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Takahisa Nakanishi,* Tomoki Ito,* Shinya Fujita, Atsushi Satake, Akiko Konishi, Masaaki Hotta, Hideaki Yoshimura, Shosaku Nomura First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan*These authors contributed equally to this workCorrespondence: Tomoki ItoFirst Department of Internal Medicine, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010, JapanTel +81-72-804-2425Fax +81-72-804-2506Email itot@hirakata.kmu.ac.jpAbstract: There have been few reports on central nervous system (CNS) involvement in chronic lymphocytic leukemia (CLL). This is an extremely rare disease with poor prognosis, owing to resistance to various treatments. We describe a 33-year-old man with intractable CLL with CNS involvement. He was diagnosed with CLL, with diplopia as the first manifestation. Magnetic resonance imaging revealed a contrast-enhancing tumor in the right temporal lobe, which was diagnosed as CNS involvement in CLL on brain biopsy. High-dose methotrexate therapy was ineffective for this lesion, which was also resistant to subsequent whole-brain irradiation, treatment with fludarabine–cyclophosphamide–rituximab chemoimmunotherapy, and ibrutinib administration. Because no standard protocol exists for CLL with CNS involvement, it is important to accumulate case data to verify the choice of new drugs for administration at an early stage. Therefore, we also conducted a literature review of 50 case reports of CNS lesions in the last 10 years to consider the pathophysiology, diagnosis, and treatment of CNS involvement in CLL. The possibility of new therapeutic agents, eg, ibrutinib and venetoclax, or a combination of these agents and methotrexate, can be envisioned as a treatment strategy for CLL with CNS involvement.Keywords: chronic lymphocytic leukemia, central nervous system involvement, literature review

Shosaku Nomura, Tomoki Ito, Hideaki Yoshimura, Masaaki Hotta, Takahisa Nakanishi, Shinya Fujita, Aya Nakaya, Atsushi Satake, Kazuyoshi Ishii First Department of Internal Medicine, Kansai Medical University, Osaka, Japan Background: Thrombosis is one of the complications in the clinical course of multiple myeloma (MM). Vascular endothelial cells and/or the hemostatic-coagulatory system are thought to play an important role in thrombosis of MM. In addition to melphalan-prednisone (Mel-P) therapy, several new therapeutic drugs such as lenalidomide or bortezomib have been developed and show effectiveness against MM. However, these new drugs also have risk of therapy-related thrombosis.Methods: We assessed 103 MM patients and 30 healthy controls, using enzyme-linked immunosorbent assays to evaluate five biomarkers: platelet-derived microparticles (PDMP), plasminogen activator inhibitor-1 (PAI-1), high mobility group box protein-1 (HMGB1), endothelial protein C receptor (EPCR), and soluble vascular cell adhesion molecule-1 (sVCAM-1). The effects of Mel-P, bortezomib, and lenalidomide on the plasma concentrations of these biomarkers were investigated.Results: The plasma concentrations of PDMP, PAI-1, HMGB1, EPCR, and sVCAM-1 were higher in MM patients than in healthy controls. Mel-P, bortezomib, and lenalidomide therapies all reduced biomarker levels after treatment. However, when only patients with higher levels of EPCR were compared, differences were seen between the three therapies in the elevation of PDMP, HMGB1, and PAI-1.Conclusion: These results suggest that both MM and therapies for MM can induce a hypercoagulable state. The elevated risk of thrombosis conferred by hypercoagulability increases patient morbidity and mortality. Attention should be paid to therapy-related thrombosis when new therapeutic regimens are selected for MM patients.Keywords: multiple myeloma, bortezomib, lenaridomide, thrombosis, biomarker

