Primary Neuroblastoma of the Thymus.

ABSTRACT: Primary neuroblastoma is the most common extracranial solid tumor in children and may occur anywhere along the sympathetic chain, but most commonly occur in abdominal/retroperitoneal region including the adrenal glands, followed by the thorax. In children, the most primary neuroblastomas in the thorax are in the posterior mediastinum. We present herein an extremely rare case of primary neuroblastoma of thymus in pediatric patient.

Survival patterns of childhood neuroblastoma: an analysis of clinical data from Southern-Eastern European countries.

The prognosis of children with neuroblastoma (NBL) can be dismal with significant variations depending on the stage and biology of the tumor. We assessed the event-free (EFS) and overall (OS) survival using harmonized data from three Southern-Eastern European (SEE) countries. Data for 520 incident NBL cases (2009-2018) were collected from Greece, Slovenia and Russia. Kaplan-Meier curves were fitted, and EFS/OS were derived from Cox proportional models by study variables including the protocol-based risk-group (low/observation, intermediate, high). Over one-third of cases were coded in the high-risk group, of which 23 children (4.4%) received treatment with anti-ganglioside 2 (GD2) mAb. Survival rates were inferior in older (OS 5-year; 1.5-4.9 years: 61%; EFS 5-year; 1.5-4.9 years: 48%) compared to children younger than 1.5 years (OS 5-year; <1.5 years: 91%; EFS 5-year; <1.5 years: 78%). Predictors of poor OS included stage 4 (hazard ratio, HR OS : 18.12, 95% confidence intervals, CI: 3.47-94.54), N-myc amplification (HR OS : 2.16, 95% CI: 1.40-3.34), no surgical excision (HR OS : 3.27, 95% CI: 1.91-5.61) and relapse/progression (HR OS : 5.46, 95% CI: 3.23-9.24). Similar unfavorable EFS was found for the same subsets of patients. By contrast, treatment with anti-GD2 antibody in high-risk patients was associated with decreased risk of death or unfavorable events (HR OS : 0.11, 95% CI: 0.02-0.79; HR EFS : 0.19, 95% CI: 0.07-0.52). Our results confirm the outstanding prognosis of the early NBL stages, especially in children <1.5 years, and the improved outcomes of the anti-GD2 treatment in high-risk patients. Ongoing high-quality clinical cancer registration is needed to ensure comparability of survival across Europe and refine our understanding of the NBL biology.

Presenting features of neuroblastoma with spinal canal invasion. A prospective study of the International Society of Pediatric Oncology Europe - Neuroblastoma (SIOPEN).

Introduction: Between 5 and 15% of children with neuroblastoma (NB) present with or develop spinal canal invasion (SCI). The majority of these children have symptoms of epidural compression of spinal cord and/or spinal nerves. Treatment of NB-SCI is considered an emergency but its modalities are not yet well-established. Independently of treatment, NB-SCI may result in significant long-term disabilities. We report on the first prospective study of NB-SCI focused on presenting characteristics of both symptomatic and asymptomatic patients and correlation between SCI-related symptoms and imaging features. Materials and methods: This SIOPEN prospective NB-SCI study opened in June 2014. Patient data including SCI symptoms evaluated by standardized measures and spinal cord imaging studies were collected for each patient. For the purpose of this study data entry was locked on July 2021. Results: Of the 208 NB-SCI patients registered, 196 were evaluable for this analysis of whom 67% were symptomatic and 33% asymptomatic. Median age was 11 months. The thorax was the commonest primary tumor site. The median intervals between initial symptoms and diagnosis and between first medical visit and diagnosis were 14 and 3 days, respectively. The was no statistical difference in frequency of presenting characteristics between symptomatic and asymptomatic patients. Presenting features of NB-SCI patients differed from other NBs for older median age, prevalence of thoracic vs. abdominal primary site, prevalence of localized vs. metastatic disease and lower incidence of MYCN gene amplification. The most common SCI features were motor deficit in the younger and pain in the older patients that correlated on imaging with both transverse and longitudinal extent but not with the level of intraspinal tumor. Spinal cord T2-hyperintensity was more frequently detected in symptomatic patients (not significant). Conclusion: This prospective study confirms that children with NB-SCI differ from NBs without SCI. Compared to previous studies, it provides more detailed information regarding presenting symptoms, time intervals between SCI symptoms, medical visit and diagnosis, and correlations between symptoms and imaging features.

Asphericity of tumor [123 I]mIBG uptake as a prognostic factor in high-risk neuroblastoma.

