Faculty Profiles - TSUKAHARA Hirokazu

Papers - TSUKAHARA Hirokazu

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肺血管内皮細胞を用いた重症インフルエンザ肺炎モデルの構築とhigh mobility group box 1抗体による肺血管透過性亢進の抑制効果

難波貴弘, 津下充, 八代将登, 塚原宏一, 森島恒雄, 西堀正洋

臨床とウイルス 48 ( 3 ) S84 - S84 2020.9

A case of alveolar rhabdomyosarcoma showing concurrent responsive bone marrow lesions and refractory pancreatic lesions to pazopanib monotherapy. Reviewed International journal

Kiichiro Kanamitsu, Hisashi Ishida, Kaori Fujiwara, Kana Washio, Akira Shimada, Hirokazu Tsukahara

Pediatric blood & cancer 67 ( 9 ) e28323 2020.9

嘔吐恐怖症に認知行動療法(Cognitive behavioral therapy:CBT)を施行した思春期女子の1例

住友裕美, 藤井智香子, 岡田あゆみ, 重安良恵, 椙原彰子, 堀内真希子, 塚原宏一

子どもの心とからだ 29 ( 2 ) 236 - 236 2020.8

Severe acute intestinal graft versus host disease requiring surgical resection Reviewed International journal

Hisashi Ishida, Takuo Noda, Seiji Kawano, Maho Sato, Hirokazu Tsukahara, Akira Shimada

eJHaem 1 ( 1 ) 328 - 329 2020.7

Laboratory changes during adrenocorticotropic hormone therapy associated with renal calcified lesions. Reviewed International journal

Hiroyuki Miyahara, Tomoyuki Akiyama, Kosei Hasegawa, Mari Akiyama, Makio Oka, Katsuhiro Kobayashi, Hirokazu Tsukahara

Pediatrics international : official journal of the Japan Pediatric Society 62 ( 5 ) 587 - 592 2020.5

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

BACKGROUND: Renal calcified lesions are known as one of the complications during adrenocorticotropic hormone (ACTH) therapy for intractable epilepsy. However, laboratory changes during the therapy or laboratory features of high-risk cases with renal calcified lesions are yet to be clarified. METHODS: In this study, 43 patients with West syndrome aged ≤2 years were included. We retrospectively reviewed age and body mass index at the beginning of ACTH therapy, as well as the amount of fluid intake, daily urinary volume, and laboratory data during therapy. In addition, we studied the urinary sediment of the cases with renal calcified lesions diagnosed by computed tomography. RESULTS: After initiating ACTH treatment, urinary calcium (Ca)/creatinine ratio and urinary pH increased within 2 weeks. Urinary crystals and renal tubular epithelial cells (RTECs) in urinary sediment were frequently found in most cases. Urinary Ca levels, proteinuria or frequency of urinary crystals, and number of RTECs in the urinary sediment were significantly higher in patients with epithelial casts (ECs) or hematuria than in patients without these findings. Among the seven patients who underwent abdominal CT, ECs or hematuria were found only in those with renal calcified lesions. These findings suggested that patients with ECs or hematuria were more likely to have calcified lesions. CONCLUSIONS: The risk of renal calcified lesions increased after 2 weeks of ACTH treatment. Abnormal findings in urinary sediments might be an early sign of renal calcification during ACTH therapy.

DOI： 10.1111/ped.14158

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マルチターゲット療法で加療中、胃腸炎を機に急性腎障害に至った全身性エリテマトーデスの一例

宮原宏幸, 石井雅人, 茂原研司, 津下充, 八代将登, 塚原宏一

日本小児腎臓病学会雑誌 33 ( 1 ) 106 - 106 2020.4

Hemophagocytic lymphohistiocytosis complicating invasive pneumococcal disease: a pediatric case report. Reviewed International journal

Mitsuru Tsuge, Machiko Miyamoto, Reiji Miyawaki, Yoichi Kondo, Hirokazu Tsukahara

