廣末 晃之

BACKGROUND: Squamous cell carcinoma of the buccal mucosa (SCCBM) is a prevalent malignancy of the oral cavity with high morbidity and mortality rates. The pterygomandibular raphe (PMR) connects the oral cavity, pharynx, and masticator space, serving as a key anatomical landmark during surgical resection. However, PMR invasion into SCCBM remains poorly understood. This study assessed the prognostic significance of PMR invasion in patients with resectable SCCBM. METHODS: The study included 82 patients with SCCBM, excluding those with T4b, who underwent radical resection at Kumamoto University Hospital between 2000 and 2017. Patients were categorized into three groups based on PMR invasion patterns: non-contact, contact, and invasion. The relationship between PMR invasion and clinicopathological characteristics was analyzed using the Fisher's exact test. The Kaplan-Meier method, log-rank test, and propensity score-matched analyses were used for survival analysis. RESULTS: Contact or invasion into the PMR was significantly associated with advanced clinical T and N stages, clinical stage, endophytic growth pattern, high-grade invasion pattern, and poor tumor differentiation. Patients with PMR invasion had a higher proportion of recurrences in the buccal subcutaneous, mandibular, and masticator spaces. Univariate analysis indicated that contact- or invasion-type PMR invasion predicted worse overall survival (OS). The impact of PMR invasion on OS was confirmed using a propensity score-matched analysis. CONCLUSION: This study revealed that PMR invasion is a potential novel grading and prognostic factor for resectable SCCBM, with significance in planning the extent of SCCBM resection.

BACKGROUND/AIM: Plasmacytomas are neoplastic proliferations of plasma cells, usually presenting as solitary lesions distinct from multiple myeloma (MM). Solitary plasmacytomas in the oral cavity and head and neck are very rare, with limited data on clinical course and treatment response. CASE REPORT: A 78-year-old woman presented with a solitary plasmacytoma on the palate. Imaging ruled out bone or systemic involvement. Pathology showed positivity for CD138, lambda light chain, CD79a, MUM1, Ki-67 (10-15%), and amyloid deposits. Although the patient received definitive radiation therapy (50 Gy/25 fractions), residual disease remained. At the patient's request, six cycles of systemic chemotherapy with daratumumab, lenalidomide, and dexamethasone (DRd) were administered, leading to further shrinkage without complete response. CONCLUSION: This rare case of solitary plasmacytoma showed residual disease post definitive radiotherapy. In those residual tumors, close long-term monitoring is crucial.

We evaluated the usefulness of an oncolytic virus (Suratadenoturev; OBP-301) against radioresistant oral squamous cell carcinoma. We confirmed the expression of human telomerase reverse transcriptase and the coxsackievirus and adenovirus receptor in cell lines. Also, we examined the potential presence in a patient who has received existing therapy that is amenable to treatment with OBP-301. We evaluated: (1) the antitumor effects of OBP-301 alone and in combination with radiotherapy on radioresistant cell lines, (2) the molecular mechanism underlying the radiosensitizing effect and cell death increased by the combination therapy, and (3) the antitumor effect of the combination therapy in vivo using xenograft models (a radioresistant cell line-derived xenograft in mouse and a patient-derived xenograft). Human telomerase reverse transcriptase and the coxsackievirus and adenovirus receptor were expressed in all cell lines. OBP-301 decreased the proliferative activity of these cell lines in a concentration-dependent manner, and significantly enhanced the antitumor effect of irradiation. Phosphorylated STAT3 and its downstream molecules, which correlated with apoptosis and autophagy, showed significant changes in expression after treatment with OBP-301. The combination therapy exerted a significant antitumor effect versus radiotherapy alone in both xenograft models. Combination of OBP-301 with radiotherapy exerts a synergistic effect and may represent a promising treatment for radioresistant oral squamous cell carcinoma.

Abstract Nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of critical antioxidant proteins, was recently demonstrated to play a key role in cancer progression. Resistance to radiotherapy is a major obstacle in treating oral squamous cell carcinoma (OSCC). However, little is known about the association between Nrf2 and radioresistance in OSCC. Two OSCC cell lines (SAS and HSC-2) and their clinically relevant radioresistant (CRR) clones (SAS-R, HSC-2-R) were used. The effects of Nrf2 downregulation on radiosensitivity and the involvement of glycolysis in Nrf2-mediated radioresistance were evaluated. Immunohistochemistry of phosphorylated Nrf2 (p-Nrf2) was performed in 110 patients with OSCC who underwent preoperative chemoradiotherapy and surgery. Nrf2 was stably upregulated in CRR cells in vitro and in a mouse xenograft model. Moreover, elevated Nrf2 expression was associated with radioresistance. The enhancement of Nrf2-dependent glycolysis and glutathione synthesis was involved in the development of radioresistance. Additionally, p-Nrf2 expression was closely related to the pathological response to chemoradiotherapy, and its expression was predictive of prognosis in patients with advanced OSCC. Our results suggest that Nrf2 plays an important role in the radioresistance of OSCC accompanied by metabolic reprogramming. Targeting Nrf2 antioxidant pathway may represent a promising treatment strategy for highly malignant OSCC.

This study aimed to assess the role of preoperative 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) for predicting late neck metastasis in clinically node-negative (cN0) early-stage oral squamous cell carcinoma (OSCC). We retrospectively investigated the standardized uptake value (SUV) parameters in patients with late neck metastasis based on the neck node level. The study population consisted of 16 patients with cT1N0 or cT2N0 oral SCC who were evaluated with dual-phase FDG-PET/CT and were treated with local resection of the primary tumor and watchful waiting for neck management. The SUV at each level was measured on the early and delayed images, and the laterality of the SUV was calculated. The laterality on the delayed images significantly differed between positive and negative pairs at the levels Ib (p = 0.002) and IIb (p = 0.013); a cut-off value of 1.4 yielded a true-positive rate of 50% and a false-positive rate of 6%. The laterality of FDG-uptake should be used to stratify the risk for nodal-level metastasis.

The CD169+ macrophages in lymph nodes are implicated in cytotoxic T lymphocyte (CTL) activation and are associated with improved prognosis in several malignancies. Here, we investigated the significance of CD169+ macrophages in oral squamous cell carcinoma (OSCC). Further, we tested the anti-tumor effects of naringenin, which has been previously shown to activate CD169+ macrophages, in a murine OSCC model. Immunohistochemical analysis for CD169 and CD8 was performed on lymph node and primary tumor specimens from 89 patients with OSCC. We also evaluated the effects of naringenin on two murine OSCC models. Increased CD169+ macrophage counts in the regional lymph nodes correlated with favorable prognosis and CD8+ cell counts within tumor sites. Additionally, naringenin suppressed tumor growth in two murine OSCC models. The mRNA levels of CD169, interleukin (IL)-12, and C-X-C motif chemokine ligand 10 (CXCL10) in lymph nodes and CTL infiltration in tumors significantly increased following naringenin administration in tumor-bearing mice. These results suggest that CD169+ macrophages in lymph nodes are involved in T cell-mediated anti-tumor immunity and could be a prognostic marker for patients with OSCC. Moreover, naringenin is a new potential agent for CD169+ macrophage activation in OSCC treatment.