Favorable Histology Wilms Tumor Research Articles

Outcomes of relapsed favorable-histology Wilms tumor in non-clinical trial setting.

The last major North American cooperative group clinical trial for relapsed favorable-histology Wilms tumor (FHWT) was completed in 2002. The outcomes of patients with relapsed Wilms tumor subsequently treated outside of clinical trials are unknown. The aim of this study was to assess the efficacy and toxicity of salvage therapies used for patients with FHWT suffering first relapse. We conducted a retrospective chart review of patients treated for first relapse of FHWT at six large North American institutions from January 2002 through August 2018. Ninety-four patients were identified. Thirty-six patients were classified as standard-risk relapse (SRR), 49 patients as high-risk relapse (HRR), and seven patients as very high-risk relapse (VHRR). Two patients were unable to be classified. Twenty-one patients with SRR were treated with Regimen I. The 4-year event-free survival (EFS) and overall survival (OS) for SRR were 82.4% and 93.3%, respectively, with median follow-up of 72months. Twenty-eight HRR/VHRR patients were treated with ICE therapy, while 13 received National Wilms Tumor Study (5th) (NWTS-5) Stratum C. No patient completed protocol therapy per Stratum C; median maintenance cycles administered were two cycles. The 4-year EFS and OS for HRR/VHRR were 32.6% and 58.3%, respectively, with median follow-up of 33months. Outcomes for all strata of relapsed WT patients treated in a non-clinical setting appear to have similar outcomes to historical cohorts treated on NWTS-5. Improved strategies are urgently needed for HRR and VHRR relapses.

Elevated preoperative plasma D-dimer level is an independent prognostic factor for pediatric patients with Wilms tumor.

Elevated plasma D-dimer levels are an unfavorable prognostic indicator for various tumors. However, its predictive value for prognosis in pediatric patients with Wilms tumor (WT) remains unknown. We aimed to investigate the clinical and prognostic value of preoperative plasma D-dimer levels and other clinicopathological characteristics in patients with favorable histology WT (FHWT). The clinical data of 74 children with FHWT from January 2010 to January 2022 were retrospectively analyzed. The clinicopathologic characteristics, preoperative laboratory parameter results, including D-dimer level, and follow-up data were collected. Based on the postoperative recovery status, the patients were divided into tumor-free survival and disease progression groups. The risk factors affecting disease progression in pediatric patients with WT and the impact of plasma D-dimer levels on overall survival (OS) were evaluated. Over a median follow-up of 33 months (range: 2-145 months), 56 patients survived without progression. Relapses and metastases occurred in 18 patients, of which four survived and 14 died. Higher preoperative plasma D-dimer levels (>0.865) (Odds ratio [OR] = 7.240, 95% confidence interval (CI) = 1.276-33.272, P = 0.011) and tumor rupture (OR = 19.984, 95% CI = 1.182-338.013, P = 0.038) were independent prognostic factors for disease progression. Additionally, patients with elevated D-dimer levels demonstrated a worse 5-year OS than those with low D-dimer levels (Hazard ratio (HR) =4.278, 95% CI = 1.074-17.035, P = 0.039). Elevated D-dimer levels are a prognostic factor for a poorer outcome in pediatric patients with WT and are expected to become a clinical biomarker for predicting the prognosis of WT.

Long-term outcomes and patterns of relapse in patients with bilateral Wilms tumor or bilaterally predisposed unilateral Wilms tumor, a report from the COG AREN0534 study.

