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BACKGROUND: Due to potential ethnic differences in the pathophysiology of type 2 diabetes, new therapeutics need to be evaluated in Japanese patients. We aimed to assess the safety and glycaemic efficacy of tirzepatide as an add-on treatment in Japanese patients with type 2 diabetes who had inadequate glycaemic control with stable doses of various oral antihyperglycaemic monotherapies. METHODS: This multicentre, open-label, parallel-group, randomised, phase 3 trial was conducted at 34 medical research centres and hospitals in Japan. Eligible participants were aged 20 years or older with inadequately controlled (HbA1c ≥7·0% to <11·0%) type 2 diabetes and were receiving oral antihyperglycaemic monotherapy (sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinedione, glinides, or SGLT2 inhibitors) for at least 3 months (stable dose for ≥8 weeks before screening), had a BMI of 23 kg/m2 or higher, and stable bodyweight (±5%) for at least 3 months before screening. After a 2-week screening and 2-week lead-in period, all participants were randomly assigned (1:1:1) to receive 5, 10, or 15 mg of tirzepatide, administered once per week subcutaneously for 52 weeks followed by a 4 week safety follow-up period, using a computer-generated random sequence and interactive web response system, stratified by oral antihyperglycaemic medication group. All participants started receiving 2·5 mg tirzepatide and doses were escalated by 2·5 mg every 4 weeks until the assigned dose was reached. The primary endpoint was safety and tolerability during 52 weeks of treatment, assessed as incidence of treatment-emergent adverse events in the modified intention-to-treat (mITT) population. This trial is registered with ClinicalTrials.gov, NCT03861039. FINDINGS: Between March 30, 2019, and Feb 16, 2021, with recruitment and enrolment continuing until Feb 4, 2020, 484 participants were assessed for eligibility and 443 were randomly assigned to receive at least one dose of tirzepatide (148 [33%] in the 5 mg group, 147 [33%] in the 10 mg group, and 148 [33%] in the 15 mg group). 398 (90%) participants completed the study and treatment. Most participants (343 [77%] of 443) had at least one treatment-emergent adverse event. Treatment-emergent adverse events were more frequent in the tirzepatide 15 mg group (125 [84%] of 148) than the 5 mg (109 [74%] of 148) and 10 mg groups (109 [74%] of 147). The most frequent treatment-emergent adverse events with tirzepatide were mild or moderate nasopharyngitis (75 [17%]), nausea (74 [17%]), constipation (54 [12%]), diarrhoea (51 [12%]), and decreased appetite (44 [10%]). At week 52, mean changes from baseline in bodyweight were -3·8 kg (SE 0·5; -5·1% reduction) in the 5 mg group, -7·5 kg (0·5; -10·1% reduction) in the 10 mg group, and -10·2 kg (0·5; -13·2% reduction) in the 15 mg group. Least squares mean HbA1c at baseline reduced from 8·5% (SE 0·1) to 6·0% (0·1) in the 5 mg tirzepatide group, from 8·6% (0·1) to 5·6% (0·1) in the 10 mg group, and from 8·6% (0·1) to 5·6% (0·1) in the 15 mg group at week 52. No adjudication-confirmed deaths were reported. INTERPRETATION: Tirzepatide was well tolerated as an add-on to oral antihyperglycaemic monotherapy in Japanese participants with type 2 diabetes and showed improvement in glycaemic control and bodyweight, irrespective of background oral antihyperglycaemic medication. Tirzepatide is a potential new treatment option for Japanese patients with type 2 diabetes that is inadequately controlled with single oral antihyperglycaemic medication. FUNDING: Eli Lilly and Company. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

DOI： 10.1016/S2213-8587(22)00187-5

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CONTEXT: The adrenal cortex consists of zona glomerulosa (ZG), fasciculata (ZF), and reticularis. Aldosterone-producing cell clusters that strongly express aldosterone synthase (CYP11B2) are frequently found in adult adrenals and harbor somatic mutations that are also detected in aldosterone-producing adenomas (APAs). Primary aldosteronism is mainly caused by APAs or idiopathic hyperaldosteronism (IHA). We presume that APCCs are causing IHA and are precursors of APAs. However, the gene expression characteristics and especially the development of APCC are not well understood. OBJECTIVE: This study aimed to analyze the transcriptome of APCC at single-cell resolution and infer the developmental trajectory. METHODS: Single-cell RNA sequencing (scRNA-seq) of two adult adrenals was performed. RESULTS: Immunohistochemical analyses confirmed the two adrenals had APCCs. scRNA-seq data of 2,928 adrenal cells were obtained and 1,765 adrenocortical cells were identified based on unsupervised clustering and the marker gene expression. The adrenocortical cells were divided into 6 clusters, of which three clusters (923 cells) were composed of APCC/ZG cells. By further sub-clustering, the APCC/ZG cells were divided into three clusters (clusters C1, C2, and C3), we finally identified APCC-cluster (C3) and ZG-cluster (C1). Cluster C2 seemed to be ZG-to-ZF transitional cells. RNA velocity analysis inferred the developmental direction from cluster ZG-cluster-C1 to APCC-cluster-C3. The scRNA-seq additionally revealed that many CYP11B2-positive cells were positive for CYP11B1 and/or CYP17A1, which were essential for cortisol but not for aldosterone production. CONCLUSIONS: Our results revealed the gene expression characteristics of APCC at single-cell resolution and show that some ZG cells remodel to APCC.

DOI： 10.1210/clinem/dgac394

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Despite recent therapeutic advances for multiple myeloma (MM), relapse is very common. Here, we conducted longitudinal single-cell transcriptome sequencing (scRNA-seq) of MM cells from a patient with relapsed MM, treated with multiple anti-myeloma drugs. We observed five subclusters of MM cells, which appeared and/or disappeared in response to the therapeutic pressure, and identified cluster 3 which emerged during lenalidomide treatment and disappeared after proteasome inhibitor (PI) treatment. Among the differentially expressed genes in cluster 3, we found a candidate drug-response gene; pellino E3 ubiquitin-protein ligase family member 2 (PELI2), which is responsible for PI-induced cell death in in vitro assay. Kaplan-Meier survival analysis of database revealed that higher expression of PELI2 is associated with a better prognosis. Our integrated strategy combining longitudinal scRNA-seq analysis, in vitro functional assay, and database analysis would facilitate the understanding of clonal dynamics of MM in response to anti-myeloma drugs and identification of drug-response genes.

DOI： 10.1016/j.isci.2022.104781

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Establishment of the DNA methylation landscape of mammalian oocytes, mediated by the DNMT3A-DNMT3L complex, is crucial for reproduction and development. In mouse oocytes, high levels of DNA methylation occur exclusively in the transcriptionally active regions, with moderate to low levels of methylation in other regions. Histone H3K36me3 mediates the high levels of methylation in the transcribed regions; however, it is unknown which histone mark guides the methylation in the other regions. Here, we show that, in mouse oocytes, H3K36me2 is highly enriched in the X chromosome and is broadly distributed across all autosomes. Upon H3K36me2 depletion, DNA methylation in moderately methylated regions is selectively affected, and a methylation pattern unique to the X chromosome is switched to an autosome-like pattern. Furthermore, we find that simultaneous depletion of H3K36me2 and H3K36me3 results in global hypomethylation, comparable to that of DNMT3A depletion. Therefore, the two histone marks jointly provide the chromatin platform essential for guiding DNMT3A-dependent DNA methylation in mouse oocytes.

DOI： 10.1038/s41467-022-32141-2

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DOI： 10.1126/sciadv.abd7924

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DOI： 10.1126/sciadv.abd7924

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DOI： 10.1007/s00125-021-05488-2

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DOI： 10.2337/dc20-0864

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DOI： 10.1507/endocrj.EJ20-0599

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DOI： 10.1172/jci.insight.143791

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DOI： 10.1084/jem.20192230

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DOI： 10.1038/s41467-020-19287-7

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DOI： 10.1038/s41467-020-19041-z

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DOI： 10.2337/dc18-1293

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DOI： 10.1038/s41467-018-03038-w

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DOI： 10.1089/thy.2017.0331.

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DOI： 10.1038/s41467-018-03038-w.

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DOI： 10.1089/thy

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DOI： 10.1016/S2213-8587(17)30327-3

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DOI： 10.1172/jci.insight.92902

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DOI： 10.1126/sciadv.aaq0723

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DOI： 10.2337/db16-1344

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DOI： 10.1038/ncomms16017

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DOI： 10.1016/j.celrep.2017.02.039

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The metabolic function of the liver changes sequentially during early life in mammals to adapt to the marked changes in nutritional environment. Accordingly, hepatic fatty acid β-oxidation is activated after birth to produce energy from breast milk lipids. However, how it is induced during the neonatal period is poorly understood. Here we show DNA demethylation and increased mRNA expression of the fatty acid β-oxidation genes in the postnatal mouse liver. The DNA demethylation does not occur in the fetal mouse liver under the physiologic condition, suggesting that it is specific to the neonatal period. Analysis of mice deficient in the nuclear receptor peroxisome proliferator-activated receptor a (PPARα) and maternal administration of a PPARα ligand during the gestation and lactation periods reveal that the DNA demethylation is PPARα dependent. We also find that DNA methylation of the fatty acid β-oxidation genes are reduced in the adult human liver relative to the fetal liver. This study represents the first demonstration that the ligand-activated PPARα-dependent DNA demethylation regulates the hepatic fatty acid β-oxidation genes during the neonatal period, thereby highlighting the role of a lipid-sensing nuclear receptor in the gene- and lifestage- specific DNA demethylation of a particular metabolic pathway.

DOI： 10.2337/db14-0158

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DOI： 10.1016/j.celrep.2015.01.027

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DOI： 10.1038/ncomms5982

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Endothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1α is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1α expression is high in diabetic rodents and humans and that PGC-1α powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1α induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endothelial cells unresponsive to established angiogenic factors. Transgenic overexpression of PGC-1α in the endothelium mimics multiple diabetic phenotypes, including aberrant re-endothelialization after carotid injury, blunted wound healing, and reduced blood flow recovery after hindlimb ischemia. Conversely, deletion of endothelial PGC-1α rescues the blunted wound healing and recovery from hindlimb ischemia seen in type 1 and type 2 diabetes. Endothelial PGC-1α thus potently inhibits endothelial function and angiogenesis, and induction of endothelial PGC-1α contributes to multiple aspects of vascular dysfunction in diabetes.

DOI： 10.1016/j.cmet.2013.12.014

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DOI： 10.2337/db13-0757

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We previously identified a quantitative trait locus for adiposity, non-insulin-dependent diabetes 5 (Nidd5), on mouse chromosome 2. In the current study, we identified the actual genetic alteration at Nidd5 as a nonsense mutation of the Acvr1c gene encoding activin receptor-like kinase 7 (ALK7), one of the type I transforming growth factor-β receptors, which results in a COOH-terminal deletion of the kinase domain. We further showed that the ALK7 dysfunction causes increased lipolysis in adipocytes and leads to decreased fat accumulation. Conversely, ALK7 activation inhibits lipolysis by suppressing the expression of adipose lipases. ALK7 and activated Smads repress those lipases by downregulating peroxisome proliferator-activated receptor γ ( PPAR γ) and CCAAT/enhancer binding protein (C/EBP) α. Although PPARγ and C/EBPα act as adipogenic transcription factors during adipocyte differentiation, they are lipolytic in sum in differentiated adipocytes and are downregulated by ALK7 in obesity to accumulate fat. Under the obese state, ALK7 deficiency improves glucose tolerance and insulin sensitivity by preferentially increasing fat combustion in mice. These findings have uncovered a net lipolytic function of PPARγ and C/EBPα in differentiated adipocytes and point to the ALK7-signaling pathway that is activated in obesity as a potential target of medical intervention.

DOI： 10.2337/db12-0295

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DOI： 10.2337/dc12-0269

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DOI： 10.2337/db11-1834

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DOI： 10.1007/s00125-012-2578-1

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DOI： 10.2337/db11-1182

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DOI： 10.2337/db10-0864

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DOI： 10.2337/db09-1554

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DOI： 10.2337/dc09-1315

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DOI： 10.2337/dc06-1179

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OBJECTIVE - Previous studies demonstrated that obese adipose tissue is characterized by increased infiltration of macrophages, suggesting that they might represent an important source of inflammation. Using an in vitro coculture system composed of 3T3-L1 adipocytes and RAW264 macrophages, we previously demonstrated that saturated fatty acids (FAs) and tumor necrosis factor (TNF)-α derived from adipocytes and macrophages, respectively, play a major role in the coculture-induced inflammatory changes. METHODS AND RESULTS - Coculture of adipocytes and macrophages resulted in the activation of nuclear factor-κB (NF-κB), a primary regulator of inflammatory responses, in both cell types. Pharmacological inhibition of NF-κB markedly suppressed the coculture-induced production of proinflammatory cytokines and adipocyte lipolysis. Peritoneal macrophages obtained from Toll-like receptor 4 (TLR4) mutant mice exhibited marked attenuation of TNFα production in response to saturated FAs. Notably, coculture of hypertrophied adipocytes and TLR4-mutant macrophages resulted in marked inhibition of proinflammatory cytokine production and adipocyte lipolysis. We also observed that endogenous FAs, which are released from adipocytes via the β3-adrenergic stimulation, resulted in the activation of the TLR4/NF-κB pathway. CONCLUSION - These findings suggest that saturated FAs, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for TLR4, thereby inducing the inflammatory changes in both adipocytes and macrophages through NF-κB activation.

DOI： 10.1161/01.ATV.0000251608.09329.9a

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DOI： 10.2337/db05-1570

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DOI： 10.1007/s00125-006-0352-y

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Objective - Weight gain is associated with infiltration of fat by macrophages, suggesting that they are an important source of inflammation in obese adipose tissue. Here we developed an in vitro coculture system composed of adipocytes and macrophages and examined the molecular mechanism whereby these cells communicate. Methods and Results - Coculture of differentiated 3T3-L1 adipocytes and macrophage cell line RAW264 results in the marked upregulation of proinflammatory cytokines, such as tumor necrosis factor α(TNF-α), and the downregulation of the antiinflammatory cytokine adiponectin. Such inflammatory changes are induced by the coculture without direct contact, suggesting the role of soluble factors. A neutralizing antibody to TNF-α, which occurs mostly in macrophages, inhibits the inflammatory changes in 3T3-L1, suggesting that TNF-α is a major macrophage-derived mediator of inflammation in adipocytes. Conversely, free fatty acids (FFAs) may be important adipocyte-derived mediators of inflammation in macrophages, because the production of TNF-α in RAW264 is markedly increased by palmitate, a major FFA released from 3T3-L1. The inflammatory changes in the coculture are augmented by use of either, hypertrophied 3T3-L1 or adipose stromal vascular fraction obtained from obese ob/ob mice. Conclusions - We postulate that a paracrine loop involving FFAs and TNF-α between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue.

DOI： 10.1161/01.ATV.0000183883.72263.13

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DOI： 10.2337/diabetes.54.8.2365

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DOI： 10.1016/j.cmet.2005.05.005

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DOI： 10.1038/nm1214

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DOI： 10.1161/01.CIR.0000147829.78357.C5

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DOI： 10.2337/diacare.27.10.2488

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DOI： 10.2337/diabetes.53.9.2443

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DOI： 10.1073/pnas.0308744101

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DOI： 10.1038/nm971

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DOI： 10.2337/diacare.26.9.2493

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DOI： 10.2337/diabetes.51.1.243

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DOI： 10.2337/diabetes.50.10.2296

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DOI： 10.2337/diabetes.50.6.1440

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DOI： 10.1073/pnas.071389098

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DOI： 10.1073/pnas.98.2.559

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DOI： 10.2337/diabetes.50.5.1093

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DOI： 10.2337/diabetes.50.2.227

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DOI： 10.1172/JCI8341

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DOI： 10.1073/pnas.070371497

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DOI： 10.1172/JCI8353

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DOI： 10.2337/diabetes.49.3.332

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DOI： 10.2337/diabetes.48.10.2028

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DOI： 10.2337/diabetes.48.9.1822

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DOI： 10.2337/diabetes.48.9.1787

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DOI： 10.1161/01.CIR.100.7.706

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DOI： 10.2337/diabetes.48.8.1615

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Background - Coronary spasm plays an important role in the pathogenesis of ischemic heart diseases in general. However, the precise mechanism(s) responsible for coronary spasm remains to be elucidated, and we examined the molecular genetics of coronary spasm. Methods and Results - We Searched for the possible mutations in the endothelial nitric oxide synthase (eNOS) gene in patients with coronary spasm. In this study, we demonstrate the existence of 3 linked mutations in the 5'-flanking region of the eNOS gene (T^-786 → C, A^-922 → G, and T^-1468 → A). The incidence of the mutations was significantly greater in patients with coronary spasm than in the control group (P < 0.0001). Multiple logistic regression analysis with forward stepwise selection using the environmental risk factors and the eNOS gene variant revealed that the most predictive independent risk factor for coronary spasm was the mutant allele (P < 0.0001). As assessed by luciferase reporter gene assays, the T^-786 → C mutation resulted in a significant reduction in eNOS gene promoter activity (P < 0.05), whereas neither the A^{- 922} → G nor the T^-1468 → A mutation had any affect. Conclusions - Taken together, these findings strongly suggest that the T^-786 → C mutation in the eNOS gene reduces the endothelial NO synthesis and predisposes the patients with the mutation to coronary spasm.

DOI： 10.1161/01.CIR.99.22.2864

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DOI： 10.1161/01.CIR.98.20.2108

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DOI： 10.1073/pnas.95.5.2337

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DOI： 10.1016/S0140-6736(05)63940-2

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DOI： 10.1161/01.CIR.96.10.3737

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DOI： 10.1007/s001250050808

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DOI： 10.1038/nm0997-1029

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DOI： 10.1038/ng1096-130

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DOI： 10.1172/JCI118204

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DOI： 10.1161/01.CIR.92.6.1558

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DOI： 10.1172/JCI118162

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DOI： 10.1172/jci117420

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DOI： 10.1172/JCI117182

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DOI： 10.1056/NEJM199309023291002

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DOI： 10.1016/0140-6736(92)92167-E

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C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, is thus far known to be distributed mainly in the central nervous system and is considered to act as a neuropeptide, in contrast to atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which act as cardiac hormones. Recently, we and others have demonstrated that the ANP-B receptor, which is selectively activated by CNP, is localized not only in the central nervous system but in peripheral tissues, including blood vessels. This finding has made us speculate regarding the peripheral production of CNP. In the present study, cultured endothelial cells were examined for CNP production by RIA and Northern blot analysis. CNP-like immunoreactivity was detected in the conditioned media of endothelial cells. Northern blot analysis detected CNPmRNA with a size of 1.2 kb. In addition, transforming growth factor (TGF)-β, one of the key growth factors for vascular remodeling, markedly stimulated the expression of CNPmRNA and induced a tremendous increase in CNP secretion. We could also detect CNP transcript in the bovine thoracic aorta using the reverse transcription- polymerase chain reaction method. The present study demonstrates the endothelial production of CNP and suggests that a member of the natriuretic peptide family may act as a local regulator in vascular walls. Since evidence for the pathophysiological importance of the vascular renin-angiotensin system has been accumulating and the natriuretic peptide system is known to be antagonistic to the renin-angiotensin system, the possible existence of 'vascular natriuretic peptide system' may prove to be of physiological and clinical relevance.

