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Background/aim: Despite the well-publicized clinical outcomes after unplanned excision (UE) and re-excision (re-excision) in patients with soft-tissue sarcoma (STS), there is little information about the real-life referral patterns for UE, such as patient profile, details of procedures, and subsequent management after UE. We aimed to investigate the characteristics of patients with UE who were referred to sarcoma-specific centers., Patients and Methods: Between May 2022 and June 2023, we registered 97 patients who underwent UE and were referred to sarcoma-specific centers in Japan. We excluded those with well-differentiated liposarcomas and dermatofibrosarcoma protuberances. We investigated the details of UE and additional treatment after UE., Results: There were 49 men and 48 women, with a mean age of 62 years. A broad range of surgeons performed UE; 36 plastic surgeons, 22 orthopedic surgeons, 17 general surgeons, 17 dermatologists, and 5 others. The mean tumor size was 4.1 cm. Local anesthesia was administered to 58 patients. Forty-five patients underwent UE without prior magnetic resonance imaging. Inappropriate transverse skin incisions were performed in 42 patients. Of the 97 patients, 82 underwent re-excision after UE. The mean time between UE and date of initial presentation at the referral hospital was 46 days. The mean interval between UE and re-excision was 96 days. Of the 82 patients, 59 underwent soft-tissue reconstruction after re-excision., Conclusion: A broad range of surgeons performed UE. Continuous education about STS should be considered for all surgeons. UE should be avoided because residual tumors are common, and reconstructive surgery may be necessary., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Previous studies have shown that iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/ml and lixisenatide, provides effective glycemic control in people with type 2 diabetes (T2D). The SIMPLIFY Japan study assessed the impact of switching from multiple daily insulin injections (MDI) to once-daily iGlarLixi on health-related quality of life (HRQOL) and glycemic parameters in Japanese people with moderately controlled T2D., Methods: This 24-week, prospective, observational cohort study enrolled Japanese adults with T2D who switched from MDI therapy to iGlarLixi. Data were collected at baseline, 12, and 24 weeks; changes in Diabetes Therapy-Related Quality of Life (DTR-QOL) questionnaire score, glycated hemoglobin (HbA1c), body weight and self-reported treatment adherence were evaluated; the primary endpoint was change in DTR-QOL at 24 weeks., Results: Sixty-six participants were enrolled and 61 were included in the full analysis set. Significant improvements were observed in total DTR-QOL score from baseline to week 24 (mean change + 10.8 points; P < 0.001), with higher scores observed in individual domains related to social/daily activities, treatment satisfaction, and reductions in treatment-related anxiety (P < 0.05). A small HbA1c increase was noted at week 24 (P < 0.001), while this did not appear to adversely affect HRQOL or treatment satisfaction. A significant reduction in body weight was observed at week 12 (mean change - 0.7 kg; P = 0.046). Self-reported treatment adherence increased from baseline to week 24, with the proportion of participants who never missed an insulin injection increasing from 55.7 to 77.6%. At week 24, the incidence of hypoglycemia and gastrointestinal adverse events was 18.2 and 27.3%, respectively., Conclusions: Switching from MDI to iGlarLixi therapy in Japanese people with T2D was associated with enhanced HRQOL (despite slight elevation in HbA1c) and improved treatment adherence, with a favorable safety profile. These findings support the beneficial role of iGlarLixi in the management of T2D in real-world Japanese clinical practice., Study Registration: Japan Registry of Clinical Trials (jRCT1041210151)., (© 2024. The Author(s).)

Background: Interleukin (IL)-23 is involved in the pathogenesis of ulcerative colitis (UC). A genome-wide significant association between IL23R p.G149R (rs76418789) and UC was previously identified in Japan and Korea. This case-control study aims to examine this association within the Japanese population., Methods: The study included 384 cases diagnosed with UC within the past 4 years and 661 control subjects. Adjustment was made for sex, age, and smoking., Results: The frequency of the AA genotype of rs76418789 was 0.0 % in cases and 0.5 % in control subjects. In comparison to study subjects with the GG genotype of rs76418789, those with the GA or AA genotype had a significantly reduced risk of UC, with an adjusted odds ratio of 0.67 (95 % confidence interval: 0.44-0.999). A significant multiplicative interaction was observed between rs76418789 and having ever smoked influencing UC (p for interaction = 0.03). A significant positive association was found between having ever smoked and UC in individuals with at least one A allele, while no such positive relationship was observed in those with the GG genotype., Conclusion: IL23R SNP rs76418789 showed a significant association with UC. This study provides new evidence regarding the interaction between rs76418789 and smoking in relation to UC., 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 Ltd. All rights reserved.)

