Tokyo Medical University

Chronic spinal subdural hematoma is an extremely rare condition. We recently encountered a case of symptomatic thoracolumbar chronic spinal subdural hematoma in an older patient caused by a fall. The patient was a man in his 80s with a history of cerebral infarction, who was receiving oral antiplatelet therapy. He was hospitalized for conservative treatment for a brain contusion and mild acute subdural hematoma, and was discharged home after 6 days. However, 9 days after the injury, the patient developed back pain, weakness in both lower limbs, and urinary incontinence and was brought to our hospital. A computed tomography scan on admission displayed a high-density area in the thoracolumbar spinal canal, and magnetic resonance imaging 2 weeks after the fall displayed a spinal subdural hematoma from 8th thoracic to sacral 2nd, with a hyperintensity signal on T1weighted image and T2 weighted image and partial low intensity on T2* imaging. On day 22 after the injury, lumbar drainage was performed, and a motor-oil-like hematoma was aspirated. A total of 330 mL of hematoma content was drained for 3 days. Immediately after treatment, the patient's back pain and lower limb weakness improved, and imaging confirmed the disappearance of the spinal subdural hematoma. Most reported cases to date of chronic spinal subdural hematoma were treated with invasive laminectomy for hematoma removal. In the present case, the authors suspected this condition from the late subacute stage of onset and were able to cure the patient with minimum invasive lumbar drainage after diagnosis of liquefaction of the hematoma by magnetic resonance imaging. Fullsize Image

Instrumental variable (IV) methods are widely applied in biometrics and related fields, offering potential solutions to problems associated with unmeasured confounders. Particularly, Mendelian randomization (MR), which uses single nucleotide polymorphisms (SNPs) as IVs, has garnered significant attention in recent years. In this review, we introduce MR and the statistical methods used, categorizing them into two types: one-sample MR and two-sample MR, with some illustrative examples. In onesample MR, the two-stage least squares (2SLS) estimator is commonly applied, while in two-sample MR, the inverse-variance weighted method is used. We also explore the relationship between these methods. Additionally, we discuss unique problems of MR, such as the weak instrument problem and the issue of invalid IVs, and present some current solutions. Furthermore, we address biometrics-specific topics applicable to binary outcomes and concerns regarding the applicability of 2SLS.

Fibularis tertius muscle (FT) was first described by Vesalius in 1543 and was subsequently studied in detail by Henle and Hyrtl in the nineteenth century. There has been a controversy over whether FT is a separate beings. With regard to the question, it has been reported that the FT is an independent muscle or a part of the adjacent muscles such as the extensor digitorum longus muscle (EDL) and the extensor digitorum brevis muscle. In this study, to clarify the origin of the FT from the perspective of neuromuscular anatomy, gross and stereomicroscopic dissections and modified Shiler’s staining were performed on 48 sides of the lower legs from 25 Japanese cadavers. Of the 48 specimens, 43 specimens (89.6%) had a FT muscle belly, while 5 specimens (10.4%) did not. Most FTs were innervated by distal nerve branches from a common trunk with the EDL. The innervations of the FT and EDL suggest that the FT and EDL were brother muscles, and we proposed here a hypothesis that the FT and EDL originate from a common muscle mass and compete in a tug-of-war for muscle belly components during their development.

To investigate the usage status and evaluate the efficacy of intravenous immunoglobulin (IVIG) for the acute treatment of optic neuritis (ON) in Japan. Multicenter retrospective case series. The study subjects were patients with steroid-resistant acute ON in whom IVIG had been initiated between January 2020 and August 2022 at 30 facilities in Japan. The clinical characteristics, visual acuity, and adverse events following IVIG were compared among anti-aquaporin 4 antibody positive ON (AQP4-ON), anti-myelin oligodendrocyte glycoprotein antibody positive ON (MOG-ON), and idiopathic ON (ION). The study included sixty-five patients (76 eyes); the main clinical department administering IVIG was ophthalmology (50 cases, 77.0 %). 43 cases had their first ON attack and 22 cases had recurrent ON. Plasmapheresis (PP) was combined in 21 cases. The efficacy endpoint, changes in logarithm of the minimum angle of resolution (logMAR) after IVIG compared with preIVIG, showed statistically significant improvement in the AQP4-ON group at one week, 4 weeks, and 12 weeks after IVIG (p=0.015, p<0.001, p<0.001, respectively). In the MOG-ON group, excluding cases with combined PP, logMAR post IVIG did not improve significantly compared with preIVIG. Among the ION group, compared with preIVIG, logMAR at 4weeks and 12 weeks post IVIG were statistically significant improved (p=0.019, p=0.023, respectively). Adverse events occurred in 7 patients with IVIG. 4 of the 7 patients continued the IVIG treatment, and 3 patients discontinued it within 5 days. This study demonstrates that IVIG may be an effective new option for acute treatment of steroid-resistant ON as an add-on to conventional therapy.

