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The purpose of this study was to evaluate the clinical outcomes of patients with stage 3 mandibular medication-related osteonecrosis of the jaw (MRONJ) treated using a submental island flap in combination with mylohyoid muscle reconstruction after rim mandibulectomy. The medical records of 12 patients treated between January 2019 and April 2022 were analysed retrospectively. Primary wound healing was assessed as the maintenance of full mucosal coverage without signs of infection at 6 months postoperatively. The follow-up period ranged from 7 to 38 months, with an average of 21.8 months. All 12 patients (100%) experienced primary wound healing, with normal mouth opening and occlusion, and without pathological mandibular fracture or facial aesthetic problems during the follow-up period. Postoperative panoramic images revealed new bone formation in the treated areas of the mandible in four patients. During the follow-up period, one patient continuing bevacizumab and zoledronate administration for the primary cancer developed MRONJ in the same area at 13 months postoperatively and finally died. Hence the total success rate was 91.7%. In summary, for patients with stage 3 mandibular MRONJ treated with rim mandibulectomy, the submental island flap combined with mylohyoid muscle is an effective reconstructive option for wound-healing and possible bone regeneration of denuded bone. [ABSTRACT FROM AUTHOR]

Abstract The sagittal split ramus osteotomy (SSRO) is generally associated with greater postoperative stability than the intraoral vertical ramus osteotomy (IVRO); however, it entails a risk of inferior alveolar nerve damage. In contrast, IVRO has the disadvantages of slow postoperative osseous healing and projection of the antegonial notch, but inferior alveolar nerve damage is believed to be less likely. The purposes of this study were to compare the osseous healing processes associated with SSRO and IVRO and to investigate changes in mandibular width after IVRO in 29 patients undergoing mandibular setback. On computed tomography images, osseous healing was similar in patients undergoing SSRO and IVRO at 1 year after surgery. Projection of the antegonial notch occurred after IVRO, but returned to the preoperative state within 1 year. The results of the study indicate that IVRO is equivalent to SSRO with regard to both bone healing and morphological recovery of the mandible. [ABSTRACT FROM AUTHOR]

Objectives: Claudin (CLD), a major component of tight junctions, is a four-transmembrane protein, and 24 subtypes have been reported in humans. CLD expression is highly tissue-specific; CLD1 has been reported to be expressed in the skin and mucosa. There have been few reports on CLD1 expression and its function in oral cancer., Materials and Methods: This retrospective study immunohistochemically evaluated CLD1 expression as prognostic predictors in 84 participants with oral squamous cell carcinoma (OSCC). Participants were classified as positive or negative based on staining intensity; the clinicopathologic characteristics and survival rates of the two groups were compared. To clarify the biological role of CLD1 in OSCC cells, we examined the effects of CLD1 overexpression on the invasion and proliferation of the OSCC cell line, SCCKN., Results: We observed the immunohistochemical CLD1 expression in the cell membranes of OSCC cells. The disease-free survival rate was significantly lower in patients with CLD1-positive OSCC than in patients with CLD1-negative OSCC (P < .05). In vitro studies showed that cell proliferative capacity, motility, proteolytic activity, and invasive growth were promoted in CLD1-overexpressing SCCKN cells compared to those in control SCCKN cells., Conclusion: CLD1 may be a useful and potential prognostic factor for OSCC treatment., Competing Interests: DECLARATIONS OF INTEREST The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The Union for International Cancer Control and American Joint Committee on Cancer tumor staging system is used globally for treatment planning. As it may be insufficient for tumor staging of lower gingival carcinomas, we proposed the mandibular canal tumor staging system. In this study, we aimed to compare the two systems for such tumor staging and to identify prognostic markers., Methods: This multicenter, retrospective study included patients with lower gingival squamous cell carcinoma who underwent radical surgery during 2001-2018. We compared survival rates (Kaplan-Meier estimator) and patient stratification according to the two systems., Results: The proposed system yielded more balanced patient stratification than the existing system. Progression in the tumor grade according to the proposed system was associated with a poorer prognosis. The 5-year overall and disease-specific survival rates for the entire cohort were 74.9% and 81.8%, respectively. Independent factors affecting overall survival were tumor stage according to the proposed system, excision margins, and number of positive nodes, whereas those affecting disease-specific survival were excision margins and number of positive nodes., Conclusions: Subsite-specific tumor classification should be used for patients with oral cancer, and our results suggest that mandibular canal tumor classification may be effective for patients with lower gingival carcinoma., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

