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Preoperative assessment is essential to prevent inferior alveolar nerve (IAN) injury during surgical extraction of the lower third molar (LM3). Here, we aimed to establish an assessment system to predict IAN injury during surgical extraction of the LM3. We conducted a retrospective cohort study on 115 patients diagnosed as 'high-risk' based on our previous risk assessment method involving three anatomical features of the inferior alveolar canal using computed tomographic (CT) images. We evaluated the occurrence of neurosensory impairment in these high-risk patients, and its association with novel anatomic features based on CT images. Neurosensory impairments were observed in 19 patients (16.5%). The inferior alveolar canal major diameter (p0.0001) and lingual bone thickness (p = 0.0039) were significantly associated with the occurrence of neurosensory impairment during LM3 extraction. Receiver operating characteristic curves were used to determine cut-off values of these quantitative factors to specifically predict IAN injury. Preoperative risk assessment with quantitative factors based on anatomical features observed on CT images may facilitate more appropriate surgical planning for patients at a high risk of IAN injury.

Herein, we report two cases of patients diagnosed with nivolumab-refractory distant metastatic squamous cell carcinoma of the tongue who were successfully treated with a combination of paclitaxel and cetuximab, thus demonstrating that some nivolumab-refractory patients with recurrent or distant metastatic oral squamous cell carcinoma may benefit from subsequent salvage chemotherapy.

Objective To examine the safety and efficacy of hyperdry amniotic membrane (HDAM) for wound closure after palatoplasty in cleft palate patients. Methods HDAMs were prepared by washing and drying under infrared rays and microwaves at temperatures less than 60°C using a hyperdrying device. A total of 16 cleft palate patients (8 males, 8 females), aged 1 to 3 years (mean age 1 year 9 months), received one-stage pushback palatoplasty. The remaining raw wound after surgery was covered by an HDAM and a plastic cover plate. The cover plate was removed 1 week after surgery and parameters including temperature, feeding, allergic reactions, postoperative bleeding, re-epithelialization, wound dehiscence, and infection were monitored during the follow-up period of 31.2 months. Results All patients could adequately ingest at 5 days postoperation and after removal of the cover plate. None of the patients had a persistent fever or allergic reactions. Ingestion was feasible immediately in all patients, and no postoperative bleeding was observed during ingestion. No secondary hemorrhages were observed during follow-up. No postoperative wound dehiscence on the midline of the palate was observed. No infections were observed after the removal of the cover plate. No patients suffered from severe scar formation or contracture of the wound in the follow-up period. Hemorrhage, undue epithelialization, and scar contracture did not occur in any patient. The mean evaluation score was 7.75 points. Conclusion HDAM can be used safely and effectively for wound closure following palatoplasty in cleft palate infants. Future studies testing the safety of patient's own amnion for palatoplasty, are required.

Sepsis is a systemic reaction to an infection and resulting in excessive production of inflammatory cytokines and chemokines. It sometimes results in septic shock. The present study aimed to identify quinolone antibiotics that can reduce tumor necrosis factor alpha (TNFα) production and to elucidate mechanisms underlying inhibition of TNFα production. We identified quinolone antibiotics reduced TNFα production in lipopolysaccharide (LPS)-stimulated THP-1 cells. Sitafloxacin (STFX) is a broad-spectrum antibiotic of the quinolone class. STFX effectively suppressed TNFα production in LPS-stimulated THP-1 cells in a dose-dependent manner and increased extracellular signal-regulated kinase (ERK) phosphorylation. The percentage of intracellular TNFα increased in LPS-stimulated cells with STFX compared with that in LPS-stimulated cells. TNFα converting enzyme (TACE) released TNFα from the cells, and STFX suppressed TACE phosphorylation and activity. To conclude, one of the mechanisms underlying inhibition of TNFα production in LPS-stimulated THP-1 cells treated with STFX is the inhibition of TNFα release from cells via the suppression of TACE phosphorylation and activity. STFX may kill bacteria and suppress inflammation. Therefore, it can be effective for sepsis treatment.

Immunotherapy with nivolumab for patients with recurrent/metastatic oral squamous cell carcinoma has not been evaluated. Here, we aimed to examine the efficacy, safety, and prognostic factors of nivolumab in these patients.This multicentre retrospective observational study involved patients who received nivolumab between April 2017 and June 2019. The patient characteristics were evaluated for association with progression-free and overall survival. Progression-free and overall survival rates were calculated; parameters that were significant in the univariate analysis were used as explanatory variables. Independent factors for progression-free and overall survival were identified using multivariate analysis.Totally, 143 patients were included. The overall response and disease control rates were 27.3% and 46.2%, respectively. The median, 1-year, and 2-year progression-free survival rates were 2.7 months, 25.4%, and 19.2%, respectively; those for overall survival were 11.2 months, 47.3%, and 33.6%, respectively. The independent factors affecting progression-free survival were performance status and immune-related adverse event occurrence, whereas those affecting overall survival were performance status, target disease, and number of previous lines of systemic cancer therapy. Eight patients reported grade ≥3 immune-related adverse events.Nivolumab was effective for recurrent/metastatic oral squamous cell carcinoma treatment and was well tolerated by patients.

