Publications by authors named "Hikaru Kobayashi"

94 Publications

Pretransplantation Red Blood Cell and Platelet Transfusion Burden in De Novo Myelodysplastic Syndrome Undergoing Allogeneic Transplantation.

Transplant Cell Ther 2021 May 12. Epub 2021 May 12.

Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan; Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Most patients of myelodysplastic syndrome (MDS) require red blood cell (RBC) or platelet transfusion during their disease courses, which could cause an increased risk of iron overload and alloimmunization. However, it remains less clear whether pretransplantation RBC or platelet transfusion burden affects transplant outcomes in patients with MDS. The objective was to examine the significance of pretransplantation RBC and platelet transfusion burden on transplant outcomes after allogeneic HCT for adults with de novo MDS. We retrospectively evaluated the effect of pretransplantation RBC or platelet transfusion burden on transplant outcomes in a cohort of 1007 adult patients with de novo MDS treated by upfront allogeneic hematopoietic cell transplantation (HCT) between 2006 and 2018. Both higher pretransplantation RBC and platelet transfusion burdens were significantly associated with higher overall mortality and relapse-related mortality, but not non-relapse mortality in the multivariate analysis. Higher pretransplantation RBC transfusion burden was also significantly associated with lower neutrophil, platelet, and reticulocyte recovery in the multivariate analysis. In summary, our study clearly demonstrated that a higher pretransplantation RBC and platelet transfusion burden was independently associated with higher overall mortality, relapse-related mortality, and lower hematopoietic recovery after allogeneic HCT for de novo MDS. Early allogeneic HCT should be considered for patients with de novo MDS who require RBC and platelet transfusion repeatedly.
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http://dx.doi.org/10.1016/j.jtct.2021.05.003DOI Listing
May 2021

Kinetics and clinical significance of human herpesvirus 6 DNA shedding in saliva after allogeneic hematopoietic stem cell transplantation.

Transpl Infect Dis 2020 Nov 20:e13512. Epub 2020 Nov 20.

Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan.

Background: Little is known about the kinetics and clinical significance of saliva human herpesvirus-6 (HHV-6) DNA after hematopoietic stem cell transplantation (HSCT).

Methods: In this observational study, we quantified HHV-6 DNA in serially collected plasma and saliva from allogeneic HSCT recipients. Associations between the status of salivary HHV-6 DNA and the development of HHV-6 encephalitis, depression, and oral mucosal graft-versus-host disease (GVHD) were retrospectively analyzed.

Results: A total of 787 plasma and 434 saliva samples were collected from 56 patients. The cumulative incidence of HHV-6 DNA in plasma and saliva at 60 days after transplantation was 51.8% and 83.9%, respectively. The peak level of salivary HHV-6 DNA was significantly higher in patients who displayed plasma HHV-6 DNA than in those who did not (median, 51,584 copies/mL vs 587 copies/mL; P < .0001). Salivary HHV-6 DNA levels increased after positive plasma HHV-6 DNA was detected and remained high during observation period. Despite the frequent occurrence of positive salivary HHV-6 DNA, no patient developed depression. Positivity of salivary HHV-6 DNA was not significantly associated with the development of HHV-6 encephalitis (P = 1.00, Fisher's exact test) or oral mucosal GVHD (P = .71, Grey's test). No significant relationship between salivary HHV-6 DNA and these diseases was found even when comparing higher HHV-6 DNA loads in saliva.

Conclusion: Salivary HHV-6 DNA levels increased after HHV-6 DNA was detected in the blood. However, no epidemiological evidence was shown to support a role of salivary HHV-6 in the development of HHV-6 encephalitis, depression, and oral mucosal GVHD.
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http://dx.doi.org/10.1111/tid.13512DOI Listing
November 2020

Efficacy of a Si-based agent against developing renal failure in a rat remnant kidney model.

Biochem Biophys Res Commun 2020 12 31;533(4):698-703. Epub 2020 Oct 31.

Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.

Chronic renal failure is exacerbated by oxidative stress, and this condition is difficult to treat in advanced stages. Because of the lack of effective treatments, the disease is a global public health concern. We developed a Si-based agent that continuously generates hydrogen for more than 24 h by reacting with water under conditions similar to those in the gastrointestinal tract. Given the efficacy of hydrogen in the treatment of conditions associated with oxidative stress, we examined whether the Si-based agent had beneficial effects on the development of renal failure. The Si-based agent was orally administered to rats that were developing renal failure. Rats underwent 5/6 nephrectomy to establish a remnant kidney model. Specifically, on day -7, rats underwent right 2/3 nephrectomy, followed by light nephrectomy on day 0. Starting on day -3, the rats were administered a control or Si-based agent-containing diet for 8 weeks. Compared with the findings in control rats, the Si-based agent greatly suppressed the increases of both serum creatinine and urinary protein levels. All analyzed parameters of oxidative stress were significantly suppressed in the Si-based agent groups. Histopathological examination illustrated that glomerular hypertrophy was suppressed by the treatment. Quantitative real-time reverse transcription-polymerase chain reaction revealed that sirtuin 1 and heme oxygenase-1 expression was increased in the Si-based agent groups, suggesting improved antioxidant activity and reduced hypoxia. In addition, caspase-3 and interleukin-6 expression was suppressed in the Si-based agent groups, indicating the alleviation of apoptosis and inflammation. In conclusion, oral administration of a Si-based agent resulted in renoprotective effects, presumably by suppressing oxidative stress via hydrogen generation.
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http://dx.doi.org/10.1016/j.bbrc.2020.10.067DOI Listing
December 2020

Sex-related differences in behavioural markers in adult mice for the prediction of lifespan.

