[Rinsho ketsueki] The Japanese journal of clinical hematology最新文献

Bone marrow examination is essential for the definitive diagnosis of myelodysplastic neoplasms (MDS). However, non-invasive diagnostic approaches are needed for patients who cannot tolerate the procedure, especially elderly patients. This study aimed to validate the diagnostic accuracy of non-invasive gradient-boosted models (GBMs) in Japanese patients with MDS. When used alone, GBMs had sensitivity of 63.2% and specificity of 43.9% for diagnosis of MDS. When combined with WT1 mRNA expression levels (WT1 levels)(cutoff: 150 copies/µg RNA), specificity remained similar at 50.0%, while sensitivity improved to 81.6%. MDS was correctly diagnosed in 87.2% of patients with probable or indeterminate MDS by GBMs who had WT1 levels higher than 150 copies/µg RNA. When patients with vitamin B12 deficiency were excluded from analysis, this percentage increased to 91.9%. These findings suggest that the combination of GBMs, WT1 levels, and vitamin B12 deficiency could non-invasively identify patients likely to have MDS.

Gene therapies for hemophilia A and B were approved in the US and EU in 2022. A single infusion of adeno-associated virus vector containing FVIII and FIX gene increases clotting factor levels within a few weeks. Around 90% of hemophilia patients treated with gene therapy no longer need clotting factor injections and show a reduced annual bleeding rate. Gene therapy vectors for hemophilia have strong liver tropism and use liver-specific promoters. This review discusses the history of hemophilia gene therapy, phase 3 trials, and unmet needs.

The iPLAT1 study was conducted from 2019 to 2020 as the first-in-human clinical trial of iPS cell-derived platelet products (iPSC-PLTs). The subject was a patient with aplastic anemia refractory to anti-HPA-1a antibody-induced platelet transfusions who had no matched HPA-1b/1b donor. Autologous iPSC-PLTs were manufactured from a megakaryocyte cell line, imMKCL, established from the patient's iPSCs. High-efficiency manufacturing of iPSC-PLTs was achieved by incorporating the concept of turbulent flow in bioreactor tanks to mimic in vivo conditions. After comprehensive non-clinical studies, the iPLAT1 study was conducted as a dose-escalation study and achieved the primary endpoint of safety. However, an increase in the platelet count after transfusion was not observed, raising the possibility of a failure in post-transfusion measurement or defective circulation of transfused iPSC-PLTs. Since then, my research team and I have been conducting reverse-translational research to improve imMKCLs and developing a larger-scale manufacturing system to improve turbulent flow in bioreactor tanks. We have also recently demonstrated properties of subset of immune megakaryocytes in imMKCLs. Building upon such efforts, we have newly begun R&D for next-generation iPSC-PLTs.

Hematopoietic stem cells have the ability to self-renew and differentiate into multilineage cells. Therefore, hematopoietic stem cell gene therapy, which involves introducing therapeutic genes into these cells, could be an effective treatment for hereditary diseases currently targeted by hematopoietic cell transplantation. In fact, gene therapies using lentiviral vectors have already received manufacturing and sales approvals for several hereditary diseases. However, there are issues with this approach, such as tumorigenesis associated with the insertion of the vector genome and insufficient response to gain-of-function diseases caused by proteins derived from mutant genes. For this reason, the development of gene therapy using genome editing technology has become an active area of research in recent years. Nevertheless, because these technologies may cause permanent changes to the human genome, it is essential to proceed carefully with clinical development, based on social consensus.

Ethics in clinical research are indispensable for participant protection and ensuring research quality, and constitute essential knowledge for all healthcare professionals involved in clinical practice. Learning from historical case studies of unethical research, such as the Nazi human experiments and the Tuskegee Syphilis Study has led to progressive development of ethical guidelines like the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report-which presents the three core principles of respect for persons, beneficence, and justice. In Japan, incidents including the Diovan case prompted the enactment of the Clinical Research Act. The 8 requirements set forth by the U.S. National Institutes of Health (social/scientific value, scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent, and respect for subjects) serve as a key framework for modern research practice. In Japan, regulations such as the Pharmaceuticals and Medical Devices Act/Good Clinical Practice, the Clinical Research Act, and associated guidelines have been established, and require compliance tailored to the specific type of research. The practice of clinical research adhering to ethical principles forms the foundation for the advancement of medicine built on trust.

Anti-MAG/SGPG antibody is an IgM antibody against myelin-associated glycoprotein and sulfate-3-glucuronyl paragloboside, which constitute the myelin sheath, and peripheral neuropathy associated with this antibody causes symptoms such as sensory disturbances and ataxia. Anti-MAG/SGPG antibodies are known to be associated with IgM monoclonal gammopathy derived from plasma cell tumors. Chemotherapy with rituximab has been shown to yield neurological improvement in patients with peripheral neuropathy positive for anti-MAG/SGPG antibodies. Here we report a very rare case of diffuse large B-cell lymphoma presenting with neurolymphomatosis along with sensorimotor neuropathy associated with anti-MAG/SGPG antibody-positive IgM monoclonal gammopathy.

The patient was a 47-year-old man. He was diagnosed with hemophilia A in childhood, and received replacement therapy with FVIII products. However, this became ineffective due to inhibitor production, and he was treated with emicizumab. He developed fever and vomiting, and abdominal CT revealed an enlarged gallbladder and gallstones. Acute cholecystitis was diagnosed, and he was hospitalized and treated conservatively with antibiotics. On the 12th day of illness, the anemia progressed and a high-density area was observed in the gallbladder by CT scan, leading to a diagnosis of hemorrhagic cholecystitis. Since the inhibitor titer was low at 3.6 BU/ml, neutralization therapy with FVIII products was attempted. FVIII activity increased to 155%, and emergency laparoscopic subtotal cholecystectomy was performed successfully. After surgery, FVIII replacement therapy was continued and FVIII activity was maintained, but on the 19th day of illness, it decreased to 16%, and inhibitor levels rose again. Emicizumab is effective in preventing bleeding in hemophilia A with inhibitors, but the risk of bleeding is high if tissue damage leads to severe inflammation or necrosis. Neutralization therapy with FVIII products might be effective in hemorrhagic emergencies and minimally invasive surgery for hemophilia A patients with inhibitors when emicizumab is used to reduce inhibitor levels.