Authorship：Lead author   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms242417487

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Platelet-rich fibrin (PRF) is a popular autologous blood-derived biomaterial that is used in regenerative therapy. Owing to its simple preparation without additional factors, the PRF quality directly reflects the characteristics of individual blood samples. Antiplatelet or anticoagulant drugs can hamper the successful preparation of PRF. We recently observed similar phenomena in metformin-taking type-2 diabetics (T2DM). Thus, we hypothesized that metformin interferes with platelet function, thereby suppressing coagulation. For practical reasons, leukocyte- and platelet-rich plasma was prepared from healthy male donors (n = 9-15, age: 26-80 years) and treated with metformin (1-10 mM) for 24-72 h. Intrinsic and extrinsic coagulation activities were evaluated using prothrombin time (PT) and activated partial thromboplastin time (ATPP). Platelet adhesion and aggregation assays were performed using ADP stimulation. Among the parameters tested, APTT was the most sensitive and was significantly prolonged in the concentration range of 1-10 mM in a time- and concentration-dependent manner. Although obtained from healthy platelets and relatively higher concentrations of metformin, these findings suggest that metformin may induce further dysfunction of platelets to suppress intrinsic coagulation activity in T2DM patients, leading to failure of PRF preparation. This phenomenon may not have a severe impact on clinical diabetology or hematology. However, clinicians using PRF are recommended to be more sensitive to such information to avoid unexpected events in clinical settings.

DOI： 10.1016/j.tiv.2023.105692

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Platelet-rich plasma (PRP) has been increasingly used in sports medicine owing to its various advantages. The purpose of our project was to standardize the parameters before performing large-scale clinical trials in the near future to precisely evaluate individual PRP quality. To examine the effects of regular exercise on PRP quality, this study focused on young female athletes, who have been relatively less studied. Blood samples were obtained from female college athletes (n = 35) and ordinary healthy adults (n = 30), which were considered as controls, and leukocyte-rich PRP (L-PRP) was prepared manually. Body composition indices were determined using a bathroom weight scale equipped with an impedance meter. Growth factors and cytokines were quantified using ELISA kits. Platelet-derived growth factor-BB (PDGF-BB) and Transforming-growth factors β1 (TGFβ1) levels (per platelet) in L-PRP were significantly lower in female athletes than in controls. In contrast, Interleukin-1β and Interleukin 1 receptor antagonist (IL-1RA) levels (per platelet and L-PRP) in L-PRP were significantly higher in athletes, and this difference was more prominent in IL-1RA. These findings suggest that L-PRP from athletes may facilitate the inflammatory phase of the healing process by regulating the pro-inflammatory and anti-inflammatory balance. These chemical compositions can be adopted as "must-check" parameters to characterize individual PRP preparations prior to clinical trials.

DOI： 10.3390/ijms241713592

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Background: Autologous platelet-rich plasma (PRP) therapy is ambiguously thought to be more effective in elite athletes than in sedentary patients, although the possible importance of recipient responsiveness remains poorly understood. To address this issue, along with the well-known PRP quality, in this initial study, we evaluated two candidate biomarkers: body composition indices (BCIs), which reflect systemic physical conditions, and resting platelet ATP levels, which reflect platelet energy expenditure and the mass of energy generation units. Methods: In this cross-sectional cohort study, blood samples were collected from male professional soccer players (PSPs) on a local professional team during the off-season and platelet ATP levels were quantified using an ATP luminescence assay kit. BCIs were measured using the body mass impedance method. Age-matched male sedentary participants were used as the controls. Results: Among the BCIs, the body mass index, basal metabolic rate (BMR), and skeletal muscle weight levels were higher in the PSPs than in the controls. The platelet ATP levels in the PSPs group were significantly lower than those in the control group. The correlation between BMR and platelet ATP levels was moderately negative in the control group, but weakly positive in the PSPs group. Conclusion: Owing to regular physical exercise, PSPs had higher BMR levels and lower platelet ATP levels without a significant mutual correlation compared to sedentary controls. This study did not indicate the influence of these biomarkers on the success of PRP therapy but provided evidence for a better understanding of PRP therapy, particularly for elite athletes.

DOI： 10.3389/fbioe.2023.1255860

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Donor T cell activation, proliferation, differentiation, and migration are the major steps involved in graft-versus-host disease (GVHD) development following bone marrow transplantation. Chondroitin sulfate (CS) proteoglycan is a major component of the extracellular matrix and causes immune modulation by interacting with cell growth factors and inducing cell adhesion. However, its precise effects on immune function are unclear than those of other proteoglycan families. Thus, we investigated the significance of CS within donor cells in acute GVHD development utilizing CSGalNAc T1-knockout (T1KO) mice. To determine the effects of T1KO, the mice underwent allogenic bone marrow transplantation from major histocompatibility complex-mismatched donors. While transplantation resulted in hepatic GVHD with inflammatory cell infiltration of both CD4+ and CD8+ effector memory T cells, transplantation in T1KO-donors showed milder cell infiltration and improved survival with fewer splenic effector T cells. In vitro T-cell analyses showed that the ratio of effector memory T cells was significantly lower via phorbol myristate acetate/ionomycin stimulation. Moreover, quantitative PCR analyses showed significantly less production of inflammatory cytokines, such as IFN-γ and CCL-2, in splenocytes of T1KO mice. These results suggest that reduction of CS in donor blood cells may suppress the severity of acute GVHD after hematopoietic stem cell transplantation.

DOI： 10.1038/s41598-023-40367-3

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Platelet polyphosphate (polyP) can be conveniently quantified by exploiting a recent methodological breakthrough using 4',6-diamidino-2-phenylindole (DAPI). However, the preservation of these biological samples has not yet been standardized. In a preliminary study, potential protocols were screened, while accepted protocols were further tested in this study. Pure-platelet-rich plasma (P-PRP) samples and washed platelet suspensions were prepared using blood obtained from non-smoking healthy male donors and were fixed with ThromboFix for 20-24 h at 4 °C. Mass polyP levels were determined using a fluorometer at wavelengths of 425 and 525 nm. Platelet polyP levels were normalized to platelet counts. Statistical analyses were performed using non-parametric tests. Platelet polyP levels significantly decreased by 20% after 7 days in the platelet suspension maintained under fixed conditions at 4 °C (control). In contrast, the platelet polyP levels in both the P-PRP and washed platelet suspensions were maintained without a significant reduction for up to 6 weeks by removing ThromboFix after fixation and subsequent freezing in pure water at -80 °C. Fluorometric polyP quantification often interferes with the low specificity of DAPI binding and the wavelength used. Our validated protocols will enable long-term preservation and high-throughput polyP quantification and can be applied to relatively large cohort studies.

DOI： 10.3390/mps6040059

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Language：Japanese   Publisher：新潟県医師会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: ABO antigens expressed on the red blood cells (RBCs) are not identical to those expressed on the renal endothelial cells. The isohemagglutinin assay employing the RBCs is the gold standard for evaluating anti-ABO antibody (Ab) levels. However, it remains unclear whether the anti-ABO Abs detected by the isohemagglutinin assay after ABO-incompatible (ABOi) kidney transplantations (KTx) that are not associated with antibody-mediated rejection can bind to renal graft endothelial cells. METHODS: Ninety plasma samples were collected from patients with stable graft function after ABO-compatible (ABOc) or ABOi KTx. Anti-ABO Ab titers were examined by both the isohemagglutinin assay and the CD31-ABO microarray, which was developed as a mimic of the ABO antigens expressed on the renal endothelial cells. RESULTS: The antibody titers detected by the isohemagglutinin assay and the CD31-ABO microarray after the ABOc KTx relatively correlated with each other. However, the CD31-ABO microarray results showed low antibody levels against donor blood group antigens after ABOi KTx and did not correlate with the isohemagglutinin assay. In contrast, the antibody levels against non-donor blood group antigens after ABOi KTx were comparable to those after the ABOc KTx. Fourteen patients received graft biopsies, and no antibody-mediated rejection was observed in ABOi KTx recipients, except for two patients who had anti-donor-HLA Abs. CONCLUSION: The present study suggested that the anti-ABO Abs detected by the isohemagglutinin assay after ABOi KTx with stable graft function were hyporeactive to the ABO antigen of graft renal endothelial cells.

