Efficacy and safety of switching to bilastine, an H1-antihistamine, in patients with refractory chronic spontaneous urticaria (H1-SWITCH): a multicenter, open-label, randomized, parallel-group comparative study.

Background: For treating patients with refractory chronic spontaneous urticaria (CSU) resistant to standard doses of 2nd generation H1-antihistamines (H1AH) the International and Japanese guidelines recommend increasing H1AH dose. The latter also recommends switching to a different H1AH. This study explored if the efficacy of the standard dose of bilastine 20 mg is non-inferior to that of double-dose of H1AH in patients with refractory CSU. Methods: This phase IV, multicenter, open-label, randomized, parallel-group trial evaluated the efficacy and safety of switching treatment to bilastine compared to treatment with a 2-fold dose of H1AH in patients with CSU refractory to standard dose H1AH. The primary endpoint was the mean total symptom score (TSS) at Day 5-7 after the start of administration. Results: Treatment efficacy and safety were evaluated in 128 patients (bilastine, n=64; 2-fold dose of H1AH, n=64). The mean TSS at Day 5-7 after the start of administration was smaller than the non-inferiority margin of 0.8, demonstrating non-inferiority of the bilastine switching group to the double-dose H1AH group (0.17 (95% CI -0.32, 0.67)). No difference in Japanese version of Epworth Sleepiness Scale (JESS), DLQI, and urticaria activity score over 7 consecutive days (UAS7) was observed between the two groups. There were no serious adverse events in either group. H1AH-related adverse events occurred in 5 subjects (8 cases) and 2 subjects (3 cases) in the double-dose H1AH and bilastine groups, respectively. Conclusions: Switching treatment to bilastine demonstrated non-inferiority to a double-dose of H1AH in terms of efficacy in patients with CSU refractory to standard dose H1AH with a favorable safety profile. Clinical trial registration: https://jrct.niph.go.jp/latest-detail/jRCTs051180105, identifier jRCTs051180105.

Effect of Frequent Computed Tomography Examinations with Contrast Media on the Renal Function of Patients with Oral Squamous Cell Cancer and an Evaluation of Risk Factors for Post-Operative Chronic Kidney Disease.

Purpose: This retrospective study aimed to investigate the effect of frequent computed tomography (CT) examinations with contrast media on the renal function of patients with oral squamous cell cancer (OSCC) that underwent radical surgery, by using estimated glomerular filtration rate (eGFR); to identify risk factors of occurrence of post-operative chronic kidney disease (CKD) in these patients; and to explore the relationship between risk factors and occurrence of postoperative CKD during follow-up. Methods: Herein, 188 patients (107 male; 81 female) who underwent radical surgery for OSCC were included. We evaluated the risk factors for postoperative CKD after treatment, including demographic, perioperative, and postoperative factors by univariate and multivariate analyses. Patients were divided into post-operative CKD and control groups based on eGFR evaluation. Overall survival (OS) rates were compared between the groups. Results: eGFR decreased over time after treatment in both patient groups. Postoperative CKD was diagnosed in 56 (29.8%) patients. The average number of contrast-enhanced CT examinations was not an independent risk factor for postoperative CKD. However, lower hemoglobin on hospital discharge [odds ratio (OR) = 0.53], lower eGFR on hospital discharge (OR = 0.84), and common use of nonsteroidal anti-inflammatory drugs (OR = 48.79) were significant risk factors associated with postoperative CKD. The control group was associated with a better OS than the postoperative CKD group; however, this difference was not significant. Conclusions: Clinicians should pay close attention to these risk factor of post-operative CKD during the management of patients with OSCC that undergo radical surgery and frequent follow-up CT examinations with contrast media.

Clinical Practice Guidelines for the Management of Congenital Cytomegalovirus Infection in Japan 2023: Executive Summary.

