Genetic and Histopathological Heterogeneity of Neuroblastoma and Precision Therapeutic Approaches for Extremely Unfavorable Histology Subgroups

Peripheral neuroblastic tumors (neuroblastoma, ganglioneuroblastoma and ganglioneuroma) are heterogeneous and their diverse and wide range of clinical behaviors (spontaneous regression, tumor maturation and aggressive progression) are closely associated with genetic/molecular properties of the individual tumors. The International Neuroblastoma Pathology Classification, a biologically relevant and prognostically significant morphology classification distinguishing the favorable histology (FH) and unfavorable histology (UH) groups in this disease, predicts survival probabilities of the patients with the highest hazard ratio. The recent advance of neuroblastoma research with precision medicine approaches demonstrates that tumors in the UH group are also heterogeneous and four distinct subgroups—MYC, TERT, ALT and null—are identified. Among them, the first three subgroups are collectively named extremely unfavorable histology (EUH) tumors because of their highly aggressive clinical behavior. As indicated by their names, these EUH tumors are individually defined by their potential targets detected molecularly and immunohistochemically, such as MYC-family protein overexpression, TERT overexpression and ATRX (or DAXX) loss. In the latter half on this paper, the current status of therapeutic targeting of these EUH tumors is discussed for the future development of effective treatments of the patients.

Wilms Tumor (Nephroblastoma), Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

The NCCN Guidelines for Wilms Tumor focus on the screening, diagnosis, staging, treatment, and management of Wilms tumor (WT, also known as nephroblastoma). WT is the most common primary renal tumor in children. Five-year survival is more than 90% for children with all stages of favorable histology WT who receive appropriate treatment. All patients with WT should be managed by a multidisciplinary team with experience in managing renal tumors; consulting a pediatric oncologist is strongly encouraged. Treatment of WT includes surgery, neoadjuvant or adjuvant chemotherapy, and radiation therapy (RT) if needed. Careful use of available therapies is necessary to maximize cure and minimize long-term toxicities. This article discusses the NCCN Guidelines recommendations for favorable histology WT.

Advanced Technology Radiation Therapy with Dose Painting: Opportunities for Outcome Improvement for Management of Lymphoma

Radiation therapy remains important in the modern management of both Hodgkin and non-Hodgkin lymphoma. Radiation is applied as both consolidation therapy post chemotherapy and primary therapy for selected limited volume clinically favorable histology. Application of modern therapy techniques permits more sparing of normal tissue in all anatomical locations. Modern image guidance permits both security in daily patient treatment set up and permits strategic titration of the planning target volume to further spare normal tissue. Four-dimensional planning makes certain targets are fully treated in all phases of the breathing cycle. Dose painting with altered fractionation permits identification of low, intermediate, and high-risk areas of concern and treat each in a single plan with multiple fractionation schemes saving both time of treatment and cost of therapy. In this paper we present multiple examples of the application of modern therapy techniques in lymphoma management and demonstrate advantages of modern radiation in several anatomical regions.

Clinical Features of Children with Retinoblastoma and Neuroblastoma

Purpose. Retinoblastoma and neuroblastoma are the most common malignant extracranial solid tumors in children. This study aimed to summarize the clinical features, especially the delayed diagnosis in children with retinoblastoma and neuroblastoma. Methods. In a single hospital-based case-control study, a retrospective cohort of 175 children with retinoblastoma and neuroblastoma diagnosed from January 2016 to January 2018 were reviewed. The state of enucleation in retinoblastomas and pathological prognosis in neuroblastomas were outcome indicators. Hereby, the patients were divided into two groups, and clinical features including age at presentation and delayed diagnosis were compared. Results. A total of 112 patients with retinoblastoma and 63 with neuroblastoma were included. In the retinoblastoma cohort, the median age at presentation was 17.2 months (0.3–110 months). The mean delay of diagnosis was 1.6 ± 2.3 months, and the rate of enucleation was 61.6%. Unilateral disease, the International Classification of Intraocular Retinoblastoma (IIRC) stage E, and delay of diagnosis over 2.5 months were independent risk factors of ocular outcomes. Notably, the risk of enucleation was increased by 474% when the delay was longer than 2.5 months. In the neuroblastoma cohort, the delay of diagnosis of the unfavorable histology (UH) group was longer than that of the favorable histology (FH) group (1.9 months vs. 1.4 months, P=.487). The levels of serum ferritin and neuron-specific enolase were higher in the UH group than in the FH group (P<.05). Conclusions. This study summarized the clinical features and diagnosis biomarkers of retinoblastoma and neuroblastoma patients in China. These results might help to focus on early detection and treatment in children with retinoblastoma and neuroblastoma.

Preclinical evaluation of XPO1 inhibition in Wilms tumors.

