Motoaki Chin

Significance of extensive Mongolian spots in Hunter's syndrome

Summary Background The importance of early diagnosis in infants with a mild form of Hunters syndrome should be emphasized. If applied sufficiently early, haematopoietic stem cell transplantation (HSCT) or recombinant enzyme therapy may improve the prognosis. At present, however, diagnosis of the mild form of Hunters syndrome tends to be delayed, especially in infants with relatively normal intelligence.

Outcome of pediatric renal tumor treated using the Japan Wilms Tumor Study-1 (JWiTS-1) protocol: a report from the JWiTS Group

PurposeIn 1996, the Japan Wilms Tumor Study (JWiTS) group was founded to elucidate the efficacy and safety of the regimen established by the National Wilms Tumor Study (NWTS) group in the USA, and a multicenter cooperative study (JWiTS-1) was started in Japan. This report reviews the results of JWiTS-1.MethodsA total of 307 patients with malignant renal tumor were enrolled in the JWiTS-1 study between 1996 and 2005. Central pathological diagnosis and follow-up data were available in 210 cases. The protocol regimens were similar to the NWTS-5 regimens. Clinical stage was classified according to the Japanese Staging System.ResultsFive-year overall survival (OS) rate was 91.1% for nephroblastoma, 72.9% for clear cell sarcoma of the kidney (CCSK), and 22.2% for rhabdoid tumor of the kidney (RTK). In the nephroblastoma patients, 5-year OS was 90.5% for stage I disease, 92.2% for stage II, 90.9% for stage III, 86.7% for stage IV, and 78.7% for stage V.ConclusionsThe OS of patients in the JWiTS-1 study were comparable with the results of other multicenter studies in the USA and Europe. The outcome for patients with nephroblastoma and CCSK was fair. In contrast, the cure rate for those with RTK was not satisfactory. New treatment strategies are needed for patients with RTK.

t(10;11)‐Acute leukemias with MLL‐AF10 and MLL‐ABI1 chimeric transcripts: Specific expression patterns of ABI1 gene in leukemia and solid tumor cell lines

The recurrent translocation t(10;11) is associated with acute myeloid leukemia (AML). The AF10 gene on chromosome 10 at band p12 and MLL at 11q23 fuse in the t(10;11)(p12;q23). Recently, we have identified ABI1 as a new partner gene for MLL in an AML patient with a t(10;11)(p11.2;q23). The ABI1 is a human homologue of the mouse Abl‐interactor 1 (Abi1), encoding an Abl‐binding protein. The ABI1 protein exhibits sequence similarity to homeotic genes, and contains several polyproline stretches and a src homology 3 (SH3) domain. To clarify the clinical features of t(10;11)‐leukemias, we investigated 6 samples from acute leukemia patients with t(10;11) and MLL rearrangement and detected MLL‐AF10 chimeric transcripts in 5 samples and MLL‐ABI1 in one. The patient with MLL‐ABI1 chimeric transcript is the second case described, thus confirming that the fusion of the MLL and ABI1 genes is a recurring abnormality. Both of the patients with MLL‐ABI1 chimeric transcript are surviving, suggesting that these patients have a better prognosis than the patients with MLL‐AF10. To investigate the roles of AF10 and ABI1 further, we examined the expression of these genes in various cell lines and fresh tumor samples using the reverse transcriptase‐polymerase chain reaction method. Although AF10 was expressed in almost all cell lines similarly, the expression patterns of ABI1 were different between leukemia and solid tumor cell lines, suggesting the distinctive role of each isoform of ABI1 in these cell lines. We also determined the complete mouse Abi1 sequence and found that the sequence matched with human ABI1 better than the originally reported Abi1 sequence. Further functional analysis of the MLL‐AF10 and MLL‐ABI1 fusion proteins will provide new insights into the leukemogenesis of t(10;11)‐AML.

