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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. [ABSTRACT FROM AUTHOR]

Simple Summary: Mitochondrial dysfunction and respiratory function changes have been associated with the initiation and progression of cancer. However, no study has comprehensively investigated the relationship between these mitochondrial-related factors and prognosis in a large number of patients with oral squamous cell carcinoma (OSCC). Here, we retrospectively investigated the expression of mitochondrial tumor-suppressor and DNA-repair proteins (PGC-1α, TFAM, OGG1, MTUS1, and SIRT3) in patients with OSCC and evaluated the relationship between their expression and prognosis. The expression levels of the five proteins were associated with patient outcomes. 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. Particularly, based on the results of multivariate analysis, negative expression of PGC-1α is related to a poor prognosis of OSCC. Low PGC-1α expression and vascular invasion may be clinically effective predictors of oral cancer prognosis. 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. [ABSTRACT FROM AUTHOR]

Background: This study investigated how cognitive function-related simple questions can be used to identify older individuals who are at risk of needing long-term care.Methods: This cohort study was conducted in Kobe city, Japan. In 2015, the municipal office distributed the Kihon Checklist by post, a 25-item questionnaire including three cognitive function-related questions (questions 18, 19, 20) to citizens aged ≥ 70 years. Need certification is routinely done by Kobe city as part of the national Long-Term Care Insurance Act. The answers to the 2015 questionnaire were merged with need certification data between the questionnaire delivery and the end of December 2019.Results: Of the 77,877 citizens (age: 72.9 ± 2.7 years) who received the questionnaire, 50,154 responded (response rate: 64.4%). During the study period, the cumulative incidence of the need for long-term care was higher in those who did not respond than in those who did (12.5% vs 8.4%; P < 0.001). Among those who responded, the incidence of the need for long-term care was progressively greater as the number of negative answers to cognitive function-related questions increased (5.0%, 8.4%, 15.7% and 30.2% at 4 years' follow-up, for respondents with, respectively, 0, 1, 2 and 3 negative answers). Similarly, when the need certification for long-term care was confined to that accompanied by dementia, the incidence also rose as the number of negative responses to the cognitive function-related questions increased (3.4%, 6.5%, 13.7% and 27.9% for respondents with, respectively, 0, 1, 2 and 3 negative answers). Using multivariate Cox regression analysis, all three cognitive function-related questions were predictive of the need for long-term care, and question 18 (about memory loss) had the highest hazard ratio for predicting the need for long-term care accompanied by dementia.Conclusions: Use of cognitive function-related simple questions may help identify older adults at risk for needing long-term care, suggesting their potential value for use in administrative and policy approaches aimed at reducing the societal burden of dementia. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this multicenter retrospective study was to investigate the demographic characteristics and treatment outcomes of patients with mucosal malignant melanoma (MM) of the oral cavity. Materials and methods: This was a multicenter study involving 8 Japanese universities. The medical records of 69 patients who were diagnosed with primary oral MM between January 2000 and December 2020 were retrospectively analyzed. Overall survival (OS) and prognostic factors for OS were analyzed statistically. Results: There were 40 (58.0%) males and 29 (42.0%) females, and their mean (range) age was 69.8 ± 14.6 (22–96) years old. The most common primary site was the palate (30 patients, 43.5%). Stage IVA was the most common disease stage (36 patients, 52.2%). Radical therapy was performed in 55 patients (79.7%). The 2-year and 5-year OS rates of the 69 patients were 64.6% and 42.5%, respectively. The 2-year and 5-year OS rates of the stage III patients were 85.9% and 72.5%, respectively, and those of the stage IVA patients were 56.3% and 26.0%, respectively. The 1-year OS rate of the stage IVB/IVC patients was 26.7%. The 2-year and 5-year OS rates of the radical therapy group were 74.1% and 50.5%, respectively, whereas the 2-year OS rate of the non-radical therapy group was 26.0%. An advanced T classification was the only identified prognostic factor for OS (hazard ratio: 6.312, 95% confidence interval: 1.133–38.522, p < 0.05). Conclusions: Early detection and radical treatment are essential for improving the prognosis of oral MM patients. Clinical relevance: Early detection and adequate radical therapy leads to the better prognosis of oral MM patients. [ABSTRACT FROM AUTHOR]