DOI： 10.1172/JCI115933

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DOI： 10.1172/JCI115146

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DOI： 10.1161/01.RES.69.2.491

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DOI： 10.1056/NEJM199009133231114

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Using an antiserum against the ring structure of rat brain natriuretic peptide (rat BNP), we have established a specific radioimmunoassay (RIA) for rat BNP and elucidated its tissue distribution and molecular form. Rat BNP-like immunoreactivity (-LI) was detected in the highest amount in cardiac extracts (574.0 ± 138.8 pmol/g in the atrium and 4.3 ± 1.1 pmol/g in the ventricle). The secretory rate of rat BNP-LI from the perfused whole heart was.50.0 ± 1.9 fmol/min, about 60% of which was maintained even after atrial removal. We also detected rat BNP-LI throughout the spinal cord (134-175 fmol/g), although no detectable amount was present (less than 100 fmol/g) in other tissues including the brain. High performance-gel permeation chromatography and reverse phase-high performance liquid chromatography coupled with the RIA revealed that rat BNP with 45 amino acids is a major storage form as well as a secretory form of rat BNP-LI in the heart. The major component in the spinal cord was also rat BNP. These findings indicate that the tissue distribution and the processing pattern of rat BNP are different from those of atrial natriuretic peptide and porcine BNP, thereby suggesting the presence of complicated diversity of the natriuretic peptide system.

DOI： 10.1210/endo-126-4-2225

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DOI： 10.1016/0140-6736(90)90925-U

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DOI： 10.1007/s10620-024-08652-x

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Major histocompatibility complex class II (MHC-II) is the most significant genetic risk factor for systemic lupus erythematosus (SLE), but the nature of the self-antigens that trigger autoimmunity remains unclear. Unusual self-antigens, termed neoself-antigens, are presented on MHC-II in the absence of the invariant chain essential for peptide presentation. Here, we demonstrate that neoself-antigens are the primary target for autoreactive T cells clonally expanded in SLE. When neoself-antigen presentation was induced by deleting the invariant chain in adult mice, neoself-reactive T cells were clonally expanded, leading to the development of lupus-like disease. Furthermore, we found that neoself-reactive CD4+ T cells were significantly expanded in SLE patients. A high frequency of Epstein-Barr virus reactivation is a risk factor for SLE. Neoself-reactive lupus T cells were activated by Epstein-Barr-virus-reactivated cells through downregulation of the invariant chain. Together, our findings imply that neoself-antigen presentation by MHC-II plays a crucial role in the pathogenesis of SLE.

DOI： 10.1016/j.cell.2024.08.025

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EP4 prostanoid receptor (EP4R) contributes to the intestinal epithelial Cl- secretion, and inhibition of prostaglandin E (PGE) production by non-steroidal anti-inflammatory drugs (NSAIDs) plays a central role in NSAID-induced enteropathy. Although M3 muscarinic acetylcholine receptor (M3R) also contributes to the intestinal epithelial Cl- secretion, it remains unclear whether M3R is involved in NSAID-induced enteropathy due to a lack of selective agents. The present study explored how M3R is involved in the regulation of the intestinal epithelial Cl- secretion and its pathophysiological role in NSAID-induced enteropathy. Using the novel highly-selective M3 positive allosteric modulator PAM-369 that we recently developed, we evaluated the role of M3R in the intestinal epithelial secretion ex vivo by measuring the short circuit current (Isc) of intestinal epithelium with a Ussing chamber system and examined whether or not M3R protects against small intestinal injury in indomethacin-treated mice. Both the PGE1 derivative misoprostol and carbachol similarly increased the Isc in a concentration-dependent manner. The Isc increases were abolished either by receptor antagonists (an EP4R antagonist and a M3R antagonist, respectively) or by removal of extracellular Cl-. PAM-369 enhanced the carbachol-induced Isc by potentiating M3R, which could contribute to enhanced intestinal epithelial secretion. Treatment with PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. Importantly, the M3R expression was significantly up-regulated, and PAM-369 potentiation of M3R was augmented in indomethacin-treated mice compared to untreated mice. These findings show that M3R plays a role in maintaining the intestinal epithelial secretion, which could contribute to protection against indomethacin-induced small intestinal injury. M3R is a promising target for treating or preventing NSAID-induced enteropathy. KEY MESSAGES: PAM-369, the M3 positive allosteric modulator, was used to potentiate M3R. PAM-369 enhanced carbachol-induced Isc in mouse ileum. PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. M3R is a promising target for treating or preventing NSAID-induced enteropathy.

DOI： 10.1007/s00109-024-02474-0

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Language：English   Publisher：Clinical and Translational Allergy  

Background: Hay fever (HF) presents with various symptoms, including allergic conjunctivitis and rhinitis, and requires cross-organ treatment. This study assessed the impact of the coronavirus disease 2019 (COVID-19) pandemic on HF treatment trends. Methods: This retrospective cohort study utilized data from the JMDC database collected between January 2018 and May 2021. Patients with HF were identified based on the relevant International Classification of Diseases 10th Revision diagnosis codes and the prescription of HF-related medications. The treatment approaches were compared during the cedar and cypress pollen allergy season (January to May in Japan) before and during the COVID-19 pandemic (2018 and 2019, and 2020 and 2021, respectively). Results: This study included 2,598,178 patients with HF. The numbers of prescribed HF-related claims in 2018, 2019, 2020, and 2021 were 3,332,854, 3,534,198, 2,774,380, and 2,786,681 times, respectively. Oral second-generation antihistamine prescriptions decreased by >10% from 2019 to 2020, with a <10% change in the subsequent year. Anti-allergic eye drop prescriptions also decreased by >10% from 2019 to 2020 but increased by >10% from 2020 to 2021. Compared with 2018, 2019, and 2020, the number of claims in the rhinitis symptoms dominant group was significantly decreased in 2021 (p < 0.001, all). In contrast, the number of claims in the eye symptoms dominant group and the rhinitis and eye symptoms dominant group increased in 2021 compared with that in 2018, 2019, and 2020 (p < 0.001, all). Conclusion: Changes in HF treatment and related outcomes could be attributed to lifestyle modifications resulting from the COVID-19 pandemic. Measures, such as limiting outdoor activities and adopting mask-wearing practices may have influenced HF symptoms, preventive behaviors, and the overall approach to treating HF.

DOI： 10.1002/clt2.12394

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CONTEXT: Adrenal incidentalomas, including nonfunctioning adrenal incidentalomas (NFAI), are associated with a high prevalence of diabetes mellitus (DM). While NFAI is diagnosed by exclusion when no hormone excess exists, subtle cortisol secretion may exist and contribute to DM development. However, it alone cannot explain the increased risk, and whether other steroid metabolites are involved remains unclear. PURPOSE: To investigate steroid metabolites associated with DM in patients with NFAI using plasma steroid profiles. METHODS: Using liquid chromatography-tandem mass spectrometry, 22 plasma steroid metabolites were measured in 68 patients with NFAI (31 men and 37 women). Data were adjusted for age before normalization. RESULTS: Discriminant analysis showed that plasma steroid profiles discriminated between patients with and without DM in men (n = 10 and = 21, respectively) but not women: 11β-hydroxytestosterone, an adrenal-derived 11-oxygenated androgen, contributed most to this discrimination and was higher in patients with DM than in those without DM (false discovery rate = .002). 11β-hydroxytestosterone was correlated positively with fasting plasma glucose (r = .507) and hemoglobin A1c (HbA1c) (r = .553) but negatively with homeostatic model assessment of β-cell function (HOMA2-B) (r = -.410). These correlations remained significant after adjusting for confounders, including serum cortisol after the 1-mg dexamethasone suppression test. Bayesian kernel machine regression analysis verified the association of 11β-hydroxytestosterone with HbA1c and HOMA2-B in men. MAIN CONCLUSION: Plasma steroid profiles differed between those with and without DM in men with NFAI. 11β-hydroxytestosterone was associated with hyperglycemia and indicators related to pancreatic β-cell dysfunction, independently of cortisol.

DOI： 10.1210/jendso/bvae140

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Pancreatic acinar cell carcinoma (PACC) is a very rare subtype of pancreatic cancer. Due to small number of patients, no standard chemotherapy protocol has been established. We experienced an extremely rare case of PACC with liver metastasis that showed a pathological complete response after modified FOLFIRINOX (mFFX) therapy. A 42-year-old man who underwent distal pancreatectomy for an 80 mm tumor at the pancreatic tail 3 years ago was referred to our hospital in September 2017 for the treatment of a recurrent liver tumor. Percutaneous biopsy revealed an acinar-neuroendocrine carcinoma, similar to the surgical specimen. He received eight cycles of irinotecan plus cisplatin chemotherapy. However, the tumor increased in size, and treatment was switched to mFFX therapy. The tumor in the liver shrank remarkably after nine cycles of mFFX therapy. Conversion surgery was selected, and the patient underwent hepatic left and caudate lobectomy 8 months after administration of mFFX. The resected specimen showed no viable tumor cells, indicating a pathological complete response. The histological diagnosis was reconsidered, and PACC was finally diagnosed via an additional immunohistological review. The patient has remained well with no recurrence for 6 years after surgery. This study is the first to report a case of pathological complete response with mFFX therapy for the recurrence of PACC.

DOI： 10.1007/s12328-024-01983-2

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Language：English  

DOI： 10.5946/ce.2023.244

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

Recently, two molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) have been proposed: the “Classical” and “Basal-like” subtypes, with the former showing better clinical outcomes than the latter. However, the “molecular” classification has not been applied in real-world clinical practice. This study aimed to establish patient-derived organoids (PDOs) for PDAC and evaluate their application in subtype classification and clinical outcome prediction.

Methods

We utilized tumor samples acquired through endoscopic ultrasound-guided fine-needle biopsy and established a PDO library for subsequent use in morphological assessments, RNA-seq analyses, and in vitro drug response assays. We also conducted a prospective clinical study to evaluate whether analysis using PDOs can predict treatment response and prognosis.

Results

PDOs of PDAC were established at a high efficiency (&gt; 70%) with at least 100,000 live cells. Morphologically, PDOs were classified as gland-like structures (GL type) and densely proliferating inside (DP type) less than 2 weeks after tissue sampling. RNA-seq analysis revealed that the “morphological” subtype (GL vs. DP) corresponded to the “molecular” subtype (“Classical” vs. “Basal-like”). The “morphological” classification predicted the clinical treatment response and prognosis; the median overall survival of patients with GL type was significantly longer than that with DP type (P &lt; 0.005). The GL type showed a better response to gemcitabine than the DP type in vitro, whereas the drug response of the DP type was improved by the combination of ERK inhibitor and chloroquine.

Conclusions

PDAC PDOs help in subtype determination and clinical outcome prediction, thereby facilitating the bench-to-bedside precision medicine for PDAC.

DOI： 10.1007/s00535-024-02103-0

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Other Link： https://link.springer.com/article/10.1007/s00535-024-02103-0/fulltext.html

Language：English   Publisher：シュプリンガー・ジャパン(株)  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Acute liver failure (ALF) is a life-threatening disorder that progresses from self-limiting acute liver injury (ALI). Microcirculatory disturbance characterized by sinusoidal hypercoagulation and subsequent massive hypoxic hepatocyte damage have been proposed to be the mechanism by which ALI deteriorates to ALF; however, the precise molecular pathway of the sinusoidal hypercoagulation remains unknown. Here, we analyzed ALI patients and mice models to uncover the pathogenesis of ALI with microcirculatory disturbance. METHODS: We conducted a single-center retrospective study for ALI and blood samples and liver tissues were analyzed to evaluate the microcirculatory disturbance in ALI patients (n = 120). Single-cell RNA sequencing analysis (scRNA-seq) was applied to the liver from the concanavalin A (Con A)‑induced mouse model of ALI. Interferon-gamma (IFNγ) and tumor necrosis factor-alpha knockout mice, and primary human liver sinusoidal endothelial cells (LSECs) were used to assess the mechanism of microcirculatory disturbance. RESULTS: The serum IFNγ concentrations were significantly higher in ALI patients with microcirculatory disturbance than in patients without microcirculatory disturbance, and the IFNγ was upregulated in the Con A mouse model which presented microcirculatory disturbance. Hepatic IFNγ expression was increased as early as 1 hour after Con A treatment prior to sinusoidal hypercoagulation and hypoxic liver damage. scRNA-seq revealed that IFNγ was upregulated in innate lymphoid cells and stimulated hepatic vascular endothelial cells at the early stage of liver injury. In IFNγ knockout mice treated with Con A, the sinusoidal hypercoagulation and liver damage were remarkably attenuated, concomitant with the complete inhibition of CD40 and tissue factor (TF) upregulation in vascular endothelial cells. By ligand-receptor analysis, CD40-CD40 ligand interaction was identified in vascular endothelial cells. In human LSECs, IFNγ upregulated CD40 expression and TF was further induced by increased CD40-CD40 ligand interaction. Consistent with these findings, hepatic CD40 expression was significantly elevated in human ALI patients with microcirculatory disturbance. CONCLUSION: We identified the critical role of the IFNγ-CD40 axis as the molecular mechanism of microcirculatory disturbance in ALI. This finding may provide novel insights into the pathogenesis of ALI and potentially contribute to the emergence of new therapeutic strategies for ALI patients.

DOI： 10.1186/s12950-024-00387-w

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Language：Japanese   Publisher：(公財)臨床薬理研究振興財団  

アナモレリンは癌悪液質に適応した初の薬剤であるが、膵癌患者でのエビデンスは少ない。著者らは進行期膵癌患者を対象にアナモレリンの有効性と安全性を評価する前向き観察研究を行った。23名の患者を登録し、アナモレリン内服を1ヵ月以上継続した16名を有効性評価の対象とし、主要評価指標は除脂肪体重(LBM)とした。アナモレリン内服開始1ヵ月後にLBMは平均0.9kg増加し、2ヵ月後には平均1.1kg増加した。内服開始3ヵ月後までLBMの増加または維持が継続していた患者を"治療応答群"とし、内服開始3ヵ月後までにLBMが一度でも低下した患者を"治療不応答群"とすると、治療応答群は9名、不応答群は7名であり、治療奏効率は56.3%であった。治療効果を予測する因子について検討した結果、有意な予測指標として「アナモレリン開始時のBMI」が抽出された。アナモレリン開始後1ヵ月以上追跡しえた22名を安全性評価の対象とし、有害反応の解析を行った。結果、開始後1ヵ月以内に高血糖が8名(36.4%)に発生しており、grade 1が2名、grade 2が5名、grade 3が1名であった。高血糖発現の予測因子について検討した結果、有意な予測指標として「インスリン分泌能の低下」が抽出された。

Language：English   Publisher：Oxford University Press  

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1542203625

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The human adrenal cortex comprises three functionally and structurally distinct layers that produce layer-specific steroid hormones. With aging, the human adrenal cortex undergoes functional and structural alteration or "adrenal aging", leading to the unbalanced production of steroid hormones. Given the marked species differences in adrenal biology, the underlying mechanisms of human adrenal aging have not been sufficiently studied. This study was designed to elucidate the mechanisms linking the functional and structural alterations of the human adrenal cortex. METHODS: We conducted single-cell RNA sequencing and spatial transcriptomics analysis of the aged human adrenal cortex. RESULTS: The data of this study suggest that the layer-specific alterations of multiple signaling pathways underlie the abnormal layered structure and layer-specific changes in steroidogenic cells. We also highlighted that macrophages mediate age-related adrenocortical cell inflammation and senescence. CONCLUSIONS: This study is the first detailed analysis of the aged human adrenal cortex at single-cell resolution and helps to elucidate the mechanism of human adrenal aging, thereby leading to a better understanding of the pathophysiology of age-related disorders associated with adrenal aging.

DOI： 10.1016/j.molmet.2024.101954

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

Language：English   Publisher：(一社)日本内分泌学会  

Language：English   Publisher：シュプリンガー・ジャパン(株)  

食道平滑筋収縮の変化および関連する炎症性反応について検討することによりアカラシアの病態を明らかにし、アカラシアの進展における食道細菌叢の意義を評価した。経口的内視鏡的筋層切開術を施行したII型アカラシア症例から得た食道粘膜および下部食道括約筋(LES)標本を解析した。患者由来の食道調整培養液をマウス食道に投与し、食道内環境がアカラシアと関連するか否かについて検討した。安静時および刺激時における対照群のLESでは、20-kDaミオシン軽鎖(LC20)の約30%がリン酸化されていた。アカラシア症例では状況に関わらずLC20のリン酸化は10%未満であった。アカラシアにおける低リン酸化は、ミオシンリン酸化阻害蛋白質CPI-17の発現低下と関連していた。IL-17A、IL-17F、IL-22、IL-23Aを含む関連サイトカインは、アカラシアでは発現が増加していた。食道細菌叢のα-Diversity指数、およびActinomycesおよびDialisterを含む数種類の細菌の割合がアカラシアで増加していた。ActinomycesレベルはIL-23Aレベルと正の相関が認められ、DialisterレベルはIL-17A、IL-17F、IL-22レベルと正の相関が認められた。マウスにおいて、食道IL-17F値は調整培地の経口投与後に増加した。

Language：English  

Background: The human adrenal cortex consists of three functionally and structurally distinct layers; zona glomerulosa, zona fasciculata (zF), and zona reticularis (zR), and produces adrenal steroid hormones in a layer-specific manner; aldosterone, cortisol, and adrenal androgens, respectively. Cortisol-producing adenomas (CPAs) occur mostly as a result of somatic mutations associated with the protein kinase A pathway. However, how CPAs develop after adrenocortical cells acquire genetic mutations, remains poorly understood. Methods: We conducted integrated approaches combining the detailed histopathologic studies with genetic, RNA-sequencing, and spatially resolved transcriptome (SRT) analyses for the adrenal cortices adjacent to human adrenocortical tumours. Findings: Histopathological analysis revealed an adrenocortical nodular structure that exhibits the two-layered zF- and zR-like structure. The nodular structures harbour GNAS somatic mutations, known as a driver mutation of CPAs, and confer cell proliferative and autonomous steroidogenic capacities, which we termed steroids-producing nodules (SPNs). RNA-sequencing coupled with SRT analysis suggests that the expansion of the zF-like structure contributes to the formation of CPAs, whereas the zR-like structure is characterised by a macrophage-mediated immune response. Interpretation: We postulate that CPAs arise from a precursor lesion, SPNs, where two distinct cell populations might contribute differently to adrenocortical tumorigenesis. Our data also provide clues to the molecular mechanisms underlying the layered structures of human adrenocortical tissues. Funding: KAKENHI, The Uehara Memorial Foundation, Daiwa Securities Health Foundation, Kaibara Morikazu Medical Science Promotion Foundation, Secom Science and Technology Foundation, ONO Medical Research Foundation, and Japan Foundation for Applied Enzymology.

