided into 3 prognostic groups: high LMR and MBR, high LMR or MBR, and low LMR and MBR.</p><p>Results</p><p>The mean patient age was 65.2 years, and 41% were men. The median PFS and OS were 10.3 and 22.0 months, respectively. The PFS in patients with high LMR and MBR, high LMR or MBR, and low LMR and MBR were 15.4, 7.1, and 2.0 months, respectively (p < 0.001), whereas the OS were 32.6, 13.7, and 5.1 months, respectively (p < 0.001).</p><p>Conclusion</p><p>A combination of baseline and trend of LMR can be used to identify patients with a high mortality risk in <i>EGFR</i>-mutant NSCLC patients receiving first-line EGFR-TKIs.</p></div

Overall survival (OS) of epidermal growth factor receptor mutant non-small-cell lung cancer patients treated with first-line tyrosine kinase inhibitors therapy.

<p>(A): OS between high and low baseline LMR patients; (B): OS between high and low 1-month-to-baseline ratio of LMR (MBR) patients; (C) OS between “high LMR and MBR”, “high LMR or MBR”, “low LMR and MBR” patients.</p

Inclusion, screening, and group assignment of patients.

<p>Among 1310 non-small-cell lung cancer patients diagnosed between January 2011 and October 2013, 253 patients were included into final analysis.</p

Clinical characteristics and therapy responses of all 253 patients.

<p>^a Exon 19 deletion and L858R mutations were defined as common mutations. Other mutations or compound mutations were defined as uncommon mutations.</p><p>DM, diabetes mellitus; EGFR, epidermal growth factor receptor; ECOG, Eastern Cooperative Oncology Group; PS, performance status; LMR, lymphocyte-to-monocyte ratio; PFS, progression-free survival; OS, overall survival</p><p>Clinical characteristics and therapy responses of all 253 patients.</p