Background: The significance of reinforcement of the duodenal stump with seromuscular sutures and the effectiveness of reinforced staplers in preventing duodenal stump leakage remain unclear. We aimed to explore the importance of duodenal stump reinforcement and determine the optimal reinforcement method for preventing duodenal stump leakage., Methods: This retrospective cohort study was conducted between January 1, 2012 and December 31, 2021, with data analyzed between December 1, 2022 and September 30, 2023. This multicenter study across 57 institutes in Japan included 16,475 patients with gastric cancer who underwent radical gastrectomies. Elective open or minimally invasive (laparoscopic or robotic) gastrectomy was performed in patients with gastric cancer., Results: Duodenal stump leakage occurred in 153 (0.93%) of 16,475 patients. The proportions of males, patients aged ≥ 75 years, and ≥ pN1 were higher in patients with duodenal stump leakage than in those without duodenal stump leakage. The incidence of duodenal stump leakage was significantly lower in the group treated with reinforcement by seromuscular sutures or using reinforced stapler than in the group without reinforcement (0.72% vs. 1.19%, p = 0.002). Duodenal stump leakage incidence was also significantly lower in high-volume institutions than in low-volume institutions (0.70% vs. 1.65%, p = 0.047). The rate of duodenal stump leakage-related mortality was 7.8% (12/153). In the multivariate analysis, preoperative asthma and duodenal invasion were identified as independent preoperative risk factors for duodenal stump leakage-related mortality., Conclusions: The duodenal stump should be reinforced to prevent duodenal stump leakage after radical gastrectomy in patients with gastric cancer., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Aim: The incidence of and factors involved in gastroesophageal varix-related events in hepatitis C virus-related cirrhosis patients, including decompensated cirrhosis, after direct-acting antiviral therapy are unclear., Methods: We conducted a multicenter study using prospective data from 478 hepatitis C virus-related cirrhosis patients treated with direct-acting antiviral therapy from February 2019 to December 2021 at 33 Japanese hospitals. Gastroesophageal varices were classified as F1 (small-caliber), F2 (moderately enlarged), or F3 (markedly enlarged) according to the Japanese criteria. Patients without varix or with F1 without red color signs were defined as low-risk varix, and patients with ≥F2 or red color signs or a history of rupture were defined as high-risk varix. Varix-related events were defined as prophylactic treatment or rupture of gastroesophageal varix., Results: The median age was 70 years, 43% of patients had decompensated cirrhosis, and 16% had high-risk varices (13% in compensated and 33% in decompensated, p < 0.001). Sustained virologic response rates were 94.9% for compensated cirrhosis and 91.3% for decompensated cirrhosis (p = 0.120). Across 35.7 months, 25 patients received prophylactic treatment, and four experienced varix rupture. The 3-year incidence rate of varix-related events was 6.2% (3.5% in compensated and 9.9% in decompensated, p = 0.001). In the multivariate analysis, high-risk varix (p < 0.001), high baseline gamma-glutamyl transpeptidase levels (p < 0.001), and virologic failure (p = 0.004) were significantly involved in varix-related events., Conclusions: The cumulative incidence rate of varix-related events was significantly higher in decompensated cirrhosis than in compensated cirrhosis. Baseline varix status, baseline gamma-glutamyl transpeptidase levels, and virologic response were related to varix-related events after direct-acting antiviral therapy., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

The present study investigated the relationship between metabolic phenotypes and the risk of cancer in a Japanese population using the criteria of metabolic phenotypes based on an examination and those based on questionnaires. We used data from 25,357 subjects for examination-based analyses and those from 53,042 subjects for questionnaire-based analyses in the Japan Multi-Institutional Collaborative Cohort Study. Metabolic phenotypes were defined by classifying subjects according to their BMI (obesity: BMI ≥25 kg/m2; normal weight: BMI <25 kg/m2) and the number of metabolic abnormalities. Metabolic abnormalities were defined according to metabolic syndrome components of the Joint Interim Statement Criteria for examination-based analyses and self-reported histories of diabetes, dyslipidemia, and hypertension for questionnaire-based analyses. Cox proportional hazards regression analyses adjusted for potential confounders were performed for total and site-specific cancer incidence according to metabolic phenotypes. Metabolically unhealthy obesity (MUHO) was significantly associated with cancer incidence in both examination-based [HR (95% CI): 1.17 (1.01-1.36)] and questionnaire-based analyses [HR (95% CI): 1.15 (1.04-1.26)]. Regarding site-specific cancer in questionnaire-based analyses, metabolically healthy obesity and MUHO were associated with colorectum and liver cancers in all subjects and with breast cancer in female subjects. Subjects with a metabolically unhealthy normal weight had a higher risk of pancreatic cancer. Moreover, MUHO was associated with corpus uteri cancer in female subjects. This prospective cohort study suggests that metabolic phenotypes are important risk factors for total and some site-specific cancers in Japanese adults.

Purpose: We describe a case of bilateral pseudo-uveitis and secondary glaucoma associated with recurrent mantle cell lymphoma (MCL) that was successfully treated with ibrutinib., Methods: Retrospective case report., Results: A 75-year-old man presented with uveitis masquerade syndrome while undergoing treatment for MCL with rituximab-bendamustine. Initial ophthalmologic examination revealed pseudohypopyon, iris thickening, and considerable vitreous opacity of both eyes. Evaluation via anterior segment optical coherence tomography revealed iris thickening in both eyes. His best-corrected visual acuities were reduced to 20/28 and 20/2000 on the right eye (OD) and left eye (OS), respectively, and his intraocular pressure (IOP) was elevated at 40 (OD) and 52 (OS) mmHg. The patient had findings suggestive of recurrent MCL, such as skin lesions, hyponatremia, elevated blood lactase dehydrogenase, and the results of the skin biopsy were consistent with the pathological diagnosis of MCL in the bone marrow biopsy that had already been performed. He was diagnosed with MCL recurrence and treated by switching to ibrutinib, a Bruton's tyrosine kinase inhibitor. After 1 week of treatment, all anterior ocular and vitreous lesions disappeared. Moreover, the skin lesions also disappeared, and the blood sample findings improved. On day 11 of treatment, BCVA improved to 20/20 in both eyes and IOP decreased to 8 (OD) and 11 (OS) mmHg. During the study course, CD5 and CD20 positive cells were identified in the anterior chamber of the eyes via flow cytometry, which was consistent with the pathological findings of biopsies., Conclusion: Ibrutinib may improve recurrent MCL intraocular lesions.