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Language：English   Publisher：(一社)日本内分泌学会  

Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

膵神経内分泌腫瘍(PanNET)は膵臓の稀な腫瘍である。特異的ホルモンの高発現症状の有無により、機能性と非機能性腫瘍に分類される。副腎皮質刺激ホルモン(ACTH)-産生PanNETは稀な機能性腫瘍で、その臨床的特徴と治療成績は十分に明らかにされていない。疾患の経過中に異所性ACTH症候群(EAS)を認めたPanNETの2例を報告した。症例1は手術時には非機能性PanNETであった。再発肝転移の治療中、肝転移巣からのACTHおよび副甲状腺ホルモン関連ペプチド(PTHrP)産生によると考えられるEASおよび腫瘍関連高カルシウム血症が認められた。症例2はガストリノーマで、症例1と同様、再発肝転移の治療中にEASが認められた。原発巣と転移巣で腫瘍表現型が異なっているにも関わらず、PanNET症例が複数のホルモンを有し、疾患の経過中に続発性のホルモン分泌をきたすことは稀ではない。以上より、機能性PanNET症例では、特に迅速な診断と治療が必要な内分泌緊急事態であるEASが認められる場合、抗ホルモン治療による症状の制御が、抗腫瘍治療と共に重要であることが明らかとなった。

DOI： 10.1007/s12185-024-03733-z

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BACKGROUND: In gastric solid-type poorly differentiated adenocarcinoma (PDA), the role of microsatellite instability and immune escape mechanism remains unclear. The current study aimed to elucidate the clinical significance of mismatch repair (MMR) status, genome profile, C-X-C motif chemokine receptor 2 (CXCR2) expression, and myeloid-derived suppressor cell (MDSC) infiltration in solid-type PDA. METHODS: In total, 102 primary solid-type PDA cases were retrieved, and classified into 46 deficient-MMR (dMMR) and 56 proficient-MMR (pMMR) cases based on immunohistochemistry (IHC) and polymerase chain reaction-based molecular testing results. The mRNA expression profiles (NanoString nCounter Assay) of stage-matched dMMR (n = 6) and pMMR (n = 6) cases were examined. The CXCR2 expression and MDSC infiltration (CD11b- and CD33-positive cells) were investigated via IHC in all solid-type PDA cases. RESULTS: mRNA analysis revealed several differentially expressed genes and differences in biological behavior between the dMMR (n = 46) and pMMR (n = 56) groups. In the multivariate analysis, the dMMR status was significantly associated with a longer disease-free survival (hazard ratio = 5.152, p = 0.002) and overall survival (OS) (hazard ratio = 5.050, p = 0.005). CXCR2-high expression was significantly correlated with a shorter OS in the dMMR group (p = 0.018). A high infiltration of CD11b- and CD33-positive cells was significantly correlated with a shorter OS in the pMMR group (p = 0.022, 0.016, respectively). CONCLUSIONS: dMMR status can be a useful prognostic predictor, and CXCR2 and MDSCs can be novel therapeutic targets in patients with solid-type PDA.

DOI： 10.1007/s10120-024-01474-w

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BACKGROUND: Achalasia is an esophageal motility disorder with an unknown etiology. We aimed to determine the pathogenesis of achalasia by studying alterations in esophageal smooth muscle contraction and the associated inflammatory response, and evaluate the role of esophageal microbiota in achalasia development. METHODS: We analyzed esophageal mucosa and lower esophageal sphincter (LES) samples, obtained from patients with type II achalasia who underwent peroral endoscopic myotomy. Esophageal conditioned media obtained from patients were transferred into the mouse esophagus to determine whether the esophageal intraluminal environment is associated with achalasia. RESULTS: Approximately 30% of 20-kDa myosin light chains (LC20) was phosphorylated in LES from the control group under resting and stimulated conditions, whereas less than 10% of LC20 phosphorylation was detected in achalasia under all conditions. The hypophosphorylation of LC20 in achalasia was associated with the downregulation of the myosin phosphatase-inhibitor protein CPI-17. Th17-related cytokines, including IL-17A, IL-17F, IL-22, and IL-23A, were significantly upregulated in achalasia. α-Diversity index of esophageal microbiota and the proportion of several microbes, including Actinomyces and Dialister, increased in achalasia. Actinomyces levels positively correlated with IL-23A levels, whereas Dialister levels were positively associated with IL-17A, IL-17F, and IL-22 levels. Esophageal IL-17F levels increased in mice after oral administration of the conditioned media. CONCLUSIONS: In LES of patients with achalasia, hypophosphorylation of LC20, a possible cause of impaired contractility, was associated with CPI-17 downregulation and an increased Th17-related immune response. The esophageal intraluminal environment, represented by the esophageal microbiota, could be associated with the development and exacerbation of achalasia.

DOI： 10.1007/s00535-024-02088-w

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Aldosterone secretion in primary aldosteronism (PA) is often regulated by adrenocorticotropic hormone (ACTH) in addition to its autonomous secretion. However, the clinical characteristics and risk of cardiovascular and cerebrovascular (CCV) events in PA patients with aldosterone responsiveness to ACTH stimulation remain unclear. This study aimed to investigate the prevalence of CCV events in PA patients with high aldosterone responsiveness to ACTH stimulation. A retrospective cross-sectional study was conducted as part of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Disease project. PA patients with adrenal venous sampling (AVS) between January 2006 and March 2019 were enrolled. The ACTH-stimulated plasma aldosterone concentration (PAC) of the inferior vena cava during AVS was used to evaluate aldosterone responsiveness to ACTH. We analyzed the relationship between responsiveness and previous CCV events. Logistic regression analysis demonstrated that the ΔPAC (the difference between the PAC measurements before and after ACTH stimulation) significantly increased the odds of previous CCV events in PA patients after adjusting for classical CCV event risk factors, baseline PAC and duration of hypertension (relative PAC: odds ratio [OR], 2.896; 95% confidence interval [CI], 0.989-8.482; ΔPAC: OR, 2.344; 95% CI, 1.149-4.780; ACTH-stimulated PAC: OR, 2.098; 95% CI, 0.694-6.339). This study clearly demonstrated that aldosterone responsiveness to ACTH is closely related to previous CCV events. The responsiveness of the PAC to ACTH could be useful in predicting CCV event risk.Registration Number in UMIN-CTR is UMIN000032525.

DOI： 10.1507/endocrj.EJ23-0659

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AIM: This study aimed to investigate the effects of diabetes care on periodontal inflammation. MATERIALS AND METHODS: This prospective cohort study included 51 Japanese patients with type 2 diabetes who underwent intensive diabetes care including educational hospitalization and regular outpatient treatment for 6 months. Dental prophylaxis without subgingival scaling was provided three times during the observational period. Associations between changes in periodontal parameters and glycaemic control levels were evaluated using multiple regression analysis. RESULTS: Overall, 33 participants (mean age: 58.7 ± 12.9) were followed up for 6 months. At baseline examination, 82% were diagnosed with Stage III or IV periodontitis. Haemoglobin A1c (HbA1c) level changed from 9.6 ± 1.8% at baseline to 7.4 ± 1.3% at 6 months. The ratio of probing pocket depth (PPD) ≥4 mm, bleeding on probing (BOP), full-mouth plaque control record (PCR), periodontal epithelial surface area (PESA) and periodontal inflamed surface area (PISA) also significantly improved. The reduction in PPD and PESA was significantly associated with changes in both HbA1c and fasting plasma glucose (FPG) levels, and the reduction in PISA was significantly associated with an improvement in FPG after adjusting for smoking, change in body mass index and full-mouth PCR. CONCLUSIONS: This is the first study to report a significant improvement in PPD and BOP after intensive diabetes care and dental prophylaxis without subgingival scaling. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000040218.

DOI： 10.1111/jcpe.13958

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japan Endocrine Society  

<p>We investigated the impact of the Coronavirus disease 2019 (COVID-19) pandemic on the management of endocrine and metabolic disorders in Japan. We conducted a cross-sectional nationwide questionnaire survey targeting board-certified endocrinologists under the auspices of the Japan Endocrine Society. The questionnaire consisted of multiple-choice questions and open-ended responses. Out of approximately 2,700 specialists, 528 (19.5%) opted to participate, suggesting a high level of interest in COVID-19 management among endocrinologists. The study found that almost half of participants had encountered cases of endocrine and metabolic disorders following COVID-19 infection or vaccination. Conditions related to thyroid diseases, glucose metabolism disorders/diabetes, and hypothalamic-pituitary disorders were particularly prevalent. Diabetes and obesity were identified as having high rates of severe cases or fatalities due to COVID-19. The study also highlighted challenges in routine diagnosis and treatment, emphasizing the potential benefits of combining remote consultations with in-person visits to optimize the frequency of examinations and check-ups during infectious disease outbreak which disrupts access to healthcare providers. The insights obtained from this survey are expected to contribute to ensuring appropriate healthcare provision for patients with endocrine and metabolic disorders by using flexible consultation formats, particularly even in the conditions where medical access may be limited due to future outbreaks of emerging or re-emerging infectious diseases.</p>

DOI： 10.1507/endocrj.EJ23-0671

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Language：Japanese   Publisher：Japan Pancreas Society  

<p>The incidence of pancreatic neuroendocrine neoplasms (PanNENs) has been increasing worldwide due to improved disease recognition and advances in diagnostic modalities such as computed tomography and endoscopic ultrasound. The number of older adult patients with PanNENs is expected to increase in Japan's rapidly aging society. Therefore, it is important to establish treatment strategies for older adult patients. The only curative treatment for PanNENs is surgical resection, which can be safely performed in older adult patients when selected appropriately. Depending on age, comorbidities, and tumor size, nonsurgical management, such as observation and systemic therapy, should also be considered. Systemic therapies, including somatostatin analogs, targeted therapies, cytotoxic chemotherapy, and peptide receptor radionuclide therapy, are available for patients with unresectable or metastatic pancreatic neuroendocrine tumors (PanNETs). When administering these therapies to older adult patients with PanNETs, it is important to balance the treatment, and the adverse events which can be linked to it, with the patient's comorbidities and cognitive function. Further studies on older adult patients with PanNETs are warranted to establish an optimal treatment strategy.</p>

DOI： 10.2958/suizo.39.33

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Publisher：東京医学社  

DOI： 10.24479/kd.0000001188

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BACKGROUND: Streptozocin has been used to treat neuroendocrine tumors in Europe and the USA; however, its actual status in Japan has not been fully clarified owing to the rarity of this disease and the relatively recent approval of streptozocin in Japan. METHODS: We retrospectively analyzed 53 patients with gastroenteropancreatic neuroendocrine tumors who were treated with streptozocin-based chemotherapy at two Japanese hospitals between January 2004 and June 2023. RESULTS: The overall response and disease control rates were 27.7 and 74.5%, respectively, and the median progression-free survival and overall survival were 7.1 and 20.3 months, respectively. Performance status ≥1 showed a significant negative correlation with progression-free survival, and performance status ≥1 and liver tumor burden ≥25% showed a significant negative correlation with overall survival. No significant differences were observed in the treatment response between pancreatic and gastrointestinal neuroendocrine tumors. No treatment-related serious adverse events were observed; however, 87.7% of patients expressed a decrease in the estimated glomerular filtration rate, which negatively correlated with the duration of streptozocin treatment (r = 0.43, P = 0.0020). In the streptozocin re-administration group (n = 5), no differences were found in efficacy between the initial and second streptozocin treatments. CONCLUSIONS: Although streptozocin is a safe, streptozocin-induced renal dysfunction is a dilemma in streptozocin responders. Streptozocin may benefit patients with gastroenteropancreatic neuroendocrine tumors, especially those with a good performance status; however, in some cases, planned streptozocin withdrawal or switching to other drugs should be considered.

DOI： 10.1093/jjco/hyae026

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Language：Japanese   Publisher：(一社)日本腹部救急医学会  

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Language：English   Publisher：(一社)日本内科学会  

重度肝障害を認めた成人発症スティル病(AOSD)患者4例の臨床的特性および組織病理学的特性を評価した。症例1は30歳女性で、症例2は39歳女性で、症例3は26歳女性で、症例4は54歳女性で、Yamaguchi基準の大項目はそれぞれ発熱/皮疹、発熱/皮疹/白血球増多、発熱/皮疹/白血球増多、発熱/皮疹/関節痛であった。全例で経口プレドニゾロン(PSL)投与歴があった。1例はAOSD診断時に重度の肝障害が存在しており、3例はAOSD再発時に肝障害が同時に出現した。肝生検のHE染色では全例で炎症細胞の浸潤を認め、浸潤炎症細胞は主にCD8陽性細胞であった。追加治療として、全例で高用量メチルプレドニゾロン静注療法、経口PSL投与、免疫抑制剤(アザチオプリン、シクロスポリン)投与を行った。

Language：Japanese   Publisher：(一社)日本膵臓学会  

膵神経内分泌腫瘍(pancreatic neuroendocrine neoplasm:PanNEN)は希少疾患であるが,近年増加傾向である.超高齢社会に伴い今後はPanNEN患者の高齢化も予想される.PanNENの唯一の根治治療は外科切除であり,適応を選んで外科切除を施行した場合,高齢者においても安全な外科切除が可能である.一方で,年齢や併存疾患,腫瘍径などから,経過観察の選択肢も考慮する.高分化型の膵神経内分泌腫瘍(pancreatic neuroendocrine tumor:PanNET)に対する全身療法として,ソマトスタチンアナログ,分子標的薬,細胞障害性抗がん剤,放射性核種標識ペプチド治療,などが挙げられる.各種治療法の特徴・有害事象を理解した上で,高齢者PanNETに適用することになるが,外科手術と同様に,併存疾患や認知機能などの事前評価が重要となる.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J02025&link_issn=&doc_id=20240401470005&doc_link_id=10.2958%2Fsuizo.39.33&url=https%3A%2F%2Fdoi.org%2F10.2958%2Fsuizo.39.33&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Endoscopic submucosal dissection (ESD) is the standard treatment for early gastric neoplasms (EGN). Controlling intraoperative bleeding is crucial for ensuring safe and reliable procedures. ESD using the spray coagulation mode (SCM-ESD) has been developed to control bleeding more effectively than ESD using the conventional forced coagulation mode (FCM-ESD). This study aims to compare the hemostatic efficacies of SCM-ESD and FCM-ESD. METHODS: This multicenter, prospective, parallel, randomized, open-label superiority trial will be conducted in five Japanese institutions. Patients with a preoperative diagnosis of intramucosal EGC will be randomized to undergo either SCM-ESD or FCM-ESD. The primary outcome measure is the completion of ESD with an electrosurgical knife alone, without the use of hemostatic forceps. Secondary outcomes include the number and duration of hemostasis using hemostatic forceps, procedure time, curability, and safety. A total of 130 patients will be enrolled in this study. DISCUSSION: This trial will provide evidence on the hemostatic efficacy of SCM-ESD compared with FCM-ESD in patients with intramucosal EGN, potentially improving the safety and reliability of ESD procedures. TRIAL REGISTRATION: The trial has been registered at the University Hospital Medical Information Network Clinical Trials Registration (UMIN-CTR) as UMIN000040518. The reception number is R000054009.

DOI： 10.1186/s13063-023-07852-6

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Pancreatic neuroendocrine tumors (PanNETs) are rare malignant tumors that occur in the pancreas. They are divided into functioning and non-functioning tumors based on the presence or absence of their specific hormonal hyper-expression symptoms. Adrenocorticotropic hormone (ACTH)-producing PanNETs are rare, functional tumors, and their clinical characteristics and outcomes have not been well reported.Here, we report the cases of two patients with PanNETs who presented with ectopic ACTH syndrome (EAS) during the course of their disease. Case 1 involved a non-functioning PanNET at the time of surgery. During treatment for recurrent liver metastases, the patient presented with EAS and tumor-associated hypercalcemia, probably due to ACTH and parathyroid hormone-related peptide (PTHrP) production from the liver tumor. Case 2 was a gastrinoma, and similar to Case 1, this patient presented with EAS during the treatment of recurrent liver metastases.It is not uncommon for patients with PanNETs to have multiple hormones and develop secondary hormone secretion during their disease course, although tumor phenotypes differ between primary and metastatic sites. In patients with functioning PanNETs, symptom control with anti-hormonal therapy is essential, in addition to anti-tumor therapy, especially for EAS, which is an endocrine emergency disease that requires prompt diagnosis and treatment.

DOI： 10.1007/s12328-023-01908-5

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DOI： 10.1055/a-2219-8130

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：医学図書出版(株)  

近年,腫瘍領域においてliquid biopsyが注目を集めているが,神経内分泌腫瘍(NEN)においても同様である。Liquid biopsyは従来の組織学的検査とは異なり,末梢血などの体液から非侵襲的にサンプルを抽出するため,腫瘍間・腫瘍内不均一性が問題となることはなく,容易にリアルタイムの病状を把握することができる。中でもmessenger RNAを用いたNETestはエビデンスが蓄積され,NETestから派生したpeptide receptor radionuclide therapy(PRRT)prediction quotientはPRRTの層別化マーカーとしての有用性が報告されている。このようにliquid biopsyは診断・モニタリング・治療効果の予測・予後と,NEN診療の全般にわたって有用でNEN診療体系の再構築が期待されるが,実臨床への導入にはさらなるエビデンスの蓄積に加えて,ハード・ソフト面の整備が必要であり,課題が多い。(著者抄録)

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japan Endocrine Society  

<p>To identify those who might benefit from weight reduction within a large population of obese individuals, Japan Society for the Study of Obesity (JASSO) advocated the concept of “obesity disease.” Here we summarize the definition, criteria, and core concepts for the management of obesity disease based on JASSO’s latest guideline. JASSO defines obesity as excessive fat storage in adipose tissue associated with a BMI of ≥25 kg/m². The threshold BMI of obesity is low as compared to Western countries given that Japanese individuals tend to develop obesity-related health disorders at lower BMI. Obesity with a BMI of ≥35 kg/m² is referred to as “high-degree obesity” as treatment strategies vary based on the degree of obesity. Obesity is diagnosed as “obesity disease” if accompanied by any of the 11 specific obesity-related health disorders that weight reduction can prevent or alleviate, or if it meets the criteria for visceral fat obesity with a visceral fat area of ≥100 cm². The initial weight reduction goals for high-degree obesity disease range from 5% to 10% of their current body weight, depending on the associated health disorders. That for those with obesity disease who do not qualify as high-degree is 3% or more. If these initial goals are not achieved, intensifying dietary therapy or introducing drug therapy (or both) may be necessary. While surgical treatment is primarily indicated for high-degree obesity disease, it might be appropriate for cases of obesity disease with a BMI <35 kg/m², depending on the accompanying health disorders. Enhancing the quality of life for individuals with obesity or obesity disease necessitates a broader societal approach, emphasizing the resolution of related stigma.</p>

DOI： 10.1507/endocrj.ej23-0593

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Publisher：Hypertension Research  

This study aims to evaluate the prevalence of unilateral hyperaldosteronism (UHA) and its clinical characteristics in patients with primary aldosteronism (PA), diagnosed using plasma aldosterone concentration (PAC) measured by chemiluminescent enzyme immunoassay (CLEIA). We retrospectively analyzed data of 199 PA patients from the Japan Primary Aldosteronism Study II (JPAS II) dataset, including patients who underwent adrenal venous sampling (AVS) and the captopril challenge test (CCT) and/or saline infusion test (SIT), with PAC measured by CLEIA. We focused on two categories: confirmed PA, where patients exhibit clear biochemical evidence of the disorder, and borderline PA, where patients present with marginal biochemical indicators, as outlined in the Japan Endocrine Society’s clinical practice guideline for the diagnosis and management of PA. In confirmed PA cases, over the half of patients was UHA, while approximately 15 to 20% of borderline cases were found to be UHA. The prevalence of hypokalemia was identified as predictor of UHA among borderline cases. Among borderline cases with no hypokalemia and adrenal nodules on CT imaging, only 6 to 8% of patients were found to have UHA. Notably, some patients exhibited UHA despite negative results on one test but confirmed result on the other, particularly those with hypokalemia or adrenal nodules on CT imaging. In conclusion, the findings validate the importance of AVS in confirmed PA cases and the need for careful assessment in borderline cases. When feasible, conducting both CCT and SIT, and interpreting their results alongside other clinical indicators, could provide a more comprehensive assessment. (Figure presented.)