Biogerontology 2021 Feb 16;22(1):49-62. Epub 2020 Oct 16.

Department of Genetics, Physiology and Microbiology (Unit of Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.

Finding biomarkers to assess the rate of ageing and consequently, to forecast individual lifespan is a challenge in ageing research. We recently published a mathematical model for lifespan prediction in adult female mice using behavioural parameters such as internal locomotion and time spent in open arms in the hole board (HB) and elevated plus maze (EPM) tests, respectively. Nevertheless, it is still not known if these behavioural variables could be useful in forecasting lifespan in male mice. Therefore, two groups of ICR-CD1 mice, male and female were subjected to the EPM, HB and T-maze tests at the adult age. Mice were monitored until they died and individual lifespans were registered. In general, adult male mice showed more anxiety-like behaviours than females. The mathematical model previously developed in females was validated with the female cohort, but found to be suboptimal for lifespan prediction in males. Thus, a new model for male lifespan prediction was constructed including the behavioural variables that were predictive of lifespan in males: time in the central platform of the EPM, inner locomotion, number of groomings and number and duration of head-dippings in the HB. These results confirm that the higher the anxiety-like behaviour at the adult age, the shorter the lifespan.
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http://dx.doi.org/10.1007/s10522-020-09902-xDOI Listing
February 2021

Novel hydrogen-producing Si-based agent reduces oxidative stress, and improves sperm motility and in vitro fertilization rate in varicocoele.

Andrology 2021 01 9;9(1):376-383. Epub 2020 Sep 9.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.

Background: Varicocoele-induced male infertility potentially involves oxidative stress. Although varicocoelectomy is recommended for varicocoele patients presenting abnormal semen findings, no pharmacotherapeutic methods currently exist. We have recently developed a silicon-based agent that produces hydrogen by the reaction with water.

Objectives: This study aimed to investigate the therapeutic effects of oral administration of a Si-based agent on varicocoele rat.

Materials And Methods: Twenty-one rats were divided into four groups: varicocoele + normal diet (n = 5), varicocoele + Si-based agent-supplemented diet (n = 6), sham + normal diet (n = 5), and sham + Si-based agent-supplemented diet (n = 5). All rats were euthanized four weeks after surgery.

Results: The mean left epididymal sperm motility was 74.4% in the sham group, 72.3% in the sham + Si group, 57.6% in the varicocoele group, and 66.9% in the varicocoele + Si group. Epididymal sperm motility was significantly lower in the varicocoele group, but was significantly higher upon Si-based agent ingestion (P < .01). The mean left testicular weight, Johnsen's score, and left epididymal sperm concentration did not differ significantly between groups. The 8-OHdG concentration and DNA fragmentation rate were significantly increased in the varicocoele group, but were significantly decreased in the Si-based agent intake group (P < .01). Additionally, the IVF rate was significantly lower in the varicocoele group (26.3%) compared with the sham group (73.4%; P < .01), and was significantly higher in the varicocoele + Si group (51.8%) compared with the varicocoele group (P < .05), indicating that the Si-based agent improves IVF rates.

Discussion And Conclusion: Oral intake of the silicon-based agent improves epididymal sperm motility and in vitro fertilization rates through hydrogen production and subsequent reduction of oxidative stress. Considering the lack of effective noninvasive methods, this Si-based agent is potentially applicable for treating varicocoele-induced abnormal semen parameters.
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http://dx.doi.org/10.1111/andr.12890DOI Listing
January 2021

Allogeneic stem cell transplantation for patients with aggressive NK-cell leukemia.

Bone Marrow Transplant 2021 02 10;56(2):347-356. Epub 2020 Aug 10.

Department of Oncology and Hematology, Shimane University Hospital, Izumo, Japan.

Aggressive NK-cell leukemia (ANKL) has a fulminant clinical course with a poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment. Using the Japanese transplant registry data, the outcomes of 59 ANKL patients who underwent first allo-HSCT were analyzed. Twenty-nine patients received stem cells from cord blood (CB), 18 from peripheral blood, and 12 from bone marrow. At the time of transplant 21 patients had complete response (CR), and 7 partial response (PR), but 31 without response. The 1-year and 5-year overall survival (OS) were 33.9% and 27.3%, respectively. The 1-year cumulative incidences of relapse or progression was 55.5%, and that of non-relapse mortality was 12.1%. The OS was significantly better for patients with CR or PR at the time of allo-HSCT (P = 0.046), which was equivalent to that for patients who experienced primary induction failure at the time of allo-HSCT but achieved CR afterwards (40.6% versus 32.0% at 5 years; P = 0.95). Patients receiving CB had a significantly better OS than those receiving stem cells from others (37.3% versus 16.2% at 5 years; P = 0.04). Patients achieving event-free survival at 12 months after allo-HSCT had good outcomes with 5-year OS of 85.2%.
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http://dx.doi.org/10.1038/s41409-020-01009-8DOI Listing
February 2021

Salvage Therapy Using Azacitidine for Relapsed Primary Myelofibrosis after Cord Blood Transplantation.

