Management of undifferentiated embryonal sarcoma of the liver: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare tumor for which there are few evidence-based guidelines. The aim of this study was to define current management strategies and outcomes for these patients using a multi-institutional dataset curated by the Pediatric Surgical Oncology Research Collaborative. METHODS: Data were collected retrospectively for patients with UESL treated across 17 children's hospitals in North America from 1989 to 2019. Factors analyzed included patient and tumor characteristics, PRETEXT group, operative details, and neoadjuvant/adjuvant regimens. Event-free and overall survival (EFS, OS) were the primary and secondary outcomes, respectively. RESULTS: Seventy-eight patients were identified with a median age of 9.9 years [interquartile range [IQR): 7-12]. Twenty-seven patients underwent resection at diagnosis, and 47 patients underwent delayed resection, including eight liver transplants. Neoadjuvant chemotherapy led to a median change in maximum tumor diameter of 1.6 cm [IQR: 0.0-4.4] and greater than 90% tumor necrosis in 79% of the patients undergoing delayed resection. R0 resections were accomplished in 63 patients (81%). Univariate analysis found that metastatic disease impacted OS, and completeness of resection impacted both EFS and OS, while multivariate analysis revealed that R0 resection was associated with decreased expected hazards of experiencing an event [hazard ratio (HR): 0.14, 95% confidence interval (CI): 0.04-0.6]. At a median follow-up of 4 years [IQR: 2-8], the EFS was 70.0% [95% CI: 60%-82%] and OS was 83% [95% CI: 75%-93%]. CONCLUSION: Complete resection is associated with improved survival for patients with UESL. Neoadjuvant chemotherapy causes minimal radiographic response, but significant tumor necrosis.

Second Malignant Neoplasms Following Treatment for Hepatoblastoma: An International Report and Review of the Literature.

Treatment intensification has improved survival in patients with hepatoblastoma (HB); however, these treatments are associated with an increased risk of late effects, including second malignant neoplasms (SMNs). Data is limited regarding SMNs following HB treatment. Cases of SMNs following treatment for HB reported in the literature and from personal communication were analyzed to further assess this late effect. Thirty-eight patients were identified. The median age at diagnosis of HB was 16 months (range: 3 to 168 mo). All patients had received a platinum agent, and almost all had anthracycline exposure. The SMNs reported were hematopoietic malignancies (n=19), solid tumors (n=12), and post-transplant lymphoproliferative disorder (n=7). Of the 36 patients with outcome data, 19 survived. SMNs following HB treatment were primarily seen in patients with chemotherapy exposure, a history of liver transplantation, hereditary tumor predisposition syndromes, and/or a history of radiation treatment. Hematopoietic malignancies were the most common SMN reported in this cohort and were diagnosed earlier than other SMNs. Prospective collection of data through a companion late effects study or international registry could be used to further evaluate the rates and risks of SMNs as well as tumor predisposition syndromes in patients treated for HB.

Utilization of Segmental Grafts Is Associated With Higher Transplant Rates in Pediatric Patients.

INTRODUCTION: In July 2017, a policy to increase the use of segmental grafts (SGs) was implemented at our institution. The aim was to compare changes in waitlist activity after implementation of this policy. METHODS: A single-center, retrospective study. Pediatric patients on the liver waiting list between January 2015 and December 2019 were screened. Patients were classified as receiving a liver transplant (LT) before (Period 1) or after (Period 2) policy changes. Primary end points were transplant rates and time to transplant. RESULTS: Sixty five first LT performed on 65 patients were included. Twenty nine LT were performed during Period 1 and 36 during Period 2. More than half (55%) of LT in Period 2 were SG, compared to 10.3% in Period 1 (P < 0.001). Forty nine and 56 pediatric candidates on the waiting list accounted for 38.78 and 24.48 person-years during Period 1 and Period 2, respectively. Transplant rates per 100 person-years on the waiting list increased from 85.09 during Period 1 to 187.87 in Period 2 (Rate ratio: 2.20; P < 0.001). Median time to receive a LT decreased from 229 d in Period 1 to 75 d during Period 2 (P = 0.013). One-year patient survival rates were 96.6% in Period 1 and 95.7% in Period 2. One-year graft survival rates were 89.7% and 88% in Period 1 and Period 2, respectively. CONCLUSIONS: A policy to increase the use of SG was associated with significantly higher transplant rates and lower waiting times. Implementation of this policy can be done successfully with no observed negative impact on patient and graft survival.