Objective Accumulating evidence has demonstrated the protumor role of estrogen receptor (ER)–mediated signaling in multiple cancer types, which is distinct from this signaling in sex steroid–dependent organs. However, its role in oral squamous cell carcinoma (OSCC) remains unclear. Study Design We assessed the expression of ERα and ERβ in human OSCC tissues by immunohistochemistry and evaluated the expression of both receptors in OSCC cell lines by immunoblotting and flow cytometry. To further assess the contribution of ER-mediated signals to oral cancer progression, proliferation, invasion, and chemosensitivity, cell lines were stimulated with the ER agonist β-estradiol. Results Immunohistochemical analysis of OSCC tissues showed that ERβ was present in the cytoplasm and nuclei of OSCC cells. In contrast, ERα was not detected in any of the cases analyzed. Additionally, the proliferation and invasiveness of OSCC cells were significantly elevated following stimulation with β-estradiol. Chemotherapeutic agent–induced apoptosis of cancer cells was attenuated by pretreatment with β-estradiol. Conclusions ER-mediated signaling plays a crucial role in oral cancer progression by facilitating the proliferation, invasion, and chemoresistance of OSCC cells, indicating its potential for developing novel targeted therapies for this type of cancer.

Although the dosage of oral antibiotics (OA) for the mandibular third molar extraction (MTME) varies among the administration periods according to the current guideline, our previous reports suggested that it might be possible to further shorten the administration period without increasing the incidence of surgical site infection (SSI). In the present study, we retrospectively evaluated the relationship between the incidence of SSI and the administration period of OA in patients who underwent the MTME in our hospital. This retrospective cohort study included 348 patients who underwent the MTME in our dental outpatient clinic from June 2020 to March 2022. The administrated antibiotic was amoxicillin (AMPC) in all patients. Patients were divided into two groups based on the administration period of AMPC single and three times before the surgery. The following information was collected: (1) patient factors (age, gender, body mass index, diagnosis, mandibular third molar status); (2) surgical factors (operation time, presence/absence of wound closure, presence/absence of hemostat, experience of surgeons); (3) relationship between administration period of OA and SSI occurrence; and (4) details of SSI. There were 217 cases in the single group and 131 cases in the three times group. The incidence of SSI was 1.1% (4/348), with 1.4% (3/217) in the single group and 0.8% (1/131) in the three times group; there was no significant difference between the two groups. Our result suggests that single administration of AMPC before the MTME would be sufficient for the prevention of SSI in Japanese patients without risk factors.

Cytology is a simple and non-invasive screening method for oral cancer. However, this method is not yet routinely used by clinicians because of its high false negative rate (FNR) and due to lack of sufficient studies examining the factors for high FNRs. The present retrospective study aimed to compare the screening performance of conventional cytology (CC) and liquid-based cytology (LBC) through histological validation, and to elucidate factors inducing false negative screening in oral cytology. Cytological specimens with histological examination and intraoral digital images of the lesion were retrospectively collected between January 2017 and December 2018 for CC and between October 2019 and September 2021 for LBC. Oral cytological screening was conducted based on the oral Bethesda system for oral cytology. Clinical subtypes were re-evaluated using intraoral digital images. The screening accuracy of oral cytology was calculated considering the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for detecting the malignant transformation of oral lesions. No statistically significant difference was noted in the inadequate rate between CC and LBC groups. For CC and LBC, the sensitivities were 60.9 and 59.2%, the specificities were 87.3 and 79.1%, the PPVs were 85.8 and 76.2%, and the NPVs were 63.9 and 63.2%, respectively. Thus, the screening accuracy was similar between methodologies. Among the clinicopathological factors investigated, histological diagnosis and cellularity contributed to false negative results. Homogeneous findings of oral epithelial dysplasia and the superficial growth of carcinoma

© 2022 The Author(s)Tetanus is an acute and vaccine-preventable disease caused by anaerobic bacteria, Clostridium tetani. This bacterium can enter the human body via a deep wound, burn injury or medical procedure; however, certain cases also originate from odontogenic infection. In the present study, a tetanus infection associated with dental origin in a 44-year-old man is reported. The case was complicated by lockjaw and difficulty swallowing that worsened over a few days, followed by a generalized spasm. Furthermore, a literature review was performed, in which six reported cases of tetanus, presumed to be of dental or oral origin, were identified between 2011and 2021. General practitioners, especially dentists, should be aware of tetanus associated with odontogenic origin even without a history of an external penetrating wound or other medical procedures:.

