研究者詳細 - 村松　秀城

論文 - 村松　秀城

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Long-term outcomes of 95 children with moderate aplastic anemia treated with horse antithymocyte globulin and cyclosporine 査読有り

Nishikawa E., Yagasaki H., Hama A., Yabe H., Ohara A., Kosaka Y., Kudo K., Kobayashi R., Ohga S., Morimoto A., Watanabe K.I., Yoshida N., Muramatsu H., Takahashi Y., Kojima S.

Pediatric Blood and Cancer 64 巻 ( 5 ) 2017年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Pediatric Blood and Cancer

Background: Currently, the standard management of moderate aplastic anemia (MAA) has not been well described, although the superiority of the combination of antithymocyte globulin (ATG) and cyclosporine (CyA) over CyA alone has been demonstrated in terms of hematological responses and failure-free survival (FFS). Procedure: We adopted this therapeutic strategy and treated 95 children with MAA who were enrolled in two consecutive prospective studies between October 1992 and August 2009. Results: For these patients, the 6-month response rate was 54.7% (complete response, 13.7%; partial response, 41.1%). There were no statistically significant differences in the overall response rates between the transfusion-dependent (48.8%, n = 41) and transfusion-independent groups (59.3%, n = 54; P = 0.4). Treatment failure was defined as the requirement of salvage treatment, and was observed in 52 patients. The 10-year FFS was 44.0% (95% confidence interval [CI], 32.9%–54.6%). Of the 22 patients who underwent a second immunosuppressive therapy (IST), 12 responded. Forty patients underwent hematopoietic stem cell transplantation as second- or third-line therapy and three died of complications. Consequently, the 10-year overall survival rate was 96.0% (95% CI, 88.0%–98.7%) with a median follow-up period of 103 months (range, 29–221 months). Conclusions: Although current guidelines recommend only observation for patients with transfusion-independent MAA, the results of our study justify early intervention with ATG and CyA in those patients. A prospective randomized trial is warranted to clarify the risks and benefits of early intervention with IST and observation alone until progression to severe AA in patients with MAA.

DOI： 10.1002/pbc.26305

Diagnostic challenge of Diamond–Blackfan anemia in mothers and children by whole-exome sequencing 査読有り

Ichimura T., Yoshida K., Okuno Y., Yujiri T., Nagai K., Nishi M., Shiraishi Y., Ueno H., Toki T., Chiba K., Tanaka H., Muramatsu H., Hara T., Kanno H., Kojima S., Miyano S., Ito E., Ogawa S., Ohga S.

International Journal of Hematology 105 巻 ( 4 ) 頁： 515 - 520 2017年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Hematology

Diamond–Blackfan anemia (DBA) is a pure red cell aplasia that arises from defective ribosomal proteins (RPs). Patients with this rare ribosomopathy present with neonatal anemia and occasional dysmorphism. Clinical heterogeneity and clusters of causative RP genes hamper the diagnosis and perinatal management. We report three mother-and-child pairs of anemia who were finally diagnosed by whole-exome sequencing. Each pair showed distinct disease severity and response to anemia treatment. Only one mother had the diagnostic dysmorphism, including short stature, webbed neck, and thenar hypoplasia. This mother had a frame-shift mutation of RPL11 (exon 3, c.58_59del). Her infant showed transient neonatal anemia, but had no mutations of RP genes. The other mother–child pairs had a missense mutation of RPS19 (exon 4, c.185G>A), and a splicing error of RPS7 (exon 3, c.76-1G>T), respectively. Other than the reported mutations, there were no variants in genes significantly associated with anemia. Our results suggested that whole-exome sequencing (WES) is effective for achieving a prompt and correct diagnosis of human ribosomopathy.

DOI： 10.1007/s12185-016-2151-7

Exome sequencing identified RPS15A as a novel causative gene for Diamond-Blackfan anemia 査読有り

Ikeda F., Yoshida K., Toki T., Uechi T., Ishida S., Nakajima Y., Sasahara Y., Okuno Y., Kanezaki R., Terui K., Kamio T., Kobayashi A., Fujita T., Sato-Otsubo A., Shiraishi Y., Tanaka H., Chiba K., Muramatsu H., Kanno H., Ohga S., Ohara A., Kojima S., Kenmochi N., Miyano S., Ogawa S., Ito E.