The Hippo pathway and its downstream effectors, Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), are essential for cell growth and organ development. Emerging evidence revealed that the Hippo pathway and YAP/TAZ are frequently dysregulated by multiple genetic alterations in solid cancers including head and neck squamous cell carcinoma (HNSCC); however, the YAP/TAZ-nuclear interactome remains unclear. RNA-binding motif protein 39 (RBM39) enhances transcriptional activity of several transcription factors and also regulates mRNA splicing. Indisulam degrading RBM39 induces alternative splicing, leading to cell death. However, clinical trials of indisulam have failed to show effectiveness. Therefore, clarifying the resistance mechanism against splicing inhibitors is urgently required. In this study, we identified RBM39 as a novel YAP/TAZ-interacting molecule by proteome analysis. RBM39 promoted YAP/TAZ transcriptional activity. We further elucidated that indisulam reduces RBM39/YAP/TAZ-mediated integrin or collagen expression, thereby inactivating focal adhesion kinase (FAK) important for cell survival. Moreover, indisulam also induced alternative splicing of cell cycle- or DNA metabolism-related genes. YAP/TAZ hyperactivation delayed indisulam-induced RBM39 degradation, which restored the integrin/collagen expression to activate FAK, and alternative splicing, thereby conferring resistance against indisulam in vitro and in vivo. Our findings may aid to develop a novel cancer therapy focusing on YAP/TAZ/RBM39 interaction., (© 2024. The Author(s).)

Background/purpose: For unresectable recurrent/metastatic head and neck cancer, pembrolizumab alone or pembrolizumab combined with cisplatin and 5-fluorouracil is the first-line therapy, depending on the PD-L1 combined positive score (CPS). However, this is based on clinical studies of head and neck cancer, and few similar studies have been conducted on oral cancer alone. This study aimed to investigate the current status of pharmacotherapy for unresectable, recurrent, or metastatic oral cancer., Materials and Methods: Patients with unresectable or recurrent/metastatic oral cancer who received cetuximab, nivolumab, or pembrolizumab as first-line treatment were reviewed. Overall survival (OS), progression-free survival (PFS), PFS 2 (PFS2), overall response rate (ORR), disease control rate (DCR), and immune-related adverse events were obtained from medical records., Results: A total of 155 patients were enrolled from six hospitals. The ORR in the nivolumab, pembrolizumab, and cetuximab groups was 17.2 %, 4.2 %, and 21.6 %, respectively, and the DCR was 37.9 %, 41.7 %, and 58.8 %, respectively. Median OS in nivolumab, pembrolizumab, and cetuximab groups was 10.3, 9.5, and 11.1 months, respectively. No significant differences were observed in survival among the three groups. The small number of cases and the retrospective nature of the study precluded the determination of the more effective first-line treatment among the three drugs., Conclusion: The current statuses of nivolumab, pembrolizumab, and cetuximab in unresectable recurrent metastatic oral cancer was reported., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2024 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Objective: Extranodal extension (ENE) is an important prognostic factor in oral squamous cell carcinoma (OSCC). This study aimed to evaluate the clinical significance of stratifying minor or major ENE in OSCC., Study Design: This retrospective cohort study included 75 patients who had undergone neck dissection for OSCC and were classified as pN+. ENE was measured using hematoxylin-eosin-stained specimens and stratified into major (ENEma, >2 mm) and minor (ENEmi, ≤2 mm) by distance. Their association with survival, locoregional relapse, and distant metastases were assessed., Results: Of 49 patients with pathological ENE, 23 had ENEmi, and 26 had ENEma. The 5-year overall survival (OS) was 38%, 66%, and 76% in the ENEma, ENEmi, and no ENE groups, respectively. Compared with no ENE, ENEma was associated with significantly decreased 5-year cumulative OS and disease-specific survival. ENEma was a risk factor for decreased OS (HR: 2.54, 95% CI: 1.04-6.18, P = .040) in the multivariable Cox regression analysis, and was associated with distant metastasis., Conclusion: In patients with OSCC, ENEma is associated with a significantly poorer prognosis; therefore stratifying ENE is clinically relevant. ENEma may increase the risk of distant metastasis; therefore, new treatment modalities that contribute to distant metastasis control are required., Competing Interests: Declaration of interest All authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The impact of gut and oral microbiota on the clinical outcomes of patients with oral squamous cell carcinoma (OSCC) is unknown. We compared the bacterial composition of dental plaque and feces between patients with OSCC and healthy controls (HCs). Fecal and dental plaque samples were collected from 7 HCs and 18 patients with OSCC before treatment initiation. Terminal restriction fragment-length polymorphism analysis of 16S rRNA genes was performed. Differences in bacterial diversity between the HC and OSCC groups were examined. We compared the occupancy of each bacterial species in samples taken from patients with OSCC and HCs and analyzed the correlation between PD-L1 expression in the tumor specimens and the occupancy of each bacterial species. The gut and oral microbiota of patients with OSCC were more varied than those of HCs. Porphyromonas and Prevotella were significantly more abundant in patients with OSCC than in HCs. The abundance of Clostridium subcluster XIVa in the gut microbiota of the PD-L1-positive group was significantly greater than that in the PD-L1-negative group. The oral and gut microbiomes of patients with OSCC were in a state of dysbiosis. Our results suggest the possibility of new cancer therapies targeting these disease-specific microbiomes using probiotics and synbiotics.

