Ingestion of ß-nicotinamide mononucleotide increased blood NAD levels, maintained walking speed, and improved sleep quality in older adults in a double-blind randomized, placebo-controlled study.

The study evaluated how ingestion of nicotinamide mononucleotide (NMN) for 12 weeks by older adults affected blood nicotinamide adenine dinucleotide (NAD +) levels and physical function, particularly walking function. Information concerning sleep, and stress was also collected as secondary endpoints. In this randomized, placebo-controlled, double-blind, parallel-group comparison study, 60 participants were randomly allocated into a placebo group or NMN group. Members of the NMN group consumed 250 mg/day NMN for 12 weeks. Motor function tests, blood NAD metabolite analysis, and questionnaires were conducted at the start of the study and 4 and 12 weeks after intake. This trial was registered at umin.ac.jp/ctr as UMIN000047871 on June 22nd, 2022.At primary outcome, at both 4 weeks and 12 weeks, the NMN and placebo groups had no significant differences in a stepping test. At secondary outcomes, after 12 weeks of NMN intake, the NMN group had a significantly shorter 4-m walking time than the placebo group as well as significantly higher blood levels of NAD + and its metabolites. A significant negative correlation was observed between the change in the 4-m walking time and the change in blood NAD + , N1-methyl-2-pridone-5-carboxamide (2-PY), and N1-methyl-4-pridone-3-carboxamide (4-PY) at 12 weeks. The NMN group had improved sleep quality at 12 weeks relative to the placebo group as evidenced by lower scores for "Daytime dysfunction" and "Global PSQI" on the Pittsburgh Sleep Questionnaire. No adverse effects related to test substance consumption were observed. Together, these results indicate that NMN intake could increase blood NAD + levels, maintain walking speed, and improve sleep quality in older adults. Interventions involving NMN aimed at maintaining walking speed could contribute to extended healthy life expectancy.

Safety evaluation of a heat-treated Bifidobacterium bifidum OLB6378 concentrate.

Several bacterial strains, including probiotic strains, have undergone evaluations for their safety and potential beneficial health effects. Some of these strains have been introduced into various markets, including that for infant products. However, certain probiotic strains have been linked to serious infections in infants, such as septicemia and meningitis. Given this, it is crucial to assess the safety of each probiotic strain, including those of Bifidobacterium, which is a common genus of probiotics. One such strain, Bifidobacterium bifidum OLB6378 (NITE BP-31), referred to as OLB6378 hereafter, has been selected for use in infants. To determine its genotoxicity and general toxicity potential, a heat-treated OLB6378 concentrate was subjected to various tests, including the bacterial reverse mutation test, in vitro chromosome aberration test, in vivo micronucleus test, and single- and 90-day oral gavage toxicity studies in rats. No significant differences were observed compared with negative controls in any of genotoxicity tests. The single-dose toxicity study employed dose levels of 560, 1,693, and 5,092 mg/kg, representing the total solid contents of culture concentrates containing OLB6378 (equivalent to 8.1 × 1011, 2.4 × 1012, and 7.4 × 1012 cells/kg of Bifidobacterium, respectively). In the 90-day toxicity study, dose levels of 280, 853, and 2,546 mg/kg/day were used (equivalent to 4.0 × 1011, 1.2 × 1012, and 3.7 × 1012 cells/kg/day, respectively). Importantly, the heat-treated OLB6378 concentrate did not induce any signs of toxicity in any of the conducted toxicity studies. In conclusion, the heat-treated OLB6378 concentrate exhibited no genotoxicity potential, and the no-observed-adverse-effect level in the 90-day toxicity study was determined to be 2,546 mg/kg/day (equivalent to 3.7 × 1012 cells/kg/day). This suggests that heat-treated OLB6378 can be safely utilized as a food source.

Development of a predictive model for nephrotoxicity during tacrolimus treatment using machine learning methods.