Purpose: Newborn screening using dried blood spot (DBS) samples for the targeted measurement of metabolites and nucleic acids has made a substantial contribution to public healthcare by facilitating the detection of neonates with genetic disorders. Here, we investigated the applicability of non-targeted quantitative proteomics analysis to newborn screening for inborn errors of immunity (IEIs)., Methods: DBS samples from 40 healthy newborns and eight healthy adults were subjected to non-targeted proteomics analysis using liquid chromatography-mass spectrometry after removal of the hydrophilic fraction. Subsequently, DBS samples from 43 IEI patients were analyzed to determine whether patients can be identified by reduced expression of disease-associated proteins., Results: DBS protein profiling allowed monitoring of levels of proteins encoded by 2912 genes, including 1110 listed in the Online Mendelian Inheritance in Man database, in healthy newborn samples, and was useful in identifying patients with IEIs by detecting reduced levels of disease causative proteins and their interacting proteins, as well as cell-phenotypical alterations., Conclusion: Our results indicate that non-targeted quantitative protein profiling of DBS samples can be used to identify patients with IEIs and develop a novel newborn screening platform for genetic disorders., (© 2024. The Author(s).)

Transgenic mice, including those created using Bacterial Artificial Chromosomes (BACs), are artificial manipulations that have become critical tools for studying gene function. While conventional transgenic techniques face challenges in achieving precise expression of foreign genes in specific cells and tissues, BAC transgenic mice offer a solution by incorporating large DNA segments that can include entire expression units with tissue-specific enhancers. This review provides a thorough examination of BAC transgenic mouse technology, encompassing both traditional and humanized models. We explore the benefits and drawbacks of BAC transgenesis compared to other techniques such as knock-in and CRISPR/Cas9 technologies. The review emphasizes the applications of BAC transgenic mice in various disciplines, including neuroscience, immunology, drug metabolism, and disease modeling. Additionally, we address crucial aspects of generating and analyzing BAC transgenic mice, such as position effects, copy number variations, and strategies to mitigate these challenges. Despite certain limitations, humanized BAC transgenic mice have proven to be invaluable tools for studying the pathogenesis of human diseases, drug development, and understanding intricate gene regulatory mechanisms. This review discusses current topics on BAC transgenic mice and their evolving significance in biomedical research., 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 B.V. All rights reserved.)

Background: Glucocorticoid (GC) treatments are often used. There is limited information on the prediction of hyperglycaemia after GC administration., Aims: This study aimed to identify the risk factors for hyperglycaemia after glucocorticoid (GC) administration and the need for hypoglycaemic agents to correct it and to develop and validate a novel scoring system for predicting GC-induced hyperglycaemia., Methods: In a development set, 508 adults receiving prednisolone (PSL) for the first time were divided into two groups based on treatment with or without hypoglycaemic agents. Clinical and laboratory parameters were compared, and risk factors were identified using logistic regression analysis after performing univariate analyses between the two groups. A point-addition scoring system with several categories and coefficients for each risk factor was constructed to predict the need for hypoglycaemic agents. The scoring system was then applied and validated on two validation sets: A and B., Results: Older age, higher glycated haemoglobin percentage, body mass index and initial PSL dosage were identified as risk factors. The sensitivity, specificity and accuracy of the scoring system were 70.6%, 81.9% and 77.1% in the development set; 75.8%, 78.4% and 77.4% in validation set A; and 79.4%, 73.9% and 75.3% in validation set B respectively. By fitting the total score in the development set and the probability of hyperglycaemia to a logistic curve, a figure was created to show the probability of GC-induced hyperglycaemia in patients scheduled to receive GC., Conclusion: This scoring system is a novel, valid and reliable tool for predicting GC-induced hyperglycaemia and the need for hypoglycaemic agents to correct it., (© 2024 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

As the number of neuroendovascular therapies in Japan increases, the current trends in periprocedural antithrombotic therapy must be understood.We retrospectively analyzed data on periprocedural antithrombotic therapy in the Japanese Registry of Neuroendovascular Therapy (JR-NET) 4, a nationwide survey carried out in Japan between January 2015 and December 2019. Details on antithrombotic therapy in neuroendovascular therapy for ruptured cerebral aneurysms, unruptured cerebral aneurysms, and percutaneous transluminal angioplasty or stenting were collected from the JR-NET 4 database. These data were analyzed and compared with those from the JR-NET 2 (January 2008 to December 2009) and JR-NET 3 (January 2010 to December 2014). A total of 36,560 cases were analyzed in the JR-NET 4. The frequency of preprocedural dual antiplatelet therapy (DAPT) significantly increased from the JR-NET 2 to 4 (48.1%, 53.4%, and 62.3%, respectively; P < 0.001), whereas the frequency of monotherapy significantly decreased (15.7%, 13.9%, and 8%, respectively; P < 0.001). Postprocedural antiplatelet therapy exhibited similar trends, and postprocedural anticoagulant therapy was discontinued. Particularly, heparin use significantly decreased from the JR-NET 2 to 4 (23.4% vs. 12.7% vs. 7.9%, respectively; P < 0.001). In terms of periprocedural complications, the incidence of ischemic complications increased from the JR-NET 3 to 4 (5.8% vs. 6.2%; P = 0.05). In the JR-NET 4, severe adverse events and hemorrhagic and all complications were significantly more frequent in the preprocedural triple or more therapy group.The rate of postprocedural anticoagulant therapy decreased, whereas that of antiplatelet therapy increased. Overall, in Japan, periprocedural DAPT has become increasingly common.