Intern Med 2020 Nov 7;59(21):2763-2767. Epub 2020 Jul 7.

Department of Hematology, Nagano Red Cross Hospital, Japan.

We present the case of a 53-year-old woman with prefibrotic stage primary myelofibrosis (PMF) who underwent cord blood transplantation. Nine years after transplantation, she relapsed, which was confirmed by a bone marrow examination. We decided to treat her using azacitidine. After three courses of azacitidine, a partial cytogenetic response was confirmed. Azacitidine maintenance therapy successfully maintained a low level of recipient-origin peripheral blood cells with a stable hematological condition. Azacitidine may therefore be a promising therapeutic option for PMF patients who relapse after allogeneic stem cell transplantation.
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http://dx.doi.org/10.2169/internalmedicine.4863-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691036PMC
November 2020

Single-cell biophysical study reveals deformability and internal ordering relationship in T cells.

Soft Matter 2020 Jun;16(24):5669-5678

Center for Biomedical Technology, Universidad Politécnica de Madrid, E-28223 Pozuelo de Alarcón, Spain. and Departamento de Ciencia de Materiales, ETSI de Caminos, Canales y Puertos, Universidad Politécnica de Madrid, E-28040 Madrid, Spain.

Deformability and internal ordering are key features related to cell function, particularly critical for cells that routinely undergo large deformations, like T cells during extravasation and migration. In the measurement of cell deformability, a considerable variability is typically obtained, masking the identification of possible interrelationships between deformability, internal ordering and cell function. We report the development of a single-cell methodology that combines measurements of living-cell deformability, using micropipette aspiration, and three-dimensional confocal analysis of the nucleus and cytoskeleton. We show that this single-cell approach can serve as a powerful tool to identify appropriate parameters that characterize deformability within a population of cells, not readably discernable in population-averaged data. By applying this single-cell methodology to mouse CD4+ T cells, our results demonstrate that the relative size of the nucleus, better than other geometrical or cytoskeletal features, effectively determines the overall deformability of the cells within the population.
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http://dx.doi.org/10.1039/d0sm00648cDOI Listing
June 2020

Comparison of reduced-intensity/toxicity conditioning regimens for umbilical cord blood transplantation for lymphoid malignancies.

Bone Marrow Transplant 2020 11 21;55(11):2098-2108. Epub 2020 May 21.

Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

To investigate which reduced-intensity conditioning (RIC)/reduced-toxicity conditioning (RTC) is superior for umbilical cord blood transplantation (UCBT) for lymphoid malignancies, we retrospectively compared three widely used RIC/RTC regimens: fludarabine/melphalan/total body irradiation (FM-TBI, n = 524), fludarabine/cyclophosphamide/total body irradiation (FC-TBI, n = 96), and fludarabine/busulfan/total body irradiation or melphalan (FB-based, n = 159). Among patients with acute lymphoblastic leukemia (ALL) (n = 314), there were no differences in overall survival (OS) by conditioning regimen. Among patients with malignant lymphoma (ML) (n = 465), FM-TBI and FC-TBI regimens had similar OS, whereas FB-based regimen had lower OS (hazard ratio [HR], 1.73; P < 0.01) than did FM-TBI regimen due to higher non-relapse mortality (HR, 1.72; P = 0.02). In addition, mycophenolate mofetil-containing GVHD prophylaxis was associated with better OS than methotrexate-containing GVHD prophylaxis among patients who received FM-TBI (HR, 0.65; P = 0.03) and FC-TBI (HR, 0.25; P < 0.01) regimens due to a decreased relapse risk. In summary, our results suggest that all three RIC/RTC regimens have comparable clinical outcomes in ALL, while the FM-TBI or FC-TBI regimens combined with mycophenolate mofetil-containing GVHD prophylaxis is preferable in RIC/RTC-UCBT for ML. Large prospective studies are warranted to confirm these results.
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http://dx.doi.org/10.1038/s41409-020-0905-6DOI Listing
November 2020

Efficacy of hypothermia therapy in patients with acute encephalopathy with biphasic seizures and late reduced diffusion.

Brain Dev 2020 Aug 9;42(7):515-522. Epub 2020 Apr 9.

Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.

Background: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized by biphasic seizures and impaired consciousness. The efficacy of hypothermia/normothermia therapy in patients with AESD has rarely been reported on.

Methods: We enrolled 15 patients with AESD admitted to Yamaguchi University Hospital and Yamaguchi-ken Saiseikai Shimonoseki General Hospital between 2005 and 2019 and retrospectively evaluated the long-term efficacy of hypothermia therapy compared to that of non-hypothermia therapy. We compared the long-term sequelae of patients with AESD treated with or without hypothermia therapy. We used the Pediatric Cerebral Performance Category (PCPC) scale and intelligence tests including the Wechsler Intelligence Scale for Children, Tanaka-Binet Intelligence Scale, and Enjoji Infantile Developmental Scale to evaluate neurological sequelae and mental disability. The preventive effect of hypothermia therapy was assessed based on the development of post-encephalopathic epilepsy (PEE).

Results: There was no significant between-group difference in the PCPC score (p = 0.53). The subjects with severe mental disability in the hypothermia therapy group were 0 (0%), while those in the non-hypothermia group were 2 (29%); however, the difference was not significant. Notably, there were no patients with onset of PEE in the hypothermia therapy group, while there were 4 (57.1%) in the non-hypothermia group (p = 0.03).