DOI： 10.1007/s10157-022-02280-3

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background</jats:title>
<jats:p>Regenerative therapy using platelet-rich plasma (PRP), a rich source of growth factors, has become popular in orthopedic sports medicine. Elite athletes prefer PRP therapy for their injured muscles and tendons primarily to avoid the possible risks of surgical treatment. However, the clinical effectiveness of PRP therapy in elite athletes compared to that in non-athletes remains unknown. Therefore, to investigate the effectiveness of PRP therapy in professional athletes (pro-athletes), we focused on the quality of PRP preparations and compared the levels of bioactive molecules between pro-athletes and non-athletes.
</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>PRP was prepared from healthy, non-smoking male professional soccer players (pro-athletes) (n = 22) and non-athletes (VEGF: n = 34, others: n = 38). The levels of TGFβ1, PDGF-BB, VEGF, and PF4 were determined using ELISA kits. Polyphosphate was probed with 4’,6-diamidino-2-phenylindole and monitored using a fluorometer. The body composition of the donors was determined using a bathroom weighing scale.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>The levels of TGFβ1 and VEGF were significantly lower in pro-athletes than in non-athletes, whereas PF4 levels were significantly higher in pro-athletes. No significant difference was found in PDGF-BB levels between these groups. Biomolecule levels were not correlated with polyphosphate levels.</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusion</jats:title>
<jats:p>TGFβ1, VEGF, and PDGF-BB levels in pro-athletes were not higher than those in non-athletes. These findings suggest that growth factor levels in PRP may not be a predominant determinant of the clinical effectiveness of PRP therapy in pro-athletes. Increased PF4 levels in pro-athletes suggest an immunological function of PRP that may positively influence tissue regeneration.</jats:p>
</jats:sec>

DOI： 10.1186/s13018-022-03362-4

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Platelets produce inorganic polyphosphate (polyP) upon activation to stimulate blood coagulation. Some researchers have linked polyP metabolism to ATP production, although the metabolic linkage is yet to be elucidated. We found evidence for this possibility in our previous study on professional athletes (versus non-athletes), and proposed that the regulatory mechanism might be different for these two groups. To explore this aspect further, we investigated the effects of modulated ATP production on polyP levels. Blood samples were obtained from Japanese healthy, non-athletes in the presence of acid-citrate-dextrose. The platelets in the plasma were treated with oligomycin, rotenone, and GlutaMAX to modulate ATP production. PolyP level was quantified fluorometrically and visualized using 4',6-diamidino-2-phenylindole. Correlations between polyP and ATP or NADH were then calculated. Contrary to the hypothesis, inhibitors of ATP production increased polyP levels, whereas amino acid supplementation produced the opposite effect. In general, however, polyP levels were positively correlated with ATP levels and negatively correlated with NADH levels. Since platelets are metabolically active, they exhibit high levels of ATP turnover rate. Therefore, these findings suggest that ATP may be involved in polyP production in the resting platelets of non-athletes.

DOI： 10.3390/ijms231911293

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Human platelet polyphosphate (polyP) is a multifunctional molecule; however, its functions are not yet fully understood. A recent study demonstrated that similar to skeletal muscle, polyP is involved in energy metabolism in platelets, which suggests that well-trained athletes may exhibit elevated platelet polyP levels for energy storage. To test this hypothesis, we quantified platelet polyP along with NADH, a component involved in ATP production in non-trained and well-trained male Japanese participants of the same generation. Washed platelets were prepared from the venous blood of young, healthy, non-athletes, and professional soccer players (pro-athletes). NADH and polyP levels were spectrophotometrically determined using tetrazolium reduction and fluorometrically determined using 4',6-diamidino-2-phenylindole at the excitation/emission wavelengths of 425/525 nm. Body weight and impedances were measured simultaneously. Statistical analyses were performed using the Mann-Whitney U test and Spearman correlation coefficient. Although basal metabolic rate levels were significantly higher, platelet polyP levels were significantly lower in pro-athletes than in that in non-athletes. No significant differences were detected in other body compositions or platelet indices between the two groups. The pro-athlete group showed a moderate, nearly significant correlation (R = 0.439; p = 0.0512) between platelet polyP and NADH levels. Taken together with the weak correlation data between polyP and body mass index, it is suggested that platelet polyP levels may be influenced by platelet and body energy metabolic activity. Further biochemical studies are needed to elucidate this mechanism.

DOI： 10.14814/phy2.15409

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.14814/phy2.15409

Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Isohemagglutinin assays employing red blood cells (RBCs) are the most common assays used to measure antibody titer in ABO-incompatible kidney transplantation (ABOi KTx). However, ABO antigens expressed on RBCs are not identical to those of kidney and antibody titers do not always correlate with clinical outcome. We previously reported that CD31 was the main protein linked to ABO antigens on kidney endothelial cells (KECs), which was different from those on RBCs. We developed a new method to measure antibody titer using a microarray of recombinant CD31 (rCD31) linked to ABO antigens (CD31-ABO microarray). Mass spectrometry analysis suggested that rCD31 and native CD31 purified from human kidney had similar ABO glycan. To confirm clinical use of CD31-ABO microarray, a total of 252 plasma samples including volunteers, hemodialysis patients, and transplant recipients were examined. In transplant recipients, any initial IgG or IgM antibody intensity &amp;gt;30,000 against the donor blood type in the CD31-ABO microarray showed higher sensitivity, specificity, positive predictive value, and negative predictive value of AABMR, compared to isohemagglutinin assays. Use of a CD31-ABO microarray to determine antibody titer specifically against ABO antigens expressed on KECs will contribute to precisely predicting AABMR or preventing over immunosuppression following ABOi KTx.

DOI： 10.3389/ti.2022.10248

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.isci.2021.103117

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Cell culture media influence the characteristics of human osteogenic periosteal sheets. We have previously found that a stem cell medium facilitates growth and collagen matrix formation in vitro and osteogenesis in vivo. However, it has not yet been demonstrated which culture medium is superior for osteoclastogenesis, a prerequisite for reconstruction of normal bone metabolic basis. To address this question, we compared chemotaxis and osteoclastogenesis in tissue-engineered periosteal sheets (TPSs) prepared with two types of culture media. Periosteal tissues obtained from adult volunteers were expanded with the conventional Medium 199 or with the stem cell medium, MesenPRO. Hematopoietic enhanced-green-fluorescent-protein (EGFP)-nude mice were prepared by γ-irradiation of Balb/c nu/nu mice and subsequent transplantation of bone marrow cells from CAG-EGFP C57BL/6 mice. TPSs were implanted subcutaneously into the chimeric mice and retrieved after intervals for immunohistopathological examination. EGFP+ cells were similarly recruited to the implantation site in both the TPSs prepared, whereas the distribution of CD11b+ cells was significantly lower in the TPS prepared with the stem cell medium. Instead, osteoclastogenesis was higher in the TPS prepared with the stem cell medium than in the one prepared with the conventional medium. These findings suggest that the stem cell medium is preferable for the preparation of more functional TPSs.

DOI： 10.3390/ijms22042169

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Language：English   Publishing type：Research paper (scientific journal)  

The bone marrow (BM) microenvironment, known as the BM niche, regulates hematopoiesis but is also affected by the interactions with hematopoietic cells. Recent evidence indicates that the extracellular matrix components are involved in these interactions. Chondroitin sulfate (CS), a glycosaminoglycan, is a major component of the extracellular matrix; however, it is not known whether CS has a physiological role in hematopoiesis. Here, we analyzed the functions of CS in hematopoietic and niche cells. CSGalNAcT1, which encodes CS N-acetylgalactosaminyltransferase-1 (T1), a key enzyme for CS biosynthesis, was highly expressed in hematopoietic stem and progenitor cells (HSPCs) and endothelial cells, but not in mesenchymal stromal cells (MSCs) in BM. In T1 knockout (T1KO) mice, a greater number of HSPCs existed compared to the wild type (WT), but HSPCs from T1KO mice showed significantly impaired repopulation in WT recipient mice upon serial transplantation. RNA sequence analysis revealed the activation of IFN-α/β signaling and endoplasmic reticulum stress in T1KO HSPCs. In contrast, the number of WT HSPCs repopulated in T1KO recipient mice was larger than that in WT recipient mice after serial transplantation, indicating that the T1KO niche supports repopulation of HSPCs better than the WT niche. There was no obvious difference in the distribution of vasculature and MSCs between WT and T1KO BM, suggesting that CS loss alters vascular niche functions without affecting its structure. Our results revealed distinct roles of CS in hematopoietic cells and BM niche, indicating that crosstalk between these components is important to maintain homeostasis in BM.

