Search

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.)

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.)

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.

One of the regulated forms of cell death is the cell-in-cell (CIC) structure, in which a surviving cell is engulfed by another cell, a mechanism that causes the death of the engulfed cell by an adjacent cell. Several investigators have previously shown that the presence of CICs is an independent risk factor significantly associated with decreased survival in patients with various types of cancer. In this review, we summarize the role of CIC in the tumor microenvironment (TME), including changes and crosstalk of molecules and proteins in the surrounding CIC, and the role of these factors in contributing to therapeutic resistance acquisition. Moreover, CIC structure formation is influenced by the modulation of TME, which may lead to changes in cellular properties. Future use of CIC as a clinical diagnostic tool will require a better understanding of the effects of chemotherapy on CIC, biomarkers for each CIC formation process, and the development of automated CIC detection methods in tissue sections of tumor specimens., 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 © 2023 Okuyama, Fukushima, Naruse and Yanamoto.)

Current clinical and observational evidence supports the EXTREME regimen as one of the standards of care for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) followed by the administration of immune checkpoint inhibitors (ICIs). In addition to the inhibition of the epidermal growth factor receptor (EGFR) pathway, cetuximab-mediated EGFR blockade has been shown to modulate tumor microenvironment (TME) characteristics, such as antibody-dependent cellular cytotoxicity (ADCC) activity, cytotoxic T-lymphocyte (CTL) infiltration into the tumor, anti-angiogenesis activity, and cytokine secretion via associated natural killer (NK) cells, etc.. On the other hand, there are reports that nivolumab affects the TME via Programmed cell death 1 (PD-1) inhibition, Interleukin-10 upregulation via T-cells, myeloid-derived suppressor cell-mediated immune escape induction, and tumor vessel perfusion by promoting CD8 + T-cell accumulation and Interferon-γ production in treatment-sensitive tumor cells. Actually, nivolumab administration can give T cells in the TME both immune superiority and inferiority. HNSCC treatment using cetuximab increases the frequency of FoxP3 + intratumoral effector regulatory T cells (Tregs) expressing CTL associated antigen (CTLA)-4, and targeting CTLA-4 + Tregs using ipilimumab restores the cytolytic function of NK cells, which mediate ADCC activity. Treg-mediated immune suppression also contributes to clinical response to cetuximab treatment, suggesting the possibility of the addition of ipilimumab or the use of other Treg ablation strategies to promote antitumor immunity. Moreover, also in hyper progression disease (HPD), intratumoral frequency of FoxP3 + effector Tregs expressing CTLA-4 is increased. Therefore, combination treatment with cetuximab plus anti-CTLA-4 antibody ipilimumab for HNSCC and this combination therapy after nivolumab administration for HPD may be expected to result in a higher tumor-control response. Based on the above evidence, we here suggest the efficacy of using these therapeutic strategies for patients with local-advanced, recurrent, and metastatic HNSCC and patients who do not respond well to nivolumab administration., (© 2023. The Author(s).)

Background: Tumor-infiltrating lymphocytes (TILs) have been used to predict the prognosis of solid tumors. In this study, we investigated which molecules in TILs play a role in the prognosis of patients with oral squamous cell carcinoma (OSCC)., Methods: In a retrospective case-control study, we immunohistochemically evaluated the expression of CD3, CD8, CD45RO, Granzyme B, and the major histocompatibility complex class I chain-related molecule A (MICA) of the histocompatibility complex as predictors of prognosis in 33 patients with OSCC. The patients were classified as TILs High or TILs Low according to the number of TILs for each molecule in the central tumor (CT) and invasive margin (IM). Furthermore, MICA expression scores were determined based on the intensity of the staining., Results: CD45RO + /TIL in the nonrecurrent group were significantly higher than those in the recurrent group in the CT and IM areas ( p < 0.05). The disease-free survival/overall survival rate of the CD45RO + /TILs Low group in the CT and IM areas and the Granzyme B + /TILs Low group in the IM area was significantly lower than that of the CD45RO + /TILs High group and the Granzyme B + /TILs High group, respectively ( p < 0.05). Furthermore, the MICA expression score of tumors around the CD45RO + /TILs High group was significantly higher than that of the CD45RO + /TILs Low group ( p < 0.05)., Conclusions: A high ratio of CD45RO-expressing TILs was associated with a disease-free/overall survival improvement in OSCC patients. Furthermore, the number of TILs that express CD45RO was associated with the expression of MICA in tumors. These results suggest that CD45RO-expressing TILs are useful biomarkers for OSCC.

Several periodontitis-associated species induce genes related to cell proliferation, cell-cycle progression, apoptosis, intracellular transport, immune and inflammatory responses, carcinogenesis, and cancer progression. Here, we reviewed studies showing strong associations between gingival squamous cell carcinoma (GSCC) and three periodontitis-related oral bacteria (Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia) in the microenvironment. These bacteria produce cytoplasmic lipopolysaccharide (LPS) and secrete cytokines and molecules related to carcinogenesis, tumor progression, and metastasis and metastasis. In GSCC, LPS levels are substantially elevated and assessable by functional analysis. Polymicrobial infections can synergistically induce inflammation and significantly upregulate proinflammatory molecules (e.g., IL1β, IL8, and TNFα) that promote carcinogenesis. This review can facilitate the identification of novel targets for treating and preventing GSCC, which is potentially associated with periodontal pathogen., (©2023 American Association for Cancer Research.)

