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Background: This study evaluates the tracking accuracy of the lung tumor volume and fiducial markers using four-dimensional computed tomography (4DCT) and fitted neural network models. Materials and Methods: This study utilized data from 31 patients (109 fiducial markers) who underwent stereotactic body radiotherapy (SBRT). The respiratory movements of fiducial markers, lung tumors, and lung volume were calculated using 4DCT. Cross-correlation coefficients were then calculated to analyze the phase movements of fiducial markers, lung tumors, lung volume, direction displacement, and lung area (upper, middle, and lower lobes). Statistical prediction models were used to evaluate the predictive accuracy of the left--right (LR), anterior--posterior (AP), cranial--caudal (CC), and three-dimensional (3D) cross-correlation coefficients between fiducial markers and lung tumors. The coefficient of determination (R2) was used to determine the accuracy of the statistical prediction models for the explanatory variables. Results: The correlation between fiducial marker and lung tumor, as well as lung tumor movement by time phase, yielded the following R² values--LR: 0.920, AP: 0.319, CC: 0.675, and 3D: 0.449 for the upper lobe; LR: 0.567, AP: 0.627, CC: 0.955, and 3D: 0.939 for the middle/lower lobes. Statistically significant differences were observed in the CC and 3D directions within each lower lobe. Conclusions: The respiratory movements of fiducial markers and lung tumors in lung SBRT show stronger correlation with the movement of lung volume in the middle/ lower lobes compared to that in the upper lobes. Combining a fiducial marker with lung volume improves the prediction accuracy of the respiratory movement of lung tumors. [ABSTRACT FROM AUTHOR]

In March 2024, a significant public health issue involving red yeast rice supplements emerged in Japan, which may have been associated with several health problems, including kidney dysfunction. A 74-year-old man without a history of urinary abnormalities developed nephrotic syndrome 10 weeks after starting "Beni-Koji Choleste Help ® ," a red yeast rice supplement. Electron microscopy showed subepithelial and intramembranous dense deposits with abnormality of the glomerular basement membrane, which led to the diagnosis of long-standing membranous nephropathy. The diagnosis of phospholipase A2 receptor (PLA2R)-positive primary membranous nephropathy was confirmed via PLA2R-positive immunostaining. Furthermore, there were findings of focal tubular necrosis without unexplained cellular infiltration. Based on previous reports, it was suggested that red yeast rice-related products have triggered the acute tubular necrosis in the patient. His nephrotic syndrome reached partial remission with oral administration of prednisolone at an initial dose of 40 mg/day. This case indicates that membranous nephropathy was coincidentally accompanied by acute tubular necrosis that was potentially associated with red yeast rice-related health foods. It may be reasonable to state that individuals consuming red yeast rice-related health products may develop subclinical focal tubular necrosis even in the absence of overt clinical symptoms or laboratory abnormalities. The currently recognized health issues associated with red yeast rice-related health foods may only represent a small portion of the overall risks., Competing Interests: Declarations Conflict of interest The authors have declared that no conflict of interest exists. Human and animal rights This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent Informed consent was obtained from all participants included in the study., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Purpose: The JCCG ALL-B12 clinical trial aimed to evaluate the effectiveness of unvalidated treatment phases for pediatric ALL and develop a safety-focused treatment framework., Patients and Methods: Patients age 1-19 years with newly diagnosed B-ALL were enrolled in this study. These patients were stratified into standard-risk (SR), intermediate-risk (IR), and high-risk (HR) groups. Randomized comparisons assessed the effectiveness of vincristine (VCR)/dexamethasone pulses in the SR group, evaluated the effects of L-asparaginase (ASP) intensification in the IR group, and compared standard consolidation including block-type treatment with experimental consolidation with high-dose methotrexate (HD-MTX) intensified with VCR and ASP in the HR group., Results: Of 1,936 patients enrolled, 1,804 were eligible for the experimental treatment. The overall 5-year event-free survival and overall survival rates were 85.2% (95% CI, 83.5 to 86.8) and 94.3% (95% CI, 93.1 to 95.3), respectively. The cumulative incidence of relapse and postremission nonrelapse mortality was 13.2% (95% CI, 11.6 to 14.8) and 0.6% (95% CI, 0.3 to 1.0), respectively. Random assignment in the SR group showed no significant benefit from pulse therapy. In the IR group, ASP intensification had limited effects. In the HR group, standard block therapy and HD-MTX yielded equivalent outcomes., Conclusion: The ALL-B12 trial achieved favorable outcomes in a nationwide cohort by stratifying treatment on the basis of risk and balancing treatment intensity. This study not only demonstrated that existing standard of care can be further refined but also indicated that improvement in outcomes with intensified chemotherapy has reached a plateau.

Background Standard laparoscopic cholecystectomy (LC) is a four-port technique in which a camera port and three additional ports are used. The advantages of minimally invasive surgery with reduced-port surgery have been reported. However, evidence on the indications for minimally invasive surgery in patients with severe acute cholecystitis or previous upper abdominal surgery in whom laparoscopic surgery is considered challenging is limited. Therefore, this study aimed to explore the factors that complicate reduced-port LC. Methods Data from 47 consecutive patients who underwent three-port LC using two 5 mm ports and 12 mm umbilical ports for symptomatic cholecystolithiasis, chronic cholecystitis, and acute cholecystitis between November 2021 and November 2023 by a single surgeon were retrospectively collected. Noncomplete LC was defined as a change of 5 mm to 12 mm port, the addition of ports, a change to subtotal cholecystectomy, or open conversion cholecystectomy. The patients were divided into two groups according to complete or noncomplete LC, and the risk factors that might have contributed to noncomplete LC were explored. Results Among the 47 patients, the median (range) age was 74 (25-97) years, 21 were men and 26 were women, 30 (63.8%) had acute cholecystitis, and 21 (44.7%) underwent emergency LC. No conversion to open cholecystectomy was performed. Six of the 47 patients had noncomplete LC, three of whom were converted to subtotal cholecystectomy, one had the midepigastric port changed from 5 mm to 12 mm to use an automatic anastomosis device, and two were converted to subtotal cholecystectomy with a 12 mm midepigastric port. In the univariate analysis, the noncomplete LC group had significantly more cases of preoperative gallbladder drainage and a smaller body mass index than the complete group. No significant differences were found in previous epigastric surgeries or in the presence of acute cholecystitis. Postoperative outcomes showed a significantly longer operative time, more intraoperative blood loss, longer postoperative hospital stay, and higher Estimation of Physiologic Ability and Surgical Stress and surgical stress score in the noncomplete LC group than in the complete group. Conclusions Three-port LC may be difficult to perform in patients with preoperative gallbladder drainage and severe scarring of the gallbladder neck. For patients with risk factors for three-port LC, adequate manpower and early conversion to subtotal or open cholecystectomy are necessary to avoid intraoperative complications. Further studies are required to determine significant risk factors for noncomplete LC., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Ethics Committee of Koga Community Hospital issued approval 2023-11. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Fujimoto et al.)

Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High-throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by poly(ADP-ribose) polymerase inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric γδ T-ALL. Significance: Patients with acute lymphoblastic leukemia expressing the gamma delta T-cell receptor under 3 years old or measurable residual disease ≥1% at end of induction showed dismal outcomes and should be classified as having high-risk disease. The STAG2/LMO2 subtype was enriched in this very young age group. STAG2 inactivation may perturb chromatin conformation and cell differentiation and confer vulnerability to poly(ADP-ribose) polymerase inhibition., (©2024 American Association for Cancer Research.)

Bilateral communication between bones and muscles is essential for healing composite bone-muscle injuries from orthopedic surgeries and trauma. However, these injuries are often characterized by exaggerated inflammation, which can disrupt bone-muscle crosstalk, thereby seriously delaying the healing of either tissue. Existing approaches are largely effective at healing single tissues. However, simultaneous healing of multiple tissues remains challenging, with little research conducted to date. Here we introduce collagen patches that overcome this overlooked issue by harnessing the plasticity of macrophage phenotypes. Phosphatidylserine liposomes (PSLs) capable of shifting the macrophage phenotype from inflammatory M1 into anti-inflammatory/prohealing M2 were coated on collagen patches via a layer-by-layer method. Original collagen patches failed to improve tissue healing under inflammatory conditions coordinated by M1 macrophages. In contrast, PSL-coated collagen patches succeeded in accelerating bone and muscle healing by inducing a microenvironment dominated by M2 macrophages. In cell experiments, differentiation of preosteoblasts and myoblasts was completely inhibited by secretions of M1 macrophages but unaffected by those of M2 macrophages. RNA-seq analysis revealed that type I interferon and interleukin-6 signaling pathways were commonly upregulated in preosteoblasts and myoblasts upon stimulation with M1 macrophage secretions, thereby compromising their differentiation. This study demonstrates the benefit of PSL-mediated M1-to-M2 macrophage polarization for simultaneous bone and muscle healing, offering a potential strategy toward simultaneous regeneration of multiple tissues. STATEMENT OF SIGNIFICANCE: Existing approaches for tissue regeneration, which primarily utilize growth factors, have been largely effective at healing single tissues. However, simultaneous healing of multiple tissues remains challenging and has been little studied. Here we demonstrate that collagen patches releasing phosphatidylserine liposomes (PSLs) promote M1-to-M2 macrophage polarization and are effective for simultaneous healing of bone and muscle. Transcriptome analysis using next-generation sequencing reveals that differentiation of preosteoblasts and myoblasts is inhibited by the secretions of M1 macrophages but promoted by those of M2 macrophages, highlighting the importance of timely regulation of M1-to-M2 polarization in tissue regeneration. These findings provide new insight to tissue healing of multiple tissues., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Riki Toita received a research grant from NGK Spark Plug Co., Ltd. (currently Niterra Co., Ltd.) Masahiro Kitamura, Atsushi Kato, Hideto Yamada, Shogo Yamaguchi, and Shinjiro Kasahara are employees of Niterra Co., Ltd. The remaining authors declare no competing interests., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Adaptation of the response to stimuli is a fundamental process for all organisms. Here, we show that the adaptation enzyme CheB methylesterase of Escherichia coli assembles to the ON state receptor array after exposure to the repellent l-isoleucine and dissociates from the array after adaptation is complete. The duration of increased CheB localization and the time of highly clockwise-biased flagellar rotation were similar and depended on the strength of the stimulus. The increase in CheB at the receptor array and the decrease in cytoplasmic CheB were both ~100 molecules, which represents 15 to 20% of the total cellular content of CheB. We confirmed that the main binding site for CheB in the ON state array is the P2 domain of phosphorylated CheA, with a second minor site being the carboxyl-terminal pentapeptide of the serine chemoreceptor. Thus, we have been able to quantify the regulation of the signal output of the receptor array by the intracellular dynamics of an adaptation enzyme.

The present study aimed to investigate the surgical, oncological and obstetric outcomes of the Shimodaira-Taniguchi (S-T) conization method. A total of 858 cases of high-grade intraepithelial lesions treated with S-T conization were retrospectively reviewed, and the surgical, oncological and obstetric outcomes were analyzed. The χ 2 test was used to compare the clinical characteristics between patients with and without cervical stenosis. The factors associated with recurrent/persistent disease were analyzed using univariate and multivariate analyses with a Cox hazards regression model. The obstetric outcomes after conization were also evaluated. Cervical stenosis and recurrent/persistent disease occurred in 2.2 and 4.9% of the patients, respectively. Older age [≥45 years; hazard ratio (HR), 3.22; 95% CI, 1.73-6.02] and surgical margin involvement (HR, 6.39; 95% CI, 3.44-11.8) were independently associated with recurrent/persistent disease. In particular, older patients with endocervical margin involvement showed a higher rate of recurrence (3-year recurrence rate, 28.1%). The proportion of patients who experienced cervical stenosis was significantly higher in older patients (0.95 vs. 5.7%; P<0.001). Among the 66 deliveries after conization, term delivery was observed in 62 cases (93.9%). The proportion of patients who experienced preterm delivery after conization was significantly higher in patients with a short interval from conization to conception (P=0.045). In conclusion, the S-T conization method was effective in terms of surgical, oncological and obstetric outcomes. A careful follow-up is required for older patients with positive surgical margins, particularly those with positive endocervical margins. In addition, a short interval of ≤3 months from conization to conception should be avoided to expect term pregnancy., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Higami et al.)

Not available.

