Goal-directed and flexible modulation of syllable sequence within birdsong.

Songs constitute a complex system of vocal signals for inter-individual communication in songbirds. Here, we elucidate the flexibility which songbirds exhibit in the organizing and sequencing of syllables within their songs. Utilizing a newly devised song decoder for quasi-real-time annotation, we execute an operant conditioning paradigm, with rewards contingent upon specific syllable syntax. Our analysis reveals that birds possess the capacity to modify the contents of their songs, adjust the repetition length of particular syllables and employing specific motifs. Notably, birds altered their syllable sequence in a goal-directed manner to obtain rewards. We demonstrate that such modulation occurs within a distinct song segment, with adjustments made within 10 minutes after cue presentation. Additionally, we identify the involvement of the parietal-basal ganglia pathway in orchestrating these flexible modulations of syllable sequences. Our findings unveil an unappreciated aspect of songbird communication, drawing parallels with human speech.

A method for measuring serum levels of melanin-associated indole metabolites using LC-MS/MS and its application to malignant melanoma.

BACKGROUND AND AIMS: With the development of novel therapies for advanced malignant melanoma (MM), biomarkers that can accurately reflect the progression of MM are needed. Serum levels of melanin-related indole metabolites such as 5-hydroxy-6-methoxyindole-2-carboxylic acid (5H6MI2C) and 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI2C) are potential biomarkers for MM. Here, we describe the development of a mass spectrometry (MS)-based assay to determine serum levels of 5H6MI2C and 6H5MI2C. MATERIALS AND METHODS: We developed a stable isotope dilution-selective reaction monitoring-MS protocol using liquid chromatography tandem mass spectrometry (LC-MS/MS) to measure human serum 5H6MI2C and 6H5MI2C levels. Analytical evaluations of the method were performed and the method was applied to serum samples from MM patients (n = 81). RESULTS: The method established in this study showed high reproducibility and linearity. This novel method also found that serum 6H5MI2C levels were significantly elevated in patients with metastatic MM compared to those with non-metastatic MM. Unfortunately, 5H6MI2C did not show a comparable significant difference. CONCLUSION: We successfully established measurement methods for serum 5H6MI2C and 6H5MI2C levels using LC-MS/MS. Serum 6H5MI2C levels offer a potential marker for MM.

Efficacy of Vitrectomy With Tamponade Versus No Tamponade for Myopic Traction Maculopathy: A Multicenter Study (SCHISIS Report No.1).

PURPOSE: To evaluate the influence of tamponade on the visual and anatomic outcomes of pars plana vitrectomy for myopic traction maculopathy (MTM). DESIGN: Multicenter, retrospective clinical cohort study. METHODS: Consecutive eyes that underwent vitrectomy for advanced MTM with tamponade of air, sulfur hexafluoride (SF6), or perfluoropropane (C3F8) or without tamponade with a minimum follow-up of 12 months were included. Main outcome measures included postoperative visual acuity (VA) at 12 months in eyes with vs without tamponade. RESULTS: We included a total of 193 eyes (193 patients) in this study; 136 eyes (70%) treated with tamponade were compared with 57 eyes (30%) treated without tamponade. Baseline characteristics did not differ significantly between the groups. Both groups showed significant visual improvement at 12 months (both P < .001). However, postoperative visual acuity and visual improvement at 12 months were significantly better (P = .003 and P = .028, respectively) in eyes without tamponade, although the MTM in these eyes without tamponade took longer to resolve (P = .039). Retinal thickness and the ellipsoid zone were more preserved in eyes without tamponade (P < .001 and P = .001, respectively). Complications such as macular holes did not differ between the groups. A novel imaging finding of "schisis bending (accordioning)" was identified during MTM resolution. CONCLUSIONS: Vitrectomy either with or without tamponade for MTM was effective in improving vision in this study. However, eyes without tamponade experienced even better visual improvement and preserved retinal anatomy, despite a longer schisis resolution time. Surgery without tamponade may achieve better visual outcomes.

