A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer.

BACKGROUND: Preclinical models show that an antiangiogenic regimen at low-dose daily (metronomic) dosing may be effective against chemotherapy-resistant tumors. We undertook a prospective, open-label, single-arm, multi-institutional phase II study to evaluate the efficacy of a "5-drug" oral regimen in children with recurrent or progressive cancer. PROCEDURE: Patients ≤21 years old with recurrent or progressive tumors were eligible. Treatment consisted of continuous oral celecoxib, thalidomide, and fenofibrate, with alternating 21-day cycles of low-dose cyclophosphamide and etoposide. Primary endpoint was to assess, within eight disease strata, activity of the 5-drug regimen over 27 weeks. Blood and urine angiogenesis markers were assessed. RESULTS: One hundred one patients were enrolled; 97 began treatment. Median age was 10 years (range: 191 days-21 years); 47 (49%) were female. Disease strata included high-grade glioma (HGG, 21 patients), ependymoma (19), low-grade glioma (LGG, 12), bone tumors (12), medulloblastoma/primitive neuroectodermal tumor (PNET, 8), leukemia (4), neuroblastoma (3), and miscellaneous tumors (18). Treatment was generally well tolerated; most common toxicities were hematologic. Twenty-four (25%) patients completed 27 weeks therapy without progression, including HGG: 1 (5%), ependymoma: 7 (37%), LGG: 7 (58%), medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%). Best response was complete response (one patient with medulloblastoma), partial response (12), stable disease (36), progressive disease (47), and inevaluable (1). Baseline serum thrombospondin levels were significantly higher in patients successfully completing therapy than in those who progressed (P = 0.009). CONCLUSION: The 5-drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata.

The impacts of total body irradiation on umbilical cord blood hematopoietic stem cell transplantation.

Background: Umbilical cord blood hematopoietic stem cells are commonly used for hematopoietic system reconstitution in recipients after umbilical cord blood transplantation (UCBT). However, the optimal conditioning regimen for UCBT remains a topic of debate. The exact impact of total body irradiation (TBI) as a part of conditioning regimens remains unknown. Objectives: The aim of this study was to evaluate the impacts of TBI on UCBT outcomes. Design: This was a multi-institution retrospective study. Methods: A retrospective analysis was conducted on the outcomes of 136 patients receiving UCBT. Sixty-nine patients received myeloablative conditioning (MAC), in which 33 underwent TBI and 36 did not, and 67 patients received reduced-intensity conditioning (RIC), in which 43 underwent TBI and 24 did not. Univariate and multivariate analyses were conducted to compare the outcomes and the post-transplant complications between patients who did and did not undergo TBI in the MAC subgroup and RIC subgroup, respectively. Results: In the RIC subgroup, patients who underwent TBI had superior overall survival (adjusted hazard ratio [aHR] = 0.25, 95% confidence interval [CI]: 0.09-0.66, p = 0.005) and progression-free survival (aHR = 0.26, 95% CI: 0.10-0.66, p = 0.005). However, in the MAC subgroup, there were no statistically significant differences between those receiving and not receiving TBI. Conclusion: In the setting of RIC in UCBT, TBI utilization can improve overall survival and progression-free survival. However, TBI does not show superiority in the MAC setting.

GOPC-ROS1 Fusion Due to Microdeletion at 6q22 Is an Oncogenic Driver in a Subset of Pediatric Gliomas and Glioneuronal Tumors.

ROS1 is a transmembrane receptor tyrosine kinase proto-oncogene that has been shown to have rearrangements with several genes in glioblastoma and other neoplasms, including intrachromosomal fusion with GOPC due to microdeletions at 6q22.1. ROS1 fusion events are important findings in these tumors, as they are potentially targetable alterations with newer tyrosine kinase inhibitors; however, whether these tumors represent a distinct entity remains unknown. In this report, we identify 3 cases of unusual pediatric glioma with GOPC-ROS1 fusion. We reviewed the clinical history, radiologic and histologic features, performed methylation analysis, whole genome copy number profiling, and next generation sequencing analysis for the detection of oncogenic mutation and fusion events to fully characterize the genetic and epigenetic alterations present in these tumors. Two of 3 tumors showed pilocytic features with focal expression of synaptophysin staining and variable high-grade histologic features; the third tumor aligned best with glioblastoma and showed no evidence of neuronal differentiation. Copy number profiling revealed chromosome 6q22 microdeletions corresponding to the GOPC-ROS1 fusion in all 3 cases and methylation profiling showed that the tumors did not cluster together as a single entity or within known methylation classes by t-Distributed Stochastic Neighbor Embedding.

