Publications by authors named "Koichi Akashi"

456 Publications

Contrasting specific antibody response to BNT162b2 mRNA vaccination in SARS-CoV-2-naive and previously infected nursing home residents.

J Infect 2021 Oct 20. Epub 2021 Oct 20.

Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences (The First Department of Internal Medicine), Fukuoka, Japan.

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http://dx.doi.org/10.1016/j.jinf.2021.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527596PMC
October 2021

The membrane-linked adaptor FRS2β fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis.

Proc Natl Acad Sci U S A 2021 Oct;118(43)

Division of Cancer Cell Biology, Cancer Research Institute, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan;

Although it is held that proinflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we demonstrate that FRS2β, an adaptor protein expressed in a small subset of epithelial cells, triggers the proinflammatory changes that induce stroma in premalignant mammary tissues and is responsible for the disease onset. FRS2β deficiency in mouse mammary tumor virus (MMTV)-ErbB2 mice markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2β-deficient premalignant tissues. We found that colocalization of FRS2β and the NEMO subunit of the IκB kinase complex in early endosomes led to activation of nuclear factor-κB (NF-κB), a master regulator of inflammation. Moreover, inhibition of the activities of the NF-κB-induced cytokines, CXC chemokine ligand 12 and insulin-like growth factor 1, abrogated tumorigenesis. Human breast cancer tissues that express higher levels of FRS2β contain more stroma. The elucidation of the FRS2β-NF-κB axis uncovers a molecular link between the proinflammatory changes and the disease onset.
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http://dx.doi.org/10.1073/pnas.2103658118DOI Listing
October 2021

Effects of Letermovir and/or Methylprednisolone Coadministration on Voriconazole Pharmacokinetics in Hematopoietic Stem Cell Transplantation: A Population Pharmacokinetic Study.

Drugs R D 2021 Oct 15. Epub 2021 Oct 15.

Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Objective: The aim of this study was to identify factors affecting blood concentrations of voriconazole following letermovir coadministration using population pharmacokinetic (PPK) analysis in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients.

Methods: The following data were retrospectively collected: voriconazole trough levels, patient characteristics, concomitant drugs, and laboratory information. PPK analysis was performed with NONMEM version 7.4.3, using the first-order conditional estimation method with interaction. We collected data on plasma voriconazole steady-state trough concentrations at 216 timepoints for 47 patients. A nonlinear pharmacokinetic model with the Michaelis-Menten equation was applied to describe the relationship between steady-state trough concentration and daily maintenance dose of voriconazole. After stepwise covariate modeling, the final model was evaluated using a goodness-of-fit plot, case deletion diagnostics, and bootstrap methods.

Results: The maximum elimination rate (V) of voriconazole in patients coadministered letermovir and methylprednisolone was 1.72 and 1.30 times larger than that in patients not coadministered these drugs, respectively, resulting in decreased voriconazole trough concentrations. The developed PPK model adequately described the voriconazole trough concentration profiles in allo-HSCT recipients. Simulations clearly showed that increased daily doses of voriconazole were required to achieve an optimal trough voriconazole concentration (1-5 mg/L) when patients received voriconazole with letermovir and/or methylprednisolone.

Conclusions: The development of individualized dose adjustment is critical to achieve optimal voriconazole concentration, especially among allo-HSCT recipients receiving concomitant letermovir and/or methylprednisolone.
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http://dx.doi.org/10.1007/s40268-021-00365-0DOI Listing
October 2021

Incidence of refractory cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.

Int J Hematol 2021 Oct 15. Epub 2021 Oct 15.

Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan.

Post-transplant cytomegalovirus (CMV) disease can be almost completely avoided by current infection control procedures. However, CMV reactivation occurs in more than half of patients, and some patients can develop clinically resistant CMV infections. Whether resistance is due to the host's immune status or a viral resistance mutation is challenging to confirm. Therefore, a prospective observational analysis of refractory CMV infection was conducted in 199 consecutive patients who received allogeneic hematopoietic stem cell transplantation at a single institution. Among them, 143 (72%) patients received anti-CMV drugs due to CMV reactivation, and only 17 (8.5%) exhibited refractory CMV infection. These patients had clinically refractory infection. However, viral genome analysis revealed that only one patient exhibited a mutation associated with the anti-CMV drug resistance. Clinical resistance was mainly correlated with host immune factors, and the incidence of resistance caused by gene mutations was low at the early stage after a transplantation.
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http://dx.doi.org/10.1007/s12185-021-03218-3DOI Listing
October 2021

A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.

Blood Adv 2021 Oct 12. Epub 2021 Oct 12.

Kyushu University Hospital, Japan.

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of "unfavorable" molecular signatures.
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http://dx.doi.org/10.1182/bloodadvances.2021004618DOI Listing
October 2021

Phase 2 study of axicabtagene ciloleucel in Japanese patients with relapsed or refractory large B-cell lymphoma.

Int J Clin Oncol 2021 Oct 1. Epub 2021 Oct 1.

Department of Lymphoma/Hematology Center, Mita Hospital, International University of Health and Welfare, 1-4-3 Mita, Minato, Tokyo, 108-8329, Japan.

