Hirosaki University Hospital

弘前大学医学部附属病院では，2013年に学会認定・臨床輸血看護師5名が認定された．現在は，学会認定・臨床輸血看護師が15名，自己血輸血看護師が3名在籍している．活動初期は在籍部署での輸血勉強会等の個人的活動だったが，徐々に院内外での活動を展開した．2017年5月に「輸血部・輸血看護師連絡会」を発足させ，輸血部職員と輸血看護師で，インシデント情報共有や対策立案，輸血教育等について計画・実行した．新人看護師研修の講義・実技デモンストレーションを担当し，院内活動も活発になった．コロナ禍には，新人看護師研修の講義と実技を動画で作成し，翌年にブラッシュアップして提供した．コロナ禍後の現在までは，院内輸血業務の疑問点を調査し「輸血のQ＆A集」を作成した．認定更新しなかった輸血看護師が10名いる一方で，毎年数名の新規輸血看護師が認定され，流れを止めることなく活動している状況を報告する．

BackgroundJapan is highly susceptible to various disasters, as exemplified by the recent Noto Peninsula Earthquake. This study targeted Aomori Prefecture, located at the northernmost tip of Japan’s main island, which faces the compound risks of natural and nuclear disasters.MethodsA vulnerability assessment was conducted for 108 medical institutions using a seven-item risk index to create a “pre-disaster list” (PL). Simulations based on Cabinet Office damage projections were integrated to develop a Hospital Support List (HSL).ResultsThe simulations revealed a potential need for the emergency evacuation of up to 2,859 patients. Critical vulnerabilities were identified across multiple indicators, including structural integrity, lifelines (power, oxygen, and water supply), and radiation protection systems.ConclusionThe findings indicate an urgent need to clarify the cooperative roles of Disaster Medical Assistance Teams (DMAT) and the Nuclear Emergency Medical Assistance Team (NEMAT). Establishing a comprehensive support system is essential for maintaining hospital functions and mitigating damage in future compound disasters.

Anticoagulant effects of direct oral anticoagulants (DOACs) are influenced by their plasma levels and anti-factor Xa (FXa) activity. Delayed bleeding is a major adverse event associated with endoscopic mucosal resection (EMR) of colorectal neoplasms. However, the association between post-EMR bleeding and pharmacodynamics in patients taking DOAC remains unknown. This study investigated the association between pharmacological risk factors and delayed bleeding in patients receiving DOAC. This multicenter prospective trial in Japan evaluated the incidence of post-EMR delayed bleeding in DOAC users between April 2018 and May 2022 and determined the association of post-EMR delayed bleeding with plasma levels and FXa activity. The incidence of post-EMR delayed bleeding was 10.5% (95% confidence interval [CI]: 5.3%-18.0%). There were large individual differences in plasma levels and FXa activity for each DOAC. At the trough and Tmax, plasma DOAC levels and plasma level/dose ratios were significantly correlated with FXa activity. Multivariate analysis showed that high anticoagulant ability was a risk factor for post-EMR delayed bleeding (adjusted OR, 12.211; 95% CI: 1.081-137.922, p = 0.043). DOAC users with high anticoagulant activity may be at higher risk of post-EMR delayed bleeding from colorectal neoplasms.

Disclosure: M. Usutani: None. S. Takayasu: None. S. Yamada: None. Y. Fujita: None.Background: Cushing disease is caused by the dysregulation of ACTH synthesis and secretion due to corticotroph tumors (ACTHomas). Typical ACTHomas exhibit a partial lack of response to glucocorticoid (GC) negative feedback, although the underlying mechanism remains largely unclear. Recently, a second POMC promoter regulated by methylation status was identified in human ACTHomas. However, it is currently unknown whether the methylation levels of the POMC promoters are involved in the GC resistance observed in ACTHomas. Method: To assess methylation/demethylation positions in the first and second promoters, we performed bisulfite-conversion-based DNA sequencing of the CpG islands in 16 ACTHoma cases. The expression levels of ten-eleven translocation (TET) enzymes and DNA methyltransferases (DNMT) were evaluated using qPCR. The same experiments were conducted using the murine corticotroph tumor cell line AtT-20. Subsequently, we investigated changes in the methylation status of the two POMC promoters in human primary cultured cells following treatment with synthetic GC Dexamethasone (DEX), and explored their association with clinical GC resistance. Results: For the first promoter, we found that in the group where methylation decreased after DEX treatment, basal cortisol levels and cortisol levels after low-dose DEX administration were significantly higher compared to the group with increased methylation. No correlation was found between methylation levels and clinical data for the second promoter. The expression levels of TET and DNMT families were significantly increased by DEX in the group where methylation of the first promoter increased after DEX treatment. In contrast, the CpG islands of the first and second promoters were highly demethylated in AtT-20 cells, and DEX treatment had no effect on their methylation levels. The expression levels of Tet and Dnmt were slightly decreased following DEX treatment in AtT-20 cells. Discussion: The decrease in methylation of the first promoter appears to correlate with an increase in basal cortisol levels and cortisol levels after the low-dose DEX test, suggesting that GC-induced demethylation in the first promoter may partially contribute to resistance to the negative regulation of POMC transcription in ACTHomas. Although DEX treatment did not alter methylation levels in the second promoter, it was confirmed that basal cortisol levels were higher in the group with low basal methylation levels in the second promoter. Thus, the methylation status of the second promoter may regulate basal cortisol levels. Furthermore, differences between species and samples should be considered, as these may affect the results. Conclusion: Low methylation of the second POMC promoter was found to increase serum cortisol levels, and the degree of resistance to GCs may be regulated by GC-induced demethylation levels of the first POMC promoter in ACTHomas.Presentation: Monday, July 14, 2025