Karyotypic Analyses of Hepatoblastoma: Report of Two Cases and Review of the Literature Suggesting Chromosomal Loci Responsible for the Pathogenesis of this Disease

Two cases of fetal hepatoblastoma with unique karyotypic changes are described. One was a 17-month-old boy with multiple unbalanced chromosomal translocations, resulting in four types of derivative chromosomes involving chromosomal loci at 1q21, 1q32, 2q23, 6q27, 7p22, and 21p12, partial tetrasomy of 1q, partial trisomy of 2q, and partial monosomy of 21p. The clonal karyotype of this tumor was 46,XY,der(2)t(1;2)(q32;q37), der(6)t(1;6)(q12;q27), der(7)t(2;7)(q23;p22), der(21)t(2;21) (q23;p12). In the other case, a 4-year-old girl, karyotypic analyses revealed trisomy 2 and 8, and the clonal karyotype of this case was 48,XX,+2,+8. Review of these cases together with previous reports suggested the significance of chromosomal changes including numerical abnormalities of 1q, 2(or 2q), 20, and 8 (or 8q), and breakage of 1q and 2q in the development of hepatoblastoma. The results presented herein underscore the significance of numerical abnormalities of chromosomal regions 1q and 2q and of chromosome 8 in the development of hepatoblastoma, in addition to abnormalities of 6q27, 7p22, and 21p12-13 as other chromosomal loci that may be responsible for the pathogenesis of this embryonal type of tumor.

Hemophagocytic syndrome and hepatosplenic gammadelta T-cell lymphoma with isochromosome 7q and 8 trisomy.

The authors describe a 15-year-old boy with hepatosplenic gammadelta T-cell lymphoma associated with hemophagocytic syndrome (HPS) along with isochromosome 7q and trisomy 8. He presented with prolonged fever, mild anemia, thrombocytopenia, and hepatosplenomegaly. Physical examination, radiography, and ultrasound tomography revealed no lymphoadenopathy. He had elevated levels of serum ferritin, interferon-gamma, soluble interleukin-2 receptor, and interleukin-6. Bone marrow aspirate showed hypercellularity with 50% lymphoblasts and erythrophagocytosis of macrophage. A cytogenetic study of bone marrow revealed an abnormal karyotype, 47,XY,I(7q),+8, in 5/30 cells. Clonal rearrangement of the genes for T-cell receptor gamma and delta chains was elucidated by polymerase chain reaction. He achieved a complete remission after intensive chemotherapy and underwent splenectomy 18 months after diagnosis. Although the patient was clinically in remission, minimal residual disease (MRD) was detected in the removed spleen by polymerase chain reaction. This might mean that this type of lymphoma is refractory, as reported previously, and might indicate that marrow ablative therapy is needed to achieve a cure. The present case illustrates the usefulness of MRD analysis, and MRD studies in this group of disorders may be helpful in the decision of whether to continue a more aggressive therapeutic approach.

The effect of haematopoietic stem cell transplant on papules with ‘pebbly’ appearance in Hunter's syndrome

Background  Hunters syndrome is associated with several cutaneous findings. For instance, papules with ‘pebbly’ appearance are a specific marker for the disease. However, it remains uncertain whether they disappear after haematopoietic stem cell transplant (HSCT).

Haematopoietic stem cell transplantation for relapsed or refractory anaplastic large cell lymphoma: a study of children and adolescents in Japan

To evaluate haematopoietic stem cell transplantation (HSCT) in children and adolescents, we reviewed the records of 47 patients who were ≤18 years, had relapsed or refractory anaplastic large cell lymphoma, and received HSCT between 1990 and 2010. At HSCT, complete remission (CR) was less common in allogeneic HSCT recipients (n = 24) than in autologous HSCT recipients (n = 23) (P = 0·01). The autologous and allogeneic HSCT groups differed in terms of 5‐year event‐free survival (EFS) (38% vs. 50%, P = 0·63), cumulative incidence of progress or relapse (49% vs. 28%, P = 0·25), and treatment‐related mortality (12% vs. 25%, P = 0·40). However, these differences were not significant. Patients with non‐CR at autologous HSCT had a significantly lower EFS rate (14% vs. 48%, P = 0·03). Conversely, although those with non‐CR at allogeneic HSCT had a lower EFS rate, this was not significant (44% vs. 63%, P = 0·26). Reduced‐intensity conditioning regimens were used for three of the 16 allogeneic HSCTs received by patients with non‐CR. These three patients achieved CR, surviving 32–65 months after HSCT. These results demonstrated that allogeneic HSCT might be a treatment option for patients who do not achieve CR through conventional chemotherapy.

