Shinsuke Suzuki

Near-infrared photoimmunotherapy (NIR-PIT) has emerged as a promising treatment for unresectable locally advanced or recurrent head and neck cancer. This study aimed to identify potential predictors of NIR-PIT efficacy before treatment by focusing on blood biomarkers in addition to pathological findings, including epidermal growth factor receptor (EGFR) expression in tumors. A retrospective analysis of the medical records of 10 patients with head and neck cancer, who exhibited confirmed EGFR expression and underwent NIR-PIT treatment at Akita University Hospital from December 2021 to April 2024, was conducted (13 cycles of NIR-PIT). EGFR expression, cluster of differentiation (CD)4/CD8 ratio, regulatory T cell (Treg) frequency, serum albumin, neutrophil-to-lymphocyte ratio (NLR), and neutrophil-to-eosinophil ratio (NER) were calculated from the tumor tissue and blood collected immediately before treatment. Correlations of these factors with tumor response to NIR-PIT were determined. The objective response rate (ORR) was 61.5% and the disease control rate (DCR) was 100%. A statistically significant association was observed between the EGFR index and tumor response. No statistically significant correlation was found between other biomarkers (CD4/CD8 ratio, Treg frequency, serum albumin, NLR, NER) and tumor response. These findings underscore the important role of EGFR expression in predicting the efficacy of NIR-PIT in the management of head and neck cancer, and highlight the significance of incorporating EGFR assessment in patient selection and optimized treatment strategies. Further studies are needed to elucidate the role that these other potential predictors, including tumor immune response markers, play in NIR-PIT outcomes.

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.

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.

Background: Hypopharyngeal squamous cell carcinoma (HPSCC) has a high rate of distant metastasis, resulting in poor prognosis. The role of the maximum standardized uptake value (SUVmax), which was assessed via pretreatment 18-fluorodeoxyglucose positron emission tomography (FDG-PET), and computed tomography (CT) was examined, for predicting distant metastasis and survival. Methods: This study included 121 patients who underwent pretreatment FDG-PET/CT scanning and subsequent treatment for HPSCC. The SUVmax was measured via FDG-PET/CT. A receiver operating characteristic (ROC) curve analysis was used to determine whether the SUVmax was a predictor of distant metastasis and to select the best cutoff value. Univariate and multivariate Cox hazard regression analyses were used in identifying associations between the SUVmax and other clinicopathological factors with distant metastasis-free survival. Results: Distant metastases were identified in 33 patients during the median follow-up of 24 months after treatment. The ROC curve analysis determined that SUVmax was predictive of distant metastasis and identified a SUVmax of 13.9 as the best potential cutoff value. The univariate analysis showed that T and N classification, clinical stage, and SUVmax were significantly related to distant metastasis. However, in multivariate analysis, an SUVmax ≥ 13.9 was the only independent predictor of distant metastasis. Patients with high SUVmax values displayed significantly shorter distant metastasis-free survival and overall survival. Conclusions: SUVmax determined via pretreatment FDG-PET/CT is useful for predicting distant metastasis, distant metastasis-free survival, and overall survival in patients with HPSCC. Graphical

Background: Cytotoxic effects of radiation play an important role in the treatment of head and neck cancer. However, irradiation is known to lead to the migration of various cancer cells, including those of head and neck cancer. Recently, fibroblasts in the cancer microenvironment have been reported to be involved in this mechanism. Nevertheless, the mechanism underlying migration of head and neck cancer cells remains unclear. Herein, we aimed to elucidate this migration mechanism induced by irradiation in terms of the interaction of head and neck cancer cells with fibroblasts. Methods: We used the head and neck squamous cell carcinoma (HNSCC) cell lines SAS and FaDu as well as fibroblast cell lines. These cells were irradiated and their viability was compared. In fibroblasts, changes in interleukin-6 (IL-6) secretion caused by irradiation were measured by enzyme-linked immunosorbent assay (ELISA). The cell migration ability of cancer cells was evaluated via a migration assay using a semipermeable membrane. HNSCC cells were cocultured with irradiated and nonirradiated fibroblasts, and their migration ability under each condition was compared. We also examined the effect of IL-6 on the migration of HNSCC cells. Furthermore, to investigate the effect of fibroblast-derived IL-6 on the migration ability of HNSCC cells, we conducted a coculture study using IL-6 neutralizing antibody. Results: Irradiation reduced the survival of HNSCC cells, whereas fibroblasts were resistant to irradiation. Irradiation also increased IL-6 secretion by fibroblasts. Migration of HNSCC cells was enhanced by coculture with fibroblasts and further enhanced by coculture with irradiated fibroblasts. We also confirmed that the migration of HNSCC cells was induced by IL-6. The enhanced migration of cancer cells caused by coculturing with fibroblasts was canceled by the IL-6 neutralizing antibody. Conclusion: These results show that fibroblasts survive irradiation and induce the migration ability of HNSCC cells through increased secretion of IL-6.

