To review race and ethnic group enrollment and outcomes for Wilms tumor (WT) across all 4 risk-assigned therapeutic trials from the current era Children's Oncology Group Renal Tumor Biology and Risk ...Stratification Protocol, AREN03B2.
For patients with WT enrolled in AREN03B2 (2006 to 2019), disease and biologic features, therapeutic study-specific enrollment, and event-free (EFS) and overall (OS) 4-year survival were compared between institutionally reported race and ethnic groups.
Among 5,146 patients with WT, no statistically significant differences were detected between race and ethnic groups regarding subsequent risk-assigned therapeutic study enrollment, disease stage, histology, biologic factors, or overall EFS or OS, except the following variables: Black children were older and had larger tumors at enrollment, whereas Hispanic children had lower rates of diffuse anaplasia WT and loss of heterozygosity at 1p. The only significant difference in EFS or OS between race and ethnic groups was observed among the few children treated for diffuse anaplasia WT with regimen UH-1 and -2 on high-risk protocol, AREN0321. On this therapeutic arm only, Black children showed worse EFS (hazard ratio = 3.18) and OS (hazard ratio = 3.42). However, this finding was not replicated for patients treated with regimen UH-1 and -2 under AREN03B2 but not on AREN0321.
Race and ethnic group enrollment appeared constant across AREN03B2 risk-assigned therapeutic trials. EFS and OS on these therapeutic trials when analyzed together were comparable regarding race and ethnicity. Black children may have experienced worse stage-specific survival when treated with regimen UH-1 and -2 on AREN0321, but this survival gap was not confirmed when analyzing additional high-risk AREN03B2 patients.
Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 ...tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%) or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition.
Renal medullary carcinomas (RMCs) are rare kidney cancers that occur in adolescents and young adults of African ancestry. Although RMC is associated with the sickle cell trait and somatic loss of the ...tumor suppressor, SMARCB1, the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving SMARCB1 in RMC remains limited.
We used linked-read genome sequencing to reconstruct germline and somatic haplotypes in 15 unrelated patients with RMC registered on the Children's Oncology Group (COG) AREN03B2 study between 2006 and 2017 or from our prior study. We performed fine-mapping of the HBB locus and assessed the germline for cancer predisposition genes. Subsequently, we assessed the tumor samples for mutations outside of SMARCB1 and integrated RNA sequencing to interrogate the structural variants at the SMARCB1 locus.
We find that the haplotype of the sickle cell mutation in patients with RMC originated from three geographical regions in Africa. In addition, fine-mapping of the HBB locus identified the sickle cell mutation as the sole candidate variant. We further identify that the SMARCB1 structural variants are characterized by blunt or 1-bp homology events.
Our findings suggest that RMC does not arise from a single founder population and that the HbS allele is a strong candidate germline allele which confers risk for RMC. Furthermore, we find that the SVs that disrupt SMARCB1 function are likely repaired by non-homologous end-joining. These findings highlight how haplotype-based analyses using linked-read genome sequencing can be applied to identify potential risk variants in small and rare disease cohorts and provide nucleotide resolution to structural variants.
Background
Anaplastic sarcoma of the kidney (ASK) is a DICER1‐related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms ...tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1‐related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear.
Methods
Individuals with known or suspected DICER1‐related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance.
Results
Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two‐year event‐free survival (EFS) for stage I–II ASK was 81.8% (95% confidence interval CI: 67.2%–99.6%), compared with 46.6% EFS (95% CI: 24.7%–87.8%) for stage III–IV (p = .07). Two‐year overall survival (OS) for stage I–II ASK was 88.9% (95% CI: 75.5%–100.0%), compared with 70.0% (95% CI: 46.7%–100.0%) for stage III–IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02–0.31) and 0.08 (95% CI: 0.02–0.42), respectively.
Conclusion
ASK is a rare DICER1‐related renal neoplasm. In the current report, we identify clinical and treatment‐related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors.
Introduction
The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas ...to target in future clinical trials.
Methods
Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia FA, or diffuse anaplasia DA) were compared. Event‐free survival (EFS) and overall survival (OS) were reported using Kaplan–Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log‐rank tests. The impact of margin status was analyzed.
Results
Twenty‐seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty‐six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty‐six percent with BWT had bilateral nephron‐sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow‐up for EFS and OS was 8.6 and 8.7 years from enrollment. Four‐ and 8‐year EFS was 53% 95% confidence interval (CI): 34%–83% for DA; 4‐year EFS was 80% 95% CI: 59%–100%, and 8‐year EFS 70% 95% CI: 47%–100% for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months.
