Search

A 12-year-old male domestic cat with multiple subcutaneous mast cell tumours (MCTs) presented with a 2-week history of pruritus and raw/bleeding skin from self-trauma at Kagoshima University Veterinary Teaching Hospital. Polymerase chain reaction (PCR) and histopathological analyses revealed intertumoral heterogeneity among tumour locations based on the mutation status of KIT. In addition, the expression pattern of KIT was characterized. After failed treatment with vinblastine (2.0-2.2 mg/m 2 , intravenous administration, two doses in total) or nimustine (25 mg/m 2 , intravenous administration, two doses in total), toceranib (2.2-2.6 mg/kg, orally administered, every other day) was administered to treat recurrent MCTs harbouring the KIT exon eight internal tandem duplication mutation, achieving a complete response. However, toceranib resistance developed 2 months after treatment initiation. Subsequent PCR analysis was conducted to identify the mutational status of KIT in each MCT and to detect the presence of secondary mutations associated with the acquisition of toceranib resistance. Secondary KIT mutations (c.998G>C and c.2383G>C), which were not initially detected in tumour cells at diagnosis, were identified after the development of resistance to toceranib. This indicates that the tumour cells in feline MCTs in the same case have diverse characteristics. Our findings encourage further investigation into the development of therapeutic strategies for feline MCTs, particularly focusing on the heterogeneous nature of KIT/KIT and overcoming acquired resistance to toceranib., (© 2024 The Author(s). Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

Objectives: To document the utility of decremental responses in the repetitive nerve stimulation test (RNS) and spontaneous activities in needle electromyography (EMG) in the trapezius muscle for the diagnosis of amyotrophic lateral sclerosis., Methods: Subjects were retrospectively identified from our EMG database. Cervical spondylosis was represented as a disease control group. We investigated the sensitivity and specificity of RNS and EMG in the trapezius muscle and those of diagnostic criteria including the Gold Coast criteria (GCC)., Results: We reviewed 120 patients with amyotrophic lateral sclerosis and 17 patients with cervical spondylosis. "RNS or EMG" achieved the highest sensitivity (85%). The specificity was the highest for RNS (94%). Addition of RNS of the deltoid muscle achieved 98% sensitivity in the upper-limb onset amyotrophic lateral sclerosis. The sensitivity of the GCC was very high (88%)., Conclusions: Neurophysiological parameters investigated in this study having close to 100% specificities or sensitivities are useful as complements to the GCC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: In recent years, clinicians have focused on the importance of preventing hypoglycemia. We evaluated the impact of different reconstruction procedures after proximal gastrectomy on glycemic variability in non-diabetic patients with gastric cancer., Methods: This prospective observational study was conducted between April 2020 and March 2023. Flash continuous glucose-monitoring, a novel method for assessing glycemic control, was used to evaluate the glycemic profiles after gastrectomy. A flash continuous glucose-monitoring sensor was placed subcutaneously at the time of discharge, and glucose trends were evaluated for 2 weeks., Results: The anastomotic methods for proximal gastrectomy were esophagogastrostomy in 10 patients and double-tract reconstruction in 10 patients. The time below this range (glucose levels < 70 mg/dL) was significantly higher in the double-tract reconstruction group than in the esophagogastrostomy group (p = 0.049). A higher nocturnal time below this range was significantly correlated with an older age and double-tract reconstruction (p = 0.025 and p = 0.025, respectively)., Conclusion: These findings provide new insights into reconstruction methods after proximal gastrectomy by assessing postoperative hypoglycemia in non-diabetic patients with gastric cancer., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

SshEstI, a carboxylesterase from the thermoacidophilic archaeon Saccharolobus shibatae, is a member of the hormone-sensitive lipase family that displays slightly alkaliphilic activity with an optimum activity at pH 8.0. In this study, three distinct strategies were explored to confer acidophilic properties to SshEstI. The first strategy involved engineering the oxyanion hole by replacing Gly81 with serine or aspartic acid. The G81S mutant showed optimum activity at pH 7.0, whereas the aspartic acid mutant (G81D) rendered the enzyme slightly acidophilic with optimum activity observed at pH 6.0; however, k cat and k cat /K m values were reduced by these substitutions. The second strategy involved examining the effects of surfactant additives on the pH-activity profiles of SshEstI. The results showed that cetyltrimethylammonium bromide (CTAB) enhanced wild-type enzyme (WT) activity at acidic pH values. In the presence of 0.1 mM CTAB, G81S and G81D were acidophilic enzymes with optimum activity at pH 6.0 and 4.0, respectively, although their enzyme activities were low. The third strategy involved engineering the active site to resemble that of kumamolisin-As (kuma-As), an acidophilic peptidase of the sedolisin family. The catalytic triad of kuma-As was exchanged into SshEstI using site-directed mutagenesis. X-ray crystallographic analysis of the mutants (H274D and H274E) revealed that the potential hydrogen donor-acceptor distances around the active site of WT were fully maintained in these mutants. However, these mutants were inactive at pH 4-8., (Copyright © 2024 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Background: The impact of transjugular intrahepatic portosystemic shunt (TIPS) on waitlist mortality and liver transplantation (LT) urgency in Budd-Chiari Syndrome (BCS) patients remains unclear., Method: We analyzed BCS patients listed for LT in the UNOS database(2002-2024) to assess TIPS's impact on waitlist mortality and LT access via competing-risk analysis. We compared trends across two phases:Phase1(2002-2011) and Phase2(2012-2024)., Results: Of 815 BCS patients, 263(32.3%) received TIPS at listing. TIPS group had lower MELD-Na scores(20vs22,p<0.01), milder ascites(p=0.01), and fewer Status1 patients(those at risk of imminent death while awaiting LT)(2.7%vs8.3%,p<0.01) at listing compared to those without TIPS. TIPS patients had lower LT rates(43.3%vs56.5%,p<0.01) and longer waitlist times(350vs113 d,p<0.01). TIPS use increased in Phase2(64.3%vs35.7%,p<0.01). Of 426 transplanted patients, 134(31.5%) received TIPS, showing lower MELD-Na scores(24vs27,p<0.01) and better medical conditions(Intensive care unit:14.9%vs21.9%,p<0.01) at LT. Status1 patients were fewer (3.7%vs12.3%,p<0.01), with longer waiting days(97vs26 d,p<0.01) in TIPS group. TIPS use at listing increased from Phase1(25.6%) to Phase2(37.7%). From Phase1 to Phase2, ascites severity improved, re-LT cases decreased(Phase1:9.8%vsPhase2:2.2%,p<0.01), and cold ischemic time slightly decreased(Phase1:7.0vsPhase2:6.4 hours,p=0.14). Median donor body mass index significantly increased. No significant differences were identified in patient/graft survival at 1-/5-/10-year intervals between phases or TIPS/non-TIPS patients. While 90-day waitlist mortality showed no significant difference(p=0.11), TIPS trended towards lower mortality(subHazard ratio[sHR]:0.70[0.45-1.08]). Multivariable analysis indicated that TIPS was a significant factor in decreasing mortality(sHR:0.45[0.27-0.77],p<0.01). TIPS group also showed significantly lower LT access(sHR:0.65[0.53-0.81],p<0.01). Multivariable analysis showed that TIPS was a significant factor in decreasing access to LT(sHR:0.60[0.46-0.77],p<0.01). Sub-group analysis excluding Status1 or HCC showed similar trends., Conclusion: TIPS in BCS patients listed for LT reduces waitlist mortality and LT access, supporting its bridging role., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Caregivers of patients with chronic dysphasia experience stress and guilt regarding their eating behaviors. Dysphagia rehabilitation, including minimal oral intake with tube feeding, may be vital for caregivers. This study investigated the effects of dysphagia rehabilitation on caregiver well-being and attitudes toward eating assistance., Methods: This cross-sectional questionnaire study was conducted at two dental university hospitals on caregivers of homebound patients with dysphagia undergoing rehabilitation. Caregivers' experiences, with an emphasis on guilt and psychological status, were assessed using the Apathy Scale and Patient Health Questionnaire-5 Depression Scale. Patients were evaluated at the time of the survey and rehabilitation commencement using the Barthel Index and Functional Oral Intake Scale (FOIS). Changes in FOIS scores and caregiver guilt were assessed using the Wilcoxon signed rank test and McNemar test, respectively. The impact of oral intake changes on caregiving motivation was assessed using the Fisher exact test., Results: Between August 2019 and January 2021, 55 of 100 targeted caregivers responded (median age=64.5 years). A significant difference in FOIS scores was found (median rehabilitation duration=9.7 months). Despite 25 pneumonia cases, 65% of the caregivers continued to encourage oral intake. Guilt decreased from 48% during peak dysphagia to 22% at survey time (odds ratio=0.2, 95% CI=0.04-0.70; P < 0.01). No association was found between caregiving motivation and improved oral intake., Conclusion: Severe dysphagia impacted caregiver well-being, indicating preferences for patients' oral intake. To support caregivers, healthcare professionals should explore and integrate new multidisciplinary approaches into dysphagia rehabilitation strategies., (© 2024 American Society for Parenteral and Enteral Nutrition.)

