Amy Heerema-McKenney

Gemtuzumab Ozogamicin in Children and Adolescents With De Novo Acute Myeloid Leukemia Improves Event-Free Survival by Reducing Relapse Risk: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531

PURPOSE To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification. PATIENTS AND METHODS Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children’s Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three). RESULTS There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v. 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P.04) but not OS (3 years: 69.4% v. 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v. 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v. 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v. 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v. 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07). CONCLUSION GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.

Propranolol for the treatment of a life-threatening subglottic and mediastinal infantile hemangioma.

An infant with a subglottic hemangioma remained in respiratory distress after multiple treatments failed and was found to have an enlarging mediastinal infantile hemangioma compressing the trachea. Treatment with oral propranolol resulted in resolution of symptoms within 2 days and a 50% reduction in lesion size within 1 week.

Diffuse myogenin expression by immunohistochemistry is an independent marker of poor survival in pediatric rhabdomyosarcoma: a tissue microarray study of 71 primary tumors including correlation with molecular phenotype.

The pathologic classification of rhabdomyosarcoma (RMS) into embryonal or alveolar subtype is an important prognostic factor guiding the therapeutic protocol chosen for an individual patient. Unfortunately, this classification is not always straightforward, and the diagnostic criteria are controversial in a subset of cases. Ancillary studies are used to aid in the classification, but their potential use as independent prognostic factors is rarely studied. The aim of this study is to identify immunohistochemical markers of potential prognostic significance in pediatric RMS and to correlate their expression with PAX-3/FKHR and PAX-7/FKHR fusion status. A single tissue microarray containing 71 paraffin-embedded pediatric RMSs was immunostained with antibodies against p53, bcl-2, Ki-67, CD44, myogenin, and MyoD1. The tissue microarray and whole paraffin blocks were studied for PAX-3/FKHR and PAX-7/FKHR gene fusions by fluorescence in situ hybridization and reverse transcription-polymerase chain reaction. Clinical follow-up data were available for each patient. Immunohistochemical staining results and translocation status were correlated with recurrence-free interval (RFI) and overall survival (OS) using the Kaplan-Meier method, the log-rank test, and Cox proportional hazard regression. The minimum clinical follow-up interval was 24 months (median follow-up=57 mo). On univariable analysis, immunohistochemical expression of myogenin, bcl-2, and identification of a gene fusion were associated with decreased 5-year RFI and 10-year OS (myogenin RFI P=0.0028, OS P=0.0021; bcl-2 RFI P=0.037, OS P=0.032; gene fusion RFI P=0.0001, OS P=0.0058). After adjustment for Intergroup Rhabdomyosarcoma Study-TNM stage, tumor site, age, tumor histology, and translocation status by multivariable analysis, only myogenin retained an independent association with RFI (P=0.034) and OS (P=0.0069). In this retrospective analysis, diffuse immunohistochemical reactivity for myogenin in RMS correlates with decreased RFI and OS, independent of histologic subtype, translocation status, tumor site, or stage.

β -Adrenergic receptor expression in vascular tumors

Propranolol has recently emerged as an effective therapy for infantile hemangiomas causing regression. The β-adrenergic receptor (AR) antagonist is thought to cause vasoconstriction by its effect on nitric oxide, block angiogenesis by its effect on vascular endothelial growth factor (VEGF), and induce apoptosis. In a prior report, we identified expression of β2-AR (B2-AR) and its phosphorylated form (B2-ARP) in a case of infantile hemangioma that responded to propranolol treatment. We now explore the expression of βARs on a variety of vascular lesions utilizing a tissue microarray containing 141 lesions, including infantile hemangiomas, angiosarcomas, hemangiomas, hemangioendotheliomas, and various vascular malformations. The array was immunostained for B2-AR, B2-ARP, and β3-AR (B3-AR), and the results scored for the intensity of endothelial cell expression as negative, weak positive, or strong positive. All phases of infantile hemangiomas had strong expression of all three receptors, with the exception of only weak expression of B2-ARP in the proliferative phase infantile hemangioma. Strong expression of all three receptors was present in many hemangiomas, hemangioendotheliomas, and vascular malformations. Absent to weak expression of all three receptors was seen in glomus tumor, hobnail hemangioendothelioma, pyogenic granuloma, and reactive vascular proliferations. This is the first study to report β-AR expression in a variety of vascular lesions. Although immunohistochemical expression of the receptors does not necessarily indicate that similar pathways of responsiveness to β-blockade are present, it does raises the possibility that β-blockade could potentially affect apoptosis and decrease responsiveness to VEGF. Additional study is warranted, as therapeutic options are limited for some patients with these lesions.

Microtubule-associated protein-2 is a sensitive marker of primary and metastatic neuroblastoma.