Haematologica 102 巻 ( 3 ) 頁： e93 - e96 2017年2月

Recurrent cellulitis caused by Helicobacter cinaedi in a patient with X-linked agammaglobulinaemia 査読有り

Sugimoto M., Takeichi T., Muramatsu H., Kojima D., Osada Y., Kono M., Kojima S., Akiyama M.

Acta Dermato-Venereologica 97 巻 ( 2 ) 頁： 277 - 278 2017年2月

Clinical utility of next-generation sequencing-based minimal residual disease in paediatric B-cell acute lymphoblastic leukaemia 査読有り

Sekiya Y., Xu Y., Muramatsu H., Okuno Y., Narita A., Suzuki K., Wang X., Kawashima N., Sakaguchi H., Yoshida N., Hama A., Takahashi Y., Kato K., Kojima S.

British Journal of Haematology 176 巻 ( 2 ) 頁： 248 - 257 2017年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：British Journal of Haematology

We assessed the clinical utility of next-generation sequencing (NGS)-based monitoring of minimal residual disease (MRD) in a uniformly treated cohort of 79 patients with paediatric B-cell acute lymphoblastic leukaemia. Bone marrow samples were collected at the time of diagnosis, days 33 and 80, pre- (4–5 months) and post- (24 months) maintenance therapy time points, and at relapse. We identified leukaemia-specific CDR3 sequences in 72 of 79 patients (91%) and detected MRD in 59 of 232 samples. Although MRD was detected in 28 of 55 samples (51%) on day 33, the frequencies of MRD detection decreased to 25% (16/65) at day 80, 19% (11/58) at 4–5 months and 7·4% (4/54) at 24 months. In a univariate analysis, positive MRD results on day 80 [relative risk (RR) 95% confidence interval (CI) = 7·438 (2·561–21·6), P < 0·001], at 4–5 months [RR (95% CI) = 10·24 (3·374–31·06), P < 0·001], and at 24 months [RR (95% CI) = 19·26 (4·974–74·59), P < 0·001] exhibited statistically significant associations with inferior leukaemia-free survival; this was confirmed using a Cox proportional hazard model. Our study suggests the promising potential of NGS-MRD for patients with B-cell ALL.

DOI： 10.1111/bjh.14420

Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome–like immunodeficiency 査読有り

Tsujita Y., Mitsui-Sekinaka K., Imai K., Yeh T.W., Mitsuiki N., Asano T., Ohnishi H., Kato Z., Sekinaka Y., Zaha K., Kato T., Okano T., Takashima T., Kobayashi K., Kimura M., Kunitsu T., Maruo Y., Kanegane H., Takagi M., Yoshida K., Okuno Y., Muramatsu H., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Kojima S., Ogawa S., Ohara O., Okada S., Kobayashi M., Morio T., Nonoyama S.

Journal of Allergy and Clinical Immunology 138 巻 ( 6 ) 頁： 1672 - 1680.e10 2016年12月

記述言語：日本語出版者・発行元：Journal of Allergy and Clinical Immunology

Background Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, PIK3CD and PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6. Objective This study aimed to identify novel genes responsible for APDS. Methods Whole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays. Results We identified heterozygous mutations of phosphatase and tensin homolog (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that PTEN expression was decreased in these patients. Patients with PTEN mutations and those with PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway. Conclusion PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.

DOI： 10.1016/j.jaci.2016.03.055

Allogeneic hematopoietic stem cell transplantation for dyskeratosis congenita 査読有り

Elmahadi S., Muramatsu H., Kojima S.

