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Background/purpose: The incidence of medication-related osteonecrosis of the jaw is increasing worldwide, mostly due to the use of antiresorptive agents (ARAs) such as bisphosphonate (BP) and denosumab (Dmab). However, the proportion of BP-related osteonecrosis of the jaw (BRONJ) and Dmab-related osteonecrosis of the jaw (DRONJ) among all ARA-related osteonecrosis of the jaw (ARONJ) cases is not clear; this hinders appropriate treatment, recurrence-prevention planning, and avoidance of unnecessary Dmab withdrawal. Moreover, the causative drug administered at each disease stage remains unknown. Therefore, we conducted a retrospective study of patients with ARONJ who visited oral and maxillofacial surgery departments at hospitals in Hyogo Prefecture, Japan, over 3 years to classify and compare patient characteristics with those having BRONJ and DRONJ. We sought to identify the proportion of DRONJ in ARONJ. Materials and methods: After excluding stage 0 patients, 1021 patients were included (471 high-dose; 560 low-dose). ARA treatment for bone metastases of malignant tumors and multiple myeloma was considered high dose, while that for cancer treatment-induced bone loss and osteoporosis was low dose. Results: Low doses of BP and Dmab accounted for >50% patients; the results differed from those in other countries. DRONJ accounted for 58% and 35% of high-dose and low-dose cases, respectively. Stage 3 ARONJ cases comprised 92 (19.5%) low-dose BRONJ, 39 (20.1%) high-dose BRONJ, 24 (30%) low-dose DRONJ, and 68 (24.5%) high-dose DRONJ. Eighty-nine patients who received switch therapy were divided into BRONJ or DRONJ, but there was no difference in the ratio of each stage compared to the non-switch therapy. Conclusion: To the best of our knowledge, this is the first study to clarify the proportion of BRONJ and DRONJ cases, causative drug, and its doses by disease stages. DRONJ accounted for approximately 30% of the ARONJ, approximately 60% of which was due to high doses.

Abstract Osteoradionecrosis (ORN) often results in pathological fractures through progression. We aimed to identify the risk factors for pathological fracture in patients with mandibular ORN. Seventy-four patients with mandibular ORN were included in this retrospective study. We investigated various risk factors for pathological fracture in patients with mandibular ORN, including number of mandibular teeth with a poor prognosis each at initial evaluation before radiation therapy (RT) and when fracture occurred, and the proportion of antibiotic administration period in a follow-up duration after RT. The rate of occurrence of pathological fractures in patients with mandibular ORN was 25.7%. The median of duration between RT completion and fracture occurrence was 74.0 months. We found that pathological fracture was significantly associated with a larger number of mandibular teeth with a poor prognosis at initial evaluation before RT (P = 0.024) and when fracture occurred (P = 0.009). Especially, a larger number of mandibular teeth with P4 periodontitis, in other words severe periodontal status, was related to pathological fracture in both timings. The proportion of antibiotic administration period in a follow-up duration was also significant risk factor (P = 0.002). Multivariate analyses showed statistically significant associations between pathological fracture and a larger number of mandibular teeth with a poor prognosis when fracture occurred (hazard ratio 3.669). The patient with a larger number of mandibular teeth with P4 periodontitis may have a risk of not only occurrence of ORN but resulting in pathological fracture by accumulation of infection. Surgeons should consider extraction of those teeth regardless of before/after RT if necessary for infection control.

BackgroundHead and neck cancers that cause severe aesthetic and functional disorders normally metastasize to the cervical lymph nodes. Patients with cervical lymph node metastasis are undergoing neck dissection. Shoulder complaints are common after neck dissection, with patients reporting symptoms such as pain, weakness, shoulder droop, and disability. However, no safe and effective treatment is available for this condition at present. We will conduct a double-blinded, randomized controlled trial to evaluate the efficacy of carbon dioxide (CO2) paste in relieving pain in patients after neck dissection. ObjectiveThis will be the first clinical study to compare the efficacy of CO2 paste with placebo in relieving postoperative pain in patients who underwent neck dissection. MethodsWe will perform this trial at the Kobe University Hospital in Japan. Patients will be randomized 1:1 into the CO2 paste and control groups. Patients in the CO2 paste group will have the CO2 paste applied to the cervical surface skin for 10 minutes once per day for 14 consecutive days. The primary end point of the study is a change in the visual analog scale (VAS) scores of neck pain from baseline on day 1 (preapplication) to the end of drug application (day 15). Secondary end points include changes in the following parameters from baseline on day 1 to the end of drug application (day 15) or the study (day 29): neck pain VAS score (days 1-29), grip strength (days 1-15 and 1-29), VAS scores for subjective symptoms (the feeling of strangulation, numbness, swelling, and warmth in the neck and shoulder region) for days 1-15 and 1-29, whether the VAS score improved more than 30% (days 1-15), the arm abduction test (days 1-15 and 1-29), shoulder range of motion (abduction and flexion) for days 1-15 and 1-29, occurrence of skin disorders, and occurrence of serious side effects. Periodic monitoring will be conducted for participants during the trial. This study was approved by the certified review board of Kobe University. ResultsThe intervention commenced in May 2021 and will continue until March 2024. The collected data will provide information on the efficacy of the CO2 paste treatment. The primary end point will be compared using the Wilcoxon test, with the 1-sided significance level set at 5%. Each evaluation item will be summarized. Secondary efficacy end points will be analyzed to provide additional insights into the primary analysis. Findings based on the treatment effects are expected to be submitted for publication in 2025. ConclusionsThis trial will provide exploratory evidence of the efficacy and safety of CO2 paste in relieving pain in patients after neck dissection. Trial RegistrationJapan Registry of Clinical Trials (jRCT) identifier: jRCTs051210028; https://jrct.niph.go.jp/en-latest-detail/jRCTs051210028 International Registered Report Identifier (IRRID)DERR1-10.2196/50500

Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. Cancer-associated fibroblasts (CAFs) are the main stromal cells in the tumor microenvironment (TME). As CAFs promote tumor progression and hypoxia in the TME, regulating the conversion of normal fibroblasts (NFs) into CAFs is essential for improving the prognosis of patients with OSCC. We have previously reported the antitumor effects of transcutaneous carbon dioxide (CO2) application in OSCC. However, the effects of reducing hypoxia in the TME remain unclear. In this study, we investigated whether CO2 administration improves the TME by evaluating CAFs marker expression. Human OSCC cells (HSC-3) and normal human dermal fibroblasts (NHDF) were coinjected subcutaneously into the dorsal region of mice. CO2 gas was applied twice a week for 3 weeks. The tumors were harvested six times after transcutaneous CO2 application. The expression of CAFs markers (α-SMA, FAP, PDPN, and TGF-β) were evaluated by using real-time polymerase chain reaction and immunohistochemical staining. The expression of α-SMA, FAP, PDPN, and TGF-β was significantly increased over time after co-injection. In the CO2-treated group, tumor growth was significantly suppressed after treatment initiation. In addition, the mRNA expression of these markers was significantly inhibited. Furthermore, immunohistochemical staining revealed a significant decrease in the protein expression of all CAFs markers in the CO2-treated group. We confirmed that transcutaneous CO2 application suppressed CAFs marker expression and tumor growth in OSCC xenograft mouse model.

Abstract Background This prospective study investigated the change of swallowing ability using the Swallowing Ability Scale System (SASS) and swallowing-related quality of life (QOL) by Performance Status Scale for Head and Neck Cancer patients (PSS-H&N). This study also investigated the risk factors for postoperative dysphagia in patients who received reconstructive surgery for oral cancer. Subjects and Methods This study included 64 patients (33 men and 31 women) who underwent radical surgery with neck dissection and reconstructive surgery for oral cancers between July 2014 and February 2018. We evaluated risk factors for poor swallowing ability after treatment, including demographic factors, preoperative factors and perioperative factors, with univariate and multivariate analyses. The change of swallowing ability by the SASS and swallowing-related QOL by PSS-H&N were evaluated prospectively prior to the initiation of surgery within 1 week and at 1 and 3 months after treatment. Results Advanced T stage (T3, 4) (odds ratio (OR) = 79.71), bilateral neck dissection (OR = 20.66) and the resection of unilateral or bilateral suprahyoid muscles (OR = 17.00) were associated with poor swallowing ability after treatment. The scores for time for food intake and Eating in Public were associated with decrease of QOL in the poor group. Conclusions We propose that clinicians consider the risk factors identified in this study and pay close attention to the management of oral cancer patients with reconstructive surgery. Graphical abstract

Abstract Background Prognostic biomarkers provide essential information about a patient’s overall outcome. However, existing biomarkers are limited in terms of either sample collection, such as requiring tissue specimens, or the process, such as prolonged time for analysis. In view of the need for convenient and non-invasive prognostic biomarkers for oral cancer, we aimed to investigate the prognostic values of neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and platelet-to-lymphocyte ratio in patient survival. We also aimed to explore the associations of these ratios with the clinicopathologic characteristics of Japanese oral squamous cell carcinoma patients. Methods This study was a non-randomized retrospective cohort study in a tertiary referral center. We included 433 patients (246 men, 187 women) who underwent radical surgery for oral cancers between January 2001 and December 2013. We evaluated various risk factors for poor prognosis including neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and platelet-to-lymphocyte ratio with univariate and multivariate analyses. The disease-specific survival and overall survival rates of patients were compared among the factors and biomarkers. Results In multivariable Cox proportional hazards analysis, high neutrophil-to-lymphocyte ratio (hazard ratio 2.87, 95% confidence interval 1.59–5.19, P