Risk Factors and Outcomes of Postoperative Macular Hole Formation after Vitrectomy for Myopic Traction Maculopathy: SCHISIS Report No. 2.

PURPOSE: To evaluate the incidence, pathogenesis, risk factors, and treatment outcomes of postoperative macular hole (MH) after pars plana vitrectomy (PPV) for myopic traction maculopathy (MTM). DESIGN: Multicenter, interventional, retrospective case series. SUBJECTS: Consecutive eyes that underwent PPV for MTM with a minimum 6-month follow-up. METHODS: We investigated the characteristics and treatment outcomes of postoperative MH after MTM surgery. MAIN OUTCOME MEASURES: Incidence, risk factors, and anatomic and visual outcomes of postoperative MH. RESULTS: We included 207 eyes (207 patients) with a mean follow-up of 25.9 months. During follow-up, 24 (11.6%) eyes developed MH (10 with concurrent MH retinal detachment); 15 eyes within 30 days (early), 4 eyes between 31 and 180 days (intermediate), and 5 eyes after 180 days (late). Logistic regression analysis revealed male gender (odds ratio [OR], 2.917; 95% confidence interval [CI], 1.198-7.100; P = 0.018), thinner preoperative choroidal thickness (OR, 0.988; 95% CI, 0.976-1.000; P = 0.048), and use of indocyanine green for internal limiting membrane peeling (OR, 2.960; 95% CI, 1.172-7.476; P = 0.022) as significant risk factors for postoperative MH. Internal limiting membrane peeling with a fovea-sparing technique tended to protect against postoperative MH, but it was not statistically significant (P = 0.096), because 1 eye still developed MH. Postoperative MHs were treated by observation (6 eyes), in-office octafluoropropane (C3F8) gas injection (7 eyes), or PPV (11 eyes). Macular hole closure was achieved in 20 eyes (83%). The hole closure rate was 67% (4/6 eyes) after observation, 71% (5/7 eyes) after C3F8 gas injection, and 91% (10/11 eyes) after PPV. However, visual outcomes were significantly worse for eyes with postoperative MH than those without (0.38 ± 0.43 vs. 0.68 ± 0.46; P = 0.002). CONCLUSIONS: Postoperative MH may occur in 11.6% of patients with MTM at any time after surgery. Retreatment resulted in relatively favorable anatomic closure but unfavorable visual outcomes. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

In vitro evaluation of Lactiplantibacillus plantarum HOKKAIDO strain, effective lactic acid bacteria for calf diarrhea.

Calf diarrhea adversely affects growth and sometimes results in mortality, leading to severe economic losses to the cattle industry. Antibiotics are useful in the treatment against bacterial diarrhea, but not against viral, protozoan, and antibiotic-resistant bacterial diarrhea. Therefore, there are growing requirements for a novel control method for calf diarrhea. Probiotics have been considered promising candidates for preventive and supportive therapy for calf diarrhea for many years. A recent study has revealed that Lactiplantibacillus plantarum HOKKAIDO strain (Lp-HKD) reduces intestinal pathology and the severity of diarrhea in bovine rotavirus (BRV)-infected calves. Lp-HKD is known to enhance the function of human immune cells and expected to be used as probiotics for humans. Therefore, it is hypothesized that Lp-HKD modulates antiviral immune response in cattle and provide the clinical benefits in BRV-infected calves. However, the detailed mechanism of Lp-HKD-induced immunomodulation remains unknown. Thus, this study aimed to elucidate the immunomodulatory and antiviral effects of Lp-HKD in cattle. Cultivation assay of bovine peripheral blood mononuclear cells (PBMCs) showed that live and heat-killed Lp-HKD stimulates the production of interleukin-1ß (IL-1ß), IL-6, IL-10, and interferon-γ (IFN-γ) from PBMCs. Stimulation by heat-killed Lp-HKD yielded stronger cytokine production than stimulation by the live Lp-HKD. Additionally, CD14+ monocytes were identified as major producers of IL-1ß, IL-6, and IL-10 under Lp-HKD stimulation; however, IFN-γ was mainly produced from immune cells other than CD14+ monocytes. Depletion of CD14+ monocytes from the PBMCs cultivation strongly decreased cytokine production induced by heat-killed Lp-HKD. The inhibition of toll-like receptor (TLR) 2/4 signaling decreased IL-1ß and IL-6 production induced by live Lp-HKD and IL-1ß, IL-6, and IFN-γ production induced by heat-killed Lp-HKD. Furthermore, live or heat-killed Lp-HKD also activated T cells and their production of IFN-γ and tumor necrosis factor-α. Then, culture supernatants of bovine PBMCs treated with heat-killed Lp-HKD demonstrated antiviral effects against BRV in vitro. In conclusion, this study demonstrated that Lp-HKD activates the functions of bovine immune cells via TLR2/4 signaling and exerts an antiviral effect against BRV through the induction of antiviral cytokines. Lp-HKD could be useful for the prevention and treatment of calf diarrhea through its immune activating effect.