Current Opinion in Hematology 23 巻 ( 6 ) 頁： 501 - 507 2016年11月

記述言語：日本語出版者・発行元：Current Opinion in Hematology

Purpose of review Dyskeratosis congenita is an inherited bone marrow failure syndrome caused by defects in telomere maintenance. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure because of dyskeratosis congenita. The present review summarizes the literature with respect to the diagnosis and treatment of patients with dyskeratosis congenita who received HSCT, and discusses the recent progress in the management of dyskeratosis congenita. Recent findings The recent systematic review of the literature showed poor long-term outcome, with 10-year survival estimates of only 23% in 109 patients with dyskeratosis congenita who received HSCT. Multivariate analysis identified age greater than 20 years at HSCT, HSCT before 2000, and alternative donor source to be poor prognostic markers. HSCT for dyskeratosis congenita is characterized by a marked decline in long-term survival because of late deaths from pulmonary complications. However, a prospective study using danazol showed promising results in gain in telomere length and hematologic responses. Summary A recent prospective study may support the recommendation that HSCT is not indicated for patients with dyskeratosis congenita; instead, they should receive androgen, particularly danazol, as a first-line therapy. Another option may be routine use of androgen after HSCT for the prophylaxis of pulmonary fibrosis.

DOI： 10.1097/MOH.0000000000000290

Successful T-cell reconstitution after unrelated cord blood transplantation in a patient with complete DiGeorge syndrome 査読有り

Kojima D., Muramatsu H., Okuno Y., Kataoka S., Murakami N., Tanahashi Y., Suzuki K., Kato T., Sekiya Y., Kawashima N., Narita A., Nishio N., Hama A., Imai K., Nonoyama S., Takahashi Y., Kojima S.

Journal of Allergy and Clinical Immunology 138 巻 ( 5 ) 頁： 1471 - 1473.e4 2016年11月

The phenotype and clinical course of Japanese Fanconi Anaemia infants is influenced by patient, but not maternal ALDH2 genotype 査読有り

Yabe M., Yabe H., Morimoto T., Fukumura A., Ohtsubo K., Koike T., Yoshida K., Ogawa S., Ito E., Okuno Y., Muramatsu H., Kojima S., Matsuo K., Hira A., Takata M.

British Journal of Haematology 175 巻 ( 3 ) 頁： 457 - 461 2016年11月

記述言語：日本語出版者・発行元：British Journal of Haematology

Studies using Fanconi anaemia (FA) mutant mouse models suggested that the combination of a defective FA pathway and aldehyde dehydrogenase-2 (ALDH2) dysfunction could provoke bone marrow failure, leukaemia and developmental defects, and that both maternal and fetal aldehyde detoxification are crucial to protect the developing embryo from DNA damage. We studied the ALDH2 genotypes of 35 Japanese FA patients and their mothers. We found that a normal maternal ALDH2 allele was not essential for fetal development of ALDH2-deficient patients, and none of the post-natal clinical parameters were clearly affected by the maternal ALDH2 genotype in these patients.

DOI： 10.1111/bjh.14243

MEF2D-BCL9 fusion gene is associated with high-risk acute B-cell precursor lymphoblastic leukemia in adolescents 査読有り

Suzuki K., Okuno Y., Kawashima N., Muramatsu H., Okuno T., Wang X., Kataoka S., Sekiya Y., Hamada M., Murakami N., Kojima D., Narita K., Narita A., Sakaguchi H., Sakaguchi K., Yoshida N., Nishio N., Hama A., Takahashi Y., Kudo K., Kato K., Kojima S.

