This editorial provides a comprehensive summary of two clinical trials on undifferentiated embryonal sarcoma of the liver from the major sarcoma groups in the American Children’s Oncology Group and ...the European Paediatric Soft Tissue Sarcoma Study Group.
Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this ...often lethal tumour. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%). Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization. In addition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours.
LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo. Here, we report that ...LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B-let-7-MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN protein expression. Interference with this pathway might offer therapeutic perspectives.
Neuroblastoma is the most common extracranial solid tumor in children. A subgroup of high-risk patients is characterized by aberrations in the chromatin remodeller ATRX that is encoded by 35 exons. ...In contrast to other pediatric cancer where ATRX point mutations are most frequent, multi-exon deletions (MEDs) are the most frequent type of ATRX aberrations in neuroblastoma. 75% of these MEDs are predicted to produce in-frame fusion proteins, suggesting a potential gain-of-function effect compared to nonsense mutations. For neuroblastoma there are only a few patient-derived ATRX aberrant models. Therefore, we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid and performed total RNA-sequencing on these and the patient-derived models. Gene set enrichment analysis (GSEA) showed decreased expression of genes related to both ribosome biogenesis and several metabolic processes in our isogenic ATRX exon 2-10 MED model systems, the patient-derived MED models and in tumor data containing two patients with an ATRX exon 2-10 MED. In sharp contrast, these same processes showed an increased expression in our isogenic ATRX knock-out and exon 2-13 MED models. Our validations confirmed a role of ATRX in the regulation of ribosome homeostasis. The two distinct molecular expression patterns within ATRX aberrant neuroblastomas that we identified imply that there might be a need for distinct treatment regimens.
Whole-genome sequencing detected structural rearrangements of TERT in 17 of 75 high-stage neuroblastomas, with five cases resulting from chromothripsis. Rearrangements were associated with increased ...TERT expression and targeted regions immediately up- and downstream of TERT, positioning a super-enhancer close to the breakpoints in seven cases. TERT rearrangements (23%), ATRX deletions (11%) and MYCN amplifications (37%) identify three almost non-overlapping groups of high-stage neuroblastoma, each associated with very poor prognosis.
Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. Since novel and improved immunotherapies may fill ...this need, we dissect the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 24 tumors (10 pre- and 14 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas are infiltrated by natural killer (NK), T and B cells, and immunosuppressive myeloid populations. NK cells show reduced cytotoxicity and T cells have a dysfunctional profile. Interaction analysis reveals a vast immunoregulatory network and identifies NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduces neuroblastoma growth, with complete responses (CR) in vivo. Moreover, addition of TIGIT+PD-L1 blockade to standard relapse treatment in a chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model induces CR. In conclusion, our integrative analysis provides promising targets and a rationale for immunotherapeutic combination strategies.
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•Single-cell RNAseq identifies 17 distinct immune subsets infiltrating neuroblastoma•Dysfunctionality of T and NK cells alternates throughout the course of chemotherapy•Interaction analysis identifies the NECTIN2-TIGIT axis as crucial immune checkpoint•TIGIT (+PD-L1) blockade enhances immune responses against neuroblastoma in vivo
Wienke et al. analyze the immune landscape of neuroblastoma pre- and post-chemotherapy and identify the NECTIN2-TIGIT axis as a crucial immune checkpoint, which correlates with dysfunction of T/NK cells. TIGIT (+PD-L1) blockade induces numerous complete responses (CR) in vivo, even against chemotherapy-resistant neuroblastoma, highlighting TIGIT blockade as promising immunotherapy for neuroblastoma.
Background
The aim of this study was to assess the clinical impact of indeterminate pulmonary nodules (no more than four pulmonary nodules of less than 5 mm or one nodule measuring between 5 and less ...than 10 mm by computed tomography CT) in children and adolescents with adult‐type non‐rhabdomyosarcoma soft tissue sarcoma (NRSTS) at diagnosis.
Methods
Patients with NRSTS treated in 11 centers as part of the European paediatric Soft Tissue Sarcoma Study Group (EpSSG) were retrospectively assessed. Local radiologists, blinded to clinical information except for patients’ age and tumor histotype, reviewed the chest CT at diagnosis and filled out a case report form. Because patients with or without indeterminate nodules in the EpSSG NRSTS 2005 study received the same type of treatment, event‐free survival (EFS) and overall survival (OS) between groups by log‐rank test were compared.