Multiple ulcers and perforation of small intestine with everolimus use in a patient with rectal neuroendocrine tumor: A case report.

INTRODUCTION: Everolimus is an orally administered inhibitor of the mammalian target of rapamycin, which is a serine/threonine protein kinase. It is used for the treatment of pancreatic and gastrointestinal neuroendocrine tumors (NETs). Gastrointestinal perforations in patients being treated with everolimus is extremely rare, with only five reported cases. CASE PRESENTATION: A 62-year-old woman, who had previously undergone surgery for rectal NET, presented to our hospital with fever and abdominal pain. Abdominal computed tomography revealed perforation of the lower gastrointestinal tract, and we performed emergency surgery. There were multiple ulcers 150 cm distal from the ligament of Treitz to the terminal ileum; an ulcer at the anastomosis of stoma closure, 35 cm from the terminal ileum, was transmural. We subsequently performed a partial intestinal resection. CLINICAL DISCUSSION: The diagnosis of NETs is increasing worldwide, owing to recent improvements in diagnostic techniques. Although the use of everolimus has increased, gastrointestinal ulcer perforations caused by everolimus treatment have rarely been reported. The mechanism may be due to the inhibition of angiogenesis by mTOR inhibitors, as well as vascular endothelial growth factor inhibitors. In this case, It was considered that everolimus use most likely caused perforation. CONCLUSION: It is necessary to recognize that drug-induced gastrointestinal ulcers and perforations may occur with the use of mTOR inhibitors, and careful follow-up should be performed during administration.

Metastasis of Ovarian Cancer to the Descending Colon.

Colonic metastasis from ovarian cancer is extremely rare, with only seven reported cases. A 77-year-old woman who had previously undergone surgery for ovarian cancer was admitted to a local hospital with anal bleeding. Histopathological analysis confirmed the presence of adenocarcinoma. Colonoscopy revealed a descending colon tumor. The patient was diagnosed with Union for International Cancer Control T3N0M0 descending colon cancer or colon metastasis of the ovarian cancer. Laparoscopic left colectomy was performed; intraoperative frozen section diagnosis confirmed metastasis from ovarian cancer, and the absence of invasion to the serosal surface suggested hematogenous metastasis. This is the first case of colonic metastasis from ovarian cancer that was diagnosed using an intraoperative frozen section and laparoscopically treated.

Optimal Administration of Glycyrrhizin Avoids Pharmacokinetic Interactions With High-dose Methotrexate and Exerts a Hepatoprotective Effect.