Conclusions: Our study suggests that hypothermia therapy may be effective in the long-term sequelae of AESD in terms of preventing the development of PEE. We propose that hypothermia therapy could contribute to improve the quality of life in these patients by preventing the subsequent onset of PEE.
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http://dx.doi.org/10.1016/j.braindev.2020.03.007DOI Listing
August 2020

Oral Administration of Si-Based Agent Attenuates Oxidative Stress and Ischemia-Reperfusion Injury in a Rat Model: A Novel Hydrogen Administration Method.

Front Med (Lausanne) 2020 20;7:95. Epub 2020 Mar 20.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.

Organ ischemia-reperfusion injury (IRI), which is unavoidable in kidney transplantation, induces the formation of reactive oxygen species and causes organ damage. Although the efficacy of molecular hydrogen (H) in IRI has been reported, oral intake of H-rich water and inhalation of H gas are still not widely used in clinical settings because of the lack of efficiency and difficulty in handling. We successfully generated large quantities of H molecules by crushing silicon (Si) to nano-sized Si particles (nano-Si) which were allowed to react with water. The nano-Si or relatively large-sized Si particles (large-Si) were orally administered to rats with renal IRI. Animals were divided into four groups: sham, IRI, IRI + nano-Si, and IRI + large-Si. The levels of serum creatinine and urine protein were significantly decreased 72 h following IRI in rats that were administered nano-Si. The levels of oxidative stress marker, urinary 8-hydroxydeoxyguanosine were also significantly decreased with the nano-Si treatment. Transcriptome and gene ontology enrichment analyses showed that the oral nano-Si intake downregulated the biological processes related to oxidative stress, such as immune response, cytokine production, and extrinsic apoptotic signaling pathway. Alterations in the regulation of a subset of genes in the altered pathways were validated by quantitative polymerase chain reaction. Furthermore, immunohistochemical analysis demonstrated that the nano-Si treatment alleviated interstitial macrophage infiltration and tubular apoptosis, implicating the anti-inflammatory and anti-apoptotic effects of nano-Si. In conclusion, renal IRI was attenuated by the oral administration of nano-Si, which should be considered as a novel H administration method.
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http://dx.doi.org/10.3389/fmed.2020.00095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099649PMC
March 2020

Renoprotective and neuroprotective effects of enteric hydrogen generation from Si-based agent.

Sci Rep 2020 04 3;10(1):5859. Epub 2020 Apr 3.

Department of Neuroscience and Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan.

We have developed Si-based agent which can generate a large amount of hydrogen. Si-based agent continues generating hydrogen for more than 24 h by the reaction with water under conditions similar to those in bowels, i.e., pH8.3 and 36 °C, and generates ~400 mL hydrogen. To investigate beneficial effects for diseases associated with oxidative stress, Si-based agent is administered to remnant kidney rats and Parkinson's disease mice. Rats are fed with control or Si-based agent-containing diet for 8 weeks. Si-based agent is found to greatly suppress the development of renal failure and the parameters of oxidative stress. Treatment with Si-based agent in a mouse model of hemi-Parkinson's disease induced by 6-hydroxydopamine attenuated degeneration of dopaminergic neurons and prevented impairment of motor balance and coordination. These findings indicate that the Si-based agent shows renoprotective and neuroprotective effects presumably via suppression of oxidative stress by generation of hydrogen.
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http://dx.doi.org/10.1038/s41598-020-62755-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125117PMC
April 2020

Pulmonary mucormycosis developed during acute myelogenous leukemia and successfully treated by surgical resection before blood stem cell transplantation.

AME Case Rep 2019 27;3:48. Epub 2019 Dec 27.

Department of Blood Medicine, Japanese Red Cross Society Nagano Hospital, Nagano, Japan.

Pulmonary mucormycosis is relatively rare and occurs in immunosuppressed patients, for example, individuals with hematologic malignancies such as leukemia. As pulmonary mucormycosis increases rapidly and is often fatal, appropriate treatment including surgical resection is necessary. We report a patient with pulmonary mucormycosis and acute myelogenous leukemia for which antifungal drugs were invalid. After rapid surgical resection, the patient was administered a peripheral blood stem cell transplantation. In conclusion, we emphasize that patients with pulmonary mucormycosis undergoing leukemia treatment should be considered for rapid surgical treatment if the infected lesion is limited, as overcoming this acute infection increases their chance to undergo hematopoietic stem cell transplantation and potential for long-term survival.
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http://dx.doi.org/10.21037/acr.2019.11.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987314PMC
December 2019

Improvement of early mortality in single-unit cord blood transplantation for Japanese adults from 1998 to 2017.

Am J Hematol 2020 04 2;95(4):343-353. Epub 2020 Jan 2.

Division of Hematology, National Defense Medical College, Tokorozawa, Japan.

