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Fabry disease (FD) is a rare X-linked lysosomal storage disorder. Enzyme replacement therapies (ERT), such as agalsidase α and β, are available treatment options. While infusion-related reactions (IRRs) are known to occur at the initiation of ERT owing to immune responses, there is limited information on IRRs during long-term ERT. We report the case of a female patient with Fabry disease who developed unexpected hypotension after six years of stable treatment with agalsidase α, leading to a switch to agalsidase β. Continuous monitoring may be essential to identify potential IRRs in female patients with Fabry disease receiving long-term ERT.

Chimeric antigen receptor (CAR) T cells are a major new treatment option for children, adolescents, and young adults (CAYA) patients with relapsed and refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL). Therefore, accumulating evidence from real-world experiences of CAR-T outcomes in various regions worldwide is important, particularly when comparing outcomes of patients with differing medical and ethnic backgrounds. More than 5 years have passed since tisagenlecleucel was approved in Japan. Here, we report a retrospective, multi-institutional investigation examining the association between baseline parameters and clinical outcomes. The aim was to investigate real-world experience and to better comprehend the efficacy of commercial tisagenlecleucel. A nationwide consortium called the Japan CAR-T Consortium conducted a retrospective, multicenter study of CAYA patients who received CAR-T cell treatment with commercial tisagenlecleucel. Forty-two patients with R/R B-ALL whose leukapheresis samples were shipped to Novartis for commercial tisagenlecleucel manufacture were included in the analysis. All infused patients were included in the response, toxicity, and survival analyses. The best overall response rate was 93%. The 1-year overall survival and event-free survival (EFS) rates after infusion were 82% and 56%, respectively. Twenty-seven (64%) had low disease burden (LB, defined as <5% bone marrow [BM] lymphoblasts) prior to tisagenlecleucel infusion. LB was associated with superior outcomes, with a 1-year EFS rate of 80% compared with 24% in high disease burden (≧5% BM lymphoblasts). Multivariate analysis identified an association between prior hematopoietic stem cell transplantation (HSCT) (n = 23, 55%) and superior outcomes, with a 1-year EFS rate of 75% compared with 24% for patients without prior HSCT. This first analysis of CAYA patients with R/R B-ALL undergoing treatment with commercial tisagenlecleucel in Japan reports an efficacy similar to that in clinical trials and other real-world studies and confirms that LB and prior HSCT are associated with superior EFS., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: HG received lecture fees from Novartis. All other authors declare no competing interests.

Gadolinium contrast medium can serve as an alternative to iodinated contrast medium when the latter is unsuitable. In this report, we describe a case of a carotid-ophthalmic aneurysm in which angiograms were obtained using gadolinium contrast medium for flow-diverter stent placement due to the patient's history of bronchial asthma and hypersensitivity reactions to iodinated contrast medium. To enhance the visibility of gadolinium contrast medium, which typically provides lower contrast compared to iodinated contrast medium, we employed a contrast-enhancing and noise-reducing protocol on our image-guided therapy system. We performed catheterization and established working angles guided by a roadmap based on previous magnetic resonance angiography, the position of which was adjusted using cone-beam computed tomography performed before the intervention. This approach helped reduce the amount of contrast medium required. The procedure was successful and did not induce hypersensitivity reactions, morbidity, or mortality. Thus, the efficacy of the contrast-enhancing imaging protocol and the magnetic resonance angiography-based roadmap was confirmed. Measures must be taken to address gadolinium contrast medium-specific adverse events, limitations on the amount of contrast medium used, and the issue of low-contrast angiograms., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Recent studies have indicated that total body irradiation (TBI)-based reduced-toxicity conditioning (RTC) may be a potential treatment modality, especially in adults with leukemia. However, its efficacy and safety in children with hematological malignancies remain unclear. To investigate the long-term outcomes and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) using an 8-Gray (Gy) TBI/fludarabine (FLU)/cyclophosphamide (CY) RTC in children with hematological malignancies. We included 66 consecutive patients with leukemia, lymphoma, or myelodysplastic syndrome in this retrospective cohort study. Participants were < 25 years old and received an 8-Gy TBI/FLU/CY RTC regimen followed by the first allo-HSCT at Shinshu University Hospital between March 2004 and March 2021. The 5-year overall and relapse-free survival probabilities were 88.2% and 76.5%, respectively, in the lymphoid malignancy group. The myeloid malignancy group had probabilities of 72.4% and 58.6%, respectively. The 5-year cumulative incidences of relapse and non-relapse mortality were 20.6% and 2.9%, respectively, in the lymphoid malignancy group. These incidences were 37.9% and 3.4%, respectively, in the myeloid malignancy group. All patients had engraftment without early relapse and none developed grade 5 regimen-related toxicity within 28 days after allo-HSCT. Nonetheless, two patients had congenital abnormalities caused by chromosomal aberrations and died without relapse. 8-Gy TBI/FLU/CY RTC was safe in children with hematological malignancies, regardless of the donor source. However, safety concerns were noted in cases of chromosomal aberration-induced congenital abnormalities. Additionally, patients in the lymphoid and myeloid malignancy groups had favorable prognoses., (© 2024 The Author(s). Hematological Oncology published by John Wiley & Sons Ltd.)

Eltrombopag is used with first-line immunosuppressive therapy for adult aplastic anemia, although its practical utility in childhood remains unclear. We retrospectively analyzed the outcomes of pediatric patients who received eltrombopag in Japan. Of the 27 eligible patients, 23 (85%) were previously treated, and 15 (56%) had severe or very-severe disease. Seventeen (63%) received eltrombopag with or after rabbit anti-thymocyte globulin plus cyclosporin-A. Within the first year of eltrombopag therapy, 12 patients showed a good or partial response, 15 showed no response, and 8 non-responders successfully underwent hematopoietic cell transplantation. Within the first 3 months after eltrombopag therapy, all but one of the transfusion-dependent responders became transfusion-independent. At 12 months, 6 of 12 responders were disease-free off-treatment. The one-year overall response rate was higher for severe or very-severe than non-severe cases (p = 0.006). Multivariable analysis showed that very-severe disease at the start of eltrombopag therapy was a predictor of being disease-free off-treatment (p = 0.03). No cytogenetic abnormalities developed, but myelofibrosis occurred 4 months after eltrombopag therapy in one non-responder with very-severe disease. The first 3 months' response to adjunctive eltrombopag may guide to the safe and effective use for the cure of disease, although prospective trials are needed to determine its long-term effects., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest in association with the present study., (© 2024. The Author(s), under exclusive licence to Japanese Society of Hematology.)

