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Hepatoblastoma (HB) requires surgical resection for cure, but only 20-30% of patients have resectable disease at diagnosis. Patients who undergo partial hepatectomy at diagnosis have historically received 4-6 cycles of adjuvant chemotherapy; however, those with 100% well-differentiated fetal histology (WDF) have been observed to have excellent outcomes when treated with surgery alone.Patients on the Children's Oncology Group non randomized, multicenter phase III study, AHEP0731, were stratified based on Evan's stage, tumor histology, and serum alpha-fetoprotein level at diagnosis. Patients were eligible for the very low risk stratum of surgery and observation if they had a complete resection at diagnosis and rapid central histologic review demonstrated HB with 100% WDF histology.A total of 8 eligible patients were enrolled on study between September 14, 2009 and May 28, 2014. Outcome current to 06/30/2020 was used in this analysis. The median age at enrollment was 22.5 months (range: 8-84 months) and the median AFP at enrollment was 714 ng/ml (range: 18-77,747 ng/mL). With a median follow-up of 6.6 years (range: 3.6-9.8 years), the 5-year event-free (EFS) and overall survival (OS) were both 100%.This report supports that HB with 100% WDF histology completely resected at diagnosis is curable with surgery only. The development of evidence-based surgical guidelines utilizing criteria based on PRETEXT group, vascular involvement (annotation factors), tumor-specific histology and corresponding biology will be crucial for optimizing which patients are candidates for resection at diagnosis followed by observation.Prognosis study, Level I evidence.

Background Talazoparib combined with irinotecan and temozolomide demonstrated efficacy in a murine Ewing sarcoma model. Based on these data, we conducted a phase I trial of talazoparib and irinotecan with/without temozolomide in paediatric patients with recurrent/refractory solid malignancies. Patients and methods Cohorts of 3–6 patients with recurrent/refractory solid malignancies received escalating doses of oral talazoparib and intravenous irinotecan (arm A) and oral talazoparib, oral temozolomide and intravenous irinotecan (arm B) in a 3 + 3 design. Talazoparib was administered on days 1–6, and intravenous irinotecan and oral temozolomide were administered on days 2–6, of a 21-day course. Serum for talazoparib and irinotecan pharmacokinetics was obtained during course 1. UGT1A1 polymorphism and Schlafen family member 11 (SLFN11) immunohistochemical staining were performed. Results Forty-one patients (20 males; median age, 14.6 years; 24 with recurrent disease) were evaluable for dose escalation. Twenty-nine and 12 patients were treated on arm A and arm B, respectively, for a total of 208 courses. The most common diagnosis was Ewing sarcoma (53%). The most common ≥grade III haematologic toxicities in arms A and B included neutropenia (78% and 31%, respectively) and thrombocytopenia (42% and 31%, respectively). In arms A and B, febrile neutropenia (24% and 14%, respectively) and diarrhoea (21% and 7%, respectively) were the most common ≥grade III non-hematologic toxicities. Six patients (Ewing sarcoma [5 patients] and synovial sarcoma [1 patient]) had a response (1 with a complete response, 5 with a partial response). The objective response rates were 10.3% (arm A) and 25% (arm B). Pharmacokinetic testing demonstrated no evidence of drug-drug interaction between talazoparib and irinotecan. UGT1A1 was not related to response. SLFN11 positivity was associated with best response to therapy. Conclusions The combination of talazoparib and irinotecan with/without temozolomide is feasible and active in Ewing sarcoma, and further investigation is warranted.

Background Angiogenesis is critical for tumour growth and metastasis. Dual inhibition of vascular endothelial growth factors and platelet-derived growth factor receptors suppresses angiogenesis. This expansion cohort of a phase I study targeted angiogenesis with sorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults with recurrent solid tumours. Methods An expansion cohort including patients with refractory or recurrent solid tumours was enrolled and received bevacizumab (15 mg/kg IV, day 1), sorafenib (90 mg/m2 po twice daily, days 1–21) and low-dose cyclophosphamide (50 mg/m2 po daily, days 1–21). Each course was 21 days. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v3.0, and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. Serial bevacizumab pharmacokinetic (PK) studies were performed during course 1. Results Twenty-four patients (15 males; median age 14.5 yrs; range 1–22 yr) received a median of 6 courses (range 1–18). Twelve patients had a bone or soft tissue sarcoma. The most common grade III/IV non-haematologic toxicities were hypertension (N = 4), hand/foot rash (N = 3) and elevated lipase (N = 3). The most common grade III/IV haematologic toxicities were neutropenia (N = 7) and lymphopenia (N = 17). Three patients (2 synovial sarcoma, 1 rhabdoid tumour) achieved a partial response and 18 had stable disease. The progression-free survival at 3 and 6 months were 78.1% (95% confidence interval [CI] 60.6–95.6%) and 54% (95% CI 30.2–78.2%), respectively. Bevacizumab PKs in 15 patients was similar to published adult PK results. Conclusions Intravenous bevacizumab combined with oral sorafenib and low-dose cyclophosphamide was tolerated and demonstrated promising activity in a subset of childhood solid tumours.