Purpose: Intervertebral disc degeneration (IDD) is a common degenerative disease associated with ageing. Additionally, IDD is recognized as one of the leading causes of low back pain and disability in the working-age population and is the first step in the process leading to degenerative spinal changes. However, the genetic factors and regulatory mechanisms of IDD remain unknown. Therefore, we selected eight single nucleotide polymorphisms of genes to reveal the progression of IDD in a 7-year longitudinal study of the general population in Japan., Methods: IDD was evaluated in the Wakayama Spine Study (WSS), which is a population-based cohort study. Overall, 574 participants from the general population cohort who underwent whole spine magnetic resonance imaging and provided clinical information were included in this longitudinal survey., Results: The progression of IDD was affected only by THBS2 at the lumbar region, T12-L1 (p = 0.0044) and L3-4 (p = 0.0045). The significant interaction between THBS2 and age with IDD negatively affected the thoracic spines and passively influenced both the thoracolumbar junction and thoracic spines. The higher progression per year of Pfirrmann's score was rapid in young people with age; however, this decelerated the IDD progression per year in different ages., Conclusion: Our longitudinal study found the genes associated with IDD progression and that genetic factors' impact on IDD differs depending on disc level and age., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Japanese spotted fever (JSF) is a tick-borne disease caused by Rickettsia japonica and primarily affects the warmer coastal areas of Japan. Early treatment with tetracycline antibiotics is crucial to prevent severe complications, such as pneumonia, meningitis, disseminated intravascular coagulation (DIC), and systemic inflammatory response syndrome. An 83-year-old man with hypertension, chronic kidney disease, and hyperuricemia presented with DIC and subsequently developed septic shock. Polymerase chain reaction confirmed JSF caused by R. japonica . Initial treatment with ceftriaxone was ineffective, leading to a switch to intravenous minocycline and levofloxacin. Considering the high levels of C-reactive protein, procalcitonin, ferritin, and soluble interleukin-2 receptor, intravenous hydrocortisone (200 mg/day) was administered to control the cytokine storm. On day 4, the patient's condition improved significantly, with increased blood pressure, reduced DIC markers, and decreased levels of inflammatory cytokines, including interleukin-6 and tumor necrosis factor-α. The patient's recovery continued, and he was transferred to a chronic care hospital. Severe JSF cases are primarily driven by a cytokine storm caused by an excessive immune response. Early administration of corticosteroids along with antibiotics effectively suppressed the cytokine storm in this case. Reports have shown mixed results, indicating the need for further research to determine the optimal type, dosage, and duration of corticosteroid treatment., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Iwamura et al.)

The measurement range of the MicroLiDAR was enhanced with multi-reference paths. The multi-reference paths were composed of four paths with polarization maintaining optical fibers, each with different lengths. 50-mm-long measurement range was demonstrated with an oscilloscope with 15-GHz bandwidth. Reducing the time of calculation of the distance, we induced the dual entry method and demonstrated it. The stable distance measurement was demonstrated up to 50 mm.

Urgent haploidentical haematopoietic cell transplantation may be considered in cases of severe aplastic anaemia (SAA) without a human leukocyte antigen-matched donor and suffering from severe infection. However, deciding on allogeneic transplantation in the setting of active systemic infection is challenging due to poor outcomes. This report presents a case of disseminated Magnusiomyces capitatus infection in a 5-year-old male who underwent immunosuppressive therapy for hepatitis-associated SAA. To address the critical situation, granulocyte transfusion was promptly administered from the patient's mother, followed by unmanipulated haploidentical peripheral blood stem cell transplantation from the patient's father with posttransplant cyclophosphamide, ultimately resulting in successful rescue., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Here, we report a case of laparoscopic trans-inguinal hernia repair (transabdominal preperitoneal repair or TAPP) for a recurrent inguinal hernia following direct Kugel surgery. A 71-year-old man underwent direct Kugel hernioplasty for a right inguinal hernia at another hospital 4 years prior to presentation. The patient subsequently underwent laparoscopic surgery using the TAPP technique, during which the abdominal cavity was visualized with a laparoscope, revealing a tubular mesh protruding towards the abdominal cavity with a direct and indirect hernia ring. Three months post-surgery, no recurrence was observed., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Research Ethics Committee of Koga Community Hospital issued approval 2024-3. June 3, 2024 Dr. Takashi Deguchi SUNHKOKAI Social Medical Corporation KOGA Community Hospital Division of Gastroenterological Surgery Dear Deguchi Re your application titled: “Transabdominal preperitoneal repair for a recurrent inguinal hernia after kugel hernioplasty using the pseudosac of direct inguinal hernia: A case report”. Thank you for submitting your application for a Literature Review. I can confirm that your application has been given approval from the date of this letter. This approval is valid until June 3, 2027. Details of the approval are as follows: Approval No. 2024-3 Project Title: Transabdominal preperitoneal repair for a recurrent inguinal hernia after kugel hernioplasty Using the pseudosac of direct inguinal hernia: A case report Approval date: June 3,2024 Expiry date: June 3, 2027 The committee would be pleased to receive a copy of the summary of your research study when completed. Good luck with your research. Yours sincerely Dr. Keisuke Koga Director of Research Ethics Chair, Ethics Review Committee (Human Research). Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Deguchi et al.)

Muse cells, identified as cells positive for the pluripotent surface marker SSEA-3, are pluripotent-like endogenous stem cells located in the bone marrow (BM), peripheral blood, and organ connective tissues. The detailed characteristics of SSEA-3(+) cells in extraembryonic tissue, however, are unknown. Here, we demonstrated that similar to human-adult tissue-Muse cells collected from the BM, adipose tissue, and dermis as SSEA-3(+), human-umbilical cord (UC)-SSEA-3(+) cells express pluripotency markers, differentiate into triploblastic-lineage cells at a single cell level, migrate to damaged tissue, and exhibit low telomerase activity and non-tumorigenicity. Notably, ~ 20% of human-UC-SSEA-3(+) cells were negative for X-inactive specific transcript (XIST), a naïve pluripotent stem cell characteristic, whereas all human adult tissue-Muse cells are XIST-positive. Single-cell RNA sequencing revealed that the gene expression profile of human-UC-SSEA-3(+) cells was more similar to that of human post-implantation blastocysts than human-adult tissue-Muse cells. The DNA methylation level showed the same trend, and notably, the methylation levels in genes particularly related to differentiation were lower in human-UC-SSEA-3(+) cells than in human-adult tissue-Muse cells. Furthermore, human-UC-SSEA-3(+) cells newly express markers specific to extraembryonic-, germline-, and hematopoietic-lineages after differentiation induction in vitro whereas human-adult tissue-Muse cells respond only partially to the induction. Among various stem/progenitor cells in living bodies, those that exhibit properties similar to post-implantation blastocysts in a naïve state have not yet been found in humans. Easily accessible human-UC-SSEA-3(+) cells may be a valuable tool for studying early-stage human development and human reproductive medicine., (© 2024. The Author(s).)

