Publications by authors named "Shinsaku Imashuku"

179 Publications

Hyperhomocysteinemia-related lung disease and hemolytic anemia with bone marrow features masquerading as myelodysplasia.

Am J Blood Res 2021 15;11(3):266-270. Epub 2021 Jun 15.

Department of Laboratory Medicine, Uji-Tokushukai Medical Center Uji, Kyoto, Japan.

Hyperhomocysteinemia is linked to TMA-related clinical symptoms such as apparent thromboembolism, microangiopathic hemolytic anemia (MAHA), and various types of end-organ damage due to microvascular thrombi; this is because high plasma levels of homocysteine impair the vascular endothelium. However, the association between hyperhomocysteinemia and pulmonary involvement is unclear. Here, we describe a 63-year-old male who was hospitalized with respiratory failure and MAHA with MDS-like features in the bone marrow. Plasma homocysteine levels were elevated significantly with 199.4 µmol/L (reference: 6.3-18.9) due to a homozygous (T/T) polymorphism for the 677C>T mutation within the gene associated with chronic alcoholism-induced folate deficiency. Pulmonary lesions showed ground-glass opacity and there was pleural effusion. The patient was managed successfully with a combination of folate/mecobalamin supplementation, plasma exchange, and a methylprednisolone pulse, followed by oral prednisolone. Clinical symptoms, lung disease, MAHA, and bone marrow abnormalities improved as plasma homocysteine levels normalized.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303007PMC
June 2021

Virus-triggered secondary hemophagocytic lymphohistiocytosis.

Acta Paediatr 2021 Jun 7. Epub 2021 Jun 7.

Director, Imabari City Hospital, Imabari, Ehime, Japan.

Primary (familial/hereditary) and secondary (non-familial/hereditary) hemophagocytic lymphohistiocytosis (HLH) are hyperinflammatory and hypercytokinemic syndromes. Secondary HLH includes infection- (eg viral/bacterial/fungal/parasitic) and non-infection- (eg collagen disease or malignancy) related diseases. Viral HLH is the major type among all age groups. Secondary viral HLH and primary HLH must be differentiated carefully because primary HLH can be associated with viral infection(s), and the outcome is dismal without a timely diagnosis and hematopoietic stem cell transplantation (HSCT). Epstein-Barr virus (EBV)-related HLH (EBV-HLH) is the most common type of viral HLH in childhood. For non-EBV-HLH, appropriate treatment of viral infection, followed by immunomodulatory agent(s) such as corticosteroids, intravenous immunoglobulin or cyclosporine A, is usually successful; however, recent SARS-CoV-2-related HLH may become life-threatening. EBV-HLH may occur heterogeneously associated with the primary infection, with chronic active EBV infection or with underlying primary HLH. Although immunomodulatory agent(s) are effective in the majority of EBV-HLH cases, management differs from that of non-EBV-HLH because severe and refractory cases may require etoposide-containing HLH-1994/2004 regimens or other experimental agents. The novel agent, emapalumab (an anti-IFN-γ monoclonal antibody) can be used to treat EBV-HLH cases to avoid the risk of secondary malignancy due to etoposide. Finally, HSCT is required for refractory EBV-HLH cases and can also be curative in some other cases.
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http://dx.doi.org/10.1111/apa.15973DOI Listing
June 2021

Protein C Gene Mutation in an Older Adult Patient with Septicemia-Related Visceral Vein Thrombosis.

TH Open 2021 Apr 26;5(2):e171-e173. Epub 2021 May 26.

Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji, Japan.

A 78-year-old Japanese male with septicemia and cholecystitis was found to have thrombosis in the left branch of intrahepatic portal vein as well as superior mesenteric vein. Visceral vein thrombosis (VVT) in this case was associated with protein C deficiency, due to a heterozygous mutation, p. Arg185Met. Our experience emphasizes that VVT, or other thromboembolic events, may occur in later life, triggered by environmental thrombosis risk factors, together with underlying hereditary protein C gene mutation.
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http://dx.doi.org/10.1055/s-0041-1728664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154515PMC
April 2021

Congenital Hypofibrinogenemia in a Neonate with a Novel Mutation in the Gene.

Pediatr Rep 2021 Mar 1;13(1):113-117. Epub 2021 Mar 1.