The long-term administration of tamoxifen to estrogen receptor α (ERα)-positive breast cancer patients is an established treatment that reduces mortality and recurrence. However, resistance to tamoxifen and an increased risk of endometrial cancer may occur; therefore, the mechanisms by which tamoxifen causes these adverse effects warrant further study. Tamoxifen has been shown to activate mitogen-activated protein kinase (MAPK) in an ERα-independent manner; therefore, we investigated its effects on the MAPK-mediated non-canonical activation of EphA2, a critical event regulating cell migration. Tamoxifen at slightly higher concentrations induced the rapid phosphorylation of EphA2 at Ser-897 via the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK-ribosomal S6 kinases (RSK) pathway in HeLa cells. In addition, tamoxifen significantly enhanced the migration ability of ERα-negative MDA-MB-231 breast cancer cells in RSK- and EphA2-dependent manners. Phosphorylated EphA2 was internalized and re-localized to the plasma membrane, including lamellipodia, in an RSK-dependent manner. Collectively, the present results provide novel insights into the tumor-promoting activity of tamoxifen.

The immune checkpoint inhibitor (ICI) nivolumab has revolutionized the treatment for recurrent or metastatic advanced oral cancer. Because the response rate remains low, the identification of predictive indicators of the response to nivolumab is among the most critical issues. The neutrophil-to-lymphocyte ratio(NLR)is a potential predictive marker of the response to nivolumab in patients with various cancer types. However, the utility of the NLR as a biomarker for predicting the response of oral cancer patients to ICIs is poorly understood.In this retrospective cohort study, we evaluated the association between NLR and nivolumab treatment outcome in 13 patients diagnosed with recurrent or metastatic oral squamous cell carcinoma(OSCC)treated with nivolumab at the Toyama University Hospital between December 2017 and December 2019.Complete response(CR)and partial response(PR)rates of 38.5%(5/13)and 0% (0/13), respectively, were observed in responders; stable disease(SD)and progressive disease(PD)rates of 7.7%(1/13) and 53.8%(7/13), respectively, were observed in non-responders. After nivolumab treatment, the median NLR among responders decreased to 3.3(3.0-3.9)from 4.1(3.7-4.3)during pre-treatment assessment and increased from 5.6(3.2- 9.2)at pre-treatment to 9.4(5.3-17.9)among non-responders. Moreover, patients with higher NLRs(≥5)in the post- treatment group had a significantly worse overall survival than those with lower NLRs(5). Specifically, patients with a higher post-treatment NLR(≥10)had significantly worse outcomes for post-nivolumab salvage chemotherapy.The NLR could be a useful marker for predicting the treatment response to nivolumab or post-nivolumab salvage chemotherapy in OSCC patients.

Paranasal sinus aplasia is a rare condition. Here, we report an extremely rare case of total paranasal sinus aplasia accompanied by 18 impacted teeth. A 77-year old man presented with a complaint of diffuse swelling in the anterior maxilla. Radiographs revealed well-demarcated radiolucent cystic lesions in the swollen maxilla. However, 14 teeth were impacted in the maxilla, and 4 were impacted in the mandible. Furthermore, paranasal sinuses were completely obliterated. The patient then underwent cystectomy and five impacted anterior maxillary teeth were extracted under general anesthesia. Furthermore, no systemic diseases, including metabolic and endocrine abnormalities, and bone diseases including osteogenesis imperfecta, which may have resulted in total paranasal sinus aplasia, were identified. The patient is healthy with no maxillary osteitis 1 year after cystectomy. To our knowledge, three cases of total paranasal sinus aplasia have been reported thus far (in English); however, no studies have reported cases of total paranasal aplasia with multiple impacted teeth. Therefore, while computed tomography is required to detect total paranasal sinus aplasia, maxillary sinus aplasia can be detected through panoramic radiography in general dental practice; hence, dental practitioners should consider the possibility, since paranasal sinus aplasia may result from severe systemic diseases or syndromes.

Intraosseous mucoepidermoid carcinoma of the jaw is a rare lesion that has been suggested to originate from the odontogenic epithelium. We report an unusual case of central mucoepidermoid carcinoma in an 18‐year‐old Japanese man with an odontogenic cyst., This report describes the clinical and histologic features of this extremely rare case of central mucoepidermoid carcinoma admixed with a calcifying odontogenic cyst.

Adenosquamous carcinoma (ASC) is an aggressive subtype of squamous cell carcinoma (SCC). Due to its poor prognosis, a precise pathological diagnosis of ASC is essential but challenging because its pathological criteria are still unclear. Here, we present a rare case of oral ASC accompanied by acantholytic features. The tumor was raised in the mandibular gingiva and recurred locally approximately 13 months after the initial surgery with cervical lymph node metastasis. Pathological specimens of the primary lesion showed acantholysis in a large area of the SCC. Mucous cells, the characteristic finding indicating glandular differentiation, were imperceptible in the initial surgical specimen but increased in the locally recurrent and metastatic lymph node specimens. In a comprehensive literature review of oral ASC cases, the present case was the only case of ASC with acantholytic features. We reconfirmed that ASC has poor prognoses, such as low 5-year overall survival and disease-free survival, high locoregional recurrence, and high distant metastasis rates. A precise diagnosis of ASC is required for estimating prognosis and undergoing close follow-up, even if the adenocarcinomatous component is limited to a small area in the lesion.