BACKGROUND/AIM: Glycyrrhizin (GZ) is widely used to treat high-dose methotrexate (MTX)-induced liver dysfunction. However, in a previous in vivo study, we showed that simultaneous administration of both drugs increased the plasma concentration of MTX and exacerbated hepatic injuries. In this study, we investigated the optimal dosing interval in rats to avoid the interaction between high-dose MTX and GZ and to demonstrate the inherent hepatoprotective effect of GZ. MATERIALS AND METHODS: Male Wistar rats were treated with high-dose MTX (2,000 mg/kg) alone, with concomitant administration of 100 mg/kg GZ or GZ administered 3, 6, and 24 h before MTX administration. Plasma concentrations of MTX, alanine aminotransferase, aspartate aminotransferase, and total bilirubin were measured. RESULTS: The plasma concentration and half-life of methotrexate were significantly increased after concomitant administration of GZ, or when GZ was administered 3 h before MTX administration, compared with MTX alone, increasing hepatic enzyme levels. However, when GZ was administered 6 and 24 h before MTX administration, the levels were not significantly different from those of MTX alone and showed a tendency to decrease MTX-induced liver injury. These results suggest that the pharmacokinetic interaction between GZ and MTX could be avoided and the hepatoprotective effect of GZ could be achieved by an optimal dosing regimen, using the half-life of GZ as an indicator. CONCLUSION: When using high-dose MTX in combination with GZ, the administration intervals should be considered to avoid unwanted interactions and to achieve the GZ hepatoprotective effect.

Impact of relative dose intensity of trabectedin with pegfilgrastim support: a single-centre retrospective study.

Relative dose intensity (RDI) has been associated with improved survival in patients with advanced solid tumours. However, there is no evidence regarding RDI in patients under long-term treatment with trabectedin for adult advanced soft tissue sarcoma (STS). Pegfilgrastim use was associated with chemotherapy dose intensity maintenance in patients with various cancers. We retrospectively evaluated the RDI in patients with STS receiving trabectedin. The patients were grouped based on whether trabectedin administration was supported by pegfilgrastim. RDI was obtained for 114 of the 140 included patients. Chemotherapy cycles that included filgrastim were excluded. Patients treated with and without pegfilgrastim had similar RDI rates (77.1% ± 17.6% vs 78.8% ± 16.4%; P = 0.485). Moreover, we found no association between patients receiving ≥4 trabectedin cycles and the use of pegfilgrastim. These results suggested that trabectedin dose delays or reductions should be considered before administering prophylactic pegfilgrastim.

High temperatures and pressures during cooking hinder the nanofibrillation of purified pulp.

Kraft pulp is an abundant raw material for producing cellulose nanofibers. However, our previous study demonstrated that kraft cooking hinders the nanofibrillation of never-dried pulp. Therefore, this study aims to elucidate the specific factors of kraft cooking hindering nanofibrillation, particularly the effects of high temperature and pressure. Undried purified pulp, produced using the Wise method, was subjected to high temperature and pressure conditions, with and without subsequent alkali treatment. After fibrillating the pulps for different durations, the degree of nanofibrillation was evaluated by sedimentation tests. Undried Wise-based pulp, with excellent nanofibrillation ability, becomes less capable of nanofibrillation after cooking at high temperature and pressure. Thus, even in the undried state, harsh cooking is considered to have caused irreversible aggregation of microfibrils or hornification in the pulp cell wall. Moreover, high temperatures and pressure should be avoided when removing the matrix, e.g., lignin and hemicellulose, for producing pulp for cellulose nanofibers.

Protocol for viral vector-mediated measurement of transcription factor activity of mouse brain.

Here, we provide a step-by-step protocol to measure the activities of multiple transcription factors (TFs) in the same mouse brain. This protocol includes a procedure to construct a virus-based TF activity reporter, in utero transfection, and PCR-based measurement of TF activity to obtain the transcription factor activity profile (TFAP). Our protocol facilitates a systematic analysis of TF activity of the brain in vivo and will aid trans-omics understanding of the molecular mechanism underlying the brain functions. For complete details on the use and execution of this protocol, please refer to Abe and Abe, (2022).

Multifunctional cellulosic materials prepared by a reactive DES based zero-waste system.