Despite numerous studies, the associations between per- and polyfluoroalkyl substances (PFAS) exposure and various lipid levels in pregnant women remain ambiguous, especially concerning the association with cord blood lipids. This analysis included 20,960 pregnant women enrolled in the Japan Environment and Children's Study, recruited between 2011 and 2014. Non-fasting plasma samples collected before 22 weeks of gestation were examined for PFAS concentrations. Additionally, non-fasting serum samples collected before, at and after 22 weeks of gestation, at birth, and from cord blood were used to measure total cholesterol (TC) and triglycerides (TG). Linear regression models were applied to quantify the association between each PFAS and various lipid metrics. Among the 28 PFAS analyzed, 7 were quantifiable in more than 80% of participants. Of these, 6 PFAS showed positive associations with TC in maternal blood before 22 weeks of gestation, a trend that remained mostly consistent for maternal blood samples in later stages. However, no associations were found with TC levels in cord blood. Regarding TG, 3 PFAS demonstrated a negative association with TG levels in maternal blood before 22 weeks of gestation, with these relationships generally persisting in later stages, while 4 PFAS were positively associated with TG in cord blood. In summary, this study identified associations between PFAS concentrations in maternal blood and lipid levels in both maternal and cord blood, with differing patterns observed between the two., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A 65-year-old man, a post living donor kidney transplant patient, was admitted to the intensive care unit (ICU) with a severe bacterial infection. He also tested positive for coronavirus disease and had a cough. On admission, heparin was administered for atrial fibrillation. On the third day of hospitalization, his general condition had recovered, and he was discharged from the ICU to the general ward. On the fourth day of hospitalization, he experienced abdominal pain, and a hard mass was palpated in the left lower abdomen. On the fifth day of hospitalization, contrast-enhanced computed tomography showed an extensive rectus sheath hematoma (RSH) extending from the left lower abdominal wall to the left side of the bladder, with extravasation from a small branch of the left inferior epigastric artery. Heparin was discontinued, and transcatheter arterial embolization was performed to control the bleeding. RSH is a rare disease, and cases of extensive hematoma in post-kidney transplant patients occur even less frequently. Patients taking anticoagulants and those with chronic kidney disease are at high risk for RSH, so physicians should be cognizant of this disease when these patients develop abdominal pain., Competing Interests: Declarations. Conflict of interest: The authors have declared that no conflict of interest exists. Research involving human participants: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional review board (approval number: 2010–1135) and with the Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from the participant included in the study., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Brain arteriovenous malformations (bAVMs) are anomalies forming vascular tangles connecting the arteries and veins, which cause hemorrhagic stroke in young adults. Current surgical approaches are highly invasive, and alternative therapeutic methods are warranted. Recent genetic studies identified KRAS mutations in endothelial cells of bAVMs; however, the underlying process leading to malformation in the postnatal stage remains unknown. Here we established a mouse model of bAVM developing during the early postnatal stage. Among 4 methods tested, mutant KRAS specifically introduced in brain endothelial cells by brain endothelial cell-directed adeno-associated virus (AAV) and endothelial cell-specific Cdh5-CreERT2 mice successfully induced bAVMs in the postnatal period. Mutant KRAS led to the development of multiple vascular tangles and hemorrhage in the brain with increased MAPK/ERK signaling and growth in endothelial cells. Three-dimensional analyses in cleared tissue revealed dilated vascular networks connecting arteries and veins, similar to human bAVMs. Single-cell RNA-Seq revealed dysregulated gene expressions in endothelial cells and multiple cell types involved in the pathological process. Finally, we employed CRISPR/CasRx to knock down mutant KRAS expression, which efficiently suppressed bAVM development. The present model reveals pathological processes that lead to postnatal bAVMs and demonstrates the efficacy of therapeutic strategies with CRISPR/CasRx.

Background: Giant cell arteritis (GCA) infrequently presents with progressive symptomatic vertebrobasilar stenosis. Vertebrobasilar GCA is often refractory to medical treatments and can lead to short-term ischemic stroke recurrence, which is associated with a poor prognosis. Endovascular treatment (EVT) is a therapeutic option; however, the optimal timing and indications for its application remain unclear., Observations: This study reports two patients with vertebrobasilar GCA who exhibited repeated ischemic strokes in the vertebrobasilar territory, along with progressive severe stenosis and occlusion of the bilateral vertebral arteries, despite receiving medical therapy. They were successfully treated with balloon angioplasty, and there were no subsequent occurrences of stroke or restenosis. A review was conducted of six cases of vertebrobasilar GCA treated with EVT. All patients had bilateral lesions and experienced recurrent strokes within 30 days. Angiography suggested ischemic complications in vertebrobasilar GCA resulting from hemodynamic ischemia caused by stenosis rather than intradural vasculitis. The improved blood flow through EVT alleviated patient symptoms and prevented recurrent strokes., Lessons: Some patients with vertebrobasilar GCA exhibit rapid stenosis progression and repeated hemodynamic ischemia despite medical therapy. EVT is a potential strategy for treating medically refractory vertebrobasilar GCA. Performing EVT prior to recurrent infarctions can lead to favorable outcomes. https://thejns.org/doi/10.3171/CASE24404.

Hypomethylating agent treatment for myeloid leukemia associated with Down syndrome (ML-DS) has been scarcely reported. Herein, we collected information on azacitidine treatment for ML-DS in Japan. Forty-eight cycles of azacitidine treatment were performed for 12 patients, including 11 relapsed or refractory (R/R) patients. In 40 cycles, azacitidine was used as monotherapy. No azacitidine-related death was observed. One cycle concurrently administered with methotrexate-based intrathecal therapy was discontinued due to toxicities. Only 4 of the 19 cycles given in non-remission achieved complete or partial remission. In conclusion, although most toxicities were acceptable, azacitidine monotherapy might be insufficient for R/R ML-DS cases., (© 2024 Wiley Periodicals LLC.)

A 50-year-old man who had undergone a living-donor kidney transplant 12 years prior for chronic renal failure due to autosomal dominant polycystic kidney disease contracted coronavirus disease 19 (COVID-19). He had a positive antigen test, mild symptoms, sore throat, and fever of 37.9 ℃. The patient was treated with molnupiravir for 5 days, and the symptoms disappeared 5 days after onset. However, 10 days after onset, he developed a fever of approximately 37 ℃ and a non-productive cough; 27 days after onset, the patient was hospitalized for anorexia and a worsening respiratory condition. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen test results on admission were negative, and no antiviral medications were administered against SARS-CoV-2. Computed tomography revealed extensive ground-glass opacities in both lung fields. The patient was treated with steroid pulse therapy, ceftriaxone, atovaquone, azithromycin, and respiratory management using a high-flow nasal cannula. The combined therapies were successful, and the patient was managed with a nasal oxygen cannula after 3 days. Oxygen administration was discontinued after 6 days of hospitalization, and the patient was discharged after 14 days. Based on the laboratory findings, bacterial, interstitial, and Pneumocystis pneumonia were unlikely. The success of the steroid pulse therapy suggested that respiratory failure was caused by pneumonia due to the immune response after COVID-19 infection., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Despite several small-molecule drugs that have revolutionized the current treatment strategy for acute myeloid leukemia (AML), hematopoietic stem cell transplantation remains the only curative treatment in most cases to date. Chimeric antigen receptor (CAR)-T cell therapy is one of the most promising next-generation cancer therapies for hematological malignancies and is clinically available for treatment of AML. However, developing AML-targeted CAR-T therapy is challenging because of the heterogeneity of target antigen expression across leukemic cells and patients, the difficulty in excluding on-/off-target tumor effects, and the immunosuppressive tumor microenvironment. To date, various targets, including CD33, NKG2D, CD123, CLL-1, and CD7, have been actively studied for CAR-T cells. Although no CAR-T cell products are close to practical use, several clinical trials have shown promising results, particularly for CAR-T cells targeting CLL-1 or CD123. Meanwhile, research exploring the ideal target for AML-targeted CAR-T therapy continues. Furthermore, as collecting autologous lymphocytes from patients with AML is difficult, development of off-the-shelf CAR-T products is being actively pursued. This review discusses the challenges in AML-targeted CAR-T cell therapy development from the perspectives of target antigen characteristics and AML-specific on-target/off-tumor toxicity. Moreover, it discusses the clinical development and prospects of AML-targeting CAR-T cells., (© 2024. Japanese Society of Hematology.)

Introduction: Immunosuppressed patients exhibit low antibody acquisition rates following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Kidney transplant recipients previously exhibited low antibody acquisition rates after two vaccine doses, which increased after the third dose. We evaluated antibody titers of Japanese post-kidney transplant patients after the fourth and fifth vaccinations., Methods: Antibody titers for SARS-CoV-2 spike protein were measured between 3 weeks and 3 months after the fourth or fifth vaccination., Results: Increased antibody acquisition rates were observed after the fourth (75.0% antibody-positive) and fifth (81.5% antibody-positive) vaccinations. The antibody-acquired group after the fourth vaccination exhibited a higher body mass index and estimated glomerular filtration rate (eGFR) than the non-acquired group. A higher eGFR was associated with antibody acquisition after the fifth vaccination., Conclusion: In Japanese post-kidney transplant patients, the antibody acquisition rate increased with each vaccine additional dose. Additional vaccinations are recommended to protect against SARS-CoV-2 infection., (© 2024 International Society for Apheresis and Japanese Society for Apheresis.)