Journal of Clinical Oncology 34 巻 ( 28 ) 頁： 3451 - 3459 2016年10月

記述言語：日本語出版者・発行元：Journal of Clinical Oncology

Purpose: Acute lymphoblastic leukemia (ALL) makes up a significant proportion of all pediatric cancers, and relapsed ALL is a leading cause of cancer-associated deaths in children. Identification of risk factors and druggable molecular targets in ALL can lead to a better stratification of treatments and subsequent improvement in prognosis. Patients and Methods: We enrolled 59 children with relapsed or primary refractory ALL who were treated in our institutions. We primarily performed RNA sequencing (RNA-seq) using patients' leukemic cells to comprehensively detect gene fusions and analyze gene expression profiles. On the basis of results obtained by RNA-seq, we performed genetic validation, functional analysis, and in vitro drug sensitivity testing using patients' samples and an exogenous expression model. Results: We identified a total of 26 gene fusions in 22 patients by RNA-seq. Among these, 19 were non-random gene fusions already described in ALL, and four of the remaining seven involved identical combination of MEF2D and BCL9. All MEF2D-BCL9-positive patients had B-cell precursor immunophenotype and were characterized as being older in age, being resistant to chemotherapy, having very early relapse, and having leukemic blasts that mimic morphologically mature B-cell leukemia with markedly high expression of HDAC9. Exogenous expression of MEF2D-BCL9 in a B-cell precursor ALL cell line promoted cell growth, increased HDAC9 expression, and induced resistance to dexamethasone. Using a primary culture of leukemic blasts from a patient, we identified several molecular targeted drugs that conferred inhibitory effects in vitro. Conclusion: A novel MEF2D-BCL9 fusion we identified characterizes a novel subset of pediatric ALL, predicts poor prognosis, and may be a candidate for novel molecular targeting.

DOI： 10.1200/JCO.2016.66.5547

Kampo patterns and radiology in children receiving choreito for hemorrhagic cystitis after hematopoietic stem cell transplantation 査読有り

Kawashima N., Sekiya Y., Narita A., Kamei M., Muramatsu H., Nishio N., Hama A., Ito Y., Takahashi Y., Kojima S.

Traditional and Kampo Medicine 3 巻 ( 2 ) 頁： 136 - 144 2016年10月

出版者・発行元：Traditional and Kampo Medicine

Aim: Choreito reduces the disease burden of hemorrhagic cystitis (HC) in children undergoing hematopoietic stem cell transplantation, but the underlying Kampo mechanism has not yet been clarified. To obtain pathophysiological insights, the present study evaluated changes in Kampo patterns and genitourinary imaging during choreito treatment. Methods: Ten consecutive children with late-onset HC after stem cell transplantation were treated with choreito. Kampo patterns and computed tomography (CT) before and after choreito treatment were retrospectively analyzed. Results: Ten children with a median age of 9.7 years (range, 5.4–14 years) were diagnosed with late-onset HC; 9 had BK virus and 1 had adenovirus. The median duration from the beginning of choreito intake to complete resolution was 12 days (range, 4–28 days). All 10 children fulfilled the Kampo pattern of Bladder damp–heat at diagnosis; all had heat and/or hardness in the lower abdomen, and 8 children had a slippery pulse. CT was obtained in 4 of the 10 children at the time of diagnosis, all of which showed bladder wall thickening and perivesical inflammation. After choreito treatment for a median of 26 days (range, 8–40 days), none of the children had any sign of damp–heat, which coincided with the disappearance of perivesical inflammation, as confirmed on CT. Conclusion: Lower abdominal heat/hardness with a slippery pulse may reflect damp–heat accumulation in the lower energizer, causing HC. Improvement in these examinations can be used as a surrogate response marker in choreito treatment for HC, which should be confirmed in future prospective studies.

DOI： 10.1002/tkm2.1053

JAK2, MPL, and CALR mutations in children with essential thrombocythemia 査読有り

Sekiya Y., Okuno Y., Muramatsu H., Ismael O., Kawashima N., Narita A., Wang X., Xu Y., Hama A., Fujisaki H., Imamura T., Hasegawa D., Kosaka Y., Sunami S., Ohtsuka Y., Ohga S., Takahashi Y., Kojima S., Shimada A.

International Journal of Hematology 104 巻 ( 2 ) 頁： 266 - 267 2016年8月

Application of extensively targeted next-generation sequencing for the diagnosis of primary immunodeficiencies 査読有り

Kojima D., Wang X., Muramatsu H., Okuno Y., Nishio N., Hama A., Tsuge I., Takahashi Y., Kojima S.

