CD146 is a potential immunotarget for neuroblastoma.

Neuroblastoma, the most common extracranial solid tumor of childhood, is thought to arise from neural crest-derived immature cells. The prognosis of patients with high-risk or recurrent/refractory neuroblastoma remains quite poor despite intensive multimodality therapy; therefore, novel therapeutic interventions are required. We examined the expression of a cell adhesion molecule CD146 (melanoma cell adhesion molecule [MCAM]) by neuroblastoma cell lines and in clinical samples and investigated the anti-tumor effects of CD146-targeting treatment for neuroblastoma cells both in vitro and in vivo. CD146 is expressed by 4 cell lines and by most of primary tumors at any stage. Short hairpin RNA-mediated knockdown of CD146, or treatment with an anti-CD146 polyclonal antibody, effectively inhibited growth of neuroblastoma cells both in vitro and in vivo, principally due to increased apoptosis via the focal adhesion kinase and/or nuclear factor-kappa B signaling pathway. Furthermore, the anti-CD146 polyclonal antibody markedly inhibited tumor growth in immunodeficient mice inoculated with primary neuroblastoma cells. In conclusion, CD146 represents a promising therapeutic target for neuroblastoma.

Chemoradiotherapy for Unresectable INI1-negative Chordoma in a Child.

The characteristics of chordomas in children are distinct from those in adults. In particular, the prognosis of patients with INI1-negative chordoma is dismal. The standard treatment for localized chordoma, complete surgical resection with a wide margin, is seldom feasible for chordomas arising at the clivus in children, mainly due to associated complications. Therefore, other treatments for unresectable chordomas in children, including chemoradiotherapy, must be explored. Here, we report a 7-year-old girl with an INI1-negative chordoma of the clivus, who responded to conventional chemotherapy plus radiotherapy. Without surgical resection, she remains alive after 1 year and 7 months of the initial diagnosis.

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.

Cytomegalovirus infection in pediatric patients with hepatoblastoma after liver transplantation.

No studies have examined CMV infection in pediatric patients with HB receiving LT. Here, we retrospectively analyzed the incidence of and risk factors for CMV infection in 24 pediatric patients with HB who underwent LT between 1997 and 2015. CMV infection was monitored by measuring expression of pp65 CMV antigen for up to 4 months post-LT. CMV infection, defined as detection of at least one pp65-positive leukocyte, was detected in nine (37.5%) patients who did not develop CMV disease. Nine (47.4%) of nineteen patients who received post-LT chemotherapy experienced CMV infection; however, no CMV infection was observed in the five patients who did not receive post-LT chemotherapy (P = 0.012). There were no significant differences in the incidence of CMV infection between patients with ACR (60.0%) and those without (21.4%, P = 0.092), or between CMV seropositive (55.6%) and seronegative patients (33.3%, P = 0.675). All nine patients with CMV infection did not experience CMV disease due to the use of preemptive antiviral therapy. Close monitoring of CMV infection is recommended for patients with HB, particularly those receiving post-LT chemotherapy. Preemptive antiviral therapy is feasible for prophylaxis of CMV disease.

Prognostic and therapeutic factors influencing the clinical outcome of hepatoblastoma after liver transplantation: A single-institute experience.

LT has contributed to an elevation in cure rates for patients with unresectable HB; however, patients with recurrent HB after LT have poor prognosis. To analyze the prognostic and therapeutic factors that influence the clinical outcome of patients with HB receiving LT, we retrospectively analyzed 24 patients with HB who underwent LT between 1997 and 2015. The 5-year OS rate of all patients was 69.6±9.7%. The 5-year OS rate of 11 patients receiving salvage LT for recurrent tumor after a primary resection was comparable to that of 13 patients receiving primary LT. Among 12 evaluable patients receiving primary LT, six of 10 patients with a decline of serum AFP >95% at LT are currently alive and in remission, whereas two patients with a decline of AFP ≤95% experienced post-LT relapse. Among 9 evaluable patients receiving salvage LT, all three patients with any decline of AFP at LT are currently alive in remission, and three of six patients with no response to pre-LT salvage chemotherapy are also alive and in remission. Response to chemotherapy may be a reliable marker for prediction of post-LT relapse, even for patients receiving salvage LT.

[Recurrent thrombosed external hemorrhoids due to L-asparaginase administration in a Philadelphia chromosome-positive acute lymphoblastic leukemia patient].