Children's Oncology Group's 2023 blueprint for research: Liver tumors.

Liver tumors account for approximately 1%-2% of all pediatric malignancies, with the two most common tumors being hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Previous Children's Oncology Group studies have meaningfully contributed to the current understanding of disease pathophysiology and treatment, laying groundwork for the ongoing prospective international study of both HB and HCC. Future work is focused on elucidating the biologic underpinnings of disease to support an evolution in risk categorization, advancements in the multidimensional care required to treat these patients, and the discovery of novel therapies.

Consensus classification of pediatric hepatocellular tumors: A report from the Children's Hepatic tumors International Collaboration (CHIC).

BACKGROUND: Liver tumors are rare in children with histologic heterogeneity that makes diagnosis challenging. Systematic histopathological review, performed as part of collaborative therapeutic protocols, identified relevant histologic subtypes that are important to distinguish. The Children's Hepatic tumors International Collaboration (CHIC) was established to study pediatric liver tumors on a global scale and led to establishment of a provisional consensus classification for use in international clinical trials. The current study is the validation of this initial classification and first large-scale application by international expert reviewers. PROCEDURE: The CHIC initiative includes data from 1605 children treated on eight multicenter hepatoblastoma (HB) trials. Review of 605 available tumors was performed by seven expert pathologists from three consortia (US, EU, Japan). Cases with discordant diagnoses were collectively reviewed to reach a final consensus diagnosis. RESULTS: Of 599 cases with sufficient material for review, 570 (95.2%) were classified as HB by all consortia, and 29 (4.8%) as non-HB, which included "hepatocellular neoplasm, NOS" and malignant rhabdoid tumors. 453 of 570 HBs were classified as epithelial by final consensus. Some patterns (i.e., small cell undifferentiated, macrotrabecular, cholangioblastic) were selectively identified by reviewers from different consortia. All consortia identified a similar number of mixed epithelial-mesenchymal HB. CONCLUSIONS: This study represents the first large-scale application and validation of the pediatric malignant hepatocellular tumors consensus classification. It is a valuable resource to train future generations of investigators on accurate diagnosis of these rare tumors and provides a framework for further international collaborative studies and refinement of the current classification of pediatric liver tumors.

Vincristine/irinotecan/temsirolimus upfront window treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 Study Committee.

BACKGROUND: Survival for children with metastatic hepatoblastoma (HB) remains suboptimal. We report the response rate and outcome of two courses of vincristine/irinotecan/temsirolimus (VIT) in children with high-risk (HR)/metastatic HB. PROCEDURES: Patients with newly diagnosed HB received HR window chemotherapy if they had metastatic disease or a serum alpha-fetoprotein (AFP) level less than 100 ng/mL. Patients received vincristine (days 1 and 8), irinotecan (days 1-5), and temsirolimus (days 1 and 8). Cycles were repeated every 21 days. Responders had either a 30% decrease using RECIST (Response Evaluation Criteria in Solid Tumors) criteria OR a 90% (>1 log10 decline) AFP decline after two cycles. Responders received two additional cycles of VIT intermixed with six cycles of cisplatin/doxorubicin/5-fluorouracil/vincristine (C5VD). Nonresponders received six cycles of C5VD alone. RESULTS: Thirty-six eligible patients enrolled on study. The median age at enrollment was 27 months (range: 7-170). Seventeen of 36 patients were responders (RECIST and AFP = 3, RECIST only = 4, AFP only = 10). The median AFP at diagnosis was 222,648 ng/mL and the median AFP following two VIT cycles was 19,262 ng/mL. Three-year event-free survival was 47% (95% confidence interval [CI]: 30%-62%), while overall survival was 67% (95% CI: 49%-80%). CONCLUSION: VIT did not achieve the study efficacy endpoint. Temsirolimus does not improve the response rate seen in patients treated with vincristine and irinotecan (VI) alone as part of the initial treatment regimen explored in this study. Additionally, AFP response may be a more sensitive predictor of disease response than RECIST in HB.

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.

Inflammatory myofibroblastic tumor: A multi-institutional study from the Pediatric Surgical Oncology Research Collaborative.

Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate malignancy. We describe the largest cohort of IMT patients to date, aiming to further characterize this rare, poorly understood tumor. This is a multi-institutional review of IMT patients ≤39 years, from 2000 to 2018, at 18 hospitals in the Pediatric Surgical Oncology Research Collaborative. One hundred and eighty-two patients were identified with median age of 11 years. Thirty-three percent of tumors were thoracic in origin. Presenting signs/symptoms included pain (29%), respiratory symptoms (25%) and constitutional symptoms (20%). Median tumor size was 3.9 cm. Anaplastic lymphoma kinase (ALK) overexpression was identified in 53% of patients. Seven percent of patients had distant disease at diagnosis. Ninety-one percent of patients underwent resection: 14% received neoadjuvant treatment and 22% adjuvant treatment. Twelve percent of patients received an ALK inhibitor. Sixty-six percent of surgical patients had complete resection, with 20% positive microscopic margins and 14% gross residual disease. Approximately 40% had en bloc resection of involved organs. Median follow-up time was 36 months. Overall 5-year survival was 95% and 5-year event-free survival was 80%. Predictors of recurrence included respiratory symptoms, tumor size and distant disease. Gross or microscopic margins were not associated with recurrence, suggesting that aggressive attempts at resection may not be warranted.

Doxorubicin in combination with cisplatin, 5-flourouracil, and vincristine is feasible and effective in unresectable hepatoblastoma: A Children's Oncology Group study.

BACKGROUND: The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. METHODS: In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. RESULTS: One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. CONCLUSIONS: The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials.

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis. METHODS: A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse. RESULTS: In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival. CONCLUSIONS: This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC. LAY SUMMARY: This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.

Hepatoblastomas with carcinoma features represent a biological spectrum of aggressive neoplasms in children and young adults.

BACKGROUND & AIMS: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS. METHODS: We tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8). RESULTS: Molecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes. CONCLUSIONS: Our study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms. LAY SUMMARY: We molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.

Implications of Tumor Characteristics and Treatment Modality on Local Recurrence and Functional Outcomes in Children With Chest Wall Sarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

OBJECTIVE: To determine the impact of tumor characteristics and treatment approach on (1) local recurrence, (2) scoliosis development, and (3) patient-reported quality of life in children with sarcoma of the chest wall. SUMMARY OF BACKGROUND DATA: Children with chest wall sarcoma require multimodal therapy including chemotherapy, surgery, and/or radiation. Despite aggressive therapy which places them at risk for functional impairment and scoliosis, these patients are also at significant risk for local recurrence. METHODS: A multi-institutional review of 175 children (median age 13 years) with chest wall sarcoma treated at seventeen Pediatric Surgical Oncology Research Collaborative institutions between 2008 and 2017 was performed. Patient-reported quality of life was assessed prospectively using PROMIS surveys. RESULTS: The most common diagnoses were Ewing sarcoma (67%) and osteosarcoma (9%). Surgical resection was performed in 85% and radiation in 55%. A median of 2 ribs were resected (interquartile range = 1-3), and number of ribs resected did not correlate with margin status ( P = 0.36). Local recurrence occurred in 23% and margin status was the only predictive factor(HR 2.24, P = 0.039). With a median follow-up of 5 years, 13% developed scoliosis (median Cobb angle 26) and 5% required corrective spine surgery. Scoliosis was associated with posteriorrib resection (HR 8.43; P= 0.003) and increased number of ribs resected (HR 1.78; P = 0.02). Overall, patient-reported quality of life is not impaired after chest wall tumor resection. CONCLUSIONS: Local recurrence occurs in one-quarter of children with chest wall sarcoma and is independent of tumor type. Scoliosis occurs in 13% of patients, but patient-reported quality of life is excellent.

Thoracoscopy vs thoracotomy for the management of metastatic osteosarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

Complete surgical resection of pulmonary metastatic disease in patients with osteosarcoma is crucial to long-term survival. Open thoracotomy allows palpation of nodules not identified on imaging but the impact on survival is unknown. The objective of this study was to compare overall survival (OS) and pulmonary disease-free survival (DFS) in children who underwent thoracotomy vs thoracoscopic surgery for pulmonary metastasectomy. A multi-institutional collaborative group retrospectively reviewed 202 pediatric patients with osteosarcoma who underwent pulmonary metastasectomy by thoracotomy (n = 154) or thoracoscopy (n = 48). Results were analyzed by Kaplan-Meier survival estimates and multivariate Cox proportional hazard regression models. With median follow-up of 45 months, 135 (67.5%) patients had a pulmonary relapse and 95 (47%) patients were deceased. Kaplan-Meier analysis showed no significant difference in 5-year pulmonary DFS (25% vs 38%; P = .18) or OS (49% vs 42%, P = .37) between the surgical approaches of thoracotomy and thoracoscopy. In Cox regression analysis controlling for other factors impacting outcome, there was a significantly increased risk of mortality (HR 2.11; P = .027; 95% CI 1.09-4.09) but not pulmonary recurrence (HR 0.96; P = .90; 95% CI 0.52-1.79) with a thoracoscopic approach. However, in the subset analysis limited to patients with oligometastatic disease, thoracoscopy had no increased risk of mortality (HR 1.16; P = .62; 0.64-2.11). In conclusion, patients with metastatic osteosarcoma and limited pulmonary disease burden demonstrate comparable outcomes after thoracotomy and thoracoscopy for metastasectomy. While significant selection bias in these surgical cohorts limits the generalizability of the conclusions, clinical equipoise for a randomized clinical trial in patients with oligometastatic disease is supported.