AIM: When administering tacrolimus, therapeutic drug monitoring is recommended because nephrotoxicity, an adverse event, occurs at supra-therapeutic whole-blood concentrations of tacrolimus. However, some patients exhibit nephrotoxicity even at the recommended concentrations, therefore establishing a therapeutic range of tacrolimus concentration for the individual patient is necessary to avoid nephrotoxicity. This study aimed to develop a model for individualized prediction of nephrotoxicity in patients administered tacrolimus. METHODS: We collected data, such as laboratory test data at tacrolimus initiation, concomitant drugs and tacrolimus whole-blood concentration, from medical records of patients who received oral tacrolimus. Nephrotoxicity was defined as an increase in serum creatinine levels within 60 days of tacrolimus initiation. We built 13 prediction models based on different machine learning algorithms: logistic regression, support vector machine, gradient-boosting trees, random forest and neural networks. The best performing model was compared with the conventional model, which classifies patients according to the tacrolimus concentration alone. RESULTS: Data from 163 and 41 patients were used to construct models and evaluate the best performing one, respectively. Most of the patients were diagnosed with inflammatory or autoimmune diseases. The best performing model was built using a support vector machine; it showed a high F2 score of 0.750 and outperformed the conventional model (0.500). CONCLUSIONS: A machine learning model to predict nephrotoxicity in patients during tacrolimus treatment was developed using tacrolimus whole-blood concentration and other patient data. This model could potentially assist in identifying high-risk patients who require individualized target therapeutic concentrations of tacrolimus prior to treatment initiation to prevent nephrotoxicity.

Olanzapine Overdose in a Two-Year-Old Girl Resulting in Both High Serum and Plasma Levels.

The antipsychotic olanzapine is used increasingly to treat various psychiatric illnesses. Accidental olanzapine overdose is uncommon among children. Here, we report a case of a child presenting with an unexplained coma. Accidental ingestion of olanzapine (20 mg) was confirmed by measurement of drug concentrations in both serum and plasma.

Factors associated with liver injury and prognosis in advanced cancer patients treated with immune checkpoint inhibitors.

AIM: The use of immune checkpoint inhibitors (ICIs) has increased remarkably, and immune-related adverse events (irAEs) have also increased. This study aimed to identify factors associated with immune-related liver injury (irLI), and the relationship between the grades of irLI and overall survival (OS) in patients treated with ICIs. METHODS: A total of 571 patients who had been treated for advanced malignancies with ICIs between January 2015 and March 2022 were retrospectively recruited. The presence of liver injury was determined by the aspartate aminotransferase and alanine aminotransferase elevation. The irLI grading was based on Common Terminology Criteria for Adverse Events version 5.0. RESULTS: A total of 50 (8.8%) patients had grade ≥2 irLI and 24 (4.2%) had grade ≥3 irLI. Treatment with anti-cytotoxic T-lymphocyte-associated protein-4 agents and baseline grade 1 aspartate aminotransferase/alanine aminotransferase elevation were independent predictive factors of grade ≥2 irLI. Treatment with anti-cytotoxic T-lymphocyte-associated protein-4 was the only independent predictive factor of grade ≥3 irLI. The median OS for patients who experienced any irAEs was significantly longer than of those without irAEs (hazard ratio 0.503, 95% CI 0.398-0.636, p < 0.001). The median OS in patients with grade ≥2 irLI was significantly longer (HR 0.570, 95% CI 0.387-0.838, p = 0.022). There was no significant difference between the median OS in patients with grade ≥3 irLI and the others (p = 0.11). CONCLUSION: The incidence of irLI was significantly higher in patients treated with anti-cytotoxic T-lymphocyte-associated protein-4 agents. Even in patients with pre-existing grade 1 aspartate aminotransferase/alanine aminotransferase elevation, appropriate follow-up and control of the irLI can improve the prognosis.

Paliperidone-Induced Acute Hyperglycemia Is Caused by Adrenaline Secretion via the Activation of Hypothalamic AMP-Activated Protein Kinase.

