Association between lymph node ratio and survival outcomes in patients with oral squamous cell carcinoma.

BACKGROUND: Recent reports have shown that the Lymph node ratio (LNR) is useful for predicting the prognosis in some cancers, however there are few reports on the usefulness of LNR in predicting the prognosis of oral squamous cell carcinoma (OSCC). The predictive value of LNR for prognosis of OSCC was investigated. MATERIALS AND METHODS: The study included 152 patients with OSCC and histologically confirmed cervical lymph node metastasis who underwent neck dissection. We analyzed the relationship between LNR and overall survival (OS) and recurrence-free survival (RFS) retrospectively in these cases, with the relationship between prognosis and clinicopathological findings also examined. RESULTS: Using a receiver operating characteristics curve, the LNR cutoff value was set at 0.095, categorizing 64 and 88 cases into high LNR (≥ 0.095) and low LNR (< 0.095) groups, respectively. Regarding OS and RFS, the prognosis was significantly worse in the high LNR group compared with the low LNR group. In multivariate analysis, sex, postoperative nodal stage, and LNR merged as independent prognostic factors. CONCLUSION: This study's findings suggest that LNR may represent a prognostic indicator in OSCC with cervical lymph node metastasis.

Horseshoe osteotomy maintains the nasal cavity and function after superior repositioning.

The aim of this prospective cohort study was to compare changes in nasal cavity and function between Le Fort I with and without horseshoe osteotomy after superior repositioning of the maxilla. The patients were divided into 2 groups, a Le Fort I alone (LF alone) group and a combination Le Fort I and horseshoe osteotomy (HS) group. The nasal cavity volume was measured using 3-dimensional computed tomographic images, and nasal resistance was assessed by anterior active mask rhinomanometry. The HS group consisted of 17 patients, and the LF alone group consisted of 15 patients. The magnitude of change in nasal cavity volume was significantly smaller in the HS group than in the LF alone group (p < 0.001), even though the mean amount of superior maxillary movement was considerably larger in the HS group than in the LF alone group (p < 0.001). Mean nasal resistance was significantly smaller postoperatively than preoperatively in the HS group (p < 0.05). Furthermore, the change in nasal resistance was smaller in the HS group than in the LF alone group (p < 0.001). Within the limitations of this study, it seems that horseshoe osteotomy is useful for maintaining the nasal cavity and function after superior repositioning of the maxilla.

Cyclic anthraquinone derivatives, unique G-quadruplex binders, selectively induce cancer cell apoptosis and inhibit tumor growth.

Cyclic anthraquinone derivatives (cAQs), which link two side chains of 1,5-disubstituted anthraquinone as a threading DNA intercalator, have been developed as G-quartet (G4) DNA-specific ligands. Among the cAQs, cAQ-mBen linked through the 1,3-position of benzene had the strongest affinity for G4 recognition and stabilization in vitro and was confirmed to bind to the G4 structure in vivo, selectively inhibiting cancer cell proliferation in correlation with telomerase expression levels and triggering cell apoptosis. RNA-sequencing analysis further indicated that differentially expressed genes regulated by cAQ-mBen were profiled with more potential quadruplex-forming sequences. In the treatment of the tumor-bearing mouse model, cAQ-mBen could effectively reduce tumor tissue and had less adverse effects on healthy tissue. These results suggest that cAQ-mBen can be a potential cancer therapeutic agent as a G4 binder.

Post-reconstruction Free Flap Complications After Oral Cancer Ablation.

Introduction: Microvascular free flap transfer is considered a standard reconstruction after the ablation of oral cancer. Although the success rate is high, flap complications occasionally occur. This study investigated the reasons for and local factors involved in complications of free flap transfer and explored how to salvage the flaps. Patients and Methods: The cases of 53 patients who underwent a free flap transfer [radial forearm flaps (n = 36), abdominis musculocutaneous flaps (n = 6), scapular osteocutaneous flaps (n = 10), and fibular osteocutaneous flap (n = 1)] were analyzed: flap complications were observed in five of the cases. Results: In the all five cases, a salvage operation was performed under general anesthesia. The flap complications occurred within 33 h after anastomosis. In the salvage operation, thrombotic occlusion in veins of flap feeders was observed in three of the five cases. The possible reasons for flap complications were a twisting of the anastomosed vein where two veins were united, pressure to the feeder due to subcutaneous hematoma, and edema of adjacent tissue and/or drain tube; the reason was not clear in one case. The flaps were successfully salvaged in four cases by thrombectomy in veins, release of pressure at the veins, and/or interposition of the vein graft. Conclusion: Surgeons should pay close attention to the pressure and/or twisting in the feeder as well as the hemostasis in the surgical field, and a salvage operation should be carried out immediately when a flap complication is identified.

