Hidetaka Niizuma

PTHrP-independent hypercalcemia with increased proinflammatory cytokines and bone resorption in two children with CD19-negative precursor B acute lymphoblastic leukemia.

Hypercalcemia in childhood acute lymphoblastic leukemia (ALL) is rare and occasionally associated with parathyroid hormone‐related protein (PTHrP). However, the pathogenesis of PTHrP‐independent hypercalcemia remains unclear. We report two children with precursor B ALL who had marked hypercalcemia (15.8 and 16.6 mg/dl, respectively) and disseminated osteolysis. Serum tumor necrosis factor‐α (TNF‐α) and IL‐6 were markedly elevated, whereas 1,25(OH)2 vitamin D3, intact PTH and PTHrP were decreased or undetected. Analysis of urinary deoxypyridinoline (DPY) or bone biopsy of the osteolytic lesion showed an increased bone resorption, and administration of bisphosphonate improved the hypercalcemia. Patients had ALL with immunophenotype positive for CD10, CD34, and HLA‐DR but negative for CD19 and obtained remission with chemotherapy. These findings suggest that increased osteoclastic bone resorption via stimulation with TNF‐α and IL‐6 may be mechanism causing PTHrP‐independent hypercalcemia in some patients with precursor B ALL lacking CD19 expression. Pediatr Blood Cancer 2007;49:990–993.

Acute renal failure due to leukemic cell infiltration followed by relapse at multiple extramedullary sites in a child with acute lymphoblastic leukemia.

Acute renal failure due to leukemic infiltration into the kidney is rare in childhood acute lymphoblastic leukemia (ALL). We report here a five year-old boy with ALL who presented acute renal failure caused by leukemic infiltration at onset. Treatment with predonisolone and hemodialysis was effective. However, he showed persistent or repeated relapses at extramedullary sites, such as central nervous system, testis, and pancreas, suggesting that leukemic cells of this patient may have had a high affinity to extramedullary organs. On the basis of previous reports and the experience of this patient, intensive treatment may be needed in ALL children with renal involvement.

Selective expansion of donor-derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome.

IPEX syndrome is a rare and fatal disorder caused by absence of regulatory T cells (Tregs) due to congenital mutations in the Forkhead box protein 3 gene. Here, we report a patient with IPEX syndrome treated with RIC followed by allogeneic BMT from an HLA‐matched sibling donor. We could achieve engraftment and regimen‐related toxicity was well tolerated. Although the patient was in mixed chimera and the ratio of donor cells in whole peripheral blood remained relatively low, selective and sustained expansion of Tregs determined as CD4+CD25+Foxp3+ cells was observed. Improvement in clinical symptoms was correlated with expansion of donor‐derived Tregs and disappearance of anti‐villin autoantibody, which was involved in the pathogenesis of gastrointestinal symptoms in IPEX syndrome. This clinical observation suggests that donor‐derived Tregs have selective growth advantage in patients with IPEX syndrome even in mixed chimera after allogeneic BMT and contribute to the control of clinical symptoms caused by the defect of Tregs.

Vincristine-resistant Kasabach–Merritt phenomenon successfully treated with low-dose radiotherapy

In 1940, Kasabach and Merritt reported the case of an infant with a huge angioma causing thrombocytopeniarelated purple spots. This condition became known as the Kasabach–Merrit phenomenon (KMP), characterized by a huge hemangioma associated with thrombocytopenia and microangiopathic hemolytic anemia due to consumption coagulopathy [1]. The incidence of KMP in infants with a huge hemangioma is approximately 0.3%, but it is said that the mortality rate exceeds 30% among patients. A number of therapies have been reported for the treatment of KMP, but none have been uniformly effective. We report a case of life-threatening KMP, in which hemangioma of the right thigh (tufted angioma type) was successfully treated by low-dose radiotherapy after concurrent therapy with the agents prednisolone (PSL), interferon a-2a (IFN a-2a), and vincristine (VCR) failed to control it. 2 Case report

Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan

BackgroundX-linked inhibitor of apoptosis protein (XIAP) deficiency is a rare immunodeficiency that is characterized by recurrent hemophagocytic lymphohistiocytosis (HLH) and splenomegaly and sometimes associated with refractory inflammatory bowel disease (IBD). Although hematopoietic stem cell transplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory compared with those for SLAM-associated protein deficiency and familial HLH.AimTo investigate the outcomes and adverse events of HSCT for patients with XIAP deficiency, a national survey was conducted.MethodsA spreadsheet questionnaire was sent to physicians who had provided HSCT treatment for patients with XIAP deficiency in Japan.ResultsUp to the end of September 2016, 10 patients with XIAP deficiency had undergone HSCT in Japan, 9 of whom (90%) had survived. All surviving patients had received a fludarabine-based reduced intensity conditioning (RIC) regimen. Although 5 patients developed post-HSCT HLH, 4 of them survived after etoposide administration. In addition, the IBD associated with XIAP deficiency improved remarkably after HSCT in all affected cases.ConclusionThe RIC regimen and HLH control might be important factors for successful HSCT outcomes, with improved IBD, in patients with XIAP deficiency.