DOI： 10.1016/j.exphem.2021.02.003

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Jaundice may be persistent in drug-induced liver injury associated with vanishing bile duct syndrome. However, recurrent jaundice is atypical, following bile flow restoration. Here, we report a 28-year-old man with prolonged, recurrent jaundice (more than 300 days) and combined immunodeficiency (CID) of B-cells, T-cells, and natural killer (NK) cells. Hypogammaglobulinemia was observed throughout his hospitalization, and peripheral blood flow cytometry detected a few B-cells (2% of CD19 + cells and 2% of CD20 + cells). We further detected the dysfunction of T-cells and NK cells. Based on these findings, CID was diagnosed. We presumed that hypogammaglobulinemia was related to the jaundice. After regular injections of intravenous immunoglobulin (IVIG), the stool color gradually turned brown. However, the color returned to white as IgG levels decreased. The brown-to-white stool pattern was repeated with another IVIG administration, suggesting that the patient's serum immunoglobulin levels were related to the jaundice. On follow-up, IVIG was performed every two to three weeks, and his total bilirubin improved gradually. Immunoglobulin replacement therapy could be one of the treatment choices for jaundice with CID.

DOI： 10.1007/s12328-021-01347-0

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Wilms' tumor 1 (WT1) is a tumor-associated antigen and immunotherapy target in myelodysplastic syndrome (MDS). Further information is needed on the characteristics of WT1-specific CD8 + T cells to develop immunotherapeutic strategies for MDS. To clarify the frequency, distribution, and phenotype of WT1-specific CD8 + T cells, which occur innately in MDS patients, we analyzed paired peripheral blood (PB) and bone marrow (BM) samples from 39 patients with MDS or acute myeloid leukemia with myelodysplasia-related changes. The median frequency of WT1 tetramer-binding CD8 + T cells in the CD8 + T cell population was 0.11% in PB and 0.18% in BM. A further tetramer assay combined with mixed lymphocyte peptide culture (MLPC assay) was used to detect functional WT1-specific CD8 + T cells that could respond to the WT1 peptide. Functional WT1-specific CD8 + T cells were detected in BM in 61% of patients, which was significantly higher than in PB (23%, p = 0.001). The frequency of these cells estimated by the MLPC assay was tenfold higher in BM than in PB. The majority of WT1 tetramer-binding CD8 + T cells in BM had a unique phenotype with co-expression of CD39 and CXCR4. These findings will facilitate the development of novel immunotherapeutic strategies for MDS.

DOI： 10.1007/s12185-021-03083-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for high-risk acute leukemia (AL), some patients still relapse. Since patients simultaneously have many prognostic factors, difficulties are associated with the construction of a patient-based prediction algorithm of relapse. The alternating decision tree (ADTree) is a successful classification method that combines decision trees with the predictive accuracy of boosting. It is a component of machine learning (ML) and has the capacity to simultaneously analyze multiple factors. Using ADTree, we attempted to construct a prediction model of leukemia relapse within 1 year of transplantation. With the model of training data (n = 148), prediction accuracy, the AUC of ROC, and the κ-statistic value were 78.4%, 0.746, and 0.508, respectively. The false positive rate (FPR) of the relapse prediction was as low as 0.134. In an evaluation of the model with validation data (n = 69), prediction accuracy, AUC, and FPR of the relapse prediction were similar at 71.0%, 0.667, and 0.216, respectively. These results suggest that the model is generalized and highly accurate. Furthermore, the output of ADTree may visualize the branch point of treatment. For example, the selection of donor types resulted in different relapse predictions. Therefore, clinicians may change treatment options by referring to the model, thereby improving outcomes. The present results indicate that ML, such as ADTree, will contribute to the decision-making process in the diversified allo-HSCT field and be useful for preventing the relapse of leukemia.

DOI： 10.1002/cam4.2401

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Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：(一社)日本輸血・細胞治療学会  

生後4ヵ月未満児は得られる採血量が少ないことから、自動輸血検査装置や試験管法では不規則抗体検査が困難である。このため、当院では検体量が試験管法の約1/4と少量の検体で検査可能なMicro Typing Systemを採用している。2007年1月から2016年12月までの10年間においてMicro Typing Systemでは不規則抗体検査依頼のあった生後4ヵ月未満児554件中、552件(99.6%)で検査可能であった。症例の内訳では55.4%が先天性心疾患の症例であった。また、検査可能であった552件中、不規則抗体が16件(2.9%)で陽性判定であった。そのうちの14件は母親からの移行抗体、1件は移行抗体が疑われた抗E、1件は自然抗体と考えられるIgM型の抗Mであった。さらに実際に358件に赤血球輸血が実施され、その内230件(64.2%)に輸血後の不規則抗体検査が行われたが、輸血後に生後4ヵ月未満児が不規則抗体を産生した症例は認められなかった。ほぼ全例に不規則抗体スクリーニング検査を可能とするMicro Typing Systemは乳児への輸血療法の安全性確保の観点において有用である。(著者抄録)

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BACKGROUND: The Rh complex contributes to cell membrane structural integrity of erythrocytes. Rhnull syndrome is characterized by the absence of the Rh antigen on the erythrocyte membrane, resulting in chronic hemolytic anemia. We recently came across 3 Rhnull phenotype probands within two families with the same novel RHAG mutation in the Japanese population. MATERIALS AND METHODS: Detailed Rh phenotyping by hemagglutination was performed using monoclonal and polyclonal anti-D, -C, -c, -E, and -e; monoclonal and polyclonal anti-Rh17 antibodies; and polyclonal anti-Rh29 antibodies. RHAG mRNA transcripts were analyzed by reverse transcription-polymerase chain reaction, and the mutation was verified by genomic sequencing. RESULTS: The genomic region spanning exon 6 contained a G > A transition in the invariant GT motif of the 5' donor splice-site of Intron 6 (c.945+1G>A). The Rhnull phenotype was caused by an autosomal recessive mutation in Probands 1 and 2, determined by family history. Regarding clinical features, the degree of hemolysis varied slightly between these individuals, with Proband 3 displaying acute hemolytic anemia with an infection. While no standard therapy has been established, the condition of the patient in this study improved with conservative treatment, including hydration and antibiotics. CONCLUSION: The mechanisms of hemolysis due to the Rhnull phenotype can vary, but our findings indicate that acute hemolytic crisis caused by the Rhnull syndrome could be associated with infection.

DOI： 10.1111/trf.15312

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Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms20051053

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Language：English   Publisher：(一社)日本血液学会  

同種造血細胞移植(HCT)の移植前リスク評価に用いられるGlasgow予後予測スコア(GPS)に改良を加え、その有用性について検討した。同種HCTを施行された血液疾患患者205例(中央値46歳)を対象とした。HCT特異的GPS(HCT-GPS)の評価に際して、CRP上昇(1mg/dL超)、低アルブミン血症(3.5g/dL未満)の両者を満たす場合は2点、いずれかを呈する場合は1点、いずれも認めない場合は0点とし、さらに血清中フェリチン1000ng/mL超を呈する場合には+1点とした。検討の結果、移植前の血清フェリチン中央値は954ng/mL、アルブミン中央値は4.1g/dL、CRP中央値は0.14mg/dLであり、HCT-GPSスコアは0点が95例、1点が75例、2点が19例、3点が16例であった。一方、オリジナルのGPSスコアでは0点が158例、1点が28例、2点が19例であった。C統計量分析では非再燃死亡率(NRM)と全生存率(OS)はHCT-GPSスコアの方がGPSスコアより高値であったが有意差は認められなかった。一方、net reclassification indexesとintegrated discrimination improvementを用いた解析では有意差がみられた。また、多変量解析ではHCT-GPSスコアの1点増分はOSとNRMの不良を示す独立予測因子であることが示された。今回作成したHCT-GPSスコアは同種HCT後の早期合併症の予測に有用なツールに成りうると思われた。