Energy consumption and post-treatment of chemical reagent residues are important issues that hinder the sustainable production of the natural building blocks of cellulose nanofibrils (CNFs). In this study, we realize a low-energy, zero-waste process for CNF production by designing a novel reactive deep eutectic solvent (DES), the residue of which can be directly used as a plant growth regulator. After pretreatment with the DES, cellulose fibers self-delaminate into thin layers referred to as pseudo-CNFs, as their strength, toughness and transmittance are comparable to those of CNFs. Pseudo-CNFs break into smaller particles during recycling and thus display unique mechanical upcycling. After facile fibrillation, the obtained CNFs can independently form freestanding sub-micrometer films that show a strong, full coloration, which is demonstrated for the first time. Our concept can enable a green process, and the developed cellulosic materials may find various applications as structural materials and optical coatings.

Hindrance to nanofibrillation of undried pulp produced by the kraft cooking process.

Kraft pulp is the most common and economically advantageous raw material for making cellulose nanofibers (CNFs). However, when kraft pulp is subjected to mechanical fibrillation, unfibrillated pulp always remains, even though the pulp is undried. In this study, the effect of the kraft pulping process on the fibrillation of undried pulp was studied. The fibrillation ability was compared with that of undried pulp prepared using Wise method and alkaline treatment. Suspensions of undried pulps were mechanically fibrillated with a high-speed blender for different durations. The degree of fibrillation of pulps was evaluated using sedimentation, morphologies from field emission scanning electron microscopy, specific surface area, and water retention values. Every analysis showed that undried, kraft-based pulp was less fibrillated than undried, wise-based pulp. These results suggested that the kraft cooking process at high temperature hindered the fibrillation of pulp. This might be related to the aggregation occur in cellulose.

Clinical role and safety of tapentadol in patients with cancer: A single-center experience.

OBJECTIVE: To evaluate real-world data on the use of tapentadol (TAP) in cancer patients. DESIGN: Single-center retrospective study. SETTING: Curative/palliative. PATIENTS, PARTICIPANTS: Patients who started TAP between October 2014 and December 2018 at our institution. MAIN OUTCOME MEASURE(S): The primary outcome was the reason for TAP initiation. Secondary outcomes included prescription duration, TAP cessation rate, reason for cessation, and adverse events (AEs). Since the palliative care team (PCT) tended to prescribe to cancer patients with intractable pain more often than patients in usual care, and also tended to prescribe opioids based on their characteristics, we decided to compare patients with and without PCT intervention. RESULTS: There were 175 patients who first received TAP during the study period, of whom 81 patients (46.3 percent) were male. The median age was 60 years. TAP was prescribed for opioid-naive patients in 45 (26 percent) cases and opioid switch in 130 (74 percent) cases. When comparing the PCT group (n = 121) and the non-PCT group (n = 54) using univariate analysis, the PCT group had a higher opioid switch rate (81.8 percent vs 57.4 percent, p < .001), higher proportion of patients with neuropathic pain (NP) (65.3 percent vs 16.7 percent, p < .001), and a higher proportion of patients with a history of nausea (41.3 percent vs 18.5 percent, p < .01). The cessation rate due to AEs was 8 percent overall. CONCLUSIONS: Palliative care physicians prescribed TAP for patients with NP or a history of nausea. Opioid-naive patients were preferred by oncologists. TAP has good tolerability in both groups, with a low dropout rate due to AEs.

PCR-based profiling of transcription factor activity in vivo by a virus-based reporter battery.

Understanding the molecular mechanisms of gene regulation is pivotal for understanding how cells establish and modify their identities and functions. Multiple transcription factors (TFs) coordinate to alter gene expression in cells; however, a method to quantitatively analyze the activity of each TF is lacking, particularly in vivo. Here, we introduce a viral-vector-based TF reporter battery that can be used to simultaneously analyze the activity of multiple TFs, visualized as the TF activity profile (TFAP) obtained by qPCR. We show that the cells possess distinct TFAPs that dynamically change according to experimental manipulation or physiological activity. We report a practical method to obtain the TFAP of a defined cell population and their experience-dependent changes in the mouse brain in vivo. The TFAP obtained by our method will help bridge the information gap between the genome and transcriptome and aid the multi-omics view of understanding the gene regulation system.

Risk Factors for Hepatic Toxicity of High-dose Methotrexate in Patients With Osteosarcoma.