Objective: To investigate an association between the gut microbiome and efficacy of poly(ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer., Methods: This study conducted fecal microbiome analysis (16S rRNA gene sequencing) and circulating tumor DNA (ctDNA) profiling for ovarian cancer patients who underwent PARPi maintenance therapy. Fecal and blood samples were collected at the baseline and the progressive disease (PD) or last follow-up. The relative abundance of gut microbes and progression-free survival (PFS) were analyzed using linear discriminant analysis of effect size and the Cox proportional hazard model according to BRCA1 / 2 mutation ( BRCA1 / 2 mut) status detected by ctDNA sequencing., Results: Baseline samples were available from 23 BRCA1 / 2 mut-positive patients and 33 BRCA1/2 mut-negative patients. The microbes enriched in the baseline samples with long PFS were Bifidobacterium , Roseburia , Dialister , Butyricicoccus , and Bilophila for BRCA1/2 mut-positive patients and Phascolarctobacterium for BRCA1/2 mut-negative patients. In multivariate analyses dividing patients by the median values of relative abundances, no bacteria were associated with PFS in BRCA1/2 mut-positive patients, whereas high Phascolarctobacterium abundances (≥1.11%) was significantly associated with longer PFS in BRCA1/2 mut-negative patients (median 14.0 vs. 5.9 months, hazard ratio=0.28; 95% confidence interval=0.11-0.69; p=0.014). In the last samples, the relative abundances of Phascolarctobacterium were significantly higher in patients without PD (n=5) than those with PD (n=15) (median 1.25% vs. 0.06%; p=0.016)., Conclusion: High fecal composition of Phascolarctobacterium was associated with prolonged PFS in patients with BRCA1/2 mut-negative ovarian cancer receiving PARPi therapy. Our results would provide new insights for future research., Competing Interests: Mika Okazawa-Sakai declares no competing interests. Shunsuke A. Sakai declares no competing interests. Ichinosuke Hyodo reports advisory roles for Asahi-Kasei, Ono, Taiho, Chugai, and Eisai Pharmaceutical Companies. Satoshi Horasawa declares no competing interests. Kentaro Sawada declares no competing interests. Takao Fujisawa reports honoraria from Amelieff Co. Ltd. Yasuko Yamamoto declares no competing interests. Shogen Boku reports honoraria from Nippon Kayaku Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bristol-Myers Squibb Japan, and MSD. Yoh Hayasaki declares no competing interests. Masanori Isobe declares no competing interests. Daisuke Shintani declares no competing interests. Kosei Hasegawa reports honoraria from AstraZeneca, GSK, MSD, and Takeda; advisory role for GSK, MSD, and Takeda; research grants from MSD. Tomomi Egawa-Takata declares no competing interests. Kimihiko Ito reports honoraria from AstraZeneca. Kei Ihira declares no competing interests. Hidemichi Watari reports honoraria from AstraZeneca, Takeda, MSD, and Chugai. Kazuhiro Takehara reports honoraria from AstraZeneca, Takeda, MSD, Chugai, Eisai, and Sanofi. Hiroshi Yagi declares no competing interests. Kiyoko Kato declares no competing interests. Tatsuyuki Chiyoda reports research grants from Takeda Pharmaceutical Company. Kenichi Harano reports honoraria from AstraZeneca, Chugai, Eizai, MSD, Taiho and Takeda, and advisory roles for AstraZeneca, Chugai, Eizai, Taiho and Takeda. Yoshiaki Nakamura declares advisory role from Guardant Health Pte Ltd., Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Exact Sciences Corporation, Gilead Sciences, Inc.; speakers' bureau from Guardant Health Pte Ltd., MSD K.K., Eisai Co., Ltd., Zeria Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., CareNet, Inc., Hisamitsu Pharmaceutical Co., Inc., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Becton, Dickinson and Company, Guardant Health Japan Corp; research funding from Seagen, Inc., Genomedia Inc., Guardant Health AMEA, Inc., Guardant Health, Inc., Tempus Labs, Inc., Roche Diagnostics K.K., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd. Riu Yamashita declares no competing interests. Takayuki Yoshino reports honoraria from Chugai Pharma, Takeda Pharma, Merck, Bayer Yakuhin, Ono Pharmaceutical and MSD K. K.; consulting fees from Sumitomo Corp.; and research grants from Amgen, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia Inc., Medical & Biological Laboratories, Merus N.V., Molecular Health, MSD, Nippon Boehringer Ingelheim, Ono, Pfizer, Roche Diagnostics, Sanofi, Sysmex, Taiho and Takeda. Daisuke Aoki reports honoraria from AstraZeneca, Takeda, MSD, Chugai, and Myriad Genetics., (© 2025. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Variant annotations are crucial for efficient identification of pathogenic variants. In this study, we retrospectively analyzed the utility of four annotation tools (allele frequency, ClinVar, SpliceAI, and Phenomatcher) in identifying 271 pathogenic single nucleotide and small insertion/deletion variants (SNVs/small indels). Although variant filtering based on allele frequency is essential for narrowing down on candidate variants, we found that 13 de novo pathogenic variants in autosomal dominant or X-linked dominant genes are registered in gnomADv4.0 or 54KJPN, with an allele frequency of less than 0.001%, suggesting that very rare variants in large cohort data can be pathogenic de novo variants. Notably, 38.4% candidate SNVs/small indels are registered in the ClinVar database as pathogenic or likely pathogenic, which highlights the significance of this database. SpliceAI can detect candidate variants affecting RNA splicing, leading to the identification of four variants located 11 to 50 bp away from the exon-intron boundary. Prioritization of candidate genes by proband phenotype using the PhenoMatcher module revealed that approximately 95% of the candidate genes had a maximum PhenoMatch score ≥ 0.6, suggesting the utility of phenotype-based variant prioritization. Our results suggest that a combination of multiple annotation tools and appropriate evaluation can improve the diagnosis of rare diseases., (© 2024. The Author(s).)