The objective of this study is to report the long-term timing and patterns of relapse for children enrolled in Children's Oncology Group AREN0534, a multicenter phase III clinical trial conducted from 2009 to 2015. Participants included children with bilateral Wilms tumor (BWT) or unilateral WT with genetic predisposition to develop BWT followed for up to 10 years. Smoothed hazard (risk) functions for event-free survival (EFS) were plotted so that the timing of events could be visualized, both overall and within pre-specified groups. Two hundred and twenty-two children (190 BWT and 32 unilateral WT with BWT predisposition) were followed for a median of 8.6 years. Fifty events were reported, of which 48 were relapse/progression. The overall 8-year EFS was 75% (95% confidence interval: 69%-83%). The highest risk for an EFS event was immediately after diagnosis with a declining rate over 2 years. A second peak of events was observed around 4 years after diagnosis, and a small number of events were reported until the end of the follow-up period. In subset analyses, later increases in risk were more commonly observed in patients with female sex, anaplastic histology, negative lymph nodes or margins, and favorable histology Wilms tumor patients with post-chemotherapy intermediate risk. Among relapses that occurred after 2 years, most were to the kidney. These patterns suggest that late events may be second primary tumors occurring more commonly in females, although more investigation is required. Clinicians may consider observation of patients with BWT beyond 4 years from diagnosis.

Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

Nomogram for personalized prognostic assessment of children with favorable histology Wilms tumor: A retrospective analysis

ObjectiveThis retrospective study aimed to construct and validate a nomogram for personalized prognostic assessment of favorable histology Wilms tumor (FHWT) based on clinical and pathological variables. Methods and MaterialsThis was a retrospective study collected data from patients who underwent surgery for FHWT between March 2007 and November 2022 at Beijing Children's Hospital. Univariate and multivariate Cox proportional hazards regression analyses were conducted to determine the significance variables and constructed the nomogram in predicting event-free survival (EFS) in FHWT patients. ResultsA total of 401 FHWT patients were included in the study, with the median age of the patients was 3.4 years. The overall 1-, 3-, and 5-year OS rates were 98.2%, 96.3%, and 93.9%. The 1-, 3-, and 5-year EFS rates were 91.2%, 88.2%, and 86.6%. Subgroup analysis revealed age greater than 2 years was associated with a worse prognosis than age less than or equal to 2 years (P < 0.001), and patients with high-risk Wilms tumors were associated with a higher rate of recurrence and death (P < 0.001). Multivariate analysis showed that age (HR: 2.449, 95%CI: 1.004–5.973), stage (HR: 1.970, 95% CI:1.408–2.756), and histological risk (HR:9.414, 95% CI: 4.318–20.525) were identified as independent predictors of EFS (P < 0.05) and used to construct the nomogram. The prognostic nomogram demonstrated good calibration, great clinical utility, and the time-dependent receiver operating curve analysis showed that the nomogram had precise predictability, with area under the curve values of 0.85(95CI:0.796–0.913), 0.85(95CI:0.80–0.91), and 0.88(95CI:0.839–0.937) for 1-,3-year and 5-year EFS. ConclusionThis study provides valuable insights into the clinical characteristics and outcomes of FHWT patients. Accurate staging and histological risk assessment are important in predicting outcomes, and the prognostic nomogram we developed can be a useful tool for clinicians to assess patient prognosis and make informed treatment decisions.

BRAF Exon 15 Mutations in the Evaluation of Well-Differentiated Epithelial Nephroblastic Neoplasms in Children: A Report From the Children's Oncology Group Study AREN03B2.

The distinction between well-differentiated epithelial favorable-histology Wilms tumor (EFHWT) and metanephric adenoma (MA) in children has historically been determined by the required absence of both a fibrous pseudocapsule and mitotic activity in MA. More recently these features have been allowed in adult MA. Mutations in exon 15 of the BRAF gene are reported in up to 88% of MAs but have not been reported in EFHWTs in children lacking MA features. To clarify the pathologic and molecular features used to distinguish between pediatric MA and EFHWT. Stage I epithelial tumors classified as EFHWT on central review (36 patients) were identified from the Children's Oncology Group AREN03B2 study. Thirteen tumors had morphologic features overlapping those of MA and 23 lacked such features; 35 of 36 had tissue available for sequencing of BRAF. Patients with EFHWTs with MA features (13) were older (mean, 8.4 versus 1.9 years; P < .001), had smaller tumor diameters (mean, 6.0 versus 9.7 cm; P < .001), and had fewer mitoses (mean, 1 versus 48 mitoses per 10 high-power fields; P < .001) than patients with EFHWT lacking MA features (23). All EFHWTs with MA features contained at least a partial fibrous pseudocapsule; 7 of 12 (58%) had a BRAF exon 15 mutation. No BRAF exon 15 mutations were identified in 23 EFHWTs lacking MA features. None of the 13 EFHWT patients with MA features have experienced relapse (median follow-up 5.9 years). Pediatric epithelial neoplasms with features of MA that show partial encapsulation and/or modest mitotic activity may be classified as MAs. Although BRAF mutation supports the diagnosis of MA, it is not required for the diagnosis.