BACKGROUND/AIM: High-dose methotrexate (HD-MTX) is widely used to treat osteosarcoma. However, some patients develop hepatic toxicity, leading to dose modification and delays in the scheduled chemotherapy. The present study aimed to identify the risk factors of hepatotoxicity in patients with osteosarcoma. PATIENTS AND METHODS: We conducted a retrospective study of patients with osteosarcoma treated with HD-MTX between January 2014 and June 2020 at the National Cancer Center Hospital, Japan. The risk factors for MTX-induced hepatotoxicity (≥grade 3) were identified using multivariate logistic regression analysis. RESULTS: The final analysis included 88 courses of 36 patients. Hepatotoxicity occurred in 51 (58.0%) of the 88 courses. Female sex, MTX dose (>10.2 g/m2), and serum calcium concentration (>9.3 mg/dl) were identified as risk factors for HD-MTX-induced hepatotoxicity. CONCLUSION: Identifying the risk factors of HD-MTX-induced hepatotoxicity may contribute to improvements in the safety and management of HD-MTX therapy.

Prognosis and etiology of traumatic and non-traumatic corneal perforations in a tertiary referral hospital: a 30-year retrospective study.

PURPOSE: To clarify the prognosis of corneal perforation, we compared the etiology and characteristics of patients with traumatic and non-traumatic corneal perforations. METHODS: This retrospective observational study included patients treated for traumatic or non-traumatic corneal perforations at a single tertiary hospital from 1989 to 2019. The variables collected included the primary cause of corneal perforation, final best-corrected visual acuity (BCVA), and treatment administered. The initial treatment administered and treatment success rates were compared between the traumatic and non-traumatic groups. Multivariate linear regression analysis was performed to determine the predictors of final visual acuity. RESULTS: Ninety eyes of 90 patients (mean age, 61.1 ± 19.7 years) were included. Traumatic and non-traumatic corneal perforations occurred in 40 (44.4%) and 50 eyes (55.6%), respectively. Among non-traumatic causes, infection and autoimmune disease were the causes for corneal perforation in 18 (20.0%) and 12 eyes (13.3%), respectively. The success rate for the closure of the perforated site with the initial procedure was significantly higher in traumatic corneal perforations than in non-traumatic corneal perforations (90.0% and 72.2%, respectively; p = 0.038). Patients with traumatic corneal perforation had significantly better final BCVA than those with non-traumatic corneal perforation (0.71 ± 1.18 and 1.52 ± 1.12, respectively; p = 0.0016). On multivariate analysis, older age and non-traumatic corneal perforation were significantly related to the final lower BCVA (p < 0.001 and p = 0.029, respectively). CONCLUSION: Traumatic corneal perforation demonstrated a significantly better prognosis than non-traumatic corneal perforation. It is critical to consider the primary cause of corneal perforation to anticipate prognosis.

Comparison of efficacy and safety of accelerated trans-epithelial crosslinking for keratoconus patients with corneas thicker and thinner than 380µm.

PURPOSE: Accelerated trans-epithelial cross-linking (ATE-CXL), a therapy to halt keratoconus progression, has the merit of widening the indications for thinner corneas (<380 µm). Since a hypotonic solution affects the swollen cornea, corneas of <380 µm thickness at preoperative measurement can be an indication for ATE-CXL. The aim of this retrospective study was to compare the efficacy and safety of ATE-CXL for keratoconus between corneas with thicknesses <380 µm and ≥380 µm. MATERIALS AND METHODS: Thirty-four eyes of 27 patients who underwent ATE-CXL (30 mW/cm2; 3 minutes) with completion of a 24-month follow-up, were enrolled and divided into two groups: Group 1, thinnest corneal thickness (TCT), <380 µm (n = 10) and Group 2, TCT, ≥380 µm (n = 24). A hypotonic solution was administered to Group 1 until the corneal thickness increased by >380 µm before UV-A irradiation. We measured uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), maximum and average keratometric values (Kmax and AveK), central corneal thickness (CCT), TCT by anterior segment optical coherence tomography, and corneal endothelial cell density (ECD) using specular microscopy. The changes from baseline to 24 months postoperatively between the two groups were compared accordingly. RESULTS: The changes in Kmax and AveK from baseline to 24 months in Group 1 (ΔKmax: -7.8 ± 7.7 D, ΔAveK: -4.3 ± 6.1 D) showed significant decreases compared to those in Group 2 (ΔKmax: 0.2 ± 3.0 D, ΔAveK: 0.6 ± 2.7 D) (p = .004 and p = .001), and there were no significant changes from baseline to 24 months postoperatively in UCVA, BCVA, CCT, TCT, and ECD in both groups. CONCLUSION: ATE-CXL is effective and safe for keratoconic corneas in both groups. The effect of reducing keratometric values was greater in the group with thinner corneas.