Uji-Tokushukai Medical Center, Department of Pediatrics, Uji, Kyoto 611-0041, Japan.

Detection of severe hypofibrinogenemia (<50 mg/dL) in a neonate soon after birth is alarming because of the risk of hemorrhage. A female neonate was noted to be hypofibrinogenemic (<50 mg/dL) on day 0 of birth; she showed no thrombocytopenia/coagulopathy or hemorrhagic symptoms. Considering the possibility of afibrinogenemia, which may cause bleeding, fresh frozen plasma (FFP) was initiated twice a week to maintain her plasma fibrinogen level at 50-100 mg/dL. Thereafter, we found hypofibrinogenemia in her father and elder sister and plasma fibrinogen levels, determined by clot formation and immunological methods, showed similarly reduced values in both the neonate (proband) and her father. Based on a presumed diagnosis of congenital hypofibrinogenemia, sequencing of the fibrinogen genes was performed, revealing a novel heterozygous mutation of (Genbank NG008833); a p.403Try>Stop. The neonate was treated with repeat FFP infusions until two months of age, when treatment was stopped because she remained asymptomatic.
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http://dx.doi.org/10.3390/pediatric13010016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930968PMC
March 2021

Pentasomy 21 in an older adult case of AML with myelodysplastic changes.

Int J Lab Hematol 2021 06 25;43(3):e122-e123. Epub 2020 Nov 25.

Division of Hematology, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan.

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http://dx.doi.org/10.1111/ijlh.13410DOI Listing
June 2021

Long-term complications in uniformly treated paediatric Langerhans histiocytosis patients disclosed by 12 years of follow-up of the JLSG-96/02 studies.

Br J Haematol 2021 02 25;192(3):615-620. Epub 2020 Nov 25.

Division of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji, Japan.

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia derived from immature myeloid dendritic cells with the mitogen-activated protein kinase (MAPK) pathway gene mutation. LCH is rarely fatal, but patients develop various permanent consequences (PCs). We report the frequencies of LCH-related PCs in paediatric patients (n = 317) treated by the JLSG-96/02 AraC-containing regimens. One-third of LCH patients had at least one PC at a median follow-up of 12 years. Central nervous system (CNS)-related PCs (neurological and endocrinological) accounted for 21·5%, non-CNS-related 16·7%. We require novel therapeutic measures to further reduce the frequency of LCH-related PCs.
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http://dx.doi.org/10.1111/bjh.17243DOI Listing
February 2021

Difficulty in controlling heavy menstrual bleeding at menarche in a patient with Glanzmann's thrombasthenia.

Blood Coagul Fibrinolysis 2021 Mar;32(2):155-158

Department of Pediatrics.

Glanzmann's thrombasthenia is a rare inherited autosomal recessive bleeding disorder caused by platelet dysfunction. Adolescent girls with Glanzmann's thrombasthenia may experience problematic heavy menstrual bleeding beginning at menarche; this can be difficult to manage. Here, we report the case of an 11-year-old girl with Glanzmann's thrombasthenia who presented with heavy menstrual bleeding at menarche, which was difficult to control. The vaginal bleeding persisted and did not respond to a treatment with packed red blood cells (16 U total), platelet concentrates (70 U total), or administration (>50 doses) of recombinant activated factor VII (rFVIIa). Eventually, a combination of rFVIIa and hormonal therapy (a combined oral contraceptive pill) was introduced. The bleeding stopped at nearly 1 month from onset of menarche. Thereafter, the condition was managed by monthly subcutaneous administration of a GnRH agonist. Management of severe menorrhagia in adolescent patients with Glanzmann's thrombasthenia requires close collaboration with gynecologists or adolescent medicine specialists. More clinical studies are required to identify an effective combination of rFVIIa and hormonal therapy for this condition.
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http://dx.doi.org/10.1097/MBC.0000000000000977DOI Listing
March 2021

Analysis of the BRAF and MAP2K1 mutations in patients with Langerhans cell histiocytosis in Japan.

Int J Hematol 2020 Oct 11;112(4):560-567. Epub 2020 Jul 11.

Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.