Abstract: Transient abnormal myelopoiesis (TAM) occurs in 10% of neonates with Down syndrome (DS). Although most patients show spontaneous resolution of TAM, early death occurs in ∼20% of cases. Therefore, new biomarkers are needed to predict early death and determine therapeutic interventions. This study aimed to determine the association between clinical characteristics and cytokine levels in patients with TAM. A total of 128 patients with DS with TAM enrolled in the TAM-10 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group were included in this study. Five cytokine levels (interleukin-1b [IL-1b], IL-1 receptor agonist, IL-6, IL-8, and IL-13) were significantly higher in patients with early death than in those with nonearly death. Cumulative incidence rates (CIRs) of early death were significantly associated with high levels of the 5 cytokines. Based on unsupervised consensus clustering, patients were classified into 3 cytokine groups: hot-1 (n = 37), hot-2 (n = 42), and cold (n = 49). The CIR of early death was significantly different between the cytokine groups (hot-1/2, n = 79; cold, n = 49; hot-1/2 CIR, 16.5% [95% confidence interval (CI), 7.9-24.2]; cold CIR, 2.0% [95% CI, 0.0-5.9]; P = .013). Furthermore, cytokine groups (hot-1/2 vs cold) were independent poor prognostic factors in the multivariable analysis for early death (hazard ratio, 15.53; 95% CI, 1.434-168.3; P = .024). These results provide valuable information that cytokine level measurement was useful in predicting early death in patients with TAM and might help to determine the need for therapeutic interventions. This trial was registered at UMIN Clinical Trials Registry as #UMIN000005418., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Urothelial carcinoma of the bladder with osteoclast-like giant cells (UCOGCs) is rare among the subtypes of poorly differentiated urothelial carcinoma. Its clinical significance and optimal treatment are unknown, and few reports on genomic analysis of UCOGCs have been reported. Detailed analysis including genetic analysis for rare type variants of cancer could be a foothold for further research. The present case describes the case of a 75-year-old man who presented with a non-papillary bladder tumor 56 mm in diameter showing gross hematuria and pain on voiding. Following transurethral resection of the bladder tumor, the pathological diagnosis was invasive UCOGCs. Neoadjuvant chemotherapy and radical cystectomy were performed with the resected tumor pathologically diagnosed as invasive UCOGCs, high grade, pT3b, pN1. The present study also analyzed the genomic features using a cancer panel test. The panel test noted six gene alterations ( PIK3CA p.E542K, HRAS p.G13R, ARAF copy number amplification, CDKN2A copy number loss, TP53 p.E285V, ARID1A p.S90Pfs*11) and telomerase reverse transcriptase ( TERT ) promoter variant. Accumulation of knowledge from molecular-based testing is anticipated to determine precise treatment for rare cancer., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Kameyama et al.)

Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a rare disease characterized by a reversible lesion in the splenium of the corpus callosum (SCC) observed on MRI. The exact etiology of MERS is unknown, although infections and antiepileptic drugs have been reported as potential causes. Herein, we present the case of a 56-year-old male patient who experienced fever and headache for 3 days. He was referred to our hospital after symptomatic treatment by his primary care physician failed to improve his symptoms. The patient had no psychiatric symptoms or significant neurological findings. Head MRI revealed a high signal on SCC on diffusion-weighted imaging, raising the suspicion of MERS. All examinations to determine the cause of MERS were negative. The patient's symptoms improved with antibiotics and B complex vitamins. Upon admission, abdominal CT incidentally revealed a well-defined mass on the dorsal surface of the rectum suspected to be a tailgut cyst, warranting surgical resection. The cranial margin of the tumor was caudal to the third sacrum, and a trans-sacral approach was used for resection. The fifth sacrum and the coccyx were resected, and the tumor was resected without damaging the rectum. A histopathological examination revealed a mature teratoma without any malignancy. A follow-up CT at four months postoperatively showed no evidence of clinical recurrence of MERS. Adult-onset MERS is relatively rare, and no association with tumors has been reported. The association between encephalitis and teratomas includes ovarian teratomas, which cause anti-N-methyl-D-aspartate receptor encephalitis and paraneoplastic limbic encephalitis. Although the cause of MERS was unknown in this case, we report the coexistence of a sacral teratoma and MERS to contribute to the knowledge of the association between them., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Research Ethics Committee of Koga Community Hospital issued approval 2024-2. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Fujimoto et al.)

MINFLUX has achieved extraordinary resolution in superresolution imaging and single fluorophore tracking. It is based on localizing single fluorophores by rapid probing with a patterned beam that features a local intensity minimum. Current implementations, however, are complex and expensive and are limited in speed and robustness. Here, we show that a combination of an electro-optical modulator with a segmented birefringent element such as a spatial light modulator produces a variable phase plate for which the phase can be scanned on the MHz timescale. Bisected or top-hat phase patterns generate high-contrast compact excitation point-spread functions for MINFLUX localization in the x, y, and z-direction, respectively, which can be scanned across a fluorophore within a microsecond, switched within 60 microseconds and alternated among different excitation wavelengths. We discuss how to compensate for non-optimal performance of the components and present a robust 3D and multi-color MINFLUX excitation module, which we envision as an integral component of a high-performance and cost-effective open-source MINFLUX., (© 2024. The Author(s).)

Lung squamous cell carcinoma (LSCC) is refractory to various therapies for non-small cell cancer; therefore, new therapeutic approaches are required to improve the prognosis of LSCC. Although immunotherapies targeting B7 family molecules were explored as treatments for several cancer types, the expression and significance of B7-H3 in the tumor microenvironment (TME) and its relationship with other immune checkpoint molecules have not yet been investigated in detail. We used high-throughput quantitative multiplex immunohistochemistry to examine B7-H3 expression in the TME. We investigated the relationship between B7-H3 expression and prognosis as well as changes in the TME with B7-H3 expression using 110 surgically resected pathological specimens retrospectively. We examined the correlation between B7-H3 and programmed cell death-ligand 1 (PD-L1) expression in single cells. High B7-H3 expression in tumor cells was associated with a better prognosis and a significant increase in the number of CD163 + PD-L1 + macrophages. Quantitative analysis revealed that there is a positive correlation between B7-H3 and PD-L1 expression in tumor and stromal cells, as well as in intratumoral tumor-infiltrating lymphocytes and tumor-associated macrophages in the same cells. CD68 + , CD163 + , and CK + cells with PD-L1 + phenotypes had higher B7-H3 expression compared to PD-L1 - cells. Our findings demonstrate a correlation between B7-H3 and PD-L1 expression in the same cells, indicating that therapies targeting B7-H3 could provide additional efficacy in patients refractory to PD-L1-targeting therapies.

