Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that remains difficult to treat. Even with current standard HLH therapy, only approximately half of patients will experience complete resolution of disease, and early mortality remains a significant problem. Salvage therapies have been described only in limited case reports, and there are no large studies of second-line therapies. Procedure We reviewed the charts of 22 pediatric and adult patients who received alemtuzumab for the treatment of refractory HLH at our center or in consultation with our group. Results Patients had received conventional therapies for a median of 8 weeks (range 2–70) prior to alemtuzumab, and treatment immediately prior to alemtuzumab included dexamethasone (100%), etoposide (77%), cyclosporine (36%), intrathecal hydrocortisone +/− methotrexate (23%), methylprednisolone (9%), and rituximab (14%). Patients received a median dose of 1mg/kg alemtuzumab (range 0.1–8.9mg/kg) divided over a median of 4 days (range 2–10). Fourteen patients experienced an overall partial response, defined as at least a 25% improvement in 2 or more quantifiable symptoms or laboratory markers of HLH 2 weeks following alemtuzumab (64%). Five additional patients had a 25% or greater improvement in a single quantifiable symptom or laboratory marker of HLH (23%). Seventy-seven percent of patients survived to undergo allogeneic hematopoietic cell transplantation. Patients experienced an acceptable spectrum of complications, including CMV and adenovirus viremia. Conclusion Alemtuzumab appears to be an effective salvage agent for refractory HLH, leading to improvement and survival to HCT in many patients. Prospective trials to define optimal dosing levels, schedules, and responses are needed.

Neuroblastoma, a childhood neoplasm arising from neural crest cells, is characterized by a diversity of clinical behavior ranging from spontaneous remission to rapid tumor progression and death. To a large extent, outcome can be predicted by the stage of disease and the age at diagnosis. However, the molecular events responsible for the variability in response to treatment and the rate of tumor growth remain largely unknown. Over the past decade, transformation-linked genetic changes have been identified in neuroblastoma tumors that have contributed to the understanding of tumor predisposition, metastasis, treatment responsiveness, and prognosis. The Children's Oncology Group recently developed a Neuroblastoma Risk Stratification System that is currently in use for treatment stratification purposes, based on clinical and biologic factors that are strongly predictive of outcome. This review discusses the current risk-based treatment approaches for children with neuroblastoma and recent advances in biologic therapy.

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in three infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (seven and twelve from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated-ERK, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, while CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, ten with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis, and provides guidance for the clinical management of this emerging histiocytic entity.

Retinoblastoma is the most common intraocular tumor in children. Current management includes broad-based treatments such as chemotherapy, enucleation, laser therapy, or cryotherapy. However, therapies that target specific pathways important for retinoblastoma progression could provide valuable alternatives for treatment. MicroRNAs are short, noncoding RNA transcripts that can regulate the expression of target genes, and their aberrant expression often facilitates disease. The identification of post-transcriptional events that occur after the initiating genetic lesions could further define the rapidly aggressive growth displayed by retinoblastoma tumors. In this study, we used two phenotypically different retinoblastoma cell lines to elucidate the roles of miRNA-31 and miRNA-200a in tumor proliferation. Our approach confirmed that miRNAs-31 and -200a expression is significantly reduced in human retinoblastomas. Moreover, overexpression of these two miRNAs restricts the expansion of a highly proliferative cell line (Y79), but does not restrict the growth rate of a less aggressive cell line (Weri1). Gene expression profiling of miRNA-31 and/or miRNA-200a-overexpressing cells identified differentially expressed mRNAs associated with the divergent response of the two cell lines. This work has the potential to enhance the development of targeted therapeutic approaches for retinoblastoma and improve the efficacy of treatment.