In Langerhans cell histiocytosis (LCH), somatic gene mutations in the mitogen-activated protein kinase pathway have been identified in more than 80% of cases in Western countries, in which mutually exclusive BRAF and MAP2K1 mutations are involved. Among them, BRAF V600E mutation is the major contributor (50-60%). In 59 patients (50 children and nine adults) with LCH (not including pulmonary LCH) in Japan, we first screened for BRAF V600E in all patients followed by target sequencing for other gene mutations in 17 of BRAF V600E-negative patients. As a result, BRAF V600E mutation was detected in 27/59 (46%) patients. We also identified BRAF mutations other than V600E in five and MAP2K1 mutations in nine patients. Thus, gene mutations in BRAF or MAP2K1 were identified in 41/44 (93%) of the fully tested patients. Regarding the correlation of clinical features and genotype in pediatric patients, we found that BRAF V600E mutation status was not correlated with sex, age at diagnosis, disease extent, response to first-line therapy, relapse, or CNS-related sequelae. Interestingly, MAP2K1 exon 2 in-frame deletion was related to the risk organ involvement; however, further studies are required to clarify the impact of these gene mutations on the clinical features of patients with LCH.
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http://dx.doi.org/10.1007/s12185-020-02940-8DOI Listing
October 2020

[Successful unrelated cord blood transplantation for extensive meningeal juvenile xanthogranuloma developing after treatment of Langerhans cell histiocytosis in a child].

Rinsho Ketsueki 2020 ;61(5):468-473

Department of Laboratory Medicine, Uji-Tokushukai Medical Center.

A 2-year and 4-month-old boy developed Langerhans cell histiocytosis (LCH) at the left parietal region of the skull. After treatment with chemotherapy, the patient achieved remission but experienced three relapses. After 3 years, he complained of headache, blurred vision, and lethargy. Brain magnetic resonance imaging revealed multiple dura-based meningeal masses. Biopsy was performed, and the patient was then diagnosed with juvenile xanthogranuloma (JXG). The analysis of both LCH/JXG tissues revealed BRAF V600E mutation. The JXG masses were not responsive to prednisolone, which was injected locally, radiotherapy (24 Gy), and chemotherapy (2-chlorodeoxy-adenosine). In addition, since the patient developed macrophage activation syndrome associated with systemic JXG progression, he received unrelated cord blood transplantation (u-CBT) at the age of 10 years and 11 months. Engraftment was performed at day 42, and significant GVHD was not observed. Four months after CBT, the patient was treated with infliximab (Remicade) and dexamethasone palmitate (Limethasone). The size of the intracranial JXG masses gradually decreased after u-CBT and disappeared after 4 years. Currently, the patient is doing well at the age of 25 years and is receiving androgen replacement therapy.
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http://dx.doi.org/10.11406/rinketsu.61.468DOI Listing
August 2020

Rivaroxaban-Related Traumatic Large Subcutaneous Hematoma in the Calf Requiring Surgical Repair in an Elderly Patient.

TH Open 2020 Apr 10;4(2):e104-e106. Epub 2020 May 10.

Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan.

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http://dx.doi.org/10.1055/s-0040-1710359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211503PMC
April 2020

Natural history of epithelioid hemangioendothelioma that progressed over 20 years.

Pediatr Blood Cancer 2020 06 19;67(6):e28261. Epub 2020 Apr 19.

Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Okayama, Japan.

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http://dx.doi.org/10.1002/pbc.28261DOI Listing
June 2020

Venous thromboembolism associated with hyperhomocysteinemia, homozygosity for the methylenetetrahydrofolate reductase 677C>T gene variant, and secondary polycythemia.

Blood Coagul Fibrinolysis 2020 Jun;31(4):270-273

Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan.

: The development of pulmonary embolism/deep vein thrombosis (DVT) in the extremities is influenced by various risk factors. Hyperhomocysteinemia is one such risk factor, which may be associated with vitamin B12/folate deficiency, or the methylenetetrahydrofolate reductase gene variant, 677C>T. Here, we report a 47-year-old male who developed pulmonary embolism/DVT, associated with hyperhomocysteinemia (plasma homocysteine: 71.9 nmol/ml; reference range: 6.3-18.9 nmol/ml) and was homozygous (T/T) for the methylenetetrahydrofolate reductase variant. Serum levels of vitamin B12 and folate were within the normal range, while secondary polycythemia (hemoglobin: 18.2 g/dl and hematocrit: 50.8%) may have acted as an additional trigger for the thromboembolism. The pulmonary embolism/DVT was successfully managed and the patient has been doing well for longer than 3 years.
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http://dx.doi.org/10.1097/MBC.0000000000000897DOI Listing
June 2020

A Rare Combination of Gastric Mucosa-associated Lymphoid Tissue Lymphoma, Autoimmune Gastritis, Thyroiditis, Hemolysis, and Systemic Lupus Erythematosus.

