Juvenile xanthogranuloma manifesting with LCH-associated neurodegenerative disease-like radiological findings.

Here, we describe two patients with juvenile xanthogranuloma (JXG) manifesting with Langerhans cell histiocytosis (LCH)-associated neurodegenerative disease (ND)-like radiological findings. One patient showed typical radiological abnormalities at onset, which worsened with progressing central nervous system symptoms 7 years after LCH-oriented chemotherapy. Another showed spontaneous regression of clinical symptoms, with a transient radiological change 1 year after salvage chemotherapy for recurrence of JXG. These data regarding JXG-associated ND will facilitate future investigation of the disease, as well as development of therapeutic interventions.

Suppression of malignant rhabdoid tumors through Chb-M'-mediated RUNX1 inhibition.

Malignant rhabdoid tumor (MRT) is a rare and highly aggressive pediatric malignancy primarily affecting infants and young children. Intensive multimodal therapies currently given to MRT patients are not sufficiently potent to control this highly malignant tumor. Therefore, additive or alternative therapy for these patients with a poor prognosis is necessary. We herein demonstrated that the inhibition of runt-related transcription factor 1 (RUNX1) by novel alkylating conjugated pyrrole-imidazole (PI) polyamides, which specifically recognize and bind to RUNX-binding DNA sequences, was highly effective in the treatment of rhabdoid tumor cell lines in vitro as well as in an in vivo mouse model. Therefore, suppression of RUNX1 activity may be a novel strategy for MRT therapy.

High-dose chemotherapy with autologous stem cell transplantation spares re-irradiation for recurrent intracranial germinoma.

The clinical outcome of high-dose chemotherapy (HDC) with autologous stem cell transplantation was retrospectively analyzed in six patients with recurrent intracranial germinoma. Prior to HDC, all patients achieved complete remission after platinum and ifosfamide-based chemotherapy. A melphalan-based conditioning regimen was administered in either a single cycle or multiple sequential cycles. Five of the six patients are alive and free from disease, with a median survival of 65 months, among which four patients avoided re-irradiation. In a significant proportion of patients, recurrent intracranial germinoma is curable by HDC without re-irradiation, provided that the disease remains sensitive to salvage chemotherapy.

[Pediatric acute lymphoblastic leukemia presenting with bone and joint pain].

We report on three cases of pediatric acute lymphoblastic leukemia presenting with bone pain and arthralgia as initial symptoms. At the first visit, their primary signs were recurrent bone pain and arthralgia, without significant peripheral blood abnormalities. It took 2-4 months to confirm the diagnosis from the onset of arthralgia due to this atypical presentation of the disease. Definitive diagnosis was obtained by bone marrow examination, and in all cases, complete remission was achieved by chemotherapy. As a feature of imaging, MRI exhibited diffuse bone marrow signal changes in T1-weighted images, and FDG-PET showed extensive abnormal bone marrow uptakes. In cases 2 and 3, it was difficult to diagnose by bone marrow aspiration from the iliac bone, but definitive diagnosis was obtained by bone marrow aspiration from the tibia, in which FDG-PET showed increased uptake. FDG-PET was therefore considered useful for the selection of bone marrow aspiration sites. In cases presenting with recurrent migratory bone pain and arthralgia, we need to consider performing bone marrow aspiration and imaging, such as MRI and FDG-PET, for early diagnosis and treatment of leukemia.

Good response to chemotherapy spares irradiation for extrarenal rhabdoid tumor conferring better activities of daily living.

A 7-year-old girl with stage IIA extrarenal rhabdoid tumor near the left cubital fossa received preoperative chemotherapy and surgical resection with median nerve reconstruction followed by postoperative high-dose chemotherapy. As preoperative chemotherapy resulted in decreased tumor size, disappearance of fluorodeoxyglucose-uptake, and pathologic complete response with total tumor resection, irradiation was successfully spared to avoid injury to the reconstructed nerve and inhibition of normal bone development. Two years after diagnosis, recurrence has not been observed and median nerve palsy is improving. This case suggests that radiation therapy could be spared for clinically and pathologically chemotherapy-good-responders in case total surgical resection is achieved.

The clinical utility of genetic testing for t(8;16)(p11;p13) in congenital acute myeloid leukemia.

Acute myeloid leukemia (AML) with t(8;16)(p11;p13) is known to have very poor prognosis in adults. In contrast, the prognosis is not clear in pediatric patients and chemotherapy is generally started immediately in cases of congenital leukemia because of its association with hyperleukocytosis and poor prognosis. This study reports a case of congenital AML where chemotherapy was discontinued after detection of a MOZ-CBP fusion, which remains in remission without additional treatment. This article stresses the importance of examination for the presence of the MOZ-CBP fusion at diagnosis to inform treatment decisions in congenital AML.

