Daisuke Toyama

Disseminated intravascular coagulation complicating acute lymphoblastic leukemia: A study of childhood and adult cases

A high incidence of disseminated intravascular coagulation (DIC) in adult patients with acute lymphoblastic leukemia (ALL) is reported. However, studies comprising both childhood and adult patients are sparse and the clinical relevance of DIC in ALL patients has been a conflicting issue. Coagulation profiles at presentation and within seven days after starting remission-induction therapy of 44 childhood and 51 adult ALL patients were studied. At presentation, two childhood (5%) and 11 adult (22%) patients had DIC (p<0.05). After starting therapy, four of 27 childhood (15%) and 14 of 33 adult (42%) patients screened for coagulopathy developed DIC (p<0.05). Overall, six of the 44 children (14%) and 25 of the 51 adults (49%) were complicated with DIC (p<0.001). In the adult cases, DIC was more frequently complicated with FAB subtype L2 than L1 (p<0.05). All hemorrhages seen in the childhood cases were minor hemorrhages. In the adult patients, two patients with DIC had WHO grade 3 hemorrhage and the other hemorrhagic complications were minor hemorrhages. While milder induction therapies starting with corticosteroid given for childhood cases should be taken into consideration when comparing the incidences of DIC after therapy, the findings indicated that childhood and adult ALL may differ in the procoagulant characteristics. Morphological distinction between L1 and L2 appears to have relevance in the procoagulant activity in adult ALL. DIC complicating ALL is generally mild, however, sometimes causes severe hemorrhages in adults.

Case series of pediatric acute leukemia without a peripheral blood abnormality, detected by magnetic resonance imaging

Although abnormal peripheral blood counts are a key diagnostic finding for acute leukemia in children, between 2003 and 2010 we observed seven pediatric cases without peripheral blood abnormalities and showing abnormal signals in the bone marrow by magnetic resonance imaging (MRI). The common chief complaint in these patients was bone pain and fever. Bone marrow tests revealed six out of the seven cases to be acute leukemia, whereas one patient was diagnosed with juvenile idiopathic arthritis (JIA). There was no evident difference in MRI findings between leukemia patients and JIA patient. In three cases of leukemia, initial bone marrow aspiration failed to show the presence of leukemic cells, and diagnosis was only made by repeated bone marrow examination. Our findings indicate that in some cases MRI detects leukemia at an earlier phase than does bone marrow aspiration, suggesting that MRI is useful for the diagnosis of acute leukemia.

Successful Treatment of Hepatic Sinusoidal Obstructive Syndrome after Hematopoietic Stem Cell Transplantation in a Child Using Recombinant Thrombomodulin

human leukocyte antigen-mismatched related donor. The interval between administration of GO and BMT was 2 months. His body weight was 8.3 kg at the time of BMT. The conditioning regimen comprised busulfan (19.2 mg/ kg), melphalan (6 mg/kg) and fludarabine (4 mg/kg). Graft-versus-host disease prophylaxis included tacrolimus (0.02 mg/kg/day) and short-term methotrexate. Ursodeoxycholic acid and low-molecular-weight heparin prophylaxis for SOS was administered from day –10 before SCT. On day 10, the antithrombin III (AT III) activity level decreased, which required consecutive administration of AT III concentrate (500 U/day) to maintain an AT III activity 1 80%. His weight began to increase at the same day and showed a 12% increase compared with the pretransplant baseline on day 12 ( fig. 1 ). Simultaneously, the total bilirubin level was elevated to 2.1 mg/dl, with massive abdominal effusion and pain in the right upper quadrant. Serum levels of aspartate aminotransferase, alanine aminotransferase, lactase dehydrogenase and alkaline phosphatase were normal. Abdominal ultrasonography revealed an enlarged liver with moderate ascites and retrograde flow in the right hepatic vein. According to the Seattle criteria [6] , the patient was diagnosed with SOS. The coagulation test showed the following: prothrombin time in international normalized ratio 1.45 (normal 0.9– 1.1); fibrin degradation products 222 mg/l (normal ! 4.0); Hepatic sinusoidal obstructive syndrome (HSOS) is recognized as one of the most common and important fatal complications after hematopoietic stem cell transplantation (SCT). It is a clinical syndrome characterized by painful hepatomegaly, jaundice, ascites, fluid retention and weight gain [1] . The incidence of HSOS in childhood was previously reported to be between 11 and 18%, and mortalities ranged from 15.4 to 38.5% [2–4] . Recombinant human soluble thrombomodulin (rTM) comprises the active, extracellular domain of thrombomodulin and inactivates coagulation by binding to thrombin. In addition, the thrombin-rTM complex activates protein C, which inactivates factors VIIIa and Va in the presence of protein S, thereby inhibiting further thrombin formation [5] . We here describe a pediatric patient with HSOS successfully treated with rTM after SCT. A 1-year-old boy was diagnosed with acute megakaryocytic leukemia in 2009. The patient achieved complete remission after induction therapy. However, he developed a first relapse after two courses of consolidation therapy. Therefore, he received FLAG-IDA-GO (fludarabine, cytarabine, granulcoyte colony-stimulating factor, idarubicin and gemtuzumab ozogamicin) as reinduction therapy and achieved a second complete remission. The dosage of GO was 3 mg/m 2 . He subsequently underwent bone marrow transplantation (BMT) from a one-locus Received: July 4, 2012 Accepted after revision: September 5, 2012 Published online: November 9, 2012