Background: Extracellular vesicles (EVs) have received considerable attention as ideal biomarkers for kidney diseases. Most reports have focused on urinary EVs, that are mainly derived from the cells in the urinary tract. However, the detection and the application of kidney-derived EVs in plasma remains uncertain., Methods: We examined the kidney-derived small EVs (sEVs) in plasma that were supposedly released from renal mesangial and glomerular endothelial cells, using clinical samples from healthy controls and patients with kidney transplants. Plasma from healthy controls underwent ultracentrifugation, followed by on-bead flow cytometry, targeting α8 integrin, an antigen-specific to mesangial cells. To confirm the presence of kidney-derived sEVs in peripheral blood, plasma from ABO-incompatible kidney transplant recipients was ultracentrifuged, followed by western blotting for donor blood type antigens., Results: Immunohistochemistry and immunoelectron microscopy confirmed α8 integrin expression in kidney mesangial cells and their sEVs. The CD9-α8 integrin double-positive sEVs were successfully detected using on-bead flow cytometry. Western blot analysis further revealed transplanted kidney-derived sEVs containing blood type B antigens in non-blood type B recipients, who had received kidneys from blood type B donors. Notably, a patient experiencing graft kidney loss exhibited diminished signals of sEVs containing donor blood type antigens., Conclusion: Our findings demonstrate the potential usefulness of kidney-derived sEVs in plasma in future research for kidney diseases., (© 2024. The Author(s).)

A 16-year-old girl with fever that appeared after taking the second COVID-19 vaccine presented to the clinic with a serum creatinine of 0.89 mg/dL and C-reactive protein of 6.9 mg/dL. She had proteinuria and microscopic hematuria, with slowly worsening kidney function. Her kidney biopsy showed fibrocellular crescents in seven of nine glomeruli that were observed under light microscopy. Another glomerulus showed endocapillary hypercellularity and mesangial cell proliferation. Electron-dense deposits were significant in the mesangial area, with monoclonal IgG1-κ and C3 deposition by immunofluorescence. The patient was diagnosed with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and atypical pathological finding of diffuse crescent formation. The treatment regimen for PGNMID has not yet been established, and the appropriate duration of treatment is unknown. In our case, considering that rituximab acts by binding to CD20 on the surface of B cells through its crystallizable fragment, it was administered in addition to prednisolone, which successfully decreased the proteinuria over time., (© 2023. The Author(s) under exclusive licence to Japanese Society of Nephrology.)

Introduction: Simple plasma exchange (PE) with fresh-frozen plasma replacement allows antibody removal for ABO-incompatible living donor kidney transplantation, but is associated with a high incidence of allergic reactions. We developed, implemented, and evaluated a protocol for safe preoperative PE., Methods: The protocol comprised pretreatment (125 mg methylprednisolone infusion, 400 mg acetaminophen and 30 mg diphenhydramine orally) with a replacement fluid rate < 20 mL/min. Allergic reaction incidence was investigated in controls who underwent ABO-incompatible living donor kidney transplantation between 2016 and March 2020 (group C) and patients who underwent the protocol and procedure between April 2020 and February 2023 (group N)., Results: Ten (group C) and 19 (group N) patients performed 11 and 30 sessions of PE, respectively. Allergic reactions occurred in 81.8% and 36.7% (p = 0.014), respectively, with an odds ratio of the protocol was 0.056 (95% CI 0.0059-0.5380, P = 0.013)., Conclusion: Our protocol resulted in a significantly lower incidence of allergic reactions., (© 2023 International Society for Apheresis and Japanese Society for Apheresis.)

Chimeric antigen receptor (CAR)-T cell therapy is among the most promising immunotherapies for hematological malignancies and can be used to treat myeloid malignancies in practice. However, developing CAR-T therapies for such diseases is particularly challenging due to the heterogeneity of target antigen expression across leukemic cells and patients, the difficulty in excluding on-target/off-target tumor effects, and the immunosuppressive tumor microenvironment. To date, various targets, including CD33, NKG2D, CD123, CLL-1, and CD7, have been actively studied for CAR-T cells, especially for acute myeloid leukemia (AML). Although no CAR-T cell products have been approved, several clinical trials have shown promising results, particularly for those targeting CLL-1 and CD123. Furthermore, new ideal targets and use of allogeneic or off-the-shelf CAR-T cell products are under investigation. Meanwhile, it remains unknown whether CAR-T therapy would be effective for other myeloid malignancies, including myelodysplastic syndromes and myeloproliferative diseases. This review discusses challenges in the development of CAR-T therapy for myeloid malignancies, especially for AML, from the perspectives of target antigen characteristics and disease-specific on-target/off-tumor toxicity. Moreover, it discusses the clinical development and prospects of CAR-T cells for these diseases.

Purpose: Liquid biopsy of cyst fluid in brain tumors has not been extensively studied to date. The present study was performed to see whether diagnostic genetic alterations found in brain tumor tissue DNA could also be detected in cell-free DNA (cfDNA) of cyst fluid in cystic brain tumors., Methods: Cyst fluid was obtained from 22 patients undergoing surgery for a cystic brain tumor with confirmed genetic alterations in tumor DNA. Pathological diagnoses based on WHO 2021 classification and diagnostic alterations in the tumor DNA, such as IDH1 R132H and TERT promoter mutation for oligodendrogliomas, were detected by Sanger sequencing. The same alterations were analyzed by both droplet digital PCR (ddPCR) and Sanger sequencing in cyst fluid cfDNA. Additionally, multiplex ligation-dependent probe amplification (MLPA) assays were performed to assess 1p/19q status, presence of CDKN2A loss, PTEN loss and EGFR amplification, to assess whether differentiating between astrocytomas and oligodendrogliomas and grading is possible from cyst fluid cfDNA., Results: Twenty-five genetic alterations were found in 22 tumor samples. All (100%) alterations were detected in cyst fluid cfDNA by ddPCR. Twenty of the 25 (80%) alterations were also detected by Sanger sequencing of cyst fluid cfDNA. Variant allele frequency (VAF) in cyst fluid cfDNA was comparable to that of tumor DNA (R = 0.62, Pearson's correlation). MLPA was feasible in 11 out of 17 (65%) diffuse gliomas, with close correlation of results between tumor DNA and cyst fluid cfDNA., Conclusion: Cell-free DNA obtained from cyst fluid in cystic brain tumors is a reliable alternative to tumor DNA when diagnosing brain tumors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and NOTCH1 and RUNX3 activation and BCL11B down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l-asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l-asparaginase.

Neuroblastoma, a prevalent extracranial solid tumor commonly afflicting pediatric patients, exhibits a diverse spectrum of clinical presentations. Preseptal cellulitis, a childhood infectious ailment, typically demonstrates a favorable response to conservative antibiotic therapy. In this report, we present the case of a two-year-old female child with refractory preseptal cellulitis, ultimately leading to an unforeseen diagnosis of neuroblastoma. Early radiological assessment upon the onset of preseptal cellulitis serves the dual purpose of excluding severe complications and uncovering latent, rare pathologies when the initial antibiotic regimen proves ineffective., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Furui et al.)

