Himeji Medical Center

Porphyrias are rare metabolic disorders caused by decreased or increased activity of one of the nine enzymes involved in the heme biosynthetic pathway, resulting in the accumulation of porphyrins or their precursors. Although nine subtypes are currently recognized, substantial overlap in clinical manifestations often makes diagnosis challenging. This article presents the English version of the first national clinical practice guidelines for porphyrias in Japan, originally published in 2025 by the Japanese Dermatological Association. The guidelines were developed by the Clinical Practice Guideline Committee, established as part of the Research Project on Intractable Diseases of the Ministry of Health, Labour and Welfare of Japan. Diagnostic and severity assessment criteria were based on those proposed by the Ministry research group. Clinical questions (CQs) were formulated, and recommendations were developed according to the principles of evidence-based medicine, incorporating both domestic and international evidence. The guidelines provide diagnostic criteria, severity classification, and evidence-based recommendations for the management of porphyrias. Although causative genes have been identified, the pathophysiology remains incompletely understood, and no curative therapy is currently available, and liver transplantation may be required in severe cases with liver failure. These guidelines aim to provide practical guidance for clinicians managing porphyrias in Japan. Future revisions will be necessary in response to advances in diagnostic technologies and therapeutic strategies.

Severe hypoglycemia (SH) is a major complication in adults with type 1 diabetes mellitus (T1DM). The multifactorial etiology of T1DM highlights the need for predictive tools that integrate clinical, behavioral, and technological factors. This study aimed to develop and evaluate machine learning (ML) models for predicting SH by incorporating hypoglycemia problem-solving ability, diabetes technology, and continuous glucose monitoring (CGM) indices. We analyzed data from 247 adults with T1DM (mean age 50.4 ± 13.7 years; 38.1% male; glycosylated hemoglobin 7.7 ± 0.9%) from the FGM-Japan study. A total of 22,517 feature-model combinations were evaluated across 11 ML algorithms, including logistic regression, L1-regularized regression, random forest, LightGBM, XGBoost, SVM, Naïve Bayes, SGD, neural networks, and k-nearest neighbors. Eleven candidate predictors included impaired awareness of hypoglycemia (IAH), diabetic peripheral neuropathy (DPN), CSII, rtCGM, and seven domains of hypoglycemia problem-solving ability. The model performance was assessed with fivefold cross-validation using the receiver operating characteristic-area under the curve (ROC-AUC), accuracy, precision, recall, and F1 score. Class imbalance was addressed using SMOTE. The mean ROC-AUC across models was 0.64 (range: 0.151-0.916). The average accuracy was 0.90, but the precision and recall were consistently low, with a mean recall of 0.08. The high-performing models (ROC-AUC > 0.90) were primarily Random Forest and LightGBM, which frequently incorporated domains such as problem perception, identifying problem attributes, seeking preventive strategies, evaluating strategies, and immediate management. factors. Tree-based models significantly outperformed logistic regression, Naïve Bayes, SVM, and SGD (adjusted p < 0.001), whereas the differences among the tree-based algorithms were not clinically meaningful. Tree-based ML models demonstrated superior discriminative ability for predicting SH in patients with T1DM. Hypoglycemia problem-solving ability was the strongest predictor, underscoring the importance of integrating behavioral self-management skills with clinical and technological factors. University hospital Medical Information Network (UMIN) Center: UMIN000039475), Approval date 13 February 2020.

Background:Orthopedic infections, including fracture-related infection and periprosthetic joint infection (PJI), remain difficult to eradicate because bacteria within biofilms exhibit high tolerance to systemic antibiotics. Conventional antibacterial strategies based on minimum inhibitory concentration often fail in the biofilm environment, where substantially higher antimicrobial concentrations are required. Continuous local antibiotic perfusion (CLAP) has emerged as a technique that enables sustained delivery of high local antibiotic concentrations directly to the infected site while providing continuous drainage using negative pressure wound therapy.Methods:This narrative review summarizes the principles, technical aspects, clinical indications, and reported outcomes of CLAP. A literature search of the MEDLINE database was conducted up to July 2025 using the term “continuous local antibiotic perfusion.” Clinical studies describing the use of CLAP in orthopedic infections, including case reports, case series, and retrospective studies, were reviewed. Perfusion strategies (iMAP, iSAP, iJAP, and TRAP), antibiotic regimens, safety considerations, and current limitations were analyzed.Results:CLAP enabled delivery of high local antibiotic concentrations exceeding the minimum biofilm eradication concentration while maintaining relatively low systemic exposure. Favorable outcomes for infection control, implant retention, and fracture union, were reported across various intractable infections, including fungal PJI. Complications such as transient elevations in serum antibiotic levels and renal dysfunction were reported but appeared to be infrequent. Although CLAP has shown potential utility in refractory infections, further high-quality studies with rigorous safety evaluations are required to strengthen the evidence base.Conclusion:CLAP is a promising adjunctive strategy for challenging orthopedic infections, offering targeted high-concentration antibiotic delivery with effective drainage. However, current evidence is limited to low-level studies. Prospective trials, standardized protocols, and long-term safety evaluations are needed to define its role in clinical practice.