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J04671&link_issn=&doc_id=20181129310007&doc_link_id=10.1007%2Fs12185-018-2463-x&url=https%3A%2F%2Fdoi.org%2F10.1007%2Fs12185-018-2463-x&type=Crossref&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00002_2.gif

Language：English   Publisher：Elsevier Ltd  

DOI： 10.1016/j.leukres.2018.05.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) is a widely used tool for pre-transplant risk assessment. Allogeneic hematopoietic cell transplantation (HCT) is performed on patients with diverse backgrounds, highlighting the need for other predictors to complement the HCT-CI and support bedside decision-making. There is a strong body of evidence supporting the use of pre-transplant serum ferritin (SF) in risk assessments of allogeneic HCT. We additionally found that the Glasgow Prognostic Score (GPS), which assesses inflammatory biomarkers and predicts survival of patients with solid organ malignancies, is a useful predictive marker for overall survival (OS) and non-relapse mortality (NRM) in allogeneic HCT, independent of HCT-CI and SF. In this study, we refined the GPS by adding pre-transplant SF to improve its prognostic ability and enable better stratification
we call this revised index the HCT-specific revised Glasgow Prognostic Score (HCT-GPS). We observed that the HCT-GPS more accurately predicted NRM and early-term OS than the GPS. Moreover, the HCT-GPS provides an independent prognostic factor adjusted for the HCT-CI and disease status, and stratifies patients into four risk groups by OS and NRM. Thus, the HCT-GPS is a useful index for predicting early-term complications after allogeneic HCT in patients with hematopoietic diseases.

DOI： 10.1007/s12185-018-2463-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Evaluation methods, such as scoring systems for predicting complications in advance, are necessary for determining the adaptation of allogeneic hematopoietic cell transplantation (HCT) and selecting appropriate conditioning regimens. The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), which is based on functions of main organs, is a useful tool for pre-transplant risk assessments and has been widely applied in determining treatment strategies for patients with hematological diseases. However, as allogeneic HCT is performed on patients with diverse backgrounds, another factor, which reinforces the HCT-CI, is required to evaluate pre-transplant risk assessments. The Glasgow Prognostic Score (GPS), which assesses the combined C-reactive protein and albumin, was reported to predict survival of patients with solid-organ malignancies independently of receiving chemo/radiotherapy and stages of cancer. In this study, we applied the GPS for pre-transplant risk assessments for allogeneic HCT. The GPS successfully stratified the patients into three risk groups of overall survival (OS) and non-relapse mortality (NRM). Moreover, the GPS could predict outcomes independently of the HCT-CI for OS and NRM in multivariate analysis. The GPS is considered to be a useful tool and reinforces the HCT-CI for determining adaptation of allogeneic HCT for patients with hematopoietic neoplasms.

DOI： 10.1111/ctr.13103

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Authorship：Corresponding author   Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Rationale: Myeloid sarcoma (MS) and leukemia cutis (LC) are extramedullary tumors comprising myeloid blasts. They can occur de novo or concurrently with hematological disorders, usually acute myeloid leukemia (AML). AML chemotherapy is generally the initial therapy for MS and LC, and hematopoietic stem cell transplantation (HSCT) can be considered as additional therapy. However, treatment for older patients who are unable to continue intensive chemotherapy is not currently standardized.
Patientconcerns: A 71-year-old Japanese woman was diagnosed with multiple MSs associated with myelodysplastic syndrome (MDS), using bone marrow aspiration and lymph node biopsy.
Diagnoses: Additionally, LC was diagnosed by skin biopsy. Extramedullary MS and LC lesions were formed by massive infiltration of myeloblastic cells.
Interventions: Twenty courses of 5-azacytidine (5-Aza) were administrated as maintenance therapy after induction therapy with daunorubicin and cytarabine.
Outcomes: Myeloblasts decreased in the bone marrow and the LC disappeared after induction therapy. The MSs completely disappeared, except for the palatine tonsil lesion, after 5-Aza maintenance therapy. 5-Aza treatment provided long-term partial response for more than 21 months.
Lessons: 5-Aza was well tolerated and may be a good option for the treatment of MS and LC associated with MDS, especially in older patients who cannot receive HSCT.

DOI： 10.1097/MD.0000000000007975

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Language：Japanese   Publishing type：Research paper (scientific journal)  

We retrospectively analyzed clinical and pathological features, treatments, and prognoses in 28 patients with newly diagnosed peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in Niigata University Medical and Dental Hospital. Of them, 16 were males and 12 were females, and their median age was 62.5 (range, 26-88) years. The International Prognostic Index was high-intermediate/high in 68% of patients. Twelve patients were treated with CHOP/THP-COP and nine with third-generation chemotherapy regimens. At a median follow-up period of 30 (range: 1-164) months, the 2-year overall survival and progression-free survival rates were 61% and 44%, respectively. Further investigation of novel agents for treating PTCL-NOS is warranted.

DOI： 10.11406/rinketsu.58.905

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 62-year-old man with CHOP refractory adult T-cell leukemia/lymphoma (ATLL) received anti-CC chemokine receptor 4 antibody (mogamulizumab) combined with CHOP and achieved complete remission. At 71 days after the final administration of mogamulizumab, he received umbilical cord blood transplantation (CBT) using reduced intensity conditioning. Umbilical cord blood engraftment was confirmed on day16. Grade II acute graft-versus-host disease (GVHD) was diagnosed on day60 and was controlled by administration of methylprednisolone. There was no evidence of relapse at 9 months after CBT. Ratios of regulatory T cells in CD4 positive T cells were remarkably low during all of these periods. Since mogamulizumab reduces regulatory T cells, the frequency and severity of acute GVHD were reported to be increased in patients administered mogamulizumab before allogenic stem cell transplantation. Further experiences are needed for selecting optimal donor sources, the portability period and GVHD prophylaxis for patients using mogamulizumab before allogeneic stem cell transplantation.

DOI： 10.11406/rinketsu.58.32

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Language：Japanese   Publisher：The Japanese Society of Hematology  

<p>A 75-year-old woman suffered a cat bite 10 months after myelodysplastic syndrome (MDS) diagnosis. She visited our hospital because the internal bleeding of the wound did not improve. Although the wound was treated, the bleeding did not stop. She was hospitalized for emergency medical treatment because the bleeding volume exceeded 200 m<i>l</i>. Although her platelet count was normal, the platelet function test showed a decrease in collagen and arachidonic acid aggregation. After platelet transfusion, her bleeding stopped. Patients with MDS may potentially have platelet dysfunction. In the case of bleeding without thrombocytopenia, a platelet function test should be performed and treatment intervention, such as platelet transfusion, should be considered.</p>

DOI： 10.11406/rinketsu.58.2402

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Other Link： http://search.jamas.or.jp/link/ui/2018121562

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

The Suppressors of Cytokine Signalling (SOCS) proteins are negative regulators of cytokine signalling required to prevent excess cellular responses. SOCS1 and SOCS3 are essential to prevent inflammatory disease, SOCS1 by attenuating responses to IFN gamma and gamma-common (gamma c) cytokines, and SOCS3 via regulation of G-CSF and IL-6 signalling. SOCS1 and SOCS3 show significant sequence homology and are the only SOCS proteins to possess a KIR domain. The possibility of overlapping or redundant functions was investigated in inflammatory disease via generation of mice lacking both SOCS1 and SOCS3 in hematopoietic cells. Loss of SOCS3 significantly accelerated the pathology and inflammatory disease characteristic of SOCS1 deficiency. We propose a model in which SOCS1 and SOCS3 operate independently to control specific cytokine responses and together modulate the proliferation and activation of lymphoid and myeloid cells to prevent rapid inflammatory disease.

DOI： 10.1371/journal.pone.0162111

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-gamma production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish(-/-) mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.

DOI： 10.1038/ni.3470

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1002/ajh.24318

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function and this could be rescued by strong IL-15 receptor stimulation or genetic ablation of Socs3. During NK cell maturation, we observed an inverse correlation between E-protein target genes and Id2. These results shift the current paradigm on the role of ID2, indicating that it is required not only to antagonize E-proteins during NK cell commitment, but constantly required to titrate E-protein activity to regulate NK cell fitness and responsiveness to IL-15.