Background: Axicabtagene ciloleucel (axi-cel) is an autologous chimeric antigen receptor T-cell based anti-CD19 therapy. The ZUMA-1 study, multicenter, single-arm, registrational Phase 1/2 study of axi-cel demonstrated high objective response rate in patients with relapsed/refractory large B-cell lymphoma. Here, we present the results of the bridging study to evaluate the efficacy and safety of axi-cel in Japanese patients (JapicCTI-183914).

Methods: This study was the phase 2, multicenter, open-label, single-arm trial. Following leukapheresis, axi-cel manufacturing and lymphodepleting chemotherapy, patients received a single infusion of axi-cel (2.0 × 10 cells/kg). Bridging therapy between leukapheresis and conditioning chemotherapy was not allowed. The primary endpoint was objective response rate.

Results: Among 17 enrolled patients, 16 received axi-cel infusion. In the 15 efficacy evaluable patients, objective response rate was 86.7% (95% confidence interval: 59.5-98.3%); complete response/partial response were observed in 4 (26.7%)/9 (60.0%) patients, respectively. No dose-limiting toxicities were observed. Grade ≥ 3 treatment-emergent adverse events occurred in 16 (100%) patients-most commonly neutropenia (81.3%), lymphopenia (81.3%) and thrombocytopenia (62.5%). Cytokine release syndrome occurred in 13 (81.3%) patients (12 cases of grade 1 or 2 and 1 case of grade 4). No neurologic events occurred. Two patients died due to disease progression, but no treatment-related death was observed by the data-cutoff date (October 23, 2019).

Conclusion: The efficacy and safety of axi-cel was confirmed in Japanese patients with relapsed/refractory large B-cell lymphoma who have otherwise limited treatment options.

Trial Registration: JapicCTI-183914.
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http://dx.doi.org/10.1007/s10147-021-02033-4DOI Listing
October 2021

Genome-wide CRISPR-Cas9 screen identifies rationally designed combination therapies for CRLF2-rearranged Ph-like ALL.

Blood 2021 Sep 29. Epub 2021 Sep 29.

Kyushu University Hospital, Japan.

Acute lymphoblastic leukemia (ALL) harboring the IgH-CRLF2 rearrangement (IgH-CRLF2-r) exhibits poor clinical outcomes and is the most common subtype of Ph-like ALL. While multiple chemotherapeutic regimens, including Ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. To identify molecules/pathways relevant for IgH-CRLF2-r ALL pathogenesis, we performed genome-wide CRISPR-Cas9 dropout screens in the presence or absence of Ruxolitinib using two IgH-CRLF2-r ALL lines that differ in RAS mutational status. To do so, we employed a baboon envelope pseudotyped lentiviral vector system, which enabled, for the first time, highly efficient transduction of human B cells. While sgRNAs targeting CRLF2, IL7RA or JAK1/2 significantly affected cell fitness in both lines, those targeting STAT5A, STAT5B or STAT3 did not, suggesting that STAT signaling is largely dispensable for IgH-CRLF2-r ALL cell survival. We show that regulators of RAS signaling are critical for cell fitness and Ruxolitinib sensitivity and that CRKL depletion enhances Ruxolitinib sensitivity in RAS wild-type (WT) cells. Gilteritinib, a pan-tyrosine kinase inhibitor that blocks CRKL phosphorylation, effectively killed RAS WT IgH-CRLF2-r ALL cells in vitro and in vivo, either alone or combined with Ruxolitinib. We further show that combining Gilteritinib with Trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status. Our study delineates molecules/pathways relevant for CRLF2-r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes.
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http://dx.doi.org/10.1182/blood.2021012976DOI Listing
September 2021

HLA-B52 allele in giant cell arteritis may indicate diffuse large-vessel vasculitis formation: a retrospective study.

Arthritis Res Ther 2021 Sep 13;23(1):238. Epub 2021 Sep 13.

Department of Medical Education, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Background: This study aimed to identify new characteristics of elderly onset large-vessel vasculitis (EOLVV) by focusing on human leucocyte antigen (HLA) genotype, polymyalgia rheumatica (PMR), and affected vascular lesions observed on positron emission tomography/computed tomography (PET/CT) imaging.

Methods: We retrospectively studied 65 consecutive Japanese patients with large-vessel vasculitis (LVV) who had extracranial vasculitis lesions and underwent PET/CT imaging. PET/CT images were assessed using the semi-quantitative PET visual score of each affected vessel, and the PET vascular activity score (PETVAS) and number of affected vessels were calculated. Subjects were subsequently grouped based on age at onset, superficial temporal artery (STA) involvement, and presence of PMR and compared each group according to HLA genotype. Unsupervised hierarchical cluster analysis was used to identify the patients with similar characteristics in terms of affected vascular lesions detected through PET/CT imaging. The clinical characteristics and PET/CT findings of the population newly identified in this study were examined.

Results: Twenty-seven patients with EOLVV did not meet the American College of Rheumatology 1990 criteria for giant cell arteritis (GCA) and Takayasu arteritis and were considered as unclassified EOLVV (UEOLVV). The unsupervised hierarchical cluster analysis revealed that UEOLVV with PMR and large-vessel GCA (LV-GCA) formed a cluster of LVV with GCA features (i.e., PMR and/or STA involvement) when restricted to patients who were HLA-B52-positive. Patients who were HLA-B52-positive with LVV and GCA features had similar clinical characteristics and patterns of affected vessels and presented with diffuse LVV lesions. HLA-B52-positive patients who had LVV with GCA features also presented with higher PETVAS, more affected vessels, and lower rates of biologics usage and relapse compared to HLA-B52-positive patients with TAK.