Background: Dysgeusia is a relatively early symptom of zinc deficiency, and zinc replacement is effective in treating dysgeusia. The administration of zinc acetate hydrate (ZAH) was approved in 2017 for patients with hypozincemia in Japan. This retrospective study was conducted to explore the efficacy and safety of ZAH administration in patients with hypozincemia-induced dysgeusia., Methods: Patients with hypozincemia-induced dysgeusia who visited our hospital from May 2013 to December 2019 were included in this study. ZAH (zinc content; 50 mg/day) was administered to 42 patients for 24 weeks. The taste test was performed using the filter paper disk method, and the total cognitive thresholds of the left and right chorda tympani regions were used. Changes in taste function, serum zinc and copper levels, and copper/zinc ratio were analyzed. A total of 28 patients who received polaprezinc (PPZ, zinc content; 34 mg/day) for 24 weeks, who were prescribed until ZAH was approved, were registered as controls., Results: Serum zinc levels at 12 and 24 weeks after ZAH or PPZ administration were higher than those before administration. These levels were significantly higher in the ZAH-treated group than in the PPZ-treated group. However, serum copper levels did not significantly change before and after administration. In the taste test, the taste thresholds for the acidity and salty at 12 and 24 weeks after ZAH administration were significantly decreased compared to before administration. In contrast, in the PPZ group, the taste thresholds for the acidity and salty were significantly decreased 24 weeks after administration., Conclusions: ZAH (50 mg/day) administration was effective in improving the gustatory sensitivity of patients with dysgeusia and hypozincemia 12 weeks after administration without affecting the serum copper level. ZAH was also more effective than PPZ., (© 2023. The Author(s).)

There are a few reports that focus on radiotherapy (RT) and cetuximab (CET) therapy exclusively for oral cancer. This retrospective study aimed to investigate the efficacy and safety of RT and CET therapy for locally advanced (LA) or recurrent/metastatic (R/M) oral squamous cell carcinoma (OSCC). Seventy-nine patients from 13 hospitals who underwent RT and CET therapy for LA or R/M OSCC between January 2013 and May 2015 were enrolled in the study. Response, overall survival (OS), disease-specific survival (DSS), and adverse events were investigated. The completion rate was 62/79 (78.5%). The response rates in patients with LA and R/M OSCC were 69% and 37.8%, respectively. When only completed cases were examined, the response rates were 72.2% and 62.9%, respectively. The 1- and 2-year OS were 51.5% and 27.8%, respectively (median, 14 months), for patients with LA OSCC, and 41.5% and 11.9% (median, 10 months) for patients with R/M OSCC. The 1- and 2-year DSS were 61.8% and 33.4%, respectively (median, 17 months), for patients with LA OSCC, and 76.6% and 20.4% (median, 12 months) for patients with R/M OSCC. The most common adverse event was oral mucositis (60.8%), followed by dermatitis, acneiform rash, and paronychia. The completion rate was 85.7% in LA patients and 70.3% in R/M patients. The most common reason for noncompletion was an inadequate radiation dose due to worsening general conditions in R/M patients. Although the standard treatment for LA or R/M oral cancer is concomitant RT with high-dose cisplatin (CCRT) and the efficacy of RT and CET therapy for oral cancer is not considered to be as high as that for other head and neck cancers, it was thought that RT and CET therapy could be possible treatments for patients who cannot use high-dose cisplatin.

Tumor budding (TB), a microscopic finding in the stroma ahead of the invasive fronts of tumors, has been well investigated and reported as a prognostic marker in head and neck squamous cell carcinoma (HNSCC). Epithelial-mesenchymal transition (EMT) is a crucial step in tumor progression and metastasis, and its status cannot be distinguished from TB. The current understanding of partial EMT (p-EMT), the so-called halfway step of EMT, focuses on the tumor microenvironment (TME). Although this evidence has been investigated, the clinicopathological and biological relationship between TB and p-EMT remains debatable. At the invasion front, previous research suggested that cancer-associated fibroblasts (CAFs) are important for tumor progression, metastasis, p-EMT, and TB formation in the TME. Although there is biological evidence of TB drivers, no report has focused on their organized functional relationships. Understanding the mechanism of TB onset and the relationship between p-EMTs may facilitate the development of novel diagnostic and prognostic methods, and targeted therapies for the prevention of metastasis in epithelial cancer. Thus far, major pieces of evidence have been established from colorectal cancer (CRC), due to a large number of patients with the disease. Herein, we review the current understanding of p-EMT and TME dynamics and discuss the relationship between TB development and p-EMT, focusing on CAFs, hypoxia, tumor-associated macrophages, laminin-integrin crosstalk, membrane stiffness, enzymes, and viral infections in cancers, and clarify the gap of evidence between HNSCC and CRC.