Journal of Allergy and Clinical Immunology 138 巻 ( 1 ) 頁： 303 - 305.e3 2016年7月

PIEZO1 gene mutation in a Japanese family with hereditary high phosphatidylcholine hemolytic anemia and hemochromatosis-induced diabetes mellitus 査読有り

Imashuku S., Muramatsu H., Sugihara T., Okuno Y., Wang X., Yoshida K., Kato A., Kato K., Tatsumi Y., Hattori A., Kita S., Oe K., Sueyoshi A., Usui T., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Ogawa S., Kojima S., Kanno H.

International Journal of Hematology 104 巻 ( 1 ) 頁： 125 - 129 2016年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Hematology

Hereditary xerocytosis (HX) or dehydrated hereditary stomatocytosis (DHS) [OMIM 194380], in which PIEZO1 gene mutation has recently been identified, is difficult to diagnose. We report here the discovery of a PIEZO1 gene mutation in a Japanese family (father, daughter, and son) who were previously diagnosed with hereditary high phosphatidylcholine hemolytic anemia (HPCHA). All of the affected family members had non-spherocytic hemolytic anemia associated with severe hemochromatosis-related diabetes mellitus. Although the causative correlation between HPCHA and PIEZO1-gene mutated HX/DHS remains to be clarified, our findings raise an important question as to whether any of the HPCHA cases previously diagnosed in Japan may have in fact been the form of hemolytic anemia known as HX/DHS with PIEZO1 gene mutation.

DOI： 10.1007/s12185-016-1970-x

Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia 査読有り

Kitamura K., Okuno Y., Yoshida K., Sanada M., Shiraishi Y., Muramatsu H., Kobayashi R., Furukawa K., Miyano S., Kojima S., Ogawa S., Kunishima S.

Journal of Thrombosis and Haemostasis 14 巻 ( 7 ) 頁： 1462 - 1469 2016年7月

記述言語：日本語出版者・発行元：Journal of Thrombosis and Haemostasis

Essentials Two groups recently reported GFI1B as a novel causative gene for congenital macrothrombocytopenia. We performed functional analysis of a novel GFI1B mutation and previous mutations. An immunofluorescence analysis of the platelet CD34 expression can be useful as a screening test. Mutant-transduced megakaryocytes produced enlarged proplatelet tips which were reduced in number. Summary: Background GFI1B is an essential transcription factor for megakaryocyte and erythrocyte development. Two groups have recently identified GFI1B as a novel causative gene for congenital macrothrombocytopenia associated with α-granule deficiency. Methods We performed whole exome sequencing and identified a novel GFI1B p.G272fsX274 mutation in a family with macrothrombocytopenia, and a decreased number of platelet α-granules and abnormally shaped red blood cells. p.G272fsX274 and the previous two mutations all predicted disruption of an essential DNA-binding domain in GFI1B. We therefore performed functional studies to characterize the biochemical and biological effects of these three patient-derived mutations. Results An immunofluorescence analysis revealed decreased thrombospondin-1 and increased CD34 expression in platelets from our patient. Consistent with the previous studies, the three patient-derived mutants were unable to repress the expression of the reporter gene and had a dominant-negative effect over wild-type GFI1B. In addition, the three mutations abolished recognition of a consensus-binding site in gel shift assays. Furthermore, transduction of mouse fetal liver-derived megakaryocytes with the three GFI1B mutants resulted in the production of abnormally large proplatelet tips, which were reduced in number. Conclusions Our study provides further proof of concept that GFI1B is an essential protein for the normal development of the megakaryocyte lineage.

DOI： 10.1111/jth.13350

Immunosuppressive therapy for patients with Down syndrome and idiopathic aplastic anemia 査読有り

Suzuki K., Muramatsu H., Okuno Y., Narita A., Hama A., Takahashi Y., Yoshida M., Horikoshi Y., Watanabe K.i., Kudo K., Kojima S.