Conclusions: Patients who had UEOLVV with PMR had similar characteristics to patients with LV-GCA. Patients who were HLA-B52-positive and had LVV with GCA features presented with diffuse vascular lesions and may comprise a core population of Japanese patients with EOLVV. The findings of HLA-B52 positivity and diffusely affected vessels in patients with EOLVV can be considered as suspicious findings of LV-GCA.
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http://dx.doi.org/10.1186/s13075-021-02618-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436550PMC
September 2021

A Japanese Patient with Anti-PM/Scl and Centromere Antibody-Positive Scleroderma-Amyopathic Dermatomyositis Overlap Syndrome Who Developed Renal Crisis.

Mod Rheumatol Case Rep 2021 Sep 10. Epub 2021 Sep 10.

The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.

Anti-PM/Scl antibodies are associated with the overlap syndrome of systemic sclerosis and dermatomyositis/polymyositis (SSc-DM/PM), and are found in 50% of SSc-DM/PM cases in Europe and the United States, whereas they are rare in Japan. We report a case of an 80-year-old Japanese female with SSc-amyopathic dermatomyositis (ADM) overlap syndrome, who developed scleroderma renal crisis (SRC), a complication of SSc. She had positive antinuclear antibodies in a discrete-speckled and nucleolar pattern and anticentromere antibodies and anti-PM/Scl antibodies were confirmed by ELISA and immunoprecipitation, respectively. The incidence rate of SRC in SSc patients varies significantly depending on the specificity of autoantibodies, with the highest incidence of ~50% in anti-RNA polymerase III antibody positive patients, followed by ~10% in anti-PM/Scl and lower incidence of 0.45% in anticentromere antibody-positive cases. Anti-PM/Scl antibodies are uncommon in Japanese patients presumably due to its strong association with certain HLA haplotype that is rare in Japanese. Clinical significance of anti-PM/Scl antibodies in Japanese patients will need to be clarified with accumulation of cases in future studies.
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http://dx.doi.org/10.1093/mrcr/rxab025DOI Listing
September 2021

Improvement in recurring nivolumab-induced pneumonitis with repetitive administration of infliximab in a patient with head and neck cancer: A case report.

Mol Clin Oncol 2021 Oct 25;15(4):221. Epub 2021 Aug 25.

Department of Oncology and Social Medicine, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka 812-8582, Japan.

Severe pneumonitis induced by nivolumab, an anti-programmed cell death-1 monoclonal antibody, is a rare but potentially fatal immune-related adverse event. In cases of steroid-refractory pneumonitis, an appropriate therapeutic strategy using anti-tumor necrosis factor-α (TNF-α) antibody has not been established. A 59-year-old female was diagnosed with hypopharyngeal squamous cell carcinoma. Previous therapies including chemoradiotherapy and throat laryngectomy were performed, but metastatic recurrence appeared in the intrapulmonary and mediastinal lymph nodes. The patient was administered nivolumab. On the 14th day of nivolumab administration, the patient experienced dyspnea and computed tomography of the chest showed multiple consolidations in the right lung. She was diagnosed with nivolumab-induced pneumonitis. Because the pneumonitis was refractory to steroid therapy, she was administered infliximab, and the pneumonitis improved. On the 72nd and 101st days of nivolumab administration, nivolumab-induced pneumonitis re-appeared with an elevated serum TNF-α concentration. In each occurrence of pneumonitis, repetitive administration of infliximab improved the pneumonitis. Repetitive administration of infliximab may be effective for treating recurrent nivolumab-induced pneumonitis that is associated with an increased serum TNF-α concentration.
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http://dx.doi.org/10.3892/mco.2021.2379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408681PMC
October 2021

Granulocyte collection by polymorphonuclear cell-targeting apheresis with medium-molecular-weight hydroxyethyl starch.

Int J Hematol 2021 Aug 28. Epub 2021 Aug 28.

Center for Cellular and Molecular Medicine, Kyushu University Hospital, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Granulocyte transfusion (GTX) is a therapeutic option for patients with prolonged neutropenia suffering from severe infections. Efficient granulocyte collection by apheresis from donors requires clear separation of granulocytes from red blood cells (RBCs), and infusion of high-molecular-weight (MW) hydroxyethyl starch (HES) facilitates RBC sedimentation. Recent research has shown that apheresis with medium-MW HES may prevent adverse effects of high-MW HES on donors, but the rationale for collection with medium-MW HES has yet to be evaluated. To validate the use of medium-MW HES, we first performed experiments with whole blood samples to determine how efficiently high-, medium- and low-MW HES separated granulocytes from RBCs, and found that medium-MW HES was just as efficient as high-MW HES. We also reviewed clinical data of granulocyte apheresis at our institution to evaluate granulocyte yields. Retrospective analysis of granulocyte collection revealed that apheresis with medium-MW HES yielded sufficient granulocytes for GTX and that donor anemia reduced collection efficiency. These results collectively may help us to establish a safer method for apheresis targeting polymorphonuclear granulocytes as an alternative to high-MW HES.
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http://dx.doi.org/10.1007/s12185-021-03207-6DOI Listing
August 2021

Association of elevated serum soluble CD226 levels with the disease activity and flares of systemic lupus erythematosus.