A 13-year-old female developed L-asparaginase (L-ASP) -associated thrombosed external hemorrhoids (TEH) during chemotherapy for Philadelphia chromosome-positive acute lymphoblastic leukemia. While undergoing induction therapy combined with imatinib, she experienced intense anal pain a day after the four-time administration of L-ASP. The anal verge contained painful bluish hemorrhoids, which reportedly were absent before the therapy commencement. Hemorrhoids occurred 5-9 days after every L-ASP treatment, which was eventually diagnosed as L-ASP-associated TEH. After the failure of conservative treatment, opioid therapy was initiated. During myeloid reconstitution, she underwent divided ligation of hemorrhoids; however, the hemorrhoids became necrotic and formed an ulcerated tissue bed. This case suggests that while undertaking L-ASP therapy in adolescents and young adults with acute lymphoblastic leukemia, physicians should monitor signs of hemorrhoids and consider divided ligation when appropriate.

Impact of post-transplant minimal residual disease on the clinical outcome of pediatric acute leukemia.

This retrospective study examined the clinical significance of FCM-MRD in 36 patients with ALL and 29 patients with AML after their first allogeneic HSCT. Hematological (FCM-MRD ≥5.0%) and molecular relapse (FCM-MRD <5.0%) were first detected in 10 and two patients with ALL and in seven and eight patients with AML, respectively. Eight of 10 patients with molecular relapse eventually progressed to hematological relapse, although most were treated with immunological intervention by aggressive discontinuation of immunosuppressive therapy or donor lymphocyte infusion. Among these 12 patients, four of seven patients that obtained MRDneg CR following post-transplant chemotherapy remain alive and disease-free after their second HSCT; however, all five patients who underwent a second HSCT in non-CR died of disease or treatment-related complications. As the FCM-MRD monitoring system used in the current study was probably not sensitive enough to detect MRD, which could be elucidated by immunological intervention, more sensitive diagnostic tools are mandatory for post-transplant MRD monitoring. Additional studies are required to address the impact of presecond transplant MRD on the clinical outcome of second HSCT.

Efficacy of Ifosfamide-Cisplatin-Etoposide (ICE) Chemotherapy for a CNS Germinoma in a Child With Down Syndrome.

Intracranial germ cell tumor is sometimes associated with Down syndrome; however, no optimal treatment has been developed due to the high risk of recurrence and treatment-related mortality. Here, we report on a patient with an intracranial germinoma in the bilateral basal ganglia. The patient received 3 courses of ifosfamide-cisplatin-etoposide in combination with whole-brain irradiation (24 Gy), with no serious complications. The patient is alive and disease free 16 months after the initial diagnosis. This regimen is a feasible treatment for intracranial germ cell tumor associated with Down syndrome, although careful attention must be paid to the increased risk for severe infection.

A Pediatric Case of Metastatic Conventional Parosteal Osteosarcoma Treated With Multidrug Chemotherapy.

Parosteal osteosarcoma (POS) is conventionally a low-grade sarcoma with limited metastatic potential; however, the tumor occasionally transforms into a high-grade dedifferentiated POS, which commonly metastasizes to distant organs. The present report describes a rare pediatric case of conventional POS with no dedifferentiated component yet had multiple pulmonary metastases at initial diagnosis. Following limb-sparing surgery and osteosarcoma-oriented neoadjuvant chemotherapy, the patient received total resection of pulmonary metastases. Despite no treatment for pulmonary recurrence 1 year after adjuvant chemotherapy, the patient is alive with stable disease 4 years and 6 months after the initial diagnosis.

Impact of pretransplant minimal residual disease on the post-transplant outcome of pediatric acute lymphoblastic leukemia.

There are few reports on the clinical significance of MRD before HSCT in pediatric ALL. We retrospectively analyzed the clinical significance of FCM-based detection of MRD (FCM-MRD) before allogeneic HSCT in pediatric ALL. Of 38 pediatric patients who underwent allogeneic HSCT for the first time between 1998 and 2014, 33 patients were in CR and five patients were in non-CR. The CR group was further divided into two groups based on the pretransplant FCM-MRD level: the MRD(neg) (<0.01%; 30 patients) group and the MRD(pos) (≥0.01%; three patients) group. There were significant differences in the three-yr event-free survival rates between the CR and non-CR group, and between the MRD(neg) and MRD(pos) group. The three-yr cumulative RI in the MRD(neg) group were 27.3% ± 8.8%, whereas two of the three patients in the MRD(pos) group relapsed within one yr after HSCT. The clinical outcome of the MRD(pos) group was as poor as that of the non-CR group in pediatric ALL. Therefore, an improvement in pretransplant treatment that aims to achieve a more profound remission would contribute to reducing the risk of relapse.

Autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency caused by a novel NFKBIA mutation, p.Ser36Tyr, presents with mild ectodermal dysplasia and non-infectious systemic inflammation.