International Journal of Hematology 104 巻 ( 1 ) 頁： 130 - 133 2016年7月

記述言語：日本語出版者・発行元：International Journal of Hematology

Idiopathic aplastic anemia (AA) is a rare hematological complication of Down syndrome (DS). The safety and efficacy of immunosuppressive therapy (IST) in individuals with DS remain unknown. We used a standard regimen of IST, comprising antithymocyte globulin and cyclosporine A, to treat three children with DS and idiopathic acquired AA. Two patients achieved a hematological (complete or partial) response and became transfusion independent at the final follow-up. The third patient failed to respond to IST and underwent bone marrow transplantation from a human leukocyte antigen (HLA)-mismatched unrelated donor. None of the patients experienced severe or unexpected adverse events during IST. Our experience suggests that IST is a safe and reasonable treatment, even in individuals with DS who suffer from AA and lack an HLA-matched sibling donor.

DOI： 10.1007/s12185-016-1997-z

Genetic predisposition to pediatric myeloid malignancies 査読有り

Muramatsu H.

[Rinsho ketsueki] The Japanese journal of clinical hematology 57 巻 ( 6 ) 頁： 730 - 735 2016年6月

記述言語：日本語出版者・発行元：[Rinsho ketsueki] The Japanese journal of clinical hematology

Various genetic disorders are known to be associated with cancer predisposition. For example, children with Down syndrome are predisposed to developing acute myeloid leukemia, and those with RASopathies, such as Noonan syndrome, are predisposed to juvenile myelomonocytic leukemia. To date, more than 250 diseases or syndromes have been reported to be associated with the development of pediatric cancers. Recently, the advent of the massive parallel sequencing technique revealed several germline mutations, including RUNX1, CEBPA, GATA2, SRP72, ETV6, and DDX41, which are associated with familial myeloid malignancies. A significant number of children with myeloid malignancies may harbor pathognomonic germline variants. It is strongly recommended that precise diagnosis, genetic counseling, familial screening, and follow-up programs be provided for patients with such a predisposition to cancer. To identify genetic disorders associated with predispositions to pediatric myeloid malignancies, the development of an efficient screening system with the massive parallel sequencer for germline and somatic mutations, which would also be useful for familial genetic studies and prediction of tumor progression, is needed.

DOI： 10.11406/rinketsu.57.730

Markedly High Plasma Thrombopoietin (TPO) Level is a Predictor of Poor Response to Immunosuppressive Therapy in Children With Acquired Severe Aplastic Anemia 査読有り

Elmahdi S., Muramatsu H., Narita A., Ismael O., Hama A., Nishio N., Okuno Y., Xu Y., Wang X., Takahashi Y., Kojima S.

Pediatric Blood and Cancer 63 巻 ( 4 ) 頁： 659 - 664 2016年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Pediatric Blood and Cancer

Background: Immunosuppressive therapy (IST) is commonly used for patients with acquired severe aplastic anemia (SAA). Because the clinical response rate and therapeutic outcome for individual patients to IST varies, an in vitro test that identifies potential responders would be desirable. Methods: We evaluated the relationship between thrombopoietin (TPO) levels at the time of diagnosis and the response to IST at 6 months in 85 children (median age, 9.0 years; range, 1.0-15.5 years) with acquired SAA using enzyme-linked immunosorbent assay. Thirty-one age-matched healthy individuals were used as controls. All patients received antithymocyte globulin and cyclosporine. Results: Overall, 39 patients (45.9%) responded to IST at 6 months. TPO plasma levels were significantly higher in nonresponders than in responders (1,555.8 vs. 1,284.7 pg/ml, respectively; P = 0.031). Multivariate analysis identified the TPO levels of >1,796.7 pg/ml (TPO-high group, 20 patients; odds ratio (OR), 8.285; 95% confidence interval (CI), 2.114-32.904; P = 0.002) as independent poor predictors of IST response at 6 months. Moreover, the TPO-high group was associated with lower 5-year failure-free survival rates (30% vs. 68%, P = 0.012) compared with the TPO-low group. Conclusion: The measurement of TPO levels at diagnosis is useful for predicting the response to IST in children with SAA and may help in decision making.