Hideaki Yoshimura, Masaaki Hotta, Takahisa Nakanishi, Shinya Fujita, Aya Nakaya, Atsushi Satake, Tomoki Ito, Kazuyoshi Ishii, Shosaku Nomura First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan Background: Biosimilar granulocyte colony-stimulating factor (G-CSF) has recently been introduced into clinical practice. G-CSFs are used to mobilize CD34+ cells and accelerate engraftment after transplantation. However, in Asia, particularly in Japan, data for peripheral blood stem cell (PBSC) mobilization by this biosimilar G-CSF are currently lacking. Therefore, the clinical efficacy and safety of biosimilar G-CSF for hematopoietic stem cell transplantation needs to be evaluated in a Japanese context.Materials and methods: The subjects included two groups of patients with malignant lymphoma and multiple myeloma. All patients received chemotherapy priming for the mobilization of PBSCs. All patients were treated with chemotherapy followed by the administration of either the biosimilar G-CSF, filgrastim XM02 (FBNK), or the originators, filgrastim, or lenograstim.Results: There were no significant differences among FBNK, filgrastim, and lenograstim treatments in the numbers of CD34+ cells in harvested PBSCs, the scores for granulocyte/macrophage colony forming units, or for malignant lymphoma and multiple myeloma patients evaluated as separate or combined cohorts. In addition, there were no significant differences in safety, side effects, complications, or the time to engraftment after autologous hematopoietic stem cell transplantation.Conclusion: Biosimilar FBNK shows the same efficacy and safety as originator G-CSFs for facilitating bone marrow recovery in Japanese malignant lymphoma and multiple myeloma patients undergoing stem cell transplantation. In addition, it is less expensive than the originators, reducing hospitalization costs. Keywords: G-CSF, biosimilar, peripheral blood stem cell, hematological malignancy, autologous hematopoietic stem cell transplantation

Ryotaro Ozasa, Masaaki Hotta, Hideaki Yoshimura, Takahisa Nakanishi, Takeshi Tamaki, Shinya Fujita, Naoto Nakamichi, Michihiko Miyaji, Kazuyoshi Ishii, Tomoki Ito, Shosaku NomuraFirst Department of Internal Medicine, Kansai Medical University, Osaka, JapanAbstract: Plasma cell leukemia (PCL) is a rare disease that represents approximately 4% of plasma cell malignant disorders. PCL consists of two variants: primary PCL presents in patients with no previous history of multiple myeloma, while secondary PCL consists of a leukemic transformation in a previously recognized multiple myeloma. Primary PCL is an extremely resistant, rapidly progressive, fatal disease, with a median overall survival of 6.8 months. There is no standard therapeutic strategy, because no treatment option has been prospectively evaluated. We describe a successful case of newly diagnosed primary PCL, treated with a regimen that included bortezomib, followed by auto stem cell transplantation and nonmyeloablative allogeneic stem cell transplantation. Our patient has maintained remission status for over 12 months since undergoing the allogeneic stem cell transplantation. This strategy is promising for PCL, which, though an extremely resistant disease, may become curable.Keywords: plasma cell leukemia, multiple myeloma, bortezomib, stem cell transplantation

Introduction: Previous studies have suggested a negative association between the duration of hearing loss and post-cochlear implantation (CI) audiometry performance. Consequently, it has been assumed that cochlear implantation may be less effective in ears without prior hearing aid (HA) use. However, some cases of CI recipients with no history of HA use (non-aided) have demonstrated favorable hearing outcomes. This study aimed to explore the relationship between the duration of hearing loss in non-aided ears and postoperative auditory performance, as well as to compare CI outcomes between non-aided and aided ears. Material and methods: This retrospective study included 153 ears (127 cases) with postlingual hearing loss that underwent CI for bilateral severe to profound hearing loss between April 2011 and March 2023. Among them, 28 patients (29 ears) received CI in non-aided ears, while 100 patients (125 ears) received CI in aided ears. One patient (2 ears) underwent CI in both non-aided and aided ears, and six patients (12 ears) received CI in non-aided ears initially, followed by CI in aided ears. Audiometry performance was assessed using the Japanese monosyllable test (CI2004). Results: No significant correlation was found between audiometry performance at 1 year postoperatively in non-aided ears and the duration of hearing loss without HA use. Additionally, there was no significant difference in audiometry performance between non-aided and aided ears at 1 year after surgery. Conclusions: This study revealed that irrespective of the duration of hearing loss, postoperative CI outcomes in non-aided ears were comparable to those in aided ears. Patients with severe-to-profound hearing loss often exhibit asymmetric hearing loss, leading to requests for CI on the worse hearing ear. While surgeons may hesitate to provide CI to ears without prior HA use, our findings suggest that such hesitancy may not be warranted, assisting the decision-making process for CI in patients with postlingual hearing loss. [ABSTRACT FROM AUTHOR]