Results
Overall, 206 patients were examined: 109 (52.9%) were without any nodules, 78 (38%) had at least one indeterminate nodule, and 19 (9.2%) had nodules meeting the definition of metastases, which were then considered to be misclassified and were excluded from further analyses. Five‐year EFS was 78.5% (95% CI, 69.4%–85.1%) for patients without nodules and 69.6% (95% CI, 57.9%–78.7%) for patients with indeterminate nodules (p = .135); 5‐year OS was 87.4% (95% CI, 79.3%–92.5%) and 79.0% (95% CI, 67.5%–86.8%), respectively (p = .086).
Conclusions
This study suggests that survival does not differ in otherwise nonmetastatic patients with indeterminate pulmonary nodules compared to nonmetastatic patients without pulmonary nodules.
Plain Language Summary
Radiologists should be aware of the classification of indeterminate pulmonary nodules in non‐rhabdomyosarcoma soft tissue sarcomas and use it in their reports.
More than a third of patients with non‐rhabdomyosarcoma soft tissue sarcoma can be affected by indeterminate pulmonary nodules.
Indeterminate pulmonary nodules do not significantly affect the overall survival of pediatric patients with non‐rhabdomyosarcoma soft tissue sarcoma.
In pediatric patients with non‐rhabdomyosarcoma soft tissue sarcoma, indeterminate pulmonary nodules detected by computed tomography may represent a diagnostic challenge. Indeterminate pulmonary nodules seem to not influence survival in otherwise non‐metastatic children and adolescents with non‐rhabdomyosarcoma soft tissue sarcoma.
An international phase 2 study combining cladribine and cytarabine (Ara-C) was initiated for patients with refractory, risk-organ–positive Langerhans cell histiocytosis (LCH) in 2005. The protocol, ...comprising at least two 5-day courses of Ara-C (1 g/m2 per day) plus cladribine (9 mg/m2 per day) followed by maintenance therapy, was administered to 27 patients (median age at diagnosis, 0.7 years; median follow-up, 5.3 years). At inclusion, all patients were refractory after at least 1 course of vinblastine (VBL) plus corticosteroid, all had liver and spleen involvement, and 25 patients had hematologic cytopenia. After 2 courses, disease status was nonactive (n = 2), better (n = 23), or stable (n = 2), with an overall response rate of 92%. Median disease activity scores decreased from 12 at the start of therapy to 3 after 2 courses (P < .0001). During maintenance therapy, 4 patients experienced reactivation in risk organs. There were 4 deaths; 2 were related to therapy toxicity and 2 were related to reactivation. All patients experienced severe toxicity, with World Health Organization grade 4 hematologic toxicity and 6 documented severe infections. The overall 5-year survival rate was 85% (95% confidence interval, 65.2%-94.2%). Thus, the combination of cladribine/Ara-C is effective therapy for refractory multisystem LCH but is associated with high toxicity.
•Patients with LCH, risk organs, refractory to standard VBL-steroid regimen have a poor survival, ∼30%.•In a phase 2 study, with 5 years' median follow-up, cladribine and Ara-C was shown to improve the survival up to 85% for this group.
Background
Malignant peripheral nerve sheath tumors (MPNST) are rare tumors of childhood. The role of standard chemotherapy in unresectable MPNST is still unclear. We report the outcome and ...prognostic factors in the EpSSG risk‐adapted prospective study for localized pediatric MPNST.
Methods
Patients were stratified into four treatment groups defined by surgical resection, tumor size, and tumor grade (G): (a) surgery‐only group—resected tumors G1; (b) adjuvant radiotherapy group—R0/R1, G2 tumors; (c) adjuvant chemotherapy group—R0/R1, G3 tumors; and (d) neoadjuvant chemotherapy group—R2 resected tumors and/or nodal involvement. Chemotherapy consisted of four courses of ifosfamide‐doxorubicin and two courses of ifosfamide concomitant with radiotherapy (50.4‐54 Gy).
Results
Overall, the study included 51 patients. The 5‐year event‐free survival (EFS) and overall survival (OS) were 52.9% (95% confidence interval, 38.1‐65.8) and 62.1% (46.7‐74.3), respectively. The 5‐year EFS was 92% (56.6‐98.9) for treatment group 1 (N = 13), 33% (0.9‐77.4) for treatment group 2 (N = 4), 29% (4.1‐61.2) for treatment group 3 (N = 7), and 42% (23.1‐60.1) for treatment group 4 (N = 27). Response rate to chemotherapy (partial response + complete response) in patients with measurable disease was 46%. The presence of neurofibromatosis type 1 (NF1; 51% of patients) was an independent poor prognostic factor for OS and EFS.
Conclusion
The outcome for patients with resectable MPNST was excellent. Standard ifosfamide‐doxorubicin for unresectable MPNST rendered the best reported outcome. Children with NF1 disease seem to have worse prognosis.