Background/purpose: The prognosis of oral squamous cell carcinoma (OSCC) with posterior invasion is poor. We examined whether the pterygomandibular raphe (PMR) is useful for the diagnosis of invasion and determination of surgical methods., Materials and Methods: Of 390 patients with OSCC treated surgically at our hospital between June 2009 and June 2020, 80 patients with posterior invasion were included in the study. Preoperative magnetic resonance imaging was used to classify the lesions into three types: non-contact with PMR (non-contact type), contact with PMR (contact type), and invasion beyond PMR (invasion type). We compared the local control, recurrence, and survival rates of each of the three types., Results: The invasion type showed a significantly higher recurrence rate than the non-contact type ( P  < 0.001) and contact type ( P  = 0.018). Overall survival rate comparisons showed that the invasion type had significantly worse prognosis than the non-contact ( P  = 0.004) and contact types ( P  = 0.041)., Conclusion: OSCCs with posterior invasion beyond the PMR showed a poor treatment outcome and, therefore, should be treated with caution. The initial surgery is especially important and must ensure local control. This study indicates that the PMR is an important criterion for surgical method determination and that invasion beyond the PMR is a predictor of local recurrence and poor prognosis., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2022 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Genetic alterations and dysregulation of signaling pathways are indispensable for the initiation and progression of cancer. Understanding the genetic, molecular, and signaling diversities in cancer patients has driven a dynamic change in cancer therapy. Patients can select a suitable molecularly targeted therapy or immune checkpoint inhibitor based on the driver gene alterations determined by sequencing of cancer tissue. This "precision medicine" approach requires detailed elucidation of the mechanisms connecting genetic alterations of driver genes and aberrant downstream signaling pathways. The regulatory mechanisms of the Hippo pathway and Yes-associated protein/transcriptional co-activator with PDZ binding motif (YAP/TAZ) that have central roles in cancer cell proliferation are not fully understood, reflecting their recent discovery. Nevertheless, emerging evidence has shown that various genetic alterations dysregulate the Hippo pathway and hyperactivate YAP/TAZ in cancers, including head and neck squamous cell carcinoma (HNSCC). Here, we summarize the latest evidence linking genetic alterations and the Hippo pathway in HNSCC, with the aim of contributing to the continued development of precision medicine.

Introduction: In early-stage oral tongue squamous cell carcinoma (OTSCC), elective neck dissection (END) is recommended when occult lymph node metastasis is suspected; however, there is no unanimous consensus on the risks and benefits of END in such cases. The management of clinically node-negative (cN0) OTSCC remains controversial. This study, therefore, aimed to evaluate the efficacy of END and its impact on the quality of life (QoL) of patients with cN0 OTSCC., Methods and Analysis: This is a prospective, multicentre, nonrandomised observational study. The choice of whether to perform END at the same time as resection of the primary tumour is based on institutional policy and patient preference. The primary endpoint of this study is 3-year overall survival. The secondary endpoints are 3-year disease-specific survival, 3-year relapse-free survival and the impact on patient QoL. Propensity score-matching analysis will be performed to reduce selection bias., Ethics and Dissemination: This study was approved by the Clinical Research Review Board of the Nagasaki University. The protocol of this study was registered at the University Hospital Medical Information Network Clinical Trials Registry. The datasets generated during the current study will be available from the corresponding author on reasonable request. The results will be disseminated internationally, through scientific and professional conferences and in peer-reviewed medical journals., Trial Registration Number: UMIN000027875., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chronic non-bacterial osteomyelitis (CNO) is a rare and severe inflammatory bone disorder that can occur in the jaw. It is often associated with systemic conditions including autoimmune deficiency. Medical management of patients and establishment of a correct diagnosis are difficult as the etiology of the disease remains unknown. Therefore, little is known about the disease characteristics at the gene expression level. Here, we explored aspects of CNO based on whole blood RNA sequencing (>6 Gb per sample) of 11 patients and 9 healthy controls in Japan and on a recently developed method that is applicable to small datasets, can estimate a directed gene network, and extract a subnetwork of genes underlying patient characteristics. We identified nine subnetworks, comprising 26 differentially regulated edges and 36 genes, with the gene encoding glycophorin C (GYPC) presenting the highest discrimination ability. The expression of the gene was mostly lower in patients with CNO than in the healthy controls, suggesting an abnormal status of red cells in patients with CNO. This study enhances our understanding of CNO at the transcriptome level and further provides a framework for whole blood RNA sequencing and analysis of data obtained for a better diagnosis of the disease., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

We evaluated whether fluorescence intensity (FI) and its coefficient of variation (CV) can be used to diagnose squamous cell carcinoma (SCC) through IllumiScan®, an oral mucosa fluorescence visualisation (FV) device. Overall, 190 patients with oral mucosal lesions (OMLs; SCC, 59; non-SCC OMLs, 131) and 49 patients with normal oral mucosa (NOM) were enrolled between January 2019 and March 2021. The FI of the images was analysed using image analysis software. After establishing regions of interest for SCC, non-SCC, and NOM, the average FI, standard deviation (SD), and CV were compared. There was a significant difference in the average FI for all pairs of comparisons. The SD was not significantly different between the SCC and NOM groups (p = 0.07). The CV differed significantly for NOM (p < 0.001) and non-SCC groups (p < 0.001) relative to the SCC group but was not different between NOM and non-SCC groups (p = 0.15). Univariate analysis of SCC and non-SCC groups showed significant differences for all factors, except age. However, multivariate analysis showed a significant intergroup difference only in the CV (p = 0.038). Therefore, analysing the CV in FV images of OML may be useful for the diagnosis of oral cancer.

The prognosis of oral cancer that has metastasized to the contralateral cervical lymph nodes is poor, although the appropriate treatment method has not been established because of its rarity. A multicenter retrospective study on the treatment and prognosis of pN2c oral cancer patients was conducted. We investigated the treatment and prognosis of 62 pN2c patients out of 388 pN+ patients with oral squamous cell carcinomas. Statistical analysis was performed on the various factors with overall survival (OS) and disease specific survival (DSS). In multivariate cox regression analysis, advanced T stage was significantly correlated with poor OS ( p = 0.011) and DSS ( p = 0.023) of patients with pN2c neck. In pN2c patients, OS, DSS, and neck control was not different between those undergoing ipsilateral neck dissection initially and those undergoing bilateral neck dissection. Thus, contralateral elective neck dissection is not recommended. The most important risk factor for prognosis in pN2c oral cancer patients is advanced T stage. No evidence was found to recommend contralateral elective neck dissection in clinically N1/2b patients. Therefore, the indication for contralateral elective neck dissection in N1/2b patients should be carefully determined in consideration of individual conditions.