Fibrillary glomerulonephritis (FGN), a rare disease is pathologically characterized by glomerular fibril accumulation ranging from 12 to 24 nm in diameter with negative Congo red staining. Recently, the identification of DnaJ homolog subfamily B member 9 (DNAJB9) as a highly sensitive and specific marker for FGN has revolutionized diagnosis of this disease. However, few recent studies have reported DNAJB9-negative glomerulonephritis with fibrillar deposits. As such, it remains unclear whether DNAJB9-negative cases can be considered equivalent to FGN. Here, we report the case of a 70-year-old woman who developed renal impairment and nephrotic-range proteinuria. Renal biopsy and pathological examination revealed focal glomerulonephritis with fibrocellular crescents. Immunofluorescence microscopy showed IgA-dominant deposition of polytypic IgG in the glomerulus. Electron microscopy revealed hump-like subepithelial electron dense deposits with fibrils of 15-25 nm in diameter. These findings were consistent with FGN; thus, Congo red and direct fast scarlet (DFS) staining, and immunohistochemistry for DNAJB9 were performed. In addition to negative Congo red/DFS/DNAJB9 staining, laser microdissection (LMD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) resulted negative for DNAJB9, which is a highly sensitive and specific marker for FGN. The patient's renal function further declined, prompting administration of rituximab weekly for 2 weeks, similar to the treatment for FGN. This is a unique case of IgA-dominant glomerulonephritis with DNAJB9-negative fibrillar polytypic immunoglobulin deposits in the subepithelium, unlike previous DNAJB9-negative cases. Thus, DNAJB9-negative cases diagnosed based on accurate electron microscopic evaluation must be gathered, and LMD and LC-MS/MS must be used to analyze the organized fibrillar deposits to reveal the disease entity., (© 2022. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Background: T-cell acute lymphoblastic leukaemia has distinct biological characteristics and a poorer prognosis than B-cell precursor acute lymphoblastic leukaemia. This trial aimed to reduce the rate of radiation and haematopoietic stem-cell transplantation (HSCT) while improving outcomes by adding nelarabine, intensified L-asparaginase, and protracted intrathecal therapy in the Berlin-Frankfurt-Münster (BFM)-type treatment., Methods: In this nationwide, multicenter, phase 2 trial, we enrolled patients with newly diagnosed T-cell acute lymphoblastic leukaemia (age <25 years at diagnosis) conducted by Japan Children's Cancer Group and Japan Adult Leukemia Study Group. Patients were stratified into standard-risk, high-risk, and very-high-risk groups according to prednisolone response, CNS status, and end-of-consolidation minimal residual disease. We used the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP)-BFM-ALL 2000-backbone chemotherapy. Nelarabine (650 mg/m 2 per day for 5 days) was given to high-risk and very high-risk patients. All patients received, until the measurement of end-of-consolidation minimal residual disease, an identical therapy schedule, which included the prednisolone pre-phase remission induction therapy with dexamethasone (10 mg/m 2 per day, for 3 weeks [for patients <10 years] or for 2 weeks including a 7-day off interval [for patients ≥10 years]) instead of prednisolone, and consolidation therapy added with Escherichia coli-derived L-asparaginase. On the basis of the stratification, patients received different intensities of treatment; L-asparaginase-intensified standard BFM-type therapy for standard risk and nelarabine-added high risk BFM-type therapy for high risk. In the very high-risk group, patients were randomly assigned (1:1) to group A (BFM-based block therapy) and group B (another block therapy, including high-dose dexamethasone) stratified by hospital, age (≥18 years or <18 years), and end-of-induction bone marrow blast percentage of M1 (<5%) or M2 (≥5%, <25%)+M3 (≥25%). Cranial radiotherapy was limited to patients with overt CNS disease at diagnosis (CNS3; >5 white blood cells per μL with blasts) and patients with no evidence of CNS disease received protracted triple intrathecal therapy. Only very high-risk patients were scheduled to receive HSCT. The primary endpoint was 3-year event-free survival for the entire cohort and the proportion of patients with disappearance of minimal residual disease between randomly assigned groups A and B in the very high-risk group. Secondary endpoints were overall survival, remission induction rate, and occurrence of adverse events. 3 years after the completion of patient accrual, a primary efficacy analysis was performed in the full analysis set and the per-protocol set. This study is registered with the Japan Registry of Clinical Trials, jRCTs041180145., Findings: Between Dec 1, 2011, and Nov 30, 2017, of 349 eligible patients (median age 9 years [IQR 6-13]), 238 (68%) were male, and 28 (8%) patients had CNS3 status. 168 (48%) patients were stratified as standard risk, 103 (30%) as high risk, 39 (11%) as very high risk, and 39 (11%) as no risk (patients who had off protocol treatment before risk assessment. The composite complete remission (complete remission plus complete remission in suppression) rate after remission induction therapy was 89% (298 of 335 patients). HSCT was performed in 35 (10%) of 333 patients. With a median follow-up of 5·2 years (IQR 3·6-6·7), 3-year event-free survival was 86·4% (95% CI 82·3-89·7%) and 3-year overall survival was 91·3% (87·7-93·8%). The proportion of minimal residual disease disappearance was 0·86 (12 of 14 patients; 95% CI 0·57-0·98) in group A and 0·50 (6 of 12 patients, 0·21-0·79) in group B. Grade 3 peripheral motor neuropathy was seen in 11 (3%) of 349 patients and sensory neuropathy was seen in 6 (2%) patients. The most common grade 3 or worse adverse event was febrile neutropenia (294 [84%] of 349 patients). Treatment-related death occurred in three patients due to sepsis, gastric perforation, or intracranial haemorrhage during remission induction., Interpretation: The ALL-T11 protocol produced encouraging outcomes with acceptable toxicities despite limited cranial radiotherapy and HSCT use., Funding: Ministry of Health, Labor and Welfare of Japan, and Japan Agency for Medical Research and Development., Translation: For the Japanese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AS has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Chugai Pharmaceutical. YH has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Kyowa Kirin, Novartis Pharma, and Nippon Shinyaku. CI has received patent royalty in Juno Therapeutics and CURED, consulting fees from CURED and, as a filing of a new patent is being planned in CURED, has a Stock option in CURED. MK received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Amgen, Chugai Pharmaceutical, and Novartis Pharma, and received grants from from Otsuka Pharmaceutical. SSu has a contract from the Division of General Pediatrics and Emergency Medicine, Oita City, and also has leadership in Japan Children's Cancer Group and The Japanese Society of Pediatric Hematology and Oncology. HK has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Abbvie, Chugai Pharmaceutical, Astellas Pharma, and Novartis Pharma. IM has received grants from Ono Pharmaceutical, Janssen Pharmaceutical, Nippon Shinyaku, Kyowa Kirin, Sumitomo Dainippon Pharma, Shionogi & Co, Teijin Pharma, Boehringer Ingelheim, Sanofi, Chugai Pharmaceutical, Eisai, MSD, Asahi Kasei Pharma Corporation, Astellas Pharma, Takeda Pharmaceutical, Nihon Pharmaceutical, Daiichi Sankyo, AbbVie, Taiho Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku, CSL Behring, Mundipharma, AYUMI Pharmaceutical Corporation, Eli Lilly Japan, Actelion Pharmaceuticals Japan, and Amgen BioPharma. IM has also received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Bristol-Myers Squibb (Celgene), Novartis, Otsuka Pharmaceutical, Pfizer Japan, Janssen, Astellas Pharma, Takeda Pharmaceutical, and Daiichi Sankyo, and has received consulting fees from Otsuka Pharmaceutical. YM has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Novartis Pharma and Kyowa-Kirin. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Hematohidrosis is a rare disorder characterized by bloody sweating on the skin without trauma. The ear, nose, and other facial areas are the most commonly affected sites. This study shows usefulness of beta-blockers in the treatment of hematohidrosis., Competing Interests: We declare that there are no conflicts of interest., (© 2023 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Purpose: Flow re-direction endoluminal device (FRED) is a novel dual-layer flow-diverting stent to treat cerebral aneurysms with high obliteration rates, however, it induces inevitable metal-related artifacts. We compared silent magnetic resonance angiography (MRA), a new MRA method using ultra-short time of echo and arterial spin-labeling, with conventional time-of-flight (TOF)-MRA for imaging aneurysms treated using FRED., Methods: Between May 2020 and September 2022, 16 patients with unruptured internal carotid aneurysms treated using FRED simultaneously underwent silent MRA and TOF-MRA after treatment, with 36 follow-up sessions in total. Two observers independently graded the quality of intra-aneurysmal flow and stented parent arteries under both types of MRA from 1 (not visible) to 4 (nearly equal to digital subtraction angiography [DSA]), with reference to DSA images as a standard criterion., Results: The mean scores for intra-aneurysmal flow and stented parent arteries were significantly better for silent MRA (3.93  ±  0.21 and 3.82  ±  0.32, respectively) than for TOF-MRA (2.08  ±  0.99 and 1.92  ±  0.79, respectively) ( P  < 0.01). Intermodality agreements for intra-aneurysmal flow and stented parent arteries were 0.87 and 0.90, respectively., Conclusion: Silent MRA is superior to TOF-MRA for assessing patients treated with FRED, with potential as an alternative imaging modality to DSA.