Actinomycosis is usually a chronic infectious disease caused by Actinomyces species, which are anaerobic Gram-positive bacteria that normally colonize the human oral cavity and digestive and urogenital tracts. Although this lesion often occurs on soft tissue around the mandible, cases localized in the lip are very uncommon. We encountered a patient with actinomycosis in the lower lip. A 76-year-old woman with a 5-mm submucosal nodule of the lower lip was referred to our hospital from a dental clinic. The clinical diagnosis was a benign submucosal tumor. Total excision and histological examination were conducted. No oral antibiotic therapy was prescribed. The histological diagnosis was actinomycosis. The postoperative course was uneventful with no signs of recurrence during the 6 months after surgery.

Advanced mandibular osteoradionecrosis (ORN) sometimes requires extended resection (e.g., hemimandibulectomy). Bacterial infection contributes to ORN pathogenesis. To control infection and determine the extent of debridement required, an understanding of bacterial spread within sites of mandibular ORN is important. The current study used a histopathological approach to assess bacterial colonization in the mandibular condyle and elucidate possible paths of bacterial spread towards the mandibular condyle. Four hemimandibulectomy specimens were selected. Areas of bone destruction were macroscopically assessed and confirmed using hematoxylin and eosin staining. Bacterial presence within mandibular condyle was confirmed with Gram staining. Bone exposure was observed in the molar area in all specimens. Macroscopic bone destruction was apparent especially near the medial side of the cortical wall. Gram staining revealed bacterial colonization of the mandibular condyle in three of the four specimens. In conclusion, bacteria tended to spread posteriorly and through the medial side of the mandibular cortical wall. In patients with advanced ORN, the potential for bacterial colonization of the mandibular condyle should be considered during treatment.

Most head and neck lymphoepithelial carcinomas (LECs) arise in the nasopharynx and harbor Epstein–Barr virus (EBV). LEC is also a rare subtype of the oral squamous cell carcinoma (SCC). Morphologically, LEC is defined as resembling non-keratinizing nasopharyngeal carcinoma, undifferentiated subtype. The histological features and pathogenesis of oral LEC are not established. We describe a case of tongue LEC with histopathological diagnostic difficulties. A 72-year-old Japanese female presented with a whitish change on her left-side tongue. The diagnosis was atypical epithelium; neoplastic change could not be ruled out by a biopsy. Although the lesion was monitored at our hospital per her request, invasive carcinoma was detected 11 months later. Microscopically, conventional SCC was observed with the characteristic features as LEC confined to the deep part of the lesion. We briefly discuss this unusual histological finding and make a novel proposal for distinguishing oral LEC from LECs in other regions based on these histological findings.

Transient receptor potential cation channel (subfamily V, members 1-4) (TRPV1-4) are expressed in skin and neurons and activated by external stimuli in normal mucosae of all oral cavity sites. The oral cavity is exposed to various stimuli, including temperature, mechanical stimuli, chemical substances, and changes in pH, and, notably, the risk factors for oncogenic transformation in oral squamous epithelium are the same as the external stimuli received by TRPV1-4 receptors. Hence, we examined the relationship between oral squamous cell carcinoma (SCC) and TRPV1-4 expression.Oral SCC patients (n = 37) who underwent surgical resection were included in this study. We investigated the expression of TRPV1-4 by immunohistochemical staining and quantification of TRPV1-4 mRNA in human oral mucosa. In addition, we compared the TRPV1-4 levels in mucosa from patients with SCC to those in normal oral mucosa.The receptors were expressed in oral mucosa at all sites (tongue, buccal mucosa, gingiva, and oral floor) and the expression was stronger in epithelia from patients with SCC than in normal epithelia. Furthermore, alcohol consumption and tobacco use were strongly associated with the occurrence of oral cancer and were found to have a remarkable influence on TRPV1-4 receptor expression in normal oral mucosa. In particular, patients with a history of alcohol consumption demonstrated significantly higher expression levels.Various external stimuli may influence the behavior of cancer cells. Overexpression of TRPV1-4 is likely to be a factor in enhanced sensitivity to external stimuli. These findings could contribute to the establishment of novel strategies for cancer therapy or prevention.