Congenital cytomegalovirus (cCMV) infection is the most common congenital infection in developed countries. Although a standard therapy has not yet been established, evidence for the management of cCMV infection has been accumulating. The first edition of the "Clinical Practice Guidelines for the Management of Congenital Cytomegalovirus Infection" was published in Japan in 2023. This summary outlines the clinical questions (CQs) in the guidelines, with reference to the Japanese Medical Information Distribution Service Manual. Overall, 20 CQs with statements regarding prenatal risk assessment, prevention and management at diagnosis (CQs 1-1-1-3), diagnosis (CQs 2-1-2-6), treatment (CQs 3-1-3-7) and follow-up requirements (CQs 4-1-4-4) have been discussed. For each statement, the levels of recommendation, evidence and consensus rates were determined. These guidelines will assist in the management of patients with cCMV infection.

Efficacy of a non-pharmaceutical multimodal intervention program in a group setting for patients with mild cognitive impairment: A single-arm interventional study with pre-post and external control analyses.

Aim: This study aimed to evaluate the efficacy of a non-pharmaceutical multimodal intervention program consisting of physical exercise, cognitive stimulation, and health education in a group setting to slow the progression of mild cognitive impairment (MCI). Methods: A single-arm interventional study was conducted on 27 patients with MCI. To evaluate the efficacy of the intervention program, a pre-post analysis was performed using EuroQol-5 Dimension (EQ-5D), Mini-Mental State Examination (MMSE), Cognitive Function Instrument (CFI), 5 Cog test, depression, and physical performance before and after the 8-month intervention. Additionally, propensity score and the semi-Bayes analyses were performed to compare the intervention program with standard medical care, using the external control patients' data for MMSE scores. Results: Twenty-four patients completed the intervention program. During the study period, although EQ-5D and MMSE scores remained unchanged (mean change 0.02 [95 % confidence interval (CI): -0.004, 0.04], 0.5 [-0.2, 1.3]), CFI and the subcategories of 5Cog (attention and reasoning) improved (mean change -1.23 [-2.24, -0.21], 4.3 [0.9, 7.7], 3.0 [0.4, 5.6]). In the additional analysis comparing changes in MMSE scores, patients who underwent the intervention program had less decline than the external control patients (mean change -1.7 [-2.1, -1.3]) with an observed mean difference of 2.25 [1.46, 3.03], and propensity score-adjusted difference of 2.26 [1.46, 3.05]. The semi-Bayesian approach also suggested that the intervention slowed the progression of MCI. Conclusion: A non-pharmaceutical multimodal intervention program could contribute to slowing cognitive decline in patients with MCI.

Interventional Prospective Studies on Xerostomia in Patients Undergoing Palliative and End-of-Life Care: A Scoping Review.

Patients undergoing palliative care often develop debilitating oral conditions, including xerostomia. These conditions may significantly impact patients' quality of life. Despite the high prevalence and adverse impact of xerostomia, effective management strategies remain unclear. This scoping review was performed to elucidate effective interventions for xerostomia in patients undergoing palliative and end-of-life care. A comprehensive search strategy was employed to identify relevant studies up to August 2023. Full-text primary articles focusing on xerostomia in patients receiving palliative care were included in the review. Eleven articles were selected for analysis, and data were extracted by six reviewers. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Among the 11 studies, interventions ranged from oral care to saliva substitutes and methods to stimulate saliva secretion. The primary method of assessing xerostomia was the performance of subjective evaluations using visual analog scale scores or numerical rating scale scores. Various interventions including oral care regimens, topical treatments, and mixed efficacy outcomes were reported. Notably, only one study directly measured the saliva volume, highlighting a reliance on subjective endpoints in most studies. Although no definitive conclusions can be drawn regarding the most effective intervention, oral care was a preferred option for managing xerostomia in patients undergoing palliative care. Additionally, adjunctive treatments such as ice cubes, saline, and moisturizers showed promise but require further investigation. Objective measures should be incorporated into future intervention trials to complement subjective assessments and provide a comprehensive evaluation of xerostomia management strategies in this patient population.