Sci Rep 2021 08 9;11(1):16162. Epub 2021 Aug 9.

Department of Medical Education, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

CD226 is an activating receptor expressed on the cell surface of natural killer cells and T cells. Although CD226 polymorphism is known to be involved in systemic lupus erythematosus (SLE), the involvement of soluble CD226 (sCD226) in SLE is still unknown. In the present study, we measured serum sCD226 levels using an enzyme-linked immunosorbent assay in 58 SLE patients and 33 healthy controls (HCs) and evaluated their associations with SLE Disease Activity Index 2000 (SLEDAI-2K), clinical manifestations, laboratory data, and the cumulative probability of flare. Serum sCD226 levels showed no significant differences between SLE patients and HCs. However, sCD226 levels were significantly elevated in active SLE patients with a SLEDAI-2K score of ≥ 20 compared with HCs. In SLE patients, sCD226 levels were significantly correlated with SLEDAI-2K scores and anti-dsDNA antibody titers. Moreover, the cumulative probability of flare was markedly higher in patients with high sCD226 than in those with low sCD226. In patients with neuropsychiatric involvement, sCD226 levels were elevated and reflected neuropsychiatric disease activity. These findings indicate that serum sCD226 levels are associated with disease activity and flares of SLE. Thus, it may be a useful biomarker for SLE, and its monitoring allows for more precise SLE management.
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http://dx.doi.org/10.1038/s41598-021-95711-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352936PMC
August 2021

Increased Proportion of CD226 B Cells Is Associated With the Disease Activity and Prognosis of Systemic Lupus Erythematosus.

Front Immunol 2021 21;12:713225. Epub 2021 Jul 21.

Department of Medical Education, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Background: CD226, an activating receptor expressed on the surface of natural killer (NK) cells and T cells, is also seen on B cells and CD226 polymorphism is associated with systemic lupus erythematosus (SLE). Because the specific roles of CD226 B cells in SLE are still unknown, we investigated the association of CD226 B cells with SLE.

Methods: We measured CD226 expression on B cells and its subsets using flow cytometry in 48 SLE patients and 24 healthy controls (HCs). We assessed the relationships between CD226 B cells and SLE Disease Activity Index 2000 (SLEDAI-2K), clinical manifestations, laboratory data, and prognosis after 12 months.

Results: The proportions of CD226 cells in whole B cells and all its subsets were significantly higher in SLE patients than HCs. In SLE patients, the proportions of CD226 B cells and CD226 switched-memory (SM) B cells were significantly correlated with SLEDAI-2K scores and anti-dsDNA antibody titers, and negatively correlated with serum complement levels. Moreover, basal percentages of CD226 B cells and CD226 SM B cells were low in patients who were in Lupus Low Disease Activity State after 12 months. In patients with renal involvement, the proportion of CD226 B cells increased. Additionally, the proportion of CD226 B cells was higher in patients who were not in complete renal remission after 12 months.

Conclusions: Increased proportion of CD226 B cells was associated with disease activity and prognosis of SLE. CD226 B cells may be a useful biomarker for the management of SLE.
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http://dx.doi.org/10.3389/fimmu.2021.713225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8334729PMC
July 2021

Ustekinumab Improves Active Crohn's Disease by Suppressing the T Helper 17 Pathway.

Digestion 2021 Jul 22:1-10. Epub 2021 Jul 22.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn's disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST.

Methods: Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated.

Results: The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action.

Conclusion: In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues.
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http://dx.doi.org/10.1159/000518103DOI Listing
July 2021

Targeting leukemia-specific dependence on the de novo purine synthesis pathway.

Leukemia 2021 Aug 3. Epub 2021 Aug 3.

Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, 812-8582, Japan.

Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.
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http://dx.doi.org/10.1038/s41375-021-01369-0DOI Listing
August 2021

Optimization of lymphapheresis for manufacturing autologous CAR-T cells.

Int J Hematol 2021 Oct 17;114(4):449-458. Epub 2021 Jul 17.

Center for Cellular and Molecular Medicine, Kyushu University Hospital, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Collection of CD3+ lymphocytes via lymphapheresis is essential for manufacturing autologous chimeric antigen receptor (CAR) T cells. Optimization of timing and procedures for lymphapheresis for each patient is critical because patients often have progressive diseases and receive medications that could reduce T cell counts. We conducted a retrospective study of clinical data from 28 patients who underwent lymphapheresis for CD19-directed CAR-T therapy with tisagenlecleucel to identify factors that could affect CD3+ lymphocyte yields. The numbers of CD3+ cells in peripheral blood were significantly correlated with CD3+ cell yields (correlation coefficient r = 0.84), which enabled us to estimate the volume of blood to process before apheresis. We also found that small cell ratio (SCR) at the apheresis site precisely reflected the proportion of lymphocytes, especially in patients without circulating blasts (coefficient of determination: r = 0.9). We were able to predict the CD3+ cell yield and prevent excessive apheresis by measuring pre-apheresis circulating CD3+ cell counts and monitoring SCR. Collectively, these results will help us to establish a strategy for optimization of lymphapheresis procedures for CAR-T cell production on a patient-by-patient basis.
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http://dx.doi.org/10.1007/s12185-021-03191-xDOI Listing
October 2021

Predictive factors of fetal and maternal pregnancy outcomes in Japanese patients with systemic lupus erythematosus.