Background/AimImmune checkpoint inhibitors (ICIs) have become central in the treatment of non-small cell lung cancer (NSCLC). The occurrence of immune-related adverse events (irAEs) is a critical issue in the management of patients with NSCLC receiving ICIs. Recent studies have suggested that patients who develop irAEs may have a better prognosis than those who do not. However, the most problematic cases involved the development of severe irAEs. This study aimed to investigate the clinical impact of severe irAEs (grade ≥3) in patients with NSCLC treated with ICIs.Patients and MethodsWe analyzed 122 patients from a prospective database of consecutive patients with NSCLC who received first-line ICI-containing treatment between November 2018 and October 2024. Patients were classified into two groups: 48 treated with anti-programmed death-ligand 1 (anti-PD-L1) therapy and 74 treated with anti-programmed death-1 (anti-PD-1) therapy. We retrospectively compared the incidence of severe irAEs between the two groups and evaluated the clinical outcomes of severe irAEs on the survival.ResultsAmong 122 patients, 24 (19.7%) experienced severe irAEs. The incidence of severe irAEs was significantly higher among patients treated with anti-PD-1 than among those treated with anti-PD-L1. The incidence of irAE-related death was also higher in the anti-PD-1 group than in the anti-PD-L1 group, with pneumonitis accounting for most of these fatalities (87.5%). There were no significant differences in the progression-free or overall survival between patients with and without severe irAEs. A multivariable analysis showed that the use of anti-PD-1 therapy was associated with a worse overall survival.ConclusionTreatment with anti-PD-1 was associated with an increased risk of severe irAEs. The incidence of severe irAEs was not associated with an improved survival rate.

Central airway adenoid cystic carcinoma (CAACC) is a rare malignancy lacking a standard treatment approach and often precluding complete resection. This study assessed the surgical outcomes of patients with CAACC treated at a single institution. We retrospectively reviewed patients who underwent surgical resection for CAACC between September 2013 and August 2021. Eight patients (mean age: 51.5 years) were included. Tumor locations were bronchus (n = 1), trachea (n = 4), carina and bronchus (n = 2), and carina and trachea (n = 1). Surgical procedures included sleeve lobectomy (n = 1), tracheal resection (n = 4), sleeve pneumonectomy (n = 2), and carinal resection with reconstruction (n = 1). Preoperative radiation and bronchoscopic tumor resection were performed in 1 patient each. One patient died from a postoperative tracheoinnominate artery fistula. Major complications included recurrent laryngeal nerve palsy (n = 3). Adjuvant therapy was provided for positive or uncertain margins. During a median follow-up of 6 years, 2 patients developed recurrence but remained alive at the last follow-up. The 5-year overall survival rate was 72.9%. Surgical resection with airway reconstruction and adjuvant therapy can offer long-term disease control in CAACC, though life-threatening complications warrant careful consideration.

Atrial fibrillation (AF) after bioprosthetic valve (BPV) replacement is common in older patients with multiple comorbidities and is associated with a heightened risk of thromboembolism. Anticoagulation therapy is often indicated, but renal impairment and other comorbidities elevate bleeding risk, making clinical decisions complex. This study compared clinical outcomes between warfarin and direct oral anticoagulants (DOACs) in this high-risk population. This subgroup analysis of the BPV-AF Registry included 612 patients treated with oral anticoagulants after BPV replacement, stratified by renal function: normal or mild impairment (creatinine clearance [CCr] ≥50 mL/min), mild-to-moderate impairment (30 mL/min ≤ CCr < 50 mL/min), and moderate-to-severe impairment (15 mL/min ≤ CCr < 30 mL/min). Baseline characteristics and outcomes were analyzed within each stratum. The composite outcome of stroke, systemic embolism, and cardiovascular events was numerically less frequent in the DOAC than warfarin group across all strata, although the differences were not statistically significant. Major bleeding also tended to be lower in the DOAC group. In this study from a Japanese nationwide registry comparing outcomes of AF patients after BPV replacement with severe renal impairment between those treated with DOACs and those treated with warfarin, comparative conclusions between DOACs and warfarin cannot be drawn because of the small sample size. Nonetheless, both anticoagulants may be acceptable in clinical practice, highlighting the need for individualized decision-making based on patient risk.