BMC pediatrics 20 ( 1 ) 15 - 15 2020.1

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

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is an infrequent but life-threatening disease due to excessive immune activation. Secondary HLH can be triggered by infections, autoimmune diseases, and malignant diseases. Streptococcus pneumoniae is a pathogenic bacterium responsible for invasive pneumococcal disease (IPD) such as meningitis and bacteremia. Although the pneumococcal conjugate vaccine (PCV) has led to reductions in IPD incidence, cases of IPD caused by serotypes not included in PCV are increasing. There are few reports of secondary HLH caused by IPD in previously healthy children. We herein report a rare case of a previously healthy boy with secondary HLH complicating IPD of serotype 23A, which is not included in the pneumococcal 13-valent conjugate vaccine (PCV-13). CASE PRESENTATION: An 11-month-old boy who had received three doses of PCV-13 was hospitalized with prolonged fever, bilateral otitis media, neutropenia and elevated C-reactive protein (CRP) levels. Blood culture on admission revealed S. pneumoniae, leading to a diagnosis of IPD. HLH was diagnosed based on a prolonged fever, neutropenia, anemia, hepatosplenomegaly, hemophagocytosis in the bone marrow, and elevated serum levels of triglycerides, ferritin, and soluble interleukin-2 receptor. He received broad-spectrum antibiotics and intravenous immunoglobulins for IPD and high-dose steroid pulse therapy and cyclosporine A for HLH; thereafter, his fever resolved, and laboratory findings improved. The serotype of the isolated S. pneumoniae was 23A, which is not included in PCV-13. CONCLUSIONS: It is important to consider secondary HLH as a complication of IPD cases with febrile cytopenia or hepatosplenomegaly, and appropriate treatment for HLH should be started without delay.

DOI： 10.1186/s12887-020-1915-7

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Breastfeeding and risk of food allergy: A nationwide birth cohort in Japan. Reviewed International journal

Naomi Matsumoto, Takashi Yorifuji, Kazue Nakamura, Masanori Ikeda, Hirokazu Tsukahara, Hiroyuki Doi

Allergology international : official journal of the Japanese Society of Allergology 69 ( 1 ) 91 - 97 2020.1

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

BACKGROUND: Although breastfeeding has been well-established as the preferred method for infant nutrition, its prophylactic effects on food allergy remain controversial. Infantile eczema has been linked to food allergy via percutaneous sensitization; however, this relationship has not been considered in previous studies. We aimed to uncover the prophylactic effects of breastfeeding on food allergy, focusing on eczema-mediated percutaneous sensitization. METHODS: This retrospective cohort study was based on 46,616 children from the Longitudinal Survey of Newborns in the 21st Century in Japan, begun in 2001. We classified participants into three groups based on infant feeding practices (exclusive breastfeeding, partial breastfeeding including only colostrum, and formula feeding only) and used information from at least one outpatient visit for food allergy during two observation periods (age 6-18 months and age 6-66 months) as health outcomes. We performed log-binomial regression analysis adjusted for potential confounders and stratified analysis according to infantile eczema status. RESULTS: Compared with formula feeding, partial breastfeeding including only colostrum reduced the risk of food allergy only in children with infantile eczema, (RR = 0.66, 95% CI: 0.46, 0.96 for age 6-66 months), whereas exclusive breastfeeding increased this risk in those without infantile eczema (RR = 2.41, 95% CI: 1.40, 4.15, age 6-66 months). The prophylactic effects of breastfeeding on food allergy in the infantile eczema group increased with shorter breastfeeding duration. CONCLUSIONS: Our results showed that breastfeeding, especially colostrum, had prophylactic effects on food allergy only among high-risk children with infantile eczema whereas prolonged breastfeeding increased the risk of food allergy.

DOI： 10.1016/j.alit.2019.08.007

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Lupus anticoagulant-hypoprothrombinemia syndrome and immunoglobulin-A vasculitis: a report of Japanese sibling cases and review of the literature. Reviewed International journal

Kaori Fujiwara, Junya Shimizu, Hirokazu Tsukahara, Akira Shimada

Rheumatology international 39 ( 10 ) 1811 - 1819 2019.10

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

Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare bleeding disorder caused by antiprothrombin antibodies. LAHPS is associated with systemic lupus erythematosus (SLE) or infections. We describe two Japanese brothers with immunoglobulin-A vasculitis (IgAV) who met the diagnostic criteria of LAHPS. They presented with palpable purpura and abdominal pain, and had a prolonged activated partial thromboplastin time (APTT) and prothrombin deficiency with the presence of lupus anticoagulant. Pediatric LAHPS was reviewed in abstracts from the Japan Medical Abstracts Society that were written in Japanese and PubMed or Web of Science-listed articles in English between 1996 and 2019. Including our cases, pediatric LAHPS has been reported in 40 Japanese and 46 non-Japanese patients. We summarized the clinical and laboratory characteristics of all 86 cases, and found only one Japanese LAHPS case with IgAV, except for our cases. Of the 86 cases, most were associated with infections followed by SLE. The presence of SLE, older age, lower prothrombin levels, severe bleeding symptoms, and positivity of immunoglobulin G anticardiolipin antibodies and anticardiolipin/β2-glycoprotein I antibodies and/or β2-glycoprotein I-dependent anticardiolipin antibodies had higher odds of requiring treatment. Measuring the APTT and prothrombin time (PT) might be required in patients with IgAV when they do not have a typical clinical course or distinctive symptoms. LAHPS should be considered with prolongation of the APTT and/or PT. Additionally, it is important to maintain a balance between the risk of thrombosis and hemorrhage when normalization of the PT and FII levels occurs in LAHPS cases under treatment.