Although the optimal treatment method for metastatic oral cancer remains largely unknown, the present case suggests that immunotherapy is a potentially promising alternative for metastatic oral cancer in which other therapies are no longer effective.

Sepsis is a systemic reaction to infection and excessive production of inflammatory cytokines and chemokines. It sometimes results in septic shock. The present study was designated to find out which quinolone antibiotic reduces TNFα production the most and to elucidate its mechanisms. We examined which quinolone antibiotic reduced TNFα production from THP-1 cells stimulated by lipopolysaccharide (LPS). Then, we examined the mechanism of inhibition of TNFα production by the antibiotic. STFX most effectively reduced TNFα concentrations within LPS-stimulated THP-1 cells supernatant. STFX suppressed TNFα production in a dose-dependent manner. We found that STFX did not inhibit the NF-kB, ERK, or p38 pathways, nor did it inhibit the production of TNFα mRNA. The percentage of intracellular TNFα was increased in cells stimulated by LPS and with STFX compared to that of cells stimulated by LPS alone. In conclusion, one of the mechanisms reducing TNFα production from LPS-stimulated THP-1 cells treated with STFX involves inhibition of TNFα release from these cells. STFX has a broad antimicrobial spectrum for gram-positive, gram-negative, and anaerobic bacteria, and may be effective for treating sepsis by both killing bacteria and suppressing inflammation.

Velopharyngeal incompetence (VPI) is a motor impairment of the soft palate that can result in functional disorders, such as stuttering. Therefore, therapeutic interventions for VPI should begin at an early stage. We examined the possibility of early detection of motor impairments of the soft palate with ultrasonographic observations. The study was conducted on five individuals without suckling disorders (two males, three females) at 6-9 postnatal weeks of age (Stage 1) and 13-23 postnatal weeks of age (Stage 2). The extent and speed of soft palate movement during suckling was measured with ultrasonography. The extent of movement of the soft palate was 5.67 ± 0.68 mm at Stage 1 and 6.42 ± 1.55 mm at Stage 2 (t = 0.929, p = 0.190). The speed of soft palate movements at Stage 1 was 44.00 ± 9.93 mm/s during elevation and 27.37 ± 8.07 mm/s during depression (t = 5.182, p = 0.007), whereas that at Stage 2 was 42.89 ± 14.37 mm/s during elevation and 26.43 ± 9.06 mm/s during depression (t = 3.195, p = 0.033). We observed regular soft palate elevations and depressions during suckling. There were no differences in the extent or speed of movements between Stages 1 and 2. Future studies are needed to compare differences in motor impairments of the soft palate between healthy children and those suspected of having a submucous cleft palate or VPI.

The repurposing of existing FDA-approved non-cancer drugs is a potential source of new treatment options for cancer patients. An anti-inflammatory drug, 5-aminosalicylic acid (5-ASA), has been clinically used to treat inflammatory bowel disease. Hyperthermia (HT) is widely applicable addendum therapy with the existing cancer treatment modalities. Here, we addressed how 5-ASA combined with HT induces lethal effects in human oral squamous cell carcinoma (OSCC) HSC-3 cells. We found that 5-ASA/HT combination significantly inhibited the viability of HSC-3 cells, while cytotoxic effects in primary human dermal fibroblast cells were minor. Apoptotic endpoints were significantly increased by the 5-ASA/HT combined treatment, as evidenced by presence of Annexin V-FITC/PI positive cells, loss of MMP, Bcl-2/Bax ratio alteration, and increased Fas, cleaved Bid, and caspase expression. Interestingly, the enhancement of apoptosis was reversed in the presence of ON/ONOO− scavengers. These findings indicate that the combination treatment enhances apoptosis via ON/ONOO− mediated ER stress-Ca2+-mitochondria signaling and caspase-dependent apoptotic pathways. Our findings provide novel evidence that the combination of 5-ASA and HT is a promising approach for the enhancement of apoptosis; it may serve as an effective strategy for treating human OSCC.

Objectives The immune status of the tumor microenvironment has a marked impact on clinical outcomes. Here we examined the immune environments of tumor-infiltrating leukocytes (TILes) in two murine models of squamous cell carcinoma and compared the effects of immunotherapeutic agents, including a TLR7 agonist and an immune checkpoint inhibitor, and a chemotherapeutic agent, gemcitabine, in these models. Materials and methods TILes from NR-S1- and SCCVII-grafted mice were analyzed by flow cytometry. NR-S1-inoculated mice received resiquimod (a synthetic TLR7 agonist), an anti-PD-L1 antibody, or both, and tumor growth and TILs were examined. Gemcitabine was administered to deplete CD11b+ cells. Results More than 50% of TILes from NR-S1- and SCCVII-inoculated mice were CD11b+Gr-1+ cells. A major fraction of NR-S1 CD11b+ cells was Ly6GhighLy6Clow-negaF4/80− tumor-associated neutrophils (TANs) and the majority of SCCVII CD11b+ cells were Ly6GlowLy6C−F4/80+ tumor-associated macrophages. NR-S1 TANs did not express MHC class II and CD86, but did express reactive oxygen species and PD-L1. Resiquimod, alone and in combination with an anti-PD-L1 antibody, did not regress NR-S1 tumors, but the combination increased the CD8/regulatory T cell-ratio, and IFN-γ and PD-1 expression in CD8+ TILes. Pre-administration of low-dose gemcitabine prior to the combination treatment suppressed the progression of NR-S1 tumors. Conclusions NR-S1 tumors with abundant recruitment of TANs were resistant to treatments with a TLR7 agonist, alone and in combination with PD-1 blockade, and required an additional gemcitabine treatment. The phenotype and status of tumor-infiltrating CD11b+ myeloid cells may influence the efficacy of immunotherapeutic agents.