Analysis of external nasal morphology and the direction of maxillary repositioning following Le Fort I osteotomy.

This study investigated the relationship between the direction of maxillary repositioning after Le Fort I osteotomy and changes in external nasal morphology using lateral cephalograms and frontal facial photographs. The results indicated greater changes in external nasal morphology, such as a more forward position of the nasal tip and an increased alar base width, with anterosuperior repositioning than with posterosuperior repositioning. In conclusion, this study demonstrated that the external nasal morphology changes after Le Fort I osteotomy, and that the changes vary depending on the direction of maxilla repositioning.

Human telomerase reverse transcriptase protein expression is associated with survival in patients with oral squamous cell carcinoma.

Despite improvements in diagnosis and treatment, the 5-year survival of oral squamous cell carcinoma (OSCC), no matter the location, remains low, averaging 50%. Telomerase is expressed in 85% of malignancies and may play an important role in human carcinogenesis. Its catalytic component is human telomerase reverse transcriptase (hTERT), which has been thought, but not proven, to be involved in survival with OSCC. We investigated whether hTERT protein was a prognostic factor in OSCC by evaluating its association with clinicopathologic findings and OSCC survival. We found that in comparison to patients with high hTERT expression, patients with low hTERT expression survived significantly longer, including a longer 5-year overall survival. In addition, overall survival was significantly correlated to hTERT expression and the histologic grade and N status of the tumor. Disease-free survival was significantly related to hTERT expression, the histologic grade and N status of the tumor, and mode of invasion. These results suggest that hTERT protein is involved in cervical lymph node metastasis, that its levels may be increased during carcinogenesis, and that it may influence tumor invasion. We believe that this study is the first to demonstrate that OSCC with high hTERT expression carries a worse prognosis than cases with low hTERT expression.

Effective ancillary role and long-term course of daily or weekly teriparatide treatment on refractory medication-related osteonecrosis of the jaw: a clinical case series.

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse side effect of antiresorptive agents. However, withdrawal of such agents in patients with osteoporosis may increase the risk of fracture. The treatment of MRONJ is challenging, and standard treatment guidelines have yet to be established. In this study, the aim was to find out whether adjuvant daily or weekly teriparatide (TPTD) injections were beneficial for exposed bony MRONJ lesions compared with standard conservative management. We also studied the complications and the patients' response to TPTD therapy. We enrolled 27 patients (January 2012 - December 2016) with chronic and refractory MRONJ. There were four men and 23 women (85% female). Nine patients who did not select TPTD therapy for several reasons formed the non-TPTD group; the remaining 18 were randomly assigned to the daily (n=9) or weekly (n=9) groups. All patients in both groups continued standard conservative therapy in addition to their daily or weekly subcutaneous injection of TPTD (20 µg or 56.5 µg, respectively). We evaluated the complications of TPTD and its benefits. Three patients in the daily group did not complete the study, resulting in six patients in the daily group, nine in the weekly group, and nine in the non-TPTD group in the final analysis. The exposed bone was completely covered with normal mucosa in all patients in the TPTD groups, and the healing period was shorter than that in the non-TPTD group. No patient had complications of atypical fractures of the femoral head. Daily and weekly TPTD treatment resulted in a shortened treatment period compared with standard conservative therapy, with no increase in the rate of complications or worsening of osteoporosis.

Effect of COVID-19 on dental telemedicine in Japan.