Idiopathic thrombocytopenic purpura complicated by an intracranial hemorrhage secondary to an arteriovenous malformation.

OBJECTIVE: To report a case of idiopathic thrombocytopenic purpura (ITP) complicated by an intracranial hemorrhage (ICH) in a child with a previously undiagnosed arteriovenous malformation. CASE: We describe a child with known ITP who developed a severe headache, was evaluated in an emergency department of a community hospital, and was found by computer tomography (CT) scan to have an ICH. Despite treatment with platelets, corticosteroids, and intravenous immunoglobulin, she subsequently developed an acute change in mental status. A second CT scan showed that the hemorrhage had significantly increased in size despite treatment. The patient underwent an emergent splenectomy prior to a craniotomy to remove the hemorrhage. At the time of surgery, it was discovered that she had an arteriovenous malformation at the sight of the hemorrhage. Her recovery was unremarkable and she was discharged to home with no neurologic sequelae. CONCLUSIONS: ICH is a rare but life-threatening complication of ITP. Neurologic symptoms in a child with ITP should be quickly evaluated by CT scan. Most experts suggest careful observation for most cases of ITP. However, when neurologic symptoms occur, more aggressive treatment options must be used. Care of this child included an emergency splenectomy prior to her craniotomy. Pediatric emergency medicine practitioners must be aware of these neurologic symptoms and must not hesitate to involve pediatric surgeons and neurosurgeons in the care of the child. Prompt recognition and early intervention are the keys to improving outcomes when ICH complicates ITP.

Immunotherapy for Epstein-Barr virus-associated tumors.

Epstein-Barr Virus (EBV) is associated with a number of tumors, including lymphomas in solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients, patients with the acquired immunodeficiency syndrome (AIDS), Burkitt's lymphoma, as well as a subset of patients with nasopharyngeal carcinoma (NPC) and Hodgkin's disease (HD). The types of latent EBV infections vary in these tumors, which influences the EBV antigens expressed and ultimately the immunogenicity of tumor cells. Not all EBV associated malignancies are directly related to altered cellular immunity, as is the case with EBV induced lymphoproliferations in immunocompromised patients. Treatment strategies have ranged from restoration of normal cellular immunity, which is generally successful in SOT and HSCT patients, anti-B cell monoclonal antibodies, and conventional chemotherapy and radiation. The fact that these tumors express EBV antigens for which many individuals have high circulating levels of protective cytotoxic T lymphocytes (CTL) has lead to investigation into the applicability of adoptive transfer of EBV specific T cells. Initial success with adoptive immunotherapy for HSCT and SOT patients has lead to current studies examining the feasibility and efficacy of this strategy for other EBV associated tumors, such as NPC and HD. We will review the pathogenesis of these disorders, current therapies, and future investigations aimed at targeting EBV antigen expression on these tumors.

Attributable costs of central line-associated bloodstream infections in a pediatric hematology/oncology population.

BACKGROUND: Although several studies have estimated the attributable cost and length of stay (LOS) of central line-associated bloodstream infections (CLABSIs) in the pediatric intensive care unit setting, little is known about the attributable costs and LOS of CLABSIs in the vulnerable pediatric hematology/oncology population. METHODS: We studied a total of 1562 inpatient admissions for 291 pediatric hematology/oncology patients at a single tertiary care children's hospital in the mid-Atlantic region between January 2008 and May 2011. Costs were normalized to year 2011 dollars. Propensity score matching was used to estimate the effect of CLABSIs on total cost and LOS while controlling for other covariates. RESULTS: Sixty CLABSIs occurred during the 1562 admissions. Compared with the patients without a CLABSI, those who developed a CLABSI tended to be older (9.0 years vs 7.5 years; P = .026) and to have a tunneled catheter (46.7% vs 27.0%) and a peripherally inserted central catheter (20.0% vs 11.2%) as opposed to other types of catheters (P < .0001). Propensity score matching yielded matched groups without significant differences in patient characteristics. In the propensity score analysis, the attributable LOS of a CLABSI was 21.2 days (P < .0001), and the attributable cost of a CLABSI was $69,332 (P < .0001). CONCLUSIONS: Among pediatric hematology/oncology patients, CLABSI was associated with an additional LOS of 21 days and increased costs of nearly $70,000. These findings may inform decisions regarding the value of investing in efforts to prevent CLABSIs in this vulnerable population.