Background: Asparaginase is essential for treating T-cell acute lymphoblastic leukemia (T-ALL). Despite the ongoing debate on whether T-ALL and T-cell lymphoblastic lymphoma (T-LBL) are the same disease entity or two distinct diseases, patients with T-LBL often receive the same or similar treatment protocols as those with T-ALL., Methods: The outcomes of patients with or without L-asparaginase discontinuation were retrospectively analyzed among four national protocols: Japan Association of Childhood Leukemia Study (JACLS) ALL-02 and ALL-97 for T-ALL and Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 and JACLS NHL-98 for T-LBL. The hazard ratio (HR) was calculated with the Cox regression model by considering L-asparaginase discontinuation as a time-dependent variable., Results: In total, 199 patients with T-ALL, and 133 patients with T-LBL were included. L-asparaginase discontinuation compromised event-free survival (EFS) of T-ALL patients (ALL-02: HR 3.32, 95% confidence interval [CI] 1.40-7.90; ALL-97: HR 3.39, 95%CI 1.19-9.67). Conversely, EFS compromise was not detected among T-LBL patients (ALB-NHL03: HR 1.39, 95%CI 0.41-4.68; NHL-98: HR 0.92, 95%CI 0.11-7.60)., Conclusion: The effects of L-asparaginase discontinuation differed between T-ALL and T-LBL. We assume that the differential impact results from (1) the inherent differential response to L-asparaginase between them and/or (2) a less stringent assessment of early treatment response in T-LBL than in T-ALL. Given the poor salvage rate of refractory or relapsed T-ALL and T-LBL, optimization of the frontline therapy is critical, and the current study provides a new suggestion for further treatment modifications. However, larger studies in contemporary intensified treatment protocols are required., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

External supravesical hernias with ovarian incarceration have not been reported previously. Here, we describe transabdominal preperitoneal (TAPP) repair of an external supravesical hernia with ovarian incarceration. A 68-year-old woman presented to our outpatient clinic with the chief complaint of right inguinal swelling and pain. A 3-cm-diameter mass in the right inguinal region that was difficult to reduce was palpable, and computed tomography (CT) revealed a suspicious lesion of the right hydrocele of the canal of Nuck. Hydrocelectomy was performed through an inguinal incision, and the external inguinal ring was repaired using the Marcy method. The histopathological examination confirmed the diagnosis of the canal of Nuck. Three months postoperatively, the patient again presented with right inguinal pain, and CT revealed a right femoral hernia requiring surgical repair. Intraoperative findings revealed a right external supravesical hernia with an incarcerated ovary, which was laparoscopically reduced and repaired with a mesh. At the three-month follow-up, there were no postoperative complications or recurrences. Incarcerated ovaries with inguinal hernias have been reported in girls; however, incarcerated ovaries with external supravesical hernias have not been reported in women. Although the preoperative diagnosis was difficult to make in this case, the laparoscopic approach led to the diagnosis and successful mesh repair. Although optimal mesh repair of external supravesical hernias using TAPP has not been established, we believe that 2-5 cm around the hernial orifice, the Hesselbach triangle, and the lateral triangle should be covered with mesh., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Fujimoto et al.)

Objectives: To assess the infrazygomatic crest (IZC) and palatal bone width, height, and angulation in patients with different vertical facial growth types as potential miniscrew insertion sites., Materials and Methods: In this retrospective cone-beam computed tomography study, 162 subjects (81 males and 81 females, mean age 16.05 ± 0.65 years) were included. They were divided into three groups (hypodivergent, normodivergent, and hyperdivergent) based on the Frankfort mandibular plane angle. Ten buccal bone measurements were made at two different coronal sections: maxillary first molar mesiobuccal and distobuccal roots (bilaterally). Six palatal bone measurements were made on a sagittal section at the maxillary central incisors (bilaterally). A total of 32 measurements per subject were considered in the study., Results: No significant difference was observed for the IZC (width and angle) at the maxillary first molar mesiobuccal root. A comparison of normodivergent and hyperdivergent groups for buccal width at the distobuccal root of the first molar showed significant differences. Palatal bone thickness at the level of 2 mm distal to the apex of the central incisor was significantly higher for the hyperdivergent group (10.43 mm) compared with the normodivergent (7.58 mm) and hypodivergent groups (7.83 mm)., Conclusions: Hyperdivergent subjects tend to present a longer and deeper IZC and increased palatal bone thickness compared with other groups. The recommended insertion angle for the IZC mini-implant at 3 mm from the alveolar crest should be between 75.5° and 77°., (© 2024 by The EH Angle Education and Research Foundation, Inc.)

Several types of fastidious bacteria can cause tract infections. We evaluated the performance of counting fastidious bacteria using a Fully Automated Urine Particle Analyzer UF-5000. The results showed that UF-5000 counts fastidious bacteria in urine without the need for culture using measurement principles based on flow cytometry., Competing Interests: Declaration of competing interest Masako Kaido and Yasumasa Akai are employees of the Sysmex Corporation. The other authors declare that they have no known competing financial interest or personal relationship 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: Increased serum cortisol (COR) concentrations may induce glucocorticoid resistance by down-regulation of glucocorticoid receptor (GCR), resulting in decreased chemotherapy efficacy in dogs with lymphoma., Hypothesis: Investigate the relationship between serum COR concentrations and chemotherapy outcomes in dogs with lymphoma., Animals: Thirty client-owned dogs with lymphoma, with serum COR concentration measured using serum samples collected at diagnosis., Methods: Retrospective study. Dogs were divided into 2 groups based on serum COR concentrations: a normal group (n = 16) with COR concentrations <6 μg/dL and a high group (14) with COR concentrations ≥6 μg/dL. We compared signalment, clinical signs, stage, type of lymphoma, adrenal gland size, alkaline phosphatase (ALP) activity, response to chemotherapy, progression-free survival (PFS), overall survival (OS), and rate of P-glycoprotein (P-gp)- and GCR-positive cells between the 2 groups., Results: No significant differences were found in the demographic characteristics between the 2 groups. However, the high COR group exhibited a significantly lower response to chemotherapy, PFS, and OS compared with the normal COR group. Serum ALP activity was significantly higher in the high COR group than in the normal COR group. Adrenal gland size was also significantly larger in the high COR group. Although no significant differences were found in the rate of P-gp-positive cells between the 2 groups, the rate of GCR-positive cells was significantly lower in the high COR group., Conclusions and Clinical Importance: Our data suggests that measurement of serum COR concentrations may serve as a potential prognostic factor and evaluation index., (© 2024 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care., Procedure: We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025)., Results: Twenty patients with post-induction MRD ≥ 10 -3 and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively., Conclusion: Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL., (© 2024. Japanese Society of Hematology.)