DOI： 10.1038/s41440-024-01786-5

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DOI： 10.1093/gastro/goad071

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Language：Japanese   Publisher：THE JAPAN DIABETES SOCIETY  

<p>We herein report a 67-year-old man with type 1 diabetes mellitus receiving combination immune checkpoint inhibitor (ICI) therapy. He was being treated with nivolumab and ipilimumab for lung metastasis from renal cancer. After one cycle, hyperthyroidism was detected, which evolved into manifest hypothyroidism over the next few weeks, requiring levothyroxine substitution therapy. Eight weeks after initiating ICI therapy, he presented at the emergency department with thirst, weight loss, and generalized weakness. Hyperglycemia (1,234 mg/dL), anion gap metabolic acidosis (pH 7.112), and ketonemia (<i>β</i>-hydroxybutyrate 1,590 <i>μ</i>mol/L) were observed. The glycated hemoglobin level was 9.1 %. Islet-related autoantibodies were all negative. The glucagon tolerance test revealed attenuated secretion of insulin. Human leukocyte antigen was heterozygous for the DRB1*0405-DQB1*0401 haplotype. We compared these findings with those of four cases of type 1 diabetes related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy at our institution. All patients showed the DRB1*0405 or DRB1*0901 HLA haplotype, which has been shown to be associated with type 1 diabetes in Japan.</p>

DOI： 10.11213/tonyobyo.66.850

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The Cre-loxP strategy for tissue-specific gene inactivation has become a widely employed tool in several research studies. Conversely, inadequate breeding and genotyping without considering the potential for non-specific Cre-recombinase expression may lead to misinterpretations of results. Nestin-Cre transgenic mice, widely used for the selective deletion of genes in neurons, have been observed to have an incidence of Cre-line germline recombination. In this study, we attempted to generate neuron-specific Glucagon-like peptide 1 receptor (Glp1r) knock-out mice by crossing mice harboring the Nestin-Cre transgene with mice harboring the Glp1r gene modified with loxP insertion, in order to elucidate the role of Glp1r signaling in the nervous system. Surprisingly, during this breeding process, we discovered that the null allele emerged in the offspring irrespective of the presence or absence of the Nestin-Cre transgene, with a high probability of occurrence (93.6%). To elucidate the cause of this null allele, we conducted breeding experiments between mice carrying the heterozygous Glp1r null allele but lacking the Nestin-Cre transgene. We confirmed that the null allele was inherited by the offspring independently of the Nestin-Cre transgene. Furthermore, we assessed the gene expression, protein expression, and phenotype of mice carrying the homozygous Glp1r null allele generated from the aforementioned breeding, thereby confirming that the null allele indeed caused a global knock-out of Glp1r. These findings suggest that the null allele in the NestinCre-Glp1r floxed breeding arose due to germline recombination. Moreover, we demonstrated the possibility that germline recombination may occur not only during the spermatogenesis at testis but also during epididymal sperm maturation. The striking frequency of germline recombination in the Nestin-Cre driver underscores the necessity for caution when implementing precise breeding strategies and employing suitable genotyping methods.

DOI： 10.1371/journal.pone.0296006

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1055/a-1982-3875

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Quantitative information on blood metabolites can be used in developing advanced medical strategies such as early detection and prevention of disease. Monitoring bioactive lipids such as steroids, bile acids, and PUFA metabolites could be a valuable indicator of health status. However, a method for simultaneously measuring these bioactive lipids has not yet been developed. Here, we report a LC/MS/MS method that can simultaneously measure 144 bioactive lipids, including steroids, bile acids, and PUFA metabolites, from human plasma, and a sample preparation method for these targets. Protein removal by methanol precipitation and purification of bioactive lipids by solid-phase extraction improved the recovery of the targeted compounds in human plasma samples, demonstrating the importance of sample preparation methods for a wide range of bioactive lipid analyses. Using the developed method, we studied the plasma from healthy human volunteers and confirmed the presence of bioactive lipid molecules associated with sex differences and circadian rhythms. The developed method of bioactive lipid analysis can be applied to health monitoring and disease biomarker discovery in precision medicine.

DOI： 10.1016/j.jlr.2023.100492

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DOI： 10.1055/a-2173-8010

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DOI： 10.1055/a-1982-3875

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OBJECTIVES: Reflux hypersensitivity (RH) is a form of refractory gastroesophageal reflux disease in which duodenogastroesophageal reflux (DGER) plays a role. This study aimed to determine the usefulness of an endoscopy system equipped with image-enhanced technology for evaluating DGER and RH. METHODS: The image enhancement mode for detecting bilirubin and calculated values were defined as the Bil mode and Bil value, respectively. First, the visibility of the Bil mode was validated for a bilirubin solution and bile concentrations ranging from 0.01% to 100% (0.002-20 mg/dL). Second, visibility scores of the Bil mode, when applied to the porcine esophagus sprayed with a bilirubin solution, were compared to those of the blue laser imaging (BLI) and white light imaging (WLI) modes. Third, a clinical study was conducted to determine the correlations between esophageal Bil values and the number of nonacid reflux events (NNRE) during multichannel intraluminal impedance-pH monitoring as well as the utility of esophageal Bil values for the differential diagnosis of RH. RESULTS: Bilirubin solution and bile concentrations higher than 1% were visualized in red using the Bil mode. The visibility score was significantly higher with the Bil mode than with the BLI and WLI modes for 1% to 6% bilirubin solutions (P < 0.05). The esophageal Bil value and NNRE were significantly positively correlated (P = 0.031). The area under the receiver operating characteristic curve for the differential diagnosis of RH was 0.817. CONCLUSION: The Bil mode can detect bilirubin with high accuracy and could be used to evaluate DGER in clinical practice.

DOI： 10.1111/den.14749

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Pancreatic islet inflammation plays a crucial role in the etiology of type 2 diabetes (T2D). Macrophages residing in pancreatic islets have emerged as key players in islet inflammation. Macrophages express a plethora of innate immune receptors that bind to environmental and metabolic cues and integrate these signals to trigger an inflammatory response that contributes to the development of islet inflammation. One such receptor, Dectin-2, has been identified within pancreatic islets; however, its role in glucose metabolism remains largely unknown. Here we demonstrated that mice lacking Dectin-2 exhibit local inflammation within islets, along with impaired insulin secretion and β-cell dysfunction. Our findings indicate that these effects are mediated by pro-inflammatory cytokines, such as IL-1α and IL-6, which are secreted by macrophages that have acquired an inflammatory phenotype because of the loss of Dectin-2. This study provides novel insights into the mechanisms underlying the role of Dectin-2 in the development of islet inflammation.

DOI： 10.1210/endocr/bqad181

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

67歳男性.糖尿病歴なし.腎癌肺転移に対しニボルマブとイピリムマブ併用療法開始し14日後に免疫関連副作用(immune-related Adverse Events:irAE)による破壊性甲状腺炎を発症し,65日後に糖尿病性ケトアシドーシスを発症し,救急搬送後の随時血糖1234mg/dL,HbA1c 9.1%,グルカゴン負荷後の血中CPR測定感度未満,膵島関連自己抗体は陰性であり,またヒト白血球抗原(HLA)検査でDRB1*04:05-DQB1*04:01のヘテロ接合を認めた.本症例を含めたirAEでの1型糖尿病発症自験例4例を比較したところ,全症例において日本人における1型糖尿病発症との関連が示されているDRB1*0405もしくはDRB1*0901のHLAハプロタイプを示し,抗PD-1抗体と抗CTLA-4抗体併用療法では抗PD-1抗体単独治療と比較し発症までの期間は明らかに短縮していた.(著者抄録)

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

67歳男性.糖尿病歴なし.腎癌肺転移に対しニボルマブとイピリムマブ併用療法開始し14日後に免疫関連副作用(immune-related Adverse Events:irAE)による破壊性甲状腺炎を発症し,65日後に糖尿病性ケトアシドーシスを発症し,救急搬送後の随時血糖1234mg/dL,HbA1c 9.1%,グルカゴン負荷後の血中CPR測定感度未満,膵島関連自己抗体は陰性であり,またヒト白血球抗原(HLA)検査でDRB1*04:05-DQB1*04:01のヘテロ接合を認めた.本症例を含めたirAEでの1型糖尿病発症自験例4例を比較したところ,全症例において日本人における1型糖尿病発症との関連が示されているDRB1*0405もしくはDRB1*0901のHLAハプロタイプを示し,抗PD-1抗体と抗CTLA-4抗体併用療法では抗PD-1抗体単独治療と比較し発症までの期間は明らかに短縮していた.(著者抄録)

Publisher：日本メディカルセンター  

DOI： 10.19020/cg.0000002867

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DOI： 10.1182/blood-2023-179252

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Acute kidney injury (AKI) is a common complication of acute liver failure (ALF); but its pathogenesis is unknown. ALF was divided into 2 subgroups; ALF with hepatic coma, which corresponds to ALF in the US and Europe, and ALF without hepatic coma. AKI has been shown to worsen the prognosis of ALF patients with hepatic coma; however, its prognostic significance in ALF without hepatic coma remains unknown. A single-center retrospective study of 174 patients with ALF was performed. AKI was defined according to KDIGO criteria. AKI developed in 29 (66.0%) of 44 ALF patients with hepatic coma and 27 (38.5%) of 130 ALF patients without hepatic coma. Systemic inflammatory response syndrome (SIRS) was found to be significantly associated with AKI incidence in ALF patients (P < .001). Tumor necrosis factor-alpha (TNF-α) was found to be significantly associated with the presence and severity of AKI (P = .0039 and P = .0140, respectively). On multivariate analysis, TNF-α was an independent risk factor linked with AKI (P = .0103). Even in the absence of hepatic coma, the transplant-free survival rate of ALF was significantly associated with the presence and severity of AKI. Even when hepatic coma is absent, AKI complicated in ALF is strongly associated with TNF-α and worsens the transplant-free survival rate. Before the onset of hepatic coma, plasma exchange, or extracorporeal blood purification to remove inflammatory cytokines should be considered in ALF patients.

DOI： 10.1097/MD.0000000000035931

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

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Obesity is recognized as an independent risk factor for abdominal aortic aneurysm (AAA). While mutations in the melanocortin-4 receptor (MC4R) gene is the most common cause of obesity caused by mutations in a single gene, the link between MC4R function and vascular disease has still remained unclear. Here, by using melanocortin-4 receptor (MC4R) deficient mice, we confirmed MC4R deficiency promotes AAA and atherosclerosis. We demonstrated the contribution of two novel factors towards vascular vulnerability in this model: leptin signaling in vascular smooth muscle cells (VSMCs) and loss of MC4R signaling in macrophages. Leptin was shown to promote vascular vulnerability via PI3K-dependent upregulation of Spp1 expression in VSMC. Additionally, Ang II-induced AAA incidence was significantly reduced when MC4R gene expression was myeloid cell-specifically rescued in MC4R deficient (MC4R^TB/TB) mice. Ex vivo analysis showed a suppression in NF-κB activity in bone marrow-derived macrophages from LysM(+);MC4R^TB/TB mice compared to LysM(−);MC4R^TB/TB mice, which exaggerates with endogenous MC4R ligand treatment; α-MSH. These results suggest that MC4R signaling in macrophages attenuates AAA by inhibiting NF-κB activity and subsequent vascular inflammation.

DOI： 10.1038/s41598-023-46831-4

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Other Link： https://www.nature.com/articles/s41598-023-46831-4

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BACKGROUND: Diabetes is associated with an increased risk of deleterious changes in muscle mass and function or sarcopenia, leading to physical inactivity and worsening glycaemic control. Given the negative energy balance during sodium-glucose cotransporter-2 (SGLT2) inhibition, whether SGLT2 inhibitors affect skeletal muscle mass and function is a matter of concern. However, how SGLT2 inhibition affects the skeletal muscle function in patients with diabetes remains insufficiently explored. We aimed to explore the effects of canagliflozin (CANA), an SGLT2 inhibitor, on skeletal muscles in genetically diabetic db/db mice focusing on the differential responses of oxidative and glycolytic muscles. METHODS: Db/db mice were treated with CANA for 4 weeks. We measured running distance and handgrip strength to assess skeletal muscle function during CANA treatment. At the end of the experiment, we performed a targeted metabolome analysis of the skeletal muscles. RESULTS: CANA treatment improved the reduced endurance capacity, as revealed by running distance in db/db mice (414.9 ± 52.8 vs. 88.7 ± 22.7 m, P < 0.05). Targeted metabolome analysis revealed that 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5'-monophosphate (AICARP), a naturally occurring AMP-activated protein kinase (AMPK) activator, increased in the oxidative soleus muscle (P < 0.05), but not in the glycolytic extensor digitorum longus muscle (P = 0.4376), with increased levels of AMPK phosphorylation (P < 0.01). CONCLUSIONS: This study highlights the potential role of the AICARP/AMPK pathway in oxidative rather than glycolytic skeletal muscles during SGLT2 inhibition, providing novel insights into the mechanism by which SGLT2 inhibitors improve endurance capacity in patients with type 2 diabetes.

DOI： 10.1002/jcsm.13350

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞慢性膵炎は,病期により臨床症状だけでなく画像所見も異なってくる.さらに,早期慢性膵炎という概念が提唱されて以降,慢性膵炎の病期と画像所見の関係はより複雑になっている.慢性膵炎診療において,画像所見の評価は必要不可欠であり,「慢性膵炎臨床診断基準2019」や「慢性膵炎診療ガイドライン2021」を参考に,どの時期にどの検査をすべきかを認識しておく必要がある.本稿では,早期慢性膵炎を含む慢性膵炎の各病期における画像診断とそのポイントについて概説する.

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：English   Publisher：Chemical Communications  

A new compound, a derivative of 3,4,5-trimethoxy-N-phenyl benzamide bearing an 8′′-methylimidazopyridine moiety, is found to demonstrate neuroprotective effects by preventing cell death caused by oxidative stress. The compound possesses high solubility and metabolic stability, and inhibits MPTP-induced effects in vivo, indicating high potential as a therapeutic drug for Parkinson's disease.

DOI： 10.1039/d3cc03069e

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: NAFLD caused by abnormalities in hepatic lipid metabolism is associated with an increased risk of developing HCC. The molecular mechanisms underlying the progression of NAFLD-related HCC are not fully understood. We investigated the molecular mechanism and role of KDM6B downregulation in NAFLD-related HCC after the KDM6B gene was identified using microarray analysis as commonly downregulated in mouse NAFLD-related HCC and human nonhepatitis B and nonhepatitis C viral-HCC. METHODS: The 5-hydroxymethylcytosine levels of KDM6B in HCC cells were determined using glycosylated hydroxymethyl-sensitive PCR. Microarray and chromatin immunoprecipitation analyses using KDM6B-knockout (KO) cells were used to identify KDM6B target genes. Lipotoxicity was assessed using a palmitate-treated cell proliferation assay. Immunohistochemistry was used to evaluate KDM6B expression in human HCC tissues. RESULTS: KDM6B expression levels in HCC cells correlated with the 5-hydroxymethylcytosine levels in the KDM6B gene body region. Gene set enrichment analysis revealed that the lipid metabolism pathway was suppressed in KDM6B-KO cells. KDM6B-KO cells acquired resistance to lipotoxicity (p < 0.01) and downregulated the expression of G0S2, an adipose triglyceride lipase/patatin like phospholipase domain containing 2 (ATGL/PNPLA2) inhibitor, through increased histone H3 lysine-27 trimethylation levels. G0S2 knockdown in KDM6B-expressed HCC cells conferred lipotoxicity resistance, whereas ATGL/PNPLA2 inhibition in the KDM6B-KO cells reduced these effects. Immunohistochemistry revealed that KDM6B expression was decreased in human NAFLD-related HCC tissues (p < 0.001), which was significantly associated with decreased G0S2 expression (p = 0.032). CONCLUSIONS: KDM6B-disrupted HCC acquires resistance to lipotoxicity via ATGL/PNPLA2 activation caused by epigenetic downregulation of G0S2 expression. Reduced KDM6B and G0S2 expression levels are common in NAFLD-related HCC. Targeting the KDM6B-G0S2-ATGL/PNPLA2 pathway may be a useful therapeutic strategy for NAFLD-related HCC.

DOI： 10.1097/HC9.0000000000000277

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：医学図書出版(株)  

術後膵液瘻(postoperative pancreatic fistula:POPF)は発生頻度の高い膵切除術後合併症であり,適切なタイミングでドレナージを行う必要がある。従来は経皮的ドレナージが主流であったが,近年では内視鏡治療,とくにEUSガイド下経消化管ドレナージ(EUS-guided transluminal drainage:EUS-TD)の報告が増えている。EUS-TDで用いるステントとして,主に経鼻胆道ドレナージチューブ,ダブルピッグテイル型プラスチックステント,lumen-apposing metal stent,などがあり,POPFの部位,大きさ,性状に応じて,適切なステント選択を心がける必要がある。事前に外科医と情報共有のうえで,内視鏡治療にあたることが重要である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本糖尿病・妊娠学会  

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Language：Japanese   Publisher：(一社)日本糖尿病・妊娠学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor-deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.