BACKGROUND/PURPOSE: In Japan, medical and dental care is provided by the universal health insurance system. The Ministry of Health, Labour, and Welfare (MHLW) in Japan sets the rules for health care services provided by health insurance. The MHLW issued a notice in 2020 permitting telemedicine and dental telemedicine for the first visit and for follow-up visits to prevent the spread of COVID-19 infection. We conducted this study to clarify the status of dental telemedicine during 2020. MATERIALS AND METHODS: We used data from lists obtained on the MHLW website in the analysis. We investigated the number of dental institutions conducing dental telemedicine for the first visit and for follow-up visits by prefecture. RESULTS: In each prefecture, fewer dental institutions conducted telemedicine for the first visit than for follow-up visits. Regions with large metropolitan areas had higher numbers of dental institutions conducting dental telemedicine for the first visit and follow-up visits. Private dental clinics provided the largest proportion of dental telemedicine for the first visit, and general hospitals provided the largest proportion for follow-up visits. CONCLUSION: Our study findings indicated that many dental institutions in Japan made efforts to provide dental services via dental telemedicine using the telephone or online with video to help prevent the spread of COVID-19 infection. Dental telemedicine can help patients to access dental services and dental care, thereby expanding the potential of dental telemedicine in Japan.

Substituent effects of cyclic naphthalene diimide on G-quadruplex binding and the inhibition of cancer cell growth.

Interaction of cyclic naphthalene diimide derivatives (cNDIs), 1-4, with TA-core and c-myc as G-quartet (G4) DNA was studied under dilute or molecular crowding condition. Binding study for TA-core based on an isothermal titration calorimetry showed that 1-4 has 106 M-1 order of binding affinity with the following order: 1 > 4 > 2 > 3 under both conditions. Meting temperature (Tm) of TA-core obtained from the temperature dependence of circular dichroism spectra shows that TA-core was most stabilized by 4, which is in agreement with the result of PCR stop assay and the stabilization effect for 1-3 was correlated with their binding affinity under dilute condition. 3 showed specific growth inhibition of cancer cell line Ca9-22 at <0.03 µM of IC50, with no inhibitory effect against normal bone marrow cells. 3, which has highest value of ΔH/ΔG, shows the highest inhibition ability for Ca9-22, carrying a highest expression level of telomerase mRNA.

Msx1 Heterozygosity in Mice Enhances Susceptibility to Phenytoin-Induced Hypoxic Stress Causing Cleft Palate.

OBJECTIVE: Cleft palate is among the most frequent congenital defects in humans. While gene-environment multifactorial threshold models have been proposed to explain this cleft palate formation, only a few experimental models have verified this theory. This study aimed to clarify whether gene-environment interaction can cause cleft palate through a combination of specific genetic and environmental factors. METHODS: Msx1 heterozygosity in mice (Msx1+/-) was selected as a genetic factor since human MSX1 gene mutations may cause nonsyndromic cleft palate. As an environmental factor, hypoxic stress was induced in pregnant mice by administration of the antiepileptic drug phenytoin, a known arrhythmia inducer, during palatal development from embryonic day (E) 11 to E14. Embryos were dissected at E13 for histological analysis or at E17 for recording of the palatal state. RESULTS: Phenytoin administration downregulated cell proliferation in palatal processes in both wild-type and Msx1+/- embryos. Bone morphogenetic protein 4 (Bmp4) expression was slightly downregulated in the anterior palatal process of Msx1+/- embryos. Although Msx1+/- embryos do not show cleft palate under normal conditions, phenytoin administration induced a significantly higher incidence of cleft palate in Msx1+/- embryos compared to wild-type littermates. CONCLUSION: Our data suggest that cleft palate may occur because of the additive effects of Bmp4 downregulation as a result of Msx1 heterozygosity and decreased cell proliferation upon hypoxic stress. Human carriers of MSX1 mutations may have to take more precautions during pregnancy to avoid exposure to environmental risks.

Depth of invasion determined by magnetic resonance imaging in tongue cancer can be a predictor of cervical lymph node metastasis.