Objectives: The receptor tyrosine kinase Kit is expressed in cells derived from the trunk neural crest (NC), such as melanocytes; however, its role in cranial NC cell development is not fully understood., Methods: We investigated the effects of the heterozygous loss of Kit in NC cells during embryonic development by mating Kit 2lox/+ mice with Wnt1-Cre mice to produce Wnt1-Cre; Kit 2lox/+ embryos. In addition, Wnt1-Cre mice were mated with Rosa26R-yellow fluorescent protein (YFP) mice to visualize the tissue regions expressing Cre recombinase. Histological studies of the craniofacial regions of these mice were performed using samples from embryonic day (E) 12.5 and postnatal day (P) 1. Cellular apoptosis and proliferation were both analyzed through the immunostaining of tissue sections collected on E13.5 and E14.5 using anti-cleaved caspase 3 (CC3) to detect apoptosis and anti-Ki67 to detect proliferation. Cells from YFP-positive tissue regions of the facial areas of Wnt1-Cre; Kit +/+ ; Rosa26R-YFP embryos and Wnt1-Cre; Kit 2lox/+ ; Rosa26R-YFP embryos collected on E12.5 and E15.5 were cultured and evaluated for cell proliferation., Results: Compared with control littermates, Wnt1-Cre; Kit 2lox/+ embryos exhibited midline cleft lip and bifid nose deformities. Substantial early (P1) postnatal lethality was observed in Wnt1-Cre; Kit 2lox/+ mice, with none surviving to 3 weeks of age. YFP-positive cells from the maxillary regions of Wnt1-Cre; Kit 2lox/+ ; Rosa26R-YFP embryos exhibited defective cell growth and self-renewal in vitro., Conclusion: Conditional heterozygous loss of Kit in Wnt1-Cre; Kit 2lox/+ embryos is associated with craniofacial dysplasia and exhibit defective NC development in vitro and in vivo., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Background: The glycocalyx (GCX) is a glycan structure on the vascular endothelium and cancer cells. It is crucial for blood flow regulation, tumor invasion, and cancer drug resistance. Understanding the role of GCX in human tumors could help develop new cancer biomarkers and therapies., Aim: This study aimed to demonstrate microstructural changes in human primary and metastatic liver tumors (henceforth termed liver tumors) by visualizing GCX using surgical specimens and comparing formalin-fixed paraffin-embedded sections (FFPEs) with frozen sections. The results of lectin staining were also compared between frozen and FFPE specimens to determine which was more useful for accurately assessing GCX structure and composition., Methods: Liver tumors and normal tissue samples from three patients were collected and processed into FFPEs and frozen sections, respectively. Lanthanum nitrate staining and scanning electron microscopy (SEM) were used to assess the GCX structures. Twenty lectins were analyzed for their glycan components in the samples., Results: SEM revealed significant differences in GCX morphology among the cancer specimens. Frozen sections provided a more accurate GCX evaluation than FFPEs, showing distinct glycan compositions in hepatocellular carcinoma, colorectal carcinoma liver metastases, and melanoma liver metastases. Hepatocellular carcinoma samples exhibited a loss of N-acetylgalactosamine-related lectins., Conclusion: The results revealed that liver tumors have distinct and bulky GCX compared to normal liver tissue, while frozen sections are more reliable for GCX evaluation. These findings highlight glycan alterations in liver tumors and contribute to the development of new cancer therapies targeting GCX on tumor cell surfaces., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hiroyuki Tomita reports financial support was provided by JSPS KAKENHI, JST FOREST Program. If there are other authors, they 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. Published by Elsevier GmbH.)

Aim: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population., Methods: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%., Results: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05)., Conclusion: We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Chemotherapy-induced ovarian toxicity in patients with cancer significantly affects future fertility depending on the age of initiation of treatment. However, the mechanisms underlying the age-related depletion of the ovarian reserve are not well understood. We investigated the effects of chemotherapy on pre- and postpubertal ovarian reserves in a mouse model. Juvenile (3-week-old) and adult (8-week-old) mice were injected with vehicle or cyclophosphamide (CPA;100 mg/kg). We assessed the short-term effects at 24 h and 72 h after injection and the long-term effects at 10 and 12 weeks of age by counting the follicles. The number of primordial follicles in the juvenile group was significantly reduced by CPA treatment compared with that in the adult group. To elucidate the mechanisms of this depletion, we performed immunostaining for γH2AX, cleaved PARP1, and FOXO3 at 24 h post-treatment. CPA-treated juvenile mice had a significantly higher proportion of γH2AX-positive primordial follicles, indicating double-strand DNA breaks. By contrast, 4-hydroperoxy CPA, an activated analog of CPA, induced γH2AX-positive primordial follicles in both groups in vitro, suggesting age-dependent differences in humoral ovarian microenvironment. Moreover, the level of cleaved PARP1 was specifically elevated in CPA-treated juvenile mice. However, primordial follicle activation was unaffected in the CPA-treated groups, as assessed by FOXO3 translocation. In conclusion, our findings suggest that ovaries in juveniles are more susceptible to DNA damage and subsequent apoptosis, leading to a higher rate of primordial follicle depletion. Therefore, it is crucial to recognize that cancer treatment, especially in children, can exert a substantial influence on future fertility., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier B.V.)