Pneumonectomy for Pediatric Tumors-a Pediatric Surgical Oncology Research Collaborative Study.

OBJECTIVE: To describe utilization and long-term outcomes of pneumonectomy in children and adolescents with cancer. SUMMARY BACKGROUND DATA: Pneumonectomy in adults is associated with significant morbidity and mortality. Little is known about the indications and outcomes of pneumonectomy for pediatric tumors. METHODS: The Pediatric Surgical Oncology Research Collaborative (PSORC) identified pediatric patients <21 years of age who underwent pneumonectomy from 1990 to 2017 for primary or metastatic tumors at 12 institutions. Clinical information was collected; outcomes included operative complications, long-term function, recurrence, and survival. Univariate log rank, and multivariable Cox analyses determined factors associated with survival. RESULTS: Thirty-eight patients (mean 12 ±â€Š6 yrs) were identified; median (IQR) follow-up was 19 (5-38) months. Twenty-six patients (68%) underwent pneumonectomy for primary tumors and 12 (32%) for metastases. The most frequent histologies were osteosarcoma (n = 6), inflammatory myofibroblastic tumors (IMT; n = 6), and pleuropulmonary blastoma (n = 5). Median postoperative ventilator days were 0 (0-1), intensive care 2 (1-3), and hospital 8 (5-16). Early postoperative complications occurred in 10 patients including 1 death. Of 25 (66%) patients alive at 1 year, 15 reported return to preoperative pulmonary status. All IMT patients survived while all osteosarcoma patients died during follow-up. On multivariable analysis, metastatic indications were associated with nonsurvival (HR = 3.37, P = 0.045). CONCLUSION: This is the largest review of children who underwent pneumonectomy for cancer. There is decreased procedure-related morbidity and mortality than reported for adults. Survival is worse with preoperative metastatic disease, especially osteosarcoma.

The importance of age as prognostic factor for the outcome of patients with hepatoblastoma: Analysis from the Children's Hepatic tumors International Collaboration (CHIC) database.

PURPOSE: Treatment outcomes for hepatoblastoma have improved markedly in the contemporary treatment era, principally due to therapy intensification, with overall survival increasing from 35% in the 1970s to 90% at present. Unfortunately, these advancements are accompanied by an increased incidence of toxicities. A detailed analysis of age as a prognostic factor may support individualized risk-based therapy stratification. METHODS: We evaluated 1605 patients with hepatoblastoma included in the CHIC database to assess the relationship between event-free survival (EFS) and age at diagnosis. Further analysis included the age distribution of additional risk factors and the interaction of age with other known prognostic factors. RESULTS: Risk for an event increases progressively with increasing age at diagnosis. This pattern could not be attributed to the differential distribution of other known risk factors across age. Newborns and infants are not at increased risk of treatment failure. The interaction between age and other adverse risk factors demonstrates an attenuation of prognostic relevance with increasing age in the following categories: metastatic disease, AFP < 100 ng/mL, and tumor rupture. CONCLUSION: Risk for an event increased with advancing age at diagnosis. Increased age attenuates the prognostic influence of metastatic disease, low AFP, and tumor rupture. Age could be used to modify recommended chemotherapy intensity.

Optimization of percutaneous biopsy for diagnosis and pretreatment risk assessment of neuroblastoma.