Although paliperidone-related hyperglycemia has been extensively examined, the underlying mechanisms have not yet been elucidated. We investigated the effects of a single intravenous injection of paliperidone (0.2, 0.4, or 0.6 mg/kg) on serum concentrations of glucose and other endogenous metabolites in rats. We also examined the effects of a single intravenous injection of paliperidone (0.4 mg/kg) on AMP-activated protein kinase (AMPK) activity in the hypothalamus and liver. To clarify the relationship between AMPK activity and adrenaline secretion, the effects of berberine, which inhibits hypothalamic AMPK, on paliperidone-induced hyperglycemia were assessed. Significant increases were observed in serum glucose, adrenaline, and insulin concentrations following intravenous injections of paliperidone at doses of 0.4 and 0.6 mg/kg. A propranolol pretreatment attenuated paliperidone-induced increases in serum concentrations of glucose, but not adrenaline. Significant increases were also noted in phosphorylated AMPK concentrations in the hypothalamus following the administration of paliperidone at a dose of 0.4 mg/kg. A berberine pretreatment attenuated paliperidone-induced increases in blood concentrations of glucose, adrenaline, and insulin and phosphorylated AMPK concentrations in the hypothalamus. Collectively, the present results demonstrated that an acute treatment with paliperidone induced hyperglycemia, which was associated with the effects of hypothalamic AMPK activation on the secretion of adrenaline.

An oncolytic virus as a promising candidate for the treatment of radioresistant oral squamous cell carcinoma.

We evaluated the usefulness of an oncolytic virus (Suratadenoturev; OBP-301) against radioresistant oral squamous cell carcinoma. We confirmed the expression of human telomerase reverse transcriptase and the coxsackievirus and adenovirus receptor in cell lines. Also, we examined the potential presence in a patient who has received existing therapy that is amenable to treatment with OBP-301. We evaluated: (1) the antitumor effects of OBP-301 alone and in combination with radiotherapy on radioresistant cell lines, (2) the molecular mechanism underlying the radiosensitizing effect and cell death increased by the combination therapy, and (3) the antitumor effect of the combination therapy in vivo using xenograft models (a radioresistant cell line-derived xenograft in mouse and a patient-derived xenograft). Human telomerase reverse transcriptase and the coxsackievirus and adenovirus receptor were expressed in all cell lines. OBP-301 decreased the proliferative activity of these cell lines in a concentration-dependent manner, and significantly enhanced the antitumor effect of irradiation. Phosphorylated STAT3 and its downstream molecules, which correlated with apoptosis and autophagy, showed significant changes in expression after treatment with OBP-301. The combination therapy exerted a significant antitumor effect versus radiotherapy alone in both xenograft models. Combination of OBP-301 with radiotherapy exerts a synergistic effect and may represent a promising treatment for radioresistant oral squamous cell carcinoma.

First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors.

BACKGROUND: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. LAY SUMMARY: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.

Extracellular N6 -isopentenyladenosine (i6A) addition induces cotranscriptional i6A incorporation into ribosomal RNAs.

N6 -isopentenyladenosine (i6A), a modified adenosine monomer, is known to induce cell death upon its addition to the culture medium. However, the molecular fate of extracellularly added i6A has yet to be identified. Here we show that i6A addition to cell culture medium results in i6A incorporation into cellular RNA in several cell lines, including the 5-fluorouracil (5-FU)-resistant human oral squamous cell carcinoma cell line FR2-SAS and its parental 5-FU-sensitive cell line SAS. i6A was predominantly incorporated into 18S and 28S rRNAs, and i6A incorporation into total RNA was mostly suppressed by treating these cell lines with an RNA polymerase I (Pol I) inhibitor. i6A was incorporated into RNA even upon inactivation of TRIT1, the only cellular i6A-modifying enzyme. These results indicate that upon cellular uptake of i6A, it is anabolized to be used for Pol I transcription. Interestingly, at lower i6A concentrations, the cytotoxic effect of i6A was substantially more pronounced in FR2-SAS cells than in SAS cells. Moreover, in FR2-SAS cells, i6A treatment decreased the rate of cellular protein synthesis and increased intracellular protein aggregation, and these effects were more pronounced than in SAS cells. Our work provides insights into the molecular fate of extracellularly applied i6A in the context of intracellular nucleic acid anabolism and suggests investigation of i6A as a candidate for a chemotherapy agent against 5-FU-resistant cancer cells.