DOI： 10.1007/s00296-019-04404-7

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Clinical outcomes after the endovascular treatments of pulmonary vein stenosis in patients with congenital heart disease. International journal

Yoshihiko Kurita, Kenji Baba, Maiko Kondo, Takahiro Eitoku, Shingo Kasahara, Tatsuo Iwasaki, Shinichi Ohtsuki, Hirokazu Tsukahara

Cardiology in the young 29 ( 8 ) 1057 - 1065 2019.8

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

BACKGROUND: Pulmonary vein stenosis (PVS) is a condition with challenging treatment and leads to severe cardiac failure and pulmonary hypertension. Despite aggressive surgical or catheter-based intervention, the prognosis of PVS is unsatisfactory. This study aimed to assess the prognosis and to establish appropriate treatment strategies. METHODS: We retrospectively reviewed endovascular treatments for PVS (2001-2017) from the clinical database at the Okayama University Hospital. RESULTS: A total of 24 patients underwent PVS associated with total anomalous pulmonary venous connection and 7 patients underwent isolated congenital PVS. In total, 53 stenotic pulmonary veins were subjected to endovascular treatments; 40 of them were stented by hybrid (29) and percutaneous procedures (11) (bare-metal stent, n = 34; drug-eluting stent, n = 9). Stent size of hybrid stenting was larger than percutaneous stenting. Median follow-up duration from the onset of PVS was 24 months (4-134 months). Survival rate was 71 and 49% at 1 and 5 years, respectively. There was no statistically significant difference between stent placement and survival; however, patients who underwent bare-metal stent implantation had statistically better survival than those who underwent drug-eluting stent implantation or balloon angioplasty. Early onset of stenosis, timing of stenting, and small vessel diameter of pulmonary vein before stenting were considered as risk factors for in-stent restenosis. Freedom from re-intervention was 50 and 26% at 1 and 2 years. CONCLUSIONS: To improve survival and stent patency, implantation of large stent is important. However, re-intervention after stenting is also significant to obtain good outcome.

DOI： 10.1017/S1047951119001495

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Neonatal hemochromatosis associated with rupture of esophageal varices. Reviewed International journal

Kazuki Hatayama, Yosuke Washio, Tomoka Okamura, Takuo Noda, Hirokazu Tsukahara

Pediatrics international : official journal of the Japan Pediatric Society 61 ( 7 ) 735 - 737 2019.7

食道静脈瘤破裂を来した新生児ヘモクロマトーシスの一例

岡村朋香, 吉本順子, 鷲尾洋介, 塚原宏一, 谷和祐, 野田卓男

日本周産期・新生児医学会雑誌 55 ( 2 ) 598 - 598 2019.6

Balloon atrial septostomy in hypoplastic left heart syndrome with restrictive atrial septum. Reviewed International journal

Yosuke Fukushima, Kenji Baba, Maiko Kondo, Yoshihiko Kurita, Takahiro Eitoku, Yusuke Shigemitsu, Kenta Hirai, Hirokazu Tsukahara, Tatsuo Iwasaki, Shingo Kasahara, Yasuhiro Kotani, Shinichi Otsuki

Pediatrics international : official journal of the Japan Pediatric Society 61 ( 4 ) 339 - 344 2019.4