BACKGROUND: Image-guided percutaneous core needle biopsy (PCNB) is increasingly utilized to diagnose solid tumors. The objective of this study is to determine whether PCNB is adequate for modern biologic characterization of neuroblastoma. PROCEDURE: A multi-institutional retrospective study was performed by the Pediatric Surgical Oncology Research Collaborative on children with neuroblastoma at 12 institutions over a 3-year period. Data collected included demographics, clinical details, biopsy technique, complications, and adequacy of biopsies for cytogenetic markers utilized by the Children's Oncology Group for risk stratification. RESULTS: A total of 243 children were identified with a diagnosis of neuroblastoma: 79 (32.5%) tumor excision at diagnosis, 94 (38.7%) open incisional biopsy (IB), and 70 (28.8%) PCNB. Compared to IB, there was no significant difference in ability to accurately obtain a primary diagnosis by PCNB (95.7% vs 98.9%, P = .314) or determine MYCN copy number (92.4% vs 97.8%, P = .111). The yield for loss of heterozygosity and tumor ploidy was lower with PCNB versus IB (56.1% vs 90.9%, P < .05; and 58.0% vs. 88.5%, P < .05). Complications did not differ between groups (2.9 % vs 3.3%, P = 1.000), though the PCNB group had fewer blood transfusions and lower opioid usage. Efficacy of PCNB was improved for loss of heterozygosity when a pediatric pathologist evaluated the fresh specimen for adequacy. CONCLUSIONS: PCNB is a less invasive alternative to open biopsy for primary diagnosis and MYCN oncogene status in patients with neuroblastoma. Our data suggest that PCNB could be optimized for complete genetic analysis by standardized protocols and real-time pathology assessment of specimen quality.

Pancreaticoduodenectomy for the treatment of pancreatic neoplasms in children: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: To better characterize short-term and long-term outcomes in children with pancreatic tumors treated with pancreaticoduodenectomy (PD). METHODS: Patients 21 years of age or younger who underwent PD at Pediatric Surgical Oncology Collaborative (PSORC) hospitals between 1990 and 2017 were identified. Demographic, clinical information, and outcomes (operative complications, long-term pancreatic function, recurrence, and survival) were collected. RESULTS: Sixty-five patients from 18 institutions with a median age of 13 years (4 months-22 years) and a median (IQR) follow-up of 2.8 (4.3) years were analyzed. Solid pseudopapillary tumor of the pancreas (SPN) was the most common histology. Postoperative complications included pancreatic leak in 14% (n = 9), delayed gastric emptying in 9% (n = 6), marginal ulcer in one patient, and perioperative (30-day) death due to hepatic failure in one patient. Pancreatic insufficiency was observed in 32% (n = 21) of patients, with 23%, 3%, and 6% with exocrine, or endocrine insufficiencies, or both, respectively. Children with SPN and benign neoplasms all survived. Overall, there were 14 (22%) recurrences and 11 deaths (17%). Univariate analysis revealed non-SPN malignant tumor diagnosis, preoperative vascular involvement, intraoperative transfusion requirement, pathologic vascular invasion, positive margins, and need for neoadjuvant chemotherapy as risk factors for recurrence and poor survival. Multivariate analysis only revealed pathologic vascular invasion as a risk factor for recurrence and poor survival. CONCLUSION: This is the largest series of pediatric PD patients. PD is curative for SPN and benign neoplasms. Pancreatic insufficiency is the most common postoperative complication. Outcome is primarily associated with histology.

Minimal adjuvant chemotherapy for children with hepatoblastoma resected at diagnosis (AHEP0731): a Children's Oncology Group, multicentre, phase 3 trial.