Intern Med 2020 1;59(1):61-65. Epub 2020 Jan 1.

Department of General Medicine, JCHO Shiga Hospital, Japan.

We herein report a case with the rare combination of mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) of the stomach, autoimmune gastritis (AIG), autoimmune thyroiditis, autoimmune hemolytic anemia (AIHA), and systemic lupus erythematosus. A 68-year-old woman was diagnosed with gastric MALT lymphoma associated with Helicobacter pylori (H. pylori) infection and AIG. Complete remission of the MALT lymphoma was achieved by H. pylori eradication and radiotherapy. Three years after the diagnosis of MALT lymphoma, the patient developed AIHA and anti-nuclear and anti-Smith autoantibody-positive lupus serositis, which were successfully managed with prednisolone administration.
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http://dx.doi.org/10.2169/internalmedicine.3191-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995723PMC
March 2020

CD4-/CD8+ adult T-cell leukemia/lymphoma with unusual morphology presenting as ascites and pleural effusion.

Int J Lab Hematol 2020 06 10;42(3):e105-e106. Epub 2019 Dec 10.

Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan.

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http://dx.doi.org/10.1111/ijlh.13139DOI Listing
June 2020

Nationwide retrospective review of hematopoietic stem cell transplantation in children with refractory Langerhans cell histiocytosis.

Int J Hematol 2020 Jan 22;111(1):137-148. Epub 2019 Nov 22.

Department of Pediatrics, Jichi Medical University of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.

The efficacy of and indications for hematopoietic stem cell transplantation (HSCT) in pediatric Langerhans cell histiocytosis (LCH) remain undetermined. This retrospective study analyzed 30 children with refractory LCH who underwent HSCT in Japan between 1996 and 2014. Eleven patients received a myeloablative conditioning (MAC) regimen, while 19 patients received a reduced-intensity conditioning (RIC) regimen. Among the 26 patients with complete data, 23 patients had risk organ (RO) involvement during clinical course. Disease status at HSCT was no active disease (NAD) (4), active disease-regression (AD-r) (2), active disease-stable (AD-s) (4), and active disease-progressive (AD-p) (16). Seventeen of the 30 patients (57%) were alive with a median follow-up of 433 days (range 9-5307) after HSCT. Death occurred within 3 months after HSCT in eight of 13 patients. RIC and MAC patients were similar in both overall survival (OS) (56.8% vs. 63.6%, respectively, p = 0.789) and failure-free survival (56.8% vs. 54.6%, respectively, p = 0.938). Regarding disease status at HSCT, the six patients with NAD/AD-r experienced better outcomes than the 20 with AD-s/AD-p (5-year OS, 100% vs. 54.5%, respectively, p = 0.040). Disease state at the time of HSCT was the most important prognostic factor.
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http://dx.doi.org/10.1007/s12185-019-02760-5DOI Listing
January 2020

Acquired Factor V Deficiency Associated with CFPM Administration.

Clin Lab 2019 Oct;65(10)

Background: Acquired factor V deficiency (AFVD) caused by Factor V (FV) inhibition is a rare event, characterized by prolonged prothrombin time and activated partial thromboplastin time. To date, various factors were reported as triggers for developing FV inhibitor. Clinical symptoms range from asymptomatic to life-threatening bleeding. Case Report and Conclusions: Here, we report an 84-year-old Japanese male on hemodialysis due to renal failure who developed subcutaneous hemorrhage after administration of cefepime (CFPM) to treat bacteremia. Deficient FV activity (< 1.0%) was identified and AFVD with FV inhibitor titer of 9 BU/mL was diagnosed. Although the patient had multiple risks for developing FV inhibitor, CFPM was thought to be the major culprit in this case. After the diagnosis, oral prednisolone (30 mg/day) was initiated, but the patient died of respiratory/cardiac failure, unrelated to AFVD.
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http://dx.doi.org/10.7754/Clin.Lab.2019.190240DOI Listing
October 2019

Aortic Mural Thrombus Associated with Congenital Protein C Deficiency in an Elderly Patient.