Autoimmune hemolytic anemia and autoimmune neutropenia in a child with erythroblastopenia of childhood (TEC) caused by human herpesvirus-6 (HHV-6).

Dear Editor, Transient erythroblastopenia of childhood (TEC) is a selflimiting disorder of young children that is characterized by moderate to severe anemia with reticulocytopenia and decreased numbers of erythroid precursors in the bone marrow. TEC was often complicated with neutropenia and thrombocytopenia [1–3]. Here, we document a unique clinical course in a child with TEC. A 1-year-old girl with anemia was admitted to our hospital. She had no recent episodes of viral infection such as fever and skin eruption. The values for hemoglobin (Hb) and reticulocytes were 57 g/L and 2.0% (Table 1). Although the direct Coombs test was highly positive, the haptoglobin level remained normal. In addition, the leukocyte fraction indicated agranulocytosis. Bone marrow findings were as follows: cellularity was normocellular, the erythroid series were reduced (M/E ratio, 4.2), and the myeloid series differentiated to a band form but not segmental neutrophils. Speculating that viral infection was involved in this bicytopenia, we performed multiplex PCR analyses for the following viruses: herpes simplex virus type 1, type 2, human herpesvirus type 6 (HHV-6), type 7, type 8, varicella-zoster virus, Epstein-Barr virus (EBV), cytomegalovirus, parvovirus B19, polyomavirus JC, and polyomavirus BK, as described previously [4]. As a result, HHV-6 DNA (10×10 copies/μg DNA) was detected in the peripheral whole blood. Because we assumed that HHV-6 infection suppressed erythropoiesis, we started ganciclovir (GCV) from day 15. The reticulocyte count responded rapidly to GCV and increased to 10.8% on day 22 (Table 1). The HHV-6 DNA level also decreased significantly (0.84 × 10 copies/μg DNA); however, the Hb level decreased to 40 g/L on day 25. As the haptoglobin level decreased, a diagnosis of hemolytic crisis was made. High-dose globulin (total dose, 1.5 g/kg) was given on days 25 to 27 with subsequent standard steroid therapy on days 37 to 74. The hemolysis resolved rapidly, and the Hb level increased up to 89 g/L on day 33. Coombs test became negative by day 67, and the patient was discharged on day 74. The level of HHV-6 antibody increased during this episode, which indicated a primary infection of HHV-6 (Table 1). At present (day 273), the patient has no relapse of anemia. In contrast, the neutrophil count did not change. Anti-neutrophil antibodies were identified by flow cytometric analysis, which was consistent with autoimmune neutropenia. The association between TEC and viral infection such as parvovirus B19, EBV, cytomegalovirus, and HHV-6 has been raised in few patients [5–7]. In our patient, HHV-6 infection was proven by a molecular technique and successfully treated using GCV. Another notable feature is that this patient presented with autoimmune hemolytic anemia and neutropenia, concurrently. We speculated that the immune response against HHV-6 has stimulated the production of multiple autoantibodies against red cells and H. Yagasaki (*) :M. Kato :H. Shichino :M. Chin : H. Mugishima Department of Pediatrics, Nihon University, Ohtaniguchi 30-1, Itabashi-ku, Tokyo, Japan 173-8610 e-mail: yagasaki@med.nihon-u.ac.jp

Successful treatment of disseminated intravascular coagulation in a child with acute myelogenous leukaemia using recombinant thrombomodulin.