[Epileptic encephalopathy associated with human herpes virus 6 (HHV-6) encephalitis after the second cord blood transplantation in a patient with pediatric acute lymphoblastic leukemia].

The incidence of HHV-6 encephalitis during hematopoietic stem cell transplantation (HSCT) in children is thought to be less than that in adults and risk factors, prognosis and complications are virtually unknown. Herein, we report a pediatric case developing epileptic encephalopathy following HHV-6 encephalitis after a second cord blood transplantation (CBT). A 7-year-old boy with relapsed B-precursor acute lymphoblastic leukemia in second remission underwent CBT. However, he received a second CBT due to graft failure. On day 25 after the second CBT, he developed short-term memory defects and seizures. He was diagnosed with HHV-6 encephalitis because HHV-6 DNA was detected in his blood and cerebrospinal fluid and abnormal hippocampal signals were seen on cranial magnetic resonance imaging (MRI). After treatment with foscarnet, HHV-6 DNA levels and MRI findings improved; however, he developed epileptic encephalopathy five months after the onset of encephalitis. There are very few reports on pediatric epileptic encephalopathy associated with HHV-6 encephalitis after HSCT. Detailed studies are needed to analyze risk factors, prognosis, and complications.

[Utility of endoscopic ultrasound-guided fine needle aspiration for diagnosis of Burkitt lymphoma in two pediatric cases].

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was performed as a diagnostic procedure for two pediatric patients with intra-abdominal tumors. Case 1 was an 8-year-old boy with a huge tumor in the portal-hepatic region. Case 2 was a 17-year-old girl with a history of diabetes and recurrent relapse of Burkitt lymphoma, who had a newly developing tumor in the pancreatic body. In both cases, EUS-FNA was performed as a less invasive diagnostic procedure than open biopsy or total resection of the tumor. Tumor cells were determined to be of the B cell lineage by flow cytometric and immunostaining analyses. Both cases were diagnosed as having Burkitt lymphoma based on detection of IgH/C-MYC translocation by FISH. The aspiration was successfully conducted without severe complications, and both patients were immediately given chemotherapy. EUS-FNA is a safe and minimally invasive procedure with high diagnostic value for pediatric cases with intra-abdominal tumors.

[Comparative study on the efficacy and safety of continuous versus twice-daily 3-hour infusion of cyclosporine A in pediatric hematopoietic stem cell transplantation].

Cyclosporine (CsA) is widely used for graft-versus-host disease (GVHD) in pediatric hematopoietic stem cell transplantation (HSCT); however, the optimal schedule of its administration has not been established. We retrospectively compared the time-course of blood CsA levels and the incidence of CsA-associated adverse effects, grade II-IV acute GVHD, and chronic GVHD among 26 pediatric HSCT recipients who were receiving CsA by continuous infusion (CIF) (n=8) or by 3h infusion twice-daily (3TD) (n=18). In the 3TD group, the target level of the C3 value, which is strongly co-related with the area under the concentration-time curve, was maintained without any serious adverse effects in most patients. No significant differences were observed in the incidence of grade II-IV acute GVHD and chronic GVHD between CIF and 3TD groups. 3TD in combination with C3 monitoring enables safe and easy control of CsA blood levels and is thought to be useful for GVHD prophylaxis in pediatric HSCT.

Descending Necrotizing Mediastinitis Caused by Streptococcus pyogenes in a Child with Primary Epstein-Barr Virus Infection.

Descending necrotizing mediastinitis (DNM) is a severe, life-threatening disease with a high mortality rate resulting from sepsis or other complications. DNM can also be a rare and severe complication of Epstein-Barr virus (EBV) infection in adolescents and young adults but has never been reported in a pre-school child. A 4-year-old girl was admitted to our hospital with a 2-day history of fever and chest pain. Computed tomography (CT) revealed a right sided pleural effusion, fluid collection in the retropharyngeal and mediastinal areas, cervical lymphadenopathy, and marked hepatosplenomegaly. She was diagnosed with empyema, retropharyngeal abscess, and mediastinitis. To improve her dyspnea, a chest tube was inserted, and antibiotic treatment was initiated. Her condition improved temporarily, but on day 5 in our hospital, she developed a fever again. A repeat CT scan showed exacerbation of fluid retention in the retropharyngeal area and the mediastinum, for which she underwent drainage and debridement of necrotic tissue in the retropharynx and mediastinum. The presence of cervical lymphadenopathy and marked hepatosplenomegaly suggested the involvement of EBV. Serological tests for EBV revealed primary EBV infection at the time of the DNM onset. Finally, she was diagnosed with DNM following primary EBV infection. At follow-up 1 year later, she was doing well. The risk of DNM should be recognized in patients, even pre-school aged children, with primary EBV infection.

RUNX1-Survivin Axis Is a Novel Therapeutic Target for Malignant Rhabdoid Tumors.

