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PurposeIn National Wilms Tumor Study 5 (NWTS-5), tumor-specific combined loss of heterozygosity of chromosomes 1p and 16q (LOH1p/16q) was associated with adverse outcomes in patients with favorable histology Wilms tumor. The AREN0533/AREN0532 studies assessed whether augmenting therapy improved event-free survival (EFS) for these patients. Patients with stage I/II disease received regimen DD4A (vincristine, dactinomycin and doxorubicin) but no radiation therapy. Patients with stage III/IV disease received regimen M (vincristine, dactinomycin, and doxorubicin alternating with cyclophosphamide and etoposide) and radiation therapy.MethodsPatients were enrolled through the AREN03B2 Biology study between October 2006 and October 2013; all underwent central review of pathology, surgical reports, and imaging. Tumors were evaluated for LOH1p/16q by microsatellite testing. EFS and overall survival were compared using the log-rank test between NWTS-5 and current studies.ResultsLOH1p/16q was detected in 49 of 1,147 evaluable patients with stage I/II disease (4.27%) enrolled in AREN03B2; 32 enrolled in AREN0532. LOH1p/16q was detected in 82 of 1,364 evaluable patients with stage III/IV disease (6.01%) in AREN03B2; 51 enrolled in AREN0533. Median follow-up for 83 eligible patients enrolled in AREN0532/0533 was 5.73 years (range, 2.84 to 9.63 years). The 4-year EFS for patients with stage I/II and stage III/IV disease with LOH1p/16 was 87.3% (95% CI, 75.1% to 99.5%) and 90.2% (95% CI, 81.8% to 98.6%), respectively. These results are improved compared with the NWTS-5 updated 4-year EFS of 68.8% for patients with stage I/II disease (P = .042), and 61.3% for patients with stage III/IV disease (P = .001), with trends toward improved 4-year overall survival. The most common grade 3 or higher nonhematologic toxicities with regimen M were febrile neutropenia (39.2%) and infections (21.6%).ConclusionAugmentation of therapy improved EFS for patients with favorable histology Wilms tumor and LOH1p/16q compared with the historical NWTS-5 comparison group, with an expected toxicity profile.

Simple Summary: Fusion oncoprotein DNAJB1-PKAc was found only in adolescent patients with fibrolamellar HCC. Expression of the fusion kinase in FLC patients causes the formation of fibrotic lamellar structures, increased proliferation, and massive alterations in transcriptome profiling that drive FLC disease. In this paper, we identified cancer cells expressing the DNAJB1-PKAc in 1–3-year-old children with pediatric liver cancers and children with biliary atresia. The expression of DNAJB1-PKAc enhances the development of pediatric liver cancers by bringing fibrolamellar-specific disorders, by increasing the rate of proliferation, and by increasing resistance to chemotherapy. Expression of DNAJB1-PKAc in patients with biliary atresia correlates with an increased expression of oncogenes. Background and Aims: Hepatoblastoma (HBL) and fibrolamellar hepatocellular carcinoma (FLC) are the most common liver malignancies in children and young adults. FLC oncogenesis is associated with the generation of the fusion kinase, DNAJB1-PKAc (J-PKAc). J-PKAc has been found in 90% of FLC patients' tumors but not in other liver cancers. Since previous studies of J-PKAc were performed with adolescent patients, we asked if young children may express J-PKAc and if there are consequences of such expression. Methods: The biobank of the pediatric HBL/HCN-NOS specimens was examined by QRT-PCR, Western blots, RNA-Seq, and immunostaining with fusion-specific antibodies. Results: J-PKAc is expressed in 70% of the HBL/HCN-NOS patients. RNA-Seq analysis revealed that HBL tumors that do not have cells expressing J-PKAc show elevated expression of the membrane attack complex (MAC), which eliminates cells expressing J-PKAc. The fusion-positive HBL/HCN-NOS samples have several signaling pathways that are different from fusion-negative HBLs. Upregulated pathways included genes involved in the G1 to S transition and in liver cancer. Downregulated pathways included over 60 tumor suppressors, the CYP family, and the SLC family. The repression of these genes involves J-PKAc-β-catenin-TCF4-mediated elevation of the HDAC1-Sp5 pathway. The identified upregulated and downregulated pathways are direct targets of the fusion kinase. The J-PKAc kinase is also detected in livers of 1-year-old children with biliary atresia (BA). Conclusions: J-PKAc is expressed in both HBL tumor and BA liver samples, contributing to the development of HBL and creating a transcriptome profiling consistent with the potential development of liver cancer in young patients. [ABSTRACT FROM AUTHOR]