Transmembrane protein 16A (TMEM16A) forms a plasma membrane-localized Ca 2+ -activated Cl- channel. Its gene has been mapped to an area on chromosome 11q13, which is amplified in head and neck squamous cell carcinoma (HNSCC). In HNSCC, TMEM16A overexpression is associated with not only high tumor grade, metastasis, low survival, and poor prognosis, but also deterioration of clinical outcomes following platinum-based chemotherapy. Recent study revealed the interaction between TMEM16A and transforming growth factor-β (TGF-β) has an indirect crosstalk in clarifying the mechanism of TMEM16A-induced epithelial-mesenchymal transition. Moreover, human papillomavirus (HPV) infection can modulate TMEM16A expression along with epidermal growth factor receptor (EGFR), whose phosphorylation has been reported as a potential co-biomarker of HPV-positive cancers. Considering that EGFR forms a functional complex with TMEM16A and is a co-biomarker of HPV, there may be crosstalk between TMEM16A expression and HPV-induced HNSCC. EGFR activation can induce programmed death ligand 1 (PD-L1) synthesis via activation of the nuclear factor kappa B pathway and JAK/STAT3 pathway. Here, we describe an interplay among EGFR, PD-L1, and TMEM16A. Combination therapy using TMEM16A and PD-L1 inhibitors may improve the survival rate of HNSCC patients, especially those resistant to anti-EGFR inhibitor treatment. To the best of our knowledge, this is the first review to propose a biological validation that combines immune checkpoint inhibition with TMEM16A inhibition., (© 2022. The Author(s).)

Objective : This retrospective study aimed to clarify the characteristics of positional obstructive sleep apnea (P-OSA) patients and to examine the relationship between sleep position and the efficacy of oral appliance (OA) therapy. Methods : Seventy-three patients who underwent polysomnography before and after OA therapy were divided into P-OSA or non-positional OSA (NP-OSA) and examined. Results : Forty-seven patients had P-OSA and 26 had NP-OSA. P-OSA was characterized by a relatively high ratio of supine to lateral apnea hypopnea index (AHI) because the lateral AHI of P-OSA was significantly lower than that of NP-OSA. OA therapy was more effective for P-OSA than NP-OSA. Younger age and the presence of P-OSA are useful as predictors of OA therapy efficacy. Discussion : Even for relatively severe OSA, in the case of younger age and/or P-OSA, the application of simple, cost-effective OA therapy might be recommended over other treatment modalities.

Objective Leg muscle strength (LMS) is decreased in early-stage Parkinson disease (PD) patients and is associated with slower walking and falls. However, LMS in advanced PD has not been well investigated. The purpose of this study was to evaluate LMS in advanced PD patients and its effects on gait performance, activities of daily living, and the cognitive function. Methods The medical records of 132 patients with idiopathic advanced PD [Hoehn and Yahr (H&Y) stages 3 and 4] with a mean disease duration of 9.6 years were retrospectively reviewed. Leg extensor muscle strength of the patients was measured using a Strength Ergo 240. The associations between the LMS and gait performance, Barthel index, H&Y stage, and Mini-Mental State Examination (MMSE) score were analyzed. Results A Spearman's correlation analysis showed that LMS was correlated with the sex, age, age of disease onset, H&Y stage, Barthel index, MMSE score, and gait parameters. A multivariable linear regression analysis for identifying predictors of LMS showed that the gait velocity (β=0.377), Barthel index (β=0.281), sex (β=-0.187), and disease duration (β=-0.155) were significant. A receiver operating characteristic curve analysis for discriminating between H&Y stage 3 and 4 was performed for LMS; the area under the curve was 0.774 (95% confidence interval=0.696-0.851). Conclusions LMS was strongly associated with multiple domains of clinical characteristics, especially gait velocity and the Barthel index. Our study also suggested that LMS can be a predictor of PD progression.