DOI： 10.1172/jci.insight.161282

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Language：Japanese   Publisher：医学図書出版(株)  

がんのリスクファクターにはさまざまなものがあり,代表的なものの一つに飲酒がある。アルコール摂取量と強い関連性を認めるがん種として口腔および喉頭・咽頭癌,食道扁平上皮癌,肝臓癌,結腸直腸癌,乳腺がんがあり,喉頭・咽頭癌,食道扁平上皮癌については禁酒による2次予防効果も報告されている。アルコールは本邦の膵癌ガイドラインにおいてリスク因子としてあげられているが,胆道癌については十分なエビデンスがない。アルコールの発癌の機序として主にアルコール代謝過程において生成されるアセトアルデヒドへの曝露が考えられているが,肝線維化,葉酸欠乏・阻害,エストロゲン濃度上昇なども報告されている。アセトアルデヒドについては日本人特有のアルコール代謝酵素遺伝子多型も大きく影響している。本稿では飲酒による発がんのメカニズム,日本人におけるアルコール代謝の特徴について述べ,各がん種について概説する。(著者抄録)

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Language：Japanese   Publisher：(NPO)日本消化吸収学会  

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Language：Japanese   Publisher：日本筋学会・筋ジストロフィー医療研究会  

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Publisher：Journal of Geophysical Research: Space Physics  

A specialized ground-based system has been developed for simultaneous observations of pulsating aurora (PsA) and related magnetospheric phenomena with the Arase satellite. The instrument suite is composed of (a) six 100 Hz sampling high-speed all-sky imagers (ASIs), (b) two 10 Hz sampling monochromatic ASIs observing 427.8 and 844.6 nm auroral emissions, (c) a 20 Hz sampling fluxgate magnetometer. The 100 Hz ASIs were deployed in four stations in Scandinavia and two stations in Alaska, which have been used for capturing the main pulsations and quasi 3 Hz internal modulations of PsA at the same time. The 10 Hz sampling monochromatic ASIs have been operative in Tromsø, Norway with the 20 Hz sampling magnetometer. Combination of these multiple instruments with the European Incoherent SCATter (EISCAT) radar enables us to detect the low-altitude ionization due to energetic electron precipitation during PsA and further to reveal the ionospheric electrodynamics behind PsA. Since the launch of the Arase satellite, the data from these instruments have been examined in comparison with the wave and particle data from the satellite in the magnetosphere. In the future, the system can be utilized not only for studies of PsA but also for other classes of aurora in close collaboration with the planned EISCAT_3D project.

DOI： 10.1029/2023JA031527

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Publisher：Materials Science and Engineering: A  

Solid-solution hardening caused by dissolved hydrogen (H) atoms in face-centered cubic metals is a favorable phenomenon that counteracts the H-induced degradation of mechanical performance in structural alloys, i.e., hydrogen embrittlement. In the present study, the changes of yield and flow stresses by solute H with the concentrations of 2000∼7600 at ppm were systematically investigated in a Fe–24Cr–19Ni-based austenitic stainless steel under the temperature range of 173∼423 K and two different strain rates: 5 × 10−5 and 5 × 10−3/s. Stress relaxation tests were subsidiarily employed in order to elaborate the underlying mechanisms predominating the H-related hardening at low and ambient temperatures. Four essential ingredients of the H-induced hardening were identified: (i) H atoms in the matrix lattice as dispersed obstacles; (ii) pinning of stationary dislocations by H atmosphere; (iii) dynamic pinning of dislocations resting at obstacles; (iv) drag force to moving dislocations by migratable H clouds. The hardening around 173 K was attributed to (i) and (ii), where the primary importance of interstitial-substitutional interaction between Cr and H was explicitly invoked. Meanwhile, the magnitude of hardening was maximized at around 298 K under the slow strain rate condition owing to the increasing contributions from (iii) and (iv).

DOI： 10.1016/j.msea.2023.145281

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Language：English  

BACKGROUND: We have determined that the impaired accommodation of the lower esophageal sphincter (LES) underlies the pathogenesis of esophagogastric junction outflow obstruction (EGJOO). We have also found that acotiamide may treat EGJOO by improving impaired LES accommodation. The effects of acotiamide in patients with EGJOO need to be further confirmed in a prospective study. METHODS: This trial is a multicenter, randomized, double-blind, placebo-controlled study to compare the efficacy and safety of acotiamide (300 mg/day or 600 mg/day) with those of a placebo in the treatment of patients with EGJOO. The primary endpoint will be the proportion of patients who report an improvement in symptom of food sticking in the chest after 4 weeks of treatment period 1. The secondary endpoints will be the proportion of patients with normalized integrated relaxation pressure (IRP), the value of change from baseline in the distal contractile integral, basal LES pressure, EGJOO-quality of life score, Gastrointestinal Symptom Rating Scale, and the correlation between IRP and each symptom score. During the 2-year trial period, 42 patients from five institutions will be enrolled. DISCUSSION: This trial will provide evidence to clarify the efficacy and safety of acotiamide as a treatment for patients with EGJOO. Acotiamide might help improve the quality of life of patients with EGJOO and is expected to prevent the progression of EGJOO to achalasia. TRIAL REGISTRATION: This study was approved by the Institutional Review Board (IRB) of Kyushu University Hospital as well as the local IRBs of the participating sites for clinical trials and registered in the Japan Registry of Clinical Trials (jRCT: 2071210072). The registration date is on October 11, 2021.

DOI： 10.1186/s13063-023-07468-w

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Language：Japanese   Publisher：(一社)日本膵臓学会  

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Language：Japanese   Publisher：(一社)日本膵臓学会  

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Publisher：FEBS Letters  

Human MutT homolog 1 (MTH1), also known as Nudix-type motif 1 (NUDT1), hydrolyzes 8-oxo-dGTP and 2-oxo-dATP with broad substrate recognition and has attracted attention in anticancer therapeutics. Previous studies on MTH1 have proposed that the exchange of the protonation state between Asp119 and Asp120 is essential for the broad substrate recognition of MTH1. To understand the relationship between protonation states and substrate binding, we determined the crystal structures of MTH1 at pH 7.7–9.7. With increasing pH, MTH1 gradually loses its substrate-binding ability, indicating that Asp119 is deprotonated at pH 8.0–9.1 in 8-oxo-dGTP recognition and Asp120 is deprotonated at pH 8.6–9.7 in 2-oxo-dATP recognition. These results confirm that MTH1 recognizes 8-oxo-dGTP and 2-oxo-dATP by exchanging the protonation state between Asp119 and Asp120 with higher pKa.

DOI： 10.1002/1873-3468.14611

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Language：Japanese   Publisher：(一社)日本膵臓学会  

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Language：Japanese   Publisher：(一社)日本膵臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

<p>Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder. Severe liver injury has rarely been reported, although liver enzyme elevation is a common complication of AOSD. We herein report four cases of relapsed AOSD with severe liver disorder by tapering or terminating corticosteroids. Liver specimens revealed robust infiltration of inflammatory cells throughout the lobule, especially cluster of differentiation (CD) 8-positive cells. Relapsed AOSD was refractory to corticosteroid reintroduction and required immunosuppressants. Severe liver injury with AOSD is pathologically characterized by extensive lobular infiltration of CD8-positive cells, and we should consider additive immunosuppressive agents on corticosteroids for treatment. </p>

DOI： 10.2169/internalmedicine.2043-23

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BACKGROUND: Pancreatic neuroendocrine neoplasms (PanNENs) are a heterogeneous group of tumors. Although the prognosis of resected PanNENs is generally considered to be good, a relatively high recurrence rate has been reported. Given the scarcity of large-scale reports about PanNEN recurrence due to their rarity, we aimed to identify the predictors for recurrence in patients with resected PanNENs to improve prognosis. METHODS: We established a multicenter database of 573 patients with PanNENs, who underwent resection between January 1987 and July 2020 at 22 Japanese centers, mainly in the Kyushu region. We evaluated the clinical characteristics of 371 patients with localized non-functioning pancreatic neuroendocrine tumors (G1/G2). We also constructed a machine learning-based prediction model to analyze the important features to determine recurrence. RESULTS: Fifty-two patients experienced recurrence (14.0%) during the follow-up period, with the median time of recurrence being 33.7 months. The random survival forest (RSF) model showed better predictive performance than the Cox proportional hazards regression model in terms of the Harrell's C-index (0.841 vs. 0.820). The Ki-67 index, residual tumor, WHO grade, tumor size, and lymph node metastasis were the top five predictors in the RSF model; tumor size above 20 mm was the watershed with increased recurrence probability, whereas the 5-year disease-free survival rate decreased linearly as the Ki-67 index increased. CONCLUSIONS: Our study revealed the characteristics of resected PanNENs in real-world clinical practice. Machine learning techniques can be powerful analytical tools that provide new insights into the relationship between the Ki-67 index or tumor size and recurrence.

DOI： 10.1007/s00535-023-01987-8

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Language：English   Publisher：Psychiatry and Clinical Neurosciences Reports  

There is insufficient research on the usefulness of psychological interventions, such as psychological first aid (PFA), during outbreaks. We searched for and critically appraised systematic reviews that examined the effectiveness of PFA during infectious disease outbreaks, such as the novel coronavirus disease (COVID-19). Systematic reviews that examined the efficacy of PFA in the severe acute respiratory syndrome, Middle East respiratory syndrome coronavirus, Ebola virus disease, and COVID-19 outbreaks were searched through PubMed on February 19, 2021. The three included systematic reviews were critically appraised and assessed using AMSTAR-2. One review's overall confidence in its findings was evaluated as “high,” which suggested that PFA training had a favorable effect on healthcare personnel. Furthermore, the review also demonstrated that PFA was commonly used during outbreaks and could be delivered through multiple methods, such as a phone or video call. Although it was anticipated that PFA would improve subjective well-being, reports showed no evidence of reduced depression or insomnia. Future studies should examine additional numbers of PFA recipients and conduct quasi-experimental studies to better understand the effectiveness of PFA. Evidence on its effectiveness in infectious disease outbreaks is still lacking, along with research and evaluation methods. Quasi-experimental studies, such as comparisons with other psychological interventions, are required to better understand the effectiveness of PFA.

DOI： 10.1002/pcn5.107

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

切除した膵神経内分泌腫瘍(PanNEN)は再発率が高いので、その予測因子を検索した。22医療機関で1987年1月～2020年7月に切除したPanNEN573例のデータベースを作成した。局在性の非機能性膵神経内分泌腫瘍(G1/G2)の371名の患者の臨床的特徴を分析した。再発を決定付ける特徴を分析するため、機械学習予測モデルを構築した。経過観察中に患者52名に再発がみられ、再発までの中央値は33.7ヵ月であった。ランダムサバイバルフォレスト(RSF)モデルはCox比例ハザード回帰モデルよりもHarrell C指数が優れていた。Ki-67指数、残存腫瘍、WHOグレード、腫瘍サイズ、リンパ節転移がRSFモデルの上位5予測因子で、腫瘍サイズ20mm以上が再発の可能性の上昇する分岐点で、Ki-67指数の上昇とともに5年無増悪生存率が直線的に低下した。

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Language：Japanese   Publisher：医学図書出版(株)  

慢性膵炎の臨床像は,病期や合併症の有無により患者ごとに大きく異なる。長期間の経過のなかで,膵石や膵管・胆管狭窄,仮性嚢胞,膵性胸腹水などさまざまな合併症を有することがあり,これらの病態には内視鏡治療が第一選択になる。慢性膵炎診療ガイドライン2021を念頭に,ERCPによる経乳頭的治療とEUSによる経消化管的治療,必要に応じて外科的治療を組み合わせて,慢性膵炎合併症の治療にあたる必要がある。本稿では慢性膵炎の合併症に対する内視鏡治療を中心に概説する。(著者抄録)

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Language：Japanese   Publisher：一般社団法人 日本内分泌学会  

DOI： 10.1507/endocrine.99.s.update_14

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

症例は68歳男性で、左眼瞼下垂、視力低下を主訴に、前医の頭部MRIにて下垂体部の腫瘍を指摘され、手術目的に当院紹介となった。下垂体腫瘍に対し外科的腫瘍摘出術を施行し、病理組織学的にトルコ鞍内脊索腫と診断された。術前後の内分泌学的所見を評価すると、術前に認めた下垂体前葉ホルモン基礎値の広範な低下は、術後にはPRLを除いて改善し、術後はホルモン補充療法を行わず経過観察する方針とした。また、眼瞼下垂と視力低下は術後改善し、術後7ヵ月の時点で再発は認めなかった。

Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：日本消化器病学会-九州支部  

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Language：English   Publisher：(一社)日本内分泌学会  

原発性アルドステロン症(PA)の診断において、血漿アルドステロン濃度(PAC)の標準的評価法を放射免疫測定法(RIA)から新規化学発光酵素免疫測定法(CLEIA)に変更したことの影響について検討した。日本の41施設のレジストリであるJapan Rare/Intractable Adrenal Diseases Study(JRAS)に登録されたPA患者2289例を対象とする後向き観察的コホート研究を行った。RIAで評価したPACを、変換式を用いてCLEIA評価PAC(推定PAC)に変換した。推定PACをカプトプリル負荷試験(CCT)および生理食塩水注入試験(SIT)のカットオフ値に適用すると、PA診断数がCCTでは36%減少し、SITでは52%減少した。これらの不適合症例のうち、CCTの87%、SITの87%が副腎静脈サンプリングで両側性であった。不適合症例のうちCCTの6%とSITの5%で外科的治療可能アルドステロン産生腺腫が観察され、大半で低カリウム血症またはCT画像上での副腎結節を認めた。

Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

レジスチンの血清中濃度および同遺伝子一塩基多型(SNP)-420とSNP-358の遺伝子型の組み合わせと潜在的サルコペニア肥満との関連について検討した。対象は愛媛県東温市在住の567名(女性365名、平均60歳)とした。内臓脂肪面積≧100cm2かつ握力低値(四分位最下位)を指標とする潜在的サルコペニア肥満は、血清レジスチン四分位最上位およびSNP-420G/SNP-358Aハプロタイプ(G-A)のホモ接合型と関連を示した。全血のRNA配列解析において、G-Aホモ型保有者はC-Gホモ型保有者に比べ、腫瘍壊死因子(TNF)が関与する経路の複数の遺伝子発現が亢進しており、RT-PCRでもTNFの発現上昇が確認された。以上の結果から、レジスチンとサルコペニア肥満の関連にTNFαが介在する可能性が示唆された。

Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The clinical practice guideline for primary aldosteronism (PA) places a high value on confirmatory tests to sparing patients with false-positive results in case detection from undergoing adrenal venous sampling (AVS). However, it is unclear whether multiple types of confirmatory tests are more useful than a single type. To evaluate whether the machine-learned combination of two confirmatory tests is more useful in predicting subtypes of PA than each test alone. DESIGN: A retrospective cross-sectional study in referral centers. PATIENTS: This study included 615 patients with PA randomly assigned to the training and test datasets. The participants underwent saline infusion test (SIT) and captopril challenge test (CCT) and were subtyped by AVS (unilateral, n = 99; bilateral, n = 516). MEASUREMENTS: The area under the curve (AUC) and clinical usefulness using decision curve analysis for the subtype prediction in the test dataset. RESULTS: The AUCs for the combination of SIT and CCT, SIT alone, and CCT alone were 0.850, 0.813, and 0.786, respectively, with no significant differences between them. The AUC for the baseline clinical characteristics alone was 0.872, whereas the AUCs for these combined with SIT, combined with CCT, and combined with both SIT and CCT were 0.868, 0.854, and 0.855, respectively, with no significant improvement in AUC. The additional clinical usefulness of the second confirmatory test was unremarkable on decision curve analysis. CONCLUSIONS: Our data suggest that patients with positive case detection undergo one confirmatory test to determine the indication for AVS. This article is protected by copyright. All rights reserved.

DOI： 10.1111/cen.14854

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Language：Others   Publisher：Cold Spring Harbor Laboratory  

Abstract

Quantitative information on blood metabolites has the potential to be utilized in medical strategies such as early disease detection and prevention. Monitoring of bioactive lipids, such as steroids, bile acids, and polyunsaturated fatty acid (PUFA) metabolites, could be a valuable indicator for health status. However, a method for simultaneous measurement of these bioactive lipids has not been reported at present. Here, we report a liquid chromatography tandem mass spectrometry (LC/MS/MS) method that can simultaneously measure more than 140 bioactive lipids, including steroids, bile acids, and PUFA metabolites, from human plasma, and a sample preparation method for these targets. Protein removal in methanol precipitation and purification operations of bioactive lipids by solid-phase extraction improved the recovery of targeted compounds in human plasma samples, demonstrating the importance of sample preparation methods in a wide range of bioactive lipid analyses. Using the developed method, we measured plasma from healthy human volunteers and confirmed the presence of bioactive lipid molecules associated with sex differences and circadian rhythms. The practical bioactive lipid analysis method developed is expected to be applied to health monitoring and disease biomarker discovery for precision medicine.

DOI： 10.1101/2023.04.13.536679

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

SGLT2阻害薬は尿糖排泄を促進する血糖降下薬として開発されたが,糖尿病を合併しない心不全や腎臓病においても有効性が報告されており,臓器保護効果があることが示唆されている。骨格筋は代謝特性の異なる遅筋線維と速筋線維から構成され,前者は酸化的リン酸化,後者は解糖系によるエネルギー産生を行い,それぞれ持久的運動と瞬発的運動で使用される。筆者らは,非糖尿病および肥満糖尿病マウスを用いて骨格筋に対するカナグリフロジン(CANA)の作用を検討した。非糖尿病マウスでは,摂餌制限下でのCANA投与は速筋機能(握力)を低下させた。一方,肥満糖尿病マウスでは,CANA投与は遅筋機能(走行距離)を改善させた。本稿では上記2つのモデルの結果を踏まえ,代謝特性の異なる2種類の骨格筋に対するSGLT2阻害薬の作用について,メタボローム解析の結果とともに紹介する。(著者抄録)

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a useful tool for the treatment of hematologic malignancies. However, transplantation-related complications are the main cause of non-relapse mortality. Previous reports suggest that endothelial damage is related to early complications after HSCT. Non-invasive reactive hyperemia peripheral arterial tonometry (RH-PAT) was performed to evaluate endothelial function as a predictive marker for these complications. METHODS: The reactive hyperemia index (RHI) obtained from RH-PAT was evaluated before the conditioning regimen. The relationship between the RHI and the appearance of engraftment syndrome, thrombotic microangiopathy, and acute graft-versus-host disease (aGVHD) was assessed. Receiver operating characteristic curve analysis showed that an RHI value of 1.58 was the optimal cut-off for predicting transplantation-related complications. RESULTS: In total, 49 patients (22 acute myelogenous leukemia, 7 acute lymphocytic leukemia, 6 myelodysplastic syndrome, 6 adult T-cell leukemia, 6 non-Hodgkin lymphoma, and 2 others) were enrolled; 34 had a normal RHI (≥ 1.59), and 15 had an abnormally low RHI (≤ 1.58). Thrombotic microangiopathy (20.2% vs 0.0%, P = 0.025) and aGVHD (80.0% vs 41.2%, P = 0.015) were significantly more frequent in patients with a low RHI. CONCLUSION: Endothelial dysfunction assessed by RH-PAT before HSCT was able to predict transplantation-related complications.