Our aims were to determine the clinical impact of oral valganciclovir (VGCV) in infants aged ≤2 months with congenital cytomegalovirus (CMV) disease and evaluate the efficacy of VGCV when initiated beyond the neonatal period. The multicenter, single-arm, open-label clinical trial was conducted in Japan. Twenty-five infants aged ≤2 months with congenital CMV disease involving the central nervous system were enrolled and treated with VGCV for 6 months. The primary endpoint was the change in the whole blood CMV load before and after treatment. The secondary endpoint was the change in the auditory brainstem response (ABR) before and after treatment. Changes in ABR were assessed between the younger and older age groups (≤ and >30 days at treatment initiation). Of the 25 patients, one was excluded owing to epilepsy before VGCV administration. The median change in the CMV DNA level in whole blood was −246.0 IU/mL. The best ear and total ear assessments based on ABR were categorized as (improved + unchanged) after treatment for 100% and 93.8%, respectively. No differences in hearing efficacy were observed between the younger and older age groups. Oral VGCV is a potential therapeutic option for treating infants aged ≤2 months with congenital CMV disease. [ABSTRACT FROM AUTHOR]

Background: With the rapid increase in the average age of society, the number of people with dementia has increased in Japan. Thus, the need to prevent dementia is greater, and prevention programs have been implemented throughout Japan. This study aims to evaluate both the short‐term and the long‐term effects of a dementia prevention program on physical and cognitive function in community‐dwelling elderly. Methods: Cognitive and physical assessments were carried out at baseline for a sample including 57 elderly participants. The participants underwent an intensive training program lasting for 2 h per week for 10 days. After the last period of training, the assessment performed was reapplied. The outcome measures used to establish effectiveness were a Mini‐Mental State Examination, Five Cognitive Tests, a Cognitive Function Instrument, a Timed Up & Go Test, a grip strength evaluation, a Geriatric Depression Scale, an EQ‐5D and a Physical Activity Scale for the Elderly. Participants were then divided randomly into two groups: a booster group and a non‐booster group. The booster group received booster training every 3 months after the intensive training period, whereas the non‐booster group did not. Both groups were monitored every 6 months for approximately two and a half years after baseline assessment. Results: The Mini‐Mental State Examination, the subtests of the Five Cognitive Tests (attention, memory, language and reasoning) and the Timed Up & Go Test revealed a significant improvement after intensive training. For most of the outcome measures, the booster training showed no additional significant improvements. Conclusions: In this study, intensive training had a short‐term positive effect. Although the effect of the booster training was not clear, the functions of the elderly participants were found to be maintained during a follow‐up assessment. The study findings recommend conducting intensive training for the community‐dwelling elderly without follow‐up training. [ABSTRACT FROM AUTHOR]

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 <  0.001), moderately or poorly differentiated histology (hazard ratio 2.37, 95% confidence interval 1.32-4.25, P <  0.001), and extranodal extension (hazard ratio 1.95, 95% confidence interval 1.13-3.35, P = 0.016) were independent predictors of disease-specific survival. High neutrophil-to-lymphocyte ratio (hazard ratio 2.30, 95% confidence interval 1.42-3.72, P <  0.001), moderately or poorly differentiated (hazard ratio 1.72, 95% confidence interval 1.07-2.76, P = 0.025), and extranodal extension (hazard ratio 1.79, 95% confidence interval 1.13-2.84, P = 0.013) were independent predictors of overall survival.Conclusions: Neutrophil-to-lymphocyte ratio might be a potential independent prognostic factor in Japanese oral squamous cell carcinoma patients. [ABSTRACT FROM AUTHOR]