Fanconi anemia in infancy: report of hematopoietic stem cell transplantation to a 13-month-old patient.

The most important clinical features of Fanconi anemia (FA) are hematologic disorders and these are responsible for high incidence of morbidity and mortality. During birth, the blood count is usually normal and macrocytosis is often the first detected abnormality. This is typically followed by thrombocytopenia and anemia; then, progresses to pancytopenia. The majority of patients develop progressive bone marrow failure or acute myelogenous leukemia, both of which are diagnosed with peak frequencies at the age of 7 and 10–15 years, respectively [1, 2]. The disease has generally been managed by the administration of blood products, treatment of infections, and prolonged administration of androgens and hematopoietic growth factors. However, the only curative treatment for the bone marrow failure is hematopoietic stem cell transplantation (HSCT). We describe a patient demonstrating pancytopenia from birth, who received HSCT at the age of 13 months. The patient showed a tendency toward intrauterine growth retardation on ultrasonographic examination at 29 weeks of gestation. He was delivered by cesarean section at 36 weeks and 6 days of gestation because of fetal distress. Birth weight was 2070 g, and 1and 5-min Apgar score were 6 and 8, respectively. He was referred to the neonatal intensive care unit in our hospital for respiratory distress and cardiac murmur on the day of birth. On admission, white blood cell count was 2.8 9 10/L, hemoglobin 5.1 g/dL, platelet count 95 9 10/L. Congenital abnormalities suggestive of FA were bilateral radial hypoplasia, bilateral defective thumbs, defect of the left kidney and L-form fused kidney on the right side, and small patent ductus arteriosus. Bone marrow showed a hypo cellular picture, being comprised mainly of lymphocytes. Karyotyping of 20 cells that were in metaphase exclusively showed 46, XY. A diagnosis of FA was established at the age of 3 months based on the increased chromosomal breakage induced by mitomycin C. The rate of chromosomal breakage in him was increased (443/ 100 cells) compared with control cells (18/100 cells). Levels of FANCA and monoubiquitinated and non-ubiquitinated forms of FANCD2 were determined using immunoblotting analyses of whole cell extracts with antiFANCA and anti-FANCD2 antibodies, and he lacked FANCA protein expression and FANCD2 monoubiquitination. For about a year before transplant, he became progressively dependent on red blood cell and platelet concentrate transfusion and the absolute neutrophil count was 0.05–0.65 9 10/L. He was not treated with any growth factors or androgens. He developed severe sepsis twice at the ages of 9 and 12 months, respectively. Bone marrow at the age of 12 months was hypo cellular with dysplastic features suggesting myelodysplastic syndrome (MDS) and the percentage of myeloblasts was \5%. That indicated refractory cytopenias with multilineage dysplasia. Karyotyping of 20 cells exclusively showed 46, XY with abnormality of add(2)(q33). Before transplant, he had been transfused with red blood cells 18 times and platelet K. Oshima (&) A. Kikuchi S. Mochizuki D. Toyama N. Uchisaka R. Hanada Division of Hematology/Oncology, Saitama Children’s Medical Center, 2100 Magome, Iwatsuki-ku, Saitama 339-8551, Japan e-mail: oshima-k@umin.ac.jp

Efficacy and Safety of Slowly Infused Propofol Sedation in Pediatric OncologyProcedures

Children with hematological malignancies frequently undergo invasive procedures such as bone marrow aspiration and lumbar punctures. Although various methods of sedation are currently used for these procedures, no standard has been established to date. midazolam and ketamine (midazolam/ketamine) have been used for procedural sedation in our department. Since both of these drugs have a long half-life, sedation may persist for an excessively long time after the procedure has been completed. Propofol is an intravenously administered anesthetic that is characterized by the easy control of the depth of anesthesia and rapid recovery. Although side effects such as hypoxia and hypotension have been associated with sedation by propofol, their severities may be reduced using slow infusions. Therefore, we herein used slowly infused propofol (0.5 mg/kg over 20 seconds) for these procedures and retrospectively compared its effects with those of midazolam/ketamine. Recovery time was significantly shorter in the propofol group. Although the frequency of side effects such as hypotension was significantly higher in the propofol group, severe side effects were not observed. This may have been because propofol was slowly infused. Although the sample size is too small, the results of the present study suggest that slowly infused propofol might be effective and safe for invasive procedures on pediatric patients. A prospective study is required to further investigate appropriate methods of sedation