The antioxidative stress regulator Nrf2 potentiates radioresistance of oral squamous cell carcinoma accompanied with metabolic modulation.

Nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of critical antioxidant proteins, was recently demonstrated to play a key role in cancer progression. Resistance to radiotherapy is a major obstacle in treating oral squamous cell carcinoma (OSCC). However, little is known about the association between Nrf2 and radioresistance in OSCC. Two OSCC cell lines (SAS and HSC-2) and their clinically relevant radioresistant (CRR) clones (SAS-R, HSC-2-R) were used. The effects of Nrf2 downregulation on radiosensitivity and the involvement of glycolysis in Nrf2-mediated radioresistance were evaluated. Immunohistochemistry of phosphorylated Nrf2 (p-Nrf2) was performed in 110 patients with OSCC who underwent preoperative chemoradiotherapy and surgery. Nrf2 was stably upregulated in CRR cells in vitro and in a mouse xenograft model. Moreover, elevated Nrf2 expression was associated with radioresistance. The enhancement of Nrf2-dependent glycolysis and glutathione synthesis was involved in the development of radioresistance. Additionally, p-Nrf2 expression was closely related to the pathological response to chemoradiotherapy, and its expression was predictive of prognosis in patients with advanced OSCC. Our results suggest that Nrf2 plays an important role in the radioresistance of OSCC accompanied by metabolic reprogramming. Targeting Nrf2 antioxidant pathway may represent a promising treatment strategy for highly malignant OSCC.

Naringenin potentiates anti-tumor immunity against oral cancer by inducing lymph node CD169-positive macrophage activation and cytotoxic T cell infiltration.

The CD169+ macrophages in lymph nodes are implicated in cytotoxic T lymphocyte (CTL) activation and are associated with improved prognosis in several malignancies. Here, we investigated the significance of CD169+ macrophages in oral squamous cell carcinoma (OSCC). Further, we tested the anti-tumor effects of naringenin, which has been previously shown to activate CD169+ macrophages, in a murine OSCC model. Immunohistochemical analysis for CD169 and CD8 was performed on lymph node and primary tumor specimens from 89 patients with OSCC. We also evaluated the effects of naringenin on two murine OSCC models. Increased CD169+ macrophage counts in the regional lymph nodes correlated with favorable prognosis and CD8+ cell counts within tumor sites. Additionally, naringenin suppressed tumor growth in two murine OSCC models. The mRNA levels of CD169, interleukin (IL)-12, and C-X-C motif chemokine ligand 10 (CXCL10) in lymph nodes and CTL infiltration in tumors significantly increased following naringenin administration in tumor-bearing mice. These results suggest that CD169+ macrophages in lymph nodes are involved in T cell-mediated anti-tumor immunity and could be a prognostic marker for patients with OSCC. Moreover, naringenin is a new potential agent for CD169+ macrophage activation in OSCC treatment.

The antiplatelet effect of mirtazapine is mediated by co-blocking 5-HT2A and α2-adrenergic receptors on platelets: An in vitro human plasma-based study.

Mirtazapine (MTZ) is a noradrenergic and specific serotonergic antidepressant that has been associated with an increased risk of bleeding. However, there is insufficient evidence confirming this association. We hypothesised that 5-HT2A and α2 receptor-mediated inhibitory effects of MTZ on platelets suppress platelet aggregation and increase the risk of bleeding. In this study, we examined the antiplatelet effect of MTZ on human platelets to test our hypothesis. Blood samples for platelet aggregation tests were obtained from 14 healthy volunteers. The antiplatelet effect of MTZ was evaluated using light transmission aggregometry. MTZ significantly suppressed platelet aggregation mediated both by the synergistic interaction of serotonin (5-HT) and adrenaline and the synergistic interaction of ADP and 5-HT or adrenaline. In conclusion, MTZ exerts its antiplatelet effects by co-blocking the 5-HT2A and α2-adrenergic receptors on platelets and also suppresses platelet aggregation induced by ADP and 5-HT or adrenaline. Therefore, when MTZ is used, especially for patients with a high risk of bleeding, the significance of its use must be considered carefully. In addition, the platelet aggregation pattern by adrenaline + 5-HT, ADP + adrenaline, and ADP + 5-HT was similar between humans and mice; however, this study did not directly compare the effects of MTZ on human and murine platelets. Therefore, under the conditions for inducing platelet aggregation using adrenaline + 5-HT, ADP + adrenaline, and ADP + 5-HT, mouse platelets can be used in the evaluation of the efficacy of antiplatelet drugs in humans.

