Overall survival in patients with osteosarcoma is only 60%. Poor response to chemotherapy is the dominant risk factor for poor survival. Pharmacogenetic research can offer possibilities to optimize ...treatment and improve outcome. We applied a pathway-based approach to evaluate the cumulative effect of genes involved in the metabolism of cisplatin and doxorubicin in relationship to clinical outcome.
We included 126 patients with osteosarcoma. To comprehensively assess common genetic variation in the 54 genes selected, linkage disequilibrium (LD; r(2) = 0.8)-based tag-single nucleotide polymorphisms (SNP) strategy was used. A final set of 384 SNPs was typed using Illumina Beadarray platform. SNPs significantly associated with 5-year progression-free survival (PFS) were replicated in another 64 patients with osteosarcoma.
We identified five variants in FasL, MSH2, ABCC5, CASP3, and CYP3A4 that were associated with 5-year PFS. Risk stratification based on the combined effects of the risk alleles showed a significant improvement of 5-year PFS. Patients that carried no or only one risk allele had a 5-year PFS of 100% compared with a 5-year PFS of 84.4% for carriers of two or three risk alleles, 66.7% PFS if a patient carried four to five alleles, and a 5-year PFS of 41.8% for patients with >5 risk alleles (P < 0.001).
We identified several genes that showed association with PFS in patients with osteosarcoma. These pharmacogenetic risk factors might be useful to predict treatment outcome and to stratify patients immediately after diagnosis and offer the possibility to improve treatment and outcome.
Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and is characterized by clonal heterogeneity. Genomic mutations can increase proliferative potential of leukemic ...cells and cause treatment resistance. However, mechanisms driving mutagenesis and clonal diversification in ALL are not fully understood. In this proof of principle study, we performed whole genome sequencing of two cases with multiple relapses in order to investigate whether groups of mutations separated in time show distinct mutational signatures. Based on mutation allele frequencies at diagnosis and subsequent relapses, we clustered mutations into groups and performed cluster-specific mutational profile analysis and de novo signature extraction. In patient 1, who experienced two relapses, the analysis unraveled a continuous interplay of aberrant activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity. The associated signatures SBS2 and SBS13 were present already at diagnosis, and although emerging mutations were lost in later relapses, the process remained active throughout disease evolution. Patient 2 had three relapses. We identified episodic mutational processes at diagnosis and first relapse leading to mutations resembling ultraviolet light-driven DNA damage, and thiopurine-associated damage at first relapse. In conclusion, our data shows that investigation of mutational processes in clusters separated in time may aid in understanding the mutational mechanisms and discovery of underlying causes.
Background
Quality indicators (QIs) may be used to monitor the quality of neuroblastoma (NBL) care during treatment, in addition to survival and treatment toxicity, which can only be evaluated in the ...years after treatment. The present study aimed to assess the feasibility of a new set of indicators for the quality of NBL therapy.
Procedure
Seven QIs have been proposed based on literature and consensus of experts: (a) duration of complete diagnostic work‐up, (b) prescription of thyroid prophylaxis before metaiodobenzylguanidine imaging, (c) treatment intensity, (d) use of tumor board meetings, (e) number of outpatient visits and sedation procedures during follow‐up, (f) protocolled follow‐up, and (g) required apheresis sessions. A retrospective data analysis from October 2014 to November 2017 including all patients with NBL in the centralized Princess Máxima Center in the Netherlands was performed to assess these parameters and determine practicality of measurement.
Results
A total number of 72 patients (aged between 2 weeks and 15 years) were analyzed. Adherence to all QIs could be determined for all eligible patients using their electronic medical records. Three indicators were compared over time, and an increase in adherence was observed.
Conclusions
Assessment of QIs in neuroblastoma treatment is feasible. Seven new QIs were found to be feasible to measure and showed improvement over time for three indicators. Monitoring of these QIs during treatment may provide tools for quality improvement activities and comparisons of treatment quality over time or between centers. Further study is required to investigate their association with long‐term outcomes.
Introduction
One‐quarter of the relapses in children with B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) occur very early (within 18 months, before completion of treatment), and prognosis in ...these patients is worse compared to cases that relapse after treatment has ended.
Methods
In this study, we performed a genomic analysis of diagnosis–relapse pairs of 12 children who relapsed very early, followed by a deep‐sequencing validation of all identified mutations. In addition, we included one case with a good initial treatment response and on‐treatment relapse at the end of upfront therapy.
Results
We observed a dynamic clonal evolution in all cases, with relapse almost exclusively originating from a subclone at diagnosis. We identified several driver mutations that may have influenced the outgrowth of a minor clone at diagnosis to become the major clone at relapse. For example, a minimal residual disease (MRD)‐based standard‐risk patient with ETV6‐RUNX1‐positive leukemia developed a relapse from a TP53‐mutated subclone after loss of the wildtype allele. Furthermore, two patients with TCF3‐PBX1‐positive leukemia that developed a very early relapse carried E1099K WHSC1 mutations at diagnosis, a hotspot mutation that was recurrently encountered in other very early TCF3‐PBX1‐positive leukemia relapses as well. In addition to alterations in known relapse drivers, we found two cases with truncating mutations in the cohesin gene RAD21.
Conclusion
Comprehensive genomic characterization of diagnosis–relapse pairs shows that very early relapses in BCP‐ALL frequently arise from minor subclones at diagnosis. A detailed understanding of the therapeutic pressure driving these events may aid the development of improved therapies.