Objectives: The trough concentration of vancomycin and the area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) ratio are crucial in determining vancomycin efficacy against methicillin-resistant Staphylococcus aureus . However, the use of similar pharmacokinetic principles in determining antibiotic efficacy against other gram-positive cocci is lacking. We performed a pharmacokinetic/pharmacodynamic analysis (association of target trough concentration values and AUC/MIC with therapeutic outcome) of vancomycin in patients with Enterococcus faecium bacteraemia., Methods: Between January 2014 and December 2021 we performed a retrospective cohort study of patients with E. faecium bacteraemia treated with vancomycin. Patients who received renal replacement therapy or had chronic kidney disease were excluded. Clinical failure, the primary outcome, was defined as a composite of 30-day all-cause mortality, vancomycin-susceptible infection requiring change of treatment, and/or recurrence. AUC 24 was estimated using a Bayesian estimation approach based on an individual vancomycin trough concentration. The MIC for vancomycin was determined using a standardised agar dilution method. Additionally, classification was used to identify the vancomycin AUC 24 /MIC ratio associated with clinical failure., Results: Of the 151 patients identified, 69 were enrolled. All MICs of vancomycin for E. faecium were ≤1.0 µg/mL. The AUC 24 and AUC 24 /MIC ratio were not significantly different between the clinical failure group and the clinical success group (432±123 µg/mL/hour vs 488±92 µg/mL/hour; p=0.075). However, 7 of 12 patients (58.3%) in the clinical failure group and 49 of 57 patients (86.0%) in the clinical success group had a vancomycin AUC 24 /MIC ratio ≥389 (p=0.041). No significant association between trough concentration or AUC 24 ≥600 µg/mL×hour and acute kidney injury was observed (p=0.365 and p=0.487, respectively)., Conclusion: The AUC 24 /MIC ratio is associated with the clinical outcome of vancomycin administration in E. faecium bacteraemia. In Japan, where vancomycin-resistant enterococcal infection is rare, empirical therapy with a target AUC 24 ≥389 should be recommended., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: In 2018, we reported the results of a study to assess the feasibility of applying the ACOSOG Z0011 criteria to Japanese patients with early-stage breast cancer (median follow-up, 3 years). Their results over the longer term can now be presented. Risk factors for axillary and locoregional recurrence in Z0011-eligible patients are unknown., Methods: Long-term survival outcomes were investigated by analyzing data from patients enrolled in the feasibility study. Data from the feasibility study patients, and from patients eligible for the Z0011 strategy after its introduction into clinical practice, were subjected to multivariate logistic regression analysis to identify risk factors for axillary and locoregional recurrence., Results: Regarding long-term outcomes for the feasibility study patients (n = 189), distant disease-free survival rates at 5 and 7 years were 90.4 ± 2.1% and 85.9 ± 2.6%, respectively, and overall survival rates at 5 and 7 years were 97.3 ± 1.2% and 95.3 ± 1.7%, respectively. Analysis of data from these patients plus the 93 who received Z0011 in clinical practice (total, n = 282) identified the following independent risk factors for axillary recurrence: absence of high axillary tangential irradiation (OR, 5.87 [95% CI, 1.09-31.35], p = 0.04) and number of positive sentinel lymph nodes (OR, 4.65 [95% CI, 1.11-19.48], p = 0.04). Only high Ki67 labeling index (OR, 5.92 [95% CI, 1.31-26.70], p = 0.02) was identified as an independent risk factor for locoregional recurrence., Conclusion: Long-term survival outcome results of the feasibility study show that the Z0011 strategy can be used to treat Japanese patients with early-stage breast cancer. Our findings regarding risk factors suggest that high axillary tangent irradiation is necessary for prevention of axillary recurrence, and that irradiation, including of the regional lymph nodes, should be considered, especially in patients with high Ki67 index values., (S. Karger AG, Basel.)

Objectives: This study aimed to delineate the natural progression of silicosis in fluorspar miners after the termination of dust exposure and identify its prognostic factors., Methods: This retrospective cohort study, conducted from 2000 to 2019, included 67 former miners. Radiological images were evaluated by comparing the initial and most recent radiographs using the International Classification of Radiographs of Pneumoconiosis. Cox multivariate proportional hazard models were used to estimate the hazard ratios using follow-up time to analyse the multivariable study of associated prognostic factors., Results: Among the participants, 50 (75%) exhibited progression over 2-16 years (median: 5.8 years). The Cox analysis highlighted older age as a likely precursor to the progression of significant opacities. Additionally, higher ILO category grades at onset were associated with disease progression., Conclusions: Nearly three-quarters of the miners diagnosed with silicosis demonstrated radiological progression even after the termination of dust exposure. Advancement in age and the degree of initial radiological opacity were associated with progression., Competing Interests: Conflict of interests: T.N received consulting fees from Otsuka Pharmaceutical Co., Takeda Pharmaceutical Co., Johnson and Johnson K.K., I&H Co.Ltd, Konica Minolta, Inc., Cocokarafine Group Co. Ltd, NTT DATA and research grant from Kyoto University. All of them were outside the submitted work. The other authors have no conflicts of interest to declare., (Copyright © 2024 American College of Occupational and Environmental Medicine.)