Conclusion
Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.
Abstract To inform clinical trial design and real-world precision pediatric oncology practice, we classified diagnoses, assessed the landscape of mutations, and identified genomic variants matching ...trials in a large unselected institutional cohort of solid tumors patients sequenced at Dana-Farber / Boston Children’s Cancer and Blood Disorders Center. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel. Diagnoses were classified according to the International Classification of Diseases for Oncology (ICD-O-3.2). Over 6.5 years, 888 pediatric cancer patients with 95 distinct diagnoses had successful tumor sequencing. Overall, 33% (n = 289/888) of patients had at least 1 variant matching a precision oncology trial protocol, and 14% (41/289) were treated with molecularly targeted therapy. This study highlights opportunities to use genomic data from hospital-based sequencing performed either for research or clinical care to inform ongoing and future precision oncology clinical trials. Furthermore, the study results emphasize the importance of data sharing to define the genomic landscape and targeted treatment opportunities for the large group of rare pediatric cancers we encounter in clinical practice.
Why does past moral behavior sometimes lead people to do more of the same (consistency), whereas sometimes it liberates them to do the opposite (licensing)? We organize the literature on moderators ...of moral consistency versus licensing effects using five conceptual themes: construal level, progress versus commitment, identification, value reflection, and ambiguity. Our review reveals that individuals are more likely to exhibit consistency when they focus abstractly on the connection between their initial behavior and their values, whereas they are more likely to exhibit licensing when they think concretely about what they have accomplished with their initial behavior-as long as the second behavior does not blatantly threaten a cherished identity. Moreover, many studies lacked baseline conditions ("donut" designs), leaving it ambiguous whether licensing was observed. And although many proposed moderators yielded significant interactions, evidence for both significant consistency and balancing simple effects in the same study was nearly nonexistent.
Reply to B. Zhang et al Fernandez, Conrad V; Perlman, Elizabeth J; Gastier-Foster, Julie ...
Journal of clinical oncology,
05/2018, Letnik:
36, Številka:
14
Journal Article
Abstract Purpose Initial Children's Oncology Group (COG) management for Wilms' tumor (WT) consists of primary nephroureterectomy with lymph node sampling. While this provides accurate staging to ...define further treatment, it may result in intraoperative spill (IOS), which is associated with higher recurrence rates and therefore requires more intensive therapy. The purpose of this study is to determine current rates and identify factors which may predispose a patient to IOS. Methods The study population was drawn from the AREN03B2 renal tumor banking and classification study of the Children's Oncology Group. All children with a first time occurrence of a renal mass were eligible for the study. At the time of enrollment and prior to risk stratification, the institution is required to submit operative notes, pathology specimens, a chest computed tomography scan (CT), and a contrast-enhanced CT or magnetic resonance imaging (MRI) of the abdomen and pelvis for central imaging review. These data are then used to determine an initial risk classification and therapeutic protocol eligibility. Patients who had a unilateral nephroureterectomy for favorable histology WT underwent further review to assure data accuracy and to clarify details regarding the spill. Analyses were performed using chi square and logistic regression. Odd ratios (OR) are shown with 95% confidence intervals. Results There were 1,131 primary nephrectomies for unilateral WT with an IOS rate of 9.7% with an additional 1.8% having possible tumor spill during renal vein or IVC tumor thrombectomy. IOS correlated with diameter (> 12cm, p < 0.0001) and laterality (right, p = 0.0414). Simple logistic regression indicated that IOS increased 2.7% p = 0.0240, OR 1.027 (1.004, 1.052) with each 1 cm increase in diameter (3 – 21cm) and 4.7% p = 0.0147 OR 1.047 (1.009, 1.086) with each 100 g increase in weight (80 – 1800 g). Multiple logistic regression indicated that laterality right p = 0.048, OR 1.46 (1.004, 2.110) and weight (p = 0.03, OR 1.039 (1.003, 1.075) were predictive of IOS when diameter was included as a continuous variable. Diameter as a binary variable was highly prognostic of IOS (p = 0.0002), while laterality and weight were not significant. Conclusions Intraoperative tumor spill occurs in about one out of every ten cases of primary nephroureterectomies for WT. Right-sided and larger tumors are at higher risk of IOS.
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