Christopher L. Moertel

Lupus anticoagulant and protein S deficiency in children with postvaricella purpura fulminans or thrombosis

OBJECTIVE The objective of this study was to determine the cause of purpura fulminans, disseminated intravascular coagulation, or thrombosis in seven children with varicella. All children were found to have a lupus anticoagulant and acquired protein S deficiency. Thrombosis in five children was associated with presumed or documented infection with streptococcus. STUDY DESIGN Coagulation tests included determinations of the activated partial thromboplastin time, the prothrombin time, the dilute Russell viper venom time, the prothrombin F 1 + 2 fragment, the C4b-binding protein (C4b), total and free protein S antigen, and clotting activities of factors II, V, VII, and X and of protein C and protein S. Autoantibodies to phospholipids, cardiolipin, and protein S were determined in enzyme-linked immunosorbent assays. RESULTS All children had a lupus anticoagulant and acquired protein S deficiency. Thrombosis in five children was associated with presumed or documented infection with streptococcus. All children transiently expressed free protein S deficiency, elevated levels of IgG, IgM, or both binding to protein S, the lupus anticoagulant, and increased concentration of the F 1+2 fragment. Four children also had antiphospholipid or anticardiolipin antibodies. In one child a purified IgG fraction cross-reacted with both protein S and a specific varicella antigen. CONCLUSIONS A subset of children with varicella infection, some of whom are coinfected with streptococcus, are prone to development of a lupus anticoagulant and an autoantibody to protein S, which results in acquired free protein S deficiency. Such children are at risk of having life-threatening thrombotic events.

Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome neurofibromatosis type 1. To identify genetic drivers of MPNST development, we used the Sleeping Beauty (SB) transposon-based somatic mutagenesis system in mice with somatic loss of transformation-related protein p53 (Trp53) function and/or overexpression of human epidermal growth factor receptor (EGFR). Common insertion site (CIS) analysis of 269 neurofibromas and 106 MPNSTs identified 695 and 87 sites with a statistically significant number of recurrent transposon insertions, respectively. Comparison to human data sets identified new and known driver genes for MPNST formation at these sites. Pairwise co-occurrence analysis of CIS-associated genes identified many cooperating mutations that are enriched in Wnt/β-catenin, PI3K-AKT-mTOR and growth factor receptor signaling pathways. Lastly, we identified several new proto-oncogenes, including Foxr2 (encoding forkhead box R2), which we functionally validated as a proto-oncogene involved in MPNST maintenance.

Excessive spinal cord toxicity from intensive central nervous system- directed therapies

Background. Intrathecal chemotherapy, radiation therapy, and systemic chemotherapy are used for both prophylaxis and treatment of central nervous system (CNS) disease in hematologic malignancies. Twenty‐three cases of myelopathy that occurred in patients who received intensive CNS‐directed therapy were evaluated to identify the determinants of this severe CNS toxicity.

Central nervous system atypical teratoid tumor/rhabdoid tumor: response to intensive therapy and review of the literature.

Central nervous system atypical teratoid/rhabdoid tumor (ATT/RT) of infancy and childhood is a unique histologic entity with an extremely aggressive natural history. Standard therapy for infant and childhood medulloblastoma, for which this entity is often mistaken, has been ineffective; most children survive less than 12 months after diagnosis. Intensified therapy has been recently used for children with this disease, with promising results [1,2].We report four cases of ATT/RT in young children; all had subtotal resections and localized disease at diagnosis. One child treated prior to bone marrow transplant availability died of progressive disease 9 months after diagnosis. Another child, treated with high-dose chemotherapy and radiotherapy in preparation for bone marrow transplant, had a recurrence and died 20 months after diagnosis, without undergoing the transplant. Two children received high-dose chemotherapy and autologous bone-marrow transplant and had a good response to treatment; one survived 19 months, the other child is free of disease 46 months from diagnosis. Intensified therapy has altered the natural history of central nervous system ATT/RT.

Type I Pleuropulmonary Blastoma: A Report From the International Pleuropulmonary Blastoma Registry

PURPOSE Type I pleuropulmonary blastoma (PPB) is a rare, cystic lung neoplasm in infants characterized by subtle malignant changes and a good prognosis. Recurrences after type I PPB are usually advanced type II or type III neoplasms with a poor prognosis. This article describes the first collection of type I PPB cases, analyzes outcome based on treatments of surgery or surgery plus chemotherapy, and presents type I PPB management recommendations. PATIENTS AND METHODS Type I PPB cases from the International PPB Registry and literature were evaluated using standard statistical methods for outcomes based on age at diagnosis, sex, thoracic side, surgical extent, length of follow-up, constitutional/familial disease, pre-existing lung cysts, intrathoracic findings, and treatments (surgery or surgery and chemotherapy). RESULTS Thirty-eight type I PPB cases were identified: Registry (n = 30) and literature (n = 8). Twenty children had surgery alone; eight (40%) experienced recurrence; and four died. Eighteen children had surgery and adjuvant chemotherapy; one experienced recurrence and died. All recurrences were type II or III PPB. Recurrence-free survival was higher in the surgery + chemotherapy group (P = .01); overall survival did not differ (P = .18). The improved recurrence-free survival was found only in males. Four of nine children with recurrence survived. CONCLUSION Adjuvant chemotherapy appears to benefit type I PPB patients. Benefit limited to males requires broader substantiation. Salvage after types II and III recurrence is poor (four of nine; 44%). A rigorous surveillance schedule after type I PPB diagnosis might detect early recurrence and be an acceptable alternative to adjuvant chemotherapy.