Aim: Liver fibrosis, heralding the potential progression to cirrhosis and hepatocellular carcinoma (HCC), compromises patient survival and augments post-hepatectomy recurrence. This study examined the detrimental effects of liver fibrosis on the antitumor functions of liver natural killer (NK) cells and the interleukin-33 (IL-33) signaling pathway., Methods: Our investigation, anchored in both human physiologies using living and deceased donor livers and the carbon tetrachloride (CCl 4 )-induced mouse fibrosis model, aimed to show a troubling interface between liver fibrosis and weakened hepatic immunity., Results: The Fibrosis-4 (FIB-4) index emerged as a salient, non-invasive prognostic marker, and its elevation correlated with reduced survival and heightened recurrence after HCC surgery even after propensity matching (n = 385). We established a strong correlation between liver fibrosis and liver NK cell dysfunction by developing a method for extracting liver NK cells from the liver graft perfusate. Furthermore, liver fibrosis ostensibly disrupted chemokines and promoted IL-33 expression, impeding liver NK cell antitumor activities, as evidenced in mouse models. Intriguingly, our results implicated IL-33 in diminishing the antitumor responses of NK cells. This interrelation, consistent across both mouse and human studies, coincides with clinical data suggesting that liver fibrosis predisposes patients to an increased risk of HCC recurrence., Conclusion: Our study revealed a critical relationship between liver fibrosis and compromised tumor immunity, emphasizing the potential interference of IL-33 with NK cell function. These insights advocate for advanced immunostimulatory therapies targeting cytokines, such as IL-33, aiming to bolster the hepatic immune response against HCC in the context of liver fibrosis., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

We provide updated results (median follow-up duration: 20.4 months) of a retrospective study on the effectiveness of trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer with brain metastases (BM) and/or leptomeningeal disease (ROSET-BM). Median progression-free survival (PFS) was 14.6 months. Median overall survival (OS) was not reached (NR); 24-month OS rate was 56.0%. Subgroup analysis showed that median PFS was 13.2 months in patients with analytical active BM, 17.5 months in patients with leptomeningeal carcinomatosis (LMC), and NR in patients with analytical stable BM (24-month PFS rates in patients with analytical active BM, LMC, and analytical stable BM were 32.7%, 25.1%, and 60.8%, respectively). Median OS was 27.0 months in patients with analytical active BM and NR in patients with LMC or analytical stable BM (24-month OS rates in patients with analytical active BM, LMC, and analytical stable BM were 52.0%, 61.6%, and 71.6%, respectively). The most common adverse event leading to discontinuation of T-DXd was interstitial lung disease (ILD; 23.1%); median ILD onset time among patients who discontinued T-DXd treatment due to ILD was 5.3 months. T-DXd has promising effectiveness in heavily pre-treated HER2+ metastatic breast cancer patients with BM and LMC. The incidence and median onset time of ILD were similar to those of Japanese subgroups in previous studies., (© 2024. The Author(s).)

Background: Thyroid hormones (TH) regulate the basal metabolic rate through their receptors THRα and THRβ. TH activates lipid metabolism via THRβ, however, an excess amount of TH can lead to tachycardia, bone loss, and muscle wasting through THRα. In recent years, TH analogs that selectively bind to THRβ have gained attention as new agents for treating dyslipidemia and obesity, which continue to pose major challenges to public health worldwide., Methods: We developed a TH analog, ZTA-261, by modifying the existing THRβ-selective agonists GC-1 and GC-24. To determine the THRβ-selectivity of ZTA-261, an in vitro radiolabeled TH displacement assay was conducted. ZTA-261 was intraperitoneally injected into a mouse model of high-fat diet-induced obesity, and its effectiveness in reducing body weight and visceral fat, and improving lipid metabolism was assessed. In addition, its toxicity in the liver, heart, and bone was evaluated., Results: ZTA-261 is more selective towards THRβ than GC-1. Although ZTA-261 is less effective in reducing body weight and visceral fat than GC-1, it is as effective as GC-1 in reducing the levels of serum and liver lipids. These effects are mediated by the same pathway as that of T 3 , a natural TH, as evidenced by similar changes in the expression of TH-induced and lipid metabolism-related genes. The bone, cardiac, and hepatotoxicity of ZTA-261 are significantly lower than those of GC-1., Conclusions: ZTA-261, a highly selective and less toxic THRβ agonist, has the potential to be used as a drug for treating diseases related to lipid metabolism., (© 2024. The Author(s).)

Objectives: This study aimed to describe the treatment selection for systemic lupus erythematosus (SLE) using data from the Kyushu Collagen Disease Network for SLE (KCDN-SLE) registry, a multicenter prospective registry in Japan., Methods: This study used data from patients registered between August 2022 and November 2023. Clinical characteristics, purpose of agent initiation, other candidate agents, and short-term efficacy and safety were evaluated., Results: We analyzed 69 previously treated patients with SLE (mean age 43.7 years; 62 females, 7 males). Hydroxychloroquine, biological agents, and immunosuppressive agents were initiated during the maintenance phase in 12, 41, and 16 patients, respectively. In patients with active organ involvement, hydroxychloroquine and biological agents were widely used for initiation. In those who already achieved treatment goals, biological agents alone were predominantly selected. The SLE Disease Activity Index 2000 score and prednisolone dose declined significantly over a 6-month follow-up period. Among 48 patients with active disease, 22 achieved a lupus low disease activity state, but this had no evident association with the initiation of a biological agent. In total, 14 adverse events, predominantly infections, were observed., Conclusions: Biological agents were used preferentially, and the therapeutic agents were appropriately effective and mostly achieved the purpose of agent initiation., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Oligonucleotide therapeutics, particularly antisense oligonucleotides (ASOs), have emerged as promising candidates in drug discovery. However, their effective delivery to the target tissues and cells remains a challenge, necessitating the development of suitable drug delivery technologies for ASOs to enable their practical application. In this study, we synthesized a library of chemically modified dipeptide-ASO conjugates using a recent synthetic method based on the Ugi reaction. We then conducted in vitro screening of this library using luciferase-expressing cell lines to identify ligands capable of enhancing ASO activity. Our findings suggest that N-(4-nitrophenoxycarbonyl)glycine may interact with the thiophosphate moiety of the phosphorothioate-modification in ASO. Through our screening efforts, we identified two ligands that modestly reduced luciferase luminescence in a cell type-selective manner. Furthermore, quantification of luciferase mRNA levels revealed that one of these promising dipeptide-ASO conjugates markedly suppressed luciferase RNA levels through its antisense effect in prostate-derived DU-145 cells compared to the ASOs without ligand modification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The necessity of biliary drainage before pancreaticoduodenectomy remains controversial in cases involving malignant obstructive jaundice; however, the benefits of biliary drainage have been reported in cases with severe hyperbilirubinemia. Herein, we present the case of a 61-year-old man suffering from jaundice due to distal cholangiocarcinoma. In this case, obstructive jaundice was refractory to repeat endoscopic drainage and bilirubin adsorption. Hyperbilirubinemia persisted despite successful implementation of biliary endoscopic sphincterotomy and two rounds of plastic stent placements. Stent occlusion and migration were unlikely and oral cholagogues proved ineffective. Owing to the patient's surgical candidacy and his aversion to nasobiliary drainage due to discomfort, bilirubin adsorption was introduced as an alternative therapeutic intervention. Following repeated adsorption sessions, a gradual decline in serum total bilirubin levels was observed and pancreaticoduodenectomy was scheduled. The patient successfully underwent pancreaticoduodenectomy with portal vein resection and reconstruction and D2 lymph node dissection. After the surgery, the serum bilirubin levels gradually decreased and the patient remained alive, with no recurrence at 26 months postoperatively. Therefore, this case highlights the feasibility and safety of performing pancreaticoduodenectomy in patients with severe, refractory jaundice who have not responded to repeated endoscopic interventions and have partially responded to bilirubin adsorption., (© 2024. Japanese Society of Gastroenterology.)