PurposeThe use of computed tomography (CT) for routine surveillance to detect recurrence in patients with Wilms tumor (WT) has increased in recent years. The utility of CT, despite increased risk and cost, to improve outcome for these patients is unknown. We conducted a retrospective analysis with patients enrolled in the fifth National Wilms Tumor Study (NWTS-5) to determine if surveillance with CT correlates with improved overall survival (OS) after recurrence compared with chest x-ray (CXR) and abdominal ultrasound (US).Patients and methodsOverall, 281 patients with recurrent unilateral favorable-histology WT were reviewed to assess how WT recurrence was detected: sign/symptoms (SS), surveillance imaging (SI) with CT scan, or SI with CXR/US.ResultsThe estimated 5-year OS rate after relapse was 67% (95% CI, 61% to 72%). Twenty-five percent of recurrences were detected with SS; 48.5%, with CXR/US; and 26.5%, with CT. Patients with SS had a 5-year OS rate of 59% (95% CI, 46% to 72%) compared with 70% (95% CI, 63% to 77%; P = .23) for those detected by SI. Recurrences detected by CT had a shorter median time from diagnosis to recurrence (0.60 years) compared with SS (0.91 years) or CXR/US (0.86 years; P = .003). For recurrences detected by SI, more tumor foci at relapse ( P < .001) and size of the largest focus greater than 2 cm ( P = .02) were associated with inferior OS. However, there was no difference in OS after relapse when recurrence was detected by CT versus CXR/US (5-year OS rate, 65% v 73%; P = .20).ConclusionIn patients with favorable-histology WT, elimination of CT scans from surveillance programs is unlikely to compromise survival but would result in substantial reduction in radiation exposure and health care costs.

Purpose The National Wilms Tumor Study (NWTS) treatment of favorable histology Wilms tumor with lung metastases was vincristine/dactinomycin/doxorubicin (DD4A) and lung radiation therapy (RT). The AREN0533 study applied a new risk stratification and treatment strategy to improve event-free survival (EFS) while reducing exposure to lung RT. Methods Patients with favorable histology Wilms tumor and isolated lung metastases showing complete lung nodule response (CR) after 6 weeks of DD4A continued receiving chemotherapy without lung RT. Patients with incomplete response (IR) or loss of heterozygosity at chromosomes 1p/16q received lung RT and four cycles of cyclophosphamide/etoposide in addition to DD4A drugs (Regimen M). AREN0533 was designed to preserve a 4-year EFS of 85% for lung nodule CR and improve 4-year EFS from 75% to 85% for lung nodule IR. Results Among 292 assessable patients, 133 had CR and 159 had IR. For patients with CR, 4-year EFS and overall survival (OS) estimates were 79.5% (95% CI, 71.2% to 87.8%) and 96.1% (95% CI, 92.1% to 100%), respectively. Expected versus observed event rates were 15% and 20.2% ( P = .052), respectively. For patients with IR, 4-year EFS and OS estimates were 88.5% (95% CI, 81.8% to 95.3%) and 95.4% (95% CI, 90.9% to 99.8%), respectively. Expected versus observed event rates were 25% and 12.2% ( P < .001), respectively. Overall, 4-year EFS and OS were 85.4% (95% CI, 80.5% to 90.2%) and 95.6% (95% CI, 92.8% to 98.4%) compared with 72.5% (95% CI, 66.9% to 78.1%; P < .001) and 84.0% (95% CI, 79.4% to 88.6%; P < .001), respectively, in the predecessor NWTS-5 study. Conclusion Excellent OS was achieved after omission of primary lung RT in patients with lung nodule CR, although there were more events than expected. EFS was significantly improved, with excellent OS, in patients with lung nodule IR using four cycles of cyclophosphamide/etoposide in addition to DD4A drugs. The overall AREN0533 treatment strategy yielded EFS and OS estimates that were superior to previous studies.