Prognostic impact of lymph node involvement and loss of heterozygosity of 1p or 16q in stage III favorable histology Wilms tumor: A report from Children's Oncology Group Studies AREN03B2 and AREN0532.

The prognostic impact of positive lymph nodes (LN+) and/or singular loss of heterozygosity (LOH) of 1p or 16q were assessed in children with stage III favorable histology Wilms tumor (FHWT) enrolled on AREN0532 or AREN03B2 alone. A total of 635 stage III FHWT vincristine/dactinomycin/doxorubicin (DD4A)-treated patients met inclusion criteria. Event-free survival (EFS) and overall survival are reported overall and by LN sampling, LN status, LOH 1p, LOH 16q, and a combination of LN status and singular LOH. Patients with unknown or positive combined LOH of 1p and 16q status and AREN03B2-only patients with unknown outcomes or treatment other than DD4A were excluded. EFS did not differ by study, supporting pooling. Lack of LN sampling (hazard ratio [HR],2.12; p=.0037), LN positivity (HR,2.78; p=.0002), LOH 1p (HR,2.18; p=.0067), and LOH 16q (HR,1.72; p=.042) were associated with worse EFS. Compared with patients with both LN- and LOH-, those with negative nodes but positive LOH 1p or 16q and those with LN+but LOH- for 1p or 16q had significantly worse EFS (HR,3.05 and 3.57, respectively). Patients positive for both LN and LOH had the worst EFS (HR,6.33; overall group factor, p<.0001). Findings confirm LN+status as an adverse prognostic factor amplified by presence of singular LOH 1p or 16q, supporting study of intensified therapy for patients with LN+ in combination with singular LOH in a prospective clinical trial.

Incidence and management of pleural effusions in patients with Wilms tumor: A Pediatric Surgical Oncology Research Collaborative study.

Wilms tumor (WT) is the most common renal malignancy in children. Children with favorable histology WT achieve survival rates of over 90%. Twelve percent of patients present with metastatic disease, most commonly to the lungs. The presence of a pleural effusion at the time of diagnosis of WT may be noted on staging imaging; however, minimal data exist regarding the significance and prognostic importance of this finding. The objectives of our study are to identify the incidence of pleural effusions in patients with WT, and to determine the potential impact on oncologic outcomes. A multi-institutional retrospective review was performed from January 2009 to December 2019, including children with WT and a pleural effusion on diagnostic imaging treated at Pediatric Surgical Oncology Research Collaborative (PSORC) participating institutions. Of 1259 children with a new WT diagnosis, 94 (7.5%) had a pleural effusion. Patients with a pleural effusion were older than those without (median 4.3 vs 3.5 years; P=.004), and advanced stages were more common (local stage III 85.9% vs 51.9%; P < .0001). Only 14 patients underwent a thoracentesis for fluid evaluation; 3 had cytopathologic evidence of malignant cells. Event-free and overall survival of all children with WT and pleural effusions was 86.2% and 91.5%, respectively. The rate and significance of malignant cells present in pleural fluid is unknown due to low incidence of cytopathologic analysis in our cohort; therefore, the presence of an effusion does not appear to necessitate a change in therapy. Excellent survival can be expected with current stage-specific treatment regimens.

