Background and Aims

Breakthrough chemotherapy-induced nausea and vomiting (CINV) is defined as CINV occurring after adequate anti-emetic prophylaxis. It affects 30-50% of children receiving chemotherapy. Olanzapine and metoclopramide are two drugs recommended for the treatment of breakthrough CINV in children, without adequate evidence. We conducted an open-label, single-center, phase III randomized controlled trial comparing the safety and efficacy of olanzapine and metoclopramide for treating breakthrough CINV.

Methods

Children aged 5-18 years who developed breakthrough CINV after receiving moderately or highly emetogenic chemotherapy, were randomly assigned to the metoclopramide or olanzapine arm. The primary end-point of the study was the proportion of patients who achieved a complete response (CR), defined as no vomiting or retching and no nausea during the 72-hours after the administration of the first dose of metoclopramide or olanzapine. We assumed that the CR rates in the metoclopramide arm would be 40% and this would improve to 70% in the olanzapine arm. A sample size of 80 (40/arm) was required to show a superiority of olanzapine over metoclopramide with a power of 80% and an alpha of 5%.

Results

Eighty-patients were analyzed (39 in olanzapine arm and 41 in metoclopramide arm). CR rates were significantly higher in the olanzapine arm compared to the metoclopramide arm for vomiting (72% vs. 39%, P = 0.003) and nausea (59% vs. 34%, P=0.026). Seven (17%) patients in the metoclopramide arm crossed over to the olanzapine arm and none crossed over in the olanzapine arm (P<0.001). The mean nausea score in the olanzapine arm was significantly lower than the metoclopramide arm after the initiation of the rescue anti-emetic (P=0.01). Hyperglycemia and drowsiness were more commonly seen in the olanzapine arm.

Conclusions

Olanzapine is superior to metoclopramide for the treatment of breakthrough CINV in children. Drowsiness and hyperglycemia need to be monitored closely in children receiving olanzapine for breakthrough CINV.

Background and Aims

Venous Thromboembolism(VTE), other TEs including Pulmonary Embolism(PE), arterial thrombosis(AT), have been extensively studied in adult cancer patients with limited data in children. We prospectively analyzed the clinical profile and outcomes of Pediatric Cancer Associated Thrombosis(PCATs) in children with malignancies.

Methods

Children<15-years age, with confirmed diagnosis of malignancy, treated at our center from July-2015 to Feb-2020 were eligible. A standardized approach for detection, management and data collection after due consent was followed on an Institutional Ethics Committee approved protocol.

Results

Of 6132 eligible children, PCATs were seen in 150(2.4%), at a median age of 8.5(1-15)years with male:female-1.83:1. Of these, 143(95.55%) had VTE, 4(2.85%)AT, 3(2%)PE. Majority developed thrombosis on chemotherapy-105(70%), 39(26%) at baseline, and 6(4%) post-operatively. Commonest site was Central Nervous System(CNS)-57(38.0%), predominantly(82%) in hematolymphoid(HL) malignancies; then upper limb venous system-42(28%). HL malignancies were more prone to PCAT(3.22%) than solid tumors(ST)(1.55%)(OR-2.11,95%CI:1.48-3.01,p<0.001). PCAT-associated malignancies were ALL-63(42.0%) of which two-thirds were in Induction, AML-24(16%) and Lymphoma-16(10.67%). Thirty-nine(26%)TEs were associated with Central-Venous Lines(CVLs). More than half patients received L-Asparaginase-78(52%), or steroids-88(58.67%). Anticoagulation was with Low-molecular-weight Heparin(LMWH) in 131(87.33%), Unfractionated Heparin(UFH) in 5, Fondaparinux in 1. Five patients with AT received aspirin. Response imaging done in 106(70.67%)children showed - 81(76.42%) complete resolution, 13(12.26%)partial resolution, 8(7.54%)stable and 4(3.77%) progression of thrombus. Death was attributable to TE in 6(4.0%)children. On univariate analysis, age>10-years, AML and Lymphoma were significantly associated with TEs, and the first two retained significance on multivariate analysis with OR-2.33(95%CI:1.59-3.41,p<0.001) and 2.32(95%CI:1.45-3.71,p<0.001)respectively. In ALL, age>10years(OR-2.60,95%CI:1.52-4.54,p<0.001) and T-ALL(OR-1.95,95%CI:1.09- 3.38,p=0.025) were significantly associated with thrombosis. The 4-year Event-Free Survival(EFS) of HL malignancies was impacted by TEs(TEs-32.5±14%,Non-TEs-55.7±2.4%;p=0.028), but not Overall Survival(OS)(TEs-53.2±22%,Non-TEs-67.6%±2.4%;p=0.264).