BACKGROUND: In recent years, many research groups have attempted to identify a subgroup of "ultra-high risk" patients within the high-risk neuroblastoma (NB) category. The aim of our study was to evaluate the prognostic significance of parameters derived from pretherapeutic 123 I-meta-iodobenzylguanidine ([123 I]mIBG) integrated single photon emission computed tomography and computed tomography in high-risk patients with NB. METHODS: The established parameters metabolic tumor volume (MTV), maximal standardized uptake value (SUVmax ) and the novel parameter tumor asphericity as well as clinical (age, stage) and genetic factors (1p/11q deletions and MYCN amplification) were analyzed in this single-center retrospective study of high-risk patients with newly diagnosed NB. Univariate/multivariable Cox regression and propensity score matching were performed for clinical and radiological parameters. RESULTS: Twenty-eight high-risk patients with NB were included (14 males, median age 28.8 (11.3-41.0), range 3-74 months). Multivariable analysis of "full" cohort identified high asphericity (≥65%, adjusted hazard ratio [HR] 5.32, 95% confidence interval [CI]: 1.18-24.07, p = .03) and MTV (≥50 ml, adjusted HR 4.31, 95% CI: 1.18-15.80, p = .027) as the only factors associated with worse event-free survival. In matched cohort, tumor asphericity was a significant predictor of relapse/progression (HR 3.83, 95% CI: 1.03-14.26, p = .046). CONCLUSION: In this exploratory study, imaging parameters related to tumor metabolic activity, tumor asphericity and MTV, provided prognostic value for event-free survival in high-risk NB patients. Asphericity ≥65% and MTV ≥50 ml may serve as additional prognostic factors to those already used.

RNA Sequencing-Based Identification of Ganglioside GD2-Positive Cancer Phenotype.

The tumor-associated ganglioside GD2 represents an attractive target for cancer immunotherapy. GD2-positive tumors are more responsive to such targeted therapy, and new methods are needed for the screening of GD2 molecular tumor phenotypes. In this work, we built a gene expression-based binary classifier predicting the GD2-positive tumor phenotypes. To this end, we compared RNA sequencing data from human tumor biopsy material from experimental samples and public databases as well as from GD2-positive and GD2-negative cancer cell lines, for expression levels of genes encoding enzymes involved in ganglioside biosynthesis. We identified a 2-gene expression signature combining ganglioside synthase genes ST8SIA1 and B4GALNT1 that serves as a more efficient predictor of GD2-positive phenotype (Matthews Correlation Coefficient (MCC) 0.32, 0.88, and 0.98 in three independent comparisons) compared to the individual ganglioside biosynthesis genes (MCC 0.02-0.32, 0.1-0.75, and 0.04-1 for the same independent comparisons). No individual gene showed a higher MCC score than the expression signature MCC score in two or more comparisons. Our diagnostic approach can hopefully be applied for pan-cancer prediction of GD2 phenotypes using gene expression data.

Multimerization through Pegylation Improves Pharmacokinetic Properties of scFv Fragments of GD2-Specific Antibodies.

Antigen-binding fragments of antibodies specific to the tumor-associated ganglioside GD2 are well poised to play a substantial role in modern GD2-targeted cancer therapies, however, rapid elimination from the body and reduced affinity compared to full-length antibodies limit their therapeutic potential. In this study, scFv fragments of GD2-specific antibodies 14.18 were produced in a mammalian expression system that specifically bind to ganglioside GD2, followed by site-directed pegylation to generate mono-, di-, and tetra-scFv fragments. Fractionated pegylated dimers and tetramers of scFv fragments showed significant increase of the binding to GD2 which was not accompanied by cross-reactivity with other gangliosides. Pegylated multimeric di-scFvs and tetra-scFvs exhibited cytotoxic effects in GD2-positive tumor cells, while their circulation time in blood significantly increased compared with monomeric antibody fragments. We also demonstrated a more efficient tumor uptake of the multimers in a syngeneic GD2-positive mouse cancer model. The findings of this study provide the rationale for improving therapeutic characteristics of GD2-specific antibody fragments by multimerization and propose a strategy to generate such molecules. On the basis of multimeric antibody fragments, bispecific antibodies and conjugates with cytotoxic drugs or radioactive isotopes may be developed that will possess improved pharmacokinetic and pharmacodynamic properties.

Malignant rhabdoid tumor of the liver presented with initial tumor rupture.

Malignant rhabdoid tumor (MRT) of the liver is a rare, highly aggressive tumor of early childhood. We report a 6-month-old boy who was diagnosed with MRT of the liver and presented with spontaneous tumor rupture. The patient underwent intensified chemotherapy and a radical surgical procedure. Twenty four months from the time of the diagnosis, he is alive without evidence of disease. This is the second report of prolonged survival after initial rupture of hepatic MRT.