The major limitation of cord blood transplantation (CBT) for adults remains the delayed hematopoietic recovery and higher incidence of graft failure, which result in a higher risk of early mortality in CBT. We evaluated early overall survival (OS), non-relapse mortality (NRM), neutrophil engraftment, acute graft-vs-host disease, and cause of early death among 9678 adult patients who received single-unit CBT in Japan between 1998 and 2017. The probability of OS at 100 days was 64.4%, 71.7%, and 78.9% for the periods 1998 to 2007, 2008 to 2012, and 2013 to 2017, respectively (P < .001). The cumulative incidences of NRM at 100 days during the same period were 28.3%, 20.8%, and 14.6%, respectively (P < .001). The cumulative incidences of neutrophil engraftment were also improved during the same period (P < .001). The most common cause of death within 100 days after CBT was bacterial infection in 1998 to 2007 and primary disease in the latter two time periods. Across the three time periods, the proportions of deaths from bacterial and fungal infection, graft failure, hemorrhage, sinusoidal obstructive syndrome, and organ failure decreased in a stepwise fashion. Landmark analysis of OS and NRM after 100 days showed that OS did not change over time in the multivariate analysis. Our registry-based data demonstrated a significant improvement of early OS after CBT for adults over the past 20 years. The landmark analysis suggested that improvement of early mortality could lead to an improvement of long-term OS after CBT.
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http://dx.doi.org/10.1002/ajh.25705DOI Listing
April 2020

Magnesium-dependent activated partial thromboplastin time assay-Simple method for lupus anticoagulant detection.

Int J Lab Hematol 2020 Feb 10;42(1):46-51. Epub 2019 Dec 10.

Department of Biomedical Laboratory Sciences, School of Health Sciences, Shinshu University School of Medicine, Matsumoto, Japan.

Introduction: Detection of lupus anticoagulant (LA), an antiphospholipid (aPL) antibody, in a clotting time test is an important finding for diagnosis of antiphospholipid syndrome (APS). However, confirmation of LA requires several different testing procedures, some of which can be difficult and require time. We report here a simple and highly specific method for detecting LA.

Materials And Methods: We examined 66 plasma samples obtained from LA-positive (LA) and 75 from LA-negative (non-LA) subjects, which included patients with acquired hemophilia and coagulation disorders, as well as from 43 healthy volunteer samples as normal controls. Activated partial thromboplastin time (APTT) was determined by adding 20 mmol of CaCl (Ca-APTT) or 25 mmol of a mixture of Mg and Ca (Mg-APTT). The ratio of Mg-APTT/Ca-APTT was then calculated and used as the Mg/Ca Index.

Results: The Mg/Ca Index value for the LA group was significantly lower than that for the non-LA and normal control groups (P < .0001). When the cutoff value of the Mg/Ca Index was less than 1.00, the sensitivity of LA determination using the Mg-APTT assay was 80.3%, while specificity was 100%.

Conclusion: Our findings indicate that the present Mg-APTT assay is a simple yet highly specific method for LA detection.
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http://dx.doi.org/10.1111/ijlh.13134DOI Listing
February 2020

Clinical practice recommendations for the diagnosis and management of human herpesvirus-6B encephalitis after allogeneic hematopoietic stem cell transplantation: the Japan Society for Hematopoietic Cell Transplantation.

Bone Marrow Transplant 2020 06 19;55(6):1004-1013. Epub 2019 Nov 19.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

Reactivation of human herpesvirus (HHV)-6B is relatively common after allogeneic hematopoietic stem cell transplantation (HSCT) and HHV-6B diseases may consequently develop. Among them, HHV-6B encephalitis is a serious and often fatal complication. The aim of these clinical practice recommendations is to provide diagnostic and therapeutic guidance for HHV-6B encephalitis after allogeneic HSCT. In this evidence-based review, we critically evaluated data from the published literature. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assist in generating recommendations. We have summarized the findings that contribute to decision-making and we have provided our recommendations. In cases where rigorous clinical data are unavailable, recommendations have been developed in discussions with physicians who have relevant expertize.
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http://dx.doi.org/10.1038/s41409-019-0752-5DOI Listing
June 2020

[Successful cord blood transplantation for myelodysplastic syndrome with Behçet disease-like refractory stomatitis and multiple ileocecal ulcerations].

Rinsho Ketsueki 2019 ;60(10):1436-1442

Department of Hematology, Nagano Red Cross Hospital.

A 12-year-old boy was diagnosed with aplastic anemia. He was followed as an outpatient without medication, and his cytopenia improved after several years. When he was 26 years old, an annual medical checkup revealed leukocytopenia, and at the age of 31 years, he was diagnosed with myelodysplastic syndrome (MDS), refractory cytopenia with multilineage dysplasia. Chromosomal analysis of his bone marrow cells revealed trisomy 8. Ten months after being diagnosed with MDS, he developed refractory stomatitis. Two months later, he experienced abdominal pain and bloody stool, and simple punched-out ulcers similar to intestinal Behçet's disease (BD) were noted in the terminal ileum on colonoscopy. Steroids, mesalazine, and adalimumab were ineffective. Nineteen months after the MDS diagnosis, he underwent cord blood transplantation from an HLA 1-locus mismatched unrelated donor in accordance with a non-myeloablative pretransplant conditioning regimen. The patient's stomatitis and ileocecal ulcers improved following the transplantation. Currently, both MDS and BD-like symptoms are in complete remission at 36 months post transplantation, and the patient continues to take low-dose oral tacrolimus for chronic skin GVHD. Allogeneic hematopoietic stem cell transplantation could become a therapeutic choice for MDS associated with BD, even if refractory intestinal BD symptoms are present.
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http://dx.doi.org/10.11406/rinketsu.60.1436DOI Listing
November 2019

Effects of Haplotype Matching on Outcomes after Adult Single-Cord Blood Transplantation.