Background: The treatment of membranous nephropathy involves a combination of conservative approaches, steroids, and immunosuppressive agents. Infection is an adverse effect of these treatments and its incidence is a critical issue for patients with membranous nephropathy, as many of them are older adults. However, the incidence of infections remains unclear; hence, this study investigated this issue using data from a large Japanese clinical claims database., Methods: From a database of patients with chronic kidney disease (n = 924,238), those diagnosed with membranous nephropathy from April 2008 to August 2021 with a history of one or more prescriptions and undergoing medical care were included. Patients who had undergone kidney replacement therapy were excluded. Patients were divided into three groups based on their prescriptions after diagnosis: prednisolone(PSL), who received steroids; PSL + IS, who were prescribed steroids and immunosuppressive agents; and C, who were treated without steroid or immunosuppressive agent use. The primary outcome was death or the initiation of kidney replacement therapy. The secondary outcome was death or hospitalization due to infection. Infectious diseases such as sepsis, pneumonia, urinary tract infections, cellulitis, cytomegalovirus infection, colitis, or hepatitis were defined as infections. Hazard ratios were expressed using group C as a reference., Results: Of 1,642 patients, the incidence of the primary outcome occurred in 62/460 individuals in the PSL group, 81/635 individuals in the PSL + IS group, and 47/547 individuals in the C group. The Kaplan-Meier survival curve showed no significant differences (P = 0.088). The incidence of secondary outcomes occurred in 80/460 individuals, 102/635 individuals, and 37/547 individuals in the PSL, PSL + IS, and C groups, respectively. The incidence of secondary outcomes was significantly higher in the PSL group (hazard ratio [HR] 2.43 [95% confidence interval [CI] 1.64-3.62, P < 0.01]) and PSL + IS group (HR 2.23 [95% CI 1.51-3.30, P < 0.01])., Conclusions: The outcome of membranous nephropathy was not completely satisfactory. Patients who use steroids and immunosuppressive agents have a high incidence of infection and may require close monitoring during the course of treatment.High-efficacy treatment with a low incidence of infections is desirable. The significance of this study lies in the fact that the impressions of membranous nephropathy, which have been recognized as tacit knowledge, were quantified using a clinical database., (© 2023. The Author(s).)

Tacrolimus is widely used as prophylaxis for graft-versus-host disease (GVHD) in allogeneic stem cell transplantation (allo-HSCT). It has a narrow therapeutic index range; high tacrolimus concentrations are associated with toxicity, whereas low concentrations are associated with an increased risk of GVHD. Although dose adjustments based on therapeutic drug monitoring are performed, unexpected large variations in tacrolimus concentration are sometimes encountered. The available evidence suggests that the factors affecting tacrolimus concentration are not fully understood. This study was aimed primarily at investigating the factors affecting day-to-day variations in tacrolimus concentration in children and young adults who received continuous tacrolimus infusion after allo-HSCT. The secondary objective was to identify the factors causing large variations (>20%) in tacrolimus concentrations. This retrospective cohort study comprised 123 consecutive pediatric and young adult patients (age <25 years) who received continuous i.v. tacrolimus infusion after allo-HSCT at Shinshu University Hospital, Matsumoto, Japan, between January 2009 and December 2021. To compare day-to-day variations in tacrolimus concentration without consideration of the tacrolimus dose, 2 consecutive days when the tacrolimus dose was not changed were selected from between the first post-allo-HSCT day of a tacrolimus concentration >7 ng/mL and day 28 post-allo-HSCT. Subsequently, information for the subsequent 24 hours was collected along with the tacrolimus concentrations and hematocrit values. Tacrolimus concentration was determined using whole blood samples. Tacrolimus concentrations were significantly higher in patients who received red blood cell concentrate (RCC) transfusions (P < .0001) and methotrexate (P = .0162), patients with persistent fever (P = .0056), and patients with a decline in fever (P = .0003). In contrast, tacrolimus concentrations were significantly lower in patients who received platelet concentrate (PC) transfusions (P < .0001), who redeveloped fever (P = .0261), and who had a replaced tacrolimus administration route set (P = .0008). Variations in tacrolimus concentration were significantly correlated with variations in hematocrit (r = .556; P < .0001). Body weight (P < .0001), RCC transfusion (P < .0001), methotrexate use (P = .0333), persistent fever (P = .0150), and decline in fever (P = .0073) were associated with a sharp increase in tacrolimus concentration. In contrast, body weight (P < .0001), PC transfusion (P = .0025), and replacement of the tacrolimus administration route set (P = .0025) were associated with a sharp decrease in tacrolimus concentration. RCC and PC transfusions, fever, methotrexate administration, and replacement of the tacrolimus administration route set were independent factors affecting day-to-day variations in tacrolimus concentration. In addition to these factors, low body weight was a risk factor for both sharp increases and decreases in tacrolimus concentration. These findings suggest the need for better control of tacrolimus concentration using whole blood samples., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Thrombocytopenia is a common abnormality encountered in the neonatal period, and immature platelet fraction (IPF) may be an informative indicator of thrombopoiesis; however, data on IPF in neonates are scarce. To define reference intervals (RIs) and factors affecting IPF in neonates, we measured the IPF of 533 consecutive neonates. With a multiple regression analysis of 330 newborns with normal platelet counts at birth, premature delivery, neonatal asphyxia, intrauterine infection, chromosomal abnormalities, and respiratory disorders were identified as independent factors for IPF%. The RIs of IPF% and absolute IPF value in neonates were determined to be 1.3% to 5.7% and 3.2 to 14.5×10 9 /L, respectively. On day 14 after birth, IPF% increased to twice the value at birth and thereafter returned to the previous value on day 28. Reticulocyte counts, in contrast, were the lowest at day 14. IPF% was increased in 16 thrombocytopenic patients with various clinical conditions, especially those with immune-mediated thrombocytopenia. IPF in neonates may be evaluated essentially based on the same RIs as in adults, although some precautions must be taken when evaluating IPF in neonates in the first 2 weeks of life. IPF may be useful for evaluating thrombopoiesis and thrombocytopenia in neonates., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Podoplanin (PDPN) is known to induce platelet aggregation via interacting with the C-type lectin-like receptor-2 on platelets and is involved in postoperative venous thromboembolism (VTE) formation. In this study, we investigate the correlation between soluble C-type lectin-like receptor (sCLEC-2) levels and PDPN expression in patients with high grade gliomas and the relationship between sCLEC-2 levels and the occurrence of VTE., Materials and Methods: Forty-four patients harboring high grade gliomas, treated surgically at the Department of Neurosurgery, Niigata University from April 2018 to August 2020, were included. Patients with high grade gliomas were divided into isocitrate dehydrogenase (IDH)- wildtype and mutant groups, and the presence or absence of VTE and the intensity of PDPN by immunohistochemistry were confirmed. Platelet counts, as well as plasma sCLEC-2 and PDPN were measured in these patients. Furthermore, the levels of sCLEC-2 concentration were divided by the platelet count (C2PAC index) for comparison., Results: IDH-wildtype glioma patients highly expressed PDPN (P < 0.001) compared to IDH-mutant glioma patients. In total, 9 (20.5 %) patients were diagnosed with VTE during the follow-up period, of which 8 patients harbored IDH-wildtype gliomas, and one patient an IDH-mutant glioma. Mean sCLEC-2 levels and C2PAC index in patients with IDH-wildtype gliomas were significantly higher than that of low or no PDPN expression group, which included patients with IDH-mutant gliomas (P = 0.0004, P = 0.0002). In patients with IDH-wildtype gliomas, the C2PAC index in patients with VTE was significantly higher than in patients without VTE (P = 0.0492). The optimal cutoff point of C2PAC for predicting VTE in IDH-wildtype glioma patients was 3.7 with a sensitivity of 87.5 % and specificity of 51.9 %., Conclusion: Platelet activation is strongly involved in the development of VTE in patients with IDH-wildtype high grade gliomas, and C2PAC index is a potential marker to detect VTE formation after surgery., Competing Interests: Declaration of competing interest Masahide Kawamura and Kamon Shirakawa are employees of LSI Medience, but were not involved in data analysis. The authors have no other conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Pulmonary veno-occlusive disease (PVOD) is a rare but fatal complication of hematopoietic stem cell transplantation (HSCT). Although literature on PVOD post-HSCT is scarce, a recent study has indicated that this condition may be underestimated. Respiratory syncytial virus (RSV) is a common respiratory pathogen that causes common cold in healthy individuals but may lead to severe lower respiratory infection accompanied by respiratory distress in infants and immunocompromised individuals, such as post-HSCT patients. However, little is known about the relationship between PVOD and RSV infections., Case Report: A 4-year-old boy was diagnosed with metastatic neuroblastoma and underwent intensive chemotherapy, autologous HSCT, and allogeneic cord blood transplantation (CBT). He experienced PVOD on day 194 following CBT after displaying upper respiratory symptoms and positive RSV antigen test results approximately one month prior. Pathological examination of a lung biopsy specimen revealed lung injury suspected to be associated with viral infection in addition to PVOD-related findings, suggesting that RSV infection might have contributed to the onset of PVOD., Conclusions: The patient's clinical history and histological findings indicated that RSV could have triggered the development of PVOD under potential endothelial damage caused by HSCT and other prior treatments. Common respiratory viral infections, such as RSV infection, may evoke the development of PVOD., Competing Interests: The authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website., (Copyright Ⓒ2023 Asia-Pacific Blood and Marrow Transplantation Group (APBMT).)