Purpose: Endovascular aneurysm repair (EVAR) is widely used to treat abdominal aortic aneurysms (AAAs), but mid-term survival remains a concern. This study aims to develop a machine learning-based random forest model to predict 3-year survival after EVAR. Methods: A random forest model was trained using data from 176 EVAR patients, of whom 169 patients were retained for analysis, incorporating 23 preoperative and perioperative variables. Model performance was evaluated using 5-fold cross-validation. Results: The model achieved an area under the receiver-operating characteristic curve (AUC) of 0.91, with an accuracy of 81.1%, a sensitivity of 81.6%, a specificity of 80.9%, and an F1 score of 0.66. Feature importance analysis identified poor nutritional status (geriatric nutritional risk index <101.4), compromised immunity (neutrophil-to-lymphocyte ratio >3.19), chronic kidney disease (CKD), octogenarian status, chronic obstructive pulmonary disease (COPD), small aneurysm size, and statin use as the top predictors of 3-year mortality. The average values of the AUC, accuracy, sensitivity, specificity, and F1 score across the 5-folds were 0.76 ± 0.10, 73.9 ± 5.8%, 60.4 ± 1.9%, 77.8 ± 0.7%, and 0.59 ± 0.17, indicating consistent performance across different data subsets. Conclusions: The random forest model effectively predicts 3-year survival after EVAR, indicating key factors such as poor nutritional status, compromised immunity, CKD, octogenarian status, COPD, small aneurysm size, and statin use.

Background MYH9-related disease (MYH9-RD) is characterized by macrothrombocytopenia, hearing loss, and progressive kidney dysfunction. Due to thrombocytopenia, kidney biopsy is seldom performed, and pathological findings remain unclear. Although case reports have described focal segmental glomerulosclerosis (FSGS) and glomerular basement membrane (GBM) abnormalities like Alport syndrome, no cross-sectional studies of MYH9-RD have been performed. This study aimed to clarify kidney pathological findings through a nationwide survey. Methods We conducted a nationwide survey of MYH9-RD patients and collected tissues from kidney biopsies, along with immunofluorescence and electron microscopy images. Multiple pathologists examined all samples. Results Nine kidney biopsy samples were included. Mesangial matrix expansion was observed in all samples (100%), while FSGS was observed in two (22%). Segmental foot process effacement was observed in all samples (100%), with irregularly aggregated podocyte dense material in seven (78%). Immunofluorescence analysis revealed that three samples (33%) had immunoglobulin and/or complement deposition: the types of depositions varied among patients. Electron dense deposits (EDD) were found in five samples (56%). GBM abnormalities – thinning, irregular thickening, and splitting of the lamina densa – were observed in five samples (56%), but no basket-weave appearance was noted. Endothelial cell swelling was found in seven samples (78%). Conclusions Mesangial expansion and segmental foot process effacement were commonly observed in MYH9-RD patients. Additional findings included immunoglobulin and complement deposition with EDD, and GBM abnormalities. Although patients may have had relatively severe disease, which limits generalizability, these results provide valuable insights into the disease mechanisms and potential therapeutic targets of MYH9-RD.