A multicenter, open-label, single-arm trial of the long-term safety of empagliflozin treatment for refractory diabetes mellitus with insulin resistance (EMPIRE-02).

AIMS/INTRODUCTION: Insulin resistance syndrome and lipoatrophic diabetes are rare conditions characterized by the development of treatment-refractory diabetes with severe insulin resistance. We recently conducted a 24 week, multicenter, single-arm trial (EMPIRE-01) that demonstrated a certain level of effectiveness and safety of empagliflozin for these conditions. To evaluate treatment safety over a longer period, we have now performed an additional 28 week trial (EMPIRE-02) that followed on from EMPIRE-01. MATERIALS AND METHODS: The primary and secondary outcomes were safety and efficacy evaluations, respectively. All eight subjects of the EMPIRE-01 trial participated in EMPIRE-02. RESULTS: Twenty adverse events (AEs) were recorded among five individuals during the combined 52 week treatment period of both trials. Whereas one case of chronic hepatitis B was moderate in severity, all other AEs were mild. There were thus no serious AEs or events necessitating discontinuation or suspension of treatment or a reduction in drug dose. Whereas ketoacidosis or marked increases in serum ketone body levels were not observed, the mean body mass of the subjects was decreased slightly after completion of EMPIRE-02. The improvement in mean values of glycemic parameters observed in EMPIRE-01 was not sustained in EMPIRE-02, mostly because of one individual whose parameters deteriorated markedly, likely as a result of nonadherence to diet therapy. The improvement in glycemic parameters was sustained during EMPIRE-02 after exclusion of this subject from analysis. CONCLUSIONS: Empagliflozin demonstrated a certain level of safety and efficacy for the treatment of insulin resistance syndrome and lipoatrophic diabetes over 52 weeks, confirming its potential as a therapeutic option.

Assessment of Patient Characteristics Influencing the Analgesic Effects of Ibuprofen Gargle After Mandibular Third Molar Extractions.

Introduction In our previous work, we investigated the analgesic effects of ibuprofen gargle after mandibular third molar extractions. However, a subsequent detailed review of individual patient data revealed variations in postoperative pain reduction among patients. Consequently, the present study was designed to conduct post-hoc subanalyses that identified factors contributing to variation in the analgesic response to ibuprofen gargle after third molar extractions. Materials and methods This study involved thirty-five Japanese patients from a prior randomized, double-blind, placebo-controlled, crossover study, which focused on the analgesic effects of ibuprofen gargle after mandibular third molar extractions. Participants were categorized as responders (n = 13) and non-responders (n = 22) based on the within-subject difference (ibuprofen-placebo, IP) of visual analog scale (VAS) changes. Baseline characteristics were compared, along with variables, such as age, sex, the reason for extraction, extraction site, Pell Gregory (space and depth) classification, Winter's classification, surgeon's experience, and surgery time. Baseline characteristics predicting responder status were examined using multivariate logistic regression. Results In the univariate analysis, variables such as age, sex, and baseline VAS scores with p-values <0.2 were evaluated using a stepwise approach. This analysis identified age (per -10 years) with an odds ratio of 4.163 (95% confidence interval (CI): 1.170-31.952, p = 0.0233) and sex (female) with an odds ratio of 9.977 (95% CI: 1.336-208.256, p = 0.0213) as significant predictors of responder status. Conclusions In young and female patients, ibuprofen gargle decreased postoperative pain after mandibular third molar extractions.

Assessment of patients' characteristics associated with the efficacy and safety of oral valganciclovir treatment for infants with symptomatic congenital cytomegalovirus disease.

INTRODUCTION: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. MATERIALS AND METHODS: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. RESULTS: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). CONCLUSIONS: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.

A Multicenter, Open-Label, Single-Arm Trial of the Efficacy and Safety of Empagliflozin Treatment for Refractory Diabetes Mellitus with Insulin Resistance (EMPIRE-01).