PURPOSE: Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is characterized by hypohidrosis, dental abnormalities, sparse hair, and immunodeficiency. Autosomal dominant (AD)-EDA-ID, caused by a heterozygous mutation within NFKBIA, is very rare and its clinical features remain largely unknown. This study describes a patient with AD-EDA-ID harboring a novel NFKBIA mutation who presented with mild EDA and non-infectious systemic inflammation. METHODS: The clinical presentation of an AD-EDA-ID patient was described and immunological, genetic, and biochemical analyses were performed, with a focus on nuclear factor kappa B (NF-κB) activation. RESULTS: The patient presented with symptoms of mild EDA-ID, namely sparse hair and hypohidrosis, although a skin biopsy confirmed the presence of sweat glands. There were no dental abnormalities. The patient also suffered from non-infectious inflammation, which responded to systemic corticosteroid therapy; however, the patient remained ill. Immunological analyses revealed reduced Toll-like receptor/IL-1 (TLR/IL-1) and tumor necrosis factor (TNF) receptor family responses to various stimuli. Genetic analysis identified a de novo heterozygous missense mutation, p.Ser36Tyr, in NFKBIA, resulting in defective NFKBIA degradation and impaired NF-κB activation. The patient was diagnosed with AD-EDA-ID and underwent hematopoietic stem cell transplantation. Engraftment was successful, with few signs of acute graft versus host disease. However, the patient suffered hemolytic anemia and thrombocytopenia, and died from a brain hemorrhage due to intractable thrombocytopenia. CONCLUSION: AD-EDA-ID patients can present with mild ectodermal dysplasia and non-infectious inflammation, rather than with recurrent infections. Also, hematopoietic stem cell transplantation for AD-EDA-ID is still a clinical challenge.

An infant with acute decompensated heart failure caused by afterload mismatch due to tumour-induced secondary hypertension: a case report.

Background: Hypertensive crisis is a relatively rare condition among infants and usually occurs secondary to an underlying disease. If not managed promptly, it is life-threatening and can lead to irreversible damage to vital organs. While secondary hypertension due to tumours has been reported previously, acute decompensated heart failure is rare, especially in the paediatric population. Case summary: A 2-month-old female infant presented with poor feeding and poor body weight gain. She was extremely ill, and blood gas analysis showed prominent acidosis (pH 6.945). The patient was intubated and referred to our hospital for further care. Her arterial blood pressure (BP) was as high as 142/62 mmHg. Echocardiography showed decreased left ventricular function with an ejection fraction of 19.5% and a left ventricular end-diastolic diameter of 25.8 mm (Z score = 2.71). We promptly started treatment with antihypertensive drugs. She had no congenital heart disease or any lesions that may have caused an increased afterload. There was no palpable mass suggestive of the tumour; however, close examination with abdominal echo and subsequent contrast-enhanced computed tomography confirmed a left kidney mass. Blood tests suggested renin-dependent hypertension due to the tumour causing an excessive afterload. Laparoscopic left nephrectomy improved cardiac function improved as BP decreased. Discussion: Blood pressure measurement is often omitted in daily practice when examining infants because of difficulty in measurement. However, BP may be the only detectable sign in patients with secondary hypertension before decompensated heart failure, and BP should also be measured in infants.

[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.

[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.

Influence of post-transplant mucosal-associated invariant T cell recovery on the development of acute graft-versus-host disease in allogeneic bone marrow transplantation.

Mucosal-associated invariant T (MAIT) and invariant natural killer T (iNKT) cells are T cell subpopulations that possess innate-like properties. We examined the impact of post-hematopoietic stem cell transplantation (HSCT) MAIT and iNKT cell recovery on the clinical outcomes of 69 patients who underwent allogeneic HSCT at Kyoto University Hospital. Multivariate analyses identified the absolute number of MAIT cells (< 0.48/µL on day 60 post-HSCT) as the sole independent risk factor for grade I-IV and grade II-IV acute graft-versus-host disease (aGVHD) among patients who underwent bone marrow transplantation; no correlation was observed between post-HSCT iNKT cell recovery and the development of aGVHD. Six of the 15 patients in the MAIThigh (≥ 0.48/µL) group developed aGVHD, five within the first 30 days post HSCT. In contrast, 13 of the 15 patients in the MAITlow (< 0.48/µL) group developed aGVHD, seven after day 30 post HSCT. The overall survival of the MAITlow group was slightly shorter than that of the MAIThigh group. Thus, the post-HSCT recovery of MAIT cells is closely related to the development of delayed onset aGVHD and the outcome of post-HSCT, suggesting its utility for identifying a subset of patients that requires more prolonged and/or intense GVHD prophylaxis.