OBJECTIVES: We evaluated the relationships between depth of invasion (DOI) of tongue cancer, as measured with preoperative T1- and T2-weighted magnetic resonance imaging (MRI) and postoperative histopathologic (Path) specimens, with cervical lymph node metastasis (CLNM) and tumor stage. We also calculated the correlation of MRI and Path DOI measurements. STUDY DESIGN: This retrospective study included 101 patients who had squamous cell carcinoma of the tongue and were treated surgically. Two observers measured DOI on all 3 modalities. RESULTS: DOI thresholds for predicting CLNM with high diagnostic efficacy were 6.99 mm and 8.32 mm for MRI and 5 mm for Path. DOI values from all modalities were significantly different for tumors with and without CLNM (P < .01) and for the 4 TNM stages (P ≤ .05), with increasing values corresponding to advancement in tumor stage. Addition of DOI changed the T level of many tumors based on the new TNM (tumor-node-metastasis) classification. The correlation coefficient between DOI calculated on each MRI sequence and Path was 0.90. CONCLUSIONS: MRI-derived DOI accurately reflected the subsequent metastatic status and degree of progression of tumor stages, with a strong positive correlation to Path values, and may be considered a predictor of tumor stage and CLNM.

A simple sandwich technique using buttons combined with a tie-over technique for an intraoral split-thickness skin graft.

A simple sandwich technique using buttons to compress grafted tissue combined with a tie-over technique for intraoral split-thickness skin grafts (STSGs) is introduced. This technique yielded an excellent engraftment rate (90.5%) and no instances of total graft failure were recorded. This simple sandwich technique for STSGs is readily applicable and inexpensive, and the present results show that it would be potentially useful for repair of defects in the oral cavity.

Oral Administration of Geranylgeraniol Rescues Denervation-induced Muscle Atrophy via Suppression of Atrogin-1.

BACKGROUND/AIM: Geranylgeraniol (GGOH), a C20 isoprenoid naturally occurs in several foods. We previously reported that GGOH treatment reduced the expression levels of Atrogin-1 which is involved in skeletal muscle degradation and stimulates the myogenic differentiation of C2C12 myoblasts. However, the effect of GGOH supplementation on skeletal muscle metabolism in vivo is unknown. MATERIALS AND METHODS: Skeletal muscle atrophy was induced by denervation. The expression levels of Atrogin-1 were assessed by western blotting or real time PCR. RESULTS: Intraoral administration of GGOH reduced the decrease in the cross-sectional area of muscle fibers and also suppressed the expression levels of Atrogin-1 in denervation induced muscle atrophy. Also, GGOH treatment suppressed the expression of Atrogin-1 and the decrease in skeletal muscle fiber size by glucocorticoid in vitro. CONCLUSION: Intraoral administration of GGOH rescues denervation-induced muscle atrophy via suppression of Atrogin-1.

Treatment outcomes of adjunctive teriparatide therapy for medication-related osteonecrosis of the jaw (MRONJ): A multicenter retrospective analysis in Japan.

BACKGROUND: Therapeutic strategies for patients with medication-related osteonecrosis of the jaw (MRONJ) remain controversial. The aim of the present study was to clarify the effectiveness and safety of teriparatide therapy in Japanese MRONJ patients based on a large number of case series with a multicenter retrospective analysis. PATIENTS AND METHODS: Between January 2012 and December 2016, 29 patients who were diagnosed with MRONJ at 10 hospitals were treated with teriparatide. The medical records of these patients were retrospectively reviewed to assess the efficacy and safety of teriparatide therapy for MRONJ patients. RESULTS: Adverse events occurred in 17.2% of patients (5/29). One patient developed severe arthralgia and discontinued teriparatide therapy after 12 days, while others continued the treatment. Among 29 patients, the median period of administration of teriparatide was 14.0 months (range, 0.3-26 months), and treatment outcomes were evaluated as effective in 75.9% of patients with complete resolution in 65.5%. Among patients treated with oral bisphosphonates (BPs), 83.3% were effectively treated with teriparatide and 40% with intravenous BPs. The oral administration of BPs was associated with successful treatment outcomes with teriparatide (p = 0.062). CONCLUSIONS: Teriparatide therapy has potential as an effective treatment option for MRONJ.

Anticancer effect of novel platinum nanocomposite beads on oral squamous cell carcinoma cells.