Background: Cystic formation due to radiation necrosis in metastatic brain tumors is a rare condition. Surgical intervention is necessary if symptoms develop. Additionally, excising radiation necrosis lesions within the cyst is essential to prevent recurrence. Neuroendoscopic surgery is a minimally invasive method suitable for treating cystic diseases and accessing deep lesions in the brain. The authors herein present a method for removing radiation necrotic tissue from deep lesions of cystic radiation necrosis using neuroendoscopy., Observations: Endoscopic surgery was performed in two patients with symptomatic cystic radiation necrosis. Both cases involved multilocular cysts, with radiation necrosis located deep within the cyst. The authors performed a small craniotomy of approximately 3 cm and opened the cyst. After removing its contents, an endoscope was used to closely observe the interior of the cyst. Removal of the septum within the cyst allowed the endoscope to be inserted deeply. The authors identified and excised the nodular lesion diagnosed as radiation necrosis in the deep tissue. Following the surgery, the cyst shrank rapidly, and symptoms disappeared. Both patients showed no recurrence of the lesions., Lessons: The authors performed minimally invasive surgery and achieved good outcomes. Endoscopic surgery was considered beneficial for treating cystic radiation necrosis. https://thejns.org/doi/10.3171/CASE24250.

Objective: Transoral surgery for early-stage pharyngeal and laryngeal cancer provides good local control and is less invasive than external incisions. Postoperative pathological findings are considered the most important indicators for determining postoperative treatment, but detailed criteria have not been established. In this study, we evaluated the impact of postoperative pathological findings on prognosis of patients undergoing transoral surgery., Methods: This study included patients with oropharyngeal, hypopharyngeal, and supraglottic cancer who underwent transoral surgery at Gifu University Hospital from April 2016 to December 2023. Resection margins were pathologically evaluated with horizontal and vertical margins, and vascular invasion was evaluated in three categories: lymphatic invasion, venous invasion, and perineural invasion. The correlation between each postoperative pathological finding and prognosis was evaluated., Results: A total of 70 cases were assessed in this study. Cases of horizontal margin positive were 38.6 %, and cases of vertical margin positive were 27.1 %. Prognoses were comparable to previous reports. Despite the high margin positive rate, the 5-year overall survival rate was 77.1 %. The 5-year disease-specific survival rate was 89.7 %, and the 5-year local control rate was 85.3 %. Notably, when evaluated by margin direction, cases with positive horizontal margins had significantly worse prognoses. Although no significant correlation was found between vascular invasion and prognosis, cases of venous invasion tended to have a higher local recurrence rate., Conclusion: This study suggests that transoral surgery has good prognosis despite a high positive-margin rate. However, detailed criteria for additional treatment have not been developed, and further case accumulation is required. Intriguingly, positive horizontal margins are correlated with significantly worse prognosis. This result may be related to a high risk of multiple cancers, and careful follow-up after surgery is recommended., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

This trial examined the effectiveness of the popliteal plexus block (PPB) and tibial nerve block (TNB) for early rehabilitation after total knee arthroplasty (TKA). We allocated 136 participants to receive PPB or TNB with 0.25% levobupivacaine 10 mL in a randomized, double-masked manner. The primary outcome was achieving rehabilitation goals with a non-inferiority 9-hour margin, including adequate pain relief, knee flexion angles over 90 degrees, and enabling ambulatory rehabilitation. The time to reach rehabilitation goals showed non-inferiority with 49.7 ± 10.5 h for TNB and 47.4 ± 9.7 h for PPB, whose mean difference (PPB - TNB) was - 2.3 h (95% CI -5.8 to 1.2 h; P < 0.001). PPB showed higher dorsal and plantar percentage of maximum voluntary isometric contraction (dorsal, PPB 87.7% ± 11.4% vs. TNB 74.0% ± 16.5%: P < 0.001; plantar, PPB 90.9% ± 10.3% vs. TNB 72.1% ± 16.0%; P < 0.001) at six hours after nerve block. No significant differences between the two groups emerged in pain scores, knee range of motion, additional analgesic requirements, success in the straight leg raise, and adverse events. PPB exhibited non-inferiority to TNB in achieving postoperative rehabilitation goals and had superiority in preserving foot motor strength after TKA. (200)., (© 2024. The Author(s).)

Background: Advances in diagnostic procedures have led to an increasing rate of diagnosis of autoimmune encephalitis or paraneoplastic neurological syndrome (AE/PNS) among patients with progressive supranuclear palsy (PSP)-like manifestations., Methods: In this narrative review, we first discuss the clinical characteristics of AE/PNS in comparison to those of PSP, followed by a discussion of diagnosis and treatment., Results: The antibodies involved in these conditions include anti-IgLON5, -Ma2, and -Ri antibodies, each of which has a characteristic clinical presentation. The steps in the diagnosis of AE/PNS in patients with PSP-like manifestations include (i) suspicion of AE/PNS based on clinical presentations atypical of PSP and (ii) antibody detection measures. Methods used to identify antibodies include a combination of tissue-based assays and confirmatory tests. The primary confirmatory tests include cell-based assays and immunoblotting. Treatments can be divided into immunotherapy and tumor therapies, the former of which includes acute and maintenance therapies., Conclusions: One of the major challenges of diagnosis is that existing reports on PSP-like patients with AE/PNS include only case reports, with the majority discussing antibodies other than anti-IgLON5 antibody. As such, more patients need to be evaluated to establish the relationship between antibodies and PSP-like manifestations.