Protosteloid amoebae are slime molds characterized by simple sporocarp comprised only of a stalk and typically single spore. Recent molecular phylogenetic studies showed that protosteloid amoebae are scattered among the Amoebozoa, but most of them belongs to the Variosea. The Cavosteliida is one of the largest protosteloid group of the Variosea. We have established novel protosteloid amoeba strain YIP-63 from the fruiting body of jelly fugus Auricularia sp. The strain YIP-63 is unique to have a tiny sporocarp and amoeba comparing to the other protosteloid species, and trophic amoebae forming both round and branched shape. The molecular phylogenetic analyses based on 18S rRNA gene suggest that YIP-63 represents a novel lineage in the Cavosteliida. Therefore, we propose the new genus and new species for the strain YIP-63 as Nannostelium ampullaceum gen. et sp. nov. We provide morphological and molecular data on this novel protosteloid amoeba., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Dyspnea is one of the most common and distressing symptoms in patients with cancer and noncancer advanced diseases. The Japanese Society for Palliative Medicine revised previous guidelines for the management of respiratory symptoms in patients with cancer and newly developed clinical guidelines for managing dyspnea in patients with advanced disease, based on the result of systematic reviews for each clinical question and consensus among experts. We describe the recommendations of the guidelines as well as provide insights into the reasoning behind the recommendations and their development process. There has been a paucity of evidence regarding the interventions for dyspnea in patients with advanced disease. Thus, more clinical research that includes not only randomized controlled trials but also real-world observational studies is warranted.

Background: A useful biomarker for the efficacy of immune checkpoint inhibitors (ICIs) in advanced renal cell carcinoma (RCC) has not yet been established. This study aims to investigate whether inflammatory markers are associated with the efficacy of nivolumab plus ipilimumab therapy before and during treatment., Methods: Data from patients with advanced clear cell RCC who received a combination treatment of nivolumab plus ipilimumab were retrospectively analyzed. The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) levels were assessed at baseline and 3, 6, and 9 weeks after treatment initiation. The correlation between these inflammatory markers and the patient's prognosis was investigated., Results: Eighty-four patients were identified. The multivariate analysis identified NLR at week 3, CRP at week 6, and NLR and CRP at week 9 as the consistent predictor associated with poor overall survival (OS) at each time point. The survival analysis and receiver operating characteristic (ROC) curve analysis revealed that an NLR of ≥ 2.4 at week 3, CRP of ≥ 1.4 mg/dL at week 6, and NLR of ≥ 4.8 and CRP of ≥ 1.0 mg/dL at week 9 were associated with worse OS (hazard ratios (HR) = 5.70, P = 0.008, HR = 3.23, P = 0.004, HR = 7.38, P < 0.001 and HR = 3.55, P = 0.002)., Conclusions: Both NLR and CRP were considered useful biomarkers for understanding the prognosis during nivolumab plus ipilimumab therapy. Furthermore, an NLR of ≥ 4.8 and CRP of ≥ 1.0 mg/dL at week 9 are helpful in reconsidering treatment continuation., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Catalytic promiscuity of enzymes plays a pivotal role in driving the evolution of plant specialized metabolism. Chalcone synthase (CHS) catalyzes the production of 2',4,4',6'-tetrahydroxychalcone (THC), a common precursor of plant flavonoids, from p-coumaroyl-coenzyme A (-CoA) and three malonyl-CoA molecules. CHS has promiscuous product specificity, producing a significant amount of p-coumaroyltriacetic lactone (CTAL) in vitro. However, mechanistic aspects of this CHS promiscuity remain to be clarified. Here, we show that the product specificity of soybean CHS (GmCHS1) is altered by CoA, a reaction product, which selectively inhibits THC production (IC 50 , 67 μM) and enhances CTAL production. We determined the structure of a ternary GmCHS1/CoA/naringenin complex, in which CoA is bound to the CoA-binding tunnel via interactions with Lys55, Arg58, and Lys268. Replacement of these residues by alanine resulted in an enhanced THC/CTAL production ratio, suggesting the role of these residues in the CoA-mediated alteration of product specificity. In the ternary complex, a mobile loop ("the K-loop"), which contains Lys268, was in a "closed conformation" placing over the CoA-binding tunnel, whereas in the apo and binary complex structures, the K-loop was in an "open conformation" and remote from the tunnel. We propose that the production of THC involves a transition of the K-loop conformation between the open and closed states, whereas synthesis of CTAL is independent of it. In the presence of CoA, an enzyme conformer with the closed K-loop conformation becomes increasingly dominant, hampering the transition of K-loop conformations to result in decreased THC production and increased CTAL production., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Migraine is a complex disorder characterized by episodes of moderate-to-severe, often unilateral headaches and generally accompanied by nausea, vomiting, and increased sensitivity to light (photophobia), sound (phonophobia), and smell (hyperosmia). Photophobia is considered the most bothersome symptom of migraine attacks. Although the underlying mechanism remains unclear, the intrinsically photosensitive retinal ganglion cells (ipRGCs) are considered to be involved in photophobia associated with migraine. In this study, we investigated the association between the sensitivity of ipRGCs and migraines and cortical spreading depression (CSD), which may trigger migraine attacks. The pupillary responses closely associated with the function of ipRGCs in patients with migraine who were irradiated with lights were evaluated. Blue (486 nm) light irradiation elicited a response from ipRGCs; however, red light (560 nm) had no such effect. Melanopsin, a photosensitive protein, phototransduces in ipRGCs following blue light stimulation. Hypersensitivity of ipRGCs was observed in patients with migraine. CSD was more easily induced with blue light than with incandescent light using a mouse CSD model. Moreover, CSD was suppressed, even in the presence of blue light, after injecting opsinamide, a melanopsin inhibitor. The hypersensitivity of ipRGCs in patients with migraine may induce CSD, resulting in migraine attacks.

Evidence-based medicine (EBM) is helpful for laypersons' decision-making. This study aimed to evaluate the effectiveness of e-learning materials on the essential components of EBM for laypersons. We conducted a web-based, open-label, randomized controlled trial with laypersons in Japan aged ≥20 years who used the internet. Participants were randomly assigned to the intervention group with the e-learning material and the control group with only the 'Introduction' section of the same material. The primary and secondary outcomes were the self-created acquirement test scores (responding correctly with confidence) immediately after using the material and after 4 weeks. A multiple linear regression analysis was conducted. Of the 122 participants, 62 were randomly assigned to the intervention group and 59 to the control group; finally, 59 and 58, respectively, were included in the full analysis set. The mean (standard deviation) of the acquirement test score immediately after learning was 14.11 and (3.11) and 11.07 (3.88) in the intervention and control groups, respectively, indicating statistical significance (multivariable P < 0.001). The secondary long-term outcome was also statistically significant. The results showed that the e-learning material was effective for laypersons in acquiring the essential components of EBM. The material may increase laypersons' confidence in appraising health information, which can be used in decision-making., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