J Atheroscler Thromb 2020 Jan 15;27(1):100-103. Epub 2019 May 15.

Department of Laboratory Medicine, Uji-Tokushukai Medical Center.

Thrombophilia increases the risk of venous thrombosis, but is rarely responsible for aortic thrombosis. Aortic mural thrombus (AMT) may be associated with a protein C deficiency. However, it is necessary to determine whether the protein C deficiency is congenital/hereditary or secondary/acquired (consumption of protein C during the process of thrombus formation). This study describes a 77-year-old Japanese woman with incidentally diagnosed AMT, who had a protein C deficiency (activity 54%, antigen 42%). Sequencing of the protein C gene revealed a heterozygous mutation of c.1268delG, p.Gly423Valfs82 in exon 9, indicating a congenital protein C deficiency. These findings indicate that very late onset AMT can occur in an adult with congenital protein C deficiency.
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http://dx.doi.org/10.5551/jat.48819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976720PMC
January 2020

Management of Chronic Disseminated Intravascular Coagulation Associated with Aortic Aneurysm/Dissection.

Case Rep Hematol 2019 2;2019:6204652. Epub 2019 Apr 2.

Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji 611-0041, Japan.

Disseminated intravascular coagulation (DIC) is a systemic life-threatening process that can cause thrombosis and hemorrhage. Chronic DIC has been associated with aortic aneurysm/dissection. Aortic aneurysm/dissection should be included in the differential diagnosis of elderly patients with hemorrhagic diathesis due to DIC of uncertain etiology. Treatment depends on various factors, including the severity of underlying disease, extent of DIC, and patient comorbidities, as well as the ability of the patient to maintain activities of daily living once discharged from the hospital. This report describes the clinical characteristics of four elderly patients with chronic DIC associated with aortic aneurysm/dissection who were treated in our institution. We also offer the recommendations around most appropriate nonsurgical treatment of these patients.
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http://dx.doi.org/10.1155/2019/6204652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466910PMC
April 2019

Fatal Invasive Cryptococcal Infection in an HIV-Negative Elderly Patient with Decompensated Hepatic Cirrhosis.

Case Reports Hepatol 2018 31;2018:5174518. Epub 2018 Dec 31.

Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji, 611-0042, Japan.

Diagnosis of invasive cryptococcal infection in apparently nonimmunocompromised patients is difficult and often delayed. Human immunodeficiency virus- (HIV-) negative patients with decompensated hepatic cirrhosis might be at high risk of cryptococcal infection. We report here an 82-year-old Japanese female with end-stage hepatic failure and undergoing renal dialysis, hospitalized with septic shock-like symptoms. The patient had had hepatitis B virus (HBV) infection in the past. She survived only 4 days following admission. During hospitalization, she was found to have pleural effusion and ascites. was obtained from blood culture but not from pleural effusion culture. Consequently, the patient was diagnosed as having invasive cryptococcosis in association with HBV-related hepatic cirrhosis. Unfortunately, the patient died prior to receiving antifungal agents. Twelve Japanese cases of hepatic cirrhosis-related invasive cryptococcal infection, consisting of previously described and this case, were summarized for discussion of the clinical features and outcomes.
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http://dx.doi.org/10.1155/2018/5174518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333006PMC
December 2018

Mesalazine-Induced Acute Focal Bacterial Nephritis-Like Features in Two Paediatric Patients with Ulcerative Colitis.

J Crohns Colitis 2019 07;13(7):958-959

Department of Pediatrics, Uji Tokushukai Medical Center, Uji, Kyoto, Japan.

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http://dx.doi.org/10.1093/ecco-jcc/jjy228DOI Listing
July 2019

Bacteremia and meningitis caused by a novel clone of Neisseria meningitidis serogroup B.

Pediatr Int 2018 Dec 11;60(12):1093-1094. Epub 2018 Dec 11.

Division of Pediatrics, Uji-Tokushukai Medical Center, Uji, Japan.

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http://dx.doi.org/10.1111/ped.13718DOI Listing
December 2018

Management of Acquired Hemophilia A in Elderly Patients.

Case Rep Hematol 2018 13;2018:6757345. Epub 2018 Nov 13.

Division of Hematology, Takasago-Seibu Hospital, Takasago 676-0812, Japan.