DOI： 10.1016/j.immuni.2015.12.007

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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DOI： 10.1513/AnnalsATS.201503-175LE

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We focused on the level of reduction of Wilms' tumor gene 1 (WT1) mRNA in bone marrow as minimal residual disease during chemotherapies in adult acute myeloid leukemia (AML) patients. Forty-eight patients were enrolled in this study. Log levels of reduction of WT1 mRNA transcript after induction therapy compared with those at diagnosis were associated with disease-free survival (DFS) (P = 0.0066) and overall survival (OS) (P = 0.0074) in patients who achieved complete remission. Also log levels of reduction of WT1 mRNA transcript after final consolidation therapy compared with those at diagnosis were associated with DFS (P = 0.015) and OS (P = 0.012). By multivariate analysis, log levels of reduction of WT1 mRNA transcript after induction therapy and after final consolidation therapy compared with those at diagnosis were extracted as risk factors for outcome. Our results suggest that early and deep reduction of tumor burden may be important for the outcome of AML patients. In addition, it may be useful for the decision to proceed with allogeneic SCT as post-remission therapy. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2015.03.021

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Language：English   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publisher：AMER SOC HEMATOLOGY  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

A 35-year-old man admitted to the hospital for oral hemorrhage was diagnosed with acute promyelocytic leukemia (APL). Remission from APL was achieved by induction therapy with all-trans retinoic acid (ATRA); the PML/RARA fusion gene was not detected on PCR analysis. Despite complete molecular remission, severe persistent pancytopenia, massive ascites, and renal failure were observed. The liver surface appeared rough and irregular on computed tomographic images. On the basis of the liver biopsy results, we diagnosed his condition as portal hypertension due to autoimmune hepatitis. Indocyanine green test showed good residual function of the liver, and therefore, 2 courses of consolidation therapy were administered; chemotherapy was stopped because of severe pancytopenia due to portal hypertension. Instead of continuing the consolidation therapy, maintenance therapy involving 8 rounds of ATRA monotherapy (45 mg/m(2), days1∼14) was initiated. Portal hypertension did not progress further with this maintenance therapy and therefore it was continued. The patient has been in remission from APL ever since, and no relapses have occurred since the past 5 years. These results suggest that ATRA can be used for long-term therapy in such cases.

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

A 61-year-old man admitted for pancytopenia was diagnosed with acute myeloid leukemia. On day 26 of induction therapy, the patient suddenly developed cardiogenic shock. The ultrasound cardiogram showed imaging features typical of takotsubo cardiomyopathy. Cardiogenic shock caused by takotsubo cardiomyopathy is rare in patients with hematological malignancies but is a severe complication during chemotherapy.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 52-year-old woman presented with isolated thrombocytosis in 2003. After 5 years of observation under a tentative diagnosis of essential thrombocythemia (ET), she was referred to our hospital because of anemia and leukopenia. Bone marrow biopsy demonstrated increases of megakaryocytes and myelofibrosis, but splenomegaly was absent. A karyotype study of bone marrow detected t(9;22) (q34;q11.2) in 6 of the 20 metaphases studied. Peripheral blood neutrophil BCA-ABL fusion signals (FISH) were not detected. Because RT-PCR assay of bone marrow detected major-BCR-ABL mRNA (b3a2), treatment with imatinib (400 mg/day) was started. After transient thrombocytopenia, normalization of blood cell counts and improvement of myelofibrosis were achieved. JAK2 V617F mutation and M-BCR-ABL mRNA was negative in peripheral blood. Clinical and laboratory data suggest that this case represents a rare and atypical myeloproliferative neoplasm with BCR-ABL translocation restricted mainly to the megakaryocyte lineage.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

We describe a 60-year-old Japanese patient with chronic myeloid leukemia (CML) who developed myelodysplastic syndrome (MDS) with Ph negative monosomy 7 chromosome following transient bone marrow dysplasia during imatinib treatment. Most cases that developed chromosomal abnormality in Ph negative cells during imatinib therapy were reported to have less clinical implications, while rare cases developed MDS/AML. The present case suggested that metaphase karyotype analysis and bone marrow examination should be performed for the long term follow-up under imatinib treatment in cases showing cytopenia. The results also suggested that monosomy 7 in Ph negative cells may be an indicator of a poor prognosis.

DOI： 10.2169/internalmedicine.50.4481

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Authorship：Lead author,　Corresponding author   Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

DOI： 10.2169/internalmedicine.50.5338

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 46-year-old woman with Graves&apos; disease was admitted for anemia and thrombocytopenia. She had previously been treated with methimazole but she self-discontinued the treatment 6 months prior to admission. She was diagnosed with Evans syndrome associated with Graves&apos; disease and treated with propylthiouracil without corticosteroids, which normalized her thyroglobulin level. Surprisingly, while Evans syndrome is characterized by frequent relapses, this patient has been in remission of Evans syndrome for approximately 4 years. The remission of Evans syndrome associated with Graves&apos; disease in the absence of immunosuppressive therapy suggests that these 2 diseases have a common pathogenetic mechanism.

DOI： 10.2169/internalmedicine.50.4319

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background and Purpose-To investigate the efficacy of bone marrow mononuclear cell (BMMNC) treatment against ischemic white matter (WM) damage in a hypoperfused brain.
Methods-Mice were administered intravenous treatment of vehicle, spleen-derived marrow mononuclear cells (MNCs), or BMMNCs (5X10(6) cells) obtained from enhanced green fluorescent protein transgenic mice 24 hours after bilateral common carotid artery stenosis (BCAS), and then euthanized at either 1 day or 30 days after treatment.
Results-Laser speckle perfusion imaging analyses revealed marked recovery of cerebral blood flow (CBF) in the early phase after BMMNC treatment (6 hours after administration), before histological evidence of angiogenesis was assessed by fluorescein-isothiocyanate-dextran perfusion assay. BMMNC treatment induced an increase in vascular endothelial growth factor and Ser1177 phosphorylated endothelial nitric oxide synthase levels in the BCAS-induced mouse brains at 1 day after the treatment. BCAS-induced ischemic WM lesions were significantly improved 30 days after BMMNC treatment despite any evidence of direct structural incorporation of donor BMMNCs into endothelial cells and oligodendrocytes. Instead, enhanced green fluorescent protein-positive donor cells with morphological features of pericytes were observed in the vessel walls. Post-BMMNC administration of an NOS inhibitor abolished early CBF recovery and produced protective effects against ischemic WM damage.
Conclusions-BMMNC treatment provides marked protection against ischemic WM damage, enhancing CBF in the early phase and in subsequent angiogenesis, both of which involve nitric oxide synthase activation. These findings suggest promise for the application of BMMNCs for subcortical ischemic vascular dementia. (Stroke. 2010;41:2938-2943.)

DOI： 10.1161/STROKEAHA.110.596379

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Hypoxia-inducible factor (HIF) functions as a master transcriptional regulator for adaptation to hypoxia by inducing adaptive changes in gene expression for regulation of proliferation, angiogenesis, apoptosis and energy metabolism. Cancers with high expression of the alpha subunit of HIF (HIF alpha) are often malignant and treatment-resistant. Therefore, the development of a molecular probe that can detect HIF activity has great potential value for monitoring tumor hypoxia. HIF prolyl hydroxylases (HPHDs) act as oxygen sensors that regulate the fate of HIF alpha protein through its oxygen-dependent degradation (ODD) domain. We constructed a recombinant protein PTD-ODD-HaloTag (POH) that is under the same ODD regulation as HIF alpha and contains protein transduction domain (PTD) and an interchangeable labeling system. Administration of near-infrared fluorescently labeled POH (POH-N) to mouse models of cancers allowed successful monitoring of HIF-active regions. Immunohistochemical analysis for intratumoral localization of POH probe revealed its specificity to HIF-active cells. Furthermore, lack of the PTD domain or a point mutation in the ODD domain abrogated the specificity of POH-N to HIF-active cells. Overall results indicate that POH is a practical probe specific to HIF-active cell in cancers and suggest its large potential for imaging and targeting of HIF-related diseases.