Biol Blood Marrow Transplant 2020 03 9;26(3):509-518. Epub 2019 Oct 9.

Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.

It remains unclear whether the HLA haplotype of unrelated cord blood (UCB) should be matched to that of the patient in single UCB transplantation. Thus, using data from a Japanese registry, we analyzed the effect of haplotype matching on outcomes. Patients with hematologic diseases aged 16 years or older who had undergone their first transplant were included (N = 1347). The effects of haplotype matching and high-frequency HLA haplotype on outcomes were analyzed. Median patient age was 55 years. The cumulative incidences of neutrophil engraftment among groups with 0, 1, and 2 HLA haplotype matches were 79%, 82%, and 88%, respectively (P = .008). In a multivariate analysis, the group with 0 haplotype matches was marginally associated with worse neutrophil engraftment (P = .087) and significantly associated with platelet engraftment (P = .044) compared with the group with 1 haplotype match. Two-haplotype matches were associated with a higher risk of relapse. In the group with 1 haplotype match, the top 3 shared haplotypes were "A*24:02-B*52:01-C*12:02-DRB1*15:02" (HP-P1), "A*33:03-B*44:03-C*14:03-DRB1*13:02" (HP-P2), and "A*24:02-B*07:02-C*07:02-DRB1*01:01" (HP-P3). The presence of HP-P2 but not HP-P1 or HP-P3 was associated with a decreased risk of grades II to IV acute graft-versus-host disease (hazard ratio, .56; P = .001) but an increased risk of relapse (hazard ratio, 1.35; P = .045). HLA haplotype matching might be considered to improve engraftment. Two-haplotype matches should be avoided if the relapse risk is high. The haplotype itself may have an effect on the risk of acute graft-versus-host disease and relapse.
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http://dx.doi.org/10.1016/j.bbmt.2019.09.035DOI Listing
March 2020

Myocarditis with Advanced Atrioventricular Block after Allogeneic Stem Cell Transplantation: A Case Report and Literature Review.

Intern Med 2020 Jan 28;59(1):113-118. Epub 2019 Aug 28.

Department of Hematology, Nagano Red Cross Hospital, Japan.

A 51-year-old woman with Philadelphia chromosome-positive acute lymphoblastic leukemia underwent a second cord blood transplantation followed by maintenance therapy with interferon-α. After 33 months, she developed cardiogenic shock caused by advanced atrioventricular block. Laboratory tests revealed increased myocardium enzymes, and ultrasonic cardiography demonstrated mild thickening of the left ventricular wall. She was diagnosed with myocarditis and successfully treated using prednisolone. Myocarditis after allogeneic stem cell transplantation is a rare but potentially fatal complication. However, it is important for physicians to be aware of this complication because all of the symptoms may be reversed with immunosuppressive treatment.
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http://dx.doi.org/10.2169/internalmedicine.3322-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995704PMC
January 2020

A case of acute encephalophathy with residual neurological sequelae induced by immunoglobulin A vasculitis.

J Clin Neurosci 2019 Sep 11;67:270-271. Epub 2019 Jun 11.

Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.

Immunoglobulin A vasculitis (IgAV) occasionally induces central nervous system (CNS) involvement, which is usually transient with no sequelae except for hemorrhagic stroke. It is thought to be useful to measure serum and cerebrospinal fluid (CSF) cytokine levels for better understanding the pathological condition in encephalopathy, but there have been no reports in acute encephalopathy with IgAV. We describe an 8-year-old boy with IgAV who had neurological sequelae after complication of acute encephalopathy, focusing on the cytokine profiles and unique biphasic findings of magnetic resonance imaging. He presented with status epilepticus and mildly intensified area in the occipital lobe on the fluid-attenuated inversion recovery view. Arterial spin labeling (ASL) revealed the reduction of cerebral blood flow in the left hemisphere. On day 5 of illness, these abnormal findings disappeared, but delayed hyperintensity lesions on diffusion-weighted images newly emerged. Furthermore, CSF interleukin (IL)-6 levels markedly increased without elevated levels of IL-10 during the acute phase of disease. He suffered from long-lasting hemiparesis and intellectual impairment. In conclusion, acute encephalopathy with IgAV could cause neurological sequelae by prolonged seizure, and elevated IL-6 in CSF and laterality of cerebral blood flow in ASL might be useful to predict the prognosis of CNS dysfunction of IgAV.
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http://dx.doi.org/10.1016/j.jocn.2019.05.061DOI Listing
September 2019

[Miliary tuberculosis with markedly elevated soluble interleukin-2 receptor levels mimicking intravascular large B-cell lymphoma].

Rinsho Ketsueki 2019 ;60(3):203-208

Department of Hematology, Nagano Red Cross Hospital.