Post-renal-transplant patients have a relatively low antibody-acquisition rate following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination. In this study, antibody titers were measured 5−6 months and 3 weeks to 3 months after the second and third SARS-CoV-2 mRNA vaccinations, respectively. Post-renal-transplant patients visiting our hospital who had received three SARS-CoV-2 mRNA vaccine doses were included in the study. SARS-CoV-2 immunoglobulin G antibody titers were measured three times: between 3 weeks and 3 months after the second vaccination, 5−6 months after the second vaccination, and between 3 weeks and 3 months after the third vaccination. A total of 62 (40 men and 22 women) were included, 44 of whom (71.0%) were antibody positive after their third vaccination. On comparing the antibody-acquired and antibody-non-acquired groups, body mass index (BMI, odds ratio [OR]: 1.44, 95% confidence interval [CI]: 1.07−1.93, p < 0.05) and the estimated glomerular filtration rate (eGFR, OR: 1.14, 95% CI: 1.06−1.24, p < 0.01) were associated with antibody acquisition. Therefore, in Japanese post-kidney-transplant patients, increases in the antibody-acquisition rate and absolute antibody titer after the third vaccination were observed, with BMI and eGFR associated with the antibody-acquisition rate.

Background and Objectives: Allergic transfusion reactions (ATRs) and febrile non-haemolytic transfusion reactions (FNHTRs) are common, although their mechanisms remain unclear. Immunoglobulin E (IgE)-mediated type I hypersensitivity may be involved in the pathogenesis of ATR. A basophil activation test (BAT) may help elucidate this process., Materials and Methods: The BAT was based on peripheral blood samples from paediatric patients with a haematological or oncological disease and on samples of residual blood products transfused in each case. Dasatinib was used to evaluate whether basophil activation was mediated by an IgE-dependent pathway., Results: Twenty-seven patients with and 19 patients without ATR/FNHTR were included in this study, respectively. The median BAT values associated with ATR- (n = 41) and FNHTR-causing (n = 5) blood products were 22.1% (range = 6.1%-77.0%) and 27.8% (range = 15.2%-47.8%), respectively, which were higher than the median value of 8.5% (range = 1.1%-40.9%) observed in blood products without a transfusion reaction. Dasatinib suppressed basophil activity. BAT values were comparable in patients with ATR regardless of severity. Meanwhile, BAT values analysed with blood products non-causal for ATR/FNHTR were higher in patients with ATR/FNHTR than in those without., Conclusion: The IgE-mediated type I hypersensitivity may be involved in the pathogenesis of ATR and FNHTR. BAT analyses may help elucidate the underlying mechanisms and identify patients at risk., (© 2022 International Society of Blood Transfusion.)

Breast cancer is a complex heterogeneous disease with unique molecular subtypes, which limits the development of optimized treatment strategies for each subtype. Cancer gene therapy and potential therapeutics for advanced/refractory cancers can be promising for breast cancer. Combining tumor-tropic lipid nanoparticles (LNPs) and inducible caspase-9 (iC9) mRNA, we aimed to develop a novel treatment strategy for refractory breast cancer. LNP's anti-tumor effects were tested in vitro in three breast cancer cell lines: MDA-MB231, SKBR3, and MCF-7. Tumor cells were treated with LNPs encapsulated with eGFP or iC9 mRNA and chemical inducers of dimerization (CID). Apoptosis-related genes were evaluated by reverse transcriptase quantitative PCR. LNPs could efficiently deliver encapsulated GFP mRNA to all three cancer cell lines (>80% GFP expression. in target cells). Furthermore, LNPs encapsulated with iC9 mRNA (iC9-LNPs) and CID showed cytotoxic activity against all cancer cell lines in vitro. Interestingly, susceptibility to iC9 gene therapy was heterogeneous among cancer cell lines. iC9-LNPs with CID-induced potent cytotoxic effects against SKBR3 and MDA-MB231 cells, but only a mild cytotoxic effect on MCF7 cells. Quantification of apoptosis-related genes suggested that a high BAX/Bcl-2 ratio might be associated with iC9-LNP + CID susceptibility. Thus, cancer gene therapy using iC9-LNPs and CID could be a promising alternative for the treatment of breast cancers, especially for aggressive breast cancers., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yozo Nakazawa reports financial support was provided by Toshiba Corporation. Yozo Nakazawa reports a relationship with Toshiba Corporation that includes: funding grants. Mitsuko Sugano-Ishihara has patent #PCT/IB2020/058307 pending to Shoji Saito, Eiichi Akahoshi, and Yozo Nakazawa. Eiichi Akahoshi and Mitsuko Sugano-Ishihara are employees of Toshiba Corporation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Neurenteric cyst (NC) shows benign histopathology and rarely demonstrate malignant transformation. We herein describe a case of NC that exhibited malignant transformation. A 65-year-old female presented with gait disturbance due to compression by a cystic mass on the dorsal surface of the medulla oblongata. Partial resection was performed twice, leading to improvement of her symptoms. Two years after the second surgery, gadolinium-perfused T1-weighted magnetic resonance imaging revealed an invasive lesion with contrast enhancement at the trigone of the left lateral ventricle for which partial resection followed by radiotherapy was performed. However, mass regrowth was observed, with the patient eventually succumbing to her disease 11 months after her third surgery. Histopathological analyses of the first and second surgical specimens identified pseudostratified cuboidal epithelial cells, with no nuclear or cellular atypia resembling gastrointestinal mucosa, lining the inner surface of the cystic wall. Based on these findings the lesion was diagnosed as NC. The third surgical specimen exhibited apparent malignant features of the epithelial cells with elongated and hyperchromatic nuclei, several mitotic figures, small necrotic foci, and a patternless or sheet-like arrangement. Based on these findings, the lesion was diagnosed as NC with malignant transformation. Next-generation sequencing revealed KRAS p.G12D mutation in all specimens. Additionally, the third surgical specimen harbored the following 12 de novo gene alterations: ARID1A loss, BAP1 p.F170L, CDKN1B loss, CDKN2A loss, CDKN2B loss, FLCN loss, PTCH1 loss, PTEN loss, PTPRD loss, SUFU loss, TP53 loss, and TSC1 loss. The aforementioned results suggest that KRAS mutation is associated with the development of the NC, and that the additional gene alterations contribute to malignant transformation of the NC., (© 2022 Japanese Society of Neuropathology.)

Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered to be indicated for children and adolescents with high-risk or relapsed T-cell acute lymphoblastic leukemia (T-ALL); however, the outcomes are unsatisfactory. Killer cell immunoglobulin-like receptors (KIRs) are the main receptors on natural killer (NK) cells that play an important role in the graft-versus-leukemia effect after allo-HSCT. In allo-HSCT, when the recipient lacks a donor KIR-ligand (KIR-ligand mismatch in the graft-versus-host [GVH] direction), donor NK cells will be activated against recipient cells. KIR-ligand mismatch in the GVH direction improves outcomes after unrelated cord blood transplantation (UCBT) with acute myeloid leukemia, but the effect in T-ALL is unclear. We evaluated the impact of KIR-ligand mismatch in the GVH direction on the transplantation outcomes of children and adolescents with T-ALL who received UCBT. We conducted a retrospective study using a nationwide registry of the Japanese Society for Transplantation and Cellular Therapy. Patients diagnosed with T-ALL, aged 0 to 19 years, and who underwent first UCBT between 1999 and 2017 were included. A total of 91 patients were included in this study. In all, 23 (25.3%) percent of patients had KIR-ligand mismatch in the GVH direction. The 5-year leukemia-free survival (LFS) and overall survival (OS) rates after UCBT were 65.8% and 69.6%, respectively. In a multivariate analysis, KIR-ligand mismatch in the GVH direction was associated with a significant reduction in the relapse rate (hazard ratio [HR], 0.19; P = .002), resulting in better LFS (HR, 0.18; P =.010) and OS (HR, 0.26; P = .048) without increasing non-relapse mortality (NRM; HR, 1.90; P = .264). The cumulative incidence of GVH disease (GVHD) did not differ between patients with and without KIR-ligand mismatch (grade II-IV acute GVHD, 39.1% versus 36.8%, P = .648, grade III-IV acute GVHD, 13.0% versus 11.8%, P =.857, and chronic GVHD, 26.1% versus 22.9%, P =.736, respectively). Furthermore, acute and chronic GVHD were not associated with good patient outcomes. Notably, no relapse was observed in patients who received KIR-ligand mismatched UCBT in complete remission. KIR-ligand mismatch in the GVH direction improved LFS and decreased relapse rates without increasing NRM in children and adolescents with T-ALL who received UCBT, which was not mediated by GVHD., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Conventional time-of-flight (TOF) magnetic resonance angiography (MRA) failed to depict clear visualization of coiled cerebral aneurysms with PulseRider due to metal-induced susceptibility artifacts. Our aim was to overcome the metal artifact using a novel imaging technique of non-contrast-enhanced ultrashort echo-time magnetic resonance angiography (UTE-MRA)., Materials and Methods: Five unruptured intracranial aneurysms were treated using PulseRider and the patients underwent silent MRA (UTE-MRA). The images were compared with TOF-MRA and digital subtraction angiography (DSA)., Results: Silent MRA can visualize the residual cavity of the coiled aneurysms, which was not well visualized and rather defective when using TOF-MRA. While a segment of the proximal marker composed of stainless steel was poorly visualized, the other parts of the parent artery and the arteries of bifurcation, including the aneurysmal neck, were clearly visualized, equivalent to that of DSA., Conclusions: UTE-MRA achieves better visualization of cerebral aneurysms after PulseRider treatment than TOF-MRA., (© 2022. The Author(s).)

Acute lymphoblastic leukemia (ALL) is the most common cancer during childhood, and some high-risk patients with ALL require hematopoietic stem cell transplantation (HSCT). Mainly due to small patient numbers, studies focusing specifically on children and adolescents with T-cell ALL (T-ALL) are limited. Using a nationwide registry, we retrospectively analyzed data from patients under 20 years old who underwent their first HSCT for T-ALL between 2000 and 2018. As a result, total 484 patients were included, and their median follow-up period was 6.9 years after HSCT for survivors. While patients receiving HSCT at first complete remission (CR) showed relatively good 5-year leukemia free survival (5yLFS, 73.5%), once relapse occurred, their prognosis was much worse (44.4%) even if they attained second remission again (p < 0.001). Among patients receiving HSCT at CR1, grade II-IV acute graft versus host disease was associated with worse overall and LFS than grade 0-I (5yLFS 69.5% vs. 82.1%, p = 0.026) mainly due to high non-relapse mortality. Among those patients, patients receiving related bone marrow transplantation, unrelated bone marrow transplantation, or unrelated cord blood transplantation showed similar survival (5yLFS, 73.2%, 76.3%, and 77.0%, respectively). For patients undergoing cord blood transplantation at CR1, total-body irradiation-based myeloablative conditioning was associated with better 5yLFS than other conditioning regimens (85.4% vs. 62.2%, p = 0.044), as it reduced the risk of relapse. These results indicate that relapsed patients have much less chance of cure, and that identifying patients who require HSCT for cure and offering them HSCT with optimal settings during CR1 are crucial for children and adolescents with T-ALL., (© 2022 John Wiley & Sons Ltd.)

Although skin complications are common adverse events from tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML), no reports have focused on skin and soft tissue infections (SSTIs) associated with TKI use. We herein present five episodes of SSTIs in three CML patients under dasatinib treatment. All patients were adolescents and had been receiving dasatinib for more than 4 years. In contrast, none of 41 adult CML patients experienced SSTIs in a retrospective analysis. Our findings suggest that long-term dasatinib treatment in adolescent patients may be associated with the increased risk of SSTIs., (© 2022 Wiley Periodicals LLC.)