Lupus 2021 Sep 16;30(10):1637-1643. Epub 2021 Jul 16.

Faculty of Medical Sciences Medical Education, Kyushu University, Fukuoka, Japan.

Objective: The number of pregnant and delivery cases in systemic lupus erythematosus (SLE) patients are increasing due to the advances in therapies. However, there are many problems such as the exacerbation of SLE during pregnancy and the risk of fetal complications. We investigated the impact of both pregnancy on lupus and lupus on pregnancy in Japanese patients.

Methods: We retrospectively analyzed 64 pregnancies in 39 cases of lupus patients at Kyushu University Hospital, Japan, from October 2002 to July 2018 and then assessed the clinical profiles and maternal and fetal outcomes.

Results: In terms of the impact of pregnancy on SLE, 29.7% of patients had lupus flare during pregnancy. Multivariate analysis showed that flare rates were significantly higher in patients who discontinued the immunosuppressants when pregnancy was detected or before pregnancy. Pregnancy results were 25.0% for preterm birth, 39.1% for low birth weight infants, and 31.3% for small-for-gestational-age infants. Regarding the effect of SLE on fetal death, the rates of stillbirth were significantly higher in cases whose C3 value at 12 weeks of gestation was lower than before conception. Preterm birth was associated with disease duration and lupus flare during pregnancy.

Conclusions: Discontinuation of immunosuppressive drugs was a predictive factor for lupus flare during pregnancy. Further, the decrease of C3 levels at 12 weeks of gestation from baseline was a predictive factor for fetal loss. It is essential for lupus pregnant patients to prevent flares, even with the use of immunosuppressive medications.
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http://dx.doi.org/10.1177/09612033211031989DOI Listing
September 2021

Azacitidine for the treatment of patients with relapsed acute myeloid leukemia after allogeneic stem cell transplantation.

Leuk Lymphoma 2021 Jun 23:1-10. Epub 2021 Jun 23.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.

We retrospectively analyzed 38 patients with AML who received azacitidine (AZA) to treat disease relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with objective response (OR) ( = 20) after AZA had significantly higher 2-year overall survival (OS) (45.0% vs 5.6%;  = 0.004) than progressive disease. The 2-year OS was significantly higher in the retransplant group ( = 23) than in the nonretransplant group ( = 15) (34.8% vs 13.3%;  = 0.034). We analyzed 167 patients who underwent the second allo-HSCT to clarify the impact of pretransplant AZA after the second allo-HSCT. Patients in the AZA group ( = 21) had significantly higher 2-year disease-free survival (DFS) (32.7% vs 14.5%;  = 0.012) and OS (38.1% vs 17.5%;  = 0.044) than those in the SOC group ( = 146). Our data demonstrate that AZA is an effective and well-tolerated bridging therapy to the second allo-HSCT.
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http://dx.doi.org/10.1080/10428194.2021.1941937DOI Listing
June 2021

Infliximab for reversible dementia in acute onset of neuro-Behçet's disease: A case report and cytokine analysis.

J Neuroimmunol 2021 08 8;357:577631. Epub 2021 Jun 8.

Department of Medical Education, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address:

We describe a 49-year-old female patient with neuro-Behçet's disease (NBD) with acute onset of fever and symptoms of dementia. High-dose glucocorticoid was partially effective for cognitive impairment, and infliximab, an anti-TNF-α antibody, gradually improved the symptoms. An analysis of cytokines showed that IP-10 in the cerebrospinal fluid was higher than that in the peripheral blood, and both decreased after treatment. This is the first known case of NBD wherein the patient with acute onset of dementia responded to a treatment with infliximab. In glucocorticoid-resistant patients, it is important to consider the introduction of infliximab to prevent irreversible brain dysfunction.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577631DOI Listing
August 2021

Platelet decrease and efficacy of platelet-rich plasma return following peripheral blood stem cell apheresis.

J Clin Apher 2021 Oct 16;36(5):687-696. Epub 2021 Jun 16.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan.

Background: Peripheral blood stem cell (PBSC) transplantation is a key treatment option for hematological diseases and is widely performed in clinical practice. Platelet loss is one of the major complications of PBSC apheresis, and platelet-rich plasma (PRP) return is considered in case of platelet decrease following apheresis; however, little is known about the frequency and severity of platelet loss and the efficacy of PRP return postapheresis.

Methods: We assessed changes in platelet counts following PBSC-related apheresis in 270 allogeneic (allo)- and 105 autologous (auto)-PBSC settings. We also evaluated the efficacy of PRP transfusion on platelet recovery postapheresis.

Results: In both allo- and auto-PBSC settings, the preapheresis platelet count (range, 84-385 and 33-558 × 10 /L, respectively) decreased postapheresis (range, 57-292 and 20-429 × 10 /L, respectively), whereas severe platelet decrease (<50 × 10 /L) was only observed in auto-PBSC patients (n = 9). We confirmed that platelet count before apheresis was a risk factor for severe platelet decrease (<50 × 10 /L) following auto-PBSC apheresis (odds ratio 0.749, P < .049). PRP return postapheresis facilitated platelet recovery in more than 80% of cases in both allo and auto settings.