Acute megakaryocytic leukemia (AMKL,FAB;M7) with Beckwith–wiedemann syndrome

Beckwith–Wiedemann syndrome (BWS) is characterized by an accumulation of multiple congenital anomalies. Although patients with BWS are known to have a higher incidence of embryonal tumors, there has been no reports associated with acute leukemia. This report describes the case of a patient with BWS who developed Acute Megakaryocytic Leukemia (AMKL,FAB;M7). Because most patients with BWS present gigantism, the therapy‐related toxicity of chemotherapy can be a very serious problem. This patient exhibited no therapy‐related toxicity after chemotherapy, suggesting that acute leukemia with BWS may not require a reduction in dosage. Pediatr Blood Cancer. 2010;55:733–735.

Wiskott–Aldrich syndrome that was initially diagnosed as immune thrombocytopenic purpura secondary to a cytomegalovirus infection:

Wiskott–Aldrich syndrome is a rare X-linked recessive disease resulting from variations in the WAS gene. Wiskott–Aldrich syndrome is sometimes difficult to differentiate from immune thrombocytopenic purpura. A 2-month-old boy was admitted to our hospital for purpura and thrombocytopenia. His mean platelet volume was reported to be normal. Treatment with intravenous immunoglobulins failed to improve the patient’s platelet count. Subsequently, an acute cytomegalovirus infection was confirmed by serological testing and antigenemia. The patient was diagnosed with immune thrombocytopenic purpura secondary to a cytomegalovirus infection. However, based on the patient’s clinical course and the refractoriness of his condition, Wiskott–Aldrich syndrome was strongly suspected. Through direct sequencing of the genomic DNA of the Wiskott–Aldrich syndrome protein (WASP) gene, we identified a novel missense mutation in exon 3 of the patient’s WASP gene (c. 343 C>T, p. H115T), and the patient was diagnosed with Wiskott–Aldrich syndrome at 3 months after onset. Children with Wiskott–Aldrich syndrome are often initially diagnosed with immune thrombocytopenic purpura, which can lead to inappropriate treatment and delays to life-saving definitive therapy. Our findings imply that Wiskott–Aldrich syndrome should be considered as a differential diagnosis in cases of refractory immune thrombocytopenic purpura combined with a cytomegalovirus infection.

Prophylactic recombinant thrombomodulin treatment prevents hepatic sinusoidal obstruction syndrome in high-risk pediatric patients that undergo hematopoietic stem cell transplants

Hepatic SOS is a potentially life‐threatening complication of conditioning for allogeneic HSCT. rTM is a new drug for treating DIC. We report our experience of the use of rTM as a prophylaxis against SOS in high‐risk pediatric patients that underwent HSCT. We evaluated the cases of 19 pediatric hematology and oncology patients who underwent HSCT at our institution between 2007 and 2016. The patients who received HSCT after 2012 (n = 8) were treated with rTM as a prophylaxis against SOS together with UDCA and LMWH, whereas the others (n = 11) were only treated with UDCA and LMWH. Although SOS occurred by post‐HSCT day 35 in 3 (27%) patients in the control group, SOS was not seen in the rTM group. Two of the former three patients suffered severe SOS, and one died of the condition. The mean peak level of PAI‐1 (a marker of endothelial damage) was significantly lower in the rTM group. rTM appears to be a safe prophylaxis for SOS. The present findings suggest that prophylactic rTM after HSCT might help to prevent SOS.

Successful low‐dose radiotherapy treatment for Kasabach–Merritt syndrome

Kasabach–Merritt syndrome (KMS) is characterized by hemangioma associated with life‐threatening thrombocytopenia, and is a consumptive coagulopathy. Although treatments available include corticosteroids, α‐interferon, vincristine, and surgery, response may be unsatisfactory, and the mortality rate remains at approximately 30%. Although radiotherapy has been used effectively for KMS, it may cause growth retardation and secondary malignancy. We report a case of KMS in which hemangioma of the left thigh was successfully treated with low‐dose radiotherapy (6 Gy in six fractions, weekly) after failure of corticosteroid therapy. No significant late effects due to the radiotherapy were noted at 5 year follow up. Thus, low‐dose radiotherapy remains an important treatment method for KMS when patients fail to respond to other treatments.