Nanoparticles are used in industry and medicine, because of their physiochemical properties, such as size, charge, large surface area and surface reactivity. Recently, metal nanoparticles were reported to show cell toxicity on cancer cells. In this study, we focused novel platinum nanoparticles-conjugated latex beads (P2VPs), platinum nanocomposite (PtNCP) beads, and investigated the possibility to incorporate novel anti-cancer effect of these combined nanoparticles. Oral squamous cell carcinoma cell lines, HSC-3-M3 cells were injected subcutaneously into the back of nude mice to produce a xenograft model. PtNCP beads were injected locally and examined by measuring tumor volume and comparing pathological histology. PtNCP beads treatment suppressed tumor growth and identified increasing pathological necrotic areas, in vivo. PtNCP beads inhibited the cell viability of HSC-3-M3 cells in dose-dependent manner and induced the cytotoxicity with extracellular LDH value, in vitro. Furthermore, SEM images were morphologically observed in PtNCP beads-treated HSC-3-M3 cells. The aggregation of the PtNCP beads on the cell membrane, the destructions of the cell membrane and globular structures were observed in the SEM image. Our results indicated that a potential anti-cancer effect of the PtNCP beads, suggesting the possibility as a therapeutic tool for cancer cell-targeted therapy. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2281-2287, 2019.

Multiple mandibular static bone depressions attached to the three major salivary glands.

A Stafne bone defect is a static bone depression in the mandible that is commonly observed in cortical bone near the mandibular angle. We herein present a rare case in which static bone depressions attached to the three major salivary glands were observed on panoramic radiography and computed tomography (CT). The three static bone depressions in the mandible were visualized on a panoramic radiograph and CT as oval radiolucent masses in a 68-year-old man. The CT numbers in the bone depressions ranged from 10 to 50 HU, and they were close to those of the respective salivary glands. Based on the CT numbers, the areas in the bone depressions were determined to be a normal parotid gland, sublingual gland, and submandibular gland. The patient underwent a follow-up examination and did not request further consultation.

Ky-2, a hybrid compound histone deacetylase inhibitor, regulated inflammatory response in LPS-driven human macrophages.

Histone deacetylase has attracted much attention as an epigenetic factor, and the modulation of histone and transcription factor acetylation status is important for regulating gene expression. Moreover, histone deacetylase inhibitors are involved in cellular growth and differentiation. In the present study, we examined the effects of Ky-2, a hybrid-compound HDAC inhibitor, on inflammatory reactions and the polarization of macrophages in vitro. Human monocyte-like THP-1 cells were polarized to macrophage-like cells using phorbol 12-myristate 13-acetate, and then polarized to M1 macrophages with LPS. Ky-2 inhibited HDAC2 expression and enhanced the acetylation of histone H3 in THP-1 cells. It also downregulated the expression of the IL-1ß-encoding gene and the LPS-induced phosphorylation of p38 mitogen-activated protein kinases in THP-1 cells. Moreover, the expression of nod-like receptor protein 3 and cleaved caspase-1 p20 was downregulated in Ky-2-treated THP-1 cells. In contrast, this agent upregulated the expression of IL-1ra in LPS-treated THP-1 cells. These results indicate that Ky-2-treatment downregulates the expression of the inflammatory cytokine, IL-1ß, in LPS-treated THP-1 cells, suggesting that Ky-2 might regulate M1 macrophage polarization through the suppression of inflammatory responses such as NLRP3 inflammasome activation.

Zoledronic acid exacerbates inflammation through M1 macrophage polarization.