Background/purpose: Recently, many reports have recommended surgical treatment for medication-related osteonecrosis of the jaw (MRONJ). However, MRONJ is more likely to occur in older patients with poor general condition and often necessitates extensive surgery, such as segmental mandibulectomy. The purpose of this study was to investigate treatment outcome of patients with MRONJ undergoing segmental mandibulectomy., Materials and Methods: This retrospective study included 137 patients with medication-related osteonecrosis of the lower jaw who underwent surgical treatment at our hospital between 2011 and 2019. A total of 168 surgeries (155 marginal mandibulectomies and 13 segmental mandibulectomies) were performed. The relationship between clinical and imaging factors and the treatment outcome was investigated in the segmental mandibulectomy cases., Results: Preoperative computed tomography (CT) showed osteolytic lesions in 13/13, periosteal reaction (PR) in 12/13, and osteosclerosis in 12/13 cases of segmental mandibulectomy. On postoperative CT, no residual osteolytic lesion and PR were noted, and 9 cases showed osteosclerosis. Twelve patients (92.3%) undergoing segmental mandibulectomy had complete healing, whereas the cure rate of those undergoing marginal mandibulectomy was 104/155 (67.1%). One patient with relapse after segmental mandibulectomy showed healing after an additional resection. In the patients who underwent segmental mandibulectomy, clinical symptoms, such as pain and purulent discharge, disappeared, and oral intake was possible., Conclusion: Segmental mandibulectomy is a treatment option for end-of-life care of refractory MRONJ, because it can eliminate clinical symptoms early. When performing segmental mandibulectomy, the area of the osteolytic lesion and periosteal reaction needs to be included., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2021 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Abstract: The aim of this study is to report the differences in clinicopathological features of oral tongue squamous cell carcinoma (OTSCC) and survival between adolescent and young adult (AYA) patients and elderly patients and to find the prognosticators. The medical records of 101 AYA patients and 175 control patients with OTSCC who underwent surgery were reviewed. Variables related to prognosis and their clinicopathological associations were analyzed. The 5-year overall survival (5y-OS) rates of AYA and control patients with stage I and II OTSCC were 94.4% and 89.6% (P = .353), respectively, and their 5-year disease-free survival (5y-DFS) rates were 82.0% and 76.6%, respectively (P = .476). The 5y-OS rates of patients with stages III and IV OTSCC were 83.3% and 66.7% (P = .333), respectively, and their 5y-DFS rates were 75.0% and 57.1% (P = .335), respectively. Logistic regression analysis revealed that there was no significant clinicopathological difference in AYA and control group. Furthermore, there was no significant difference in 5y-OS rates between patients who underwent elective neck dissection (END) and those who underwent therapeutic neck dissection (TND) in both group (P = 0.717 and 0.688). Overall, the present study revealed the clinicopathological features and prognosis of OTSCC were similar in AYA patients and elderly patients. Moreover, as there was no significant difference in OS between patients who underwent END and those who underwent TND in AYA and control groups, our results suggest that the indication for END in AYA patients with clinical N0 OTSCC is similar to that for elderly patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background/purpose: Radiotherapy for head and neck cancer often causes severe oral mucositis. The purpose of this retrospective study was to further examine the risk factors for developing severe oral mucositis in patients with oral cancer undergoing radiotherapy as a compliment to a previous study performed by our group., Materials and Methods: A total of 181 patients with oral cancer undergoing radiotherapy were enrolled in the study. The association between a number of potential risk factors and grade 3 oral mucositis were analyzed using the cox proportional hazard model and a logistic regression analysis., Results: Grade 3 oral mucositis occurred in 56 patients. The cox proportional hazard model analysis revealed that those with lower hemoglobin levels, concurrent cisplatin and cetuximab administration, and a larger number of teeth showed a significantly higher incidence of severe oral mucositis. Logistic regression analysis revealed that patients who had lower hemoglobin levels, received concurrent cisplatin or cetuximab treatment, and were not administered pilocarpine showed a significantly higher incidence of severe oral mucositis. The presence of teeth may stimulate the oral mucosa and become a risk factor for mucositis, and the administration of pilocarpine might reduce the risk., Conclusion: This study describes the risk factors of severe radiation-induced oral mucositis in oral cancer patients and shows the possibility of risk reduction by pilocarpine. This information could help patients avoid painful mucositis., (© 2021 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Tooth extraction has been avoided since it has been considered a major risk factor for medication-related osteonecrosis of the jaw (MRONJ). However, MRONJ may also develop from tooth that is an infection source. This study aimed to clarify whether tooth extraction is a risk factor for the development of MRONJ in cancer patients receiving bone-modifying agents (BMAs). This retrospective observational study included 189 patients (361 jaws) from two hospitals. The risk factors of MRONJ were identified by comparing patient characteristics between those who did and did not develop MRONJ. Furthermore, the effect of tooth extraction during BMA therapy was analyzed after adjusting for confounding factors using the propensity score matching method. MRONJ occurred in 33 patients jaws. A longer duration of BMA administration, fewer number of teeth, presence of symptoms of local infection, and infected teeth were independent risk factors of MRONJ. However, tooth extraction during BMA therapy did not increase the risk. Propensity score matching analysis showed that tooth extraction significantly lowered the risk of MRONJ development. Teeth that can be an infection source increases the risk of MRONJ, and thus, they need to be extracted even during BMA administration., (© 2021. The Author(s).)

Background/purpose: Because the anatomy and the nature of the bone tissue between the mandible and maxilla are largely different, more site-specific studies are required to improve the healing rate on medication-related osteonecrosis of the jaw (MRONJ). The present study assessed maxillary MRONJ that was treated by surgery to understand its clinical characteristics, and to identify critical factors that influenced outcomes., Materials and Methods: The medical records of 54 patients with maxillary MRONJ who underwent surgery were retrospectively reviewed. Variables related to the prognosis of MRONJ were extracted from the medical records and imaging, and were statistically analyzed. We also evaluated the concomitant maxillary sinusitis (MS) after the surgical treatment of MRONJ, based on CT evaluation and change of symptoms., Results: The healing rate of surgery for maxillary MRONJ was 85.2%, which suggested that surgical treatment is an effective strategy for treating maxillary MRONJ. Multivariate analysis revealed that postoperative residual necrotic bone was a poor prognosticator for maxillary MRONJ. Among 10 patients who did not obtain healing of MS postoperatively, 8 patients showed an improvement., Conclusion: Our results indicate that surgical treatment is an appropriate strategy for maxillary MRONJ and complete resection of necrotic bone (i.e., extensive surgery) is needed to obtain complete healing of maxillary MRONJ. Concomitant MS tends to be healed or improved clinically in combination with the healing of maxillary MRONJ., (© 2021 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Intraoral vertical ramus osteotomy (IVRO) is used to treat mandibular prognathism and temporomandibular disorders. However, the improvement of temporomandibular disorders after IVRO is considered to be due to the anterior and downward movement of the mandibular condyle, which may lead to condylar sag, and in the worst case, condylar luxation. In this retrospective cohort study, we examined factors potentially associated with condylar sag. Univariate analysis indicated that condylar sag was significantly associated with the following factors: magnitude of setback (P = 0.001), less than 3 mm setback (P < 0.001), presence of temporomandibular joint (TMJ) symptoms (P = 0.002), Wilkes classification (P = 0.039), occlusal cant correction ≥ 2 mm (P = 0.018), and mandibular condyle deformation (P < 0.001). Setback magnitude (P = 0.032) and TMJ symptoms (P = 0.007) remained significant in the multivariate analysis. In the receiver operating characteristic curve, the setback magnitude cut-off value for condylar sag after IVRO was 3.25 mm. Thus, the incidence of condylar sag after IVRO is increased with a smaller setback magnitude (≤ 3.25 mm) and the presence of TMJ symptoms. These factors should be evaluated by surgeons during treatment planning for IVRO to estimate condylar sag, and it may be possible to predict the risk of condylar luxation.