Extracellular vesicles derived from radioresistant oral squamous cell carcinoma cells contribute to the acquisition of radioresistance via the miR-503-3p-BAK axis.

Despite advancements in treatments, oral squamous cell carcinoma (OSCC) has not significantly improved in prognosis or survival rate primarily due to the presence of treatment-resistant OSCC. The intercellular communication between tumour cells is a molecular mechanism involved in acquiring OSCC treatment resistance. Extracellular vesicles (EVs) and encapsulated miRNAs are important mediators of intercellular communication. Here, we focused on EVs released from clinically relevant radioresistant (CRR) OSCC cells. Additionally, we evaluated the correlation between miRNA expression in the serum samples of patients who showed resistance to radiotherapy and in EVs released from CRR OSCC cells. We found that EVs released from CRR OSCC cells conferred radioresistance to radiosensitive OSCC cells via miR-503-3p contained in EVs. This miR-503-3p inhibited BAK and impaired the caspase cascade to suppress radiation-induced apoptosis. Furthermore, OSCC cells with BAK knockdown had increased radioresistance. Additionally, the expression of circulating miR-503-3p in patients with OSCC was correlated with a poor treatment response and prognosis of radiotherapy. Our results provide new insights into the relationship between EVs and the radioresistance of OSCC and suggest that the miR-503-3p-BAK axis may be a therapeutic target and that circulating miR-503-3p is a useful prognostic biomarker in the radiotherapy of OSCC.

Risk Factors Associated With Unplanned Acute Care in Outpatient Chemotherapy With Oral Anticancer Drugs as Monotherapy or Combination Therapy With Injectable Anticancer Drugs.

BACKGROUND/AIM: Recently, the number of patients with cancer receiving outpatient chemotherapy using oral anticancer drugs has increased, but the currently available outpatient cancer chemotherapy is not safer than that available before. The present study aimed to identify risk factors associated with unplanned acute care (UAC) requiring outpatient chemotherapy-related consultation and hospitalisation. PATIENTS AND METHODS: We conducted a case- control study among 1,674 patients who received oral anticancer drug treatment either alone or in combination with injectable anticancer drugs at National Cancer Center Hospital East, Japan, between December 1, 2014, and November 30, 2015. RESULTS: Body mass index (BMI) was identified as a risk factor for UAC during chemotherapy. Patients with a BMI of <18.5 kg/m2, classified as underweight according to the World Health Organization classification of nutritional status, had a significantly higher risk of UAC. CONCLUSION: A low BMI immediately before the occurrence of chemotherapy-related UAC is a risk factor for adverse effects; therefore, underweight patients need more careful monitoring and supportive care.

Comparison of the Safety and Effectiveness of Four Direct Oral Anticoagulants in Japanese Patients with Nonvalvular Atrial Fibrillation Using Real-World Data.