Background: Chronic spontaneous urticaria (CSU) is characterized by the spontaneous appearance of wheals, angioedema, or both for > 6 weeks. Continuous treatment with H1-antihistamines is used as a first-line treatment for CSU. However, H1-antihistamine treatment leads to absence of symptoms in less than 50% of patients with CSU. Although Japanese guidelines for the diagnosis and treatment of urticaria recommend an increase in the H1-antihistamine dose or a switch to other H1-antihistamines, there is no evidence supporting a switch to other H1-antihistamines in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose.Methods: We will conduct a multicenter, open-label, non-inferiority, randomized, parallel, comparison study to determine if the efficacy of bilastine 20 mg is not inferior to that of a twofold H1-antihistamine dose increase in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose. This study will be performed at 15 academic hospitals in Japan, and the administration period (increasing the H1-antihistamine dose twofold vs. switching to bilastine 20 mg) will be 7 days. Participants (n = 150) will be randomized to either an increased H1-antihistamine dose or a switch to bilastine 20 mg at a 1:1 ratio. The primary endpoint, mean of the total symptom score of 5-7 days after the intervention, will be evaluated. The secondary objective is to determine if the safety of bilastine 20 mg regarding somnolence is superior to that of a twofold dose increase of H1-antihistamines. This will be measured by a change in the Japanese version of the Epworth Sleepiness Scale from baseline to 7 days after starting the intervention.Discussion: This multicenter, open-label, non-inferiority, randomized, parallel, comparison study will be, to our knowledge, the first well-designed clinical study to evaluate the efficacy of a switch to other H1-antihistamines in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed doses. This trial will provide evidence of the efficacy and safety of bilastine when treatment is switched in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose.Trial Registration: Japan Registry of Clinical Trials (jRCT), jRCTs051180105. Registered on 8 March 2019. [ABSTRACT FROM AUTHOR]

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/mm 3 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., Competing Interests: Declaration of competing interest Mitsubishi Tanabe Pharm Corp. provided Valixa™ dry syrup during the study period for treatment, but this company had no role in this clinical trial. None of the authors have any conflict of interest to declare., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: This study retrospectively investigated relationships among risk factors and post-hepatectomy surgical site infection (SSI) and other complications in patients who underwent hepatectomy for hepatocellular carcinoma (HCC)., Methods: We included 334 patients who underwent hepatectomies for liver cancers between January 2011 and December 2015 in this study. We evaluated risk factors for SSI and other post-hepatectomy complication, including demographic factors, preoperative factors, and preoperative intervention including oral management, perioperative factors, and length of hospital stay, with univariate and multivariate analyses. The oral management intervention included self-care instructions, extraction of infected teeth, removal of dental plaques and calculus (scaling), professional mechanical teeth cleaning, removal of tongue coating, and cleaning of dentures. SSI was defined in accordance with the guideline issued by the Centers for Disease Control and Prevention; it included purulent discharge from any incision or organ space within 30 days postoperatively, with or without microbiological evidence. Complications of grade II or greater, according to the Clavien-Dindo classification, were regarded as postoperative complications., Results: We found bacterial infection of ascites (Odds ratio (OR) = 13.72), lack of preoperative oral management intervention (OR = 10.17), and severe liver fibrosis (OR = 2.76) to be associated with SSI and severe liver fibrosis (OR = 2.28), hypoalbuminemia (OR = 2.02), blood transfusion (OR = 1.86), and longer operation time (OR = 1.80) to be associated with postoperative complications., Conclusions: Preoperative oral management may reduce the risk of SSI in patients with HCC who undergo hepatectomy.