DOI： 10.1002/pbc.25820

A Cytokine-Based Diagnostic Program in Pediatric Aplastic Anemia and Hypocellular Refractory Cytopenia of Childhood 査読有り

Elmahdi S., Hama A., Manabe A., Hasegawa D., Muramatsu H., Narita A., Nishio N., Ismael O., Kawashima N., Okuno Y., Xu Y., Wang X., Takahashi Y., Ito M., Kojima S.

Pediatric Blood and Cancer 63 巻 ( 4 ) 頁： 652 - 658 2016年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Pediatric Blood and Cancer

Background: Distinguishing hypocellular refractory cytopenia of childhood (RCC) from aplastic anemia (AA) is challenging. Thus far, no studies have compared the cytokine profiles in patients with AA to those with hypocellular RCC. In the present study, we addressed whether thrombopoietin (TPO) and interleukin 17 (IL-17) plasma levels are useful for differentiating between the two diseases. Methods: We measured the endogenous plasma concentrations of TPO and IL-17 in 29 patients with AA, 34 patients with hypocellular RCC, and 31 healthy controls using sensitive enzyme-linked immunosorbent assays. Results: The TPO and IL-17 plasma levels were significantly lower in patients with hypocellular RCC than in patients with AA (P < 0.001 and P = 0.007, respectively). The multivariate logistic regression analysis identified moderate disease severity, TPO levels of <1,369.8 pg/ml (TPO-low group, n = 32; odds ratio (OR), 13.40; 95% confidence intervals (CI), 3.001-51.254; P < 0.001), and IL-17 levels of <22.2 pg/ml (IL-17-low group, n = 33; OR, 4.11; 95% CI, 1.033-19.404; P = 0.031) as independent factors discriminating hypocellular RCC from AA. Importantly, 25 (78.1%) of 32 patients in the TPO-low group and 25 (75.8%) of 33 patients in the IL-17-low group were diagnosed as having hypocellular RCC. Moreover, 22 (71%) of 31 patients in the TPO-high group and 21 (70%) of 30 patients in the IL-17-high group were diagnosed as having AA. Conclusions: TPO and IL-17 levels are useful for differentiating hypocellular RCC from AA. Prospective studies are required to confirm our findings.

DOI： 10.1002/pbc.25799

Leukostasis in Children and Adolescents with Chronic Myeloid Leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group 査読有り

Kurosawa H., Tanizawa A., Tono C., Watanabe A., Shima H., Ito M., Yuza Y., Hotta N., Muramatsu H., Okada M., Kajiwara R., Moriya Saito A., Mizutani S., Adachi S., Horibe K., Ishii E., Shimada H.

Pediatric Blood and Cancer 63 巻 ( 3 ) 頁： 406 - 411 2016年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Pediatric Blood and Cancer

Background: The details of leukostasis in children and adolescents with chronic myeloid leukemia (CML) are unknown. This study determined the characteristics of leukostasis in children and adolescents with CML. Procedure: A total of 256 cases from a retrospective study of patients with CML conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group from 1996 to 2011 were analyzed, and of these, 238 cases were evaluated in this study. Results: Leukostasis was diagnosed in 23 patients (9.7%). The median leukocyte count and spleen size below the left costal margin in cases with leukostasis were significantly higher and larger when compared to those in cases without leukostasis (458.5 × 109/l vs. 151.8 × 109/l (P < 0.01), and 13 vs. 5 cm (P < 0.01), respectively). Leukostasis occurred with ocular symptoms in 14 cases, priapism in four cases, and dyspnea, syncope, headache, knee pain, difficulty hearing, and aseptic necrosis of the femoral head in one case each. One case had two leukostasis symptoms simultaneously. Three cases were diagnosed before imatinib became available. Five cases received special treatment, and in the remaining 15 cases, all of these symptoms resolved after treatment with imatinib. Conclusions: This retrospective study represents the largest series of children and adolescents in which leukostasis of CML has been reported. Our data provide useful insight into the characteristics of leukostasis in recent cases of children and adolescents with CML.

DOI： 10.1002/pbc.25803

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