INTRODUCTION: Insulin resistance syndrome and lipoatrophic diabetes are characterized by severe insulin resistance and are often refractory to treatment. Trials assessing the efficacy of antidiabetes drugs for these rare conditions have been limited, however. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower glycemia independently of insulin action, have shown efficacy for type 2 diabetes with insulin resistance. We here investigated the efficacy and safety of the SGLT2 inhibitor empagliflozin for treatment of insulin resistance syndrome and lipoatrophic diabetes. METHODS: The trial was conducted at five academic centers in Japan and included seven patients with insulin resistance syndrome and one patient with lipoatrophic diabetes. Participants received 10 mg of empagliflozin daily. If the hemoglobin A1c (HbA1c) level was ≥ 7.0% (52 mmol/mol) after 12 weeks, the dose was adjusted to 25 mg. The study duration was 24 weeks, and the primary outcome was the change in HbA1c level by the end of the treatment period. Safety evaluations were performed for all participants. RESULTS: By the end of the 24-week treatment period, the mean HbA1c level for all eight patients had decreased by 0.99 percentage points (10.8 mmol/mol) (95% confidence interval [CI], 0.59 to 1.38 percentage points, 6.6 to 14.9 mmol/mol) and the mean fasting plasma glucose concentration had declined by 63.9 mg/dL (3.55 mmol/L) (95% CI 25.5 to 102.3 mg/dL, 1.42 to 5.68 mmol/L). Continuous glucose monitoring revealed a reduction in mean glucose levels from 164.3 ± 76.1 to 137.6 ± 46.6 mg/dL (9.13 ± 4.23 to 7.65 ± 2.59 mmol/L) as well as an increase in the time in range (70-180 mg/dL) from 58.9 ± 36.1% to 70.8 ± 18.3%. Seventeen mild adverse events were recorded in five individuals throughout the study period. No severe events were reported. The mean body mass showed a slight decrease and the mean serum ketone body concentration showed a slight increase during treatment. CONCLUSION: Our results demonstrate that empagliflozin shows a certain level of efficacy and safety for treatment of insulin resistance syndrome and lipoatrophic diabetes. TRIAL REGISTRATION: jRCTs2051190029 and NCT04018365.

Tooth Loss as a Predictor of Long-Term Care Requirements in the Elderly: A Study in Kobe City, Japan.

INTRODUCTION: The Kobe project, which utilizes prospective data from the national health insurance system, focuses on early detection and preventive strategies through the Frail Kenshin health check-up program. Previous research has underscored the correlation between tooth loss and the decline in physical and cognitive functions. In this study, using Kobe project data, we examined the link between remaining teeth and long-term care needs in individuals aged 64-65 years, with primary and secondary objectives involving various health parameters and quality of life. METHODS: We analyzed baseline data from a prospective study conducted alongside the Frail Check program for generally healthy individuals aged 64-65 years to examine the relationship between the number of remaining teeth and various health indicators. This study focused on citizens aged 64-65 years to identify those at risk of needing long-term care by the age of 65 years. RESULTS: Data from 1,530 participants were obtained, excluding eight individuals for specific reasons. At the end of the follow-up period, 41 (2.7%) individuals required support and 15 (1.0%) needed long-term care alone. The data revealed a significant association between the number of remaining teeth and the need for long-term care or support, as demonstrated by the Cochran-Armitage trend test (p<0.001). Although trends were noted for nutrition and total Cognitive Functional Instrument Self scores, they did not reach statistical significance. Additionally, a decrease in the number of remaining teeth was significantly associated with worse European Quality of Life Five Dimensions (EQ-5D-5L) visual analog scale scores, mobility, and regular activities (p<0.001). CONCLUSION: Tooth loss indicates the potential long-term care needs of older adults. Monitoring oral health is crucial for addressing care requirements.

Gold Nanoparticles Enhance the Tumor Growth-Suppressing Effects of Cetuximab and Radiotherapy in Head and Neck Cancer In Vitro and In Vivo.