Conclusion: Lower platelet count preapheresis is a useful predictor of severe platelet decrease following auto-PBSC apheresis and PRP return is an effective process to facilitate platelet recovery postapheresis.
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http://dx.doi.org/10.1002/jca.21917DOI Listing
October 2021

Prominent PD-L1-positive M2 macrophage infiltration in gastric cancer with hyper-progression after anti-PD-1 therapy: A case report.

Medicine (Baltimore) 2021 May;100(19):e25773

Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Rationale: Anti-PD-1 antibody is the standard therapy for treatment-resistant gastric cancer, but only a limited number of patients respond. Additionally, cases of hyper-progressive disease (HPD) in which tumor growth accelerates after anti-PD-1 antibody administration have been reported; however, the biological mechanism has not been elucidated.

Patient Concerns: In the present case, metastatic gastric cancer was treated with the anti-PD-1 antibody, nivolumab, as third-line treatment.

Diagnosis: After the initiation of nivolumab therapy, a rapidly enlarging para-aortic lymph nodes were observed leading to the diagnosis of HPD.

Interventions: Multiplex immunohistochemistry was used to examine immune cells infiltrating in the primary tumor and in liver metastasis which were obtained before nivolumab treatment, and in lymph node metastasis which presented with HPD after nivolumab therapy.

Outcomes: In the primary tumor, helper T (Th) cells, cytotoxic T lymphocytes (CTLs), regulatory T (Treg) cells, and PD-L1-negative macrophages were observed. On the other hand, in metastatic lymph nodes presenting with HPD, PD-L1-positive macrophages prominently increased, while Treg cells, CTLs, and Th cells decreased. PD-L1 expression was not observed in gastric cancer cells among the three specimens.

Lessons: The findings suggest the possibility that PD-L1-positive M2 macrophage might contribute to acceleration of tumor growth with anti-PD-1 therapy in the present case.
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http://dx.doi.org/10.1097/MD.0000000000025773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133284PMC
May 2021

Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression.

Cancer Lett 2021 Aug 5;512:15-27. Epub 2021 May 5.

Department of Surgery and Oncology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic reaction caused by cancer-associated fibroblasts (CAFs), which provokes treatment resistance. CAFs are newly proposed to be heterogeneous populations with different functions within the PDAC microenvironment. The most direct sources of CAFs are resident tissue fibroblasts and mesenchymal stem cells, however, the origins and functions of CAF subtypes remain unclear. Here, we established allogeneic bone marrow (BM) transplantation models using spontaneous PDAC mice, and then investigated what subtype cells derived from BM modulate the tumor microenvironment and affect the behavior of pancreatic cancer cells (PCCs). BM-derived multilineage hematopoietic cells were engrafted in recipient pancreas, and accumulated at the invasive front and central lesion of PDAC. We identified BM macrophages-derived CAFs in tumors. BM-derived macrophages treated with PCC-conditioned media expressed CAF markers. BM-derived macrophages led the local invasion of PCCs in vitro and enhanced the tumor invasive growth in vivo. Our data suggest that BM-derived cells are recruited to the pancreas during carcinogenesis and that the specific subpopulation of BM-derived macrophages partially converted into CAF-like cells, acted as leading cells, and facilitated pancreatic cancer progression. The control of the conversion of BM-derived macrophages into CAF-like cells may be a novel therapeutic strategy to suppress tumor growth.
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http://dx.doi.org/10.1016/j.canlet.2021.04.013DOI Listing
August 2021

Outcomes of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs.

Br J Haematol 2021 Jul 6;194(1):101-110. Epub 2021 Apr 6.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.
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http://dx.doi.org/10.1111/bjh.17456DOI Listing
July 2021

Human PD-1CD8 T Cells Are a Cellular Source of IL-21 in Rheumatoid Arthritis.

Front Immunol 2021 19;12:654623. Epub 2021 Mar 19.

Department of Medical Education, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Rheumatoid arthritis (RA) is a prototypical autoantibody-driven autoimmune disease in which T-B interactions play a critical role. Recent comprehensive analysis suggests that PD-1CD8 T cells as well as two distinct IL-21-producing PD-1CD4 T cell subsets, follicular helper T (Tfh) and peripheral helper T (Tph) cells, are involved in the pathogenesis of RA. Herein, we aimed to clarify a generation mechanism of IL-21-producing CD8 T cells in humans, and to characterize this novel subset in patients with RA.

Methods: CD8 T cells in the peripheral blood (PB) and synovial fluid (SF) of healthy control (HC) and patients with RA were subject to the analysis of IL-21 mRNA and protein. We evaluated the surface marker, cytokine and transcription profiles of IL-21-producing CD8 T cells in HCPB, RAPB and RASF.

Results: IL-21-producing CD8 T cells were enriched in the CD45RA(memory) PD-1, especially PD-1 subpopulation, and IL-12 and IL-21 synergistically induced IL-21 production by naïve CD8 T cells. Memory PD-1CD8 T cells in HCPB facilitated plasmablast differentiation and IgG production in an IL-21-dependent manner. In addition, PD-1CD8 T cells in RASF and RAPB produced large amounts of IL-21 and were characterized by high levels of CD28, ICOS, CD69, HLA-DR, and CCR2 but not CXCR5. Furthermore, PD-1CD8 T cells expressed high levels of transcripts of and , a feature observed in Tph cells.

