Risk-based treatment approaches for neuroblastoma have been ongoing for decades. However, the criteria used to define risk in various institutional and cooperative groups were disparate, limiting the ability to compare clinical trial results. To mitigate this problem and enhance collaborative research, homogenous pretreatment patient cohorts have been defined by the International Neuroblastoma Risk Group classification system. During the past 30 years, increasingly intensive, multimodality approaches have been developed to treat patients who are classified as high risk, whereas patients with low- or intermediate-risk neuroblastoma have received reduced therapy. This treatment approach has resulted in improved outcome, although survival for high-risk patients remains poor, emphasizing the need for more effective treatments. Increased knowledge regarding the biology and genetic basis of neuroblastoma has led to the discovery of druggable targets and promising, new therapeutic approaches. Collaborative efforts of institutions and international cooperative groups have led to advances in our understanding of neuroblastoma biology, refinements in risk classification, and stratified treatment strategies, resulting in improved outcome. International collaboration will be even more critical when evaluating therapies designed to treat small cohorts of patients with rare actionable mutations.

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A B S T R A C T PurposeAlthough health disparities are well-described for many cancers, little is known about racial and ethnic disparities in neuroblastoma. To evaluate differences in disease presentation and survival by race and ethnicity, data from the Children's Oncology Group (COG) were analyzed. Patients and MethodsThe racial/ethnic differences in clinical and biologic risk factors, and outcome of patients with neuroblastoma enrolled on COG ANBL00B1 between 2001 and 2009 were investigated. ResultsA total of 3,539 patients (white, 72%; black, 12%; Hispanic, 12%; Asian, 4%; and Native American, Ͻ 1%) with neuroblastoma were included. The 5-year event-free survival (EFS) rates were 67% for whites (95% CI, 65% to 69%), 69% for Hispanics (95% CI, 63% to 74%), 62% for Asians (95% CI, 51% to 71%), 56% for blacks (95% CI, 50% to 62%), and 37% for Native American (95% CI, 17% to 58%). Blacks (P Ͻ .001) and Native Americans (P ϭ .04) had a higher prevalence of high-risk disease than whites, and significantly worse EFS (P ϭ .01 and P ϭ .002, respectively). Adjustment for risk group abrogated these differences. However, closer examination of the EFS among high-risk patients who remained event free for 2 years or longer, revealed a higher prevalence of late-occurring events among blacks compared with whites (hazard ratio, 1.5; 95% CI, 1.0 to 2.3; P ϭ .04). ConclusionBlack and Native American patients with neuroblastoma have a higher prevalence of high-risk disease, accounting for their worse EFS when compared with whites. The higher prevalence of late-occurring events among blacks with high-risk disease suggests that this population may be more resistant to chemotherapy. Studies focused on delineating the genetic basis for the racial disparities observed in this study are planned.

Purpose Case reports and small prospective trials suggest that administering targeted therapies to patients with advanced cancer and an identified genomic target may be associated with clinical benefit. The Targeted Agent and Profiling Utilization Registry (TAPUR) study, a phase II prospective, nonrandomized, multibasket pragmatic clinical trial, aims to identify signals of drug activity when US Food and Drug Administration–approved drugs are matched to prespecified genomic targets in patients with advanced cancer, outside of approved indications. Methods Patients eligible to participate in TAPUR are age ≥ 12 years and have advanced measurable or evaluable solid tumors, multiple myeloma, or B-cell non-Hodgkin lymphoma. Eligible participants are matched to any of the 16 US Food and Drug Administration–approved study drugs based on protocol-specified genomic inclusion and exclusion criteria. Genomic profiling from any Clinical Laboratory Improvement Amendments–certified, College of American Pathologists–accredited laboratory is acceptable. The treating physician selects the treatment from the available study therapies or consults with the TAPUR Molecular Tumor Board. Participants are placed into multiple parallel cohorts defined by tumor type, genomic alteration, and drug. The primary study end point within each cohort is objective response or stable disease of at least 16 weeks duration. Secondary end points include safety, progression-free survival, and overall survival. Results More than 1,000 participants have thus far been registered, and more than 800 have been treated with a TAPUR study drug. Two study cohorts have permanently closed to enrollment because of lack of antitumor activity, and 12 have expanded to the second stage of enrollment after promising preliminary activity. Conclusion The TAPUR study will describe the efficacy and toxicity of the targeted drugs used outside of their approved indications when matched to a somatic genomic variant.