The aim of this study was to investigate the awareness and experience, among dental practitioners, of adverse events resulting from dental treatment of patients undergoing therapy with drugs that affect the immune system [angiogenesis inhibitors, biological agents, immunosuppressants, and disease-modifying anti-rheumatic drugs (DMARDs)]. For this purpose, a nationwide questionnaire survey was conducted. Questionnaires were sent to 2,050 dentists, of which 206 (10.1%) were completed and returned. The results showed that most dentists were aware of complications associated with dental treatment of patients treated with drugs that affect the immune system, and about half had actually experienced such complications. Delayed wound healing, osteonecrosis of the jaw (ONJ), and postoperative infections were reported. Whereas approximately 50% of dentists did not discontinue the drugs during dental treatment, about 18% did. During temporary drug discontinuation, some patients experienced aggravation of the primary disease, such as worsening of rheumatism, growth of tumors, and rejection reactions of transplanted organs. As for medical cooperation, only less than half of the dentists were asked for oral hygiene management by a physician prior to starting the drug treatment. Prospective studies are needed because evidence for dental treatments in patients treated with these drugs remains limited., Competing Interests: No potential conflict of interest relevant to this article was reported.

Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is an efficient anti-tumor therapeutic agent that inhibits the activation of EGFR; however, data related to the cellular effects of prolonged cetuximab treatment are limited. In this study, the long-term cellular outcome of prolonged cetuximab treatment and the related molecular mechanism were explored in a head and neck squamous cell carcinoma cell line constitutively expressing a fluorescent ubiquitination-based cell cycle indicator. Fluorescent time-lapse imaging was used to assess clonal growth, cell motility, and cell-cycle progression. Western blot analysis was performed to measure the level of phosphorylation and protein-expression following cetuximab treatment. Over 5 days cetuximab treatment decreased cell motility and enhanced G1 phase cell arrest in the central region of the colonies. Significantly decreased phosphorylation of retinoblastoma, Skp2, and Akt-mTOR proteins, accumulation of p27 Kip1 , and induction of type II LC3B were observed over 8 days cetuximab treatment. Results of the present study elucidate the cetuximab-dependent inhibition of cell migration, resulting in high cell density-related stress and persistent cell-cycle arrest at G1 phase culminating in autophagy. These findings provide novel molecular insights related to the anti-tumor effects of prolonged cetuximab treatment with the potential to improve future therapeutic strategy.