Somatic BRAF c.1799T>A p.V600E Mosaicism syndrome characterized by a linear syringocystadenoma papilliferum, anaplastic astrocytoma, and ocular abnormalities

Genetic mosaicism for somatic mutations of oncogenes is common in genodermatoses, which can be complicated with extra‐cutaneous abnormalities. Here we describe an infant with a congenital anaplastic astrocytoma, a linear syringocystadenoma papilliferum, and ocular abnormalities. The BRAF c.1799T>A p.V600E mutation was detected in both the brain and skin tumor cells but not in the blood or normal skin cells, suggesting somatic mosaicsism for the mutation. Clinically, the brain tumor gradually became life threatening without any response to conventional chemotherapies including carboplatin, etoposide, and temozolomide. Vemurafenib, a BRAF p.V600E inhibitor, was administered daily after the detection of the BRAF mutation. This single‐agent therapy was dramatically effective against the anaplastic astrocytoma; the tumor regressed, the cerebrospinal fluid cell count and protein levels decreased to normal levels, and hydrocephalus resolved. Moreover, other lesions including a corneal cyst also responded to vemurafenib. The brain tumor continued shrinking after 6 months of treatment. We present a genodermatosis syndrome associated with BRAF c.1799T>A p.V600E mosaicism. This syndrome may represent a new entity in the mosaic RASopathies, partly overlapping with Schimmelpenning‐Feuerstein‐Mims syndrome, which is driven by mosaicism of HRAS and/or KRAS activating mutations. Screening for BRAF c.1799T>A p.V600E is especially useful for those with malignant tumors, because it is one of the most‐druggable targets.

Successful cord blood transplantation with reduced-intensity conditioning for childhood cerebral X-linked adrenoleukodystrophy at advanced and early stages.

Niizuma H, Uematsu M, Sakamoto O, Uchiyama T, Horino S, Onuma M, Matsuhashi T, Rikiishi T, Sasahara Y, Minegishi M, Tsuchiya S. Successful cord blood transplantation with reduced‐intensity conditioning for childhood cerebral X‐linked adrenoleukodystrophy at advanced and early stages. 
Pediatr Transplantation 2012: 16: E63–E67.

Refractory chronic immune thrombocytopenic purpura in a child with acute lymphoblastic leukemia

Immune thrombocytopenic purpura (ITP) has been associated with several hematologic malignancies such as Hodgkin and non-Hodgkin lymphomas and chronic lymphocytic leukemia, but it is rare in children with acute lymphoblastic leukemia (ALL). Here, we report a 7-year-old girl with chronic ITP during early intensive phase of chemotherapy for ALL. She underwent splenectomy because thrombocytopenia had persisted even after treatment with intravenous immunoglobulin (IVIG), steroids, vincristine, rituximab, and anti-D antibody. After splenectomy, her platelet count had recovered, and maintenance therapy could be resumed with a support of IVIG. To our knowledge, this is the first child case of chronic ITP during chemotherapy for ALL and splenectomy was effective in this patient.

A case series of CAEBV of children and young adults treated with reduced‐intensity conditioning and allogeneic bone marrow transplantation: a single‐center study

Epstein–Barr virus (EBV)‐infected T or NK cells cause chronic active EBV infection (CAEBV). Allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment for CAEBV patients. However, chemotherapy prior to HSCT and optimal conditioning regimen for allogeneic HSCT are still controversial.

Eosinophilic Pustular Folliculitis Occurring after Bone Marrow Transplantation in a Child with Aplastic Anaemia

Sin Eosinophilic pustular foiliculitis (EPF), first described by Ofuji. is characterized by the development of pruritic follicular papules and pustules, mainly on the face, trunk and upper arms ( I ). It is classified into three subtypes: classieal, paediatric and HlV-associated EPF (2). In addition, there have been several reported cases of an assoeiation between EPF and haematological diseases (3-6). We deseribe here the development of EPF in a ehild with aplastic anaemia after bone marrow transplantation (BMT).