DOI： 10.1371/journal.pone.0015736

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background: Many diseases associated with bone marrow transplantation (BMT) are caused by transplanted hematopoietic cells, and the onset of these diseases occurs after homing of donor cells in the initial phase after BMT. Noninvasive observation of donor cell homing shortly after transplantation is potentially valuable for improving therapeutic outcomes of BMT by diagnosing the early stages of these diseases.
Methodology/Principal Findings: Freshly harvested near-infrared fluorescence-labeled cells were noninvasively observed for 24 h after BMT using a photon counting device to track their homing process. In a congenic BMT model, the homing of Alexa Fluor 750-labeled donor cells in the tibia was detected less than 1 h after BMT. In addition, subsequent cell distribution in an intraBM BMT model was successfully monitored for the first time using this method. In the allogeneic BMT model, T-cell depletion decreased the near-infrared fluorescence (NIRF) signals of the reticuloendothelial system.
Conclusions/Significance: This approach in several murine BMT models revealed that the transplanted cells homed within 24 h after transplantation. NIRF labeling is useful for tracking transplanted cells in the initial phase after BMT, and this approach can contribute to in vivo studies aimed at improving the therapeutic outcomes of BMT.

DOI： 10.1371/journal.pone.0011114

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Severe acute pancreatitis is poor prognosis. Continuous regional arterial infusion of protease inhibitors and antibiotics were developed in Japan. We evaluated whether arterial infusion both celiac artery and superior mesenteric artery for this disease would reduce mortality.
Methodology: Seventeen patients were treated arterial infusion of protease inhibitor and antibiotics via both celiac artery and superior mesenteric artery. Changes of Acute Physiology and Chronic Health Evaluation II score and mortality were evaluated.
Results: Arterial infusion via two routes reduced the mortality rate and improved Acute Physiology and Chronic Health Evaluation II score. The overall mortality rate was 11.8%. The mortality rate in patients in whom were treated within Mays after the onset was significantly lower than that in patients in whom were treated without 3days after the onset
Conclusions: Arterial infusion via superior mesenteric artery might prevent both bacterial translocation and non-occlusive mesenteric ischemia. Continuous arterial infusion both celiac artery and superior mesenteric artery might be effective for reducing mortality and preventing the development of pancreatitis, especially when initiated within Mays after the onset. Further prospective randomized studies using a larger number of patients are required.

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Language：English   Publisher：ELSEVIER IRELAND LTD  

Youshi Fujita, Takashi Ushiki, Masafumi Ihara, Hidefumi Ito, Shinae Kizaka-Kondoh, Ryosuke Takahashi, 2009, &#039;Intravenously administered bone marrow cells alleviates white matter lesions in a model of chronic cerebral hypoperfusion&#039;, &lt;i&gt;Neuroscience Research&lt;/i&gt;, vol. 65, p. S123

DOI： 10.1016/j.neures.2009.09.586

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Language：Japanese   Publisher：(株)アークメディア  

高齢者切除不能膵癌患者に動注化学療法を施行し、局所療法として本治療法が症状緩和を含めた緩和治療の一方法となりうるか検討した。切除不能膵癌患者で、動注化学療法を施行した18例を65歳以上の高齢者群10例と65歳未満の非高齢者群8例の2群に分け、生存期間、症状緩和効果、在宅期間率、副作用を比較検討した。高齢者群に女性の比率が高い傾向を認めた。全体の50%生存期間は293日で、6ヵ月生存率は76.2%、1年生存率は30.4%であった。Kaplan-Meier法による生存曲線では、50%生存期間は非高齢者群242日、高齢者群は301日で有意差は認めなかった。全体の症状緩和効果は77.7%、Tumor Responseは50.0%、CA19-9 Responseは55.5%であった。高齢者群10例中8例、非高齢者群8例中6例に症状緩和効果を認め、全例外来治療に移行できた。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W J G PRESS  

AIM: To improve the preoperative diagnosis of liver metastasis from pancreatic cancer, we estimated computed tomography during arterial angiography (CTA) with/without administration of angiotensin-II (AT-II).
METHODS: Thirty-five patients with pancreatic cancer were examined in this study. After conventional CTA was performed, pharmacoangiographic CTA was performed with a 1-3 microgram/5 mL solution of angiotensin II injected through a catheter into the celiac artery during spiral computed tomography. We prospectively analyzed the relative region of interest (ROI) ratio of tumor to liver with/without AT-II.
RESULTS: In all patients, the relative ratio of each computed tomography (CT) number in the ROI was larger at pharmacoangiographic CT than at conventional angiographic CT. Administration of angiotensin-II enhanced the metastatic liver tumor as compared with normal tissue. Intratumoral blood flow increased in all patients with malignant tumors due to the pressure effect of AT-II. Furthermore, the metastatic lesions in the liver of three patients were represented by only pharmacoangiographic CT, not by conventional CT and conventional CT angiography. In even peripheral and central areas of metastatic liver tumor, the lesions were enhanced after administration of AT-II.
CONCLUSION: These results support that high detection rate of liver metastasis revealed by pharmacoangiographic CT suggests the improvement of diagnosis on preoperative staging. Moreover, chemotherapy under AT-II induced hypertension may have a better effect on the treatment of metastatic liver tumors. (c) 2007 The WJG Press. All rights reserved.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 59-year-old man was admitted to our hospital because of continuous C-reactive protein elevation. Abdominal computed tomography scan revealed a low density mass on the surface of the spleen. Magnetic resonance imaging showed low intensity at peripheral area and slightly high intensity in the central area of the mass lesion on T1 and T2-weighted image. Splenectomy was performed since we could not rule out the possibility of malignant neoplasm only by diagnostic imaging. The pathological diagnosis of the tumor was inflammatory pseudotumor. Splenectomy is considered to be significant from the standpoints of both diagnosis and therapy in cases in which diagnostic imaging is difficult to interpret.

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

症例1:56歳男。心窩部痛が増悪し、ショック状態を来たした。検査所見で白血球数、amylaseなどの上昇、CTで両側傍腎腔の液体貯留などを認め、急性膵炎、Grade Vと診断し、APACHE II scoreも11点であったため、蛋白分解酵素阻害薬および抗菌薬の動注療法を行った。加療開始後改善傾向を認めたが、全身性炎症反応症候群に伴う急性肺障害を合併したため、人工呼吸管理と同時にsivelestat sodium、利尿薬、アルブミン製剤の投与を開始した。病態は改善し6日間で抜管でき、内科的治療の継続により退院となった。症例2:27歳男。腹痛が増悪し、ショック状態となった。CTで膵融解像、膵・腎周囲滲出液を認め、急性膵炎、Grade IV、APACHE II score 8点と診断し、動注療法および持続血液濾過透析を施行した。更に、PaO2/FIO2比の低下傾向を認めたため、急性呼吸窮迫症候群の危険性を考えsivelestat sodiumを併用した。その結果、早期改善を認め、発症23日で退院した。

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Gemcitabine hydrochloride (GEM) is a first-line therapeutic agent for advanced pancreatic cancer, but there is no established second-line treatment after GEM failure. We assessed the clinical benefit of systemic combined chemotherapy with 5-fluorouracil and cisplatin (FP therapy) in 19 patients compared with GEM in 32 patients, respectively. Tumor response rates were 10.5% and 15.6% for FP therapy and GEM, respectively. The median survival time in the FP therapy and GEM was 137 days and 241 days, respectively. Although clinical benefit was similar in both types of therapy, median survival time was more favorable for GEM, especially for Stage IVb. Nausea and vomiting were the most commonly observed toxicity in the FP therapy group. Our data indicate that FP therapy is not considered to be a useful second-line agent in patients with GEM pretreated pancreatic cancer.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BAISHIDENG PUBL GRP CO LTD  

AIM: To evaluate the efficacy of CT-maximum intensity projection (CT-MIP) in the detection of gastric varices and their inflowing and outflowing vessels in patients with gastric varices scheduled to undergo balloon-occluded retrograde transvenous obliteration (B-RTO).
METHODS: Sixteen patients with endoscopically confirmed gastric varices were included in this study. All patients were evaluated with CT-MIP using three-dimensional reconstructions, before and after B-RTO.
RESULTS: CT-MIP clearly depicted gastric varices in 16 patients (100%), the left gastric vein in 6 (32.5%), the posterior gastric vein in 12 (75.0%), the short gastric veins in 13 (81.3%), gastrorenal shunts in 16 (100%), the hemiazygos vein (HAZV) in 4 (25.0%), the pericardiophrenic vein (PCPV) in 9 (56.3%), and the left inferior phrenic vein in 9 patients (56.3%). Although flow direction itself cannot be determined from CT-MIP, this modality provided clear images of the inflowing and the outflowing vessels. Moreover, in one patient, short gastric veins were not seen on conventional angiographic portography images of the spleen, but were clearly revealed on CT-MIP.
CONCLUSION: We suggest that CT-MIP should be considered as a routine method for detecting and diagnosing collateral veins in patients with gastric varices scheduled for B-RTO. Furthermore, CT-MIP is more useful than endoscopy in verifying the early therapeutic effects of B-RTO. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