DOI： 10.1007/s12185-022-03498-3

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Acute liver failure (ALF) is a disorder defined by coagulopathy and encephalopathy with a poor prognosis. No effective therapies have been established except for liver transplantation. We previously reported a subgroup of patients with acute liver injury who developed microcirculatory disturbance. We also established and reported transcatheter arterial steroid injection therapy (TASIT) as a new treatment of ALF. Here, we analyze the effectiveness of TASIT in a larger cohort and evaluate the impact on ALF patients with or without microcirculatory disturbance. We conducted a single-center retrospective study to evaluate the effectiveness of TASIT in patients with ALF admitted at Kyushu University Hospital between January 2005 and March 2018. TASIT is performed by injecting methylprednisolone via the proper hepatic artery for 3 days. One hundred ninety-4 patients with ALF were enrolled and analyzed in this study. Of the 87 patients given TASIT, 71 (81.6%) recovered without any complications and 16 (18.4%) died or underwent liver transplantation. Of the 107 patients not administered TASIT, 77 (72.0%) recovered and 30 (28.0%) progressed to irreversible liver failure. In the high-lactate dehydrogenase subgroup, 52 (86.7%) of the 60 patients with TASIT recovered, and the survival rate was significantly higher than that in patients who did not receive TASIT. Multivariate regression analysis revealed that the TASIT procedure was one of the significant prognostic factors in the high-lactate dehydrogenase subgroup and was significantly associated with prothrombin activity percentage improvement. TASIT is an effective treatment for patients with ALF, especially in those with microcirculatory disturbance.

DOI： 10.1097/MD.0000000000033090

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AIM/INTRODUCTION: Resistin, which induces insulin resistance, is mainly expressed in monocytes/macrophages in humans. We reported previously that serum resistin was highest in the G-A haplotype defined by resistin single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and - 358 (rs3219175). As sarcopenic obesity is associated with insulin resistance, we aimed to examine whether serum resistin and its haplotypes were associated with sarcopenic obesity at a latent stage. MATERIALS AND METHODS: We cross-sectionally analyzed 567 community-dwelling Japanese participants attending annual medical check-ups in which the sarcopenic obesity index was evaluated. The age- and gender-matched normal glucose tolerance subjects with G-A homozygotes and those with C-G homozygotes were examined via RNA-sequencing and pathway analysis (each n = 3), and RT-PCR (each n = 8). RESULTS: In multivariate logistic regression analyses, the fourth quartile (Q4) of serum resistin and G-A homozygotes were both associated with the latent sarcopenic obesity index defined by a visceral fat area of ≥ 100 cm2 and grip strength Q1 after adjustment for age and gender, with or without other confounding factors. RNA sequencing and pathway analysis showed that tumor necrosis factor (TNF) was involved in the top five pathways in the whole blood cells of G-A homozygotes compared with C-G homozygotes. RT-PCR revealed that TNF mRNA was higher in G-A homozygotes than in C-G homozygotes. CONCLUSIONS: The G-A haplotype was associated with the latent sarcopenic obesity index defined by grip strength in the Japanese cohort, could be mediated by TNF-α.

DOI： 10.1111/jdi.13998

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publisher：(一社)日本血液学会  

移植前処置前の同種造血幹細胞移植レシピエントにおける内皮機能を「反応性充血末梢動脈トノメトリー(RH-PAT)」でモニターし、同種造血幹細胞移植後早期の移植関連合併症発症との関係を検討した。RH-PATから得られた反応性充血指数(RHI)を、移植前処置前に評価した。RHIと生着症候群、血栓性微小血管症、急性移植片対宿主病(aGVHD)の発症との関係を解析した。合計49例(急性骨髄性白血病22例、急性リンパ性白血病7例、骨髄異形成症候群6例、成人T細胞白血病6例、非ホジキンリンパ腫6例、その他2例)を対象とした。その結果、34例(年齢24～66歳)が正常RHI(≧1.59)、15例(年齢23～67歳)が異常に低いRHI(≦1.58)であった。血栓性微小血管症とaGVHDは、RHIが低い患者で有意に頻度が高かった。以上より、造血幹細胞移植前にRH-PATで評価した内皮機能障害は移植関連合併症を予測することが示唆された。

Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：THE JAPAN DIABETES SOCIETY  

<p>We report the case of a 95-year-old woman who had been diagnosed with diabetes mellitus with HbA1c 9.7 % and a fasting blood glucose level of 199 mg/dL at 94 years of age. Despite the administration of oral hypoglycemic therapy for 5 months, her blood glucose was poorly controlled. On admission, we found that her HbA1c was 11.0 %, her casual blood glucose was 394 mg/dL and her glutamic acid decarboxylase antibody titer was 1740 U/mL (ELISA); she was then diagnosed with SPIDDM. While the development of SPIDDM is commonly reported in patients in their 40s to 50s, recent studies showed that around 10 % of elderly patients who developed diabetes were diagnosed with SPIDDM. We searched clinical characteristics of latter-stage elderly patients who developed SPIDDM and found that majority were female and showed reduced insulin secretion with poor glycemic control. It is important to consider the possibility of type 1 diabetes, including SPIDDM, even in elderly patients who have developed diabetes with poor glycemic control.</p>

DOI： 10.11213/tonyobyo.66.139

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This study aimed to develop a machine-learning algorithm to diagnose aldosterone-producing adenoma (APA) for predicting APA probabilities. A retrospective cross-sectional analysis of the Japan Rare/Intractable Adrenal Diseases Study dataset was performed using the nationwide PA registry in Japan comprised of 41 centers. Patients treated between January 2006 and December 2019 were included. Forty-six features at screening and 13 features at confirmatory test were used for model development to calculate APA probability. Seven machine-learning programs were combined to develop the ensemble-learning model (ELM), which was externally validated. The strongest predictive factors for APA were serum potassium (s-K) at first visit, s-K after medication, plasma aldosterone concentration, aldosterone-to-renin ratio, and potassium supplementation dose. The average performance of the screening model had an AUC of 0.899; the confirmatory test model had an AUC of 0.913. In the external validation, the AUC was 0.964 in the screening model using an APA probability of 0.17. The clinical findings at screening predicted the diagnosis of APA with high accuracy. This novel algorithm can support the PA practice in primary care settings and prevent potentially curable APA patients from falling outside the PA diagnostic flowchart.

DOI： 10.1038/s41598-023-29653-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japan Endocrine Society  

<p>In Japan, the standard method for measuring plasma aldosterone concentration (PAC) for primary aldosteronism (PA) diagnosis was changed from radioimmunoassay (RIA) to a novel chemiluminescent enzyme immunoassay (CLEIA). The purpose of this study is to simulate the possible impact of the change on PA diagnosis. This retrospective study assessed 2,289 PA patients. PACs measured by conventional RIA were transformed to estimated PACs (CLEIA) as follows: RIA (pg/mL) = 1.174 × CLEIA (pg/mL) + 42.3. We applied the estimated PAC (CLEIA) to the conventional cut-off of aldosterone-to-renin activity ratio ≥200 for screening and captopril challenge test (CCT) and PAC ≥60 pg/mL for saline infusion test (SIT). Application of the estimated PAC to screening and confirmatory tests decreased the number of PA diagnoses by 36% (743/2,065) on CCT and 52% (578/1,104) on SIT (discrepant cases). Among the discrepant cases, 87% (548/628) of CCT and 87% (452/522) of SIT were bilateral on adrenal venous sampling (AVS). Surgically treatable aldosterone-producing adenomas (APAs) were observed in 6% (36/579) and 5% (23/472) of discrepant cases on CCT and SIT, respectively; most were characterized by hypokalemia and/or adrenal nodule on CT imaging. Application of the PAC measured by the novel CLEIA to conventional cut-offs decreases the number of PA diagnoses. Although most discrepant cases were bilateral on AVS, there are some APA cases that were characterized by hypokalemia and/or adrenal tumor on CT. Further studies which evaluate PACs measured by both RIA and CLEIA for each patient are needed to identify new cut-offs for PAC measured by CLEIA.</p>

DOI： 10.1507/endocrj.EJ22-0585

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

症例は95歳,女性.X-1年11月にHbA1c 9.7%,空腹時血糖199mg/dLであり,糖尿病と診断された.X年4月にHbA1c 11.0%,随時血糖394mg/dL,空腹時血中Cペプチド0.92ng/mL,GAD抗体(ELISA法)1740U/mLであり,緩徐進行1型糖尿病(SPIDDM)と診断された.SPIDDMは40,50歳代の発症が多いが,65歳以上の高齢発症糖尿病においても10%程度の割合で存在する.後期高齢で糖尿病を発症し,その後SPIDDMと診断された症例を検索した結果,女性に多く,インスリン分泌能が低下している症例が多かった.記載のある全例(1例を除く)が診断時HbA1c 8.0%以上であった.高齢発症糖尿病患者においても,緩徐進行型を含む1型糖尿病が存在するため,血糖コントロール不良の症例は1型糖尿病も鑑別に精査を行う必要がある.(著者抄録)

Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publisher：Modern Rheumatology  

Pathological findings are important in the diagnosis of vasculitis. However, due to the rarity of the disease, standard textbooks usually devote only a few pages to this topic, and this makes it difficult for clinicians not specializing in vasculitis to fully understand the pathological findings in vasculitis. To address the paucity of information, we present representative pathological findings in vasculitis classified in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012). The CHCC2012 classifies 26 vasculitides into seven categories: (1) large-vessel vasculitis, (2) medium-vessel vasculitis, (3) small-vessel vasculitis, including antineutrophil cytoplasmic antibody-associated vasculitis and immune complex small-vessel vasculitis, (4) variable-vessel vasculitis, (5) single-organ vasculitis, (6) vasculitis associated with systemic disease, and (7) vasculitis associated with probable aetiology. Moreover, representative pathological findings of vasculitis-related diseases and non-inflammatory vasculopathy not mentioned in the CHCC2012 are also presented. This will be useful for clinicians to refer to typical pathological findings of vasculitis in daily practice.

DOI： 10.1093/mr/roac043

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Language：Japanese   Publisher：医学図書出版(株)  

長らく進行性膵神経内分泌腫瘍(PanNETs)の予後の改善は得られていなかったが,薬物療法の進歩によって,進行性PanNETsの治療成績は飛躍的に向上してきている。多くのPanNETsは細胞膜上にソマトスタチン受容体を高発現するため,診断や治療のターゲットとされてきた。ソマトスタチンアナログ(SSA)であるoctreotideは,従来ホルモン過剰症状の緩和目的に使用されてきたが,その後消化管NETsに対して抗腫瘍効果が示され,2011年に保険承認された。一方で,PanNETsに対しても近年の臨床試験結果に基づいて,持続性SSA徐放性製剤であるlanreotideが2017年に保険承認された。SSAは有害事象も少なく,実臨床でも汎用されているが,一方で各薬剤との使い分けなど,解決すべき課題も多い。本稿ではlanreotideを中心に,SSAの腫瘍増殖抑制効果について述べる。(著者抄録)

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Publisher：ISIJ International  

For the wall-thickness reduction of the components destined for pressurized gaseous hydrogen, widespread use of high-strength martensitic steels has long been desired. However, their strong susceptibility to hydrogen-assisted fatigue crack growth (HA-FCG) is still limiting their proactive applications. Here, we instead focused on pearlite as another potential reinforcing agent for the development of new hydrogen-compatible steels with acceptable cost performance. Fatigue crack growth (FCG) behavior of three eutectoid steels with different microstructure sizes (i.e., ferrite/cementite interlamellar spacing, colony and block sizes) and strength levels was investigated in a 90 MPa hydrogen gas, an essential evaluation when attempting to perform a defect tolerant design of the components used for high-pressure gases. The pearlitic steels clearly exhibited the acceleration of their FCG rate in hydrogen gas up to a hundred times that in air, wherein its magnitude was greater in the material with finer microstructure and concomitant higher strength. The delamination of ferrite/cementite lamellae, which were inclined largely from the loading axis, was determined to be the primary cause of such HA-FCG in pearlitic steels. Nevertheless, the extent of FCG acceleration was minor with respect to martensitic steels. The fact was ascribed to the barrier role of the cementite platelets oriented nearly perpendicularly to the crack as well as to the geometrical retardation effects arising from the crack deflection and blanching. Ultimately, pearlite was superior to martensite from the perspective of HA-FCG resistance; besides, the superiority was more substantial as the loading rate became slower.

DOI： 10.2355/isijinternational.ISIJINT-2023-011

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Language：Japanese   Publisher：一般社団法人 日本DOHaD学会  

DOI： 10.51067/dohad.11.1_28

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Publisher：東京医学社  

DOI： 10.24479/endo.0000000565

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Purpose: Bone and vascular diseases are considered to share pathogenic mechanisms. Excess glucocorticoids, key regulators of cardiovascular and metabolic homeostasis, may promote both diseases simultaneously. We used endogenous Cushing's syndrome (CS) to investigate whether glucocorticoid excess underlies coexisting bone and vascular diseases. Methods: We included 194 patients with adrenal tumors (ATs): autonomous cortisol secretion (ACS, n = 97) and non-functional AT (n = 97). ACS was further classified into overt CS (n = 17) and subclinical CS (SCS, n = 80). Arterial stiffness was defined as a brachial-ankle pulse wave velocity (baPWV) ≥ 1800 cm/s. Results: Patients with ACS had higher coexistence rates of vertebral fracture and arterial stiffness (23 % vs. 2 %; p < 0.001) and vertebral fracture and abdominal aortic calcification (22 % vs. 1 %; p < 0.001) than those with non-functional AT. In patients with ACS, baPWV was negatively correlated with trabecular bone score (TBS, r = -0.33; p = 0.002), but not with bone mineral density, and vertebral fracture was associated with arterial stiffness in the logistic regression analysis. In the multivariate analysis of variance, the degree of cortisol excess (defined as CS, SCS, and non-functional AT) determined the correlation between TBS and baPWV (partial η2 = 0.07; p < 0.001). In the analysis of covariance, patients with coexisting vertebral fracture and arterial stiffness had higher levels of serum cortisol after the 1-mg dexamethasone suppression test than those without. Conclusion: In endogenous glucocorticoid excess, bone and vascular diseases frequently coexisted, and deteriorated bone quality, not bone loss, was related to arterial stiffness. Thus, glucocorticoid excess may perturb the bone-vascular axis.

DOI： 10.1016/j.bonr.2022.101610

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AIM: Drug-induced interstitial lung disease (DI-ILD) is a serious adverse event during chemotherapy. This study aimed to obtain real-world data of the incidence, clinical characteristics, predictive factors, and prognosis of patients with pancreatic cancer who developed DI-ILD. METHODS: In patients with locally advanced or metastatic pancreatic cancer who underwent standard chemotherapy at our hospital and its participating facilities between April 2014 and March 2019, the clinical features, occurrence rate and clinical course of DI-ILD, and prognosis were retrospectively evaluated. RESULTS: Altogether, 390 patients were finally enrolled. DI-ILD occurred in 24 cases (6.2%). The median period from diagnosis of pancreatic cancer to the onset of DI-ILD was 2.2 months (.6-13.3 months). The rate of DI-ILD onset according to each regimen was 5.8% of gemcitabine (GEM) plus albumin-bound paclitaxel therapy (18/308), 3.8% of GEM (4/106), and 2.3% of FOLFIRINOX (2/88). The incidence of DI-ILD in GEM-based regimens was significantly higher than that in non-GEM-based regimens (p < .01). The median overall survival (OS) of the patients with and without DI-ILD after propensity score matching was 11.5 months and 11.4 months (p = .99), respectively. After the resolution of DI-ILD, no statistical significance in the median OS of the patients with and without subsequent treatment (11.0 vs. 6.8 months, p = .18) was observed. CONCLUSION: DI-ILD is not a rare adverse event in the current standard chemotherapy for pancreatic cancer in Japan. With appropriate management of DI-ILD, the prognosis of patients with DI-ILD can be equivalent to that of patients without DI-ILD.

DOI： 10.1111/ajco.13903

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Language：Japanese   Publisher：日本消化器病学会-九州支部  

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Language：English   Publisher：(一社)日本血液学会  

レニン-アルドステロン-アンジオテンシン系阻害剤(RAASi)を含む特定の降圧薬の偶発的使用が、TKI治療中の慢性骨髄性白血病(CML)の推算糸球体濾過量(eGFR)の変化に及ぼす影響を評価した。対象は当院のCML患者142名で、混合効果モデルを用いてeGFR変化率を推定し、TKI治療中の全てのeGFR測定値を遡及的に分析した。全体的に、使用した降圧薬の種類とeGFRの年間変化との間に有意な相互作用を認め、RAASi使用者が最も急速なeGFR減少(-5.5%/年)を示した。TKI別の分析では、イマチニブ(IMA)とボスチニブ(BOS)の間でのみ相互作用が有意であった。eGFRの年間減少率はRAASi使用者で最も顕著で、IMAとBOSでは-5.7と-10.1であった。以上より、上記TKIを服用している患者はeGFRを監視する必要があると考えられた。

Language：Japanese   Publisher：日本消化器病学会-九州支部  

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We aimed to establish a novel murine model of autoimmune autonomic ganglionopathy (AAG), which represents autoimmune dysautonomia, associated with MHC class II to understand its pathomechanism and the pathogenicity of nicotinic acetylcholine receptor (nAChR) antibodies. The amino acid sequence of the mouse nAChRα3 protein was analyzed using an epitope prediction tool to predict the possible MHC class II binding mouse nAChRα3 peptides. We focused on two nAChRα3 peptides in the extracellular region, and experimental AAG (EAAG) was induced by immunization of C57BL/6 mice with these two different peptides. EAAG mice were examined both physiologically and histologically. Mice with EAAG generated nAChRα3 antibodies and exhibited autonomic dysfunction, including reduced heart rate, excessive fluctuations in systolic blood pressure, and intestinal transit slowing. Additionally, we observed skin lesions, such as alopecia and skin ulcers, in immunized mice. Neuronal cell density in the sympathetic cervical ganglia in immunized mice was significantly lower than that in control mice at the light microscopic level. We interpreted that active immunization of mice with nAChRα3 peptides causes autonomic dysfunction similar to human AAG induced by an antibody-mediated mechanism. We suggested a mechanism by which different HLA class II molecules might preferentially affect the nAChR-specific immune response, thus controlling diversification of the autoantibody response. Our novel murine model mimics AAG in humans and provides a useful tool to investigate its pathomechanism.