Although ionizing radiation induces germline mutations in animals, human studies of radiation-exposed populations have not detected an effect. We conducted a case-control study of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation, to investigate gonadal radiation exposure of parents from medical sources before their child's conception. Parents of 206 cases from 9 North American institutions and 269 controls participated; fathers of 184 cases and 223 friend and relative controls and mothers of 204 cases and 260 controls provided information in telephone interviews on their medical radiation exposure. Cases provided DNA for RB1 mutation testing. Of common procedures, lower GI series conferred the highest estimated dose to testes and ovaries. Paternal history of lower GI series was associated with increased risk of retinoblastoma in the child (matched odds ratio (OR)=3.6, 95% confidence interval (CI) 1.2, 11.2, 2-sided P=0.02), as was estimated total testicular dose from all procedures combined (OR for highest dose=3.9, 95% CI 1.2, 14.4, P =0.02). Maternal history of lower GI series was also associated with increased risk (OR=7.6, 95% CI 2.8, 20.7, P <0.001) as was estimated total dose (OR for highest dose=3.0, 95% CI 1.4, 7.0, P =0.005). The RB1 mutation spectrum in cases of exposed parents did not differ from that of other cases. Some animal and human data support our findings of an association of gonadal radiation exposure in men and women with new germline RB1 mutation detectable in their children, although bias, confounding, and/or chance may also explain the results.

10506 Background: Metastatic RB is associated with a poor prognosis. Previous small series suggested that intensified systemic chemotherapy with or without radiation therapy (RT) may improve outcomes in this population. COG opened this prospective, multi-institutional, international trial to study the effectiveness of this approach. Methods: Patients with regional extra-ocular RB (stage 2 or 3) were treated with 4 cycles of intensive conventional chemotherapy (vincristine 0.05 mg/kg/day, cisplatin 3.5 mg/kg/day, cyclophosphamide 65 mg/kg x 2 days, etoposide 4 mg/kg x 2 days) followed by involved-field RT (4500 cGy). Two strata of patients with metastatic RB [stage 4a: distant metastases not involving the central nervous system involvement (CNS); and stage 4b (CNS metastases)/trilateral RB)] were treated with 4 cycles of the same chemotherapy. Patients with ≥ partial response then received 1 cycle of high-dose carboplatin (Calvert formula with AUC = 7/day, maximum 16.7 mg/kg/day) on days -8 to -6, thiotepa (10 mg/kg/day), & etoposide (8.3 mg/kg/day) on days -5 to -3 with autologous hematopoietic stem cell rescue on day 0. Patients with metastatic RB who did not achieve an adequate response to chemotherapy also received RT. Results: Sixty subjects (20 in each stratum) were enrolled; 57 were eligible and included in the analyses (based on data current to June 30, 2016). Toxicity was significant as expected and there were 2 therapy related deaths. Event-free survival (EFS) at 36 months was 87.7% (90% CI 65.4 to 96.0%) for subjects with stage 2 or 3 disease, 79.3% (90% CI 54.2 to 91.6%) for subjects with stage 4a disease and 8.0% (90% CI 1.0 to 25.1%) for subjects with stage 4b/trilateral disease. The observed results significantly improved the EFS in each stratum compared with historical results used for planning the study. Conclusions: This is the first prospective, multi-institutional, international study to show that intensive multi-modality therapy is highly effective for patients with regional extra-ocular RB and metastatic RB not involving the CNS. More effective therapy is required for patients with CNS RB. Clinical trial information: NCT00554788.

Background Adherence to oral chemotherapy, including 6‐mercaptopurine (6‐MP), is suboptimal in pediatric acute lymphoblastic leukemia (ALL), which is associated with increased risk of relapse. Study objectives were to examine self‐reported adherence to 6‐MP and related barriers to adherence, mapped to the capability, opportunity, motivation, and behavior (COM‐B) model for behavior change. Procedure Forty‐nine parents (median, 39 years old; 76% females) and 15 patients (median, 17 years old, 20% females) completed the study survey. Results Suboptimal adherence was reported in 43% of parents and 73% of patients. Most parents and patients (80% and 90%, respectively) reported ≥1 adherence barrier. Parents reported difficulty helping their child meet others with ALL (43%), contacting community organizations (39%), and meeting other parents (37%). Patients reported difficulty finding out what their medications are (40%), finding out what 6‐MP does (47%), and meeting other patients (40%). Using the COM‐B, we found that parents and patients endorsed barriers in multiple components, especially physical (55%, 67%) and social opportunity (56%, 47%), highlighting that barriers to adherence may be multifaceted. Conclusions Our results suggest that parents and patients with ALL face various prevalent barriers to medication adherence and provide insight into the development of behavioral interventions focused on promoting adherence, which is essential to prevent relapse and optimize health outcomes in ALL.

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