The authors encountered a patient with gastric varices draining to the IVC not only via the usual route of the left renal vein but also via a circumaortic renal vein. Balloon-occluded retrograde transvenous obliteration (B-RTO) of the gastric varix was performed with balloon occlusion of the circumaortic renal vein and retrograde injection of sclerosing agent (5% of ethanolamine oleate) into the varix. Eradication of the gastric varix was confirmed on endoscopic examination 2 months later. We document the first case of B-RTO performed for gastric varix via the circumaortic renal vein. Details of this rare occurrence and implications for treatment are presented herein. (c) 2005 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.hepres.2005.03.011

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Language：English   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：English   Publisher：(一社)日本血液学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00083&link_issn=&doc_id=20221028010394&doc_link_id=%2Fcl8isoke%2F2022%2Fs057s1%2F157%2F0324-0324%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcl8isoke%2F2022%2Fs057s1%2F157%2F0324-0324%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本移植学会  

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Publisher：Frontiers Media SA  

Isohemagglutinin assays employing red blood cells (RBCs) are the most common assays used to measure antibody titer in ABO-incompatible kidney transplantation (ABOi KTx). However, ABO antigens expressed on RBCs are not identical to those of kidney and antibody titers do not always correlate with clinical outcome. We previously reported that CD31 was the main protein linked to ABO antigens on kidney endothelial cells (KECs), which was different from those on RBCs. We developed a new method to measure antibody titer using a microarray of recombinant CD31 (rCD31) linked to ABO antigens (CD31-ABO microarray). Mass spectrometry analysis suggested that rCD31 and native CD31 purified from human kidney had similar ABO glycan. To confirm clinical use of CD31-ABO microarray, a total of 252 plasma samples including volunteers, hemodialysis patients, and transplant recipients were examined. In transplant recipients, any initial IgG or IgM antibody intensity &amp;gt;30,000 against the donor blood type in the CD31-ABO microarray showed higher sensitivity, specificity, positive predictive value, and negative predictive value of AABMR, compared to isohemagglutinin assays. Use of a CD31-ABO microarray to determine antibody titer specifically against ABO antigens expressed on KECs will contribute to precisely predicting AABMR or preventing over immunosuppression following ABOi KTx.

DOI： 10.3389/ti.2022.10248

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Language：English   Publisher：(一社)日本血液学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

DOI： 10.2337/db21-421-P

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Language：Japanese   Publisher：(一社)日本血栓止血学会  

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DOI： 10.1182/blood-2020-137448

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Language：Japanese   Publisher：(一社)日本輸血・細胞治療学会  

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生後4ヵ月未満児は得られる採血量が少ないことから、自動輸血検査装置や試験管法では不規則抗体検査が困難である。このため、当院では検体量が試験管法の約1/4と少量の検体で検査可能なMicro Typing Systemを採用している。2007年1月から2016年12月までの10年間においてMicro Typing Systemでは不規則抗体検査依頼のあった生後4ヵ月未満児554件中、552件(99.6%)で検査可能であった。症例の内訳では55.4%が先天性心疾患の症例であった。また、検査可能であった552件中、不規則抗体が16件(2.9%)で陽性判定であった。そのうちの14件は母親からの移行抗体、1件は移行抗体が疑われた抗E、1件は自然抗体と考えられるIgM型の抗Mであった。さらに実際に358件に赤血球輸血が実施され、その内230件(64.2%)に輸血後の不規則抗体検査が行われたが、輸血後に生後4ヵ月未満児が不規則抗体を産生した症例は認められなかった。ほぼ全例に不規則抗体スクリーニング検査を可能とするMicro Typing Systemは乳児への輸血療法の安全性確保の観点において有用である。(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

DOI： 10.2337/db19-1910-P

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DOI： 10.1182/blood-2018-99-113251

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DOI： 10.1182/blood-2018-99-115844

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DOI： 10.1182/blood-2018-99-115796

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

DOI： 10.2337/db18-547-P

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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症例は75歳の女性。血液検査で貧血と末梢血に芽球を認められたため、当院を紹介受診した。骨髄穿刺で骨髄異形成症候群(myelodysplastic syndrome with excess blasts 2, MDS-EB-2)と診断された。血球減少の進行や芽球の増加、および出血症状はなく経過していた。診断から10ヵ月後、左手母指球に外傷を負い、内出血が持続し、止血困難となったため緊急入院した。血小板数は正常範囲であったが、血小板機能検査でコラーゲン凝集能とアラキドン酸凝集能の低下を認められた。抗血小板薬の内服はなく、またこれまで出血傾向の既往もなかったことから、MDSによる二次性の血小板機能低下による出血と判断し、血小板輸血を行い止血した。MDSの患者では、潜在的に血小板凝集能が低下していることが多く、血小板数の割に出血傾向が強い場合には血小板凝集能を調べ、血小板輸血などの治療介入を検討する必要がある。(著者抄録)

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1998年から2015年までに新潟大学医歯学総合病院血液内科で診断したPTCL,NOS 28例について臨床像,病理学的特徴,治療内容,予後を後方視的に解析した。性別は男性16例,女性12例で年齢中央値62.5(26〜88)歳。IPIはHIが10例,Hが9例であり高リスク群が68%を占めていた。初回治療としてCHOPまたはTHP-COP療法が12例に行われ,第三世代化学療法が9例に行われた。予後の確認ができた26例の観察期間中央値30ヵ月(範囲1〜164ヵ月)における2年OSは61%,2年PFSは44%であった。初回治療における効果がCRであった11例は5年OS 83%,5年PFS 75%であり,CRに至らなかった9例に比べ予後良好であった(p&lt;0.005)。PTCL,NOSに対する新規薬剤を用いた治療法の開発が望まれる。(著者抄録)

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Language：Japanese   Publisher：(一社)日本輸血・細胞治療学会  

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症例は成人T細胞白血病/リンパ腫(ATLL)急性型の62歳男性。CHOP療法単独では治療抵抗性であったが,抗CCR4抗体mogamulizumab併用CHOP療法が奏効し寛解を得た。HLA一致血縁・非血縁ドナーが得られず,mogamulizumab最終投与後71日目に骨髄非破壊的前処置を用いた臍帯血移植を施行した。急性移植片対宿主病(GVHD)grade II(皮膚stage2)を発症したが,methylprednisolone投与により制御可能であり,移植後9ヵ月時点まで寛解を維持している。経過中,制御性T細胞(Treg)は著減したままの状態であった。同種造血幹細胞移植はATLLの根治的治療であるが,移植前にmogamulizumabを使用する際,Tregの減少による急性GVHDの発症頻度・重症度が増加する可能性が報告されている。寛解期移植を目指すためにmogamulizumabを使用せざるを得ない症例における至適なドナーソースや移植時期,GVHD予防法に関して,更なる症例の蓄積が望まれる。(著者抄録)

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DOI： 10.1182/blood.V128.22.3690.3690

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DOI： 10.1182/blood.V128.22.3619.3619

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DOI： 10.1182/blood.V128.22.2297.2297

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DOI： 10.1002/ajh.24318

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：American Thoracic Society  

DOI： 10.1513/AnnalsATS.201503-175LE

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DOI： 10.1182/blood.V122.21.2744.2744

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：FERRATA STORTI FOUNDATION  

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Language：Japanese   Publisher：新潟市民病院  