Gene therapy holds promise as a curative therapeutic method with the potential to suppress HL progression or restore hearing function, something unattainable with hearing aids or cochlear implants. To expand the scope of target genes for cochlear gene therapy, patients with progressive genetic hearing loss (HL) are considered suitable candidates in terms of the therapeutic time window for gene therapy intervention. CDH23 is a common deafness gene that can cause either Usher syndrome type 1D or non-syndromic HL (DFNB12). The phenotype range of DFNB12 is variable from congenital to adult-onset HL. Adult-onset, CDH23-related HL is progressive, beginning as high-frequency HL that gradually affects low frequencies, ultimately resulting in HL across all frequencies. While this gene is an ideal target for cochlear gene therapy, the size of the CDH23 coding sequence is 10.1 kb; therefore, the development of gene therapy using triple adeno-associated virus (AAV) vectors is necessary. In this study we aimed to investigate the transduction efficiency of triple-AAV. This study aimed to investigate the transduction efficiency of triple AAV vectors in the cochleae of adult mice, focusing on large-gene-associated HL. Additionally, we sought to evaluate the feasibility of cochlear gene therapy in a mouse model of human CDH23-mediated HL using the triple AAV approach. To create a reporter protein, we fused EGFP to mCherry, which was then divided into three parts, each packaged in a separate AAV2/2 vector. Four weeks after co-injecting the triple AAV vectors into 4-5-week-old mice, we assessed transduction efficiency. We found that up to 5.9% of inner hair cells were positive for both EGFP and mCherry. Subsequently, we developed triple CDH23-AAV vectors for therapeutic purposes. After administering these vectors to 4- to 5-week-old C57/BL6 mice, we conducted auditory tests and immunohistochemistry studies over a period of 60 weeks. Co-injecting triple CDH23-AAVs did not alter auditory function or lead to hair cell degeneration. In conclusion, this study confirms the feasibility of the triple-AAV approach for cochlear gene delivery. While this strategy did not produce any treatment effects, our findings suggest that large deafness genes could be potential future targets for cochlear gene therapy. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the etiology of hearing loss (HL) based on the rate of its progression. Material and methods: Pure tone audiometry was conducted on 42,744 tests (9,269 cases) at Shinshu University Hospital between 2012 and 2022. Cases with unilateral HL, conductive HL, postoperative ear issues, functional hearing loss, and those with bilateral scaling-out at initial examination or lacking detailed data were excluded. A retrospective review was performed on 838 cases followed for over 5 years. Hearing progression was categorized as "Stable" (0-1 dB HL/year), "Slow progression" (1-3 dB HL/year), and "Fast progression" (>3 dB HL/year). Causes were classified as genetic, middle ear disease, Meniere's disease-related, other known causes, and unknown etiology. Results: Of the 838 cases, 302 were classified as "Stable", 402 as "Slow progression", and 134 as "Fast progression". Across all groups, unknown etiology was the predominant cause of HL, followed by genetic factors in Stable and Slow progression groups, and others in the Fast progression group. Regarding genetic etiology, the GJB2 and STRC genes were most prevalent in the Stable group, while genes such as SLC26A4 and CDH23 were identified across all groups. Conclusions: Regardless of progression rate, over half of bilateral HL cases had an unknown etiology. Genes such as GJB2 and STRC were identified to exhibit stable hearing, consistent with our findings. This study suggests that genes responsible for progressive HL manifest in an intermittent, rather than continuous, manner, highlighting the clinical utility of genetic testing, particularly in cases lacking long-term follow-up data. [ABSTRACT FROM AUTHOR]

The article studies the layout dependence for stress-enhanced MOSFETs like contact positioning, the second neighboring poly effect, and bent diffusion in 45-nm CMOS logic technology. Results conclude that the sensitivity of contact position in the channel direction is larger for PMOS with a higher stress liner than for NMOS.