BACKGROUND: Zoledronic acid (Zol), one of the bisphosphonates, is frequently utilized for the treatment of osteoporosis and bone metastasis. However, the onset of medication-related osteonecrosis of the jaw (MRONJ) following dental treatments has become a serious issue. We reported previously that osteonecrosis can be induced by Zol and lipopolysaccharide (LPS) in vivo, suggesting the involvement of Zol in inflammation. Macrophages are divided into M1/M2 macrophages. M1 macrophages are involved in the induction and exacerbation of inflammation and express proinflammatory mediators including interleukin (IL)-1. On the other hand, M2 macrophages are associated with anti-inflammatory reactions through the expression of anti-inflammatory cytokines, such as IL-10. In the present study, we clarified the effects of Zol on M1/M2 macrophage polarization in vitro. METHODS: Human monocytic THP-1 cells were polarized to macrophage-like cells by phorbol 12-myristate 13-acetate (PMA), and, after culturing for an additional 24 h with or without Zol, then polarized to M1 macrophages by LPS or to M2 macrophages by IL-4. Cell viability was examined by the WST-8 assay. Gene expression was confirmed by the real-time polymerase chain reaction. Protein expression was detected by western blotting and enzyme-linked immunosorbent assays. RESULTS: Zol treatment upregulated the expression of IL-1ß mRNA and protein through NLRP3 inflammasome activation in LPS-treated THP-1 cells. Zol treatment did not affect the expression of IL-10, IL-1ra, or CD206 in IL-4-treated THP-1 cells. CONCLUSIONS: Zol enhanced LPS-induced M1, but not M2, macrophage polarization through the NLRP3 inflammasome-dependent pathway, resulting in the production of inflammatory cytokines in THP-1 cells.

Significance and usefulness of imaging characteristics of gubernaculum tracts for the diagnosis of odontogenic tumors or cysts.

We aimed to determine the significance and usefulness of imaging characteristics of gubernaculum tracts (GT) for the diagnosis of odontogenic tumors or cysts. This was a retrospective analysis of relationships between odontogenic or non-odontogenic tumors or cysts and the GT that were visualized using multi-detector computed tomography (MDCT). The relationship between the size of a mass and expansion of the GT in all odontogenic tumors or cysts to which GTs were contiguous on MDCT, was statistically analyzed. Intact or expanded GTs were detected in MDCT images on the top of almost all odontogenic tumors or cysts, but not on non-odontogenic tumors or cysts. Characteristic image findings regarding the relationship between the GT and the odontogenic mass were detected for the respective odontogenic tumors or cysts in which the GTs were contiguous to the mass on MDCT. In ameloblastomas, expansion of the GTs significantly and very strongly correlated with tumor size (r = 0.741, p = 0.0001), but this correlation was very weak in dentigerous cysts (r = 0.167, p = 0.028) and there was no correlation between these parameters in odontogenic keratocysts (r = -0.089, p = 0.557). The imaging characteristics of GTs at the top of masses should be very useful for both the differential diagnosis of the pathological diagnosis of odontogenic masses and for differentiation between odontogenic and non-odontogenic masses.

Mechanisms involved in enhancement of osteoclast formation by activin-A.

Several growth factors in bone tissues are reported to be associated with osteoclastogenesis. Activin-A, a member of the transforming growth factor-ß (TGF-ß) family is known to be present in bone tissues and an important regulator in osteoclastogenesis with SMAD-mediated signaling being crucial for inducing osteoclast differentiation. In the present study, we examined the effect and underlying mechanisms of activin-A on osteoclast formation in vitro culture systems. Activin-A enhanced osteoclast formation in both mouse bone marrow cells and monocyte/macrophage cell line RAW 264.7 cells induced by receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) and/or macrophage stimulating factor (M-CSF). We also found that activin-A stimulated bone resorption and actin ring formation induced by RANKL and/or M-CSF. Furthermore, activin-A enhanced RANKL-induced expression of nuclear factor of activated T cell cytoplasmic 1 (NFATc1), a key regulator of osteoclastogenesis, thereby increasing osteoclastogenesis-related marker gene expression, including tartrate-resistant acid phosphatase, osteoclast stimulatory transmembrane protein, and cathepsin K. Blockage of receptor binding by follistatin, an activing-binding protein suppressed the activin-A-mediated stimulation of NFATc1. In addition, activin-A increased RANKL-induced c-fos expression without significantly affecting the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathway. Pre-treatment of the cells with a specific inhibitor of SMAD2/3 attenuated the activin-A-induced expression of NFATc1 and co-immunoprecipitation assay revealed that treatment with activin-A increased physical interaction of phosphorylated-c-fos and phosphorylated-SMAD2 protein induced by RANKL. These results suggest that activin-A enhances RANKL-induced osteoclast formation mediated by interaction of c-fos and smad2/3.