Background Microtubule-associated protein-2 (MAP-2) is a protein expressed in high levels in cells derived from the neural crest. To the best of our knowledge, MAP-2 expression has not been thoroughly evaluated in tissues outside of the central nervous tissue. We examined the diagnostic utility of MAP-2 as a marker of neuroblastoma and attempted to characterize the expression of this protein in other tumors in the morphologic differential diagnosis of neuroblastoma. Results MAP-2 showed significant cytoplasmic reactivity in 95% of primary and 100% of metastatic neuroblastomas. Included within this set of tumors were 3 undifferentiated neuroblastomas, all of which showed strong staining. MAP-2 did not show significant staining in the majority of other small round blue cell tumors within the morphologic differential. Additionally, MAP-2 showed comparable sensitivity in staining primary neuroblastomas as compared with synaptophysin, chromogranin, CD56, and β-catenin. In contrast to other markers of neuroblastoma, MAP-2 did not show significant cross reactivity to native bone marrow precursors, thus eliminating a potential source of confusion. In normal tissues, MAP-2 staining was essentially restricted to organs derived from the neural crest (adrenal medulla, endocrine organs). Variant patterns of staining were seen in exocrine organs, monocyte/macrophages and solitary fibrous tumor/hemangiopericytoma family of tumors. Rarely, high-grade adult sarcomas exhibiting strong cytoplasmic MAP-2 staining were seen. Conclusions MAP-2 is a sensitive and specific marker of neuroblastoma, both in the primary tumor and bone marrow biopsy settings. We think that MAP-2, in conjunction with synaptophysin, is a very powerful immunohistochemical marker in differentiating neuroblastoma from its morphologic mimics.

Fetal thrombotic vasculopathy: significance in liveborn children using proposed society for pediatric pathology diagnostic criteria.

Fetal thrombotic vasculopathy (FTV) is a recently described placental diagnosis associated with adverse perinatal outcomes. The Society for Pediatric Pathology proposed criteria for grading; however, no study has evaluated the proposed thresholds or established standards for large-vessel lesions. Using the Society for Pediatric Pathology criteria of 2 or more foci of 15 or more avascular villi or villous stromal-vascular karyorrhexis to represent severe FTV, this study examines the outcomes of liveborn infants with placentas demonstrating severe or nonsevere distal villous FTV (DV-FTV) and large-vessel FTV (LV-FTV). Control placentas over the same 3-year period were selected with minimal findings. Electronic medical records were queried for birth data, infant laboratory values, morbidities, and neurological development. The 139 cases included 102 with DV-FTV and 94 with LV-FTV. Compared with 111 controls, the 52 severe DV-FTV cases were significantly associated with delivery for fetal indications and small placental weight. The children with severe DV-FTV were more likely to be born small for gestational age, have intracranial hemorrhage, coagulopathy, neurological impairment, growth retardation, and evidence of systemic thrombosis/vasculopathy. Compared with controls, the 67 cases with severe LV-FTV were associated with maternal preeclampsia, delivery for fetal indications, small placental weight, umbilical cord abnormalities, and small size per gestational age. The 45 cases of DV-FTV or LV-FTV not classified as severe had similar characteristics as those without any FTV. In conclusion, severe FTV does appear associated with neurological injury, whereas those with nonsevere lesions have similar rates of morbidities as controls.

Pediatric acute myeloid leukemia as classified using 2008 WHO criteria: a single-center experience.

The classification of acute myeloid leukemia (AML) has evolved to the most recent World Health Organization (WHO) schema, which integrates genetic, morphologic, and prognostic data into a single system. However, this system was devised using adult data and how this system applies to a pediatric cohort is unknown. Performing a retrospective chart review, we examined our single-center experience with AML in 115 children and classified their leukemia using the WHO 2008 schema. We examined patient samples for mutations of FLT3, NPM1, and CEBPA. Overall survival was calculated within categories. In our pediatric population, most cases of AML had recurrent genetic abnormalities of favorable prognosis. More than 10% of patients in our series were categorized as AML, with myelodysplasia-related changes, an entity not well-described in pediatric patients. In addition, a large proportion of patients were categorized with secondary, therapy-related AML. To our knowledge, this is the first application of the WHO 2008 classification to a pediatric cohort. In comparison to adult studies, AML in the pediatric population shows a distinct distribution within the WHO 2008 classification.

Subinvolution of the Placental Site

Subinvolution of the placental site is characterized by the abnormal persistence of low-resistance widely dilated uteroplacental arteries in the absence of substantial amounts of retained products of conception. It is an important cause of secondary postpartum hemorrhage (PPH) that can result in considerable morbidity and mortality. Sonographically, subinvolution of the placental site manifests as increased vascularity within the myometrium in the location of the prior placental implantation site with increased low-resistance flow. Methods for treating patients with subinvolution of the placental site include conservative medical therapy, hysterectomy, and fertility-sparing percutaneous embolotherapy.

Gemtuzumab ozogamicin in infants with AML: Results from the Children’s Oncology Group trials AAML03P1 and AAML0531

To the editor: Infants younger than 1 year of age with acute myeloid leukemia (AML) often exhibit high-risk clinical and cytogenetic features.[1][1][⇓][2][⇓][3]-[4][4] They are also at increased risk of pulmonary and infectious toxicities, early death (ED), and treatment-related mortality (TRM

Successful treatment of systemic and central nervous system post-transplant lymphoproliferative disorder without the use of high-dose methotrexate or radiation.

Post‐transplant lymphoproliferative disorder (PTLD) describes a spectrum of conditions with highest incidence in the first year post‐solid organ transplant in pediatric patients. Central nervous system (CNS) involvement with PTLD carries high mortality risk with no consensus on optimal therapeutic regimen. We present the case of a 7‐year old heart transplant patient diagnosed with widespread monomorphic, CD20+, Epstein–Barr virus‐positive PTLD, including CNS involvement. In addition to immunosuppression reduction and rituximab, she was treated with multiagent systemic and intrathecal chemotherapy. She achieved a prompt and complete clinical and radiologic remission, which has been sustained for over 46 months since diagnosis. Pediatr Blood Cancer 2014;61:2107–2109.