The incidence of subarachnoid hemorrhages (SAHs) in Japan has recently decreased. However, trends in the annual rates of unruptured cerebral aneurysms (UCAs) are unclear because calculations based on follow-up periods are limited to patients with ruptured cerebral aneurysms. We aimed to clarify current trends in the estimated annual rupture rates of UCAs in Japan and to identify the most relevant contributing factors. We analyzed data from the Japanese Ministry of Health, Labour and Welfare and records of the Japan Neurosurgical Society. The estimated annual rupture rates of UCAs between 2003 and 2018 were calculated according to age-adjusted mortality rates of SAH and number of treated ruptured cerebral aneurysms (RCAs). We estimated trends in annual rupture rates using sensitivity analysis and assessed associations between estimated annual rupture rates and the prevalences of hypertension and current smoking. The estimated annual rupture rate of UCAs significantly decreased from 1.44 to 0.87% and from 0.92 to 0.76%, respectively, in terms of age-adjusted mortality rates of SAH and number of treated RCAs (p < 0.001). The range of changes in estimated annual rupture rates of UCAs was - 1.13%‒0.83%, representing a declining UCA trend of 88%. The estimated annual rupture rates of UCAs declined by 0.02-0.10% and 0.01-0.05% with every percent decrease in hypertension and current smoking prevalence, respectively. The estimated annual rupture rate of UCAs has recently decreased in Japan, possibly due to a decrease in the prevalence of hypertension rather than smoking., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The International Committee of Medical Journal Editors (ICMJE) has published Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. These provide a global standard for writing and editing medical articles, including research integrity. However, no study has examined the research integrity-related content of Japanese medical journals' Instructions for Authors. We therefore compared research integrity content in ICMJE member journals with those in the English- and Japanese-language journals of the Japanese Association of Medical Sciences (JAMS)., Materials and Methods: This was a descriptive literature study. We obtained Instructions for Authors from English- and Japanese-language journals listed on the JAMS website and the ICMJE member journals listed on the ICMJE website as of September 1, 2021. We compared the presence of 20 topics (19 in the ICMJE Recommendations plus compliance with ICMJE) in the Instructions for Authors, and analyzed the content of the conflict of interest disclosure., Results: We evaluated 12 ICMJE member journals, and 82 English-language and 99 Japanese-language subcommittee journals. The median number of topics covered was 10.5 for ICMJE member journals, 10 for English-language journals, and three for Japanese-language journals. Compliance with ICMJE was mentioned by 10 (83%) ICMJE member journals, 75 (91%) English-language journals, and 29 (29%) Japanese-language journals. The ICMJE Conflicts of Interest Disclosure Form was requested by seven (64%) ICMJE member journals, 15 (18%) English-language journals, and one (1%) Japanese-language journal., Conclusions: Although the topics in the JAMS English-language journals resembled those in the ICMJE member journals, the median value of ICMJE-related topic inclusion was approximately one-third lower in JAMS Japanese-language journals than in ICMJE member journals. It is hoped that Japanese-language journals whose conflict of interest disclosure policies differ from ICMJE standards will adopt international standards to deter misconduct and ensure publication quality., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KI received research grants from The Nippon Foundation – Osaka University Project for Infectious Disease Prevention, the Watanabe Memorial Foundation for the Advancement of New Technology, (R2-524), the Inamori Foundation, and the Japan Society for the Promotion of Science (Grant-in-Aid for Early-Career Scientists, 23K12845); and received honoraria from Mimir, Inc., outside the submitted work. YN reports donation from Datack, outside the submitted work. HO reports research grants from I&H Co., Ltd., KRAFT Inc., donation from Neo Plus Pharma Co., Ltd., and YUYAMA Co., Ltd. TN reports research grants from I&H Co., Ltd., Cocokarafine Co., Ltd., and Konica Minolta Inc.; consulting fees from Otsuka Pharmaceutical; honoraria from Pfizer Japan, Merck Sharp & Dohme, Chugai Pharmaceutical, Takeda Pharmaceutical, Janssen Pharmaceutical K.K., Boehringer Ingelheim, Eli Lilly Japan K.K., Maruho, Mitsubishi Tanabe Pharma, Novartis Pharma, Allergan Japan, Novo Nordisk Pharma, Toa Eiyo, Dentsu, and GlaxoSmithKline, Abbott; Stock options from Bon Bon Inc.; and donations from CancerScan and YUYAMA Co., Ltd. All other authors declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous five years; no other relationships or activities that could appear to have influenced the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Koizumi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hemodialysis (HD)-induced myocardial stunning, characterized by transient left ventricular systolic dysfunction during HD, has been reported to be common and associated with a poor prognosis. However, the pathophysiology is not fully understood. We herein report a case of HD-induced myocardial stunning without obstructive coronary artery disease complicated by coronary microvascular dysfunction (CMD), suggesting that CMD plays a crucial role in the pathophysiology of this disease.

Recently, live-attenuated measles, rubella, varicella, and mumps vaccines have been administered to carefully selected post-liver transplant patients. Although attention has been focused on post-vaccination antibody titers and adverse events, the real-life clinical benefits remain unclear. A comprehensive analysis of breakthrough infections and natural boosters (asymptomatic cases with significant elevation in virus antibody titers) following immunization post-liver transplantation was conducted from 2002-2023, exploring the timing, frequency, correlation with domestic outbreaks, and degree of antibody elevation. During the median 10-year observation period among 68 post-liver transplant patients, breakthrough infections occurred only in chickenpox, with 7 mild cases (1 episode/64 person-years). A total of 59 natural booster episodes (1, 5, 20, and 33 for measles, rubella, chickenpox, and mumps, respectively) were observed, with incidence rates of 1 per 569, 110, 22, and 17 person-years, respectively. The timing of natural boosters closely correlated with domestic outbreaks (P < .05 in chickenpox and mumps), influenced by local vaccine coverage. The degree of antibody elevation was significantly higher in individuals with breakthrough infections than in those with natural boosters (P < .05). These findings suggest that immunization with live-attenuated vaccines for post-liver transplant patients has demonstrated clinical benefits. Furthermore, mass vaccination has a positive impact on post-transplant patient outcomes., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose, as described by the American Journal of Transplantation. M. Shinjoh has received speaking honoraria from Meiji Seika Pharma Co, Ltd, Shionogi & Co, Ltd, MSD K.K., FUJIREBIO Inc, Mitsubishi Tanabe Pharma Corporation, Taisho Pharmaceutical Co, Ltd, FUJIFILM Toyama Chemical Co, Ltd, The Mainichi Newspapers Co, Ltd, Maruho Co, Ltd, Astellas Pharma Inc, Sumitomo Pharma Co, Ltd, Daiichi Sankyo Co, Ltd, Takeda Pharmaceutical Co, Ltd, Japan Vaccine, a consultation fee from Pfizer Japan Inc, and grant support from JSPS KAKENHI, Japan (Grant Number JP20K10546, 2020-2023), none of which were in connection with the work presented here (all were less than JPY 500,000 USD370 per year). T. Nakayama received research funds from EIKEN Chemicals and Daiichi Sankyo, and lecture fees from Takeda Pharmaceuticals. The other authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: During the COVID-19 pandemic, much misinformation and disinformation emerged and spread rapidly via the internet, posing a severe public health challenge. While the need for eHealth literacy (eHL) has been emphasized, few studies have compared the difficulties involved in seeking and using COVID-19 information between adult internet users with low or high eHL., Objective: This study examines the association between eHL and web-based health information-seeking behaviors among adult Japanese internet users. Moreover, this study qualitatively shed light on the difficulties encountered in seeking and using this information and examined its relationship with eHL., Methods: This cross-sectional internet-based survey (October 2021) collected data from 6000 adult internet users who were equally divided into sample groups by gender, age, and income. We used the Japanese version of the eHL Scale (eHEALS). We also used a Digital Health Literacy Instrument (DHLI) adapted to the COVID-19 pandemic to assess eHL after we translated it to Japanese. Web-based health information-seeking behaviors were assessed by using a 10-item list of web sources and evaluating 10 topics participants searched for regarding COVID-19. Sociodemographic and other factors (eg, health-related behavior) were selected as covariates. Furthermore, we qualitatively explored the difficulties in information seeking and using. The descriptive contents of the responses regarding difficulties in seeking and using COVID-19 information were analyzed using an inductive qualitative content analysis approach., Results: Participants with high eHEALS and DHLI scores on information searching, adding self-generated information, evaluating reliability, determining relevance, and operational skills were more likely to use all web sources of information about COVID-19 than those with low scores. However, there were negative associations between navigation skills and privacy protection scores when using several information sources, such as YouTube (Google LLC), to search for COVID-19 information. While half of the participants reported no difficulty seeking and using COVID-19 information, participants who reported any difficulties, including information discernment, incomprehensible information, information overload, and disinformation, had lower DHLI score. Participants expressed significant concerns regarding "information quality and credibility," "abundance and shortage of relevant information," "public trust and skepticism," and "credibility of COVID-19-related information." Additionally, they disclosed more specific concerns, including "privacy and security concerns," "information retrieval challenges," "anxieties and panic," and "movement restriction.", Conclusions: Although Japanese internet users with higher eHEALS and total DHLI scores were more actively using various web sources for COVID-19 information, those with high navigation skills and privacy protection used web-based information about COVID-19 cautiously compared with those with lower proficiency. The study also highlighted an increased need for information discernment when using social networking sites in the "Health 2.0" era. The identified categories and themes from the qualitative content analysis, such as "information quality and credibility," suggest a framework for addressing the myriad challenges anticipated in future infodemics., (©Seigo Mitsutake, Koichiro Oka, Orkan Okan, Kevin Dadaczynski, Tatsuro Ishizaki, Takeo Nakayama, Yoshimitsu Takahashi. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 11.07.2024.)

