The optimal treatment strategy for N0 tongue cancer, whether to use simultaneous elective neck dissection or careful observation, remains controversial.^1-5 The rate of occult nodal metastasis in N0 tongue cancer has been estimated as 25% to 40%.^6,7 Elective neck dissection for N0 tongue cancer might thus result in unnecessarily invasive procedures in at least 60% of patients. Recently, the sentinel lymph node (SLN) concept has been accepted in local-stage oral cancer treatment.^8-10 Although preoperative lymphoscintigraphy using radioisotopes (RI) and intraoperative γ-probe detection with or without blue dye mapping are generally used to detect SLNs, the RI method has disadvantages such as exposure to radiation, masking of the SLN owing to shine-through radioactivity when the SLN is close to the RI injection site, and high cost.¹¹ Recently, to increase the detection rate of SLNs through better visualization, indocyanine green (ICG) fluorescence imaging-guided SLN biopsy has been developed as a new non-RI technique for breast cancer and gastrointestinal cancer.^12-14 Although this new method has shown clinical potential for axillary and abdominal lymph nodes, the ICG method alone is unsuitable for cervical SLN biopsy because of poor transcutaneous identification of the fluorescent signal. We recently reported a new method of preoperative SLN mapping using computed tomographic (CT) lymphography in cases with localized tongue cancer.¹⁵ The CT lymphographic method of SLN mapping is simple and quite useful for accurately localizing SLNs, lymph vessels, and the tumor before SLN biopsy without using RI. We hypothesized that combining preoperative CT lymphography mapping and intraoperative ICG fluorescence-guided SLN biopsy would provide a good method without using RI and may have clinical potential for SLN biopsy of cN0 tongue cancer. This study evaluated the identification rate of SLNs using the new technique of combined preoperative CT lymphography and intraoperative ICG fluorescence for cN0 localized tongue cancer.

Epithelial‑mesenchymal transition (EMT) is a physiological process in which epithelial cells attain the motile and invasive characteristics of mesenchymal cells, which results in the development of increased migratory and invasive cell behavior, serving as a vital mechanism of cancer progression. Hence, controlling the EMT for cancer treatment, including head and neck squamous cell carcinoma (HNSCC), is imperative. Among EMT‑associated factors, transforming growth factor‑β (TGF‑β) is a well‑established potent inducer. Recent research has revealed that CD147, a member of the immunoglobulin superfamily, promotes the EMT. However, the role of CD147 in the EMT and the following tumorigenicity in HNSCC has not been completely elucidated. This study aims to investigate the role of CD147 in the EMT and related tumorigenicity in HNSCC. The present study used two HNSCC cell lines, SAS and FaDu, for in vitro studies. In HNSCC cells, TGF‑β1 induced spindle‑shaped morphological changes, and western blot analysis revealed that TGF‑β1 induced changes in EMT markers, downregulation of vimentin, and upregulation of E‑cadherin, yet increased CD147. In addition, TGF‑β1 increased cell migration in HNSCC cells. However, a TGF‑β1‑induced alteration in EMT makers was attenuated with CD147 silencing by small interfering RNA (siRNA) in SAS cells. In addition, the TGF‑β1‑induced cell invasion of SAS was attenuated with CD147 silencing. In conclusion, the present study suggests that CD147 mediates TGF‑β1‑induced EMT and tumorigenicity in HNSCC. Hence, CD147 may serve as a vital therapeutic target in HNSCC.

Background: Nivolumab has been shown to improve the overall survival (OS) of patients with recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, there is a need to identify factors associated with long-term survival (beyond 2 years) in these patients. This study investigated the relationship between pretreatment factors and long-term survival in patients with R/M HNSCC treated with nivolumab. Methods: Forty-nine patients with R/M HNSCC who were treated with nivolumab were retrospectively reviewed. Baseline characteristics, clinical data, and survival outcomes were evaluated. Univariate and multivariate analyses were performed to identify factors associated with long-term survival (OS ≥ 2 years). Results: The median OS in the overall cohort was 11.0 months, and the 2-year survival rate was 34.7%. Long-term survivors (OS ≥ 2 years) had significantly higher proportions of patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of 0 or 1, serum albumin levels ≥ 3.5 g/dL, and neutrophil-to-eosinophil ratio (NER) < 32.0 compared to non-long-term survivors. On multivariate analysis, serum albumin levels ≥ 3.5 g/dL, in addition to ECOG-PS score of 0 or 1, were independent predictors of long-term survival. Conclusions: Pretreatment serum albumin levels may be useful for predicting long-term survival in R/M HNSCC patients treated with nivolumab.