Background/Purpose MYCN-amplification in neuroblastoma is associated with an aggressive clinical phenotype. We evaluated the association of MYCN amplification with tumor response to neoadjuvant chemotherapy. Methods Primary tumor response, assessed by percentage volume change on CT scan and degree of tumor resection, assessed by the operating surgeon, were retrospectively compared in 84 high-risk neuroblastoma patients. There were thirty-four (40%) with MYCN-amplified tumors and fifty (60%) with non-amplified tumors treated at our institution from 1999 to 2016. Metastatic disease response was assessed on MIBG scan by change in Curie score. Results MYCN-amplification was associated with a greater mean percentage reduction in primary tumor volume after neoadjuvant chemotherapy (72.27% versus 46.83% [non-amplified tumors], p = 0.001). The percentage of patients with a Curie score > 2 at diagnosis who then had a score ≤ 2 after neoadjuvant chemotherapy was not significantly different (8 [61.5%] and 8 [34.8%], respectively, p = 0.37). Twenty-eight (85.7%) patients with MYCN-amplification had ≥ 90% surgical resection compared to 45 (91.84%) patients with non-amplified tumors (p = 0.303). Conclusions MYCN-amplification in high-risk neuroblastoma was associated with a better response of the primary tumor to neoadjuvant chemotherapy, but not metastatic sites, than in patients with non-amplified tumors. This did not significantly impact the ability to resect ≥ 90% of the primary tumor/locoregional disease. Type of Study Treatment Study Level of Evidence Level III

The predictive value of Image-Defined Risk Factors (IDRFs) developed by the International Neuroblastoma Risk Group Task Force as it relates to primary-site management is undefined and may aid patient selection for de-escalation of adjuvant radiation therapy to the primary site in high-risk neuroblastoma.Patients (N = 76) with high-risk neuroblastoma treated on prospective trials at our institution from 1997 to 2014 were eligible for inclusion. IDRFs were defined based on pretherapy imaging. Overall survival, progression-free survival, and locoregional failure-free survival (LRFFS) were described using the Kaplan-Meier estimator and tested across strata by using the log-rank test.Twenty of 76 patients (26%) experienced local (n = 6), regional (n = 6), or combined locoregional failure (n = 8) with or without distant failure. Ten (50%) of the locoregional failures had concurrent distant relapse. Of patients who completed all therapy, both those with no IDRFs and those with90% resection had a 3-year LRFFS of 100%, with or without radiation therapy. Patients with either ≥1 IDRF or Gross Total Resection (GTR) or the inability to complete all therapy had inferior 3-year LRFFS of 77.8% and 14.4% with or without radiation therapy, respectively (P .04). Patients treated with a dose ≥30.6 Gy as part of therapy for residual disease had an 83.3% locoregional control rate.Patients with90% tumor resection and no primary site IDRFs at diagnosis may be candidates for de-escalation of adjuvant primary-site radiation therapy, although validation of these findings in future studies is required.

To investigate associations between germline genetic variations in the epidermal growth factor receptor (EGFR) and toxicity in paediatric patients treated with gefitinib.Gefitinib treatment and toxicity data from five paediatric clinical trials were combined. EGFR genotypes evaluated included -191CA, -216GT, Arg497Lys and intron 1 CA sequence repeat number. The genetic variations were evaluated for associations with grade one or greater rash or diarrhoea during the first course of treatment.The analysis included 110 patients, 60 (55%) with grade one or greater rash and 47 (43%) with grade one or greater diarrhoea. Among patients with the -216 GG (n=51), GT (n=41) and TT (n=16) genotypes, grade one or greater rash occurred in 52.9%, 46.3% and 87.5% of patients (p=0.003, recessive model), respectively. Diarrhoea occurred in 27.5%, 58.5% and 43.8% of patients with respective GG, GT and TT genotypes (p=0.004, dominant model). The -191CA, intron 1 CA repeat number and Arg497Lys genotypes were not significantly associated with either rash or diarrhoea. EGFR -216 and -191 polymorphisms were in linkage disequilibrium (D'=0.66, p=0.01). The haplotype (-191C, -216T) was associated with increased risk for rash (p=0.049), but was not more predictive of rash than the single -216 polymorphism.These findings indicate that EGFR -216GT genotype is a predictive marker for the development of skin rash and diarrhoea in paediatric patients treated with gefitinib. Continued investigation of relationships between germline EGFR polymorphisms and the efficacy of EGFR inhibitors in paediatric patients is warranted.