3580 Background: XPO1 is a nuclear export protein that selectively transports tumor and growth regulatory proteins out of the nucleus, thereby effectively inhibiting their function. We previously utilized the Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER) algorithm to discover that malignant rhabdoid tumors were dependent upon XPO1 inhibition and then evaluated a preclinical cohort using selinexor (KPT-330), the first-in-class selective inhibitor of nuclear export, to demonstrate that XPO1 inhibition was sufficient to cause cell cycle arrest, apoptosis, and disease control in multiple cell line and patient derived xenograft (PDXs) models. Our subsequent analysis revealed that the most common childhood kidney tumor, Wilms tumor, has even high higher inferred activity of XPO1 than rhabdoid tumors leading to our hypothesis that XPO1 inhibition is an effective therapeutic strategy to treat Wilms tumors. Methods: A panel of 9 Wilms tumor cell lines and 3 Wilms tumor PDXs were genomically characterized and tested to evaluate the pre-clinical efficacy of XPO1 inhibition in Wilms tumors. Results: Proliferation rate, increased XPO1 protein expression, and loss of function mutations in TP53 correlated with in vitro Wilms tumor cell line sensitivity to selinexor. Evaluation of co-segregation of all single nucleotide variant changes using with inferred activity of XPO1 on VIPER in all TGCA tumors demonstrates a strong association with TP53 alterations. XPO1 inhibition was effective in all Wilms tumor models tested, most significantly in MSKREN-57196, a favorable histology Wilms tumor PDX with somatic 1q gain as well as WTX and MYCN mutations, as well as in MSKREN-31827, a diffusely anaplastic TP53 mutant Wilms tumor PDX. Eltanexor (KPT-8602) is an XPO1 inhibitor with decreased CNS penetration and an improved toxicity profile; this drug was tested in these in vivo models and found to be at least as effective as selinexor. Conclusions: Somatic 1q gain in favorable histology Wilms tumors and TP53 mutations in diffusely anaplastic Wilms tumors have a particularly poor prognosis in the relapsed setting. Our study demonstrates that XPO1 inhibition may provide a rational therapeutic option to treat such high-risk Wilms tumors. Future clinical trials evaluating XPO1 inhibitors should evaluate its efficacy in children with relapsed Wilms tumors.

Segmental chromosome aberrations and clinical response impact outcome of inss stage III patients ≥18 months with unfavorable histology and without MYCN amplification: A Children’s Oncology Group (COG) report.

10502 Background: Patients with INSS stage III neuroblastoma represent a heterogeneous population with respect to disease presentation and prognosis and controversy exists regarding the most effective treatment algorithms. Patients ≥18 months of age with INSS Stage 3 tumors that are unfavorable histology (UH) and MYCN-non-amplified ( MYCN-NA) represent a small cohort of patients with an outcome intermediate of those with favorable histology tumors and MYCN amplified tumors. The presence of Segmental Chromosome Aberrations (SCA) may predict outcome; however, their impact specifically in this cohort of patients has not been reported. Methods: Eligible patients enrolled on therapeutic protocols A3973 (n=34), ANBL0532 (n=27), and biology protocol ANBL00B1 (n=101 with 29 treated on A3973/ANBL0532) with stage III disease, MYCN–NA, UH and age ≥18 months at diagnosis were analyzed. Copy number alterations and loss of heterozygosity (LOH) for relevant loci were scored for gains/losses by two independent reviewers. Results: The 5-year EFS/OS for children ≥18 months with stage III, MYCN–NA, UH disease treated on A3973 and ANBL0532 was 73.0±8.1%/87.9±5.9% and 61.4±10.2%/ 73.0±9.2%, respectively, with no statistical differences in EFS or OS between the two cohorts (p=0.1286 and p=0.2180, respectively). In the combined cohort of patients enrolled on A3973 and ANBL0532, statistically significant differences were found (p(s) <0.0001) in patients with CR/VGPR (n=39) and PR (n=13) having better outcomes than <PR (n=5) (5-year EFS: 74.0±7.6% vs. 75.0±12.5% vs. 0%; 5-year OS: 84.4±6.2% vs. 100% vs. 20.0±17.9%). Subjects with chromosome 11q loss/LOH had an inferior outcome in comparison to those without 11q loss/LOH (10-year EFS: 44.4+/-24.1% vs. 78.1+/-9.4%, p=0.01; 10-year OS: 62.4+/-15.9% vs. 85.9+/-7.8%, p=0.02)). Patients with 1p loss/LOH and 2p gain also showed trend towards worse event-free survival (p=0.086 and p=0.088, not statistically significant) but not in overall survival. Conclusions: High-risk therapy that included single myeloablative therapy led to an 81.6±5.3%5-year OS in patients ≥18 months with UH and MYCN–NA stage III neuroblastoma. Response to therapy is a powerful predictor of survival and the presence of chromosome 11q loss/LOH is also associated with inferior outcomes. These patients should continue to be treated on high-risk clinical trials.

Loss of Heterozygosity at Chromosome 16q Is a Negative Prognostic Factor in Korean Pediatric Patients with Favorable Histology Wilms Tumor: A Report of the Korean Pediatric Hematology Oncology Group (K-PHOG)

Purpose Loss of heterozygosity (LOH) at chromosomes 1p and 16q is a poor prognostic factor in favorable histology Wilms tumor (FHWT). This study investigated the prevalence of LOH at 1p and 16q and evaluated its prognostic value in Korean children with FHWT. Materials and Methods We analyzed 101 FHWT patients who were diagnosed between 1996 and 2016 in Korean Society of Pediatric Hematology Oncology Group hospitals. Using paraffin-embedded kidney tissue samples sent from each center, we reviewed LOH at 1p and 16q in each patient and assessed the prognostic value of LOH status for clinical parameters affecting event-free survival (EFS). Results Of the 101 patients, 12 (11.9%) experienced recurrence; the 3-year EFS was 87.6%. LOH at 1p or 16q was detected in 19 patients (18.8%), with five having LOH at both 1q and 16q. The frequency of LOH at 1p was higher among younger patients (p=0.049), but there was no difference in LOH prevalence according to tumor stage. In the multivariate analysis, LOH at 16q was a significant negative prognostic factor affecting EFS (3-year EFS, 73.7% vs. 91.1%; hazard ratio, 3.95; p=0.037), whereas LOH at 1p was not (p=0.786). Conclusion LOH at 16q was a significant negative prognostic factor affecting outcome in Korean pediatric FHWT patients. Due to the small sample size of this study, large-scale multicenter trials are warranted to investigate the prognostic value of LOH at 1p and 16q in Korean children with FHWT.