Abstract 1674: FGF8 as a modulator of Wilms' tumor in vitro growth and longevity

Abstract Wilms’ tumor is the most common pediatric renal tumor accounting for 6-7% of all childhood cancers. Development of faithful Wilms’ tumor cell lines is needed to identify novel therapeutics. Currently, established Wilms’ tumor cell lines that are suitable for high throughput studies only represent anaplastic Wilms, a rare subtype. In contrast, cell lines representing the more common favorable histology Wilms’ tumor (FHWT) often have poor proliferative capacity and are unable to passage long-term (e.g. &amp;gt;20 passages). For this reason, there is a need to establish robust cell lines representing FHWT. We hypothesize that there are core factors missing from the cell culture medium which prevent proper growth signaling and proliferation. We first performed bulk RNA-sequencing from patients and associated cell lines at Aflac Cancer and Blood Disorders Center with an underlying diagnosis of FHWT. Transcriptomic analyses showed that the reduced growth and proliferation in these FHWT cell lines may be due to reduced presence of the mitogenic fibroblast growth factor 8 (FGF8) in the cell culture environment as compared to the tumor environment. Wilms’ tumor has notably high FGF8 expression levels compared to all other pediatric tumors, implicating FGF8 as a potential driving factor in tumor maintenance. To characterize the phenotypic effects of FGF8 reintroduction in short term FHWT cell lines, we both endogenously overexpressed FGF8 via a lentiviral vector and ectopically added recombinant FGF8 to the cell culture medium. Qualitatively, endogenous overexpression of FGF8 induced distinct morphological changes in cells, converting the enlarged and flattened cells into more focal cells resembling proliferative early passage cells. Quantitatively, overexpression of FGF8 in one favorable histology cell line led to an increased rate of cellular proliferation and extended the cellular longevity by seven passages (47% above baseline). RNA-sequencing analysis of these FGF8 overexpressing cells implicated the anti-apoptotic gene, NTSR1, and an extracellular matrix protein, SNED1, as potential downstream targets of FGF8 overexpression. However, ectopic addition of recombinant FGF8 protein to the cellular medium had less pronounced effects, with seemingly cell-line specific effects. These data demonstrate FGF8 as possibly being required for survival in certain Wilms’ tumor cell lines that can be modulated to influence in vitro proliferation and longevity. Citation Format: Garrett Cooper, Benjamin Lee, Nate Smyth, Karuna Mittal, Taylor Lawrence, Hunter Jonus, Jenny Shim, Kelly Goldsmith, Andrew Hong. FGF8 as a modulator of Wilms' tumor in vitro growth and longevity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1674.

Finding the way to Wilms tumor by comparing the primary and relapse tumor samples

In this issue of Cell Reports Medicine, Gadd and colleagues presented on behalf of the Children’s Oncology Group their comprehensive analysis of genetic changes associated with relapse in children with favorable histology Wilms tumor.

Genetic changes associated with relapse in favorable histology Wilms tumor: A Children’s Oncology Group AREN03B2 study

SummaryOver the last decade, sequencing of primary tumors has clarified the genetic underpinnings of Wilms tumor but has not affected therapy, outcome, or toxicity. We now sharpen our focus on relapse samples from the umbrella AREN03B2 study. We show that over 40% of relapse samples contain mutations in SIX1 or genes of the MYCN network, drivers of progenitor proliferation. Not previously seen in large studies of primary Wilms tumors, DIS3 and TERT are now identified as recurrently mutated. The analysis of primary-relapse tumor pairs suggests that 11p15 loss of heterozygosity (and other copy number changes) and mutations in WT1 and MLLT1 typically occur early, but mutations in SIX1, MYCN, and WTX are late developments in some individuals. Most strikingly, 75% of relapse samples had gain of 1q, providing strong conceptual support for studying circulating tumor DNA in clinical trials to better detect 1q gain earlier and monitor response.

TERT Expression in Wilms Tumor Is Regulated by Promoter Mutation or Hypermethylation, WT1, and N-MYC.