Follicular lymphoma (FL) is the second most common subtype of non‐Hodgkin lymphoma (NHL) in Japan, the United States, and Western Europe. Parsaclisib is a potent, selective next‐generation PI3Kδ inhibitor that has demonstrated clinical efficacy and tolerability in phase II studies of patients with relapsed or refractory (R/R) B‐cell NHL, including FL. We report results from CITADEL‐213 (NCT04434937), a phase II study evaluating the efficacy and safety of parsaclisib in Japanese patients with R/R FL. Eligible patients were aged ≥ 18 years with histologically confirmed R/R FL (grade 1, 2, or 3a), had received two or more prior systemic therapies, and were ineligible for hematopoietic stem cell transplantation. Patients received parsaclisib 20 mg once daily for 8 weeks, followed by parsaclisib 2.5 mg once daily thereafter. The primary endpoint was the objective response rate (ORR). At the data cut‐off (February 16, 2023), 42 patients had received treatment with parsaclisib, of whom 41 were evaluable for change in target tumor size. Median (range) age at baseline was 66.5 (52–87) years. ORR (95% confidence interval [CI]) was 88.1% (74.4–96.0), with 10 patients (23.8%) experiencing a complete response and 27 patients (64.3%) experiencing a partial response. Median (95% CI) duration of response was not reached (8.0 months−not estimable). The most common treatment‐emergent adverse events (TEAEs) were diarrhea (28.6%; grade ≥ 3, 7.1%) and stomatitis (23.8%; grade ≥ 3, 11.9%); TEAEs led to parsaclisib discontinuation in five patients (11.9%). There were no fatal TEAEs. In conclusion, parsaclisib monotherapy demonstrated durable responses with a manageable safety profile in Japanese patients with R/R FL. Trial Registration: ClinicalTrials.gov, NCT04434937

Immunotherapy has revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), significantly improving survival outcomes and offering renewed hope to patients. However, the presence of interstitial lung abnormalities (ILAs) in patients with NSCLC presents unique challenges, especially due to the elevated risk of immune checkpoint inhibitor (ICI)-related pneumonitis, which can result in treatment interruptions and adversely affect prognosis. ILAs, often detected incidentally on computed tomography imaging, are associated with an increased risk of progression to interstitial lung disease and have been identified as a potential predictor of poor clinical outcomes in patients with NSCLC receiving immunotherapy. This review offers an overview of the current understanding of the interaction between ILAs and ICI therapy, discussing prevalence, radiological features, risk stratification, and management strategies. Additionally, it highlights the need for prospective, multicenter studies to establish optimal treatment modalities for patients with NSCLC having ILAs, to ensure safer and more effective immunotherapy.

Background Evidence on structural valve deterioration (SVD) after aortic valve neocuspidization (AVNeo) remains limited. While transcatheter aortic valve replacement (TAVR) offers a less invasive option, its feasibility is unclear. This study aimed to characterize SVD patients post‐AVNeo and to assess TAVR feasibility. Methods This retrospective study included 11 patients who underwent TAVR for SVD after AVNeo in Sendai Kousei Hospital between June 2017 and August 2024. Four patients with aortic stenosis (AS) and seven with aortic regurgitation (AR) due to SVD were included. Results AS‐SVD group showed shorter time interval from AVNeo to TAVR (50.5 [28.3–98.3] vs. 107.0 [97.0–131.0] months, p = 0.04) and smaller aortic annulus area (316.5 [259.8–375.0] vs. 538.0 [440.0–582.0] mm ² , p = 0.005) than AR‐SVD group. In TAVR, technical success was achieved in 91% of cases. Although coronary obstruction is a concern due to the long leaflet, no case occurred. Misidentification of the basal ring plane caused by the slack cusp resulted in second valve implantation (one case) and new conduction disturbance (two cases) due to deep implantation, and aortic contained rupture (one case) for oversized valve selection. Conclusions Rapid AS‐SVD progression and AR‐SVD occurring later than previously reported were observed, highlighting the need for further studies on AVNeo durability. TAVR after AVNeo was feasible. Special precautions for coronary obstruction may be unnecessary. Careful hinge point placement at the boundary between pericardial cusps and the annulus was a key to CT‐based basal ring determination in patients after AVNeo.