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) treatment includes surgery, radiotherapy, and immunotherapy with the aim of eradicating cancer cells without affecting normal tissues. HNSCC expresses epidermal growth factor receptor (EGFR) and cetuximab, an IgG1 monoclonal antibody targeting epidermal growth factor receptor, has been approved for the treatment of HNSCC. However, cetuximab has low reactivity and induces serious side effects. Gold nanoparticles (AuNPs) were reported to enhance the local antitumor effects of radiotherapy without damaging normal cells. METHODS AND RESULTS: This study investigated the in vitro effects of single and combination therapy with AuNPs (1.0 nM), cetuximab (30 nM), and radiotherapy (4 Gy) on a human HNSCC cell line, HSC-3. Combination treatment of AuNPs + cetuximab + radiotherapy markedly reduced HSC-3 numbers and proliferation and enhanced apoptosis compared with single and double combination treatments. Furthermore, the in vivo combination treatment (AuNPs + cetuximab + radiotherapy) of a xenograft model of HSC-3 cells transplanted into nude mice (BALB/cAJcl-nu/nu) reduced the tumor volume compared with the controls. Scanning electron microscopy demonstrated the presence of AuNPs in tumor tissues and toxicity analysis indicated that AuNPs had no toxic effect on normal tissues. CONCLUSIONS: This study showed that AuNPs alone do not have a tumor-suppressing effect, but they sensitize tumors to radiotherapy and bind to cetuximab, leading to enhanced antitumor effects.

The Efficacy of Carbon Dioxide Paste in Alleviating Pain in Patients After Neck Dissection: Protocol for a Double-Blinded, Randomized Controlled Trial.

BACKGROUND: Head 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. OBJECTIVE: This 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. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: This trial will provide exploratory evidence of the efficacy and safety of CO2 paste in relieving pain in patients after neck dissection. TRIAL REGISTRATION: Japan 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.

Efficacy and safety of ibuprofen gargle for postoperative pain after mandibular third molar extraction: A phase II, placebo-controlled, double-blind, randomized crossover trial.

OBJECTIVE: This study was designed to evaluate the postoperative efficacy and safety of using an ibuprofen gargle as a pain management strategy for patients who have undergone mandibular third molar extraction. We also ensured that the quality of treatment was not compromised throughout the study. MATERIAL AND METHODS: Patients were randomized in a 1:1 ratio into two groups: the ibuprofen-placebo (IP) group and the placebo-ibuprofen (PI) group. On postoperative Day (POD) 1, the IP group initiated ibuprofen administration, while the PI group started taking placebo. On POD 2, the IP group switched to using placebo, whereas the PI group switched to ibuprofen. From PODs 3-5, both groups were prescribed ibuprofen gargle. The primary endpoint was within-subject visual analog scale (VAS) score before and 5 min after the first use of the ibuprofen or placebo gargle on PODs 1 and 2 (ΔVAS5_ibuprofen - ΔVAS5_placebo ). The incidence and severity of adverse events were assessed using the Common Terminology Criteria for Adverse Events version 5.0 and a subjective rating scale. RESULTS: This study enrolled 40 patients. The within-subject VAS5 of the IP and PI groups were 1.25 ± 12.0 and -5.26 ± 8.93 mm, respectively. The treatment effect of ibuprofen gargle was -2.01 ± 10.62 mm (p = .246). None of the patients in each group presented with serious adverse events or clinically significant complications (including dry sockets) after extraction. Transient adverse events, such as throat tingling and oral discomfort (grade 1), were observed in each group. CONCLUSION: Ibuprofen gargle was safe but did not provide significant pain relief when used after mandibular third molar extraction.

Photodynamic therapy with verteporfin accelerates apoptotic bleb formation in human ameloblastoma.

