Gary M. Woods

Reduced intensity transplantation for congenital amegakaryocytic thrombocytopenia: Report of a case and review of the literature

CAMT is a bone marrow failure syndrome that usually presents with isolated thrombocytopenia soon after birth. HSCT is curative, and MAC is associated with increased transplant‐related morbidity and mortality, especially in the unrelated setting. We used a RIC regimen with alemtuzumab, fludarabine, and melphalan in a seven‐month‐old patient with CAMT who underwent a MUD HSCT. The transplant was well tolerated with few complications. Neutrophil and platelet engraftment occurred on day +12 and +29, respectively, and she had 100% donor chimerisms on days +19.

A multi-institutional experience in pediatric high-grade glioma.

Introduction: Pediatric high-grade gliomas are rare tumors with poor outcomes and incompletely defined management. We conducted a multi-institutional retrospective study to evaluate association of clinical, pathologic, and treatment characteristics with outcomes. Materials and methods: Fifty-one patients treated from 1984 to 2008 at the Ohio State University or University of Michigan were included. Histologic subgroups were compared. Log-rank and stepwise Cox proportional hazard modeling were used to analyze progression-free survival (PFS) and overall survival (OS) within the whole group, grade III subgroup, grade IV subgroup, and sub-total resection/biopsy subgroup. Results: Median OS was 27.6 months. Grade III histology, complete tumor resection, and cerebral tumor location correlated with improved PFS and OS. Temozolomide use and chemotherapy after radiotherapy or chemoradiation (CRT) were associated with better PFS while seizure at presentation was associated with better OS. In multivariate analysis, complete resection and chemotherapy following radiotherapy or CRT were independent predictors for improved PFS and OS. For grade III and IV subgroups, complete resection was associated with improved OS (grade III) and seizure presentation was associated with improved OS (grade IV). In the incompletely resection subgroup, temozolomide use and concurrent CRT independently correlated with improved PFS, while higher radiation dose (≥59.4 Gy) and adjuvant chemotherapy were independently associated with improved OS. Discussion: Total resection and receiving chemotherapy adjuvant to radiation or CRT are most closely associated with improved PFS and OS. For higher risk incompletely resected patients, temozolomide use and treatment intensification with concurrent CRT, adjuvant chemotherapy, and higher radiation dose were associated with improved outcomes.

Radiation therapy may increase metastatic potential in alveolar rhabdomyosarcoma

We previously determined that radiation could be safely administered using a mouse‐flank in vivo model to both alveolar (Rh30) and embryonal (Rh18) rhabdomyosarcoma xenografts. Mice from both tumor lines in this experiment developed metastases, an event not previously described with these models. We sought to determine if radiation‐induced changes in gene expression underlie an increase in the metastatic behavior of these tumor models.

FANCD2 is a potential therapeutic target and biomarker in alveolar rhabdomyosarcoma harboring the PAX3-FOXO1 fusion gene.

Purpose: Alveolar rhabdomyosarcoma that harbors the PAX3–FOXO1 fusion gene (t-ARMS) is a common and lethal subtype of this childhood malignancy. Improvement in clinical outcomes in this disease is predicated upon the identification of novel therapeutic targets. Experimental Design: Robust mouse models were used for in vivo analysis, and molecular studies were performed on xenografts treated in parallel. Two independent patient sets (n = 101 and 124) of clinically annotated tumor specimens were used for analysis of FANCD2 levels and its association with clinical and molecular characteristics and outcomes. Results: Our xenograft studies reveal a selective suppression of FANCD2 by m-TOR kinase inhibition and radiosensitization of the t-ARMS line only. In the initial patient set, we show that FANCD2 transcript levels are prognostic in univariate analysis, and are significantly associated with metastatic disease and that the copresence of the translocation and high expression of FANCD2 is independently prognostic. We also demonstrate a significant and nonrandom enrichment of mTOR-associated genes that correlate with FANCD2 gene expression within the t-ARMS samples, but not within other cases. In the second patient set, we show that on a protein level, FANCD2 expression correlates with PAX3–FOXO1 fusion gene and is strongly associated with phospho-P70S6K expression in cases with the fusion gene. Conclusions: Our data demonstrate that FANCD2 may have a significant role in the radiation resistance and virulence of t-ARMS. Indirectly targeting this DNA repair protein, through mTOR inhibition, may represent a novel and selective treatment strategy. Clin Cancer Res; 20(14); 3884–95. ©2014 AACR.

Light Transmission Aggregometry Does Not Correlate With the Severity of δ-Granule Platelet Storage Pool Deficiency.