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

BACKGROUND: Rashkind balloon atrial septostomy (BAS) can be challenging in infants with hypoplastic left heart syndrome (HLHS) and small atrial septal defect (ASD). METHODS: We retrospectively reviewed all infants with HLHS who underwent surgery and BAS between January 2006 and December 2015. The infants were divided into three groups: no BAS; catheter BAS; and open AS. Infants who underwent catheter BAS were divided into two groups based on atrial septal anatomy: standard and complex. RESULTS: Of the 70 patients, 57 (81%) underwent Glenn surgery. Subsequently, a significant difference in survival was observed: 86% (44/51), 91% (10/11), and 25% (2/8) in the no BAS, catheter BAS, and open AS groups, respectively (P = 0.0002). No significant difference was seen between the no BAS and the catheter BAS groups (P = 1.0). In the 56 patients who underwent catheterization after surgery, no intergroup differences in mean pulmonary artery pressure, pulmonary vascular resistance, or pulmonary artery index were found. We classified catheter BAS into standard (n = 5) and complex (n = 5) based on ASD location, and septum thickness. All patients in the standard group underwent complete Rashkind BAS, but in the complex group, only one patient underwent complete Rashkind BAS, with the remaining requiring initial static BAS (P = 0.048). Following septostomy, ASD size, ASD flow, and percutaneous oxygen saturation (SpO2 ) were not significantly different between the two groups. CONCLUSIONS: Catheter BAS is effective in infants with HLHS and a restrictive atrial septum. Infants with standard or complex atrial septum can achieve equivalent outcomes despite more patients often requiring static BAS.

DOI： 10.1111/ped.13716

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Exchange Transfusion and Cytarabine for Transient Abnormal Myelopoiesis in Hydrops Fetalis. Reviewed

Tomoka Okamura, Yousuke Washio, Junko Yoshimoto, Kazumasa Tani, Hirokazu Tsukahara, Akira Shimada

Acta medica Okayama 73 ( 2 ) 181 - 188 2019.4

Language：English

Most cases of transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) resolve spontaneously; however, DS-TAM neonates with hydrops fetalis (HF) show poor clinical outcomes. We report three infants with DS-TAM and HF who were treated with exchange transfusion (ET) followed by low-dose cytarabine (LD-CA). All of them survived without developing liver failure, acute leukemia, or other serious adverse events. Our results suggest that this combination treatment with ET and LD-CA would be safe, tolerable and effective as an novel approach for DS-TAM patients with HF.

DOI： 10.18926/AMO/56655

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Early childhood exposure to maternal smoking and Kawasaki Disease: A longitudinal survey in Japan. Reviewed International journal

Takashi Yorifuji, Hirokazu Tsukahara, Hiroyuki Doi

The Science of the total environment 655 141 - 146 2019.3

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

Kawasaki disease is the leading cause of acquired childhood heart disease in most developed countries, but the etiology of the disease is unknown. An aberrant immune response to some environmental triggers may play a role and involuntary exposure to tobacco smoke can alter immune functions. We thus prospectively examined the association between early childhood exposure to maternal smoking and the incidence of Kawasaki disease. We used a large, nationwide population-based longitudinal survey ongoing since 2010 and restricted participants to a total of 38,444 children for whom information on maternal smoking was available. Maternal smoking status was ascertained at 6months of age, and responses to questions about hospital admission for Kawasaki disease between the ages of 6 and 30months were used as outcome. We conducted binomial log-linear regression analyses adjusting for children's, parental, and residential factors with children of non-smoking mothers as our reference group. Maternal smoking increased the risk of admission, in particular for the period between 6 and 18months of age, in a dose-dependent manner. Compared with children of non-smoking mothers, the children of mothers who smoked had a risk ratio of 1.83 (95% confidence interval: 1.06, 3.35) for hospital admissions between 6 and 30months of age and a risk ratio of 2.69 (95% confidence interval: 1.56, 4.64) for hospital admissions between 6 and 18months of age. Early childhood exposure to maternal smoking may increase the risk of Kawasaki disease hospitalizations in childhood.

DOI： 10.1016/j.scitotenv.2018.11.194

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Panel-based next-generation sequencing identifies prognostic and actionable genes in childhood acute lymphoblastic leukemia and is suitable for clinical sequencing. Reviewed International journal

Hisashi Ishida, Akihiro Iguchi, Michinori Aoe, Takahide Takahashi, Kosuke Tamefusa, Kiichiro Kanamitsu, Kaori Fujiwara, Kana Washio, Takehiro Matsubara, Hirokazu Tsukahara, Masashi Sanada, Akira Shimada