IKZF1 deletions are an established prognostic factor in childhood acute lymphoblastic leukemia (ALL). However, their relevance in patients with good risk genetics, namely ETV6::RUNX1 and high ...hyperdiploid (HeH), ALL remains unclear. We assessed the prognostic impact of IKZF1 deletions in 939 ETV6::RUNX1 and 968 HeH ALL patients by evaluating data from 16 trials from 9 study groups. Only 3% of ETV6::RUNX1 cases (n = 26) were IKZF1‐deleted; this adversely affected survival combining all trials (5‐year event‐free survival EFS, 79% versus 92%; P = 0.02). No relapses occurred among the 14 patients with an IKZF1 deletion treated on a minimal residual disease (MRD)‐guided protocols. Nine percent of HeH cases (n = 85) had an IKZF1 deletion; this adversely affected survival in all trials (5‐year EFS, 76% versus 89%; P = 0.006) and in MRD‐guided protocols (73% versus 88%; P = 0.004). HeH cases with an IKZF1 deletion had significantly higher end of induction MRD values (P = 0.03). Multivariate Cox regression showed that IKZF1 deletions negatively affected survival independent of sex, age, and white blood cell count at diagnosis in HeH ALL (hazard ratio of relapse rate 95% confidence interval: 2.48 1.32‐4.66). There was no evidence to suggest that IKZF1 deletions affected outcome in the small number of ETV6::RUNX1 cases in MRD‐guided protocols but that they are related to higher MRD values, higher relapse, and lower survival rates in HeH ALL. Future trials are needed to study whether stratifying by MRD is adequate for HeH patients or additional risk stratification is necessary.
Neuroblastoma (NBL) is a childhood malignancy of the sympathetic nervous system. For high-risk NBL patients, the mortality rate is still over 50%, despite intensive multimodal treatment. Anti-GD2 ...monoclonal antibody (mAB) in combination with systemic cytokine immunotherapy has shown clinical efficacy in high-risk NBL patients. Targeted therapy using histone deacetylase inhibitors (HDACi) is currently being explored in cancer treatment and already shows promising results. Using our recently developed transplantable TH-MYCN NBL model, we here report that the HDAC inhibitor Vorinostat synergizes with anti-GD2 mAb therapy in reducing NBL tumor growth. Further mechanistic studies uncovered multiple mechanisms for the observed synergy, including Vorinostat-induced specific NBL cell death and upregulation of the tumor antigen GD2 on the cell surface of surviving NBL cells. Moreover, Vorinostat created a permissive tumor microenvironment (TME) for tumor-directed mAb therapy by increasing macrophage effector cells expressing high levels of Fc-receptors (FcR) and decreasing the number and function of myeloid-derived suppressor cells (MDSC). Collectively, these data imply further testing of other epigenetic modulators with immunotherapy and provide a strong basis for clinical testing of anti-GD2 plus Vorinostat combination therapy in NBL patients.
Neuroblastoma is an embryonal tumor derived from poorly differentiated neural crest cells. Current research is aimed at identifying the molecular mechanisms that maintain the progenitor state of ...neuroblastoma cells and to develop novel therapeutic strategies that induce neuroblastoma cell differentiation. Mechanisms controlling neural crest development are typically dysregulated during neuroblastoma progression, and provide an appealing starting point for drug target discovery. Transcriptional programs involved in neural crest development act as a context dependent gene regulatory network. In addition to BMP, Wnt and Notch signaling, activation of developmental gene expression programs depends on the physical characteristics of the tissue microenvironment. TRPM7, a mechanically regulated TRP channel with kinase activity, was previously found essential for embryogenesis and the maintenance of undifferentiated neural crest progenitors. Hence, we hypothesized that TRPM7 may preserve progenitor-like, metastatic features of neuroblastoma cells. Using multiple neuroblastoma cell models, we demonstrate that TRPM7 expression closely associates with the migratory and metastatic properties of neuroblastoma cells in vitro and in vivo. Moreover, microarray-based expression profiling on control and TRPM7 shRNA transduced neuroblastoma cells indicates that TRPM7 controls a developmental transcriptional program involving the transcription factor SNAI2. Overall, our data indicate that TRPM7 contributes to neuroblastoma progression by maintaining progenitor-like features.
Highlights • We audio-taped diagnostic consultations in pediatric oncology. • We analyzed oncologists’ assistance in shared decision-making (SDM). • Decision-making appears to focus on non-treatment ...related decisions. • Oncologists’ assistance mostly concerned sharing information, instead of SDM. • Research is needed to provide insight in how to increase oncologists’ assistance.
The Psychosocial Assessment Tool (PAT) was developed to screen for psychosocial risk in families of a child diagnosed with cancer. The current study is the first describing the cross-cultural ...adaptation, reliability, validity, and usability of the PAT in an European country (Dutch translation).
A total of 117 families (response rate 59%) of newly diagnosed children with cancer completed the PAT2.0 and validation measures.
Acceptable reliability was obtained for the PAT total score (α = .72) and majority of subscales (0.50-0.82). Two subscales showed inadequate internal consistency (Social Support α = .19; Family Beliefs α = .20). Validity and usability were adequate. Of the families, 66% scored low (Universal), 29% medium (Targeted), and 5% high (Clinical) risk.
This study confirms the cross-cultural applicability, reliability, and validity of the PAT total score. Reliability left room for improvement on subscale level. Future research should indicate whether the PAT can be used to provide cost-effective care.
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