Along with blood vessels, lymphatic vessels play an important role in the circulation of body fluid and recruitment of immune cells. Postnatal lymphangiogenesis commonly occurs from preexisting lymphatic vessels by sprouting, which is induced by lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C). However, the key signals and cell types that stimulate pathological lymphangiogenesis, such as human cystic lymphangioma, are less well known. Here, we found that mouse dermal fibroblasts that infiltrate to sponges subcutaneously implanted express VEGF-D and sushi, Von Willebrand factor type A, EGF, and pentraxin domain containing 1 (SVEP1) in response to PDGFRβ signal. In vitro, Pdgfrb knockout (β-KO) fibroblasts had reduced expression of VEGF-D and SVEP1 and overproduced Amphiregulin. Dysregulation of these three factors was involved in the cyst-like and uneven distribution of lymphatic vessels observed in the β-KO mice. Similarly, in human cystic lymphangioma, which is one of the intractable diseases and mostly occurs in childhood, fibroblasts surrounding cystic lymphatics highly expressed Amphiregulin. Moreover, fibroblast-derived Amphiregulin could induce the expression of Amphiregulin in lymphatic endothelial cells. The dual source of Amphiregulin activated EGFR expressed on the lymphatic endothelial cells. This exacerbation cascade induced proliferation of lymphatic endothelial cells to form cystic lymphangioma. Ultimately, excessive Amphiregulin produced by fibroblasts surrounding lymphatics and by lymphatic endothelial cells per se results in pathogenesis of cystic lymphangioma and will be a fascinating therapeutic target of cystic lymphangioma.

Cleft lip and cleft alveolus are caused by incomplete fusion of the frontonasal and maxillary prominences. However, milder forms of cleft lip are rarely accompanied by cleft alveolus. Here, we report a rare case of mini‐microform cleft lip with complete cleft alveolus and cleft palate. No findings suggestive of cleft lip were evident on initial examination. However, three‐dimensional facial measurements confirmed the presence of cleft lip despite no evidence of orbicularis oris muscle (OOM) rupture on ultrasonography. Collapsed nostril, as observed in this case, is usually associated with OOM rupture. However, it can also be caused by skeletal abnormalities, such as cleft alveolus. Three‐dimensional facial measurements and ultrasonography can assist in accurate diagnosis when visual examination is ambiguous.

Background/Aims: The migration of mesenchymal cells is a fundamental cellular process that has been implicated in many pathophysiological conditions and is induced by chemoattractants such as platelet-derived growth factors (PDGFs). However, the regulatory mechanisms shaping this migration remain to be elucidated. Methods: Here, we prepared mouse skin fibroblasts inactivated for different PDGF receptor genes and systematically measured their chemotactic responses within a gradient of different chemoattractants. Results: We found that PDGFRαβ and PDGFRββ dimers were strong inducers of random and directionally-persistent migration, respectively, that was sustained for up to 24 h. MAPK and PI3K were necessary to mediate random and directional migration, respectively. Directional migration was accompanied by abundant ventral stress fiber formation and consistent cell shape with less frequent formation of branch-like processes. Conclusion: This is the first systematic study that characterized the chemotaxis mediated by three-different types of PDGFR dimers in mesenchymal cell migration. Our data demonstrate that PDGFR dimer formation is the critical step to determine the specific mode of fibroblast chemotaxis, while the accompanying cytoskeletal remodeling might contribute to migration persistence.

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas that originate in peripheral nerves or neurilemma cells. Here, we report an extremely rare case of an intraosseous MPNST in the mandible of a patient with neurofibromatosis type 1 (NF1). A 57-year-old woman with a history of NF1 was referred to our hospital because she had abnormal sensations at her left mandible. She was diagnosed with MPNST and underwent radical resection, although local recurrence and multiple metastases were detected during follow-up. Despite receiving palliative radiotherapy, the patient died at 13 months after the initial diagnosis.