OBJECTIVE: Although benign, ameloblastoma is a locally aggressive lesion in some patients and the development of additional treatments is needed. Verteporfin (VP) is a photosensitizer exhibiting considerable photocytotoxicity in various tumor cells. We aimed to investigate the effects of verteporfin photodynamic therapy (VP PDT) on ameloblastoma. METHODS: Eighteen patients who underwent surgery for ameloblastoma were randomly selected. We performed an immunohistochemical assessment to investigate the expression of low-density lipoprotein receptor (LDLR) and Yes-associated protein (YAP), targets of VP, in human ameloblastoma tissues and cultured human ameloblastoma cell line (HAM1). The effect of VP PDT on cell proliferation and apoptosis in HAM1 was analyzed. RESULTS: The expression of LDLR and YAP were detected in human ameloblastoma tissues and HAM1. LDLR expression was significantly higher in patients who had previously undergone surgery than in patients who were receiving it for the first time. The cytotoxic effect of the combination of low-concentration VP administration and laser irradiation was comparable to high-concentration VP administration with and without laser irradiation. The addition of laser irradiation to VP administration significantly accelerated apoptotic bleb formation compared with VP administration alone. CONCLUSION: VP PDT has the potential to become an additional treatment for large-sized ameloblastoma.

Transcutaneous carbon dioxide application suppresses the expression of cancer-associated fibroblasts markers in oral squamous cell carcinoma xenograft mouse model.

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-ß) were evaluated by using real-time polymerase chain reaction and immunohistochemical staining. The expression of α-SMA, FAP, PDPN, and TGF-ß 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.

Relationship of Mitochondrial-Related Protein Expression with the Differentiation, Metastasis, and Poor Prognosis of Oral Squamous Cell Carcinoma.

Mitochondrial dysfunction and respiratory function changes have been consistently associated with the initiation and progression of cancer. The purpose of this study was to retrospectively investigate the expression of mitochondrial tumor-suppressor and DNA-repair proteins in patients with oral squamous cell carcinoma (OSCC) and to evaluate the relationship between their expression and prognosis. We enrolled 197 patients with OSCC who underwent surgical resection between August 2013 and October 2018. Clinical, pathological, and epidemiological data were retrospectively collected from hospital records. The expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), mitochondrial transcription factor A, mitochondrial tumor suppressor gene 1, silent information regulator 3, and 8-hydroxyguanine DNA glycosylase was investigated using immunochemistry. The 3-year disease-specific survival (DSS) rates of patients showing positive expression of all selected proteins were significantly higher than those of patients showing a lack of expression. Multivariate analysis revealed that the expression of PGC-1α (hazard ratio, 4.684) and vascular invasion (hazard ratio, 5.690) can predict the DSS rate (p < 0.001). Low PGC-1α expression and vascular invasion are potential clinically effective predictors of the prognosis of OSCC.

Four-Dimensional Computed Tomographic Image Evaluation of the Change of Condylar Movement With and Without Implant-Supported Removable Prostheses in the Fibular Mandible: A Pilot Case Series Report.

Implant-supported removable prostheses (ISrP) improve the quality of life, especially in patients who underwent mandibular reconstruction, but few studies have focused on the effect of ISrP in the fibular mandible on the function of the temporomandibular joint. The purpose of this pilot case series was to determine the usefulness of four-dimensional computed tomography (4DCT) images for the evaluation of differences in condylar movements with and without ISrP. Three patients who underwent ISrP following segmental mandibulectomy and free-flap reconstruction were evaluated. The participants were instructed to masticate a cookie during the 4DCT scan. The distance between the most anterior and posterior positions of the condyles on the sagittal view of the 4DCT images during the chewing of the cookies was measured and compared with and without ISrP. 4DCT revealed changes in the distances of condylar protrusion with and without wearing ISrP, but there were no obvious differences among the three patients. The 4DCT motion analysis was useful for the evaluation of the effect of wearing ISrP on condylar movements during mastication in patients with mandibular reconstruction and may become a useful objective evaluation method for the functional evaluation of ISrP.