Osteomyelitis of the jaw is a severe inflammatory disorder that affects bones, and it is categorized into two main types: chronic bacterial and nonbacterial osteomyelitis. Although previous studies have investigated the association between these diseases and the oral microbiome, the specific taxa associated with each disease remain unknown. In this study, we conducted shotgun metagenome sequencing (≥10 Gb from ≥66,395,670 reads per sample) of bulk DNA extracted from saliva obtained from patients with chronic bacterial osteomyelitis (N = 5) and chronic nonbacterial osteomyelitis (N = 10). We then compared the taxonomic composition of the metagenome in terms of both taxonomic and sequence abundances with that of healthy controls (N = 5). Taxonomic profiling revealed a statistically significant increase in both the taxonomic and sequence abundance of Mogibacterium in cases of chronic bacterial osteomyelitis; however, such enrichment was not observed in chronic nonbacterial osteomyelitis. We also compared a previously reported core saliva microbiome (59 genera) with our data and found that out of the 74 genera detected in this study, 47 (including Mogibacterium) were not included in the previous meta-analysis. Additionally, we analyzed a core-genome tree of Mogibacterium from chronic bacterial osteomyelitis and healthy control samples along with a reference complete genome and found that Mogibacterium from both groups was indistinguishable at the core-genome and pan-genome levels. Although limited by the small sample size, our study provides novel evidence of a significant increase in Mogibacterium abundance in the chronic bacterial osteomyelitis group. Moreover, our study presents a comparative analysis of the taxonomic and sequence abundances of all genera detected using deep salivary shotgun metagenome data. The distinct enrichment of Mogibacterium suggests its potential as a marker to distinguish between patients with chronic nonbacterial osteomyelitis and chronic bacterial osteomyelitis, particularly at the early stages when differences are unclear., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Yahara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Episil® is a nonabsorbable liquid medical material used to coat and protect the mucosa in patients with oral mucositis. A few studies have reported its efficacy in patients with head and neck cancer. However, reports on its use in patients with hematologic malignancies are scarce. Thus, we aimed to evaluate the efficacy of Episil for the treatment of oral mucositis in patients with acute myelogenous leukemia, malignant lymphoma, acute lymphocytic leukemia, multiple myeloma, and myelodysplastic syndrome., Methods: Between May 2018 and March 2019, a total of thirty-seven patients with acute myelogenous leukemia, malignant lymphoma, acute lymphocytic leukemia, multiple myeloma, and myelodysplastic syndrome who received Episil® for the treatment of oral mucositis were included in this study. All patients were treated at the Hiroshima Red Cross and Atomic-bomb Surgery Hospital. To determine the severity of oral mucositis, 22 out of the 37 patients were interviewed and compared objectively using the Common Terminology Criteria for Adverse Events, version 3.0. In addition, subjective measures of the effects of oral mucositis were assessed using an original evaluation protocol (a unique evaluation chart specific to the Department of Oral Surgery, Hiroshima Red Cross & Atomic-bomb Survivors Hospital)., Results: Out of 37 participants recruited in the study, 31 (84%) described the sensation of Episil® as very good or good. Moreover, the severity of mucositis was found to decrease after the use of Episil® in seven patients out of 22 (19%), particularly in those with mucositis at multiple sites. Participants' evaluations revealed pain relief and improvement in speech and feeding functions. Participants with grade 3 mucositis reported a greater improvement in pain relief, speech, and feeding functions than those with grade 2 mucositis., Conclusions: This study suggests the efficacy of Episil® in treating oral mucositis in patients with hematologic malignancies, particularly in those with oral mucositis at multiple sites. In addition to pain relief, Episil® may improve speech and feeding functions., (© 2024. The Author(s).)