Conclusions

Incidence of PCATs in our cohort was 2.4%, predominantly in older children with HL malignancies, early in treatment, usually resolves completely and rarely results in mortality. In HL malignancies, TEs reduce EFS, indicating that strategies for prevention may improve outcomes.

Background and Aims

Few studies have evaluated social determinants of outcomes disparities for children with acute lymphoblastic leukemia (ALL). We investigated the association of Area Deprivation Index (ADI), a composite measure of neighborhood socioeconomic disadvantage, with overall survival (OS) among children and adolescents with ALL.

Methods

We obtained demographic and clinical data, geocoded addresses at diagnosis, and vital status on all Texas children diagnosed with ALL from 1995 to 2011 (N=4,104). Using the US Census Bureau 2010 census tracts geography, we computed ADI scores for all census tract in Texas and grouped the tracts into quartiles: least, third-most, second-most, and most disadvantaged. We mapped children to ADI quartiles based on residence at diagnosis, and estimated OS using Cox regression models adjusted for sex, race/ethnicity, age at diagnosis and metropolitan/non-metropolitan residence.

Results

Estimated five-year OS ranged from 89% (95% confidence interval [CI] 87-91%) for children in the least disadvantaged tracts to 79% (95% CI 76-81%) for children in the most disadvantaged tracts (p<0.001). Estimated ten-year OS ranged from 85% (95% CI 82-88%) for children in the least disadvantaged Census tracts to 75% (95% CI 72-77%) for children in the most disadvantaged tracts (p<0.001).

Increased hazard ratios (HRs) for death were observed for children in the third-most (HR 1.30, 95% CI 1.02-1.65), second-most (HR 1.40, 95% CI 1.10-1.76) and most (HR 1.82, 95% CI 1.46-2.27) disadvantaged tracts relative to children in the least disadvantaged tracts after adjustment for sex, race/ethnicity, age at diagnosis, and urban/rural residence. In stratified analyses, area disadvantage was more strongly associated with OS in males than females.

Conclusions

We demonstrate a strong association between neighborhood socioeconomic disadvantage and 5-year OS in this analysis of over 4,100 children with ALL, which differed by sex, highlighting the substantial contributions of social-environmental factors to childhood cancer survival.

Background and Aims

Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A gene rearrangements and a poor outcome. In infants, data on MRD are scarce. We evaluated the value of MRD in a large series of KMT2A rearranged infant ALL patients treated according to Interfant-06. This protocol used a randomization between lymphoid-style consolidation (IB) versus myeloid-style consolidation (ADE/MAE).

Methods

MRD was measured in 241 infants with KMT2A rearranged ALL by PCR of rearranged MLL, immunoglobulin and/or T-cell receptor genes, at end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5*10^-4), and high (≥5*10^-4).

Results

MLL MRD PCR and Ig/TcR MRD results were concordant in 92-94% of samples. EOI MRD levels predicted outcome, albeit less than in older children; 6-year disease free survival (DFS [SE]) was 59.1% (8.0), 44.1% (5.8), 32.5 % (5.4), for negative, intermediate and high MRD levels, respectively (p= 0.0036).

Surprising results were seen when analyzing MRD results according to consolidation treatment given. In patients treated with lymphoid-style consolidation 6-year DFS (SE) was 76.9% (10.3), 46.2% (7.1), 21.8% (7.4) for negative, intermediate and high MRD levels, respectively (p<0.0001), while in myeloid-style treated patients the corresponding figures were 45.0% (10.7), 40.5% (9.7) and 44.4% (8.4). This implies that patients with low EOI MRD benefit from lymphoid IB consolidation (DFS 76.9% versus 45.0%) and patients with high MRD benefit from myeloid ADE/MAE consolidation (DFS 44.4% versus 21.8%).

Negative, intermediate and high EOC MRD levels were associated with 6-year DFS in both treatment groups: 68.2 %(5.7), 36.2% (6.6), 12.3% (8.8) (p<0.0001).