Background/purpose: Although mandibular advancement oral appliances (OAs) are the most widely used and accepted therapeutic modality for obstructive sleep apnea (OSA), whether these maxillary and mandibular appliances should be semi-fixed or fixed remains uncertain. This randomized crossover pilot study compared the efficacy, side effects, and patient preference of semi-fixed and fixed OAs for the treatment of OSA., Materials and Methods: Patients with mild to moderate OSA were recruited and randomly assigned to either the semi-fixed or fixed OA group, whereby they used their assigned OA for the first 4 weeks, followed by assessments for sleep parameters (including the Apnea-Hypopnea Index [AHI]) and temporomandibular joint pain as a side effect. After a two-week washout period, patients were switched to the alternative OA for 4 weeks, followed by repeated assessments. Patient preference was assessed at the end of the completed treatment period., Results: Fifteen patients were enrolled and completed the full study protocol. Both types of OAs were efficient in reducing the patient's AHI in comparison to baseline (i.e., without OA). However, there was no significant difference in AHI reduction between the semi-fixed and fixed OA devices. Regarding the side effect of temporomandibular joint pain and patient preference, the semi-fixed OA device was superior to the fixed OA device on both measures., Conclusion: While both semi-fixed and fixed OAs are effective in treating patients with OSA, semi-fixed OAs are superior in regards to both patient preference and reduced side effects. Thus, semi-fixed OAs may be the preferred therapeutic modality for OSA., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2020 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background/purpose: The prevalence of oral adverse events and dental treatments related complications during the molecular targeted drugs therapy remains unclear. The purpose of this study was to investigate the contents of dental treatment-related complications in Japanese patients during molecular targeted therapy., Materials and Methods: The nation-wide survey of dental treatment related complications was performed by the Japanese Society of Dentistry for Medically Compromised Patient as retrospective cohort study., Results: Among 212 dentists, 87.3% recognized the possibility of dental treatments related complications in patients with angiogenesis inhibitors. The oral adverse events including dental treatment-related complications associated with angiogenesis inhibitors were 79 cases. In patients with angiogenesis inhibitors, 73.4% of patients were administrated with bevacizumab. The average administration period of angiogenesis inhibitors was 14.0 ± 10.0 months. As the dental treatment related complications, delayed wound healing was most commonly seen in 45 patients (57.0%), followed by osteonecrosis of the jaw in 25 (31.6%). The triggered factor of complications was tooth extraction in 51 cases (96.2%)., Conclusion: The extraction of the tooth with pre-existing inflammation may be suggested as one of risk factors for angiogenesis inhibitor-related dental treatment complications., Competing Interests: The authors declare no conflicts of interest associated with this manuscript., (© 2020 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background/purpose: TThe bone cavities after extirpation of cysts or tumor of the jawbone requires the insertion of gauze containing various antibiotics/antiseptics to minimize the risk of pain, bleeding, and surgical site infection (SSI). However, there have been few reports on the efficacy of topical administration of antibiotics/antiseptics to an open wound of the jawbone. To compare the inhibitory effects of topical povidone-iodine gel and tetracycline ointment on the jawbone wound bacterial growth after extirpation of cyst or tumor., Materials and Methods: This is a preliminary, randomized controlled, open-labeled trial. Eighteen patients were randomly assigned into two groups. In povidone-iodine (PI) group, gauze mixed with povidone-iodine gel was inserted into the bone cavity wound, and in tetracycline (TC) group gauze mixed with tetracycline ointment was inserted after extirpation of cyst or tumor of the jaw bone. In both groups, gauze was removed 48 h after surgery, and examined by bacterial culture and real-time polymerase chain reaction (PCR) using primers detecting total bacteria and MRSA., Results: The topical application of tetracycline ointment was superior to that of povidone-iodine gel concerning inhibitory effects of total bacteria and methicillin-resistant Staphylococcus aureus (MRSA)., Conclusion: This preliminary study suggests that the insertion of gauze mixed with tetracycline ointment is recommended for bone wounds after extirpation of cyst or tumor of the oral cavity., (© 2020 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background/purpose: Bioadhesive barrier-forming oral liquid, is a recently developed medical material for the management of pain caused by oral mucositis associated with cancer radiotherapy or chemotherapy. The purpose of this study was to evaluate the effectiveness of this liquid in relieving pain resulting from radiation-induced oral mucositis in patients with head and neck cancer., Materials and Methods: This randomized, crossover trial investigated the analgesic effects of bioadhesive barrier-forming oral liquid using dexamethasone ointment as a control. Fifteen patients with mild or moderate pain due to radiation-induced oral mucositis were randomly assigned to two groups. Group A applied dexamethasone ointment once on day 1, had a wash-out period on day 2, and used bioadhesive barrier-forming oral liquid once on day 3. Conversely, group B used bioadhesive barrier-forming oral liquid on day 1, had a wash-out period on day 2, and applied dexamethasone ointment once on day 3. The effectiveness in relieving pain was compared between the two groups., Results: One patient reported nausea immediately after the application of bioadhesive barrier-forming oral liquid and was therefore excluded from the analysis. Dexamethasone ointment and bioadhesive barrier-forming oral liquid relieved pain in 85.7% and 71.4% patients, respectively (p = 0.682). Nine patients wished to continue dexamethasone ointment after the study, while only five wished to continue bioadhesive barrier-forming oral liquid., Conclusion: Our findings suggest that the analgesic effect of bioadhesive barrier-forming oral liquid is comparable or inferior to that of dexamethasone ointment in patients with radiation-induced oral mucositis. Further studies are needed to verify these findings., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2020 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background: There is insufficient evidence for the efficacy of silicone soft reliner on the obturator prosthesis after maxillectomy for oral malignant tumors., Objective: To verify the efficacy of silicone soft reliner on the obturator prosthesis after maxillectomy, by evaluating masticatory performance and quality of life (QoL)., Methods: This was a single-arm prospective interventional study, verifying the efficacy of silicone soft reliner (GC RELINE II®) on the maxillary obturator prosthesis. Data were obtained from a comparison of the endpoints after 14 days of continuous use of acrylic and silicone soft-lined prostheses. The primary endpoint was masticatory performance. The secondary endpoints were occlusal performance and oral health-related QoL (OHRQoL). The masticatory performance, occlusal performance, and OHRQoL were assessed by glucose concentration, maximum bite force, and the Japanese version of Oral Health Impact Profile (OHIP-J49), respectively., Results: This study included five patients (two males, three females), aged between 71 and 88 years, with a median of 74 years. The median of glucose concentration indicated a statistically significant improvement between the acrylic resin (99.6 mg/dL) and silicone soft reliner (126.0 mg/dL) obturator prosthesis (p = .043). There was no significant difference in the median of maximum bite force between the acrylic resin (302.0 N) and silicone soft reliner (250.0 N) obturator prosthesis (p = .893). Functional limitations domain of the OHIP-J49 indicated a statistically significant improvement between the acrylic resin and silicone soft reliner obturator prosthesis (p = .043)., Conclusions: This study indicated that an obturator relined with soft silicone improved masticatory performance and the OHRQoL post-maxillectomy., (© 2020 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