Background: The incidence of sleep apnea syndrome (SAS) is reported to be markedly high in patients with chronic kidney disease (CKD). Therefore, it is extremely important to know whether SAS affects prognosis in patients with CKD. Further, it is imperative to understand the prognostic impact of home continuous positive airway pressure (CPAP) therapy, which is one of the most common treatments for SAS., Materials and Methods: We used a clinical database to identify patients with CKD using diagnosis codes. We included patients with CKD aged 20 years or more, not on renal replacement therapy, with a known change in renal function for at least 1 year. The propensity score was used to compare event rates for patients with SAS and those without SAS. In addition, the prognostic impact of CPAP therapy was investigated. The primary outcome is a composite of death, initiation of renal replacement therapy, hospitalization for heart failure, ischemic heart disease, and cerebrovascular disease., Results: From the database, 31,294 patients with CKD without SAS and 1,026 with SAS were found to be eligible. Of these, 419 (41%) patients with SAS and 10,713 (34%) patients without SAS ( P < 0.01) reached the primary outcome. After adjustment with the propensity score, the SAS group was found to have a similarly poor prognosis ( P < 0.01): the hazard ratio for the primary outcome was 1.26 (95% CI, 1.08-1.45, P < 0.01) in the group with SAS compared with the group without SAS. Conversely, in patients with SAS and using CPAP, the hazard ratio was lower and did not differ significantly (HR 0.96, 95% CI: 0.76-1.22, P = 0.76)., Conclusion: In patients with CKD and SAS, the risk of death and cardiovascular disease is high. In addition, patients treated with CPAP may have improved life expectancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Watanabe, Tanaka, Furuhashi, Saito and Maruyama.)

Introduction: Immunoglobulin A (IgA) nephropathy is a disease that presents with urinary symptoms such as glomerular hematuria and urinary protein positivity, with predominant deposition of IgA in the mesangial region of the glomerulus. Corticosteroids are mainly used for treatment; however, infection is a serious adverse event, and evidence regarding therapeutic efficacy is insufficient, thus new treatments are strongly desired. Mesenchymal stem cells (MSCs) contribute to the amelioration of inflammation and recovery of organ function in inflammatory environments by converting the character of leukocytes from inflammatory to anti-inflammatory and inducing the proliferation and differentiation of organ component cells, respectively. These properties of MSCs have led to their clinical application in various inflammatory diseases, but this study is the first clinical trial of MSCs for refractory glomerulonephritis in the world. This study is registered and assigned the number, jRCT2043200002 and NCT04342325., Methods: This will be a phase 1, open-label, multiple-center, dose-escalation study of adult patients with refractory IgA nephropathy resistant to or difficult to treat with existing therapies. ADR-001 will be administered intravenously to from three to six patients at a dose of 1 × 10 8 cells once in the first cohort and to six patients twice at 2-week intervals in the second cohort, and observation will continue until 52 weeks. The primary endpoint will be the evaluation of adverse events up to 6 weeks after the start of ADR-001 administration. Secondary endpoints will be the respective percentages of patients with adverse events, clinical remission, partial remission, remission of urine protein, remission of hematuria, time to remission, changes in urine protein, hematuria, and estimated glomerular filtration rate., Results: Following the administration of ADR-001 to patients with IgA nephropathy, the respective percentages of patients with adverse events, asymptomatic pulmonary emboli, clinical remission, partial remission, urine protein remission, hematuria remission, their time to remission, changes in urine protein, hematuria, and glomerular filtration rate will be determined., Conclusion: This study will evaluate the safety and tolerability of ADR-001 and confirm its therapeutic efficacy in adult patients with refractory IgA nephropathy., Competing Interests: The authors declare a potential conflict of interest and state it below: We received research funding and the investigational product ADR-001 from ROHTO Pharmaceutical Co., Ltd., (Copyright © 2022 Tanaka, Furuhashi, Fujieda, Maeda, Saito, Mimura, Saka, Naruse, Ishimoto, Kosugi, Kinoshita, Kuwatsuka, Shimizu, Nakai and Maruyama.)

A 7-year-6-month-old female was diagnosed with a pelvic malignant peripheral nerve sheath tumor and lymph node metastases. Tumorectomy was performed after four cycles of chemotherapy. A 33-mm cystic lesion was observed around the left iliac muscle after three cycles of postoperative chemotherapy, and proton beam therapy (PBT) was recommended. She was referred for absorbable spacer (AS) placement. The left ovarian appendage (OA) was resected due to the direct tumor infiltration. The right OA was fixed to the uterosacral ligament. The AS was fixed to the lateral pelvis. The PBT (70.3 Gy relative biological effectiveness) was performed successfully with the AS, and she also had the reproducing possibility due to prevention of severe irradiation damage of the right OA. AS eliminated the surgical removal of spacers and enabled us high-dose PBT for residual tumor without severe irradiation damage including infertility., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2022 by S. Karger AG, Basel.)

Objective: De novo bleb formation at the aneurysm neck after coil embolization of unruptured intracranial aneurysms is a rarely observed type of recurrence. The aim of this study was to elucidate the clinical characteristics of recurrent aneurysms in the long-term period., Methods: Between January 2002 and December 2015, 290 unruptured intracranial aneurysms were treated with coil embolization at our institution. Patients who underwent retreatment due to aneurysm recurrence were divided into 2 patterns of recanalization: de novo bleb formation at the neck of a coiled sac (type DNV) and an enlarged residual cavity without de novo bleb formation (type non-DNV)., Results: Twenty-seven patients with aneurysms (9.3%) underwent retreatment (type DNV, 7; type non-DNV, 20). The initial aneurysm size of type DNV aneurysms was significantly smaller than that of type non-DNV (6.1 ± 2.2 mm vs. 10.1 ± 3.6 mm; P < 0.01), and time to retreatment in type DNV was significantly longer than that in type non-DNV (9.4 ± 5.3 years vs. 2.0 ± 2.0 years; P < 0.01). Two type DNV basilar artery (BA) aneurysms ruptured after a few years; however, the other type DNV aneurysms, including 4 anterior circulation aneurysms (including the internal carotid artery), were observed to grow gradually without rupture for >10 years until retreatment., Conclusions: De novo bleb formation at the neck of a coiled sac emerges with insidious growth during long-term follow-up. Constant caution should be exercised, even in cases of small- and medium-sized anterior circulation aneurysms. A risk of rupture risk may be anticipated, especially in BA lesions., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The selective provocative test (SPT) under local anesthesia aids in protecting against ischemic complications during endovascular treatment. However, the use of this test under general anesthesia is not well described. Herein, we present a case of a 51-year-old man with a ruptured fusiform aneurysm in the middle cerebral artery M4 segment, which was thought to possibly supply the motor cortex. Internal trapping of the affected vessel and aneurysm by endovascular intervention was successfully performed after SPT using transcranial motor evoked potential (MEP) monitoring under general anesthesia. Transcranial MEP is suitable for neurological assessment during SPT under general anesthesia., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Allergic transfusion reactions (ATRs) manifest frequently as transfusion reactions, and their onset may be related to a patient's allergic predisposition. Moreover, although pediatric patients with hematological/oncological disease are more susceptible to ATRs, the relationship between allergic predisposition and ATRs remains to be fully clarified., Study Design and Methods: Patients who were diagnosed with pediatric hematological/oncological disease and received transfusion at the study institutions were included. We determined patient background information related to their allergy history, measured the levels of allergen-specific immunoglobulin E (IgE) using sera obtained on diagnosis, and analyzed their associations with ATR onset., Results: Of the 363 patients analyzed, 144 developed ATRs. Multivariate analysis identified cases with high basophils in the peripheral blood, and Dermatophagoides pteronyssinus- and egg white-specific IgEs were involved in the development of ATR in all age groups. Meanwhile, a history of food allergies, and positivity for Japanese cypress- and D. pteronyssinus-specific IgEs were risk factors for developing ATRs in the <5 years age group. Moreover, patients aged 5-<10 years with a history of asthma, allergic rhinitis, pollinosis, or atopic dermatitis, and those aged ≥10 years with positivity for dog dander-specific IgE were at risk for developing ATRs., Conclusion: The allergic constitution of patients plays a role in ATR onset even in pediatric hematological/oncological diseases. Therefore, advance confirmation of a patient's allergic constitution may partly predict the onset of ATRs. However, since multiple allergic predispositions within complex mechanisms may be involved in the onset of ATRs, further verification is required., (© 2022 AABB.)