Simple SummaryThe telomerase enzyme adds repetitive genetic sequences to the ends of chromosomes called telomeres to prevent cellular senescence. Gain of telomerase function is one of the hallmarks of human cancer. The telomerase protein is coded by the gene TERT and increased TERT RNA levels have been associated with disease relapse in Wilms tumor, the most common kidney cancer of childhood. This study aimed to determine the mechanisms of increased TERT expression in Wilms tumor. This study found mutations in the TERT promoter, increased methylation of the TERT promoter, and genomic copy number amplifications of TERT as potential mechanisms of TERT activation. Conversely, this study found that inactivating WT1 mutation was associated with low TERT RNA levels and telomerase activity. N-MYC overexpression in Wilms tumor cells resulted in increased TERT promoter activity and TERT transcription. TERT transcription is associated with molecular and histologic subgroups in Wilms tumor and telomere-targeted therapies warrant future investigation.Increased TERT mRNA is associated with disease relapse in favorable histology Wilms tumor (WT). This study sought to understand the mechanism of increased TERT expression by determining the association between TERT and WT1 and N-MYC, two proteins important in Wilms tumor pathogenesis that have been shown to regulate TERT expression. Three out of 45 (6.7%) WTs and the corresponding patient-derived xenografts harbored canonical gain-of-function mutations in the TERT promoter. This study identified near ubiquitous hypermethylation of the TERT promoter region in WT compared to normal kidney. WTs with biallelic inactivating mutations in WT1 (7/45, 15.6%) were found to have lower TERT expression by RNA-seq and qRT-PCR and lower telomerase activity determined by the telomerase repeat amplification protocol. Anaplastic histology and increased percentage of blastema were positively correlated with higher TERT expression and telomerase activity. In vitro shRNA knockdown of WT1 resulted in decreased expression of TERT, reduced colony formation, and decreased proliferation of WiT49, an anaplastic WT cell line with wild-type WT1. CRISPR-Cas9-mediated knockout of WT1 resulted in decreased expression of telomere-related gene pathways. However, an inducible Wt1-knockout mouse model showed no relationship between Wt1 knockout and Tert expression in normal murine nephrogenesis, suggesting that WT1 and TERT are coupled in transformed cells but not in normal kidney tissues. N-MYC overexpression resulted in increased TERT promoter activity and TERT transcription. Thus, multiple mechanisms of TERT activation are involved in WT and are associated with anaplastic histology and increased blastema. This study is novel because it identifies potential mechanisms of TERT activation in Wilms tumor that could be of therapeutic interests.

Kidney Preservation and Wilms Tumor Development in Children with Diffuse Hyperplastic Perilobar Nephroblastomatosis: A Report from the Children's Oncology Group Study AREN0534.

Diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) represents a unique category of nephroblastomatosis. Treatment has ranged from observation to multiple regimens of chemotherapy. Wilms tumors (WTs) develop in 100% of untreated patients and between 32 and 52% of treated patients. Renal preservation rates have not been previously reported. An aim of the Children's Oncology Group (COG) study AREN0534 was to prospectively evaluate the efficacy of chemotherapy in preserving renal units and preventing WT development in children with DHPLN. Patients were enrolled through the COG protocol AREN03B2 with central radiological review. DHPLN was defined as the cortical surface of the kidney being composed of hyperplastic rests, with the entire nephrogenic zone involved, and with a thick rind capping all of one or both kidneys. Treatment was with vincristine and dactinomycin (regimen EE4A), with cross-sectional imaging at weeks 6 and 12. If the patient's disease was stable or decreasing, treatment was continued for 19 weeks. Renal preservation, WT development rates at 1year, and overall survival (OS) are reported. Nine patients were enrolled (five females and four males), with a median age at enrollment of 10.22months (range 2.92-29.11). One patient who was enrolled was deemed unevaluable because they did not meet the radiological criteria for DHPLN, resulting in eight evaluable patients. These eight patients had DHPLN confirmed via radiological criteria (all bilateral). Initial chemotherapy was EE4A for all eight patients, with seven of eight patients starting chemotherapy without tissue diagnosis.One patient who had an upfront partial nephrectomy was found to have DHPLN in the specimen and was subsequently treated with EE4A. All patients remained alive, with a median follow-up of 6.6years (range 4.5-9.1). No patients were anephric; 14 of 16 kidneys were functioning (87.5%). Six of eight patients (75%) did not have WT on therapy, but two of these patients relapsed within 6months of stopping therapy; both had favorable histology WT. One patient who was diagnosed with WT on therapy relapsed at 12 months (one of eight [12.5%]) and developed anaplastic histology. Chemotherapy for patients with DHPLN was effective in preserving kidney function. Five-year OS is excellent, however the ideal type and duration of chemotherapy to prevent WT development remains elusive.