An 81-year-old woman with type 2 diabetes mellitus presented to our hospital due to anorexia, leg edema, and respiratory distress. Laboratory results revealed anemia, thrombocytopenia, elevated lactate dehydrogenase, and markedly elevated soluble interleukin-2 receptor levels. Computed tomography showed ground-glass opacities and consolidation in both lung fields, but no lymphadenopathy was noted. Intravascular large B-cell lymphoma (IVLBCL) was considered as a differential diagnosis; therefore, bone marrow and random skin biopsy were performed. Her respiratory condition deteriorated, with the occurrence of acute respiratory distress syndrome, disseminated intravascular coagulation, hemophagocytic syndrome, and further alveolar hemorrhage. Methylprednisolone pulse therapy was performed, but did not improve the patient's condition. On hospital day 6, the acid-fast bacterial smear of the sputum using the Gaffky scale was 2, and on the next day, tuberculosis DNA was detected in the polymerase chain reaction. In the bone marrow biopsy, multiple epithelioid cell granulomas were found; thus, the patient was diagnosed with miliary tuberculosis. Although anti-tuberculosis therapy was started immediately, she died on hospital day 22. The soluble interleukin-2 receptor level increased up to 19,400 U/ml. The differential diagnosis should be cautiously made because miliary tuberculosis can mimic IVLBCL.
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http://dx.doi.org/10.11406/rinketsu.60.203DOI Listing
August 2019

Comparison of Outcomes of Allogeneic Transplantation for Primary Myelofibrosis among Hematopoietic Stem Cell Source Groups.

Biol Blood Marrow Transplant 2019 08 1;25(8):1536-1543. Epub 2019 Mar 1.

Department of Hematology, Aiiku Hospital, Sapporo, Japan.

The choice of alternative donor is a major issue in allogeneic hematopoietic stem cell transplantation (HSCT) for patients with primary myelofibrosis (PMF) without an HLA-matched related donor. We conducted this retrospective study using the Japanese national registry data for 224 PMF patients to compare the outcomes of first allogeneic HSCT from HLA-matched related donor bone marrow (Rtd-BM), HLA-matched related donor peripheral blood stem cells (Rtd-PB), HLA-matched unrelated donor bone marrow (UR-BM), unrelated umbilical cord blood (UR-UCB), and other hematopoietic stem cell grafts. Nonrelapse mortality (NRM) rates at 1 year after Rtd-BM, Rtd-PB, UR-BM, UR-UCB, and other transplantations were 16%, 36%, 30%, 41%, and 48%, respectively. Multivariate analysis identified UR-UCB transplantation, other transplantation, frequent RBC transfusion before transplantation, and frequent platelet (PLT) transfusion before transplantation as predictive of higher NRM. Relapse rates at 1 year after Rtd-BM, Rtd-PB, UR-BM, UR-UCB, and other transplantation were 14%, 17%, 11%, 14%, and 15%, respectively. No specific factor was associated with the incidence of relapse. Overall survival (OS) at 1 and 4 years after Rtd-BM, Rtd-PB, UR-BM, UR-UCB, and other transplantation were 81% and 71%, 58% and 52%, 61% and 46%, 48% and 27%, and 48% and 41%, respectively. Multivariate analysis identified older patient age, frequent RBC transfusion before transplantation, and frequent PLT transfusion before transplantation as predictive of lower OS. In conclusion, UR-UCB transplantation, as well as UR-BM transplantation, can be selected for PMF patients without an HLA-identical related donor. However, careful management is required for patients after UR-UCB transplantation because of the high NRM. Further studies including more patients after HLA-haploidentical related donor and HLA-mismatched unrelated donor transplantation would provide more valuable information for patients with PMF when making decisions regarding the choice of alternative donor.
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http://dx.doi.org/10.1016/j.bbmt.2019.02.019DOI Listing
August 2019

Lymphoproliferation Impairment and Oxidative Stress in Blood Cells from Early Parkinson's Disease Patients.

Int J Mol Sci 2019 Feb 12;20(3). Epub 2019 Feb 12.

Department of Genetics, Physiology and Microbiology, Faculty of Biology, Complutense University of Madrid, 28040 Madrid, Spain.

In Parkinson's Disease (PD), the peripheral changes in the functional capacity and redox state of immune cells has been scarcely investigated, especially in the early PD stages. Aging is a risk factor for PD, and the age-related impairment of the immune system, based on a chronic-oxidative stress situation, is involved in the rate of aging. We analyzed several functions in isolated peripheral blood neutrophils and mononuclear cells from PD stage 2 patients, and compared the results to those in healthy elderly and adult controls. Several oxidative stress and damage parameters were studied in whole blood cells. The results showed an impairment of the lymphoproliferative response in stimulated conditions in the PD patients compared with age-matched controls, who also showed typical immunosenescence in comparison with adult individuals. Higher oxidative stress and damage were observed in whole blood cells from PD patients (lower glutathione peroxidase activity, and higher oxidized glutathione and malondialdehyde contents). Our results suggest an accelerated immunosenescence in PD stage 2, and that several of the parameters studied could be appropriate peripheral biomarkers in the early stages of PD.
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http://dx.doi.org/10.3390/ijms20030771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386872PMC
February 2019

Prognostic impact of melphalan dose and total body irradiation use in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation with reduced-intensity conditioning.

Leuk Lymphoma 2019 06 20;60(6):1493-1502. Epub 2018 Nov 20.

m Division of Clinical Oncology and Hematology , The Jikei University School of Medicine , Tokyo , Japan.