Background/aim: The prognostic impact of the administration of antibiotics and proton pump inhibitors (PPIs) in immune checkpoint inhibitor (ICI) therapy for advanced cancer has recently been documented. However, how these drugs affect the outcomes of first-line ICI combination therapy for advanced renal cell carcinoma (RCC) remains unclear., Patients and Methods: We retrospectively evaluated the data of 128 patients with RCC who received first-line ICI combination therapy. The patients were grouped according to their history of antibiotics and PPIs use one month before the initiation of ICI combination therapy. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) after ICI combination therapy were compared between patients treated with and without antibiotics or PPIs., Results: Of the 128 patients, 30 (23%) and 44 (34%) received antibiotics and PPIs, respectively. Patients treated with antibiotics exhibited shorter PFS and OS compared to those who did not receive antibiotics (median PFS: 4.9 vs. 16.1 months, p<0.0001; OS: 20.8 vs. 49.0 months, p=0.0034). Multivariate analyses showed that antibiotic administration was an independent predictor of shorter PFS (hazard ratio: 2.54: p=0.0002) and OS (hazard ratio: 2.56: p=0.0067) after adjusting for other covariates. In contrast, there were no significant differences in either PFS or OS between patients who received PPIs and those who did not. (PFS: p=0.828; OS: p=0.105)., Conclusion: Antibiotics administration before ICI combination therapy was negatively associated with outcomes of first-line ICI combination therapy for advanced RCC. Therefore, careful monitoring is required for potentially high-risk patients undergoing ICI combination therapy., Competing Interests: Toshio Takagi received honoraria from Bristol-Myers Squibb and Ono Pharmaceutical. Tsunenori Kondo received honoraria from Pfizer, Novartis, and Bristol-Myers Squibb and Ono Pharmaceutical., (Copyright 2024, International Institute of Anticancer Research.)

Background: Vaccination is the primary method of preventing influenza infection and complications in young children. We evaluated the efficacy and safety of a single dose of MEDI3250 (intranasal, quadrivalent, live attenuated influenza vaccine) in healthy Japanese children during the 2016/17 influenza season., Methods: In this multicenter, randomized, double-blind, phase 3 study (jRCT2080223345), participants aged 2-18 years received MEDI3250 or placebo (2:1), stratified by age (2-6 years, 7-18 years). The primary and secondary endpoints were the incidence of confirmed symptomatic onset of influenza caused by a circulating wild-type strain or by a vaccine-matched strain, respectively. Safety outcomes included the incidence of adverse events (AEs) and vaccine-related AEs., Results: Overall, 910 participants received MEDI3250 (n = 608) or placebo (n = 302). For the primary endpoint (regardless of the influenza subtype), the incidence of influenza onset was 25.5 % (MEDI3250) and 35.9 % (placebo); relative risk reduction, 28.8 % (95 % confidence interval, 12.5 %-42.0 %). For the secondary endpoint (vaccine-matched strain), the incidence was 10.9 % (MEDI3250) and 17.2 % (placebo); relative risk reduction, 36.6 % (95 % confidence interval, 6.5 %-56.8 %). Solicited AEs occurred in 67.6 % (MEDI3250) and 63.6 % (placebo). Most events were mild; nasal discharge was most common (59.2 % [MEDI3250] and 52.6 % [placebo]). Unsolicited AEs occurred in 36.0 % (MEDI3250) and 33.1 % (placebo). The most common unsolicited vaccine-related AE was diarrhea (2.3 %, both groups)., Conclusions: MEDI3250 had a greater preventive effect against influenza onset in Japanese children than placebo; no new safety signals were observed relative to previous clinical and post-marketing studies of MEDI3250., (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.)

Objective: The development of acquired middle ear cholesteatoma is associated with a single nucleotide polymorphism, 538G>A, in the human adenosine triphosphate-binding cassette transporter C11 (ABCC11) gene, which is a determinant of the earwax morphotype, such as wet- and dry-type earwax; however, the mechanism underlying this association is unclear. We focused on the earwax pH and aimed to elucidate the mechanism between ABCC11 genotypes and acquired middle ear cholesteatoma., Study Design: Prospective observational study., Setting: Single-center, academic hospital., Methods: We recruited 40 patients with acquired middle ear cholesteatoma who underwent surgery and 115 controls with no history of middle ear cholesteatoma. We assessed the earwax pH and ABCC11 genotypes in all participants. Clinical information was collected from the patients with cholesteatoma., Results: The earwax pH was significantly less acidic in patients with cholesteatoma and those carrying wet earwax genotypes (ABCC11 538G/G or 538G/A) than in the controls and those carrying the dry earwax genotype (ABCC11 538A/A), respectively. Furthermore, earwax pH was significantly positively correlated with high preoperative cholesteatoma stages in the patients with cholesteatoma., Conclusion: Our results show that the less acidic earwax pH was significantly related to the development and progression of acquired middle ear cholesteatoma. The less acidic earwax pH may play an important role in the mechanism underlying the association between acquired middle ear cholesteatoma and the ABCC11 gene at site 538., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

The resection of middle ear paragangliomas can be challenging given their vascular nature and the small volume of the tympanic cavity, particularly when the tumor in the hypotympanum is close or attached to the internal carotid artery (ICA). We performed combined underwater endoscopic and microscopic surgery for a Class B1 middle ear paraganglioma according to the modified Fisch classification. The suspicious bone in the hypotympanum and around the petrous ICA was drilled with underwater endoscopy. The feeding arteries, the caroticotympanic and inferior tympanic arteries, were suctioned and cauterized under microscopy. To the best of our knowledge, no case of middle ear paraganglioma treated with underwater endoscopy has been reported. Underwater endoscopy, providing a clear operative field with blood and bone dust irrigation, is a good indication for middle ear paragangliomas. In contrast, microscopic preparation for unexpected bleeding is important, particularly when the tumor closely extends to vital structures, such as the ICA or the jugular bulb., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: A recent large real-world study conducted in the United States reported the effectiveness of palbociclib plus aromatase inhibitor in HR+/HER2- advanced breast cancer (ABC). However, local clinical practice and available medical treatment can vary between Japan and Western countries. Thus, it is important to investigate Japanese real-world data. This observational, multicenter study (NCT05399329) reports the interim analysis of effectiveness of palbociclib plus ET as first-line or second-line treatment for HR+/HER2- ABC by estimating real-world progression-free survival (rwPFS) and overall survival (OS) in Japanese routine clinical practice., Methods: Real-world clinical outcomes and treatment patterns of palbociclib plus ET were captured using a medical record review of patients diagnosed with HR+/HER2- ABC who had received palbociclib plus ET in the first-line or second-line treatment across 20 sites in Japan. The primary endpoint was rwPFS; secondary endpoints were OS, real-world overall response rate, real-world clinical benefit rate, and chemotherapy-free survival., Results: Of the 677 eligible patients, 420 and 257 patients, respectively, had received palbociclib with ET as first-line and second-line treatments. Median rwPFS (95% confidence interval) was 24.5 months (19.9-29.4) for first-line and 14.5 months (10.2-19.0) for second-line treatment groups. Median OS was not reached in the first-line group and was 46.7 months (38.8-not estimated) for the second-line group. The 36-month OS rates for de novo metastasis, treatment-free interval (TFI) ≥ 12 months, and TFI < 12 months were 80.2% (69.1-87.7), 82.0% (70.7-89.3), and 66.0% (57.9-72.9), respectively., Conclusion: The addition of palbociclib to ET was effective for treating HR+/HER2- ABC in Japanese routine clinical practice., (© 2024. The Author(s).)