Tapentadol Safety and Patient Characteristics Associated with Treatment Discontinuation in Cancer Therapy: A Retrospective Multicentre Study in Japan.

INTRODUCTION: Tapentadol has analgesic effects comparable to those of conventional opioids and is associated with fewer side effects, including gastrointestinal symptoms, drowsiness, and dizziness, than other opioids. However, the safety of tapentadol in the Japanese population remains unclear; the present multicentre study aimed to examine the safety of tapentadol and the characteristics of patients likely to discontinue this treatment owing to adverse events. METHODS: The safety of tapentadol was assessed retrospectively in patients with any type of cancer treated between August 18, 2014 and October 31, 2019 across nine institutions in Japan. Patients were examined at baseline and at the time of opioid discontinuation. Multivariate analysis was performed to identify factors associated with tapentadol discontinuation owing to adverse events. RESULTS: A total of 906 patients were included in this study, and 685 (75.6%) cases were followed up until tapentadol cessation for any reason. Among patients who discontinued treatment, 119 (17.4%) did so because of adverse events. Among adverse events associated with difficulty in taking medication, nausea was the most common cause of treatment discontinuation (4.7%), followed by drowsiness (1.8%). Multivariate analysis showed that those who were prescribed tapentadol by a palliative care physician (odds ratio [OR] 2.60, 95% confidence interval [CI] 1.36-4.99, p = 0.004), patients switching to tapentadol due to side effects from previous opioids (OR 2.19, 95% CI 1.05-4.56, p = 0.037), and patients who did not use naldemedine (OR 5.06, 95% CI 2.47-10.37, p < 0.0001) had an increased risk of treatment discontinuation owing to adverse events. CONCLUSIONS: This study presents the safety profile of tapentadol and the characteristics of patients likely to discontinue this treatment owing to adverse events in the Japanese population. Prospective controlled trials are required to evaluate the safety of tapentadol and validate the present findings. TRIAL REGISTRATION NUMBER: UMIN 000044282 (University Hospital Medical Information Network).

Concomitant Use of High-dose Methotrexate and Glycyrrhizin Affects Pharmacokinetics of Methotrexate, Resulting in Hepatic Toxicity.

BACKGROUND/AIM: High-dose methotrexate is a therapy for acute leukemia, malignant lymphoma, and osteosarcoma. Glycyrrhizin has been used to treat hepatic dysfunction caused by high-dose methotrexate. However, few studies have investigated the interaction between glycyrrhizin and high-dose methotrexate. MATERIALS AND METHODS: Male Wistar rats were treated with high-dose methotrexate (500 or 1,000 mg/kg) alone, or with co-administration of 100 mg/kg glycyrrhizin. Plasma concentrations of methotrexate, alanine aminotransferase, aspartate aminotransferase, and total bilirubin were measured. RESULTS: At both methotrexate doses, the blood concentration of methotrexate was significantly increased and total clearance was significantly reduced using co-administration of glycyrrhizin compared with methotrexate alone, which led to increased levels of hepatic enzymes. These results suggest that glycyrrhizin significantly increases the plasma level and delays the clearance of methotrexate, resulting in hepatic toxicity. CONCLUSION: The concomitant use of methotrexate and glycyrrhizin should be considered with caution.