This report describes six elderly patients with acquired hemophilia A (AHA), including four individuals aged ≥90 years. Bleeding symptoms were subcutaneous or intramuscular hemorrhage (=4), hematuria (=1), and hemorrhagic shock after tooth extraction (=1). Factor VIII (FVIII) activity ranged from <1.0% to 3.0%, and anti-FVIII inhibitor titers ranged from 8.8 to 240 BU/mL. Treatment was administered at the discretion of the responsible physician. Hemostatic agents applied in the six patients comprised rFVIIa (NovoSeven®) (=4), APCC (Feiba®) (=2), and fresh frozen plasma/plasma exchange (=1). Agents employed for inhibitor eradication comprised prednisolone only (=3), prednisolone with cyclophosphamide (=1), prednisolone with cyclosporine (=1), and prednisolone with rituximab (=1). In five patients, management was successful, with complete response. Treatment failed in the patient with the highest inhibitor level (240 BU/mL) in whom treatment with APCC (Feiba®; 100 U/kg/dose, three doses) and prednisolone (0.5 mg/kg/day) was followed by several episodes of relapse. The present data demonstrate that AHA severity shows wide variation in elderly subjects, indicating the necessity of individualized management.
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http://dx.doi.org/10.1155/2018/6757345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260550PMC
November 2018

Splenic mass in a case of -mutated essential thrombocythemia.

Clin Case Rep 2018 Nov 9;6(11):2291-2292. Epub 2018 Oct 9.

Division of Pathology Uji-Tokushukai Medical Center Uji Kyoto Japan.

We report here an intrasplenic large mass in an elderly case of essential thrombocythemia (ET)-myelofibrosis. Laparoscopic splenectomy revealed extramedullary hematopoiesis (EMH) and a type 1 gene mutation (CALR-c.1092_1143del52) in the splenic mass. It remains to be determined if mutated ET has an increased tendency to develop mass-forming EMH.
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http://dx.doi.org/10.1002/ccr3.1857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230599PMC
November 2018

Central diabetes insipidus in pediatric patients with Langerhans cell histiocytosis: Results from the JLSG-96/02 studies.

Pediatr Blood Cancer 2019 01 11;66(1):e27454. Epub 2018 Sep 11.

Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Purpose: We analyzed central diabetes insipidus (CDI) development in pediatric patients with Langerhans cell histiocytosis (LCH) treated according to the Japan LCH Study Group (JLSG) regimen, which is the combination chemotherapy including cytarabine (Ara-C).

Methods: Retrospective data from 317 patients (multisystem disease (MS), n = 206; multiple focal bone (MFB), n = 111) treated according to the JLSG-96/02 regimens were analyzed.

Results: The median follow-up duration was 10.6 years (range, 0.1-21.1). A total of 50/317 (15.8%) patients developed CDI (MFB, n = 4; MS, n = 46). Of the 50 cases, CDI was already present at the time of LCH diagnosis (pre-CDI) in 25, and it newly developed after the diagnosis and initiation of treatment (post-CDI) in the other 25 cases. The cumulative incidence of post-CDI at 10-year calculated by Kaplan-Meier analysis was 9.0% for total and 12.0% for MS patients. A positive correlation with LCH lesions at the CNS risk sites at diagnosis was found in pre-CDI cases (17/164 vs 8/171; P = 0.0359), but not in post-CDI cases (14/129 vs 11/163; P = 0.254). Multivariate analysis showed that relapse at the CNS risk sites was significantly associated with post-CDI development (hazard ratio: 4.70; 95% CI, 1.29-17.1, P < 0.05).

Conclusions: In the JLSG-96/02 studies, CDI developed in 15.8% of the cohort in which half as pre- and the other half as post-CDI. Relapse, particularly at the CNS risk sites, was linked with the development of post-CDI.
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http://dx.doi.org/10.1002/pbc.27454DOI Listing
January 2019

KMT2A-rearranged infantile acute myeloid leukemia masquerading as juvenile myelomonocytic leukemia.

Int J Hematol 2018 Dec 24;108(6):665-669. Epub 2018 Aug 24.

Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Mixed lineage leukemia [MLL; now known as lysine methyltransferase 2A (KMT2A)] rearrangement-positive acute myeloid leukemia (AML) and juvenile myelomonocytic leukemia (JMML) are distinct diseases, although age of susceptibility (infancy or early childhood) and abnormal monocytosis are common clinical features. Here, we report two cases of KMT2A-rearranged infantile AML masquerading as JMML at initial presentation. Both cases showed leukocytosis accompanied by atypical monocytosis. However, in both cases, leukemic blasts were absent at the initial examination. Thus, a diagnosis of JMML was suspected. However, initial cytogenetic analysis revealed that both cases had an 11q23 rearrangement, which is atypical in JMML. Eventually, due to the emergence of leukemic blasts and further cytogenetic studies, both cases were diagnosed with infantile AML with a KMT2A rearrangement. Although one patient remains in complete remission after the completion of AML appropriate chemotherapy, the other died of AML due to treatment failure. Our experience suggests that AML with KMT2A rearrangement should be considered for the differential diagnosis of infantile cases with atypical monocytosis suggestive of JMML. Cytogenetic studies, including fluorescence in situ hybridization analysis of KMT2A, may be helpful in distinguishing between AML with KMT2A rearrangement and JMML.
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http://dx.doi.org/10.1007/s12185-018-2522-3DOI Listing
December 2018

Merkel cell polyomavirus and Langerhans cell neoplasm.

Cell Commun Signal 2018 08 22;16(1):49. Epub 2018 Aug 22.

AP-HP Hôpital Necker-Enfants Malades, University Paris Descartes (Paris 5), 75006, Paris, France.

Background: The relationship between various external agents such as pollen, food, and infectious agents and human sensitivity exists and is variable depending upon individual's health conditions. For example, we believe that the pathogenetic potential of the Merkel cell polyomavirus (MCPyV), the resident virus in skin, is variable and depends from the degree of individual's reactivity. MCPyV as well as Epstein-Barr virus, which are normally connected with humans under the form of subclinical infection, are thought to be involved at various degrees in several neoplastic and inflammatory diseases. In this review, we cover two types of Langerhans cell neoplasms, the Langerhans cell sarcoma (LCS) and Langerhans cell histiocytosis (LCH), represented as either neoplastic or inflammatory diseases caused by MCPyV.

Methods: We meta-analyzed both our previous analyses, composed of quantitative PCR for MCPyV-DNA, proteomics, immunohistochemistry which construct IL-17 endocrine model and interleukin-1 (IL-1) activation loop model, and other groups' data.

Results: We have shown that there were subgroups associated with the MCPyV as a causal agent in these two different neoplasms. Comparatively, LCS, distinct from the LCH, is a neoplastic lesion (or sarcoma) without presence of inflammatory granuloma frequently observed in the elderly. LCH is a proliferative disease of Langerhans-like abnormal cells which carry mutations of genes involved in the RAS/MAPK signaling pathway. We found that MCPyV may be involved in the development of LCH.

Conclusion: We hypothesized that a subgroup of LCS developed according the same mechanism involved in Merkel cell carcinoma pathogenesis. We proposed LCH developed from an inflammatory process that was sustained due to gene mutations. We hypothesized that MCPyV infection triggered an IL-1 activation loop that lies beneath the pathogenesis of LCH and propose a new triple-factor model.
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http://dx.doi.org/10.1186/s12964-018-0261-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103986PMC
August 2018

Plasmapheresis for Spur Cell Anemia in a Patient with Alcoholic Liver Cirrhosis.

Case Rep Hematol 2018 21;2018:9513946. Epub 2018 Jun 21.

Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji 611-0042, Japan.

Background: Spur cell anemia (SCA) is a cause of hemolytic anemia in patients with alcoholic liver cirrhosis. Because dyslipidemia is related to the development of spur cells, SCA was previously treated with plasmapheresis.

Case Report: A 52-year-old Japanese man with SCA associated with alcoholic liver cirrhosis (Child-Pugh C) underwent two rounds of plasmapheresis. Clinical features and serum lipid concentrations were compared before and after plasmapheresis. Although indirect hyperbilirubinemia and SCA persisted after plasmapheresis, reticulocyte counts significantly decreased from 22.4% to 4.5%, and Hb levels improved without red cell transfusions. Analysis of lipids showed that total and free cholesterol, HDL cholesterol, phospholipid, and apo-AI concentrations, all of which were reduced before plasmapheresis, had improved after treatment, while LDL cholesterol, lipoprotein (a), and apo-AII concentrations, which were also reduced before plasmapheresis, remained unchanged.