NEXT [NOBORI biolimus-eluting stent (BES) versus XIENCE/PROMUS everolimus-eluting stent (EES) trial] was a multicenter, randomized, prospective trial that included 3235 patients with 8-12 months of follow-up imaging at 18 centers. IB-IVUS images were analyzed at an interval of 0.5 mm using a motorized pull-back system in each plaque that required stent implantation. We analyzed seven cross-sections at the site of minimal lumen area and ten cross-sections in proximal and distal peripheral sites prior to the procedure, after stent implantation and after 8 months. We averaged the relative blue volume, relative green volume, relative yellow volume, and relative red volume across seven cross-sections using the manufacturer's default setting. Fifty-four lesions in 50 patients were analyzed. There were 28 lesions in 25 patients in the EES group and 26 lesions in 25 patients in the BES group. The patient characteristics did not differ significantly between the two groups except high-density lipoprotein cholesterol. There were no significant differences before and after stent implantation after 8 months in relative red volume, relative yellow volume, relative green volume or relative blue volume. Although the present study was likely underpowered for statistical analyses and larger populations are needed to confirm the conclusions, the vascular response regarding tissue characterization was similar between EES and BES, even though the thickness and releasing materials differed between the stents., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

RHOV and RHOU are considered atypical Rho-family small GTPases because of the existence of N- and C-terminal extension regions, abnormal GDP/GTP cycling, and post-translational modification. Particularly, RHOV and RHOU both have a proline-rich (PR) motif in the N-terminal region. It has been reported that the PR motif of RHOU interacts with GRB2, a SH3 domain-containing adaptor protein, and regulates its activity through EGF receptor signaling. However, it is unknown whether RHOV, like RHOU, interacts with SH3 domain-containing adaptor proteins. In this study, we investigated the interactions between RHOV and SH3 domain-containing adaptor proteins, including GRB2 and NCK2. The RHOV-induced serum response factor (SRF)-dependent gene transcriptional activity was attenuated in cells co-expressing either GRB2 or NCK2 compared to cells expressing RHOV alone. From the results of experiments using various gene mutants of RHOV and GRB2, it appears that the PR motif of the N-terminal region of RHOV is the crucial binding site for the SH3 domain-containing proteins. Furthermore, we found that Ser25 in the N-terminal region of RHOV is phosphorylated by PKA and that its phosphorylation is suppressed by interaction with NCK2 but not GRB2. We have found a novel regulatory mechanism for the phosphorylation of RHOV and its interaction with SH3 domain-containing adaptor proteins., 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.)