The energy requirement of renal proximal tubular cells depends on mitochondrial fatty acid β-oxidation. Enoyl-CoA hydratase-l-3-hydroxyacyl-CoA dehydrogenase (EHHADH) is a crucial enzyme in mitochondrial fatty acid oxidation, and mutations in EHHADH reportedly cause Fanconi syndrome. Here, we report the case of a 28-year-old Japanese woman with a long-term history of low-molecular-weight proteinuria (LMWP) who exhibited a missense mutation in the EHHADH gene. She was diagnosed with LMWP at 4years of age. The search for the CLCN5 gene was unremarkable, and kidney biopsy revealed no significant tubulointerstitial changes. The LMWP persisted, and glucosuria gradually developed thereafter. Unexpectedly, next-generation sequencing identified a heterozygous missense mutation in the EHHADH gene. Her father, who harbored LMWP, also had the same mutation. Furthermore, immunostaining of the stored kidney specimens showed decreased immunoreactivity for cytochrome coxidase subunit 4 in the proximal tubules, suggesting an underlying mitochondrial impairment.

TPS4618 Background: Urothelial carcinoma (UC) has a high mortality rate in patients (pts) with metastatic disease. While immune checkpoint inhibitors (CPI), including programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy (CTx) or enfortumab vedotin (EV), have been approved for first-line treatment of metastatic (m)UC, many pts have de novo or develop acquired resistance. For pts without response to frontline treatment or whose disease has progressed on prior CPI combinations, optimal treatment is unclear and new therapies are urgently needed. Glycoprotein A repetitions predominant (GARP) is a membrane-bound receptor that complexes with latent transforming growth factor (TGF)-β1; the release of active TGF-β1 from this complex suppresses antitumor responses. Livmoniplimab (livmo), an antibody targeting the GARP:TGF-β1 complex, prevents release of active TGF-β1, thereby promoting antitumor activity. A first-in-human phase 1 study (NCT03821935) demonstrated that combining livmo and the anti–PD-1 mAb budigalimab (budi) resulted in a manageable safety profile and promising antitumor activity in pts with PD-1–refractory advanced UC (J Clin Oncol 2024;42[suppl 4]: abs 617). Herein, we describe the phase 2 study that is evaluating livmo + budi vs CTx in pts with mUC (NCT06632951). Methods: This multicenter, open-label, randomized study is enrolling pts aged ≥18 years who have mUC, measurable disease per RECIST v1.1, ECOG PS 0–1, and have experienced disease progression on anti–PD-1 or anti–PD-1 ligand 1 therapy. Platinum (Pt)-eligible pts must have received a Pt-containing regimen; pts who can receive EV must have experienced disease progression on/after receiving EV treatment. Primary objectives are to identify the recommended phase 3 livmo dose in combination with budi and evaluate overall survival. Secondary objectives include evaluating progression-free survival, best overall response of complete or partial response, duration of response, and assessment of safety and tolerability, pharmacokinetics, and immunogenicity of the combination. Pts will be randomized 1:1:1 to 3 arms: 1) livmo dose 1 Q3W + budi Q3W; 2) livmo dose 2 Q3W + budi Q3W; or 3) investigator’s choice of CTx (paclitaxel, docetaxel, or gemcitabine). Pts will be stratified by ECOG PS (0 vs 1) and first-line therapy (pembrolizumab + EV vs CTx). Treatment for pts in Arms 1 and 2 will continue until a maximum of 35 cycles. For pts in Arm 3, treatment will continue for the duration that is consistent with local guidelines/practice for this pt population. No crossover between arms will be permitted. For all pts, treatment is discontinued at disease progression or if other protocol-defined discontinuation criteria are met. In total, approximately 150 pts (50 pts/arm) are planned for enrollment globally. Clinical trial information: NCT06632951 .