Background: The impact of glucocorticoid administration for adverse events (AEs), including immune-related AEs, on the effectiveness of immune checkpoint inhibitor (ICI) combination therapy for advanced renal cell carcinoma (RCC) remains unknown., Objectives: To clarify the prognostic impact of glucocorticoid use for AEs during first-line ICI combination therapy for advanced RCC., Patients and Methods: We retrospectively evaluated data from 194 patients who received dual ICI combination therapy [i.e., immunotherapy (IO)-IO] or combinations of ICIs with tyrosine kinase inhibitors (TKIs) as first-line therapy. The patients were divided into two groups according to the history of glucocorticoid administration in each treatment group. Survival based on glucocorticoid administration was assessed., Results: A total of 101 (52.0%) and 93 (48.0%) patients received IO-IO and IO-TKI combination therapy, respectively. Glucocorticoids were administered to 46 (46%) and 22 (24%) patients in the IO-IO and IO-TKI groups, respectively. In the IO-IO group, progression-free survival (PFS) and overall survival (OS) were significantly longer in patients with glucocorticoid administration than in those without administration (median PFS: 14.4 versus 3.45 months, p = 0.0005; median OS: 77.6 versus 33.9 months, p = 0.0025). Multivariable analysis showed that glucocorticoid administration was an independent predictor of longer PFS (hazard ratio: 0.43, p = 0.0005) and OS (hazard ratio: 0.35, p = 0.0067) after adjustment for covariates. In the IO-TKI group, neither PFS nor OS significantly differed between patients treated with and without glucocorticoid administration (PFS: p = 0.0872, OS: p = 0.216)., Conclusions: Glucocorticoid administration did not negatively impact the effectiveness of ICI combination therapy for RCC, prompting glucocorticoid treatment use when AEs develop., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Mastectomy has been the standard surgical treatment for ipsilateral breast tumor recurrence (IBTR). Recently, there has been growing interest in repeat breast-conserving surgery (rBCS) for IBTR among breast surgeons; however, there is currently little information regarding patient preferences for surgical procedure for IBTR. The purpose of this study was to evaluate preference for surgical procedure (mastectomy vs. rBCS) among breast cancer patients who had undergone salvage surgery for IBTR., Methods: Overall, 100 breast cancer patients who had undergone salvage surgery for IBTR were asked about their preferred surgical methods for IBTR and the reason. The association of patient preference and the reasons related to various clinical and pathological factors were assessed., Results: Of the 100 respondents, only 11 patients (11%) preferred rBCS. Patients who had undergone rBCS and radiotherapy for IBTR were significantly more likely to prefer to undergo rBCS than other groups (p = 0.030). The most frequent reason for choosing rBCS was the patient's desire to minimize breast deformity and surgical wounds., Conclusions: Our study revealed that there is a low rate of patients who opt to undergo rBCS among patients who had undergone salvage surgery for IBTR. Discrepancies in perceptions regarding the surgical procedure for IBTR between patients and their surgeons may exist., (© 2024. Society of Surgical Oncology.)

Background: Postoperative pneumonia in patients with esophageal cancer occurs due to swallowing dysfunction and aspiration. Recently, maximum phonation time (MPT) assessment and repetitive saliva swallowing test (RSST) have been focused on as swallowing function assessment methods that can identify patients as high risk for pneumonia. We aimed to evaluate the clinical utility of MPT assessment and RSST in patients undergoing oncological esophagectomy., Methods: In total, 47 consecutive patients who underwent esophagectomy for esophageal cancer between August 2020 and July 2023 were eligible. The perioperative changes in MPTs and RSST scores were examined. In addition, univariate and multivariate analyses were performed to identify the predictive factors of postoperative pneumonia., Results: The median MPTs before surgery and on postoperative days (PODs) 3, 6, and 10 were 18.4, 7.2, 10.6, and 12.4 s, respectively; postoperative MPTs were significantly lower than preoperative MPT. In addition, the MPT of POD 6 was significantly longer than that of POD 3 (P < 0.05). Meanwhile, there were no significant changes in perioperative RSST scores. Overall, 8 of 47 patients (17.0%) developed pneumonia postoperatively. A short MPT on POD 6 was one of the independent predictive factors for the incidence of postoperative pneumonia (odds ratio: 12.6, 95% confidence interval: 1.29-123, P = 0.03) in the multivariate analysis., Conclusions: The MPT significantly decreased after esophagectomy. However, the RSST score did not. The MPT on POD6 can be a predictor of postoperative pneumonia., (© 2024. The Author(s), under exclusive licence to The Author(s) under exclusive licence to The Japan Esophageal Society.)

The quality of indoor environment is a risk factor for early childhood eczema and atopic dermatitis; however, its influence during pregnancy on childhood eczema in Japan has not been investigated. In this study, we aimed to determine the indoor environmental factors that are associated with eczema in children up to 3 years of age, using national birth cohort data from the Japan Environment and Children's Study (JECS). Information on indoor environments and eczema symptoms until 3 years of age was collected using self-administered questionnaires to the mothers. A total of 71,883 and 58,639 mother-child pairs at 1.5- and 3-years-old, respectively, were included in the former analyses. To account for prenatal indoor risk factors, 17,568 (1.5-years-old) and 7063 (3-years-old) children without indoor mold and/or ETS exposure were included in the final analysis. A higher mold index, gas heater use, parquet flooring use, and frequent insecticide use showed significantly increased risks for childhood eczema up to 3 years of age. These associations were consistent after stratification analysis among children whose parents did not have a history of allergies. The updated WHO guidelines on indoor air quality should be implemented based on recent findings regarding the effects of prenatal exposure to indoor dampness on health effects of children further in life, including asthma, respiratory effects, eczema, and other immunological effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Dialysis patients are susceptible to developing severe coronavirus disease 2019 (COVID-19) due to hypoimmunity. Antibody titers against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) after the primary vaccinations are lower in hemodialysis (HD) patients than in healthy individuals. This study aimed to evaluate the effect of a SARS-CoV-2 booster vaccination in HD and peritoneal dialysis (PD) patients based on antibody titers and cellular and humoral immunity., Methods: Participants of the control, HD, and PD groups were recruited from 12 facilities. SARS-CoV-2 antigen-specific cytokine and IgG-antibody levels were measured. Regulatory T cells and memory B cells were counted using flow cytometry at 6 months after primary vaccination with BNT162b2 and 3 weeks after the booster vaccination in HD and PD patients and compared with those of a control group., Results: Booster vaccination significantly enhanced the levels of antibodies, cytokines, and memory B cells in three groups. The HD group showed significantly higher levels of IgG-antibodies, IL-1β, IL-2, IL-4, IL-17, and memory B cells than those in the control group at 3 weeks after the booster dose. The PD group tended to show similar trends to HD patients but had similar levels of IgG-antibodies, cytokines, and memory B cells to the control group., Conclusions: HD patients had significantly stronger cellular and humoral immune responses than the control 3 weeks after the booster dose. Our findings will help in developing better COVID-19 vaccination strategies for HD and PD patients., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Hand, foot, and mouth disease (HFMD) is a common infectious disease caused by enteroviruses. Coxsackievirus A6 (CV-A6)-associated HFMD has recently emerged as a predominant disease worldwide. Here, we describe five HFMD cases caused by CV-A6 in Japan from 2019 to 2022. All clinical courses were not severe and were self-limited, and the skin exanthema with vesicles differed from that in classical HFMD. Phylogenetic analysis showed that the major epidemic strain cluster of CV-A6 was formed independently in 2011, and our latest CV-A6 strains in Japan were detected within this cluster. The five cases described in this report indicate the recent shift in the predominant and continuous disease manifestation of CV-A6-associated HFMD.