Direct oral anticoagulants (DOACs) are widely used for the prevention of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). However, the differences in safety and effectiveness among four DOACs, dabigatran, rivaroxaban, apixaban, and edoxaban, in Japanese patients have not been clarified. Therefore, we conducted a retrospective cohort study to directly compare the safety and effectiveness among the four DOACs using the Japan Medical Data Center (JMDC) claims database. We identified 3823 patients with NVAF who started receiving a DOAC between March 2011 and June 2017. The safety outcome was major bleeding (a composite outcome of intracranial, gastrointestinal, respiratory, or renal/urinary tract bleeding) and the effectiveness outcome was the composite of ischemic stroke including transient ischemic attack (TIA) or systemic embolism. We constructed a Cox proportional hazard model to calculate the hazard ratio (HR) for all four DOAC combinations. The risk of major bleeding was significantly lower in the dabigatran group than in the apixaban group (HR, 0.55; 95% confidence interval (CI), 0.31-0.93; p = 0.03). In contrast, there was no significant difference in the risk of major bleeding among the other DOACs. In the composite risk of ischemic stroke including TIA or systemic embolism, there was no significant difference among the four DOACs. This study suggested that in the current use of DOACs in Japanese patients with NVAF, dabigatran had a significantly lower risk of major bleeding than apixaban, but there was no significant difference in effectiveness among the four DOACs.

miR-30a attenuates drug sensitivity to 5-FU by modulating cell proliferation possibly by downregulating cyclin E2 in oral squamous cell carcinoma.

We aimed to determine the functional role of the miRNA, which affects drug sensitivity to 5-FU in oral squamous cell carcinoma (OSCC), using two types of 5-FU-resistant and parental OSCC cell lines. MiRNA microarray data showed that miR-30a was significantly upregulated in two resistant cell lines. Therefore, we investigated the effects and molecular mechanism of miR-30a on 5-FU sensitivity. Stable overexpression of miR-30a in parental OSCC cells decreased cell proliferation and attenuated drug sensitivity to 5-FU. Cell cycle analysis indicated that miR-30a overexpression increased the proportion of G1 phase cells and decreased the proportion of S phase cells. MiR-30a knockdown using siRNA reversed the effects of miR-30a overexpression. DNA microarray analysis using miR-30a-overexpressing cell lines and a TargetScan database search showed that cyclin E2 (CCNE2) is a target of miR-30a. A luciferase reporter assay confirmed that a miR-30a mimic interacted with the specific binding site in the 3' UTR of CCNE2. CCNE2 knockdown with siRNA in OSCC cells yielded decreased drug sensitivity to 5-FU, similar to miR-30a overexpressing cells. These findings suggest that miR-30a in OSCC may be a novel biomarker of 5-FU-resistant tumors, as well as a therapeutic target for combating resistance.

Re-evaluating the clinical significance of serum p53 antibody levels in patients with oral cancer in Japanese clinical practice.

TP53 gene mutations can lead to mutant p53 protein accumulation in cancer cells, thereby inducing the production of serum antip53 antibodies (Ap53Ab) in patients with various types of cancer. The aim of the present study was to re-evaluate the clinicopathological and prognostic significance of Ap53Ab using the Ap53Ab ELISA kit, approved by the Japanese Health Insurance System in 2007. Ap53Ab was measured as a tumor marker in 94 patients with oral squamous cell carcinoma (OSCC), by subjecting paraffin-embedded sections obtained from biopsy specimens to immunohistochemical analysis to confirm p53 expression. The associations among Ap53Ab status, p53 expression and clinical significance in OSCC were examined. A total of 23% of the patients were Ap53Ab-positive. Ap53Ab status was found to be significantly associated with p53 expression status in primary tumors (P=0.027), clinical T-category, pathological N-category and pathological stage (P=0.04, P=0.010 and P=0.013, respectively). Kaplan-Meier curve analysis revealed that Ap53Ab status was significantly associated with poor disease-free survival (DFS; P=0.043), and Cox regression analysis revealed that Ap53Ab status was a significant prognostic factor for DFS in patients with OSCC (hazard ratio=2.807; 95% confidence interval: 1.029-7.160; P=0.044). These results suggested that Ap53Ab measurement may reflect the p53 mutation status and an aggressive malignant phenotype, and it may serve as a useful predictive marker candidate for OSCC in clinical practice.

Laser-Trélat sign improved after the resection of a tiny ground-grass nodule: a case report.