Predicting the response to chemotherapy can lead to the optimization of neoadjuvant chemotherapy (NAC). The present study aimed to develop a non-invasive prediction model of therapeutic response to NAC for rectal cancer (RC). A dataset of the prechemotherapy computed tomography (CT) images of 57 patients from multiple institutions who underwent rectal surgery after three courses of S-1 and oxaliplatin (SOX) NAC for RC was collected. The therapeutic response to NAC was pathologically confirmed. It was then predicted whether they were pathologic responders or non-responders. Cases were divided into training, validation and test datasets. A CT patch-based predictive model was developed using a residual convolutional neural network and the predictive performance was evaluated. Binary logistic regression analysis of prechemotherapy clinical factors showed that none of the independent variables were significantly associated with the non-responders. Among the 49 patients in the training and validation datasets, there were 21 (42.9%) and 28 (57.1%) responders and non-responders, respectively. A total of 3,857 patches were extracted from the 49 patients. In the validation dataset, the average sensitivity, specificity and accuracy was 97.3, 95.7 and 96.8%, respectively. Furthermore, the area under the receiver operating characteristic curve (AUC) was 0.994 (95% CI, 0.991-0.997; P<0.001). In the test dataset, which included 750 patches from 8 patients, the predictive model demonstrated high specificity (89.9%) and the AUC was 0.846 (95% CI, 0.817-0.875; P<0.001). The non-invasive deep learning model using prechemotherapy CT images exhibited high predictive performance in predicting the pathological therapeutic response to SOX NAC.

BackgroundEdoxaban, the only factor Xa inhibitor with active metabolites, is metabolized by carboxylesterase-1 to its main active metabolite, M-4, which is a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) and is excreted in bile and urine. Because the area under the plasma concentration–time curve ratio of M-4 to parent compound is typically less than 10% in healthy subjects, M-4 is generally considered to exhibit negligible antithrombotic activity in patients treated with edoxaban. However, we identified a case in which drug interactions and kidney impairment led to a substantive increase in plasma M-4 concentrations.Case presentationThis case report involved a 68-year-old man with pancreatic cancer who was orally administered edoxaban tablets for prevention of thrombus formation in non-valvular atrial fibrillation, in addition to rifampin and clarithromycin (CAM) for treatment of mycobacterium avium complex lung disease. These medications were temporarily discontinued for a pancreaticoduodenectomy but were resumed 8 days post-surgery (POD8). On POD9, the patient developed acute kidney injury, and the trough concentrations of edoxaban and M-4 were 131.1 ng/mL and 115.8 ng/mL, respectively (M-4 ratio: 88.3%). On POD11, the M-4 trough concentration and M-4 ratio increased to 216.2 ng/mL and 186.2%, respectively. The plasma concentration of coproporphyrin-I, an endogenous biomarker of OATP1B1 activity, increased during this period.ConclusionsThis case suggests that in patients with impaired renal function taking edoxaban, co-administration of carboxylesterase-1 inducers such as rifampin and/or OATP1B1 inhibitors such as rifampin or clarithromycin may increase plasma concentrations of M-4 to clinically non-negligible levels.

We have previously reported the mid-term efficacy and safety of tacrolimus (Tac)-based immunosuppressive therapy in such patients, and herein, we aimed to determine their long-term outcomes (over 10 years). We retrospectively evaluate the data of 13 consecutive patients with biopsy-proven long-standing LN who underwent a long-term Tac-based treatment regimen. Tac was administered once daily at a dose of 3 mg as reinduction or maintenance treatment. Treatment outcomes were defined using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), urinary protein/creatinine ratio (Up/cr), serum creatinine, estimated glomerular filtration rate (eGFR) and serological lupus markers (complement C3, complement hemolytic activity [CH 50], and anti-dsDNA antibody titre), and the concomitantly administered prednisolone (PDN) dose. Data on clinical parameters and serological lupus activity were collected annually from each patient throughout the study period. The patients' baseline characteristics at the treatment initiation were as follows: mean age, 18 years; Up/cr, 0.63 ± 0.69; serum C3 level, 57.2 ± 22.4 mg/dL (normal range, 79-152 mg/dL); CH50, 27.9 ± 15.7 U/mL (normal range, 23.0-46.0 U/mL); serum anti-dsDNA antibody titre, 111.7 ± 123.4 IU/mL (normal range, <12.0 IU/mL); serum creatinine, 0.60 ± 0.19 mg/dL; eGFR, 115.6 ± 21.3 mL/min and SLEDAI, 13 ± 8.1. Despite the gradual tapering of the concomitantly administered PDN dose from 18.7 ± 13.5 mg/day at baseline to 3.5 ± 2.8 mg/day at 10 years (p = .002), a marked improvement in the outcomes, compared with the baseline values, was observed within a year. Additionally, these favourable changes persisted throughout study period in most patients. Compared with the baseline values, the following measures confirmed sustained outcome improvements after a 10-year treatment: SLEDAI, 1.7 ± 2.0; serum C3 level, 83.8 ± 16.1 mg/dL; CH50, 45.6 ± 10.9 U/mL (all p < .01) and Up/cr, 0.16 ± 0.18 and serum anti-dsDNA antibody titre, 25.8 ± 28.8 IU/mL (both p < .05). Serum creatinine level and eGFR remained within the normal range in all study participants except for one patient who experienced several flare-ups. No serious adverse effects were observed. Our results suggest that long-term Tac-based immunosuppressive treatment as maintenance therapy is beneficial and has low cytotoxicity. Therefore, it represents an attractive option for the treatment of selected patients with paediatric-onset LN in a real-world setting.