Lymphoproliferative disorders (LPDs) result from the dysregulated production of lymphocytes and include polyclonal benign and monoclonal malignant conditions. LPDs occur in immunocompromised hosts and are sometimes observed in children with primary immunodeficiency. The Epstein-Barr virus (EBV) infects B cells, which are immortalized, and thus EBV-associated B-cell LPD is frequently observed. X-linked lymphoproliferative syndrome (XLP) is a prototype of hereditary EBV-LPD, but XLP-like diseases have recently been reported. They include ITK deficiency, CD27 deficiency, MAGT1 deficiency, STK4 deficiency, coronin-1A deficiency, activated PI3K syndrome, CTPS1 deficiency, autoimmune lymphoproliferative syndrome, and chronic active EBV infection. These diseases are clinically characterized by hemophagocytic lymphohistiocytosis, chronic EB viremia, lymphoma, and dysgammaglobulinemia. Some diseases are associated with a diminished number of invariant NKT cells, which play an important role against EBV infection. EBV-LPD is observed only in humans, and the study of hereditary EBV-LPD will lead to the understanding of human immunology.

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L-Asparaginase (ASP)-induced thrombosis (AIT) is a serious complication related to the treatment of acute lymphoblastic leukemia (ALL) and lymphoma. However, its epidemiology and management remain to be determined in the pediatric population in Japan. Here, to investigate the incidence and characteristics of AIT, and to survey the coagulation tests performed and anticoagulant prophylaxis during ASP-containing induction therapy for childhood ALL and lymphoma in Japan, a retrospective survey of 96 JACLS treatment centers was conducted. Forty-seven (49%) of the centers responded. Among 1,586 patients treated with ASP from 2002 to 2011, eight (0.50%) were found to have AIT. Of these eight patients, seven experienced AIT during the induction phase, and in six of them, AIT was located in the central nervous system. A steroid was concurrently used in all the patients with AIT. Four of the eight patients had fever and two had bacteremia. At the onset of AIT, the median antithrombin (AT) activity was 71% (range, 53–90%), the fibrinogen concentration was 93 mg/dL (29.8–260 mg/dL), and the D-dimer concentration was 2.2 μg/mL (1.0–4.6 μg/mL). One patient died of AIT and another suffered from AIT-related sequelae. Among the 45 centers that provided information, 40 (89%) measured AT activity twice or three times a week, 43 (96%) prophylactically administered an AT concentrate, and 21 (47%) routinely transfused with fresh frozen plasma during the induction therapy with ASP. AIT occurred despite the prophylaxis with the AT concentrate. No test could predict the onset of AIT accurately. Novel markers and a preventive strategy for AIT need to be established.

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The radiation field of craniospinal irradiation (CSI) for malignant brain tumor includes the entire skull and vertebra. Therefore, aggressive chemotherapy after CSI causes severe myelosuppression and prolonged duration of treatment; eventually, the dose intensity decreases. To maintain the dose intensity, we performed peripheral blood stem cell (PBSC) collection with granulocyte colony-stimulating factor (G-CSF) alone and administered aggressive chemotherapy followed by autologous peripheral blood stem cell transplantation (aPBSCT) in eight patients with malignant brain tumors. We attempted to complete PBSC collection so as to start CSI within 2 weeks of surgery. In six patients with initial presentation of their tumors, the median CD34⁺ cell number harvested was 12.6×10⁶/kg (3.9–21.6×10⁶/kg). However, in two out of the six and in two additional patients with relapsed disease, the number of cells collected for several transplants was insufficient. Therefore, in these four patients, chemotherapy with aPBSCT was started and a second PBSC collection was attempted. A sufficient number of CD34⁺ cells (13.7–42.1×10⁶/kg) could be collected after one cycle of aPBSCT. Although WBC counts tended to be higher during the administration of G-CSF, possibly owing to the postoperative acute phase reaction, we did not observe any severe adverse events. In all the patients enrolled, chemotherapy followed by aPBSCT was accomplished at planned intervals without prolonged myelosuppression. Although our cohort is too small to yield a conclusion, PBSC collection with G-CSF alone within 2 weeks of surgery is feasible and appears to be safe. Further study is needed to assess the usefulness of our approach to treating malignant brain tumors requiring CSI during the early postoperative period.