Conclusions

Induction therapy selects patients for subsequent therapy: Patients with high EOI MRD benefit from AML-like consolidation whereas patients with low MRD benefit from ALL-like consolidation. Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.

Background and Aims

Neuroblastoma arises at prenatal stages from the sympatho-adrenal neural crest lineage, but a stem cell has not yet been identified. It is a remarkably heterogeneous disease, with outcomes ranging from spontaneous regression to relapse and death. Heterogeneity is reflected at the cellular level, with two distinct tumor cell subtypes: adrenergic and mesenchymal; the latter being more chemotherapy resistant. The ability of these lineages to interconvert may contribute to therapeutic resistance. However, mechanisms underlying neuroblastoma plasticity remain poorly understood. To understand neuroblastoma plasticity, we analyzed patient tumors using single-cell transcriptomics.

Methods

Fresh human neuroblastomas and normal fetal adrenals were collected and SNP array CGH was performed on all tumor samples. Single-cell RNA sequencing (scRNAseq; 10x Chromium) was performed on neuroblastomas and normal fetal adrenal tissue. scRNAseq data analysis was performed using conos and velocyto algorithms. Sample-wise cross-comparison of SNP array CGH and scRNA-seq data identified cells harboring tumor-specific copy number variations (CNVs). Findings were validated using immunohistochemistry and fluorescent in situ hybridization (FISH).

Results

We sequenced 17 samples from 15 children, obtaining 72,606 high quality single transcriptomes. The clinical cohort included all genetic subsets of various age and risk groups with different clinical outcomes. We identified 18 cell types common to most samples, spanning tumor, immune and stromal compartments. In addition to heterogeneous adrenergic and mesenchymal populations, we identified a subpopulation of stem-like malignant cells resembling multipotent Schwann cell precursors (SCPs). This SCP-like population connected adrenergic and mesenchymal neuroblastoma compartments through transitions reminiscent of the SCP cell-fate fork that occurs during normal development.

Conclusions

By performing in-depth profiling of human neuroblastoma at single-cell level, we expand the potential reservoirs of malignant cells significant for tumor development. We identify intratumoral plasticity mechanisms relevant for therapeutic resistance and relapse. Knowledge of such mechanisms provide an important basis for improving clinical management and treatment.

Background and Aims

The importance of immune checkpoint markers in tumor microenvironment of retinoblastoma remains unclear. Therefore, the aim of this study was to identify the prognostic significance of pathological findings and expression of immune checkpoint marker (PD-1 and PD-L1) in the tumor microenvironment of both primary and chemoreduced retinoblastoma and correlate with clinicopathological parameters.

Methods

There were total of 262 prospective cases included prospectively in which 144 cases underwent primary enucleation and 118 cases received chemotherapy/radiotherapy before enucleation (chemoreduced retinoblastoma) in this study. Immunohistochemistry, qRT-PCR and western blotting were performed to evaluate the expression pattern of immune checkpoint markers in primary and chemoreduced retinoblastoma. In-vitro study was also performed to validate these finding in retinoblastoma cells.

Results

Tumor microenvironment was different for both primary and chemoreduced retinoblastoma. Expression of PD-1 was found in 29/144 (20.13%) and 48/118 (40.67%) in primary and chemoreduced retinoblastoma respectively, whereas PD-L1 was expressed in 46/144 (31.94%) and 22/118 (18.64%) in cases of primary and chemoreduced retinoblastoma respectively. In-vitro studies showed the expression of PD-L1 not PD-1 in Y79 cells. On multivariate analysis, massive choroidal invasion, bilaterality and PD-L1 expression (p=0.034) were found to be statistically significant factors in primary retinoblastoma whereas PD-1 expression (p=0.015) and foamy macrophages were significant factors in chemoreduced retinoblastoma. Overall survival reduced in cases of PD-L1 (80.76%) expressed primary retinoblastoma, and PD-1 (63.28%) expressed chemoreduced retinoblastoma.

Conclusions

This study predicts a relevant role of the immune checkpoint markers in primary and chemoreduced retinoblastoma with their prognostic significance. Differential expression of these markers in both group of retinoblastoma is a novel finding and might be an interesting and beneficial target for chemoresistant tumors.