Annals of hematology 98 ( 3 ) 657 - 668 2019.3

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

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although the cure rate of ALL has greatly improved, a considerable number of patients suffer from relapse of leukemia. Therefore, ALL remains the leading cause of death from cancer during childhood. To improve the cure rate of these patients, precisely detecting patients with high risk of relapse and incorporating new targeted therapies are urgently needed. This study investigated inexpensive, rapid, next-generation sequencing of more than 150 cancer-related genes for matched diagnostic, remission, and relapse samples of 17 patients (3 months to 15 years old) with relapsed ALL. In this analysis, we identified 16 single-nucleotide variants (SNVs) and insertion/deletion variants and 19 copy number variants (CNVs) at diagnosis and 28 SNVs and insertion/deletion variants and 22 CNVs at relapse. With these genetic alterations, we could detect several B cell precursor ALL patients with high-risk gene alterations who were not stratified into the highest-risk group (5/8, 62.5%). We also detected potentially actionable genetic variants in about half of the patients (8/17, 47.1%). Among them, we found that one patient harbored germline TP53 mutation as a secondary finding. This inexpensive, rapid method can be immediately applied as clinical sequencing and could lead to better management of these patients and potential improvement in the survival rate in childhood ALL.

DOI： 10.1007/s00277-018-3554-8

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Population-based longitudinal study showed that children born small for gestational age faced a higher risk of hospitalisation during early childhood. Reviewed International journal

Junko Yoshimoto, Takashi Yorifuji, Yosuke Washio, Tomoka Okamura, Hirokazu Watanabe, Hiroyuki Doi, Hirokazu Tsukahara

Acta paediatrica (Oslo, Norway : 1992) 108 ( 3 ) 473 - 478 2019.3

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

AIM: We examined the effects of being born small for gestational age (SGA) on the risk of being hospitalised for common diseases during childhood. METHODS: This Japanese nationwide, population-based longitudinal survey followed babies born before 42 weeks of gestation from 10 to 17 January and from 10 to 17 July 2001, using data from the Government's Longitudinal Survey of Babies in the 21st Century. Our study followed 41 268 children until 5.5 years of age: 39 107 full term (8.7% SGA) and 2161 preterm (15.5% SGA). We evaluated the relationship between SGA status and hospitalisation using their history of hospitalisation for common diseases and comparing full-term or preterm births. Logistic regression analysis, adjusted for potential confounders, estimated the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The full-term and preterm children who were born SGA were more likely to be hospitalised during infancy and early childhood than those born non SGA. The ORs for hospitalisation from six months to 18 months of age were 1.23 (95% CI: 1.10-1.37) for full-term and 1.67 (95% CI: 1.23-2.25) for preterm subjects. Higher risks of hospitalisation due to bronchitis, pneumonia, bronchial asthma and diarrhoea were also observed. CONCLUSION: Being born SGA was associated with all-cause and cause-specific hospitalisation in early childhood, particularly for term infants.

DOI： 10.1111/apa.14507

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Combined effect of anti-high-mobility group box-1 monoclonal antibody and peramivir against influenza A virus-induced pneumonia in mice. Reviewed International journal

Kazuki Hatayama, Nobuyuki Nosaka, Mutsuko Yamada, Masato Yashiro, Yosuke Fujii, Hirokazu Tsukahara, Keyue Liu, Masahiro Nishibori, Akihiro Matsukawa, Tsuneo Morishima

Journal of medical virology 91 ( 3 ) 361 - 369 2019.3

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

Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury due to the excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti-inflammatory effect of anti-high-mobility group box-1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti-HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine-week-old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post-infection (dpi). The anti-HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi. The combination of peramivir with the anti-HMGB1 mAb significantly improved survival rate whereas the anti-HMGB1 mAb alone did not affect virus proliferation in the lungs. This combination therapy also significantly ameliorated histopathological changes, neutrophil infiltration, and macrophage aggregation by inhibiting HMGB1, inflammatory cytokines, and oxidative stress. Fluorescence immunostaining showed that the anti-HMGB1 mAb inhibited HMGB1 translocation from type I alveolar epithelial cells. In summary, combining anti-HMGB1 with conventional anti-influenza therapy might be useful against severe influenza virus infection.

DOI： 10.1002/jmv.25330

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個人情報保護法の改訂における当院の取り組み

木口隆, 宮村純子, 草野展周, 塚原宏一

日本環境感染学会総会プログラム・抄録集 34回 [P - 556] 2019.2

当院における播種性帯状疱疹の感染防止策

宮村純子, 木口隆, 草野展周, 八代将登, 塚原宏一

日本環境感染学会総会プログラム・抄録集 34回 [P - 127] 2019.2

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Papers - TSUKAHARA Hirokazu