Extracellular matrix remodeling crucial to tumorigenesis involves proteolytic enzymes, primarily matrix metalloproteinases (MMPs). MMP production is stimulated by multiple factors, including the extracellular matrix metallo-proteinase inducer EMMPRIN/CD147. Overexpression of EMMPRIN, a member of the immunoglobulin superfamily, promotes invasion, metastasis, growth and survival of malignant cells. Cyclophilin A (CypA) is a multifunctional protein that promotes cancer progression in various cancer types. CypA can interact with and activate EMMPRIN; however, the role of CypA-EMMPRIN interaction in oncogenicity is not completely understood. To investigate tumorigenicity induced by the CypA-EMMPRIN interaction, we stimulated EMMPRIN-expressing head and neck squamous cell carcinoma (HNSCC) cells with CypA. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye assay revealed that HNSCC cell proliferation increased upon stimulation of the cells with CypA, whereas cisplatin-induced cell death decreased after stimulation. Gelatin zymography showed that CypA also induced MMP-9 up-regulation. Moreover, HNSCC cell invasion through Matrigel™-coated membranes was increased upon stimulation of cells with CypA. This elevated invasive potential was abrogated by an EMMPRIN function-blocking antibody. These findings suggest that CypA, through its interaction with EMMPRIN, contributes to HNSCC tumorigenesis.

It has been reported that the epidermal growth factor receptor (EGFR) expression is associated with the extracellular matrix metalloproteinase inducer (EMMPRIN) in some solid tumors; however, the relationship of EMMPRIN with EGFR in head and neck cancers is not fully understood. To determine the relationship between EMMPRIN and EGFR in head and neck squamous cell carcinoma (HNSCC), HNSCC cells were stimulated with epidermal growth factor (EGF), a ligand of EGFR. EMMPRIN expression in HNSCC cells was upregulated by EGF. In addition, EGF stimulation induced HNSCC cell invasion and MMP-9 expression. This increase in invasion and MMP-9 expression was abrogated by downmodulation of EMMPRIN. Furthermore, to determine the effects of combined EMMPRIN and EGFR targeting in HNSCC, HNSCC cells were treated with an EMMPRIN function-blocking antibody and the EGFR inhibitor AG1478. This combined treatment resulted in greater inhibition of HNSCC cell proliferation and migration compared with the individual agents alone. These results suggest that EMMPRIN mediates EGFR-induced tumorigenicity and that combined targeting of EMMPRIN and EGFR may be an efficacious treatment approach.

Background: There is a need to develop biomarkers for a more efficient use of immune checkpoint inhibitors (ICIs). Recently, it has been reported that peripheral blood components, including eosinophils, may be effective ICI biomarkers. This study was designed to evaluate the prognostic value of eosinophils for measuring the effects of nivolumab on recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Materials and Methods: The study included 47 patients with R/M HNSCC treated with nivolumab. Eosinophil-related biomarkers, such as absolute eosinophil count (AEC), relative eosinophil count (REC), and neutrophil-to-eosinophil ratio (NER), were measured from the peripheral blood of the patients before nivolumab treatment. For each biomarker, the patients were divided into a high- and a low-value group according to their cutoff values, and these groups were compared. Results: Regarding AEC and REC, no significant improvement in the objective response rate (ORR) was observed between patients with AEC > 0.9 × 10³/μL and those with AEC < 0.9 × 10³/μL (p = 0.147) and between patients with REC > 2.2% and those with REC < 2.2% (p = 0.110). However, patients with NER < 32 had improved ORR compared with those with NER > 32 (P = 0.0361). Additionally, although patients with AEC > 0.9 × 10³/μL, REC > 2.2%, and NER < 32 had longer overall survival (OS) than those with AEC < 0.9 × 10³/μL, REC < 2.2%, and NER > 32, only patients with NER < 32 showed prolonged progression-free survival (PFS) compared with those with NER > 32 according to the Log rank test (p = 0.046, 0.027, and 0.035, respectively). Furthermore, the multivariate analysis revealed that baseline NER > 32 (p = 0.027) was an independent prognostic factor for worse OS. Conclusion: A pretreatment feature of low NER (NER < 32) may predict better clinical outcomes in patients with R/M HNSCC treated with nivolumab.