Mononuclear cell apheresis for chimeric antigen receptor T-cell therapy is well tolerated and safe, and it is possible to obtain an adequate quantity of CD3+ lymphocytes for chimeric antigen receptor T-cell manufacturing in heavily pretreated patients who have low lymphocyte counts.

Aims: The classification of paediatric spindle mesenchymal tumours is evolving, and the spectrum of socalled 'infantile fibrosarcoma' has expanded to include tumours with NTRK, BRAF and MET gene fusions. RETrearranged paediatric spindle cell neoplasms are an emerging group; there is sparse literature on their clinical, pathological and genetic features, and their nosological place in the canon of soft tissue tumours is uncertain. In this study, we report five RET-rearranged paediatric spindle cell tumours with fusion partners MYH10, KIAA1217 and CLIP2. Methods and results: The tumours occurred in the pelvic region, paraspinal region, kidney and subcutaneous tissue of hand and abdomen. The patients' ages ranged from 6 months to 13 years (median 1 year). The tumours were composed of monomorphic spindle cells arranged in a fascicular pattern. Lesional cells had minimally atypical ovoid or tapered nuclei and pale cytoplasm with indistinct borders. Necrosis was not identified. Mitoses numbered three to 12 per 10 high-power field. Cases showed inconsistent and variable expression of S100, CD34 and SMA. Clinical behaviour ranged from small lesions potentially cured by simple resection to large lesions exhibiting metastasis, but responsive to kinase inhibitor therapy. Conclusions: Our findings help to define RET-rearranged spindle cell tumours. Although it is likely that these tumours comprise part of the morphological and clinical spectrum of infantile fibrosarcoma (IFS), identification of RET gene alteration is important for its unique therapeutic implications.

Background The incidence of SMN within the first ten years of diagnosis in high-risk neuroblastoma patients treated with modern, intensive therapy is unknown. Further, the underlying germline genetics that contribute to SMN in these survivors are not known. Methods The International Neuroblastoma Risk Group (INRG) database of patients diagnosed from 1990–2010 was analyzed. SMN risk was accessed by cumulative incidence, standardized incidence ratios (SIR), and absolute excess risk (AER). A candidate gene-based association study evaluated genetic susceptibility to SMN in neuroblastoma survivors. Results Of the 5,987 patients in the INRG database with SMN data enrolled in a clinical trial, 43 (0.72%) developed a SMN. The 10-year cumulative incidence of SMN for high-risk patients was 1.8% (95% CI 1.0–2.6%) compared to 0.38% (95% CI: 0.22–0.94%) for low-risk patients (P=0.01). High-risk patients had an almost 18-fold higher incidence of SMN compared to age and sex matched controls (SIR=17.5 (95% CI: 11.4–25.3), AER=27.6). For patients treated on high- and intermediate-risk clinical trials, the SIR of acute myelogenous leukemia (AML) was 106.8 (95% CI: 28.7–273.4) and 127.7 (95%CI: 25.7–373.3), respectively. Variants implicating DNA repair genes XRCC3 (rs861539: P=0.006; Odds Ratio: 2.04, 95%CI: 1.19–3.46) and MSH2 (rs17036651: P=0.009; Odds Ratio: 0.26, 95% CI: 0.08–0.81) were associated with SMN. Conclusion The intensive multi-modality treatment strategy currently used to treat high-risk neuroblastoma is associated with a significantly increased risk of secondary AML. Defining the interactions of treatment exposures and genetic factors that promote the development of SMN is critical for optimizing survivorship care