BACKGROUND: Hepatoblastoma treatment with curative intent requires surgical resection, but only about a third of newly diagnosed patients with hepatoblastoma have resectable disease at diagnosis. Patients who have upfront resection typically receive a total of 4-6 cycles of adjuvant chemotherapy post-surgery, with the combination of cisplatin, fluorouracil, and vincristine. We aimed to investigate whether event-free survival in children with hepatoblastoma who had complete resection at diagnosis could be maintained with two cycles of adjuvant chemotherapy. METHODS: In this Children's Oncology Group, multicentre, phase 3 trial, patients were enrolled in four risk groups on the basis of Evans surgical stage, tumour histology, and levels of α-fetoprotein at diagnosis to receive risk-adapted therapy. Here, we report on the low-risk stratum of the trial. Eligible patients were younger than 21 years and had histologically confirmed, stage I or II hepatoblastoma without 100% pure fetal stage I or small-cell undifferentiated histology; elevated serum α-fetoprotein level (>100 ng/mL); a complete resection at diagnosis; at least 50% Karnofsky (patients >16 years) or Lansky (patients ≤16 years) performance status; and had received no previous chemotherapy or other hepatoblastoma-directed therapy. Patients received two 21-day cycles of cisplatin, fluorouracil, and vincristine within 42 days of resection, consisting of cisplatin (100 mg/m2 per dose or 3·3 mg/kg per dose for children <10 kg) intravenously over 6 h on day 1; fluorouracil (600 mg/m2 per dose or 20 mg/kg per dose for children <10 kg) intravenous push on day 2; and vincristine (1·5 mg/m2 per day to a maximum dose of 2 mg, or 0·05 mg/kg per day for children <10 kg) intravenous push on days 2, 9, and 16. The primary outcome was investigator-assessed event-free survival. As prespecified by protocol, we analysed the primary endpoint 6 years after enrolment (cutoff date June 30, 2017). This trial is registered with ClinicalTrials.gov, number NCT00980460, and is now permanently closed to accrual. FINDINGS: Between May 18, 2010, and May 28, 2014, 51 patients in 32 centres in two countries were enrolled into the low-risk stratum of this trial, of whom 49 received c hemotherapy treatment after surgery and were evaluable for activity and safety. Median follow-up time for all evaluable patients was 42 months (IQR 36-62). 4-year event-free survival was 92% (95% CI 79-97) and 5-year event-free survival was 88% (72-95). Two (4%) of 49 patients had surgical complications (bile leaks). The most common grade 3-4 adverse events were febrile neutropenia in seven (14%) patients, decreased neutrophil count in three (6%) patients, infections in four (8%) patients, and diarrhoea in four (8%) patients. Ototoxicity occurred in one (2%) patient. One (2%) patient of the three who relapsed in this cohort died from disease. Two (4%) patients died in clinical remission after therapy discontinuation. One patient died of pneumonia and bacterial sepsis 1 year after therapy discontinuation and another patient died of unrelated causes 57 months after therapy completion. There were no treatment-related deaths. INTERPRETATION: Minimal postoperative chemotherapy with two cycles of cisplatin, fluorouracil, and vincristine can ensure disease control in patients with hepatoblastoma resected at diagnosis. Our results show that dose reduction of ototoxic agents is a safe, effective treatment for these children. FUNDING: National Institutes of Health.

Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups.

Despite being the most common liver cancer in children, hepatoblastoma (HB) is a rare neoplasm. Consequently, few pretreatment tumors have been molecularly profiled, and there are no validated prognostic or therapeutic biomarkers for HB patients. We report on the first large-scale effort to profile pretreatment HBs at diagnosis. Our analysis of 88 clinically annotated HBs revealed three risk-stratifying molecular subtypes that are characterized by differential activation of hepatic progenitor cell markers and metabolic pathways: high-risk tumors were characterized by up-regulated nuclear factor, erythroid 2-like 2 activity; high lin-28 homolog B, high mobility group AT-hook 2, spalt-like transcription factor 4, and alpha-fetoprotein expression; and high coordinated expression of oncofetal proteins and stem-cell markers, while low-risk tumors had low lin-28 homolog B and lethal-7 expression and high hepatic nuclear factor 1 alpha activity. CONCLUSION: Analysis of immunohistochemical assays using antibodies targeting these genes in a prospective study of 35 HBs suggested that these candidate biomarkers have the potential to improve risk stratification and guide treatment decisions for HB patients at diagnosis; our results pave the way for clinical collaborative studies to validate candidate biomarkers and test their potential to improve outcome for HB patients. (Hepatology 2017;65:104-121).

2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT).

Imaging is crucial in the assessment of children with a primary hepatic malignancy. Since its inception in 1992, the PRETEXT (PRE-Treatment EXTent of tumor) system has become the primary method of risk stratification for hepatoblastoma and pediatric hepatocellular carcinoma in numerous cooperative group trials across the world. The PRETEXT system is made of two components: the PRETEXT group and the annotation factors. The PRETEXT group describes the extent of tumor within the liver while the annotation factors help to describe associated features such as vascular involvement (either portal vein or hepatic vein/inferior vena cava), extrahepatic disease, multifocality, tumor rupture and metastatic disease (to both the lungs and lymph nodes). This manuscript is written by members of the Children's Oncology Group (COG) in North America, the International Childhood Liver Tumors Strategy Group (SIOPEL) in Europe, and the Japanese Study Group for Pediatric Liver Tumor (JPLT; now part of the Japan Children's Cancer Group) and represents an international consensus update to the 2005 PRETEXT definitions. These definitions will be used in the forthcoming Trial to Pediatric Hepatic International Tumor Trial (PHITT).