Purpose The purpose of the study was to compare outcomes of pediatric patients with high-risk metastatic neuroblastoma who received radiotherapy (RT) with those of patients who did not. Patients and methods We reviewed the records of 63 patients with newly diagnosed metastatic neuroblastoma treated at our institution (1989-2001) to investigate their characteristics at presentation, dose and field of RT, treatment response, and failure patterns. Results Seventeen patients received RT, and 46 did not. In the RT group, a greater percentage of patients had residual disease before consolidation than did those in the no-RT group (88.2% vs 69.6%, P = .008). Gross total resection was achieved less often in the RT group (65% vs 89%, P = .055), but the 5-year cumulative incidences of local failure were similar (35.3% ± 12.4% vs 32.6% ± 7.1%). Although there was no difference in 5-year event-free survival, overall survival was better in the no-RT group (47.8% ± 7.2% vs 23.5% ± 9.2%, P = .026). Conclusion The addition of RT to the therapy of a group of patients with more residual locoregional disease appeared to improve the local failure rate to approximately that of patients with less residual disease. Radiotherapy may provide even greater benefit to those with less residual disease before consolidation.

Parents of terminally ill children with cancer frequently ask clinicians when their child will die. Such information helps parents prepare for the child's death. To identify how parents perceived when their child's cancer-related death would occur, we conducted a secondary analysis of telephone interviews with 49 bereaved parents 6–10 months after their child's death to extract their descriptions of this occurrence. The parents knew in advance that their child was going to die, but they described when their child's death would occur in three different ways: anticipated (parents observed changes that alerted them that death was imminent; n = 22, 52.4%), surprising (parents were surprised that their child died on that particular day; n = 13, 31.0%), and overdue (parents had been waiting for the end of their child's apparent suffering; n = 7, 16.7%). These categories did not differ by patients' diagnosis, sex, or location of death but differed slightly by symptom patterns. Parents who reported the occurrence of their child's death as surprising reported fewer symptom changes on the last day of their child's life, compared with the last week of life, than did the parents in the other two categories. These findings indicate that parents of children with terminal cancer can perceive when their child's death would occur very differently: Some are surprised, whereas others feel they have waited too long for their child's release from suffering. Clinicians can use these descriptions and the associated symptom patterns to help families prepare for their child's last week and last day.

Background Purpose: The organs and soft tissues of the pelvis are some of the most common primary sites for rhabdomyosarcoma (RMS) in children and adolescents. In most cases a mass is detectable on clinical examination, and the initial concern is focused on the possibility of a neoplasm. The current report concerns 11 patients, each presented with a painful perineal-perianal mass suggesting an abscess to the extent that each one of these patients was treated initially with antibiotics or incision and drainage for several weeks to months before the pathologic diagnosis of RMS was established. Methods: The authors reviewed the clinical histories of all patients with perirectal/perianal RMS from their respective institutions to identify cases in which the initial clinical diagnosis or impression was that of a perirectal abscess. Pathologic material was reviewed in all cases. Results: Eleven patients, 7 of whom were girls, ranged in age from 1 to 16 years at diagnosis (median age, 14 years). Fever accompanied the clinical presentation in 2 patients. None of the patients had a past medical history of illness that may have predisposed them to a perirectal abscess, although one patient had a family history of inflammatory bowel disease. Duration of symptoms ranged from 1 month to 1 year (mean, 4.6 months). Each patient presented with a tender perianal/perineal nodule or mass. Inguinal adenopathy was present in 6 patients at diagnosis. White blood cell counts ranged from 6,600/mm 3 to 24,500/mm 3 . LDH levels ranged from 414 to 3,432 U/L. The average time from presentation to pathologic diagnosis of RMS was 2.1 months. Nine of the 11 cases showed an alveolar pattern. All were high-stage disease. Of 7 patients with follow-up longer than 1 year, 2 (29%) are alive without disease. Conclusion: This report presents the need to consider the possibility of a malignant neoplasm, in this case RMS, in a child or adolescent with a putative perirectal abscess that fails to respond in the expected manner to incision and drainage and antibiotic therapy. J Pediatr Surg 37:576-581. Copyright 2002, Elsevier Science (USA). All rights reserved.