Conclusions: Despite plasmapheresis partially ameliorating the degree of hemolysis, the persistence of SCA may have been linked with the lack of improvement in certain types of lipid metabolism.
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http://dx.doi.org/10.1155/2018/9513946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033239PMC
June 2018

Thrombotic Microangiopathy-Like Hemolysis in Vitamin B12 Deficiency-Related Macrocytic Anemia.

Clin Lab 2018 Apr;64(4):639-643

Background: Hemolytic features in patients with pernicious anemia have not been emphasized.

Methods: Seven Japanese patients at 60 - 88 years of age with vitamin B12 deficiency-related hemolytic anemia were assessed.

Results: Serum vitamin B12 levels in these cases were 46 - 89 pg/mL (normal reference range: 233 - 914 pg/mL). Clinically, the patients presented with thrombotic microangiopathy (TMA)-like hemolytic features (including macrocytic anemia, schistocytes on blood smears, high serum lactate dehydrogenase, hyperbilirubinemia, and low serum haptoglobin). Six cases had type A gastritis (assessed by esophagogastroduodenoscopy with hypergastrinemia) with additional laboratory data of high plasma homocysteine levels and anti-intrinsic factor/anti-parietal cell antibodies. One case was in post-gastrectomy condition. Following treatment with vitamin B12, anemia resolved within 4 weeks in five of the seven cases except for two cases of delayed response.

Conclusions: In elderly patients exhibiting hemolytic features in association with macrocytic anemia, vitamin B12 deficiency should be considered in the differential diagnosis.
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http://dx.doi.org/10.7754/Clin.Lab.2017.171138DOI Listing
April 2018

Acute encephalopathy with biphasic seizures and late reduced diffusion associated with sepsis.

Pediatr Rep 2018 Mar 29;10(1):7424. Epub 2018 Mar 29.

Division of Pediatrics, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) develops in association with systemic as well as central nervous system (CNS) viral or bacterial infections. AESD is most often noted with influenza or human herpesvirus 6 infection in previously healthy infants. However, AESD has also been reported in an infant with developmental retardation and in a mentally and motor-disabled adolescent. Here, we report the case of a 4- year-old female with significant development delay due to spinal muscular atrophy, who developed AESD during sepsis with no apparent CNS infection. Although the patient had extremely high serum procalcitonin (45.84 ng/mL, reference; <0.4) on admission indicating a poor prognosis, she was successfully managed for sepsis and AESD.
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http://dx.doi.org/10.4081/pr.2018.7424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907728PMC
March 2018

Intensification of induction therapy and prolongation of maintenance therapy did not improve the outcome of pediatric Langerhans cell histiocytosis with single-system multifocal bone lesions: results of the Japan Langerhans Cell Histiocytosis Study Group-02 Protocol Study.

Int J Hematol 2018 Aug 28;108(2):192-198. Epub 2018 Mar 28.

Department of Laboratory Medicine, Uji-Tokushukai Medical Center, Uji, Japan.

Langerhans cell histiocytosis (LCH) with single-system (SS) multifocal bone (MFB) lesions is rarely fatal, but patients may experience relapses and develop LCH-associated sequelae. To evaluate effect on outcomes of pediatric multifocal LCH, we tested a treatment protocol modified from the Japan Langerhans Cell Histiocytosis Study Group (JLSG)-96 study. We assessed the outcomes of all consecutive newly diagnosed pediatric patients with LCH with SS-MFB lesions who were treated with JLSG-02 protocol in 2002-2009. JLSG-02 was modified from JLSG-96 as follows: increased prednisolone dosage at the induction phase and extension of maintenance therapy duration from 24 to 48 weeks. In total, 82 patients with a median follow-up duration of 8.0 years were eligible for analysis. At 6 weeks, 92.7% responded to induction; however, 27.6% of responders experienced relapses. In total, 4.8% developed central nervous system-related sequelae, including central diabetes insipidus and neurodegeneration, which were associated with relapse. None of the patients died. The 5-year event-free survival rates were not different between JLSG-02 and -96 cohort (66.7 vs. 65.1%; p = 0.697). Modification of previous treatment protocol did not contribute to improvement of outcomes in LCH with SS-MFB lesions.
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http://dx.doi.org/10.1007/s12185-018-2444-0DOI Listing
August 2018
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