Conclusions: Identification of IL-21-producing PD-1CD8 T cells expands our knowledge of T cell subsets with B helper functions in RA. Selective targeting of these subsets could pave an avenue for the development of novel treatment strategies for this disease.
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http://dx.doi.org/10.3389/fimmu.2021.654623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017303PMC
September 2021

Autoimmune manifestations associated with myelodysplastic syndrome predict a poor prognosis.

Medicine (Baltimore) 2021 Apr;100(13):e25406

Department of Medical Education, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Abstract: We evaluated the clinical characteristics of autoimmune manifestations (AIMs) associated with myelodysplastic syndrome (MDS) to elucidate whether AIMs impacted MDS outcomes in Japan.This retrospective study including 61 patients who received a new diagnosis of MDS between January 2008 and December 2015 was conducted by the review of electronic medical records for the presence of AIMs within a 1-year period prior to or following the diagnosis of MDS.AIMs were identified in 12 of the 61 (20.0%) patients with MDS. The neutrophil counts and C-reactive protein levels in peripheral blood were significantly elevated in patients with AIMs, and the survival was shorter in those with AIMs compared to those without AIMs. Multivariate analysis demonstrated that the presence of AIMs and higher-risk disease according to the International Prognositic Scoring System (IPSS) were independent risk factors for increased mortality (hazard ratio, 4.76 and 4.79, respectively).This retrospective study revealed that the prognosis was poor in patients with MDS-associated AIMs. The treatment of MDS using the current algorithms is based on prognostic scoring systems such as IPSS. Treatment strategies for patients with MDS-associated AIMs should be reconsidered, even in those with low-risk MDS according to the IPSS.
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http://dx.doi.org/10.1097/MD.0000000000025406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021323PMC
April 2021

Use of F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography to successfully diagnose central nervous system vasculitis in systemic lupus erythematosus and antiphospholipid syndrome: a case report.

Mod Rheumatol Case Rep 2021 07 15;5(2):278-284. Epub 2021 Apr 15.

Department of Medical Education, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

A 53-year-old woman was admitted to our hospital for headache secondary to an acute subdural haematoma in the right cerebellar tentorium. She had been diagnosed with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) two years before presentation and was initiated on prednisolone (PSL) 40 mg/day as induction therapy, which was subsequently tapered to 5 mg/day. Her thrombocytopenia and renal impairment were managed by warfarin with a target prothrombin time-international normalised ratio of 2-3. Her history also included 5 instances of triggerless acute subdural haematoma in the right cerebellar tentorium in the preceding 8 months. Warfarin therapy was suspected as the cause of her bleeding; however, dose adjustment was ineffective. During the current admission, neither magnetic resonance imaging nor cerebral angiography could reveal the cause of the bleeding. However, spinal fluid IL-6 was 25.7 pg/mL, and F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography showed fluorodeoxyglucose accumulation in the right medial occipital lobe cortex in the proximity of the haemorrhage site. Based on these two findings, we suspected vasculitis as the cause of recurrent bleeding. After ruling out malignancy, re-induction therapy with intravenous cyclophosphamide 500 mg/m/month and PSL 30 mg/day was initiated. PSL was tapered to 2 mg/day and no signs of relapse have developed at 2 years after discharge. Her clinical course also supported vasculitis as the cause of recurrent central nervous system (CNS) bleeding and we discuss the usefulness of F-Fluorodeoxyglucose-Positron Emission Tomography in the diagnosis and treatment of CNS vasculitis in SLE and/or APS.
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http://dx.doi.org/10.1080/24725625.2021.1905220DOI Listing
July 2021

Activation of caspase-1 is mediated by stimulation of interferon genes and NLR family pyrin domain containing 3 in monocytes of active systemic lupus erythematosus.

Clin Exp Rheumatol 2021 Mar 22. Epub 2021 Mar 22.

Department of Medical Education, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objectives: Emerging evidence has shown the importance of inflammasome activation in the progression of autoimmune diseases. In this study, we aimed to identify the main cell types activating inflammasome in autoimmune diseases and to clarify the intracellular pathway of inflammasome activation in systemic lupus erythematosus (SLE).

Methods: Active caspase-1 in each subset of human peripheral blood cells from healthy controls (n=18), SLE (n=51), and other rheumatic diseases (n=36) were fluorescently probed with FLICA™-caspase-1 followed by flow cytometric analysis. The correlation of caspase-1 activation in monocytes and clinical parameters in SLE patients were evaluated. In-vitro experiments were performed to identify the pathway involved in caspase-1 activation induced by SLE serum in monocytes.

Results: Active caspase-1 in monocytes was upregulated in SLE patients. Cluster of differentiation 14 (CD14)-positive and CD16-positive monocytes showed considerable activation of caspase-1 compared with the other subsets of monocytes. Serum titres of anti-double stranded DNA antibodies were positively correlated with active caspase-1 in monocytes, and serum complement component 3 and platelet count were negatively correlated with active caspase-1 in monocytes. The SLE serum-induced activation of caspase-1 and IL-1β secretion were down-regulated by inhibition of NLR family pyrin domain containing 3 (NLRP3), cyclic GMP-AMP synthase (cGAS), or stimulator of interferon genes (STING).