DOI： 10.3389/fnins.2022.1006923

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INTRODUCTION: Endoscopic ultrasound guided fine-needle aspiration/biopsy (EUS-FNA/B) is the gold standard for diagnosing subepithelial lesions (SELs); however, its diagnostic ability for SELs <20 mm is low. We developed a new diagnostic method to differentiate between gastrointestinal stromal tumor (GIST) and non-GIST by measuring high-frequency impedance (H-impedance) using an EUS-FNB needle. METHODS: The H-impedance of gastric epithelial neoplasms from 16 cases were measured using a conventional impedance probe to confirm whether H-impedance is clinically useful for assessing cell density (Study 1). The H-impedance values of exposed SELs from 25 cases using the conventional probe (Study 2) and non-exposed SELs from 20 cases using the EUS-FNB needle probe (Study 3) were measured to determine the diagnostic ability of H-impedance for differentiating GISTs from non-GISTs. RESULTS: H-impedance significantly positively correlated with cell density (P=0.030) (Study 1). The H-impedance of GIST (99.5) measured using conventional probe was significantly higher than those of the muscular layer (82.4) and leiomyoma (89.2) (P<0.01) (Study 2). The H-impedance of GIST measured using the EUS-FNB needle was also significantly higher than that of leiomyoma (GIST: 80.2 vs. leiomyoma: 71.8, P=0.015). The diagnostic yield of the impedance method for differentiating GISTs from non-GISTs had 94.4% accuracy, 88.9% sensitivity, 100% specificity, and 0.95 area under the curve. Diagnostic ability was not affected by lesion size (P=0.86) (Study 3). CONCLUSION: Auxiliary differential diagnosis between gastric GISTs and non-GISTs by the H-impedance measurement during EUS-FNB could be a good option especially when the lesion is smaller than 20 mm.

DOI： 10.1016/j.gie.2022.11.022

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BACKGROUND & AIMS: Hybrid endoscopic submucosal dissection (H-ESD), which incorporates ESD with endoscopic mucosal resection, has been developed to make ESD technically easier. This study aimed to determine if H-ESD is superior to conventional ESD (C-ESD) for small early gastric neoplasms (EGN). METHODS: We conducted a multi-center, prospective, open-label, randomized controlled trial to compare the treatment outcomes of H-ESD and C-ESD (Hybrid-G Trial). The patients with differentiated-type intramucosal EGN ≤ 20 mm in diameter and without ulceration were randomly assigned (1:1) to groups that underwent H-ESD or C-ESD. A single multi-functional snare, SOUTEN (ST1850-20, Kaneka, Medix, Tokyo, Japan), was used for H-ESD. The primary outcome was procedure time. Secondary outcomes included mucosal incision time, time and speed of submucosal dissection, curability, and endoscopic procedural adverse events. RESULTS: A total of 39 and 40 patients underwent H-ESD and C-ESD, respectively. The procedure time of H-ESD was significantly shorter than that of C-ESD (33.16 min vs. 62.46 min, H-ESD/C-ESD ratio: 0.53, 95% confidence interval 0.41-0.69, P<0.0001). There was no significant difference in mucosal incision time between the two groups; the time and speed of submucosal dissection of H-ESD were significantly shorter than those of C-ESD. No difference was observed between the two groups in other outcomes. CONCLUSIONS: H-ESD has significantly shorter procedure time than C-ESD, with high and comparable curability and safety for both H-ESD and C-ESD. H-ESD can be a good option for the endoscopic treatment of small EGNs.

DOI： 10.1016/j.cgh.2022.10.030

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PURPOSE: The distribution of tissue infiltrating lymphocytes has been shown to affect the prognosis of patients with pancreatic cancer in some previous studies. However, the role of peripheral lymphocytes in pancreatic cancer remains debated. The purpose of this study was to analyze the peripheral subtypes of T lymphocytes, and establish their association with the prognosis of patients with pancreatic cancer. METHODS: Blood and tissue samples were collected from patients with metastatic pancreatic cancer (n = 54), resectable pancreatic cancer (n = 12), and benign pancreatic cysts (n = 52) between April 2019 and January 2022 and analyzed. RESULTS: Patients with metastatic pancreatic cancer had a larger proportion of both tumor-suppressive and tumor-promoting cells than those with benign pancreatic cysts. In addition, the proportion of peripheral CD4+ T cells positively correlated with the survival of patients with metastatic pancreatic cancer, and the proportion of peripheral CD8+CD122+ T cells was associated with early mortality (< 90 days). After chemotherapy, CD8+CD122+ T cells decreased in patients who had a partial response or stable disease. Moreover, by analyzing resected specimens, we first proved that the existence of CD8+CD122+ T cells in a tumor microenvironment (TME) depends on their proportion in peripheral blood. CONCLUSION: Circulating CD8+CD122+ T cells can be a prognostic indicator in patients with pancreatic cancer.

DOI： 10.1186/s12885-022-10207-0

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

食道運動障害性疾患(EMD)を診断するための新たな2所見を用いたバリウム食道造影検査(BE)によるスクリーニングを評価した。2013年1月から2020年10月にEMDが疑われ高解像度マノメトリー検査(HRM)とBEの両方が施行された244例を対象とした。EMDの診断はシカゴ分類第3.0版を用いてHRM所見に基づいて行った。BEは硫酸バリウムを用いて食道連続撮影を行った。従来からのBE所見(ニボー、数珠状/コルク栓抜き様所見、蠕動の消失/減弱)に加え、新規2所見(蠕動波出現、胃食道接合部上膨隆所見)を診断に用いた。新規2所見と従来の3所見を診断に用いた場合のBEスクリーニングの感度は79.4%、特異度は88%であった(受信者動作特性曲線下領域(AUC)=0.837)。新規2所見を診断に用いない場合には、感度は63.9%、特異度は96%(AUC=0.800)であった。アカラシアはニボー形成と特に関連性が強かった(88.7%)。収縮の消失は蠕動の消失/減弱と強く関連していた(85.7%)。遠位食道痙攣と数珠状/コルク栓抜き様所見との間(60%)およびアカラシアと蠕動波出現(59.7%)との間には比較的高い関連性が認められた。個々のBE所見の観察者内再現性、観察者間一致率はそれぞれ84.4%、75%であった。蠕動波出現は積算弛緩圧(IRP)高値および遠位潜時短縮と関連していた。食道胃接合部上膨隆はIRP高値と関連していた。新規の2所見を追加したBEスクリーニングによるEMDの診断は一般診療において有用である可能性が示された。

Language：Japanese   Publisher：(一社)日本肥満学会  

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DOI： 10.1055/a-1937-9781

Language：English  

DOI： 10.1055/a-1937-9781

Language：English   Publishing type：Research paper (scientific journal)  

Background/Aims: Patients with acute cholecystitis (AC) after metallic stent (MS) placement for malignant biliary obstruction (MBO) have a high surgical risk. We performed percutaneous transhepatic gallbladder aspiration (PTGBA) as the first treatment for AC. We aimed to identify the risk factors for AC after MS placement and the poor response factors of PTGBA. Methods: We enrolled 401 patients who underwent MS placement for MBO between April 2011 and March 2020. The incidence of AC was 10.7%. Of these 43 patients, 37 underwent PTGBA as the first treatment. The patients' responses to PTGBA were divided into good and poor response groups. Results: There were 20 patients in good response group and 17 patients in poor response group. Risk factors for cholecystitis after MS placement included cystic duct obstruction (p<0.001) and covered MS (p<0.001). Cystic duct obstruction (p=0.003) and uncovered MS (p=0.011) demonstrated significantly poor responses to PTGBA. Cystic duct obstruction is a risk factor for cholecystitis and poor response factor for PTGBA, whereas covered MS is a risk factor for cholecystitis and an uncovered MS is a poor response factor of PTGBA for cholecystitis. Conclusions: The onset and poor response factors of AC after MS placement were different between covered and uncovered MS. PTGBA can be a viable option for AC after MS placement, especially in patients with covered MS.

DOI： 10.5946/ce.2021.244

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Gastrointestinal stromal tumors (GISTs) are common subepithelial lesions (SELs) and require treatment considering their malignant potential. We recently developed an endoscopic ultrasound-based artificial intelligence (EUS-AI) system to differentiate GISTs from non-GISTs in gastric SELs, which were used to train the system. We assessed whether the EUS-AI system designed for diagnosing gastric GISTs could be applied to non-gastric GISTs. Between January 2015 and January 2021, 52 patients with non-gastric SELs (esophagus, n = 15; duodenum, n = 26; colon, n = 11) were enrolled. The ability of EUS-AI to differentiate GISTs from non-GISTs in non-gastric SELs was examined. The accuracy, sensitivity, and specificity of EUS-AI for discriminating GISTs from non-GISTs in non-gastric SELs were 94.4%, 100%, and 86.1%, respectively, with an area under the curve of 0.98 based on the cutoff value set using the Youden index. In the subanalysis, the accuracy, sensitivity, and specificity of EUS-AI were highest in the esophagus (100%, 100%, 100%; duodenum, 96.2%, 100%, 0%; colon, 90.9%, 100%, 0%); the cutoff values were determined using the Youden index or the value determined using stomach cases. The diagnostic accuracy of EUS-AI increased as lesion size increased, regardless of lesion location. EUS-AI based on gastric SELs had good diagnostic ability for non-gastric GISTs.

DOI： 10.1038/s41598-022-20863-8

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publisher：(一社)日本内分泌学会  

1987～2021年9月に当大学病院で治療された機能性膵神経内分泌腫瘍患者293例の診療記録を後向きに検討し、VIPomasの診断および治療上の特徴および予後を他の膵神経内分泌腫瘍と比較検討した。患者を、非機能性膵神経内分泌腫瘍213例(男性107例、中央値57歳)、機能性膵神経内分泌腫瘍80例(VIPomas 4例[男性3例、中央値63.5歳]、インスリノーマ45例[男性16例、中央値59歳]、ガストリノーマ27例[男性11例、中央値51歳]、その他4例[男性3例、中央値57歳])に分けた。その結果、VIPomas患者4例中3例は当初、非機能性膵神経内分泌腫瘍と診断されたが、経過中にVIPomasと診断されていた。ホルモン症状の再発は初期コントロールにもかかわらず、VIPomas全例で認められ、全例がホルモン症状により死亡した。他の膵神経内分泌腫瘍と比較して、VIPomasはすべて膵尾部に位置しており、サイズが大きく、Ki-67 indexが高く、転移も多かった。VIPomasの生存期間中央値は非機能性膵神経内分泌腫瘍、インスリノーマ、ガストリノーマと比較して有意に短かった(p<0.0001、p<0.0001、p<0.0325)。以上のように、VIPomasが成長するにつれて無症候から症候性へと移行する可能性や非機能性膵神経内分泌腫瘍からVIPomasへと変化する可能性が示された。

Publisher：南江堂  

DOI： 10.15106/j_naika130_502

CiNii Research

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A recent report stated that patients with primary aldosteronism who remain renin suppressed during mineralocorticoid receptor antagonist treatment might have a higher risk of developing cardiovascular disease than those with unsuppressed renin activity. We retrospectively investigated the incidence of composite cardiovascular disease and risk factors for cardiovascular disease in 1115 Japanese patients with primary aldosteronism treated with mineralocorticoid receptor antagonists. The median follow-up period was 3.0 years, and the incidence of cardiovascular events was very low (2.1%) throughout 5 years of follow-up. Changes in plasma renin activity from before to after mineralocorticoid receptor antagonist treatment were divided into three groups based on tertile, low, intermediate, and high plasma renin activity change groups, with incidences of cardiovascular disease events of 2.1%, 0.5%, and 3.7%, respectively. Multivariate Cox regression analysis revealed age (adjusted hazard ratio, 1.07; 95% confidence interval, [1.02-1.12]) and body mass index (adjusted hazard ratio, 1.13 [1.04-1.23]) as independent risk factors for cardiovascular disease. The high plasma renin activity change group had significantly higher cardiovascular disease risk with mineralocorticoid receptor antagonist treatment than the intermediate plasma renin activity change group (adjusted hazard ratio, 5.71 [1.28-25.5]). These data suggest that a high change in renin level after mineralocorticoid receptor antagonist treatment may not necessarily predict a better prognosis of cardiovascular disease in patients with primary aldosteronism.

DOI： 10.1038/s41440-022-00960-x

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The incidence of atrial fibrillation (AF) and risk of cardiovascular events are reportedly higher in patients with primary aldosteronism (PA) than essential hypertension. However, associated factors of comorbid AF and cardiovascular events in PA patients after PA treatment remain unclear. This nationwide registration study included PA patients ≥20 years old. Incident cardiovascular events were observed with a mean follow-up of approximately 3 years. A total of 3654 patients with PA were included at the time of analysis. Prevalence of AF was 2.4%. PA patients with AF were older, more frequently male and had longer duration of hypertension than those without AF. No significant difference in basal plasma and adrenal venous aldosterone concentration, renin activity, potassium concentration, confirmatory tests of PA, laterality or surgery rate were seen between groups. Logistic regression analysis showed age, male sex, cardiothoracic ratio, past history of coronary artery disease and heart failure were independent factors associated with AF. PA patients with AF showed a higher frequency of cardiovascular events than those without AF (P < 0.001). Multivariate Cox analyses demonstrated AF in addition to older age, duration of hypertension, body mass index and chronic kidney disease as independent prognostic factors for cardiovascular events after PA treatment. Incidence of cardiovascular events were significantly lower in PA patients with AF than AF patients from the Fushimi registry during follow-up after adjusting age, sex and systolic blood pressure. Early diagnosis of PA may prevent AF and other cardiovascular events in PA patients by shortening the duration of hypertension and appropriate PA treatment.

DOI： 10.1038/s41371-022-00753-2

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Context: Adrenocorticotropin (ACTH) loading is used to increase the success rate of adrenal vein sampling (AVS). Objective: We aimed to determine the effect of intraprocedural cortisol measurement (ICM) on ACTH-stimulated AVS (AS-AVS) owing to a lack of reliable data on this topic. Methods: This multicenter, retrospective, observational study took place in 28 tertiary centers in Japan. Among 4057 patients enrolled, 2396 received both basal AVS (B-AVS) and AS-AVS and were divided into 2 groups according to whether ICM was used. The effect of ICM on AS-AVS was measured. Results: In patients who underwent both AVS procedures, the ICM group had significantly higher success rates for both B-AVS and AS-AVS than the non-ICM group did. However, the probability of failure of AS-AVS after a successful B-AVS and the probability of success of AS-AVS after a failed B-AVS were not significantly different in the 2 groups. For subtype diagnosis, propensity-score matching revealed no significant difference between the 2 groups, and the discrepancy rate between B-AVS and AS-AVS for subtype diagnosis was also not significantly different. Conclusion: ICM significantly increased the success rate of B-AVS and AS-AVS in protocols in which both AVS procedures were performed and had no effect on subtype diagnosis. However, in protocols in which both AVS procedures were performed, the results suggest ICM may not be necessary when performing AS-AVS if ICM is used only when B-AVS is performed. Our study suggests that ICM during AVS plays an important role and should be recommended.

DOI： 10.1210/jendso/bvac104

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Language：English   Publisher：Nature Publishing Group  

ミネラルコルチコイド受容体拮抗薬(MRA)治療下の原発性アルドステロン症患者における心血管疾患発症率とその危険因子を後方視的に検討した。1115名(平均54±11歳)を解析対象とした。その結果、中央値3.0年の追跡期間中、全体の2.1%に心血管イベントが発症していた。MRA開始前後の血漿レニン活性変化量(三分位)低位群で2.1%、中位群で0.5%、高位群で3.7%であった。多変量Cox比例ハザード解析では、高位群は中位群に比べMRA治療による複合心血管イベント発症リスクが有意に高かった。心血管イベント発症に関連する他の危険因子として年齢とBMIが抽出された。以上より、MRA治療によって血漿レニン活性が大きく変化することは必ずしも予後良好の指標とはならないと考えられた。

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Acute graft-versus-host disease (aGVHD) is a major cause of treatment-related mortality after allogeneic hematopoietic stem cell transplantation. Endothelial cell damage may trigger the initiation of aGVHD. METHODS: Endothelial damage and repair were evaluated by counting circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) in 17 allogeneic hematopoietic stem cell transplantation patients at pre-conditioning, day 0, day 7, day 14, day 30, and day 60 by multicolor flow cytometry. Von Willebrand factor activity was simultaneously measured. RESULTS: Eight patients developed aGVHD and were compared to non-aGVHD patients. Patients' characteristics were not different, except for previous treatment courses. There was no difference in von Willebrand factor activity between the two groups. Both CEC and EPC counts were decreased on day 7 and day 14 and then increased thereafter. The CEC count on day 7 was significantly lower in the aGVHD group than in the non-aGVHD group (P = 0.0401). Restoration of the EPC count on day 60 was significantly suppressed in the aGVHD group (P = 0.0464). The CEC count on day 7 could predict aGVHD development (AUC 0.8214, P = 0.0372). CONCLUSION: The present results showed that CEC count on day 7 could be a predictor of aGVHD.

DOI： 10.1111/ejh.13781

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DOI： 10.5812/hepatmon-128106

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Although the combination of nanoliposomal irinotecan plus fluorouracil/folinic acid (nal-IRI/FF) exhibited survival benefits in gemcitabine-refractory patients with advanced pancreatic cancer (APC) in the phase III NAPOLI-1 trial, there is limited data on the efficacy and safety of this regimen in real-world settings in Japan. This multicenter, prospective observational study enrolled patients with APC who received nal-IRI/FF after a gemcitabine-based regimen from July 2020 to June 2021. We collected and analyzed clinical data and conducted survival and multivariate analyses. Thirty-one (78%) of the 40 patients had metastases. Nal-IRI/FF was the second-line therapy in 36 patients (90%). The median duration was 3.2 months. The disease control rate was 57%. The median progression-free survival and overall survival (OS) were 4.5 months (95% confidence interval [CI]: 2.8-5.5) and 7.4 months (95% CI: 5.1-10.6), respectively. Common ≥grade 3 toxicities included neutropenia (28%) and fatigue (23%). Fatigue led to treatment discontinuation in 6 out of 10 patients. Multivariate analysis showed that a neutrophil-to-lymphocyte ratio &gt; 4 was a significant risk factor for a short OS (hazard ratio (HR) = 3.08, 95% CI: 1.21-7.85, p = 0.02). In conclusion, nal-IRI/FF is an appropriate treatment option for APC following gemcitabine-containing regimens.

DOI： 10.3390/jcm11175084

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Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). However, TKI-related chronic renal toxicity has been reported, particularly in patients with hypertension. We assessed whether incidental use of specific types of antihypertensive drugs, including renin-aldosterone-angiotensin system inhibitors (RAASis), affects the change in estimated glomerular filtration rate (eGFR) during TKI treatment. We retrospectively analyzed all eGFR measurements during TKI treatment for 142 CML patients at Kyushu University Hospital, estimating the rate of eGFR change using a mixed-effects model. Overall, a significant interaction was found between the type of antihypertensive medication used and the yearly change in eGFR (P < 0.01), with RAASi users exhibiting the most rapid decrease in eGFR (- 5.5%/year). The analysis by TKI used showed that the interaction was significant only in imatinib and bosutinib users (P < 0.01 and P = 0.04, respectively). The yearly rate of eGFR decrease was the most notable in RAASi users, at - 5.7 (- 6.6, - 4.9) and - 10.1 (- 12.3, - 7.9) for imatinib and bosutinib users, respectively. Our findings indicate that eGFR should be carefully monitored in patients taking these TKIs.