Delta-granule platelet storage pool deficiency (&dgr;-PSPD) is a poorly studied bleeding diathesis resulting from either decreased granule content or decreased average number of platelet &dgr;-granules. Light transmission aggregometry (LTA) is commonly used to evaluate for &dgr;-PSPD and platelet electron microscopy (EM) is used to confirm the diagnosis. Currently, little data exist examining the relationship between the likelihood of abnormal platelet aggregation findings, severity of &dgr;-granule deficiency on platelet EM, and severity of bleeding symptoms in patients with &dgr;-PSPD. Patients diagnosed with &dgr;-PSPD by platelet EM who also underwent LTA testing were identified at a single institution for correlation between severity of bleeding, average number of platelet &dgr;-granules, and number of agonist abnormalities on LTA. No statistically significant association was identified between the average number of &dgr;-granules per platelet and likelihood of an abnormal LTA. LTA abnormalities were quite varied and only 50% diagnosed with &dgr;-PSPD on EM had abnormal aggregation testing. Also, no correlation was seen between the number of clinical bleeding symptoms, number of average &dgr;-granules per platelet, and the number of LTA agonist abnormalities. Our findings highlight the difficulties inherent in the laboratory evaluation of platelet function.

Activated Partial Thromboplastin Time versus Anti-Factor Xa Levels for Monitoring Unfractionated Heparin Therapy in Children: An Institutional Experience

To the Editor: Epidemiologic studies from Canada and the Netherlands estimated the incidence of venous thrombo-embolism (VTE) to be 0.07 to 0.14/10,000 children (and neonates), respectively.1,2 A recent study, however, has indicated a 70% increase in the annual rate of VTE in hospitalized children from 2001 to 2007.3 This increase is likely an outcome of improved survival of critically ill children with multiple comorbid conditions and increased use of central venous lines (CVL).3 Unfractionated heparin (UFH), low–molecular-weight heparins and warfarin are the most commonly used anticoagulants in children. Given its short half-life and immediate, complete reversibility with protamine sulfate, heparin remains the therapeutic modality of choice for critically ill children, children on extracorporeal membrane oxygenation (ECMO) and children with left ventricular assist devices (LVADs). A prospective audit of UFH use in a tertiary care children’s hospital indicated that 15% of children admitted to the inpatient service were exposed to UFH.4 The activated partial thromboplastin time (APTT) has historically been used to monitor heparin anticoagulation. The traditional anticoagulation range of APTT (1.5 to 2.5 times the control) in children receiving UFH is based on a prospective, adult study which documented a low risk of recurrent thrombosis with an APTT >1.5 times the control.5 APTT measurement, particularly in children, is affected by several confounders—(i) baseline APTT is prolonged in neonates and infants, additionally infants have low levels of natural anticoagulants, (ii) faster clearance of heparin in infants and younger children, and (iii) elevated levels of factor VIII and fibrinogen in critically ill children may cause shortening of the APTT.6–8 The current American College of Chest Physicians (ACCP) guidelines recommend that the APTT range in children on UFH anticoagulation correspond to an antiFactor Xa (FXa) activity of 0.35 to 0.7U/mL or a protamine titration range of 0.2 to 0.4U/mL. Recent pediatric publications, however, report a poor correlation between APTT and anti-FXa activity.9–13 While many children’s hospitals are transitioning from an APTT-based dose adjustment nomogram to an anti-FXa-based nomogram, it is unclear if this change is associated with improved patient outcomes with regards to bleeding and/ or recurrent VTE.9

Pediatric Oral/Maxillofacial Soft Tissue Sarcomas: A Clinicopathologic Report of Four Cases

Pediatric soft tissue sarcomas of the oral/maxillofacial region are rare neoplasms that present significant difficulty with respect to treatment and local control measures. We report four cases of pediatric oral/maxillofacial soft tissue sarcomas from our tertiary care pediatric hospital and emphasize the rarity of these malignancies and the challenges encountered in treating these lesions, and suggest areas for further research. We conclude that multimodal therapy and interdisciplinary cooperation are paramount to successful management of these lesions.

Secondary Acute Myeloid Leukemia in a One-Year-Old Girl Diagnosed with JAK2-V617F Mutation Positive Myeloproliferative Neoplasm.

Myeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by hyperproliferation of hematologic cell lines and have been associated with tyrosine kinase JAK2-V617F mutations. Secondary acute myeloid leukemia (sAML) is a known complication of JAK2-V617F+ MPNs and bears a poor prognosis. Although the evolution of a JAK2-V617F+ MPN to a mixed-lineage leukemia has been reported in the pediatric population, no evolutions into sAML have been described. We present a case of a one-year-old girl diagnosed with JAK2-V617F+ MPN with evolution into sAML. Despite initial morphologic remission, she eventually relapsed and succumbed to her disease.