The use of implantable venous access devices (IVADs) in children with hemophilia

PURPOSE Implantable venous access devices (IVADs), either centrally or peripherally implanted, have become increasingly popular in children with hemophilia to assist in the early treatment of bleeding episodes and in the prevention of arthropathy. Their use has been associated with complications including thrombosis, thrombophlebitis, and infection. We attempted to better define whether the benefits associated with IVADs in this population outweight the associated risks. PATIENTS AND METHODS We studied the medical records of 35 children from the University of Minnesotas Comprehensive Hemophilia Center who received IVADs between 1992 and 1996. RESULTS There was no bleeding or thrombophlebitis associated with IVADs in our population. One patient required removal of a central IVAD due to thrombosis. The central IVADs were associated with local infection and bacteremia rates of 3% and 33%, respectively. The rates of local infection and bacteremia associated with peripheral IVADs were both 25%. The majority of infections were cleared with antibiotics, and ports remained intact. Both types of IVADs were associated with a high patient/parent satisfaction. CONCLUSION Despite being associated with a significant incidence of infection, we believe the benefits of IVADs for children with hemophilia and their families outweigh the risks. Possible explanations for the observed infection rates are discussed.

Cerebral metastasis and other central nervous system complications of pleuropulmonary blastoma

Pleuropulmonary blastoma (PPB) is a rare tumor of pleura and lung in young children. Central nervous system (CNS) complications, particularly cerebral parenchymal metastases, occur in aggressive forms of PPB: Types II and III PPB. This article evaluates cerebral and meningeal metastases, cerebrovascular events (CVA) caused by tumor emboli, spinal cord complications, and intracranial second malignancies in PPB.

PTEN and NF1 inactivation in Schwann cells produces a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumors.

The genetic evolution from a benign neurofibroma to a malignant sarcoma in patients with neurofibromatosis type 1 (NF1) syndrome remains unclear. Schwann cells and/or their precursor cells are believed to be the primary pathogenic cell in neurofibromas because they harbor biallelic neurofibromin 1 (NF1) gene mutations. However, the phosphatase and tensin homolog (Pten) and neurofibromatosis 1 (Nf1) genes recently were found to be comutated in high-grade peripheral nerve sheath tumors (PNST) in mice. In this study, we created transgenic mice that lack both Pten and Nf1 in Schwann cells and Schwann cell precursor cells to validate the role of these two genes in PNST formation in vivo. Haploinsufficiency or complete loss of Pten dramatically accelerated neurofibroma development and led to the development of higher grade PNSTs in the context of Nf1 loss. Pten dosage, together with Nf1 loss, was sufficient for the progression from low-grade to high-grade PNSTs. Genetic analysis of human malignant PNSTs (MPNST) also revealed downregulation of PTEN expression, suggesting that Pten-regulated pathways are major tumor-suppressive barriers to neurofibroma progression. Together, our findings establish a novel mouse model that can rapidly recapitulate the onset of human neurofibroma tumorigenesis and the progression to MPNSTs.

Homozygous α-Thalassemia Treated with Intrauterine Transfusions and Unrelated Donor Hematopoietic Cell Transplantation

Recently, intrauterine transfusions and hematopoietic cell transplantation (HCT) have changed homozygous alpha-thalassemia from a frequently fatal disease to a potentially survivable condition. We present a patient with Hemoglobin Barts disease who was cured after failing to engraft with 1 unrelated HCT, but engrafting after a second unrelated donor HCT.

Pilomyxoid astrocytoma treated successfully with vemurafenib

The BRAF V600E missense mutation is known to be present in a subset of central nervous system tumors. We report a patient with a BRAF V600E mutated pilomyxoid astrocytoma who failed multiple conventional chemotherapy regimens. Treatment with vemurafenib, a molecularly targeted therapy against the mutant BRAF V600E kinase, combined with vinblastine resulted in tumor regression. Furthermore, this patient experienced almost immediate progression of disease after holding vemurafenib for only 2–3 weeks, suggesting that the tumor response is vemurafenib dependent. This population of patients may benefit from targeted therapy and testing of individual tumors for BRAF mutations is justified. Pediatr Blood Cancer 2014;61:2099–2100.