Disseminated intravascular coagulation (DIC) is a serious complication that can occur during treatment of haematological malignancies, such as acute leukaemia. Conventional treatment of DIC consists of the administration of heparins as well as platelet transfusion or fresh frozen plasma (FFP) supplementation (Levi et al, 2009). Recombinant thrombomodulin (rTM, Recomodulin ; Asahi Kasei Pharma, Tokyo, Japan) has been developed as a novel treatment that inhibits activated Factors V and VIII (FVa and FVIIIa respectively) by activating protein C (Maruyama, 1999; Moll et al, 2004). This report presents a case study of a child with acute myeloid leukaemia (AML) in whom associated DIC was improved dramatically by administration of rTM. A 9-year-old girl, diagnosed with osteosarcoma at age 5 years and treated with multi-agent chemotherapy and surgery 3 years previously, presented to us for a regular follow up. She had purpura on her extremities and complained of gingival bleeding. A bone marrow finding showed acute myelomonocytic leukaemia (French-American-British classification M4) with a MLL-MLLT3 fusion transcript. The clinical course is shown in Fig 1. Induction therapy with fludarabine, high-dose cytarabine, idarubicin and granulocytecolony stimulating factor was started. However, on the second day of treatment, her general condition deteriorated and a coagulation test showed the following abnormalities: platelet count, 30 · 10/l; prothrombin time (PT) ratio, 2Æ0 (normal: 0Æ9–1Æ1); fibrin degradation products (FDP), 390 mg/l (normal: <4Æ0 mg/l); d-dimer, 170Æ1 mg/l FEU (normal: <0Æ5 mg/l FEU) and thrombin-antithrombin complex (TAT) level of 23Æ2 lg/l (normal: <3Æ0 lg/l) (Table I). A diagnosis of DIC was subsequently made according to the diagnostic criteria of the International Society of Thrombosis and Hemostasis (Taylor et al, 2001). Intravenous administration of rTM (380 U/kg/d) was started on the same day. The high-grade fever resolved and her general condition had improved very rapidly by the next morning. After 2 d of administration, the PT ratio, FDP, d-dimer and TAT levels were 1Æ16, 10Æ6 mg/l, 4Æ9 mg/l FEU and 2Æ7 lg/l respectively, indicating a significant improvement (Table I). We subsequently determined that the patient had recovered from the DIC state and discontinued the administration of rTM. No adverse events, such as bleeding, were observed and there was no recurrence of coagulation abnormalities after completing the administration of rTM. Consequently, we were able to carry out the induction therapy as originally scheduled. Following therapy, she received cord blood transplantation and is currently alive and well. Heparin has been shown to improve laboratory abnormalities associated with DIC, while recent reports have shown that antithrombin concentrate and human-activated protein C possess survival benefits for patients with DIC (Dhainaut et al, 2004; Kienast et al, 2006). However, serious bleeding is a concern in patients who are administered these drugs. Thrombomodulin (TM) is an endothelial cell surface glyco-

Application of radiofrequency ablation for giant solid pseudopapillary tumor of the pancreas

Solid pseudopapillary tumors (SPT) of the pancreas are rare exocrine pancreatic tumors that are well-known for their predilection for young women. They were first described by Frantz in 1959, and have been variously designated as solid-and-cystic tumors, solid-and-papillary epithelial neoplasms, papillary cystic neoplasms, solid-and-cystic acinar-cell tumors, papillary-andsolid neoplasms, and Frantz’s tumor. In 1996, the World Health Organization renamed this tumor as SPT of the pancreas for the international histological classification of tumors of the exocrine pancreas. The tumor is more frequently localized in the pancreas (80%) and is rarely a metastatic disease (20%). Because of the malignant potential of the tumors, surgical resection has been the standard of care in the management of SPT of the pancreas to prevent recurrence, and surgical resection can result in cure. Radiofrequency ablation (RFA), a technique first described in 1990 by Rossi et al., is based on the electrical energy of a high-frequency, alternative current flowing from an electrode into the surrounding tissue. This leads to ion agitation, which is converted by friction into the head and, ultimately, induces irreparable cellular damage and coagulation necrosis. RFA is an evolving technology used to treat unresectable liver tumors, renal tumors, and lung tumors. The efficacy and safety has been reported. We report a case of a young girl for whom we carried out complete resection of unresectable SPT of the pancreas after having reduced the size of the tumor using RFA. The hospital’s institutional review board approved this study.