Conclusions: These findings suggest that targeting inflammasome by regulating cGAS/STING and NLRP3 are potential therapeutic strategies for SLE.
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March 2021

Clinical features and chromosomal/genetic aberration in adult acute lymphoblastic leukemia in Japan: results of Fukuoka Blood & Marrow Transplant Group Studies ALL MRD 2002 and 2008.

Int J Hematol 2021 Jun 16;113(6):815-822. Epub 2021 Mar 16.

Division of Hematology and Oncology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.

Acute lymphoblastic leukemia (ALL) is a common neoplasm in children, but less frequent in adults. Since information on clinical features and genetics of adult ALL in Japan is limited, we analyzed 215 subjects aged 16-65 years with untreated ALL enrolled in the Fukuoka Blood & Marrow Transplant Group studies ALL MRD 2002 and 2008. The prevalence of ALL was bimodal, with the larger group aged 56-65 years. Immunophenotypic characterization showed B-lineage is more frequent than T-lineage ALL (78.6 vs 13.0%), with age-related differences. The proportion with BCR-ABL1 rearrangement increased progressively with age, up to 55.7% among subjects aged over 56-65 years. Rearrangements involving the KMT2A gene, ETV6-RUNX1, and TCF3-PBX1 were rare in this study cohort. The overall incidence of hyperdiploidy was only 1.7%, and there were no cases with hypodiploidy. Overall survival varied by age and cytogenetics. Older subjects and those with BCR-ABL1 tended to have inferior outcomes. In this epidemiological study of Japanese adult ALL, the majority of subjects had B-lineage ALL, the T-cell phenotype was most frequent in those aged 16-25, and BCR-ABL1 rearrangement was very common, with prevalence increasing with age. These types of adult ALL are potentially manageable with targeted therapies.
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http://dx.doi.org/10.1007/s12185-021-03116-8DOI Listing
June 2021

Genetic testing and serological screening for SARS-CoV-2 infection in a COVID-19 outbreak in a nursing facility in Japan.

BMC Infect Dis 2021 Mar 15;21(1):263. Epub 2021 Mar 15.

Medical Corporation SOUSEIKAI, Kanenokuma Hospital, Fukuoka, Japan.

Background: The Pandemic of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has critically impacted the spread of infection within nursing facilities. We evaluated the usefulness of genetic and serological tests conducted during a COVID-19 outbreak in a nursing facility in Japan.

Methods: After the first identification of SARS-CoV-2 infection, a comprehensive, facility- and/or unit-wide PCR testing from nasopharyngeal swabs was repeatedly performed in a three-unit facility including 99 residents with dementia and 53 healthcare personnel. Additionally, PCR testing was conducted separately for residents and staff with fever of ≥37.5 °C. Facility-wide serological testing, including rapid kit testing and quantitative assay, was conducted twice over 1 month apart.

Results: A total of 322 PCR and 257 antibody tests were performed. 37 (24.3%) of the 152 individuals (25/99 residents, 25.3%; 12/53 staff, 22.6%) were identified as PCR-positive. Seven residents died with a mortality of 7.1% (7/99). Among the 37 individuals, 10 (27.0%) were asymptomatic at the time of testing. PCR positivity was concentrated on one unit (Unit 1) (20/30 residents, 66.7%; 9/14 staff, 64.3%). The other units showed a limited spread of infection. In unit-wide and separate tests, PCR positivity detection was highly prevalent (22.9 and 44.4%, respectively) in Unit 1, compared with that in the other units. Serological testing identified two additional infected residents with a negative PCR result and showed that no staff was newly identified as infected.

Conclusions: Thorough PCR testing, in combination with comprehensive and separate tests, is critical for managing COVID-19 outbreaks in nursing facilities, particularly, in units considered an epicenter. Serological testing is also beneficial for tracing contacts, confirming the number of infected individuals, and authorizing the termination of the outbreak.
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http://dx.doi.org/10.1186/s12879-021-05972-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957465PMC
March 2021

Predictive impact of C-reactive protein to albumin ratio for recurrent or metastatic head and neck squamous cell carcinoma receiving nivolumab.

Sci Rep 2021 02 2;11(1):2741. Epub 2021 Feb 2.

Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Although the neutrophil to lymphocyte ratio (NLR) was reported to be a predictive biomarker for clinical outcomes in various types of cancer, including recurrent or metastatic head and neck cancer (R/M HNSCC) treated with nivolumab, the usefulness of the pretreatment C-reactive protein/albumin ratio (CAR) as a prognostic marker remains to be clarified. This study aimed to analyze the clinical usability of the CAR in comparison with that of the NLR. 46 R/M HNSCC patients treated with nivolumab were retrospectively analyzed. The optimal cutoff value for the CAR was calculated using receiver operating characteristic curve analysis. The optimal cutoff value for the CAR was set to 0.30. On multivariate analyses, a high CAR was significantly associated with poor overall survival (adjusted HR, 2.19; 95% CI, 1.42-3.47; p < 0.01) and progression-free survival (adjusted HR, 1.98; 95% CI, 1.38-2.80; p < 0.01). The overall response rate and disease control rate for the high CAR patients were lower than for the low CAR patients. The CAR had significantly higher area under the curve values than the NLR at 2 and 4 months. The pretreatment CAR might be an independent marker for prognosis and efficacy in R/M HNSCC patients treated with nivolumab.
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http://dx.doi.org/10.1038/s41598-021-82448-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854616PMC
February 2021
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