Background and Objectives: In recent years, the effectiveness of chemotherapy after immune checkpoint inhibitor administration has attracted attention in various cancers, including head and neck cancers. However, individual assessments of the administered chemotherapy regimens are insufficient. This study aimed to evaluate the efficacy and safety of chemotherapy after immune checkpoint inhibitor administration in recurrent metastatic head and neck cancer by focusing on a single regimen. Materials and Methods: We retrospectively reviewed clinical and radiological data from the medical records of 18 patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who received systemic chemotherapy with weekly cetuximab and paclitaxel (Cmab + PTX) after progression following immune checkpoint inhibitor (ICI) therapy. The objective response rate (ORR) and disease control rate (DCR) were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Adverse events (AEs) were recorded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Results: In all patients, the ORR, DCR, median PFS, and median OS were 44.4%, 72.2%, 3.8 months, and 9.6 months, respectively. Regarding AEs, three patients developed grade 3 neutropenia. Grade 3 anemia, paronychia, asthenia, and peripheral neuropathy were observed in one patient each. There were no treatment-related deaths. Conclusions: Cmab + PTX was shown to maintain high efficacy and acceptable safety for R/M HNSCC that progressed after ICI therapy. Further research is needed to establish optimal treatment sequences and drug combinations for recurrent R/M HNSCC.

Background The cytotoxic effect of radiation plays an important role in the treatment of head and neck cancer. However, irradiation is known to lead to the migration of various cancer cells, including those of head and neck cancer. Recently, fibroblasts in the cancer microenvironment have been reported to be involved in this mechanism. Nevertheless, the mechanism underlying the migration of head and neck cancer cells remains unclear. The purpose of this study was to elucidate this migration mechanism induced by irradiation in terms of the interaction of head and neck cancer cells with fibroblasts. Methods We used the head and neck squamous cell carcinoma (HNSCC) cell lines SAS and FaDu as well as fibroblast cell lines. These cells were irradiated and their viability was compared. In fibroblasts, changes in interleukin-6 (IL-6) secretion caused by irradiation were measured by enzyme-linked immunosorbent assay (ELISA). The cell migration ability of cancer cells was evaluated via a migration assay using a semipermeable membrane. HNSCC cells were cocultured with irradiated and nonirradiated fibroblasts, and their migration ability under each condition was compared. We also examined the effect of IL-6 on the migration of HNSCC cells. Furthermore, to investigate the effect of fibroblast-derived IL-6 on the migration ability of HNSCC cells, we conducted a coculture study using IL-6 neutralizing antibody. Results Irradiation reduced the survival of HNSCC cells, whereas fibroblasts were resistant to irradiation. Irradiation also increased IL-6 secretion by fibroblasts. Migration of HNSCC cells was enhanced by coculture with fibroblasts and further enhanced by coculture with irradiated fibroblasts. We also confirmed that the migration of HNSCC cells was induced by IL-6. The enhanced migration of cancer cells caused by coculturing with fibroblasts was canceled by the IL-6 neutralizing antibody. Conclusion These results show that fibroblasts survive irradiation and induce the migration ability of HNSCC cells through increased secretion of IL-6.

Background. Hypopharyngeal cancer is one of the most frequent head and neck cancers and is associated with a poor prognosis because of recurrence and metastases. Therefore, there is a need to improve the prognosis, which requires the identification of prognostic factors and elucidation of the mechanisms involved in tumor progression. Accumulated evidence has demonstrated that cluster of differentiation 147 (CD147) is strongly expressed in malignant tumors, including head and neck squamous cell carcinoma (HNSCC), and contributes to tumor progression. Objectives. To investigate CD147-induced signaling pathways in HNSCC cells to evaluate the mechanisms of tumor progression mediated by CD147, and the association between CD147 expression in tumors and the survival rate of hypopharyngeal cancer patients. Material and methods. To determine the downstream signaling of CD147 in HNSCC, expression levels of phosphorylated AKT1, MEK1, p38 MAPK, STAT3, and NF-kappa B were evaluated using enzyme-linked immunosorbent assay (LISA) in FaDu, a hypopharyngeal cell line, exposed to cyclophilin A, a CD147 ligand. Results. We found that hypopharyngeal cancer patients expressing CD147 showed a poor five-yea r overall survival (OS) of 11.1% compared with those without CD147 expression (43.0%) (p = 0.02). We confirmed that the expression of phosphorylated MEK and matrix metalloproteinase-9 (MMP-9), as well as cell invasion ability, were enhanced in hypopharyngeal cancer cells. In addition, this increased cell infiltration and enhancement of MMP-9 expression induced by CD147 were abolished by a MEK inhibitor. Conclusions. These results suggest that CD147 can be a predictor of a poor prognosis, and that a CD147-induced MEK-mediated intracellular signaling pathway plays a crucial role in tumor progression in hypopharyngeal carcinoma.