CLINICAL EXPERIENCE IN THE MANAGEMENT OF PEDIATRIC WILMS TUMOR

Wilms tumor is the commonest renal tumor in children. This study aimed to evaluate the characteristics, diagnosis, treatment, and outcome of Wilms tumor in pediatric age group and to analyze factors affecting the outcome. This retrospective study included 61 children younger than 15 years with Wilms tumor who were managed at Basrah Children Specialty Hospital during the period between 2011 and 2016. Patients` characteristics, mode of diagnosis, treatment modalities, complications, relapse, and outcome were all reviewed. The results showed that Wilms tumor was the commonest tumor affecting the kidneys (85%). The median age of onset was 30 months, and mostly in children aged 2-4 years. The most common presenting feature was abdominal mass (44.3%). Twenty three patients were diagnosed as stage 1 (37.7%). Favorable histology Wilms tumor was encountered in only 65.6%. Tumor relapse was seen in 12 patients (19.7%), eight of them died (66.7%). The overall 2-year survival was 70.5% (43 cases). In conclusion, Wilms tumor is the most common renal tumor with high rate of unfavorable histology (anaplasia) in our society. Stage I tumor is the predominant stage but unfortunately carries a relatively high mortality. Advanced stages still represent a significant proportion which may reflect poor awareness and delayed diagnosis which thereafter worsens the outcome. Advanced stages, presence of anaplasia, and tumor relapse are the major factors affecting survival of children with Wilms tumor. Keywords: Renal tumors, Wilms, Staging, Histology, Outcome

The prognosis of prechemotherapy blastemal predominant histology subtype in Wilms tumor: A retrospective study in China

This study aimed to retrospectively analyze survival outcomes for Chinese patients with prechemotherapy blastemal predominant histology type Wilms tumors (WTs). We collected and analyzed clinical data concerning patients aged<15 years with favorable histology (FH) WTs treated at the Sun Yat-Sen University Cancer Center from December 2005 to May 2016, based on the Children's Oncology Group protocol. Pathological specimens were collected through biopsy or surgical resection before initiation of chemotherapy. We analyzed survival outcomes involving different prechemotherapy histology subtypes. We enrolled 97 patients with FH WTs (median follow-up, 71.5 months; range, 22.2-170.7). The total recurrence rate was 17.5%, and the subtype recurrence rates were as follows: blastemal predominant (45.5%), mixed (7.5%), epithelial (14.3%), and mesenchymal (9.5%) (P=.010). Five-year event-free survival (EFS) and overall survival (OS) rates were 84.9% and 81.4%, respectively. Respective 5-year EFS and OS rates for subtypes were as follows: blastemal predominant (54.5% and 68.2%), mixed (90.0% and 88.9%), epithelial (85.7% and 85.1%), and mesenchymal (90.5% and 94.7%). Multivariate survival analyses showed that the blastemal predominant subtype was an independent prognostic factor of EFS (P=.001) and OS (P=.017). Our findings showed that prechemotherapy blastemal predominant WTs had higher recurrence and lower EFS and OS rates. Our findings suggested that, albeit with some deficiencies, blastemal predominant histology WT-diagnosed prechemotherapy may have prognostic relevance.Further research into other potential confounding variables are required to determine whether such patients warrant altered risk-stratified therapy.

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.

Outcome analysis of stage I epithelial-predominant favorable-histology Wilms tumors: A report from Children's Oncology Group study AREN03B2.