Vasoactive intestinal peptide (VIP) receptor 2 (VIPR2) is a G protein-coupled receptor that binds to Gαs, Gαi, and Gαq proteins to regulate various downstream signaling molecules, such as protein kinase A (PKA), phosphatidylinositol 3-kinase (PI3K), and phospholipase C. In this study, we examined the role of VIPR2 in cell cycle progression. KS-133, a newly developed VIPR2-selective antagonist peptide, attenuated VIP-induced cell proliferation in MCF-7 cells. The percentage of cells in the S-M phase was decreased in MCF-7 cells treated with KS-133. KS-133 in the presence of VIP decreased the phosphorylation of extracellular signal-regulated kinase (ERK), AKT, and glycogen synthase kinase-3β (GSK3β), resulting in a decrease in cyclin D1 levels. In MCF-7 cells stably-expressing VIPR2, KS-133 decreased PI3K activity and cAMP levels. Treatment with the ERK-specific kinase (MEK) inhibitor U0126 and the class I PI3K inhibitor ZSTK474 decreased the percentage of cells in the S phase. KS-133 reduced the percentage of cells in the S phase more than treatment with U0126 or ZSTK474 alone and did not affect the effect of the mixture of these inhibitors. Our findings suggest that VIPR2 signaling regulates cyclin D1 levels through the cAMP/PKA/ERK and PI3K/AKT/GSK3β pathways, and mediates the G1/S transition to control cell proliferation., Competing Interests: Declaration of competing interest Kotaro Sakamoto is a full-time employee of Ichimaru Pharcos Co. Ltd. The authors declare that this study received funding from Ichimaru Pharcos Co. Ltd. The funder had the following involvement in the study: interpretation of data. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Keratoameloblastoma (KA) and solid variant of odontogenic keratocyst (SOKC) are rare odontogenic lesions, and their relationship and differences are unclear. The present study described a case that started as an odontogenic keratocyst (OKC) and transformed to SOKC/KA upon recurrence. Briefly, a 26‑year‑old man presented with swelling in the right cheek and was referred to the Department of Oral and Maxillofacial surgery, Hiroshima University Hospital (Hiroshima, Japan). At the initial visit, unicystic bone permeation was observed extending from the right canine to the molar, maxillary sinus and nasal cavity. After the biopsy, the patient underwent excisional surgery and was diagnosed with OKC. Thereafter, the lesion recurred six times over a period of 13 years and showed different histopathological features from those of the primary lesion, all consisting of numerous cysts with keratinization, which were diagnosed as SOKC/KA. The Ki‑67 positivity rate was ~10%, which was higher than that of the primary lesion, but there was no atypia. Genetic analysis of the recurrent lesion revealed mutations in adenomatous polyposis coli and Kirsten rat sarcoma viral oncogene homolog. This case originated from OKC, and the morphological features of OKC and KA were mixed upon recurrence, supporting the commonality and association between the two. However, multiple mutations different from those of OKC and ameloblastoma were detected, suggesting an association of SOKC/KA with increased proliferative activity and a high recurrence rate.

Background: Early-stage tongue cancer has a good prognosis in general; however, high-risk patients with late cervical lymph node and distant metastases have a poor prognosis. Elective neck dissection and postoperative chemoradiotherapy are considered for these patients, although no clear criteria have been identified for their evaluation. Methods : This retrospective observational study aimed to determine the predictive factors for late cervical lymph node and distant metastases in 102 patients with cT1-2N0 tongue cancer. The data regarding the demographic characteristics, as well as the depth of invasion, tumor budding, histological grade, and tumor-stromal ratio, among other things, were extracted from medical records. Results : We found that the potential lymph node metastasis rate was 27.5%. The significant clinical predictors of late cervical lymph node metastasis were the tumor thickness and endophytic growth pattern and the significant histopathological factors were poorly and moderately differentiated tumors and ≥3 tumor buds. In addition, the prognostic factors for distant metastasis included ≥4 lymph node metastases, ≥7 tumor budding, and moderate and poor tumor differentiation. Conclusions: The usefulness of tumor budding as a predictor of metastasis for tongue cancer was suggested. The findings of this study can help establish the criteria for evaluating the metastasis risk and prognosis of patients with tongue cancers.