Scimitar syndrome is a rare congenital cardiac condition with a poor prognosis. It is frequently accompanied by concordant pulmonary hypoplasia and aortopulmonary collateral arteries connected to the hypoplastic lung. Here we report a case involving a 58-year-old woman with scimitar syndrome who developed stage II oral cancer. Surgical treatment was deemed high risk because of difficulty in respiratory management through mechanical ventilation during general anesthesia, and hence, she was treated with chemoradiotherapy, which was successfully completed. The findings from this case suggest that chemoradiotherapy is a useful strategy that can contribute to improved clinical outcomes for oral cancer in patients with scimitar syndrome.

A retrospective cohort study was performed to assess the clinical usefulness of combination assessment using computed tomography (CT) images in patients undergoing third molar extraction. This study included 85 patients (124 extraction sites). The relationship between cortication status, buccolingual position, and shape of the inferior alveolar canal (IAC) on CT images and the incidence of inferior alveolar nerve (IAN) injury after third molar extraction was evaluated. IAN injury was observed at eight of the 124 sites (6.5%), and in five of 19 sites (26.3%) in which cortication was absent+the IAC had a lingual position+the IAC had a dumbbell shape. Significant relationships were found between IAN injury and the three IAC factors (cortication status, IAC position, and IAC shape; P=0.0001). In patients with the three IAC factors, logistic regression analysis indicated a strong association between these factors and IAN injury (P=0.007). An absence of cortication, a lingually positioned IAC, and a dumbbell-shaped IAC are considered to indicate a high risk of IAN injury according to the logistic regression analysis (P=0.007). These results suggest that a combined assessment of these three IAC factors could be useful for the improved prediction of IAN injury.

Cold atmospheric plasmas (CAPs) have been proposed as a novel therapeutic method for its anti-cancer potential. However, its biological effects in combination with other physical modalities remain elusive. Therefore, this study examined the effects of cold atmospheric helium plasma (He-CAP) in combination with hyperthermia (HT) 42 °C or radiation 5 Gy. Synergistic enhancement in the cell death with HT and an additive enhancement with radiation were observed following He-CAP treatment. The synergistic effects were accompanied by increased intracellular reactive oxygen species (ROS) production. Hydrogen peroxide (H2O2) and superoxide (O2•–) generation was increased immediately after He-CAP treatment, but fails to initiate cell death process. Interestingly, at late hour’s He-CAP-induced O2•– generation subsides, however the combined treatment showed sustained increased intracellular O2•– level, and enhanced cell death than either treatment alone. He-CAP caused marked induction of ROS in the aqueous medium, but He-CAP-induced ROS seems insufficient or not completely incorporated intra-cellularly to activate cell death machinery. The observed synergistic effects were due to the HT effects on membrane fluidity which facilitate the incorporation of He-CAP-induced ROS into the cells, thus results in the enhanced cancer cell death following combined treatment. These findings would be helpful when establishing a therapeutic strategy for CAP in combination with HT or radiation.

The effect of resveratrol on various human cancer cells was investigated with special focus on apoptotic cell death, in an attempt to further characterize its mechanism of action. There were great differences in the anti-viability effect of resveratrol between different types of human cancer cells. While the inhibition of cell viability by resveratrol was marked in U937 and MOLT-4 leukemia cells, resveratrol moderately inhibited cell viability in MCF-7 breast, HepG2 liver, and A549 lung cancer cells, and the effect was slight on cell viability in Caco-2, HCT116, and SW480 colon cancer cells. Following resveratrol treatment, U937 and MOLT-4 markedly increased the population of late apoptotic cells but MCF-7 and HepG2 underwent apoptosis with an increased population of early apoptosis, and resveratrol-induced DNA fragmentation was observed only in leukemic cells. Activation of sirtuin 1 and adenosine-monophosphate-activated protein kinase was not responsible for resveratrol-induced cancer cell death. Instead, resveratrol significantly reduced Akt activation with the downregulation of H-Ras, resulting in facilitation of Bax translocation to mitochondria in leukemic cells. This study suggests that resveratrol can induce apoptotic cell death in human leukemic cells to a greater extent than in human solid tumor cells via reducing Akt activation due to Ras downregulation.

Methadone, a synthetic opioid agonist, is used for pain that is refractory to other opioids. However, limited data on its ability to control pain in patients with oral cancer are available. In this study, we present a case of recurrent oral cancer, in which pain was poorly controlled with high-dose oxycodone but successfully controlled with methadone. A 36-year-old male patient was referred to our hospital for the treatment of recurrent oral cancer. His pain no longer responded to increased dosages of oxycodone, and thus oxycodone was switched to methadone. Ultimately, his pain was successfully controlled with methadone throughout his end-of-life stage.