Stage I epithelial-predominant favorable-histology Wilms tumors (EFHWTs) have long been suspected to have an excellent outcome. This study investigates the clinical and pathologic features of patients with stage I EFHWTs to better evaluate the potential for a reduction of chemotherapy and its associated toxicity. All patients registered in the Children's Oncology Group (COG) AREN03B2 study between 2006 and 2017 with stage I EFHWTs were identified. EFHWTs were defined as tumors with at least 66% epithelial differentiation, regardless of the degree of differentiation. Clinical information was abstracted from COG records. Event-free survival (EFS) and overall survival (OS) were calculated and compared between groups based on age and therapy. The 4-year EFS rate was 96.2% (95% confidence interval, 92%-100%), and the OS rate was 100%; EFS and OS did not statistically significantly differ with the age at diagnosis (<48 vs ≥48 months; P=.37) or treatment (EE4A vs observation only; P=.55). Six events were reported. Three patients developed contralateral tumors and did not otherwise relapse; none of these had nephrogenic rests or a recognized predisposition syndrome. Three patients developed metastatic recurrence; all 3 had received EE4A as their primary therapy after nephrectomy. These findings demonstrate an excellent outcome for stage I EFHWTs with >95% EFS and OS. These data support the utility of investigating the treatment of stage I EFHWTs with observation alone after nephrectomy.

Novel therapy for pediatric and adolescent kidney cancer.

Pediatric and adolescent renal tumors account for approximately 7% of all new cancer diagnoses in the USA each year. The prognosis and treatment are varied based on factors including the underlying histology and tumor stage, with survival rates ranging from greater than 90% in favorable histology Wilms tumor to almost universally fatal in other disease types, including those patients with advanced stage malignant rhabdoid tumor and renal medullary carcinoma. In recent years, our understanding of the underlying genetic drivers of the different types of pediatric kidney cancer has dramatically increased, opening the door to utilization of new targeted biologic agents alone or in combination with conventional chemotherapy to improve outcomes. Several ongoing clinical trials are investigating the use of a variety of targeted agents in pediatric patients with underlying genetic aberrations. In this manuscript, the underlying biology and early phase clinical trials relevant to pediatric renal cancers are reviewed.

From Favorable Histology to Relapse: The Clonal Evolution of a Wilms Tumor.

Favorable histology (FH) Wilms tumor (WT) is one of the most curable of all human cancers, yet a small minority of patients fail treatment. The underlying biological pathways that lead to therapy resistance are unknown. We report a case of initially unresectable, FH WT which revealed limited necrosis and persistent blastemal predominant histology following neoadjuvant chemotherapy. Despite intensification of therapy and whole abdominal radiation, the patient relapsed and succumbed to her disease. In an effort to discover candidate drivers of drug resistance, whole exome sequencing and copy number analysis were performed on samples from all 3 tumor specimens. Sequencing results revealed outgrowth of clones with a dramatically different genetic landscape including dominant mutations that could explain therapy evasion, some of which have not been previously reported in WT. Our results implicate PPM1D, previously shown to be associated with drug resistance in other tumors, as the major driver of treatment failure.

Renal Tumors in Children and Young Adults Older Than 5 Years of Age.

Renal masses are most common in children between ages 1 to 3 years, with less known about renal tumors in older children and young adults. The aim of this study was to review the presentation, demographics, histology, and outcomes in patients over 5 years of age with renal tumors compared with younger children. 111 renal tumors were diagnosed in patients 5 years of age and older (median, 7 y; range, 5 to 31 y) between 1950 and 2017 at a single institution. Wilms tumor (WT) was the most common histology in 84 patients (75%), followed by renal cell carcinoma in 12 patients (10.7%). Abdominal pain was the most common presenting symptom (46%) followed by hematuria (28.8%), and a palpable abdominal mass (24.3%). For WT, older children more commonly presented with advanced-stage disease (stages 3 and 4) than younger children (57.7% vs. 11.5%; P<0.001). Event-free survival (EFS) and overall survival (OS) for favorable histology WT were not different between younger and older children (OS, P=0.43; EFS, P=0.46). In this cohort, older children more frequently present with variable signs and symptoms, less common histopathologies although WT was still most frequent, and more advanced-stage disease compared with younger cohorts, but without differences in EFS or OS.