Objectives: Integrins are heterodimeric transmembrane plasma membrane proteins composed of α- and β-chains. They bind to extracellular matrix (ECM) and cytoskeletal proteins as ECM protein receptors. Upon ECM protein binding, integrins activate focal adhesion kinase (FAK) and transduce various signals. Despite their importance, integrin and FAK expression in oral squamous cell carcinoma (OSCC) tissue and the prognosis of patients with OSCC remains elusive. Methods: In a retrospective observational study, we immunohistochemically evaluated integrin αV, β1, β3, β5, β6, FAK, and phosphorylated-FAK (pFAK) expressions as prognostic predictors in 96 patients with OSCC. Patients were classified as positive or negative based on staining intensity, and clinicopathologic characteristics and survival rates of the two groups were compared. The association between above integrin-related proteins and PD-1 or PD-L1 in OSCC tissues was investigated. Results: We observed immunohistochemical integrin αV, β1, β6, β8, and FAK expressions in the cell membrane and cytoplasm but not integrin β3 and β5 in the OSCC tissues. pFAK was expressed in the cytoplasm of OSCC cells. The overall survival rate significantly decreased in pFAK-positive OSCC patients compared to the negative group, and cervical lymph node metastasis significantly increased in integrin β8-positive patients with OSCC ( p < 0.05). No association between integrin-related proteins and PD-1 or PD-L1 in OSCC tissues was observed. Conclusion: Our results indicate that pFAK and integrin β8 are prognostic factors for OSCC. Therefore, pFAK- and integrin β8-targeting new oral cancer diagnostic and therapeutic methods hold a promising potential., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sakurai, Ishida, Shintani, Yamasaki, Matsui, Hamana, Nobumoto, Yanamoto and Hayashido.)

Local anesthesia is administered to reduce pain-induced stress during dental treatment. However, local anesthetic injections are extremely painful; thus, methods to minimize this pain should be developed. Clinical studies on the pain-relieving effects of dental topical anesthetics have shown that few topical anesthetics provide fast and adequate pain relief without harming the oral mucosa. We examined the efficacy and safety of lidocaine tape, which has a potent topical anesthetic effect. Lidocaine tape was applied to the oral mucosa of 14 healthy participants, and its suppression effect was assessed by examining the pain intensity at the non-lidocaine tape-applied site using the visual analog evaluation scale and the verbal evaluation scale. Lidocaine tape application significantly reduced visual analog scale (VAS) scores during mucosal puncture compared to non-application ( p < 0.01). Moreover, lidocaine tape application significantly reduced VAS scores during local anesthetic injection compared to non-application ( p < 0.001). Adverse events were evaluated using the Common Terminology Criteria for Adverse Events, version 5.0. No adverse events attributed to the application of lidocaine tape were observed in any participant. The findings in this study suggest that the application of lidocaine tape before infiltration anesthesia can reduce patient distress.

Background/aim: The interaction of integrin αvβ8 with type I collagen was shown to promote oral squamous cell carcinoma (SCC) cell proliferation via the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. However, the role of integrin αvβ8 in SCC progression remains poorly understood. In this study, the role of integrin αvβ8 in oral SCC progression was therefore investigated., Materials and Methods: Integrin αv and β8 protein expression in oral SCC cells was examined by western blotting. Oral SCC cell motility was investigated using modified Boyden chamber assays. Behavior of oral SCC cells was examined in three-dimensional culture using type I collagen gel. Ras homolog family member A (RHOA), Ras-related C3 botulinum toxin substrate 1 (RAC1), and cell division control protein 42 homolog (CDC42) activity of oral SCC cells was analyzed by pull-down assays., Results: SCC cells with high integrin αvβ8 expression levels had a high ability to migrate on type I collagen and exhibited enhanced invasion into type I collagen gel. In SCC cells with high integrin αvβ8 expression level, cultivation on type I collagen induced RAC1 activation. Treatment with RAC1 inhibitor reduced type I collagen-induced motility of SCC cells. Down-regulation of integrin β8 by specific antisense oligonucleotide reduced type I collagen-induced RAC1 activation and suppressed cell motility and invasion into type I collagen gel., Conclusion: The interaction of integrin αvβ8 with type I collagen facilitates SCC cell motility and invasion via RAC1 activation. Therefore, integrin αvβ8 and RAC1 may represent new targets for inhibiting metastasis and invasion in patients with oral SCC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)