Disclosure: H. Shichi: None. T. Kawarai: None. T. Kasamatsu: None. M. Amano: None. Y. Ohnishi: None. M. Watanabe: None. T. Takeuchi: None. H. Komada: None. N. Hashimoto: None. K. Iida: None.Case: A 58-year-old man. Complaint: Lower back pain. History of the present illness: The patient experienced lower back pain after getting up from lying down. The patient was unable to move and transported to another hospital. The patient was diagnosed with multiple thoracic and lumbar vertebral fractures and referred to our hospital for an investigation of the cause. Laboratory results revealed a low serum ALP level of 27 U/L (IFCC, reference range [RR]; 38-113 U/L) despite the acute stage of the fracture. At 39 years of age, laboratory examination showed low serum ALP level of 70 U/L (JSCC, RR; 102-302 U/L). As the patient’s urinary phosphoethanolamine was elevated at 164.8 μmol/day, hypophosphatasia (HPP) was suspected. Genetic testing was considered to confirm the diagnosis. The patient was discharged and referred for genetic counseling. Two days after genetic counseling in the outpatient clinic, the patient was transferred to our hospital with generalized convulsions. The seizures disappeared before arriving at the hospital. Neuroimaging and laboratory investigation demonstrated no potential causes for generalized seizure. Considering the possibility of HPP-associated vitamin B6-dependent epilepsy, vitamin B6 supplementation was initiated. Subsequently, ALPL gene mutations (c.529G>A/p.Ala177Thr and c.1559delT/p.Leu520ArgfsTer86) was identified, leading to the diagnosis of adult-onset HPP. Discussion: Based on the low ALP levels, HPP was suspected to be the cause of the vertebral fracture, and the diagnosis was confirmed by genetic testing. Adult-onset generalized seizure was seen in the case, which might have been associated with underlying the metabolic abnormalities due to HPP. Convulsions in patients should be considered as vitamin B6-dependent epilepsy, but are typically seen in severe perinatal cases. Because of decreased ALP activity, vitamin B6-dependent epilepsy is caused by the impaired conversion of pyridoxal 5-phosphate to pyridoxal, which is permeable to the blood-brain barrier. Although this was an adult-onset case that was believed to be atypical, the existence of a similar pathology was considered. Therefore, vitamin B6 supplementation may be necessary to improve pathogenesis.Presentation: Sunday, July 13, 2025

BackgroundFerroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a pivotal mechanism in cancer progression and therapeutic resistance. Concurrently, glycosylation, as a key post-translational modification, plays a critical role in regulating cell signaling, immune evasion, and metastasis. Although both processes are independently implicated in tumor biology, the intersection between ferroptosis and glycosylation remains largely unexplored.MethodsWe performed a comprehensive pan-cancer multi-omics analysis, integrating bulk transcriptomics, epigenomics, and single-cell RNA sequencing datasets. Ferroptosis and glycosylation-related genes were curated from The Molecular Signatures Database (MSigDB), leading to the identification of the metal ion transporter, SLC39A14 (solute carrier family 39 member 14), as a key intersecting gene. A ferroptosis-related gene signature was constructed using machine learning and Cox regression models, followed by survival analyses, immune microenvironment profiling, and a pathway enrichment analysis across The Cancer Genome Atlas (TCGA) cohort.ResultsSLC39A14 was found to be significantly upregulated across multiple tumor types and associated with a poor prognosis, immune-stromal infiltration, and ferroptosis resistance. Among all cancer types analyzed, glioblastoma multiforme (GBM) and kidney renal cell carcinoma (KIRC) exhibited the significantly prognostic associations and the most pronounced differential expression of SLC39A14. Single-cell analysis revealed that SLC39A14 expression was enriched between stromal and immune populations, hypoxic perivascular niches, confirming its microenvironment-specific functions. These findings were corroborated by DNA methylation data showing promoter hypomethylation of SLC39A14 in tumors compared to normal tissues. Functionally, SLC39A14 was highly enriched in pathways related to angiogenesis, the epithelial-to-mesenchymal transition, cytokine signaling, and oxidative stress adaptation including vascular endothelial growth factor (VEGF) and cell metabolism-related signaling. A nomogram integrating SLC39A14 expression with clinical parameters improved overall survival predictions.ConclusionsIn this study, we identified SLC39A14 as a dual regulator at the interface of ferroptosis and glycosylation, with significant impacts on tumor microenvironmental remodeling and therapeutic resistance. By leveraging multi-omics and single-cell transcriptomic data, we establish SLC39A14 as a promising prognostic biomarker and therapeutic target, particularly in brain and kidney cancers where ferroptosis modulation could offer novel clinical strategies.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12935-025-04003-6.