Malignant rhabdoid tumor (MRT) is a highly aggressive pediatric malignancy with no effective therapy. Therefore, it is necessary to identify a target for the development of novel molecule-targeting therapeutic agents. In this study, we report the importance of the runt-related transcription factor 1 (RUNX1) and RUNX1-Baculoviral IAP (inhibitor of apoptosis) Repeat-Containing 5 (BIRC5/survivin) axis in the proliferation of MRT cells, as it can be used as an ideal target for anti-tumor strategies. The mechanism of this reaction can be explained by the interaction of RUNX1 with the RUNX1-binding DNA sequence located in the survivin promoter and its positive regulation. Specific knockdown of RUNX1 led to decreased expression of survivin, which subsequently suppressed the proliferation of MRT cells in vitro and in vivo. We also found that our novel RUNX inhibitor, Chb-M, which switches off RUNX1 using alkylating agent-conjugated pyrrole-imidazole polyamides designed to specifically bind to consensus RUNX-binding sequences (5'-TGTGGT-3'), inhibited survivin expression in vivo. Taken together, we identified a novel interaction between RUNX1 and survivin in MRT. Therefore the negative regulation of RUNX1 activity may be a novel strategy for MRT treatment.

[Early relapse of hemophagocytic syndrome after reduced-intensity cord blood transplantation for relapsed acute lymphoblastic leukemia].

We report a 4-year-old girl who presented with acute onset of hemophagocytic syndrome (HPS) after induction therapy and HPS relapsed immediately after reduced-intensity cord blood transplantation (RI-CBT) for relapse of acute lymphoblastic leukemia. The patient underwent CBT from 2 locus-mismatched donor, after reduced-intensity conditioning therapy consisting of fludarabine, melphalan, and total body irradiation 4Gy. Prednisolone and cyclosporine were administered for prophylaxis against graft-versus-host disease. Bone marrow examination on day 20 revealed activated macrophages displaying hemophagocytosis. The origin of macrophages was 2(nd) donor derived. After administration of steroids, intravenous immunoglobulin and VP-16, the patient exhibited complete chimerism and remained in complete remission for over one year.

Pluripotent stem cell model of Shwachman-Diamond syndrome reveals apoptotic predisposition of hemoangiogenic progenitors.

Shwachman-Diamond syndrome (SDS), an autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, which plays a role in ribosome biogenesis. Although the causative genes of congenital disorders frequently involve regulation of embryogenesis, the role of the SBDS gene in early hematopoiesis remains unclear, primarily due to the lack of a suitable experimental model for this syndrome. In this study, we established induced pluripotent stem cells (iPSCs) from patients with SDS (SDS-iPSCs) and analyzed their in vitro hematopoietic and endothelial differentiation potentials. SDS-iPSCs generated hematopoietic and endothelial cells less efficiently than iPSCs derived from healthy donors, principally due to the apoptotic predisposition of KDR+CD34+ common hemoangiogenic progenitors. By contrast, forced expression of SBDS gene in SDS-iPSCs or treatment with a caspase inhibitor reversed the deficiency in hematopoietic and endothelial development, and decreased apoptosis of their progenitors, mainly via p53-independent mechanisms. Patient-derived iPSCs exhibited the hematological abnormalities associated with SDS even at the earliest hematopoietic stages. These findings will enable us to dissect the pathogenesis of multiple disorders associated with ribosomal dysfunction.

[Relapsed acute myeloid leukemia with Down syndrome showing long disease-free survival after bone marrow transplantation].

We report a sixteen-year-old boy with Down syndrome and relapse of AML (M7), who has been in complete remission (CR) more than 12 months after bone marrow transplantation (BMT) from an HLA-matched sibling donor. Because monosomy 7 was detected at onset of AML and he experienced relapse after the treatment of AML 99 Down protocol, his prognosis was considered very poor. However, he achieved CR following chemotherapy that included high-dose AraC and BMT from an HLA-matched sibling donor without severe complication. He has remained in CR for more than 12 months after BMT. In this case, GATA1 mutation was not detected at either onset or relapse of AML and it is suggested that this case is in a different risk group than the usual Down syndrome patient with AML showing GATA1 mutation.

Primary jejunal Burkitt lymphoma in a child: ultrasonic detection.

Gastrointestinal Burkitt lymphoma (BL) is a highly aggressive malignancy in childhood, and early treatment is critical for its favorable prognosis. Ultrasonography is a widely accepted initial imaging workup; therefore, recognition of the sonographic features of BL should contribute to its early diagnosis and initiation of treatment. We present a 4-year-old boy with primary jejunal BL with intussusception mimicking presentation, in which initial abdominal US allowed sustainable detection and characterization of the intestinal lesion. Jejunotomy was performed and histopathological analysis revealed a 'starry sky' pattern and c-myc split signals characteristic of BL. The patient remains disease-free following chemotherapy.