Expression of JCAD and EGFR in Perineurial Cell-Cell Junctions of Human Inferior Alveolar Nerve.

Although perineurium has an important role in maintenance of the blood-nerve barrier, understanding of perineurial cell-cell junctions is insufficient. The aim of this study was to analyze the expression of junctional cadherin 5 associated (JCAD) and epidermal growth factor receptor (EGFR) in the perineurium of the human inferior alveolar nerve (IAN) and investigate their roles in perineurial cell-cell junctions using cultured human perineurial cells (HPNCs). In human IAN, JCAD was strongly expressed in endoneurial microvessels. JCAD and EGFR were expressed at various intensities in the perineurium. In HPNCs, JCAD was clearly expressed at cell-cell junctions. EGFR inhibitor AG1478 treatment changed cell morphology and the ratio of JCAD-positive cell-cell contacts of HPNCs. Therefore, JCAD and EGFR may have a role in the regulation of perineurial cell-cell junctions.

Efficacy and safety of apalutamide in patients with metastatic castration-resistant prostate cancer (GENESIS): protocol for a multicentre, open-label, single-arm clinical trial.

INTRODUCTION: This is a multicentre, open-label, single-arm clinical trial to evaluate the efficacy and safety of apalutamide in patients with metastatic castration-resistant prostate cancer. METHODS AND ANALYSIS: The trial will be performed at 4 university hospitals and 14 city hospitals in Japan. The target number of patients will be 110. The patients will be orally administered 240 mg apalutamide once daily during the treatment period. The primary outcome is the prostate-specific antigen (PSA) response rate. PSA response is defined as ≥50% decline from baseline at 12 weeks. Secondary outcomes are time to PSA progression, progression-free survival, overall survival, progression-free survival during second therapy, ≥50% decline in PSA from baseline at 24 and 48 weeks, ≥90% decline in PSA from baseline or lower PSA detection sensitivity after the initial dose at 12, 24 and 48 weeks, PSA maximal changes, accumulated PSA response from screening to 24 and 48 weeks, and grade 3 or 4 adverse events according to the Common Terminology Criteria for Adverse Events version 4.0. ETHICS AND DISSEMINATION: This study has been approved by the Certified Research Review Board of Kobe University (No. CRB5180009). All participants will be required to provide written informed consent. Findings will be disseminated through scientific and professional conferences and peer-reviewed journal publications. The datasets generated during the study will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: jRCTs051220077.

Clinical trial on the efficacy and safety of NPC-15 for patients with xeroderma pigmentosum exaggerated sunburn reaction type: XP-1 study protocol for a multicentre, double-blinded, placebo-controlled, two-group crossover study followed by a long-term open study in Japan.

INTRODUCTION: Xeroderma pigmentosum (XP) is a rare intractable disease without a fundamental treatment, presenting with severe photosensitivity, freckle-like pigmented and depigmented maculae and numerous skin cancers before the age of 10 years without strict sun protection. About 70% of the patients exhibit extremely severe sunburn reactions and most of them develop neurological symptoms, including sensorineural hearing impairment and progressive peripheral and central nervous disorders beginning from childhood ages. In the preclinical study, we found that N-acetyl-5-methoxytryptamine was effective in suppressing skin tumour development in addition to improvement of auditory brainstem response in chronically ultraviolet-irradiated XP-A model mice. METHODS AND ANALYSIS: On the bases of the preclinical study, we conduct a clinical trial on the efficacy of NPC-15 for patients with XP with exaggerated sunburn reaction type by a multicentre, double-blinded placebo-controlled, two-group crossover study followed by a 52 weeks open study. ETHICS AND DISSEMINATION: Ethics approval is overseen by the Kobe University Institutional Review Board and Osaka Medical and Pharmaceutical University Institutional Review Board, and the study is conducted in accordance with the approved protocol. All participants will be required to provide written informed consent. Findings will be disseminated through scientific and professional conferences and peer-reviewed journal publications. The data sets generated during the study will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: jRCTs051210181.