The Laser-Trélat sign refers to eruptive seborrheic keratoses accompanied by internal malignancies, mainly abdominal advanced ones. Detailed associations remain unclear, and the skin lesions do not improve with the treatment of internal malignancies in half of the patients. Herein, we report a rare case of Laser-Trélat sign that improved after resection of a 0.6-cm pulmonary ground-glass nodule: adenocarcinoma in situ. The patient requested the resection with the hopes of improving the skin lesions, though immediate resection was not indicated oncologically. With informed consent, despite possible failure in improving cutaneous diseases, thoracoscopic partial resection of the right lower lobe was performed. Fortunately, her seborrheic keratoses substantially improved after the resection, without exacerbation. To our knowledge, this is the first report describing such a clinical course. It is essential to inform patients regarding the indication of treatment for internal malignancy and its limitation in improving eruptive seborrheic keratoses.

Comprehensive Exploration of Medications That Affect the Bleeding Risk of Oral Anticoagulant Users.

Oral anticoagulants (OACs) pose a major bleeding risk, which may be increased or decreased by concomitant medications. To explore medications that affect the bleeding risk of OACs, we conducted a nested case-control study including 554 bleeding cases (warfarin, n = 327; direct OACs [DOACs], n = 227) and 1337 non-bleeding controls (warfarin, n = 814; DOACs, n = 523), using a Japanese health insurance database from January 2005 to June 2017. Major bleeding risk associated with exposure to concomitant medications within 30 d of the event/index date was evaluated, and adjusted odds ratios (aORs) were calculated using logistic regression analysis. Several antihypertensive drugs, such as amlodipine and bisoprolol, were associated with a decreased risk of bleeding (warfarin + amlodipine [aOR, 0.64; 95% confidence interval (CI): 0.41-0.98], DOACs + bisoprolol [aOR, 0.51; 95% CI, 0.33-0.80]). As hypertension is considered a significant risk factor for intracranial bleeding in antithrombotic therapy, antihypertensive drugs may suppress intracranial bleeding. In contrast, telmisartan, a widely used antihypertensive drug, was associated with an increased risk of bleeding [DOACs + telmisartan (aOR, 4.87; 95% CI, 1.84-12.91)]. Since telmisartan is an inhibitor of P-glycoprotein (P-gp), the elimination of rivaroxaban and apixaban, which are substrates of P-gp, is hindered, resulting in increased blood levels of both drugs, thereby increasing the risk of hemorrhage. In conclusion, antihypertensive drugs may improve the safety of OACs, and the pharmacokinetic-based drug interactions of DOACs must be considered.

Postoperative delirium in patients undergoing tumor resection with reconstructive surgery for oral cancer.

Many attempts have been made to identify the risk factors for postoperative delirium, but this has proved difficult due to its complex morbidity. Furthermore, there is little information on postoperative delirium in patients undergoing tumor resection and reconstructive surgery for oral cancer. The aim of the current study was to investigate the incidence of and risk factors for postoperative delirium in patients undergoing resection and reconstructive surgery for oral cancer. The present study included 104 patients with pedicle or free flap reconstruction. Postoperative delirium developed in 22 (21.2%) of these patients. The mean time to onset of postoperative delirium was 2.5±1.0 days and the duration of delirium was 1.9±1.2 days. Univariate analysis demonstrated that the occurrence of postoperative delirium was significantly correlated with operating time (P=0.033), duration of anesthesia (P=0.039), amount of blood loss (P=0.027), method of reconstruction (P=0.008), type of flap used (P=0.009) and time until postoperative ambulation (P=0.0008). Low postoperative red blood cell count (P=0.004), hemoglobin (P=0.004) and hematocrit (P=0.004) were significantly associated with delirium, but preoperative blood test results were not. The multiple logistic regression analysis of these risk factors revealed that the only significant correlation that remained was between postoperative delirium and the time to ambulation after surgery (P=0.005). Since 2009, the Department of Oral and Maxillofacial Surgery, Kumamoto University Hospital has promoted ambulation after the first two postoperative days for patients with oral cancer undergoing tumor resection with reconstruction, and the occurrence of postoperative delirium has decreased from 29.2 to 14.0%. The results of the current study suggest that early postoperative ambulation in patients who undergo reconstructive surgery for oral cancer is effective for preventing postoperative delirium.