Objectives Aging has been suggested to be associated with immune dysregulation. An understanding of alterations in the host immunity with advancing age is, therefore, important for designing immune therapy for elderly cancer patients. In this context, not much is known about age-associated alterations in the immune system in oral cancer. Methods To evaluate age-associated alterations in the immune system, which might affect anti-tumor immune responses in oral cancer, we performed a comparative analysis of the proportion of different immune cells, the proliferative capacity of T cell compartment, and the response against immune therapies targeting immune check point molecules between young and aged oral cancer-bearing mice. Results The proportion of immune regulatory cells, such as regulatory T cells and myeloid derived suppressor cells, was significantly increased in aged mice compared to that in young mice. Moreover, the expression of PD-1 and CTLA-4 on both CD4+ and CD8+ T cells was elevated in aged mice compared to that in young mice, and the proliferative abilities of CD4+ and CD8+ T cells derived from aged mice were significantly reduced following stimulation of T-cell receptors. Moreover, tumor growth was significantly enhanced in aged mice compared to that in young mice. However, immunotherapies targeting PD-1, CTLA-4, and PD-L1 resulted in faster tumor regression in aged mice than in young mice. Conclusions Together, our results indicate that age-associated alterations in the immune system are directly associated with the impairment of anti-tumor immunity in aged mice bearing oral cancer, and might facilitate the progression of the tumor.

Objective Recent studies have demonstrated the pro-tumour role of CD36 in multiple cancer types. However, its role has not been well elucidated in oral squamous cell carcinoma (OSCC). Here, we aimed to evaluate the role of CD36 in proliferation and migration of OSCC cells. Methods Human OSCC cell lines HSC-2, HSC-3, HSC-4 and Ca9-22 were assessed for proliferation by staining with the cell proliferation marker Ki-67. We also assessed migration activity, and the expression of cell adhesion molecules such as E-cadherin and β-catenin and platelet-derived growth factor receptors (PDGFRs) of CD36-positive cells. Results CD36-positive cells showed increased expression of Ki-67 and migration activity compared with CD36-negative cells. Moreover, CD36-positive cells showed reduced expression of E-cadherin and β-catenin, whereas the expression of PDGFRs increased compared with that in CD36-negative cells. Conclusions Our results strongly suggest that CD36 has an important role in facilitating the proliferation and migration activity of OSCC cells, indicating its usefulness in the diagnosis of high-grade tumour and targeted therapy of oral cancer.

Cancer is often associated with dysregulation of both the humoral and cellular immune response, which in some instances is believed to result from changes in immune cell populations. For example, immunosuppressive CD11b(+)Gr-1(+) myeloid-derived suppressor cells have been shown to proliferate in the tumor microenvironment and surrounding tissues, highlighting the relationship between tumor growth and impairment of the immune response. However, the role of myeloid-derived suppressor cells in cancer progression has not been fully characterized because these cells are heterogeneous with properties influenced by the type and location of the tumor. Here, we show that CD11b(+)Gr-1(+) cells are elevated in the peripheral blood, spleen, and tumor of mice with oral squamous cell carcinoma. The phenotype and function of these cells varied depending on the tissue of origin. In particular, CD11b(+)Gr-1(+) cells in tumors expressed PD-L1 more abundantly than those in other tissues. Accordingly, CD11b(+)Gr-1(+) cells from tumors, but not from the spleen, suppressed T cell proliferation in vitro. The results suggest that tumor-derived or immune factors result in the accumulation of phenotypically and functionally diverse populations of CD11b(+)Gr-1(+) cells in mice with oral squamous cell carcinoma. The data also indicate that PD-L1 expression in CD11b(+)Gr-1(+) cells contributes to immune suppression, implying that targeting both myeloid-derived suppressor cells and PD-L1 would be an effective immunotherapeutic strategy against oral cancer.

Dyskeratosis congenita (DC) is an inherited disease characterized by the triad of skin pigmentation, nail dystrophy, and oral leukoplakia. Among other abnormalities, bone marrow failure and a predisposition to cancer are recognized as the major causes of premature mortality in patients with DC. This disease is associated with short telomeres and mutations in 10 genes associated with telomerase and telomere components. The case of a 35-year-old male patient diagnosed with DC, who presented with leukoplakia of the tongue and had a high degree of hypoplastic marrow, but no haematological abnormalities, is reported here. The diagnosis of DC was confirmed by detection of short telomeres in the blood cells and mutations in the DKC1 gene. This encounter with the case presented suggests that an awareness of the classical forms of DC is important for oral clinicians so that an early diagnosis can be made and the patient can be managed appropriately. Furthermore, genetic analysis is necessary to establish the diagnosis of DC.