A spinal cord injury (SCI) can cause severe lifelong functional disability and profoundly affect an individual's daily life. We investigated the prediction of patients' post-SCI functional outcomes by evaluating sensory scores rather than motor scores, as the latter's association with functional outcomes is well established. We examined patients' responses to a light touch (LT) and pin prick (PP) at admission and the response data's usefulness as predictors of functional outcomes (i.e., ability to perform activities of daily living) at discharge. This exploratory observational study used data from the Japanese National Spinal Cord Injury Database (SCI-J). Data from 3,676 patients who met the inclusion criteria and were admitted for an SCI between 1997 and 2020 were analyzed. The motor score of the Functional Independence Measure (mFIM) at discharge was used as an index of functional outcome. A multiple regression analysis revealed that the mFIM was associated with both the LT response (β=0.07 (0.01), p<0.001) and the PP response (β=0.07 (0.01), p<0.001) at admission. The false discovery rate log-worth values for LT and PP were 6.6 and 8.5, respectively. Our findings demonstrate that LT and PP scores at admission can help predict patients' functional outcomes after an SCI, although the magnitude of their contributions is not high., Competing Interests: No potential conflict of interest relevant to this article was reported.

This study aimed to determine the efficacy of assessing the severity of diabetic polyneuropathy (DPN) in patients with untreated diabetes. Seventy-two patients with untreated type 2 diabetes who were hospitalized for glycemic control were enrolled and divided into the following two groups: patients who had no prior diagnosis and patients who were unattended or had discontinued treatment. Electrophysiological criteria consistent with Baba's classification were used to diagnose and assess the severity of DPN. The patients were divided into three subgroups: no DPN (stage 0), mild DPN (stage 1), and moderate or more-severe DPN (stages 2-4). Intergroup comparisons were performed for the clinical characteristics and the results of the nerve conduction studies. Twenty-two (30%), 25 (35%), and 25 (35%) patients were categorized into the no DPN, mild DPN, and moderate or more-severe DPN subgroups, respectively. The number of patients who were unattended or had discontinued treatment in the moderate or more-severe DPN subgroup was significantly higher than that in the no DPN subgroup. The patients in the moderate or more-severe DPN subgroup had an increased risk of developing diabetic retinopathy and nephropathy, with odds ratios of 19.5 and 11.0 for advanced stages of retinopathy and nephropathy, respectively. Thus, the assessment of the severity of DPN could aid in the prediction of the risk of developing diabetic complications in patients with untreated diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Horinouchi, Deguchi, Mukai, Ijuin, Kawamoto and Nishio.)

Background/aim: A genomic analysis based on next-generation sequencing is important for deciding cancer treatment strategies. Cancer tissue sometimes displays intratumor heterogeneity and a pathologic specimen may contain more than two tumor grades. Although tumor grades are very important for the cancer prognosis, the impact of higher tumor grade distribution in a specimen used for a genomic analysis is unknown., Patients and Methods: We retrospectively analyzed the data of 61 clear cell carcinoma and 46 prostate cancer patients that were diagnosed between December 2018 and August 2022 using the GeneRead Human Comprehensive Cancer Panel or SureSelect PrePool custom Tier2. Genome annotation and curation were performed using the GenomeJack software., Results: Tumor mutation burden (TMB) was increased in proportion to the higher tumor grade distribution in grade 2 clear cell renal cell carcinoma (ccRCC). In PC, Grade Group 3/4 specimens that included an increased distribution of Gleason pattern 4 had more frequent gene mutations., Conclusion: Our results suggest the importance of selecting the maximum distribution of higher tumor grade areas to obtain results on the precise gene alterations for genomics-focused treatments., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

HLA-haploidentical stem cell transplantation (haplo-SCT) using post-transplant high-dose cyclophosphamide (PT-CY) is an alternative choice when a suitable donors is unavailable. However, PT-CY is difficult in patients with Fanconi anemia (FA) due to their high vulnerability to alkylating agents. For FA, we prefer haplo-SCT by T-cell receptor αβT-cell and B-cell depletion (αβT/B-depleted haplo-SCT), which can reduce the risks of PT-CY-related complications and graft-versus-host disease (GVHD). An 11-year-old boy with diagnosed FA (FANCG mutation) and bone marrow failure was to receive αβT/B-depleted haplo-SCT from his father (HLA 4/8 allele matched) due to absence of an HLA-matched donors. αβT/B-depleted peripheral blood stem cells (CD34 + cell count, 1.17 × 10 7 /kg; αβ + T-cell count, 1.3 × 10 5 /kg) were infused following conditioning consisting of fludarabine (150 mg/m 2 ), cyclophosphamide (40 mg/kg), anti-thymocyte globulin (5 mg/kg), rituximab (375 mg/m 2 ), and thoraco-abdominal irradiation (3 Gy). Tacrolimus was used for GVHD prophylaxis until day + 30. Neutrophil engraftment was achieved on day + 9, and complete chimerism was confirmed on days + 28 and + 96. At 12-month post-SCT, the patient was well without GVHD or any other complications. αβT/B-depleted haplo-SCT is a good choice not only for patients unsuitable for PT-CY, but also for all pediatric recipients to reduce SCT-related complications., (© 2024. Japanese Society of Hematology.)