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Mesenchymal stem cells (MSCs) have been reported to be effective against refractory acute graft-versus-host disease (GVHD) following stem cell transplantation because of their immunosuppressive properties. The cases of two pediatric patients who underwent MSC infusions against grade III steroid-refractory acute GVHD that developed after cord blood transplantation (CBT) are reported. One patient was a 4-year-old boy with juvenile myelomonocytic leukemia who developed grade III GVHD involving the liver and gut. His GVHD subsided markedly after the MSC infusion. The other patient was a 6-year-old girl with acute myeloid leukemia who developed grade III GVHD involving the gut. MSC infusion was not effective, but her condition improved gradually with the subsequent administration of conventional immunosuppressive drugs. These two are considered to be the first pediatric patients treated with MSCs in Japan.

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L-Asparaginase (L-Asp) therapy for pediatric acute lymphoblastic leukemia often results in coagulopathy. In this report, we describe two cases of first remission during reinduction therapy and one onset case during induction therapy in all cases without coagulopathy. We evaluated the comprehensive functions of coagulation and fibrinolysis by simultaneous thrombin and plasmin generation assay (T/P-GA). The ratios of endogenous potential of thrombin (T-EP) and plasmin peak height (P-peak) of patients’ plasmas to those of normal plasma were calculated. All patients showed increased T-EP ratios and decreased P-peak ratios. The most significant difference in both ratios of 1.5–2.6-fold was shown at the later phase of L-Asp therapy, consistent with the lowest levels of fibrinogen (59–106 mg/dL). The patients’ hemostatic dynamics indicate a thrombotic tendency, since their coagulation state was procoagulant and low fibrinolytic. We will study more cases to elucidate the pathologic condition of coagulopathy associated with L-Asp therapy.

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We present a rare neonatal case of tuberous sclerosis complex (TSC) associated with sacrococcygeal chordoma. A male infant was found to have a sacrococcygeal tumor at birth. Then, he was diagnosed as having TSC from various imaging examinations that demonstrated other multiple tumors of the brain, heart and mediastinum. During the neonatal period, we excised the sacrococcygeal tumor invading the spinal canal, and an intracranial tumor was removed at the age of 5 months. Pathologically, both tumors were identified as chordomas, and a germline TSC2 mutation of these tumors was proved by heterozygosity analysis. At the age of 4 years, tumors of the heart and mediastinum decreased in size without local recurrence and he is presently being followed up in our hospital.

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We describe an EBV-related lymphoproliferative disorder in a 12-year-old boy who neither has evidence of recurrent infection nor family history of immunodeficiency disease. He had suffered from prolonged high fever, general fatigue and cervical lymphadenopathy for six months before admission. The EBV-related B cell lymphoproliferative disorder was confirmed by surgical open biopsy of the lymph nodes. Corticosteroid treatment was temporarily effective, and lymph node enlargement recurred in multiple areas. Although memory B cells disappeared from the patient’s peripheral blood 4 months after the initiation of steroid treatment, no hypogammaglobulinemia was observed during his clinical course. Rituximab monotherapy was initiated for this steroid-resistant and recurrent disease. After the administration of rituximab, the enlarged lymph nodes dramatically shrunk, and steroid administration was stopped immediately after rituximab therapy. No recurrence occurred for 24 months after rituximab therapy.

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A four-month-old girl with nausea and pale skin was brought to our hospital. Her blood pressure was unmeasurable. Laboratory analysis revealed an Hb level of 4.7 g/dL and an AFP level of 960,215 ng/mL. CT showed a giant liver tumor and intra-abdominal bleeding. We tried to stabilize her with a transfusion; however, 5 h after she was brought to our hospital, her condition deteriorated, and she went into hemorrhagic shock. We tried to treat her by transcatheter arterial embolization, but we had difficulty in securing the blood flow of the femoral artery and internal carotid artery owing to abdominal compartment syndrome. Then, we found that the axillary artery was palpable and finally we secured the blood flow of the axillary artery and performed a transcatheter arterial embolization. After that, she underwent chemotherapy and hepatectomy. No recurrence has been observed for three years. We consider that the axillary artery is a viable option for securing blood flow in cases of abdominal compartment syndrome.

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