Human epidermal growth factor receptor 2 (HER2) status is crucial for the classification of breast cancer and the selection of its treatment. Although HER2-low breast cancer is a recognized therapeutic subgroup, the classification of HER2 immunohistochemistry (IHC) 0 remains unclear. We reassessed 58 HER2-null breast cancer cases using an enhanced HER2 IHC protocol and the VENTANA OptiView detection system. HER2 expression was evaluated based on membrane positivity rate (%) and staining intensity. Microscopic assessment was performed to determine the percentage of HER2-positive tumor cells. Digital image analysis was used to quantify staining intensity. Detectable membrane HER2 positivity was observed in all tumors previously classified as HER2-null; the positivity rates ranged from 0.33% to 90% and the staining intensity indicated both inter- and intratumoral heterogeneity. These findings suggest that enhanced HER2 IHC protocols can improve detection sensitivity. This approach may help to refine HER2 classification and optimize patient selection for HER2-targeted therapies. Further research is needed to determine the clinical significance of HER2 expression detected using enhanced protocols.

Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) are salivary gland tumors with biphasic differentiation, composed of luminal ductal cells and abluminal basal cells with a high nuclear-to-cytoplasmic ratio. While BCA is a relatively common benign tumor, BCAC is a rare malignancy, and its genetic context and relationship with BCA remain unclear. We investigated 93 BCA and 36 BCAC cases to further characterize these two tumor entities from histological and molecular perspectives. BCA/BCAC proliferated in a mixture of tubular, trabecular, solid, cribriform, and membranous patterns. A jigsaw puzzle pattern, peripheral palisading, S100-positive stroma, cystic change, and sclerosis were observed in approximately 50% of the cases. BCAC demonstrated the following malignant features: infiltration to surrounding tissue, tumor necrosis, and increased mitotic activity (81%, 22%, and 22%, respectively). The nuclear expression of β-catenin was frequently observed in both BCA and BCAC (89% and 60%), and CTNNB1 hotspot mutations were detected in 46% and 48% of BCA and BCAC cases, respectively. Tubular patterns of growth, jigsaw puzzle patterns, peripheral palisading, S100-positive stroma, and cystic changes were more common in β-catenin-positive BCA/BCAC than in β-catenin-negative BCA/BCAC. Among the β-catenin-negative BCA/BCAC cases, one case each harbored PLAG1 and MYB rearrangements. We concluded that β-catenin-positive BCA and BCAC share common histologic and molecular features, and BCAC is considered a malignant counterpart of BCA. β-Catenin-negative BCA/BCAC might include morphological mimickers, which can be genetically classified into other tumor types, including pleomorphic adenoma and adenoid cystic carcinoma.

Background : Accumulating more steps/day provides considerable health benefits; however, studies of steps/day trends among a working population are quite limited. Moreover, steps/day trends may differ among occupations. We aimed to assess changes in steps/day by occupations in the Japanese working population. Methods : Workers aged 20–65 years were identified from the Japanese National Health and Nutrition Examination Survey conducted between 2001 and 2019. Steps/day were assessed using a pedometer. Occupations with or without income were categorized as professionals, managers, and clerks; sales workers, service workers, protective service workers, and agricultural/forestry/fishery workers; transport/machine operators; manufacturing/construction/cleaning laborers; homemakers; and unemployed individuals. Steps/day per decade were compiled for 2001–2010 and 2011–2019, and differences in age-adjusted steps/day between 2001–2010 and 2011–2019 were evaluated by an analysis of covariance. Results : A total of 105,492 workers among occupational categories were analyzed. Changes in age-adjusted steps/day (95% CI) per decade among occupations with income ranged from −873 (−1426 to −321) to 352 (−19 to 722) while those for homemakers and the unemployed ranged from −766 (−875 to −677) to −659 (−890 to −429). Only transport/machine operators did not reduce their steps/day (Δ = 352 [−19 to 722]); all other occupations significantly decreased their steps/day. Among occupations with income, the largest decrease was observed in protective service workers, followed by clerks. Moreover, clerks remained the occupational group with the lowest amount of steps/day in both periods. Conclusions : Most included occupations reduced their steps/day, and the degree of change varied widely among occupations. Further promotion of steps/day is warranted, especially for clerks.