We present a case of an angioimmunoblastic T-cell lymphoma (AITL) and tubulointerstitial nephritis with storiform fibrosis in a 76-year-old man. The patient exhibited lymphadenopathy, polyclonal hypergammaglobulinemia, and renal dysfunction and was diagnosed with AITL on the basis of lymph node biopsy findings. The serum IgG4 level was highly elevated. Renal biopsy revealed IgG4-positive plasma cells and storiform fibrosis without infiltration of AITL, and the findings indicated IgG4-related kidney disease (IgG4-RKD). Following THPCOP therapy for AITL, the renal function improved. While diagnosing IgG4-RKD in a patient with AITL poses challenges, follicular helper T cell involvement appeared crucial in AITL and renal tubulointerstitial lesions in this case., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Purpose: This Phase III, multicenter, open-label, single-arm study evaluated the safety and immunogenicity of the measles-mumps-rubella (MMR) combined vaccine, JVC-001, as a second MMR vaccination., Methods: Healthy Japanese children aged 5-6 years received a single dose of JVC-001 following a first measles, mumps, and rubella vaccination (measles-rubella bivalent and mumps monovalent vaccine [Hoshino or Torii strain] or JVC-001) or the MMR vaccine received between ages 1 to <4 years. Immunogenicity was evaluated using antibody titers before and after vaccination (Day 1/Day 43). The primary endpoint was the seroprotection rate of antibody titers against each virus; geometric mean titer (GMT) was also evaluated. Adverse events (AEs) and adverse drug reactions (ADRs) were monitored., Results: One-hundred participants completed the study. The seroprotection rate of antibody titers against measles, rubella, and mumps virus (genotype D) were 100.0 % (95 % confidence interval [CI] 96.4 %, 100.0 %), 100.0 % (95 % CI 96.4 %, 100.0 %), and 100.0 % (95 % CI 96.3 %, 100.0 %), respectively. GMT (fold) increases (Day 1 to Day 43) were 16.0 to 55.7 for measles virus, 35.5 to 99.0 for rubella virus, and 25.7 to 89.5 for mumps virus (genotype D). Solicited ADRs occurred in 40.0 % of participants (injection site, 34.0 %; systemic, 13.0 %)., Conclusions: The second MMR vaccination with JVC-001 demonstrated sufficient antibody coverage against all three viruses; the safety profile was tolerable., Clinical Trial Registration: jRCT2080225022., Competing Interests: Declaration of competing interest Tetsuo Nakayama received consultant fees from Daiichi Sankyo Co., Ltd.; scholarship research funding from Eiken Chemical Co., Ltd.; lecture fees from Takeda Pharmaceutical Co., Ltd., MSD K.K., and Meiji Seika Pharma Co., Ltd.; honoraria for attending the meeting from Nitta Gelatin Inc.; fees for lecture and manuscript writing from GlaxoSmithKline K·K.; was honorary member of the Japanese Society for Vaccinology; secretary of the General Affairs Department of the Japanese Society of Clinical Virology; delegates of the Japanese Association for Infectious Diseases and the Japanese Society for Virology. Asuka Kawamura, Yoshitaka Sogawa, Sachiko Sakakibara, Takafumi Nakatsu, Motoshi Kimata, and Keiji Oe are employees of Daiichi Sankyo Co., Ltd., (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.)

Rationale & Objective: Little is known regarding the association between chronic tonsillitis and the onset of IgA nephropathy (IgAN). In the present study, we examined the potential relationship between chronic tonsillitis and a subsequent risk of developing IgAN., Study Design: Observational cohort study., Setting & Participants: 4,311,393 individuals without a history of IgAN identified between January 2005 and May 2022 within a Japanese nationwide epidemiological database, the JMDC Claims Database, representing health claims to over 60 insurers., Exposure: Comorbid chronic tonsillitis based on diagnosis codes., Outcome: IgAN occurrence., Analytical Approach: Cause-specific Cox proportional hazards analysis adjusting for potential confounding factors was employed to estimate hazard ratios (HRs)., Results: Comorbid chronic tonsillitis was identified in 12,842 individuals, constituting 0.3% of the cohort. The cohort had a median age of 44 years (IQR, 36-53), and males accounted for 57.9%, with a follow-up of 1,089 days (IQR, 532-1,797), during which 2,653 cases of IgAN developed. Cumulative incidence curve showed a higher cumulative incidence of IgAN in individuals with chronic tonsillitis compared with their counterparts without this condition. Multivariable cause-specific analysis further demonstrated that individuals with chronic tonsillitis had an elevated risk of developing IgAN, with HR of 2.72 (95% CI, 1.79-4.14)., Limitations: Potential residual confounders, and lack of consideration for ethnic distinctions., Conclusions: Using a large-scale epidemiological dataset, these findings suggest a relationship between chronic tonsillitis and an elevated risk of IgAN development in the general Japanese population., Plain-Language Summary: IgA nephropathy (IgAN), the most prevalent form of primary glomerulonephritis worldwide, is associated with unfavorable long-term kidney survival and life expectancy. Despite the substantial implications, the early detection of IgAN still remains challenging due to its commonly asymptomatic clinical presentation. Consequently, the exploration of risk factors assumes a critical research priority. Prior studies have reported the potential role of tonsilitis in the pathogenesis of IgAN. In this study, we assessed whether chronic tonsillitis was associated with the subsequent development of IgAN using a nationwide epidemiological dataset incorporating over 4,000,000 individuals. Within this large-scale cohort, our findings revealed an association between a history of tonsillitis and a greater risk of developing IgAN. These findings should heighten awareness of the potential susceptibility of people with chronic tonsilitis to IgAN., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: This study was performed to investigate the relationship between the amount of femorotibial alignment correction and the amount of improvement of hindfoot alignment in total knee arthroplasty (TKA)., Methods: A total of 159 knees undergoing TKA in 120 patients were assessed preoperatively and at 2 weeks, 1 month, 3 months and 6 months postoperatively. Standing hindfoot alignment was evaluated using the leg-heel angle (LHA). The amount of change in hindfoot alignment was compared between patients with severe varus knee (Group 1) and those with moderate varus, neutral or valgus knee (Group 2)., Results: The mean values of pre- and postoperative hip-knee-ankle (HKA) angle were -14 ± 4° and -1 ± 3° in Group 1 and -7 ± 5° and -1 ± 3° in Group 2, respectively. The differences between pre- and postoperative LHA were significantly larger in Group 1 than in Group 2 at 2 weeks, 1 month and 3 months postoperatively ( p  = 0.006, 0.001 and 0.03, respectively). At 6 months postoperatively, no differences were observed between the two groups ( p  = 0.31)., Conclusion: The amount of change in hindfoot alignment was larger in Group 1 than in Group 2 at 2 weeks, 1 month and 3 months after TKA, but there was no significant difference between the two groups at 6 months after TKA., Level of Evidence: Prognostic Level II., Competing Interests: One of the authors (ST) certifies receipt of personal payments during the study period, in an amount of less than USD 10,000 from Stryker Japan and Zimmer‐Biomet Japan., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)