DOI： 10.1007/s12185-022-03433-6

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BACKGROUND: High-resolution manometry (HRM) is the gold standard for diagnosing esophageal motility disorders (EMDs); however, it requires specialized equipment. The development of more accessible screening examinations is expected. We evaluated the utility of barium esophagography (BE) screening using two novel findings to diagnose EMDs. METHODS: Between January 2013 and October 2020, 244 patients with suspected EMDs who underwent both HRM and BE were analyzed. The EMD diagnosis was based on HRM findings using Chicago Classification version 3.0. BE was performed using sequential esophagography with barium sulfate. Three conventional BE findings (air-fluid level, rosary-bead/corkscrew appearance, and absent/weak peristalsis) and two novel BE findings (wave appearance and supra-junctional ballooning) were used for diagnosis. RESULTS: The sensitivity and specificity of BE screening using the two novel findings and conventional findings to diagnose EMDs were 79.4% and 88%, respectively [area under the receiver-operating characteristic curve (AUC) = 0.837]. Without these novel findings, they were 63.9% and 96%, respectively (AUC = 0.800), respectively. Achalasia was highly correlated with the air-fluid level (88.7%). Absent contractility was highly correlated with absent/weak peristalsis (85.7%). Relatively high correlations were observed between distal esophageal spasm and rosary-bead/corkscrew appearance (60%), and between achalasia and wave appearance (59.7%). The intra-observer reproducibility and inter-observer agreement for individual BE findings were 84.4% and 75%, respectively. Wave appearance was associated with higher integrated relaxation pressure (IRP) and shorter distal latency. Supra-junctional ballooning was associated with higher IRP. CONCLUSIONS: BE screening using two additional novel findings to diagnose EMDs could be useful in general practice.

DOI： 10.1007/s00535-022-01913-4

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CONTEXT: Pheochromocytoma and paraganglioma (PPGL) may appear as a complication of cyanotic congenital heart disease (CCHD-PPGL) with frequent EPAS1 mutations, suggesting a close link between EPAS1 mutations and tissue hypoxia in CCHD-PPGL pathogenesis. OBJECTIVE: Our aim is to further investigate the role of EPAS1 mutations in the hypoxia-driven mechanism of CCHD-PPGL pathogenesis, particularly focusing on metachronous and/or multifocal CCHD-PPGL tumors. METHODS: We performed whole exome sequencing (WES) for somatic and germline mutations in 15 PPGL samples from 7 CCHD patients, including 3 patients with metachronous and/or multifocal tumors, together with an adrenal medullary hyperplasia (AMH) sample. RESULTS: We detected EPAS1 mutations in 15 out of 16 PPGL/AMH samples from 7 cases. Conspicuously, all EPAS1 mutations in each of three cases with multifocal or metachronous tumors were mutually independent and typical examples of parallel evolution, which is suggestive of strong positive selection of EPAS1-mutated clones. Compared to 165 TCGA non-CCHD-PPGL samples, CCHD-PPGL/AMH samples were enriched for 11p deletions (13/16) and 2p amplifications (4/16). Of particular note, the multiple metachronous PPGL tumors with additional copy number abnormalities developed 18-23 years after the resolution of hypoxemia, suggesting that CCHD-induced hypoxic environments are critical for positive selection of EPAS1 mutants in early life, but may no longer be required for development of PPGL in later life. CONCLUSIONS: Our results highlight a key role of activated HIF2α due to mutated EPAS1 in positive selection under hypoxic environments, although hypoxemia itself may not necessarily be required for the EPAS1-mutated clones to progress to PPGL.

DOI： 10.1210/clinem/dgac362

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DOI： 10.5812/hepatmon-128106

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The specific role of the M3 muscarinic acetylcholine receptor in gastrointestinal motility under physiological conditions is unclear, due to a lack of subtype-selective compounds. AIMS: The objective of this study was to determine the region-specific role of the M3 receptor in gastrointestinal motility. METHODS: We developed a novel positive allosteric modulator (PAM) for the M3 receptor, PAM-369. The effects of PAM-369 on the carbachol-induced contractile response of porcine esophageal smooth muscle and mouse colonic smooth muscle (ex vivo) and on the transit in mouse small intestine and rat colon (in vivo) were examined. RESULTS: PAM-369 selectively potentiated the M3 receptor under the stimulation of its orthosteric ligands without agonistic or antagonistic activity. Half-maximal effective concentrations of PAM activity for human, mouse, and rat M3 receptors were 0.253, 0.345, and 0.127 μM, respectively. PAM-369 enhanced carbachol-induced contraction in porcine esophageal smooth muscle and mouse colonic smooth muscle without causing any contractile responses by itself. The oral administration of 30 mg/kg PAM-369 increased the small intestinal transit in both normal motility and loperamide-induced intestinal dysmotility mice but had no effects on the colonic transit, although the M3 receptor mRNA expression is higher in the colon than in the small intestine. CONCLUSIONS: This study provided the first direct evidence that the M3 receptor has different region-specific roles in the motility function between the small intestine and colon in physiological and pathophysiological contexts. Selective PAMs designed for targeted subtypes of muscarinic receptors are useful for elucidating the subtype-specific function.

DOI： 10.1007/s10620-022-07637-y

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OBJECTIVE: Previous reports have demonstrated the association of serum bilirubin levels with the progression of diabetic nephropathy. The objective of this study is to assess the association of basal bilirubin levels with progressive renal decline (PRD) and end-stage kidney disease (ESKD). METHODS: A total of 298 patients with diabetes who visited Kyushu University Hospital (Japan) were recruited and followed up for 10 years. PRD was defined as a negative change in estimated glomerular filtration ratio (eGFR) >3.7%/year, 2.5th percentile. Logistic regression analysis was performed to evaluate the association of total bilirubin levels with PRD and its cut-off point was determined by receiver operating characteristic (ROC) analysis. Kaplan-Meier method and Cox hazard regression analysis were used to evaluate the predictive ability of its cut-off point for ESKD. RESULTS: Logistic regression model showed that total bilirubin levels were significantly associated with PRD, and ROC analysis showed that its cut-off point was 0.5 mg/dL. Kaplan-Meier method showed that the percent of patients who reached two endpoints, composite endpoint (ESKD or doubling of creatinine level) or 30% eGFR decline, was significantly higher in the low bilirubin group than in the high bilirubin group (18.5% vs 11.0%, P = 0.045; 49.1% vs 42.1%, P = 0.045, respectively, log-rank test). Cox hazard regression models confirmed the independence of the predictive ability of its cut-off point. CONCLUSIONS: Serum total bilirubin levels were negatively associated with PRD in diabetic nephropathy and its cut-off point was 0.5 mg/dL. It may be clinically useful for identifying patients at high risk of ESKD.

DOI： 10.1371/journal.pone.0271179

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Publisher：南江堂  

DOI： 10.15106/j_naika130_77

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Fractalkine is one of the CX3C chemokine family, and it is widely expressed in the brain including the hypothalamus. In the brain, fractalkine is expressed in neurons and binds to a CX3C chemokine receptor 1 (CX3CR1) in microglia. The hypothalamus regulates energy homeostasis of which dysregulation is associated with obesity. Therefore, we examined whether fractalkine-CX3CR1 signalling involved in regulating food intake and hypothalamic inflammation associated with obesity pathogenesis. In the present study, fractalkine significantly reduced food intake induced by several experimental stimuli and significantly increased brain-derived neurotrophic factor (BDNF) mRNA expression in the hypothalamus. Moreover, tyrosine receptor kinase B (TrkB) antagonist impaired fractalkine-induced anorexigenic actions. In addition, compared with wild-type mice, CX3CR1-deficient mice showed a significant increase in food intake and a significant decrease in BDNF mRNA expression in the hypothalamus. Mice fed a high-fat diet (HFD) for 16 weeks showed hypothalamic inflammation and reduced fractalkine mRNA expression in the hypothalamus. Intracerebroventricular administration of fractalkine significantly suppressed HFD-induced hypothalamic inflammation in mice. HFD intake for 4 weeks caused hypothalamic inflammation in CX3CR1-deficient mice, but not in wild-type mice. These findings suggest that fractalkine-CX3CR1 signalling induces anorexigenic actions via activation of the BDNF-TrkB pathway and suppresses HFD-induced hypothalamic inflammation in mice.

DOI： 10.1038/s41598-022-16944-3

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BACKGROUND: Mucosal incision-assisted biopsy (MIAB) is a valuable alternative to endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNAB) for sampling gastric subepithelial lesions (SELs). This study aimed to evaluate the potential risk of dissemination and impact on postoperative prognosis associated with MIAB, which has not yet been investigated. METHODS: Study 1: A prospective observational study was conducted to examine the presence or absence and growth rate of tumor cells in gastric juice before and after the procedure in patients with SELs who underwent MIAB (n = 25) or EUS-FNAB (n = 22) between September 2018 and August 2021. Study 2: A retrospective study was conducted to examine the impact of MIAB on postoperative prognosis in 107 patients with gastrointestinal stromal tumors diagnosed using MIAB (n = 39) or EUS-FNAB (n = 68) who underwent surgery between January 2001 and July 2020. RESULTS: In study 1, although no tumor cells were observed in gastric juice in MIAB before the procedure, they were observed in 64% of patients after obtaining samples (P < 0.001). In contrast, no tumor cells were observed in the gastric juice in EUS-FNAB before and after the procedure. In study 2, there was no significant difference in 5-year disease-free survival between MIAB (100%) and EUS-FNAB (97.1%) (P = 0.27). CONCLUSION: MIAB is safe, with little impact on postoperative prognosis, although the procedure releases some tumor cells after damaging the SEL's pseudocapsule.

DOI： 10.1007/s00464-022-09419-z

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Liver cancer is an aggressive cancer associated with a poor prognosis. Development of therapeutic strategies for liver cancer requires fundamental research using suitable experimental models. Recent progress in direct reprogramming technology has enabled the generation of many types of cells that are difficult to obtain and provide a cellular resource in experimental models of human diseases. In this study, we aimed to establish a simple one-step method for inducing cells that can form malignant human liver tumors directly from healthy endothelial cells using nonintegrating episomal vectors. To screen for factors capable of inducing liver cancer-forming cells (LCCs), we selected nine genes and one short hairpin RNA that suppresses tumor protein p53 (TP53) expression and introduced them into human umbilical vein endothelial cells (HUVECs), using episomal vectors. To identify the essential factors, we examined the effect of changing the amounts and withdrawing individual factors. We then analyzed the proliferation, gene and protein expression, morphologic and chromosomal abnormality, transcriptome, and tumor formation ability of the induced cells. We found that a set of six factors, forkhead box A3 (FOXA3), hepatocyte nuclear factor homeobox 1A (HNF1A), HNF1B, lin-28 homolog B (LIN28B), MYCL proto-oncogene, bHLH transcription factor (L-MYC), and Kruppel-like factor 5 (KLF5), induced direct conversion of HUVECs into LCCs. The gene expression profile of these induced LCCs (iLCCs) was similar to that of human liver cancer cells, and these cells effectively formed tumors that resembled human combined hepatocellular-cholangiocarcinoma following transplantation into immunodeficient mice. Conclusion: We succeeded in the direct induction of iLCCs from HUVECs by using nonintegrating episomal vectors. iLCCs generated from patients with cancer and healthy volunteers will be useful for further advancements in cancer research and for developing methods for the diagnosis, treatment, and prognosis of liver cancer.

DOI： 10.1002/hep4.1911

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Language：English   Publisher：Allergology International  

Background: Adrenaline is the first-line medication for managing anaphylaxis. A better understanding of prescription trends for adrenaline auto-injectors (AAIs) is important to improving patient care as well as information on health education interventions and medical guidelines. However, it has been difficult to gather comprehensive data in a sustainable manner. Thus, we aimed to investigate trends in AAI prescriptions in Japan. Methods: We searched the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), a unique and comprehensive database of health insurance claims, and investigated prescriptions for AAIs for all ages (April 2017 to March 2018). We assessed the annual number of prescriptions per person as well as prescription rates per 100,000 population per year by age, sex, and geographic region. Results: A total of 88,039 subjects (56,109 males, 31,930 female) and 116,758 devices (1.33 AAIs per patient per year) were prescribed AAIs at least once a year for all ages. The prescription rate for AAIs was 69.5 per 100,000 population-years. Patients aged 0–9 years were prescribed AAIs at the rate of 278.9 per 100,000 population-years. Patients aged 0–19 years were 6.4 times more likely to be prescribed AAIs than those over 20 years of age. Males were more frequently prescribed AAIs than females in all age groups, except for those aged 20–24 years. We also evaluated differences in prescription rates by geographic region. Conclusions: This comprehensive evaluation revealed trends in AAI prescriptions, thus helping develop preventive strategies with respect to anaphylaxis in Japan.

DOI： 10.1016/j.alit.2022.02.002

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Recently, endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) procedures have been gradually established; nonetheless, some adverse events (AEs) have been reported. Dilation procedures using a non-cautery or cautery device increase the incidence of AEs in EUS-HGS. AIMS: We evaluated EUS-HGS procedures without dilation and the factors associated with dilation. METHODS: We enrolled 79 patients who underwent EUS-HGS between July 2015 and March 2021 at two centers, 72 of whom had technical success (72/79, 91%). During the EUS-HGS procedures, we defined patients without dilation procedures as the dilation (-) group. We divided the patients into two groups: the dilation (+) (35 patients) and dilation (-) (37 patients) groups. We performed a propensity score matching analysis to adjust for confounding bias between the two groups. Multivariable logistic regression analysis was conducted to identify factors associated with dilation. RESULTS: There was no difference in clinical success rate between the dilation (+) and dilation (-) groups (91% vs. 95%, P = 0.545). The AE rate (P = 0.013) and long procedure time (P = 0.017) were significantly higher in the dilation (+) group than in the dilation (-) group before and after propensity score matching. Factors associated with dilation were plastic stent placement (odds ratio [OR], 6.96; 95% confidence interval [CI], 1.68-28.7; P = 0.007) and puncture angle of ≤ 90° (OR, 44.6; 95% CI, 5.1-390; P < 0.001). CONCLUSIONS: A dilation procedure in EUS-HGS may not always be necessary. However, patients with an angle of ≤ 90° between the needle and intrahepatic biliary tract or plastic stent deployment require dilation procedures.

DOI： 10.1007/s10620-022-07555-z

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Language：English  

DOI： 10.1055/a-1841-5907

Language：English   Publishing type：Research paper (scientific journal)  

Endoscopic duodenal stent (DS) placement for malignant gastric outlet obstruction (GOO) is rapidly increasing in clinical practice; however, the most suitable patient candidates for DS placement have not been determined. One hundred and thirty-five patients with GOO who underwent DS placement in three Japanese referral centers between January 2010 and October 2019 were retrospectively evaluated. Overall survival (OS) after DS placement, technical/clinical success rates, adverse events, and predictive factors affecting OS after DS placement were also analyzed. The median OS after DS placement of all patients was 81 (7-901) days. Technical and clinical success rates were 99.3% and 83.7%, respectively. The GOO Scoring System score significantly increased before and after DS placement (0.9 vs. 2.7, P < 0.001). The procedure-related complication rate was 6.0%. All 19 patients (14.1%) with stent occlusion underwent endoscopic re-intervention successfully. Multivariate analyses revealed chemotherapy after DS placement (P = 0.01), stricture site in D3 (distal part of the papilla) (P = 0.01), and a Glasgow Prognostic Score (GPS) of 0-1 before duodenal stent placement (P < 0.001) were factors significantly associated with prolonged OS. In conclusion, patients with a GPS of 0-1 and D3 stricture who are tolerant of chemotherapy are suitable candidates for DS placement.

DOI： 10.1038/s41598-022-13209-x

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Language：English   Publishing type：Research paper (scientific journal)  

Although a large-caliber endoscope (LCE) is indispensable for through-the-scope placement of a self-expandable metallic stent (SEMS) in patients with malignant colonic obstruction (MCO), inaccessibility of the target obstructing lesion (TOL) by the endoscope is a significant cause of unsuccessful procedures. We herein present a novel salvage procedure when the TOL is not directly accessible by an LCE in conditions such as coexisting peritoneal carcinomatosis involving the colon. The salvage procedure, termed over-the-catheter endoscope replacement (OCER), starts with an ultraslim endoscope suitable for deep insertion beyond a tortuous colon for traversing a guidewire through the TOL. The ultraslim endoscope is then withdrawn and replaced by an LCE through the following steps. An endoscopic retrograde cholangiopancreatography catheter is preloaded in the LCE, the catheter alone is passed over the guidewire already traversed through the TOL, and the LCE is navigated over the catheter as far as possible toward the TOL to deliver the SEMS delivery system in a standard through-the-scope manner or further in an over-the-wire manner even if LCE insertion is incomplete. Among the 165 patients with MCO who underwent stenting during our study period, OCER led to successful procedures in all 9 patients whose TOLs were initially inaccessible because of colon-involving peritoneal carcinomatosis. By utilizing the functions of distinctive endoscopes in a unique and complementary way, OCER can be a practical salvage option for challenging cases of MCO that are highly prone to unsuccessful palliation by conventional SEMS placement.

DOI： 10.1111/den.14385

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1055/a-1841-5907

Language：Japanese   Publisher：(株)アークメディア  

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Publisher：医歯薬出版(株)  

DOI： 10.32118/j01436.2022194614

CiNii Research

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japan Endocrine Society  

<p>VIPomas are generally rare functioning pancreatic neuroendocrine tumors (PanNETs) that cause watery diarrhea, hypokalemia, and achlorhydria. Due to their extreme rarity, the clinicopathological features and outcomes of VIPomas have not been well reported. This study aimed to determine the diagnostic and therapeutic characteristics and prognosis of VIPomas and to compare them with other PanNETs at a Japanese reference hospital. Medical records of 293 patients with PanNETs were collected. Patient and tumor characteristics and outcomes were retrospectively reviewed. This cohort had only 1.4% (four patients) of patients with VIPomas, and three of these patients changed from non-functioning (NF-) PanNETs during their disease course. Recurrences of hormonal symptoms were observed in all patients despite the initial controls, and all of them died from their disease, more specifically mainly from hormonal symptoms. Compared to the other PanNETs, VIPomas were all located at the pancreatic tail, were larger, and had a higher Ki-67 index and more metastasis. The median survival time was significantly shorter for patients with VIPoma than for those with NF-PanNET (5.9 <i>vs.</i> 26.7 years, <i>p</i> < 0.0001), insulinoma (21.8 years, <i>p</i> < 0.0001), and gastrinoma (12.3 years, <i>p</i> = 0.0325). This study presents the possibility of shifting from non-symptomatic to symptomatic VIPomas as they grow or of transforming from NF-PanNETs to VIPomas. VIPomas should be considered in patients with relatively large NF-PanNETs, especially those located in the pancreatic tail, when diarrhea is continuously observed. As hormonal symptoms are an important cause of death in VIPomas, long-term symptomatic control, which is relatively difficult, is of great significance.</p>

DOI： 10.1507/endocrj.EJ22-0111

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CiNii Research