Background: Congenital cytomegalovirus (CMV) disease, a common mother-to-child infection, can lead to neurological sequelae. Some clinical trials have shown that oral valganciclovir (VGCV) can improve hearing and neurodevelopmental impairment in infants with congenital CMV disease. However, VGCV has neither been approved in Japan nor other countries as a treatment for this disease by the government health insurance., Methods: This study is a non-randomized, prospective, open-label, multicenter, single-arm clinical trial and will include subjects meeting the following criteria: confirmation of positive CMV-DNA amplification in urine by an in vitro diagnostic test within 21 days of age; congenital CMV disease with one or more central nervous system disorders-microcephaly, hydrocephalus or ventricular enlargement, periventricular calcification, cortical hypoplasia or white matter injury, retinal choroiditis, and abnormal auditory brainstem response (ABR); and infants within 2 months of age with a gestational age ≥32 weeks at birth and weighing ≥1800 g at the time of registration. Subjects will be orally administered 16 mg/kg VGCV twice daily for 6 months. The target number of cases for enrollment between February 3, 2020 and July 31, 2021 is 25. Primary endpoint is the change in whole blood CMV loads before and after 6 months of treatment. The important secondary endpoint is the change in ABR (both best and total ear hearing assessments) before and after 6 months of treatment. The safety endpoints are adverse events and drug side effects., Discussion: To the best of our knowledge, this multicenter, open-label, single-arm study will be the first well-designed clinical trial to evaluate the efficacy of oral VGCV in infants with congenital CMV diseases. The findings will reveal the efficacy and safety of oral VGCV treatments and enable the approval of oral VGCV as a treatment for infants with congenital CMV disease by the government health insurance of Japan.

Background: The purpose of this study was to retrospectively describe the characteristics and outcomes of patients with oral squamous cell carcinoma and level IV/V metastasis and to compare patients who underwent no postoperative therapy with those who underwent postoperative radiotherapy (RT) and concomitant chemoradiotherapy (CCRT)., Methods: We evaluated 669 patients. Clinicopathological data, postoperative therapy, and clinical course were investigated., Results: Sixty-one patients (9.1%) developed level IV/V metastasis. The 3-year cumulative overall survival rates of patients with and without level IV/V metastasis were 47.3% and 64.3%, respectively. Tongue tumors, pN2 or N3 classification, and moderate or poor differentiation were significantly associated with the development of level IV/V metastasis. The surgery+RT/CCRT group was associated with better 3-year cumulative disease-specific survival and overall survival rates than the surgery only group., Conclusion: Adjuvant therapy (RT alone or CCRT) after surgery is recommended for patients with level IV/V metastasis., (© 2019 Wiley Periodicals, Inc.)

Purpose: Patients with oral cancer who undergo resection with simultaneous reconstruction are presumed to be at high risk for developing venous thromboembolism (VTE) according to current criteria. The primary purpose of this retrospective study was to report the incidence of VTE after oral cancer surgery requiring primary reconstruction and to identify the potential risk factors for VTE in this population., Materials and Methods: This retrospective study evaluated 133 consecutive patients who had undergone oral cancer resection with simultaneous reconstruction from April 2007 through December 2014. Bilateral lower-extremity venous duplex ultrasonography (VDUS) was routinely performed 2 days after surgery. Pulmonary embolism was confirmed with computed tomography. The Caprini risk score (CRS) was obtained for each patient. Patients with and without VTE were compared using the χ2 test and Student t test with some variables. Univariate predictors associated with VTE were entered into a multivariate logistic regression analysis. A P value less than .05 was regarded as indicating statistical significance., Results: The incidence of VTE after oral oncologic surgery with simultaneous reconstruction was 26.3% (35 of 133 patients): deep vein thrombosis (DVT) and pulmonary embolism occurred in 2.3% (3 of 133) and DVT alone was found in 24.0% (32 of 133). Multivariate logistic regression analysis showed that only a high CRS was statistically relevant to VTE occurrence., Conclusions: Because a high incidence of VTE was found after major oral and maxillofacial surgery, lower-extremity VDUS should be undertaken in patients who undergo oral cancer surgery with simultaneous reconstruction, especially those with a high CRS., (Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)