Background: Some studies have reported topical application of 1.0%-2.0% fluoride gel in a custom tray for 4-5 minutes every day for the prevention of radiation-related dental caries. However, in Japan, the concentration of fluoride used by patients is limited to less than 0.15%. The efficacy of a low-concentration fluoride gel in a custom tray for the prevention of radiation-related dental caries has not been investigated. Methods and Material: In this preliminary study, we enrolled 13 patients with head and neck cancer who underwent radiotherapy. They wore a custom tray containing 0.145% sodium fluoride gel during sleep every night and were examined for newly developed dental caries 1 year later. Results: No new dental caries were found in the 13 patients 1 year after radiotherapy, and no adverse events were observed., Conclusions: We conclude that low-concentration fluoride gel in a custom tray during sleep could prevent radiation-related dental caries, and we plan to conduct a multi-center phase III randomized controlled trial to examine the efficacy of this method for the prevention of radiation-related dental caries., Competing Interests: None

Introduction: The present study is a randomised, multicentre, open-label, phase III study, to evaluate the efficacy of low concentration of fluoride gel, applied using custom trays, in preventing radiation-related dental caries in patients with head and neck cancer who have undergone or are undergoing radiotherapy., Methods and Analysis: Patients will be randomised into fluoride and control groups (1:1 ratio). In the fluoride group, patients will wear custom trays loaded with 0.145% fluoride gel after brushing every night while sleeping. In the control group, patients will receive oral hygiene instructions as usual. Patients in both the groups will be followed up every 3 months for 1 year. The primary endpoint is the incidence of newly developed dental caries. Target accrual is 80 patients with a two-sided type I error rate of 5% and 80% power to detect 80% risk reduction., Ethics and Dissemination: This study was approved by the Clinical Research Review Board in Nagasaki University The protocol of this study was registered at Japan Registry of Clinical Trials (jRCT) and University hospital Medical Information Network Clinical Trials Registry (UMIN). The datasets generated during the current study will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBERS: jRCTs 072190039 and UMIN000041426., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

While neoadjuvant chemotherapy (NAC) for patients with oral tongue squamous cell carcinoma (OTSCC) may improve tumor microenvironment, it may lead to local immune suppression caused by residual cancer cells. The efficacy of NAC is therefore controversial. In our study, we investigated tumor microenvironments after NAC using immune checkpoint molecules, and evaluated the association between tumor microenvironments, clinicopathological factors and outcomes. We reviewed the records of 121 patients who underwent radical surgery for OTSCC between April 2001 and March 2015. Patients with a positive surgical margin and a follow up period of less than 6 months were excluded. For these patients, programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) expressions were immunohistochemically examined. The expression of PD-1 and PD-L1 were significantly associated with local recurrence in patients with OTSCC (P < 0.01 and P < 0.01, respectively). We found a significant decrease in 5-year disease specific survival rate for patients with combined PD-1+/PD-L1+ expressions (P < 0.05). In the subgroup analysis of local recurrence between the NAC treated group and those who received surgery alone, high levels of PD-1 and PD-L1 expressions were significantly found in the former, but not in the latter group. Local recurrence in the NAC-treated group may contribute to local immune suppression in OTSCC. NAC lead to local immune suppression and immune checkpoint molecules play an important role in local recurrence in patients with OTSCC who received NAC. NAC modality can't be recommended for patients with OTSCC at present.

This study aimed to evaluate the factors contributing to postoperative anterior relapse or posterior drift of the distal segment after intraoral vertical ramus osteotomy. A retrospective cohort study was conducted which included 31 patients who underwent setback surgery for mandibular prognathism by the intraoral vertical ramus osteotomy technique. Uni- and multivariate analyses were performed to determine the association of potential explanatory variables (sex, age, magnitude of setback, differences in setback magnitude between sides (right/left), duration of splint use, Angle's classification of malocclusion, mandibular angle, and tightness of occlusion of the molars) with positional changes in the distal segment. The setback magnitude was only significant factor affecting (P = 0.015) for posterior drift, with significant posterior in setback magnitudes of less than 7.25 mm. Posterior drift after intraoral vertical ramus osteotomy is less likely if setback magnitude exceeds 7.25 mm. For setbacks less than 7.25 mm, posterior drift should either be carefully corrected postoperatively, or an alternative surgical technique should be used. The setback magnitude showed a significant association with the risk of posterior drift following intraoral vertical ramus osteotomy, and the determined cut-off value may serve as a predictor for postoperative outcomes.

Background and Objective: The delayed-on phenomenon (DOP) related to levodopa treatment frequently disturbs quality of life in advanced-stage Parkinson's disease (PD) patients. The objective of this study was to explore the impact of swallowing dysfunction on the development of DOP., Methods: Swallowing function was investigated by endoscopic evaluation in 11 PD patients with the DOP and 9 PD patients without the DOP during the on phase. Residual drug in the pharynx after taking the drug in tablet, capsule, and powder forms was also observed., Results: Residual drug was seen in the pharynx in six cases (30.0%). Pooling of saliva, delayed swallowing reflex, and residual drug were more frequent in the DOP group than in the group without the DOP ( P  < 0.05). The odds ratios for residual drug in the pharynx, pooling of saliva, and delayed swallowing reflex for the DOP were 42.7 (95% confidence interval, 1.89-962.9), 14.0 (95% confidence interval, 1.25-156.6), and 15.8 (95% confidence interval, 1.75-141.4), respectively., Conclusions: These results suggest that swallowing dysfunction leading to residual antiparkinsonian drug in the pharynx has substantial impacts on the DOP in PD patients., Competing Interests: This study was funded by JSPS KAKENHI Grants 15K19501 and 17K12069. The authors have no conflict of interest to declare., (© 2020 International Parkinson and Movement Disorder Society.)