Dental rehabilitation with osseointegrated implants in reconstructed mandibles is a common procedure, but the technique still requires improvement, especially in its reliability and technical simplification. We herein report dental rehabilitation of a free fibula-reconstructed mandible with scar contracture. A vestibuloplasty technique with application of a polyglycolic acid (PGA) sheet is described. The implants were inserted into a viable fibula flap with severe scar contracture of the overlying epithelium resulting from vascular instability in skin paddle. Only the fibula periosteum was sutured after implant insertion; exposed surfaces were covered with a combination of PGA sheet and fibrin sealant. The area with PGA sheet coverage gradually healed with moderate contracture. The epithelium around the almost implants became immobilized. The implant-supported removable partial denture with custom titanium bar was acceptable. Dental rehabilitation is possible for reconstructed mandibles with severe scar contracture. Application of a PGA sheet may be useful for vestibuloplasty in patients with reconstructed mandibles.

Squamous cell carcinoma (SCC) is the main histological type of oral cancer. Its growth rate and incidence of metastasis to regional lymph nodes is influenced by various factors, including hypoxic conditions. We have previously reported that transcutaneous CO2 induces mitochondrial apoptosis and decreases lung metastasis by reoxygenating sarcoma cells. However, previous studies have not determined the sequential mechanism by which transcutaneous CO2 suppresses growth of epithelial tumors, including SCCs. Moreover, there is no report that transcutaneous CO2 suppresses lymphogenous metastasis using human cell lines xenografts. In this study, we examined the effects of transcutaneous CO2 on cancer apoptosis and lymphogenous metastasis using human SCC xenografts. Our results showed that transcutaneous CO2 affects expressions of PGC-1α and TFAM and protein levels of cleavage products of caspase-3, caspase-9 and PARP, which relatives mitochondrial apoptosis. They also showed that transcutaneous CO2 significantly inhibits SCC tumor growth and affects expressions of HIF-1α, VEGF, MMP-2 and MMP-9, which play essential roles in tumor angiogenesis, invasion and metastasis. In conclusion, transcutaneous CO2 suppressed tumor growth, increased mitochondrial apoptosis and decreased the number of lymph node metastasis in human SCC by decreasing intra-tumoral hypoxia and suppressing metastatic potential with no observable effect in vivo. Our findings indicate that transcutaneous CO2 could be a novel therapeutic tool for treating human SCC.

Osteomyelitis of the jaw (OMJ) is a serious bacterial infection that affects the jaw bones, which can be caused by a variety of bacteria. Osteonecrosis of the jaw (ONJ) is bone necrosis following a bacterial infection. Symptoms may include pain, swelling, redness, fever, and bone exposure. Treatment typically involves antibiotics to kill the bacteria and surgery to remove all necrotic bone, and recent researches suggested that the early surgical resection improves the prognosis. However, it is difficult to determine the necrotic bone in pre-operative CT images. A non-invasive ONJ region recognition system is required for the precise pre-operative surgical planning, and also it has possibility of early diagnosis. This study proposes a ONJ region detection method using contrastive learning (CL) and support vector machine. The proposed method trains the CNN for feature extraction according to the CL framework, and the extracted feature is fed into support vector machine to perform two-class (normal or ONJ) classification on each subdivided image patch. In the experiment, we compared patch- and label-based CL with two types of patch extraction criteria. The proposed method was validated on 3D CT images of nine subjects, and the patch-based CL extracted ONJ region in the highest F1 of 0.734. Experimental results also suggested that the smaller stride should improve detection accuracy, and it has applicability to pixel-level ONJ detection. [ABSTRACT FROM AUTHOR]

Production of various combinations of bispecific variable domain of heavy chain of heavy chainonly antibody (VHH) constructs to evaluate their therapeutic potential usually requires several gene-engineering steps. Here, we present an alternative method of creating bispecific VHH constructs in vivo through protein trans-splicing (PTS) reaction; this method may reduce the number of gene manipulation steps required. As a proof-of-concept, we constructed a bispecific antibody (bsAb) containing an anti-epidermal growth factor receptor VHH and anti-green fluorescent protein VHH, and we evaluated and confirmed its bispecificity. We also tested antibody labeling by fluorescent protein tagging using the PTS reaction. Compared with the conventional gene construction method, bsAb construction via PTS is a promising alternative approach for generating multiple bsAb combinations. [ABSTRACT FROM AUTHOR]

For a given finite-type quiver $varGamma $, we will consider scalar-removed representations $(S_{d}, R_{d}(varGamma ))$, where $S_{d}$ is a direct product of special linear algebraic groups and $R_{d}(varGamma )$ is the representation defined naturally by $varGamma $ and a dimension vector $d$. In this paper, we give a necessary and sufficient condition on $d$ that $R_{d}(varGamma )$ has only finitely many $S_{d}$-orbits. This condition can be paraphrased as a condition concerning lattices of small rank spanned by positive roots of $varGamma $. To determine such scalar-removed representations having only finitely many orbits is very fundamental to the open problem of classification of the so-called semisimple finite prehomogeneous vector spaces. We consider everything over an algebraically closed field of characteristic zero. [ABSTRACT FROM AUTHOR]