An 89-year-old Japanese woman presented with erythroderma associated with significant scaling. A histological examination showed acanthosis with hyperkeratosis and hyperkeratinization of the hair follicles. Genetic analyses using DNA from the peripheral blood revealed heterozygous mutations in IL36RN (c.115+6T>C) and CARD14 c.2648G>A (p.Arg883His). Based on these findings, we diagnosed her with erythroderma attributable to autoinflammatory keratinization disease. She then developed more than 30 small, round, well-defined, spots on her back and extremities that appeared histologically normal. We suspected that these spots might be revertant mosaicism. Immunohistochemical staining with p65, which is a component of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), revealed nuclear staining in epidermal keratinocytes in erythematous lesions, but not in the normal-looking spots. However, mutations in IL36RN and CARD14 unexpectedly persisted in the epidermis and dermis of the normal-looking spots., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Objectives: To evaluate changes in the age at menarche in Asian populations., Study Design: Retrospective cohort study., Methods: We included 548,830 women from six countries in Asia. The data were sourced from 20 cohorts participating in the Asia Cohort Consortium (ACC) and two additional cohort studies: Japan Multi-institutional Collaborative Cohorts (J-MICC), and Japan Nurse Health Study (JNHS) with data on age at menarche. Joinpoint regression was used to evaluate changes in age at menarche by birth year and by country., Results: The study includes data from cohorts in six Asian countries namely, China, Iran, Japan, Korea, Malaysia and Singapore. Birth cohorts ranged from 1873 to 1995. The mean age of menarche was 14.0 years with a standard deviation (SD) of 1.4 years, ranged from 12.6 to 15.5 years. Over 100 years age at menarche showed an overall decrease in all six countries. China showed a mixed pattern of decrease, increase, and subsequent decrease from 1926 to 1960. Iran and Malaysia experienced a sharp decline between about 1985 and 1990, with APC values of -4.48 and -1.24, respectively, while Japan, South Korea, and Singapore exhibited a nearly linear decline since the 1980s, notably with an APC of -3.41 in Singapore from 1993 to 1995., Conclusions: Overall, we observed a declining age at menarche, while the pace of the change differed by country. Additional long-term observation is needed to examine the contributing factors of differences in trend across Asian countries. The study could serve as a tool to strengthen global health campaigns., (Copyright © 2024 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background: Over the last decade, novel anticancer drugs have improved the prognosis for recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN). However, this has increased healthcare expenditures and placed a heavy burden on patients and society. This study investigated the frequency of use and costs of select palliative chemotherapy regimens in Japan., Methods: From July 2021 to June 2022 in 54 healthcare facilities, we gathered data of patients diagnosed with RM-SCCHN and who had started first-line palliative chemotherapy with one of eight commonly used regimens. Patients with nasopharyngeal carcinomas were excluded. The number of patients receiving each regimen and the costs of each regimen for the first month and per year were tallied., Results: The sample comprised 907 patients (674 were < 75 years old, 233 were ≥ 75 years old). 330 (36.4%) received Pembrolizumab monotherapy, and 202 (22.3%) received Nivolumab monotherapy. Over 90% of patients were treated with immune checkpoint inhibitors as monotherapy or in combination with chemotherapy. Treatment regimens' first-month costs were 612 851-849 241 Japanese yen (JPY). The cost of standard palliative chemotherapy until 2012 was about 20 000 JPY per month. The incremental cost over the past decade is approximately 600 000-800 000 JPY per month, a 30- to 40-fold increase in the cost of palliative chemotherapy for RM-SCCHN., Conclusion: First-line palliative chemotherapy for RM-SCCHN exceeds 600 000 JPY monthly. Over the last decade, the prognosis for RM-SCCHN has improved, but the costs of palliative chemotherapy have surged, placing a heavy burden on patients and society., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dietary habits may impact the prevention and management of schizophrenia (SCZ) and bipolar disorder (BD), and genetic and environmental factors can influence both these habits and these disorders. This study investigated the effects of genetic predispositions to SCZ and BD on current dietary habits among older adults with lifestyle-related diseases, potentially offering insights for preventive mental health strategies. A cohort of 730 older patients who were diagnosed with or suspected of having lifestyle-related diseases was assessed for eight current dietary categories: miso soup, Japanese tea, green and yellow vegetables, light-colored vegetables, fruits, pickles, meats, and soybeans. Polygenic risk scores (PRSs) for the risk of SCZ and BD, including BD types I and II, the shared risk of SCZ and BD, and the differentiation of SCZ from BD, were calculated utilizing data from large-scale genome-wide association studies (GWASs). Our findings revealed that PRSs for SCZ and BD risk significantly influenced specific dietary habits, particularly decreased consumption of nutrient-rich foods such as light-colored vegetables (SCZ, R 2  = 0.0096, p = 3.54 × 10 -3 ; BD, R 2  = 0.0074, p = 9.09 × 10 -3 ) and soybeans (SCZ, R 2  = 0.0061, p = 0.019; BD, R 2  = 0.014, p = 8.38 × 10 -4 ). Notable differences in dietary effects were observed between PRSs for BD I and BD II, with a more pronounced impact associated with BD I (e.g., light-colored vegetables, BD I, R 2  = 0.015, p = 3.11 × 10 -4 ; BD II, p > 0.05). Moreover, shared genetic factors for SCZ and BD were correlated with lower intakes of miso soup (R 2  = 0.013, p = 1.21 × 10 -3 ), Japanese tea (R 2  = 0.0092, p = 5.59 × 10 -3 ), light-colored vegetables (R 2  = 0.010, p = 2.92 × 10 -3 ), and soybeans (R 2  = 0.014, p = 3.13 × 10 -4 ). No significant correlations were found between PRSs for differentiating SCZ from BD and any dietary patterns (p > 6.25 × 10 -3 ). Genetic risks shared by individuals with SCZ and BD may influence dietary choices in older adults, emphasizing the potential for dietary modifications as part of comprehensive strategies for the prevention of the SCZ and BD onset, as well as for the treatment of individuals at risk of or diagnosed with SCZ and BD., (© 2024. The Author(s).)

Background: The prognostic impact of additional resection based on intraoperative frozen section analysis (FSA) of the pancreatic transection margin in patients with pancreatic ductal adenocarcinoma (PDAC) is controversial. The purpose of this study was to evaluate the prognosis based on the results of the first FSA of the pancreatic transection margin (1st FSA) and the clinical significance of additional resection., Methods: Patients who underwent pancreaticoduodenectomy for PDAC from 2000 to 2020 at a single center were included. Patients were divided into 3 groups based on the 1 st FSA. Survival and prognostic factors were analyzed according to the 1 st FSA., Results: A total of 311 patients were included in this study. The 1 st FSA was negative in 272 patients (1 st FSA-R0) and positive in 39 patients [carcinoma in situ (1 st FSA-CIS), 21 patients; invasive carcinoma (1 st FSA-IC), 18 patients]. Additional resections were performed on 37 patients [1 st FSA-CIS, 20 patients; 1 st FSA-IC, 17 patients], and R0 resection was achieved in 34 patients intraoperatively. Comparing median survival time to 1 st FSA-R0 (36.4 months), 1 st FSA-CIS was comparable (27.8 months, p = 0.276), although 1 st FSA-IC was significantly worse (18.8 months, p = 0.001). On multivariate analysis, 1 st FSA-IC was an independent prognostic factor (hazard ratio 2.68, 95 % confidence interval 1.16-6.17, p = 0.020)., Conclusions: 1 st FSA-CIS and 1 st FSA-R0 had similar OS, implying that additional resection may be acceptable for 1 st FSA-CIS. 1 st FSA-IC was still an independent prognostic factor based on additional resection, and the prognostic significance of additional resection is uncertain for 1 st FSA-IC., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)