Acute zoster-associated pain develops in most patients with herpes zoster. Nonopioid analgesics are usually used to treat acute zoster-associated pain but are frequently ineffective. We administered intravenous fosphenytoin, the prodrug of phenytoin, to patients with acute zoster-associated pain to examine its analgesic efficacy and safety. At 13 medical institutions in Japan, we conducted a phase II, double-blind, placebo-controlled, randomized trial of intravenous fosphenytoin in Japanese inpatients with acute zoster-associated pain for whom nonopioid analgesics had shown an insufficient analgesic effect. The patients were randomly assigned (1:1:1) to receive a single intravenous dose of fosphenytoin at 18 mg/kg (high dose), a single intravenous dose of fosphenytoin at 12 mg/kg (low dose), or placebo. The primary endpoint was the mean change per hour (slope) in the numerical rating scale score from the baseline score until 120 min after dosing. Seventeen patients were randomly assigned to the low-dose fosphenytoin group (n = 6, median age 62.5 years, range 39-75 years), high-dose fosphenytoin group (n = 5, median age 69.0 years, range 22-75 years), and placebo group (n = 5, median age 52.0 years, range 38-72 years). One patient was excluded because of investigational drug dilution failure. This study was discontinued because of the influences of coronavirus disease 2019. The slope was significantly lower in the high- and low-dose fosphenytoin groups than in the placebo group (P < 0.001 and P = 0.016, respectively). Responsiveness to intravenous fosphenytoin (≥2-point reduction in the numerical rating scale score from baseline to 120 min after dosing) was inferred at plasma total phenytoin concentrations of 10-15 μg/mL. Treatment-emergent adverse events caused no safety concerns in the clinical setting and intravenous fosphenytoin was well tolerated. Intravenous fosphenytoin appears to be an effective and promising alternative treatment for acute zoster-associated pain. Trial Registration: ClinicalTrials.gov NCT04139330., (© 2023 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Deep dermatophytosis is an invasive and sometimes life-threatening fungal infection mainly reported in immunocompromised patients. However, a caspase recruitment domain-containing protein 9 (CARD9) deficiency has recently been reported to cause deep dermatophytosis. Herein, we report the first Japanese case of deep dermatophytosis associated with CARD9 deficiency. An 80-year-old Japanese man with tinea corporis presented with subcutaneous nodules on his left sole. Histopathological findings revealed marked epithelioid cell granulomas with filamentous fungal structures in the deep dermis and subcutis, and the patient was diagnosed with deep dermatophytosis. Despite antifungal therapy, the subcutaneous nodule on his left sole gradually enlarged, his left calcaneal bone was invaded, and the patient finally underwent amputation of his left leg. Genetic analysis revealed a homozygous CARD9 c.586 A > G (p. Lys196Glu) variant, suggesting a CARD9 deficiency. Here, we discuss the clinical features of CARD9 deficiency-associated deep dermatophytosis with a case report and review of the literature., (© 2023 Japanese Dermatological Association.)

Competing Interests: Conflicts of interest the authors declare no conflicts of interest.

Flow cytometry (FCM) remains an essential test in the diagnosis of leukemia despite advances in genomic testing. However, the role of FCM results as a risk factor is already extremely limited. International diagnostic criteria for leukemia already prioritize diagnosis based on genetic abnormalities, with FCM diagnosis only serving as an aid to morphological diagnosis for subtypes without genetic abnormalities. However, rapid lineage diagnosis of leukemia by FCM remains important for selecting initial treatment. FCM is also an important tool for evaluating response to molecular targeted therapy, which requires repeated measurements and rapid results. Furthermore, FCM enables prediction of specific genetic abnormalities by immunophenotypic patterns, which could make it useful for verifying the clinical impact of genetic abnormalities detected by multi-gene panel testing.

Infancy associated eosinophilic pustular folliculitis (I-EPF) is a clinical variant of EPF that develops in childhood. Previous studies have suggested that I-EPF exhibits clinical and histological differences distinct from other variants, including classic EPF. Herein, we report two patients with I-EPF treated with topical indomethacin. These two cases exhibited less perifollicular and more perivascular eosinophilic infiltration, which is different in distribution from that of classic EPF. Immunohistochemical study demonstrated that the infiltrating mononuclear cells were CD4-dominant T cells in classic EPF and I-EPF, whereas the number of CD68-positive cells was significantly higher in classic EPF than in I-EPF. Immunohistochemical staining was also performed for eosinophilic pustular folliculitis (HPGDS), which has been reported to induce eosinophils and is a therapeutic target of indomethacin in classic EPF. HPGDS-positive cells were also observed in I-EPF, which may explain the effectiveness of topical indomethacin. Although clinical and histopathological features of I-EPF are different from other variants, the arachidonic acid pathway could be involved in eosinophil infiltration, not only in classic EPF but also in I-EPF., (© 2023 Japanese Dermatological Association.)

Background: Air pollution and a number of metabolic disorders have been reported to increase the risk of severe COVID-19 outcomes. This study explored the association between severe COVID-19 outcomes, metabolic disorders and environmental air pollutants, at regional level, across 38 countries., Methods: We conducted an ecological study using COVID-19 data related to countries of the Organization for Economic Cooperation and Development (OECD), with an estimated population of 1.4 billion. They were divided into 3 regions: 1. Europe & Middle east; 2. Americas (north, central & south America); 3. East-Asia & West Pacific. The outcome variables were: COVID-19 case-fatality rate (CFR) and disability-adjusted life years (DALYs) at regional level. Freely accessible datasets related to regional DALYs, demographics and other environmental pollutants were obtained from OECD, WHO and the World in Data websites. Generalized linear model (GLM) was performed to determine the regional determinants of COVID-19 CFR and DALYs using the aggregate epidemiologic data (Dec. 2019-Dec. 2021)., Results: Overall cumulative deaths were 65,000 per million, for mean CFR and DALYs of 1.31 (1.2)% and 17.35 (2.3) years, respectively. Globally, GLM analysis with adjustment for elderly population rate, showed that COVID-19 CFR was positively associated with atmospheric PM 2.5 level (beta = 0.64(0.0), 95%CI: 0.06-1.35; p < 0.05), diabetes prevalence (beta = 0.26(0.1), 95%CI: 0.12-0.41; p < 0.001). For COVID-19 DALYs, positive associations were observed with atmospheric NOx level (beta = 0.06(0.0), 95%CI: 0.02-0.82; p < 0.05) and diabetes prevalence (beta = 0.32(0.2), 95%CI: 0.04-0.69; p < 0.05). At regional level, adjusted GLM analysis showed that COVID-19 CFR was associated with atmospheric PM 2.5 level in the Americas and East-Asia & Western Pacific region; it was associated with diabetes prevalence for countries of Europe & Middle east and East-Asia & Western Pacific region. Furthermore, COVID-19 DALYs were positively associated with atmospheric PM 2.5 and diabetes prevalence for countries of the Americas only., Conclusion: These findings confirm that diabetes and air pollution increase the risk of disability and fatality due to COVID-19, with disparities in terms of their impact. They suggest that efficient preventive and management programs for diabetes and air pollution countermeasures would have curtailed severe COVID-19 outcome rates.