Sulfasalazine (SSZ) is a well-known anti-inflammatory drug and also an inhibitor of the cystine-glutamate antiporter that is known to reduce intracellular glutathione (GSH) level and increase cellular oxidative stress, indicating its anti-tumor potential. However, the combination of SSZ with other physical modalities remains unexplored. Here, the effects of SSZ on cold atmospheric helium plasma (He-CAP), which produces approximately 24 x higher concentration of hydroxyl radicals (. OH) compared to X-irradiation (IR) in aqueous solution, and on IR-induced apoptosis in human leukemia Molt-4 cells were studied to elucidate the mechanism of apoptosis enhancement. Both the Annexin V-FITC/PI and DNA fragmentation assay revealed that pre-treatment of cells with SSZ significantly enhanced He-CAP and IR-induced apoptosis. Similar enhancement was observed during the loss of mitochondrial membrane potential, intracellular Ca2+ ions, and mitochondria- and endoplasmic reticulum-related proteins. The concentration of intracellular reactive oxygen species (ROS) was much higher in He-CAP treated cells than in X-irradiated cells. On the other hand, strong enhancement of Fas expression and caspase-8 and -3 activities were only observed in X-irradiated cells. It might be possible that the higher concentration of intracellular and extracellular ROS suppressed caspase activities and Fas expression in He-CAP-treated cells. Notably, pretreating the cells with an antioxidant N-acetyl-L-cysteine (NAC) dramatically decreased apoptosis in cells treated by He-CAP, but not by IR. These results suggest that IR-induced apoptosis is due to specific and effective ROS distribution since intracellular ROS formation is marginal and the high production of ROS inside and outside of cells plays unique roles in He-CAP induced apoptosis. We conclude that our data provides efficacy and mechanistic insights for SSZ, which might be helpful for establishing SSZ as a future sensitizer in He-CAP or IR therapy for cancer.

The growth of maxillary bone and the development of dentition are often impaired in patients who have had pushback operations for repair of a cleft palate. There has been considerable discussion about the most suitable technique or material used in such repairs to resolve the problem. Hyperdry amniotic membrane, a new preservable material derived from human amnion, has recently been introduced in several procedures. We have evaluated its use during pushback surgery in animal studies to try to correct the inhibition of growth and development of the maxilla. Mucosal defects were created in 3-week-old rats, and then covered with hyperdry amniotic membrane or not. Healing was assessed by histological and morphological examination at 1 week and 7 weeks postoperatively. In the group treated with hyperdry amniotic membrane, submucosal tissue was reconstructed successfully during the early postoperative period. Lateral palatal growth was not inhibited as much, and medial inclination of the teeth was less, after a period of growth using this material. The results suggest that hyperdry amniotic membrane is a suitable new dressing material for use in the treatment of cleft palate.

This study aimed to assess the effects of induction chemotherapy (ICT) using intra-arterial high-dose cisplatin (CDDP) infusion and concurrent peroral tegafur (TS-1) for the management of locally advanced oral cancer. We analyzed 30 patients diagnosed with locally advanced oral squamous cell carcinoma who were treated at our university hospital from April 2007 to March 2011. Eleven patients were diagnosed with stage II tumors, 10 with stage III, and 9 with stage IVA. Six patients demonstrated complete response to ICT, and the overall response rate, including the partial response rate, was 77%. Definitive therapies comprised “wait and see” for 3 patients, chemoradiotherapy for 3, brachytherapy for 1, and ablation surgery for 23 (limited, standard, and extended surgeries in 9, 13, and 1 patients, respectively). Locoregional recurrence was observed in 7 patients, 4 of whom died. ICT can potentially predict good outcome in the management of locally advanced oral cancer. Definitive therapy should be determined on the basis of patients’ response to ICT. Further investigations to determine the criteria indicating the appropriate therapy to be employed after ICT are required.

Background Major risk factors for oral squamous cell carcinoma (SCC) are tobacco smoking, a betel quid chewing habit, and heavy alcohol consumption. However, around 15% of oral SCCs cannot be explained by these risk factors. Although oral SCC associated with dental implants is quite rare, there has been a recent gradual accumulation of reports about it. Here, we report a case of primary peri-implant oral intra-epithelial neoplasia/carcinoma in situ (OIN/CIS) in a woman without the major risk factors for oral SCC. Case presentation A 65-year-old woman was referred to our clinic with a tumor in the right lower gingiva. She had no history of tobacco smoking and only drank socially. Ten years previously, mandibular right posterior teeth had been replaced with an implant-supported porcelain-fused-to-metal restoration in a dental clinic. About 7 years later, she noticed swelling on the lingual side of the gingiva around the implant-supported restoration, and was eventually referred to our clinic with the suspicion of a neoplasia around the dental implant. The upper part of the implant body was exposed on the implant corresponding to the first molar of the right side of the mandible; this was associated with painless, elastic soft, and relatively well circumscribed gingival swelling on the lingual site. A panoramic radiograph showed slight vertical bone resorption around the implants. An incisional biopsy was conducted under the suspicion of neoplasia. Pathological microscopic examination of the biopsy specimen revealed thickened squamous epithelia with slight nuclear atypism and disorders of the epithelial rete pegs. Immunohistochemical findings showed positive staining for keratin 17 and a negative staining mosaic pattern for keratin 13. High p53, p63, and Ki-67 reactivity was also observed. From these findings, OIN/CIS of the gingiva was pathologically diagnosed, and a wide local excision with rim resection of the mandible, including the implants, was performed. The pathological findings for the resected specimen were same as those for the biopsy specimen. After 1 year of follow-up, there was no evidence of recurrence. Conclusion In this case, prolonged peri-implant mucositis or peri-implantitis may have been a plausible risk factor for carcinogenesis.