To evaluate the prognostic impact of melphalan dose and total body irradiation (TBI) use in acute myeloid leukemia patients undergoing reduced-intensity allogeneic transplantation, we retrospectively compared outcomes of patients receiving a higher-dose (120-140 mg/m,  = 379) or lower-dose melphalan (80-110 mg/m,  = 128) with or without TBI of ≤4 Gy. At 3 years, overall survival was 48.9% in the higher-dose group versus 40.3% in the lower-dose group ( = .013). This survival benefit was attributed to lower tumor-related mortality (23.9% vs. 31.7%;  = .049). Non-relapse mortality did not differ (24.8% vs. 23.5%,  = .59). The beneficial effect of a higher-dose melphalan was more evident when combined with TBI in younger patients, those not in complete remission, and those with good performance status. Our findings support the use of a higher-dose melphalan in combination with TBI for reduced-intensity conditioning in physically fit patients.
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http://dx.doi.org/10.1080/10428194.2018.1535115DOI Listing
June 2019

[Successful treatment with mecobalamin in a pernicious anemia patient presenting with false-normal serum vitamin B12].

Rinsho Ketsueki 2018;59(6):675-681

Department of Hematology, Nagano Red Cross Hospital.

An 81-year-old woman presented to our hospital with anemia. Complete blood counts revealed macrocytic anemia; however, serum vitamin B12 and folate levels were normal. Bone marrow aspiration revealed multilineage dysplasia, and the patient was initially diagnosed with refractory cytopenia and multilineage dysplasia subtype of myelodysplastic syndrome. However, blood smear revealed hypersegmented neutrophils and bone marrow aspiration showed remarkable megaloblastic changes of erythroid cells. Based on these findings, the patient was administered 1,500 µg mecobalamin per day on a trial basis. Three weeks after initiating mecobalamin, macrocytic anemia improved. Her hemoglobin levels were also normalized along with immediate resolution of peripheral blood dysplasia. The final diagnosis was pernicious anemia (PA) based on anti-intrinsic factor positivity and the efficacy of mecobalamin. Use of automated analyzers may be associated with falsely normal or falsely elevated vitamin B12 levels in the presence of anti-intrinsic factor antibodies. Our case suggests that trial administration of mecobalamin may be an important step to correctly diagnose PA associated with falsely normal or falsely elevated vitamin B12 levels, particularly when typical morphological features of PA are present.
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http://dx.doi.org/10.11406/rinketsu.59.675DOI Listing
July 2019

[Clinical characteristics of vascular adverse events and significance of peripheral artery disease as a risk factor in chronic myeloid leukemia patients treated with nilotinib].

Rinsho Ketsueki 2018;59(2):137-144

Department of Hematology, Nagano Red Cross Hospital.

Vascular adverse events (VAEs) in chronic myeloid leukemia (CML) patients treated with nilotinib (NIL) has become a; however, studies on strategies to prevent VAEs remain limited. Therefore, the present study investigated VAEs in 19 CML patients treated with NIL at our hospital. The median age of the patients was 65 years and median follow-up period was 55 months after the initiation of NIL. VAEs occurred in 8 patients (peripheral artery disease (PAD), n=6; cerebral infarction (CI), n=3; coronary artery disease (CAD), n=4). The median elapsed time from the initiation of NIL to VAEs was 42 months. The 4-year cumulative incidence of VAEs was 23.5%. Majority of the patients with VAEs were smokers (P=0.074). All the six patients with PAD were diagnosed on the basis of the ankle-brachial index (ABI<0.9) in the asymptomatic phase; 4 of these patients had other VAEs (CI, n=1; CAD, n=2; CI and CAD, n=1). However, antecedent asymptomatic PAD was diagnosed even before CAD was diagnosed in two patients. Nevertheless, in cardiology, extensive studies have indicated that asymptomatic PAD is a risk factor for the development of cardiovascular events. In conclusion, for the effective management of CML patients treated with NIL, a routine screening with ABI to diagnose asymptomatic PAD may be beneficial in preventing severe VAEs.
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http://dx.doi.org/10.11406/rinketsu.59.137DOI Listing
February 2019

Emergence of anti-mitochondrial M2 antibody in patient with angioimmunoblastic T-cell lymphoma.

Clin J Gastroenterol 2018 Aug 10;11(4):302-308. Epub 2018 Feb 10.

Division of Gastroenterology, Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.

A 68-year-old woman was referred to our hospital due to fever and rash on the neck and extremities. Laboratory findings revealed hepatic dysfunction and positivity for anti-mitochondrial M2 antibody (AMA-M2). Hepatosplenomegaly and systemic lymphadenopathy were detected by enhanced computed tomography. One week after her first visit, hypoxemia, ascites, and Coomb test-positive autoimmune hemolytic anemia had newly appeared in addition to worsened fever, hepatosplenomegaly, and lymphadenopathy. Results of axillary lymph node, skin, and bone-marrow biopsies led to the diagnosis of angioimmunoblastic T-cell lymphoma (AITL), for which CEPP therapy (cyclophosphamide, etoposide, procarbazine, and prednisolone) was initiated. Her serum levels of hepatobiliary enzymes normalized and AMA-M2 became negative after treatment. The unexpected positivity for AMA-M2 might have been caused by AITL cell-activated intrahepatic immune cells or the tumor cells themselves inflicting bile duct injury that mimicked primary biliary cholangitis. Alternatively, cross reactivity due to the overproduction of immunoglobulins may have caused this phenomenon. The present case may shed light on of the mechanisms of liver dysfunction accompanying AITL.
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http://dx.doi.org/10.1007/s12328-018-0831-yDOI Listing
August 2018