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. [ABSTRACT FROM AUTHOR]

Introduction: A retrospective review of patients treated for retinoblastoma who developed a non-pineoblastoma second primary malignant neoplasm (SPMN) was performed. Methods: The demographics, clinical features and treatments for retinoblastoma, pathologic types of non-pineoblastoma second primary malignant neoplasm (SPMN), intervals between the retinoblastoma diagnosis and treatment and diagnosis of non-pineoblastoma SPMN, treatment provided for the SPMN, and the survival outcomes of the patients were evaluated. Results: Of 550 patients treated initially for retinoblastoma, this series used the 15 (2.7) that developed a non-pineoblastoma SPMN, 14 of which (93.3%) had been treated for bilateral retinoblastoma. All patients had carried a germline mutations in the RB1 gene. The median time from retinoblastoma diagnosis to SPMN diagnosis was 19.0 years (extremes 3.4 and 39.4 years). Six of the fifteen patients died during the follow-up of their SPMN. The median interval between initial retinoblastoma diagnosis and death in the 6 patients who died of their SPMN was 18.8 years (extremes 6.2 and 34.6 years) and between diagnosis of the SPMN and death was 1.2 years (extremes 0.25 and 4 years). Discussion: Of the patients who had been treated with External Beam Radiotherapy (EBRT), 13 developed a SPMN within the previously irradiated field. [ABSTRACT FROM AUTHOR]

Background: On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5‐year event‐free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk‐adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH‐1). Patients who had stage II/III disease received regimen I with RT. Methods: Four‐year EFS was analyzed for patients enrolled on AREN0321 and on those enrolled on AREN03B2 who received AREN0321 stage‐appropriate chemotherapy. Results: Eighty‐two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4‐year EFS rate was 82.7% (95% confidence interval [CI], 74.8%–91.4%) for AREN0321 and 89.6% (95% CI, 81.3%–98.7%) for AREN03B2 only (p =.28). When combining studies, the 4‐year EFS rates for patients who had stage I (n = 10), II (n = 47), III (n = 65), and IV (n = 10) disease were 90% (95% CI, 73.2%–100.0%), 93.4% (95% CI, 86.4%–100.0%), 82.8% (95% CI, 74.1%–92.6%), and 58.3% (95% CI, 34%–100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic. Conclusions: Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin‐containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients with advanced‐stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365). The results of this study indicate that treatment of clear cell sarcoma of the kidney can be risk‐adapted based on disease stage, radiotherapy should be omitted for patients with stage I disease if lymph nodes are sampled, and patients with stage IV disease appear to benefit from a carboplatin‐containing regimen. With treatment according to the Children's Oncology Group AREN0321 study, most relapses occurred within 3 years, and the most common sites of recurrence were in the central nervous system. [ABSTRACT FROM AUTHOR]

Background: Patients with stage IV favorable histology Wilms tumor (FHWT) with extrapulmonary metastases (EPM) constitute a small subset of patients with FHWT. Because of their rarity and heterogeneity, optimal FHWT treatment is not well understood. Children's Oncology Group protocol AREN0533 assigned patients with FHWT and EPM to intensified chemotherapy, regimen M, after initial DD‐4A chemotherapy. To improve understanding of prognostic factors and best therapies, experiences of patients with EPM on AREN0533, as well as on protocols AREN03B2 and NWTS‐5, were reviewed. Methods: Combined outcomes for patients with EPM from NWTS‐5, AREN0533, and AREN03B2 were determined. Those treated on AREN0533 were compared with those treated on NWTS‐5. Prognostic factors were explored in the pooled cohort. Results: Forty‐seven patients with FHWT with EPM enrolled on AREN0533, 37 enrolled on NWTS‐5, and 64 were followed only on AREN03B2. The pooled cohort of all 148 patients demonstrated a 4‐year event‐free survival (EFS) of 77.3% (95% CI, 70.8–84.4) and 4‐year overall survival of 88.9% (95% CI, 83.9–94.2). Four‐year EFS of patients with EPM treated on AREN0533 was 76.0% (95% CI, 64.6–89.4) vs 64.9% (95% CI, 51.7–82.2) on NWTS‐5; hazard ratio, 0.64, p =.26; no difference in overall survival was observed. Increasing linear age and slow incomplete lung response were associated with worse EFS in a pooled cohort. Conclusions: Outcomes for patients with EPM are among the lowest for children with FHWT. Further trials with standardized surgical and radiation treatment to metastatic sites, and prospectively collected biologic and treatment details are needed. Clinical trial registration: Clinical Trials.gov identifiers: NCT00379340, NCT00898365, and NCT00002611. Pooled outcomes across three studies of patients with favorable histology Wilms tumor and extrapulmonary metastases revealed 4‐year event‐free survival of 77.3% and overall survival of 88.9%, with no statistical differences seen between patients on AREN0533 compared with those on NWTS‐5. Missing details on local management of metastatic sites informs a critical need for better data capture in future studies to optimize local control strategies and chemotherapy regimens for this higher‐risk favorable histology Wilms tumor patient group. [ABSTRACT FROM AUTHOR]