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症例は35歳男性。口腔内出血で来院し,急性前骨髄球性白血病と診断された。all-trans-retinoic acid(ATRA)を併用した寛解導入療法を行い,PCR法にてPML/RARA fusion geneの分子遺伝学的寛解状態が確認されたが,長期の血球回復不全,大量腹水,腎機能障害が出現した。CTにて肝表の凹凸不整を認め,肝生検により自己免疫性肝炎及び門脈圧亢進症と診断した。肝予備能が良好であり地固め療法2コース行ったが門脈圧亢進症による汎血球減少のため地固め療法の継続が不可能と判断し,ATRAによる維持療法(45mg/m2,day1〜14)8コースへ移行した。その後,門脈圧亢進症の増悪は認めず,5年間寛解を維持している。本例は門脈圧亢進症を有する症例においてATRAが長期にわたり使用可能であることを示唆する。(著者抄録)

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

61歳男。近医にて汎血球減少を認め、急性白血病の疑いで当科に入院した。acute myeloid leukemia with myelodysplasia-related changesと診断し、Daunorubicin+Cytarabineにて完解導入療法を開始した。中心静脈カテーテル局所感染に対しMEPM+VCMの投与を行ったが、発熱が持続し血小板輸血不応となり抗HLA抗体が検出された。Pseudomonous AeruginosaおよびStaphylococcus Epidermidisが検出され、薬剤感受性によりCPFX+CLDM+VCMに変更した。SpO2が低下したため、酸素を開始したが歩行時に喘鳴が発現し、全身チアノーゼが出現し、意識混濁状態のためICU管理とした。両肺に広範な浸潤影と右葉間胸水を認め急性心不全と考えられた。心電図ではV1-V3誘導にかけ異常Q波を伴うST上昇が認められ、心臓超音波検査では心基部以外はakinesisの状態で、たこつぼ型心筋症として典型的所見であった。フロセミド静注したところ突然に収縮期血圧が低下したが、抗HLA抗体陽性であり侵襲的処置は困難であった。ノルアドレナリンを併用し、ドパミンのフラッシュを繰り返した。感染症の合併を否定できず、CPFX+CLDM+LZD+VRCZ+GCV+Pentamidine+IVIG投与を開始し、最終的にドパミン10γ+ノルアドレナリン0.1γ+アドレナリン0.05γを維持量とし、昇圧剤を漸減しday33にICUを退室した。High-dose cytarabineにて施行した地固め療法ではEFは開始時にはほぼ正常化し2コース終了以後、たこつぼ型心筋症の再燃は認めていない。

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

症例は52歳の女性。2003年1月から高度の血小板増加を認め,本態性血小板血症の疑いで経過観察中に,貧血,白血球減少が出現し,2007年11月当院を受診した。骨髄生検で巨核球増加と骨髄線維化を認めたが脾腫を認めず。骨髄染色体分析で,t(9;22)(q34;q11.2)を6/20細胞に認めたが,末梢血好中球BCR-ABL(FISH)融合シグナルは正常範囲内であった。骨髄液のRT-PCR法でM-BCR/ABL mRNA(b3a2型)を認め,2008年5月からimatinib400mg内服を開始した。一過性の血小板減少後末梢血は正常化し,骨髄線維症も軽快傾向にある。なお,末梢血でJAK2 V617F変異は陰性,M-BCR-ABL mRNA(TMA)は検出感度以下である。考察:経過中好中球増加がみられず,好中球にBCR-ABL融合遺伝子を認めないこと,imatinibにより骨髄巨核球の減少と線維化が改善したことから,BCR-ABL転座が主として巨核球系細胞に発現した極めてまれな骨髄増殖性腫瘍と考えられる。(著者抄録)

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Language：Japanese   Publisher：新潟医学会  

【目的】近年のin vivo imagingの技術革新は著しく、これまで追跡困難であった骨髄移植後の造血幹細胞を体外よりイメージングすることが試みられている。In vivo imagingに基づいた造血幹細胞の生体内動態解析は、骨髄移植に関連した病態を理解する上で重要な情報である。今回、我々は細胞数が少数であるため、in vivo imagingが特に困難であった骨髄再構築前の移植ドナー細胞の細胞動態について検討した。【方法】BALB/c nu/nu(H-2d)に対し、Alexa Fluor 750により細胞外標識したドナー骨髄単核球を用いて、静注法による骨髄移植や骨髄内骨髄移植などの移植法を施行した。また、その近赤外蛍光をIVIS SPECTRUM(Xenogen)を用い、経時的に移植後24時間の観察を行った。【結果】ドナー細胞の蛍光標識に際し、細胞膜を均一に標識することで、細胞種によらず100%の標識効率が得られた。骨髄移植モデルでは脛骨へのホーミングは移植後1時間より認められ、移植後6時間まで蛍光強度は増強した。また、これまで骨髄移植後の細胞動態が不明であった骨髄内骨髄移植においてもその移植後の生体内動態を可視化することに成功した。今回考案した近赤外蛍光色素標識を用いた細胞動態解析法は、これまで病理学的手法以外に評価困難であった移植細胞の骨髄内への移行及び網内系臓器での捕捉量の変化をreal-timeで観察することが可能であり、骨髄移植の病態解明に有用な手法である。(著者抄録)

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Language：Japanese   Publisher：日本分子イメージング学会  

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Language：Japanese   Publisher：日本分子イメージング学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese  

J-GLOBAL

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

Web of Science

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：新潟医学会  

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Other Link： http://search.jamas.or.jp/link/ui/2007306251

Language：Japanese   Publisher：(一財)日本消化器病学会  

脾炎症性偽腫瘍(inflammatory pseudotumor)の1例を経験したので報告する。症例は59歳男性、CRP持続陽性精査のため、腹部CT施行。CT検査にて脾に単純で低吸収、造影にて脾実質より相対的に低吸収となる腫瘤性病変を認めた。MRI検査ではT1強調、T2強調ともに内部に一部高信号をともなう低信号の腫瘤像を呈した。血管造影でも悪性所見に乏しく、無症状であるが、CRP上昇の原因と考え、また、悪性リンパ腫の可能性が否定しきれず治療的診断的意義を兼ねて、脾臓摘出術を施行した。病理組織学的に脾炎症性偽腫瘍と診断した。脾炎症性偽腫瘍は極めてまれであり、悪性腫瘍との鑑別診断が困難である。確定診断は術後の病理組織診断によるため、脾臓摘出が治療的意義と同時に診断的意義を有し、予後も良好である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本内科学会  

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J-GLOBAL

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

症例1:56歳男。心窩部痛が増悪し、ショック状態を来たした。検査所見で白血球数、amylaseなどの上昇、CTで両側傍腎腔の液体貯留などを認め、急性膵炎、Grade Vと診断し、APACHE II scoreも11点であったため、蛋白分解酵素阻害薬および抗菌薬の動注療法を行った。加療開始後改善傾向を認めたが、全身性炎症反応症候群に伴う急性肺障害を合併したため、人工呼吸管理と同時にsivelestat sodium、利尿薬、アルブミン製剤の投与を開始した。病態は改善し6日間で抜管でき、内科的治療の継続により退院となった。症例2:27歳男。腹痛が増悪し、ショック状態となった。CTで膵融解像、膵・腎周囲滲出液を認め、急性膵炎、Grade IV、APACHE II score 8点と診断し、動注療法および持続血液濾過透析を施行した。更に、PaO2/FIO2比の低下傾向を認めたため、急性呼吸窮迫症候群の危険性を考えsivelestat sodiumを併用した。その結果、早期改善を認め、発症23日で退院した。

J-GLOBAL

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Language：Japanese   Publisher：(株)癌と化学療法社  

gemcitabine hydrochloride(GEM)は切除不能膵癌に対する第一選択薬剤と評価されている。今回、当科におけるGEMとCDDP・5-FU療法(FP療法)の効果をretrospectiveに比較検討し、FP療法がGEMのsecond-lineになり得るか否か評価した。対象はFP群19例(II1例、III2例、IV a2例、IV b14例)とGEM群32例(IV a3例、IV b29例)。奏効率はFP群10.5%、GEM群15.6%。50%平均生存期間はFP群137日、GEM群241日で統計的有意差は認めなかったが、IV b症例に限ればGEM群で有意な延命効果が認められた。副作用ではFP群で消化器症状が強かった。今回の検討からFP療法はGEMのsecond-lineとすることは困難と思われた。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2006&ichushi_jid=J00296&link_issn=&doc_id=20060925480011&doc_link_id=%2Fab8gtkrc%2F2006%2F003309%2F011%2F1267-1271%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2006%2F003309%2F011%2F1267-1271%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：日本臨床血液学会  

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