Background: Bleeding risk factors in elderly patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) are unclear and data on the use of antithrombotic drugs are lacking. We investigated the bleeding risk factors in elderly patients with atrial fibrillation undergoing PCI to help optimize antithrombotic therapy according to bleeding risk. We also investigated the association between the actual use of antithrombotic therapy and bleeding events., Methods: A retrospective cohort study was conducted on 134 elderly patients with atrial fibrillation who underwent primary PCI at the Department of Cardiology, Showa University Fujigaoka Hospital. The endpoint was a bleeding event within 1-year. Bleeding risk factors were identified using multivariate analysis. The association between the number of antithrombotics and bleeding events was evaluated using the chi-squared test., Results: The mean age of the patients was 76.0 ± 6.2 years. Bleeding events occurred in 41 (30.6%) patients. Age > 80 years (odds ratio [OR]: 2.54, 95% confidence interval [CI]: 1.10-5.85), multivessel disease (OR: 2.76, 95% CI: 1.22-6.23), and history of surgery (OR: 3.03, 95% CI: 1.14-8.06) were identified as bleeding risk factors. The proportion of patients receiving triple therapy was significantly higher in the bleeding group compared to the non-bleeding group (70.7% vs. 27.5%, p < 0.001)., Conclusions: Age > 80, multivessel disease, and history of surgery were found to be risk factors for bleeding in elderly patients with atrial fibrillation undergoing PCI. In addition, dual therapy after PCI in elderly patients at high risk of bleeding should be considered to avoid bleeding events., (© 2023. The Author(s).)

The transcription factor hypoxia-inducible factor 1α (HIF-1α) drives metabolic reprogramming in gliomas (GLs) under hypoxic conditions, promoting glycolysis for tumor development. Evofosfamide (EVO) releases a DNA-alkylating agent within hypoxic regions, indicating that it may serve as a hypoxia-targeted therapy. The aim of this study was to investigate the glycolytic metabolism and antitumor effects of EVO in a canine GL model. Our clinical data showed that overall survival was significantly decreased in GL dog patients with higher HIF-1α expression compared to that of those with lower HIF-1α expression, and there was a positive correlation between HIF-1α and pyruvate dehydrogenase kinase 1 (PDK1) expression, suggesting that glycolytic activity under hypoxia conditions may contribute to poor outcomes in canine GL. Our glycolysis assay tests showed that the glycolytic ATP level was higher than the mitochondrial ATP level in three types of canine GL cell lines by activating the HIF-1 signal pathway under hypoxia conditions, resulting in an overall increase in total cellular ATP production. However, treatment with EVO inhibited the glycolytic ATP level in the GL cell lines under hypoxia conditions by targeting HIF-1α-positive cells, leading to decrease in total cellular ATP production. Our in vivo tests showed that EVO significantly reduced tumor development compared to controls and temozolomide in murine GL models. A metabolic analysis demonstrated that EVO effectively suppressed glycolytic metabolism by eliminating HIF-1α-positive cells, suggesting that it may restore metabolism in canine GLs. The evidence presented here supports the favorable preclinical evaluation of EVO as a potential improvement in cancer metabolism.

Immune checkpoint inhibitors (ICIs) have been developed for canine tumour treatment, and pilot clinical studies have demonstrated their antitumour efficacy in dogs with oral malignant melanoma (OMM). Although ICIs have been approved for various human malignancies, their clinical benefits in other tumour types remain to be elucidated in dogs. Here, we conducted a clinical study of c4G12, a canine chimeric anti-PD-L1 antibody, to assess its safety and efficacy in dogs with various advanced malignant tumours (n = 12) at the Veterinary Teaching Hospital of Hokkaido University from 2018 to 2023. Dogs with digit or foot pad malignant melanoma (n = 4), osteosarcoma (n = 2), hemangiosarcoma (n = 1), transitional cell carcinoma (n = 1), nasal adenocarcinoma (n = 1), B-cell lymphoma (n = 1), or undifferentiated sarcoma (n = 2) were treated with 2 or 5 mg/kg c4G12 every 2 weeks. Treatment-related adverse events of any grade were observed in eight dogs (66.7%), including elevated aspartate aminotransferase (grade 3) in one dog (8.3%) and thrombocytopenia (grade 4) in another dog (8.3%). Among dogs with target disease at baseline (n = 8), as defined by the response evaluation criteria for solid tumours in dogs (cRECIST), one dog with nasal adenocarcinoma and another with osteosarcoma experienced a partial response (PR), with an objective response rate of 25.0% (2 PR out of 8 dogs; 95% confidence interval: 3.2-65.1%). These results suggest that c4G12 is safe and tolerable and shows antitumor effects in dogs with malignant tumours other than OMM. Further clinical studies are warranted to identify the tumour types that are most likely to benefit from c4G12 treatment., Competing Interests: SY and KY are employed by Fuso Pharmaceutical Industries, Ltd. NM, S Konnai, Y Kagawa, ST, YS, TO, SM, and KO are the authors of patent applications covering materials and techniques described in this paper (PCT/JP2017/029055, PCT/JP2018/011895). All other authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Maekawa 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.)

Acute myeloid leukemia (AML) is known as one of the subsequent malignant neoplasms that can develop after cancer treatment, but it is difficult to distinguish from relapse when the preceding cancer is leukemia. We report a 2-year-old boy who developed acute megakaryoblastic leukemia (AMKL, French-American-British classification [FAB]: M7) at 18 months of age and achieved complete remission with multi-agent chemotherapy without hematopoietic stem cell transplantation. Nine months after diagnosis and 4 months after completing treatment for AMKL, he developed acute monocytic leukemia (AMoL) with the KMT2A::LASP1 chimeric gene (FAB: M5b). The second complete remission was achieved using multi-agent chemotherapy and he underwent cord blood transplantation 4 months after AMoL was diagnosed. He is currently alive and disease free at 39 and 48 months since his AMoL and AMKL diagnoses, respectively. Retrospective analysis revealed that the KMT2A::LASP1 chimeric gene was detected 4 months after diagnosis of AMKL. Common somatic mutations were not detected in AMKL or AMoL and no germline pathogenic variants were detected. Since the patient's AMoL was different from his primary leukemia of AMKL in terms of morphological, genomic, and molecular analysis, we concluded that he developed a subsequent leukemia rather than a relapse of his primary leukemia., (© 2023. Japanese Society of Hematology.)