Abnormalities in nuclear morphology are specific features of the nuclear envelopathies, including Emery‐Dreifuss muscular dystrophy (EDMD). The presence of abnormally shaped nuclei in the skeletal muscles of EDMD patients and murine models has been reported both in vivo and in vitro; however, how the presence of nuclear architectural abnormalities affects disease development and progression remains unclear. In this study, we analyzed slow‐twitch soleus (SOL) muscles and fast‐twitch extensor digitorum longus (EDL) muscles from the following EDMD model mice: emerin knockout (Emd), LmnaH222P/H222P knockin (H222P), and Emd/H222P double‐mutated (EH), to elucidate the effects of altered nuclear shapes on fiber‐type‐specific disease development. Dystrophic phenotypes were exclusively detected in the SOL muscles of EH mice, and myonuclear shape irregularities were observed only in the SOL muscle but not in the EDL muscle. Recovery from cardiotoxin (CTX) injection improved the shapes of peripheral myonuclei, and muscle histology and function, concomitant with an increase in the number and size of type 1 fibers in the regenerated SOL muscles of EH mice 42 days after the muscle damage. Importantly, nuclear morphology was relatively retained even after 126 days from the CTX injection, although dystrophic pathology gradually progressed. Taken together, our results indicate that the presence of nuclear morphological changes plays a minor role in the fiber‐type‐specific progression of muscular dystrophy in EDMD.

Apremilast is a phosphodiesterase 4 inhibitor approved for moderate to severe psoriasis in Japan. Apremilast significantly improved Physician's Global Assessment (PGA) and Dermatology Life Quality Index (DLQI) both at 6 and 12 months in a previously published primary post‐surveillance study. Here, we performed a post hoc analysis of the surveillance data to evaluate patient characteristics, effectiveness, and safety among psoriasis patients who continued apremilast for 6 and 12 months. The PMS included 992 patients, of whom 646 of 992 patients continued treatment for 6 months and 509 of 992 patients subsequently continued treatment for 12 months. Baseline characteristics between these groups were similar. Among 992 patients, the treatment persistence rate was 65.1% at 6 months and 51.3% at 12 months after the start of apremilast treatment. PGA 0/1 response was 47.9% at 6 months and 60.8% at 12 months, whereas DLQI 0/1 responses at 6 months and 12 months were 38.5% and 58.7%, respectively. Among 646 patients who continued apremilast for 6 months, diarrhea was reported in 60 patients (9.3%), nausea in 35 patients (5.4%), and headache in 11 (1.7%) patients, which were mainly observed within the first month since treatment initiation. In 509 patients who continued apremilast for 12 months, diarrhea was reported in 43 patients (8.5%), nausea in 24 patients (4.7%), and headache in 6 (1.2%) patients; similar frequencies of these adverse reactions were observed within 6 months and between 6 and 12 months of follow‐up. It is important to continue apremilast by appropriately managing diarrhea and nausea in real‐world practice.

Osteosarcoma (OS) is the most common malignant tumor of bone in children and adolescents. Although lung metastasis is a major obstacle to improving the prognosis of OS patients, the underlying mechanism of lung metastasis of OS is poorly understood. Tumor-associated macrophages (TAMs) with M2-like characteristics are reportedly associated with lung metastasis and poor prognosis in OS patients. In this study, we investigated the metastasis-associated tumor microenvironment (TME) in orthotopic OS tumor models with non-metastatic and metastatic OS cells. Non-metastatic and metastatic tumor cells derived from mouse OS (Dunn and LM8) and human OS (HOS and 143B) were used to analyze the TME associated with lung metastasis in orthotopic OS tumor models. OS cell–derived secretion factors were identified by cytokine array and enzyme-linked immunosorbent assay (ELISA). Orthotopic tumor models with metastatic LM8 and 143B cells were analyzed to evaluate the therapeutic potential of a neutralizing antibody in the development of primary and metastatic tumors. Metastatic OS cells developed metastatic tumors with infiltration of M2-like TAMs in the lungs. Cytokine array and ELISA demonstrated that metastatic mouse and human OS cells commonly secreted CCL2, which was partially encapsulated in extracellular vesicles. In vivo experiments demonstrated that while primary tumor growth was unaffected, administration of CCL2-neutralizing antibody led to a significant suppression of lung metastasis and infiltration of M2-like TAMs in the lung tissue. Our results suggest that CCL2 plays a crucial role in promoting the lung metastasis of OS cells via accumulation of M2-like TAMs. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-025-04051-x.