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BACKGROUND: The Childrens 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

PURPOSE: Small cell undifferentiated (SCU) histology in hepatoblastoma (HB) tumors has historically been associated with a poor prognosis. Tumors from patients enrolled on Childrens Oncology Group (COG) study AHEP0731 underwent institutional and central pathologic review for identification of SCU histology. PATIENTS AND METHODS: Patients with SCU histology identified at the local treating institution who had otherwise low-risk tumors were upstaged to the intermediate-risk treatment stratum, whereas those only identified by retrospective central review were treated per the local institution as low-risk. Patients with otherwise intermediate- or high-risk tumors remained in that treatment stratum, respectively. Central review was to be performed for all tissue samples obtained at any time point. Treatment was per local review, whereas analysis of outcome was based on central review. RESULTS: Thirty-five patients had some elements (1%-25%) of SCU identified on central review of diagnostic specimens. All but two patient tissue sample retained nuclear INI1 expression. The presence of SCU histology did not correlate with age, alpha-fetoprotein level at diagnosis, or sex. The presence of SCU did not affect event-free survival (EFS). EFS at 5 years for patients with low-risk, intermediate-risk, and high-risk with SCU HB was 86% (95% CI, 33 to 98), 81% (95% CI, 57 to 92), and 29% (95% CI, 4 to 61), respectively, compared with EFS at 5 years for patients without SCU enrolled with low-risk, intermediate-risk, and high-risk of 87% (95% CI, 72 to 95), 88% (95% CI, 79 to 94), and 55% (95% CI, 32 to 74; P = .17), respectively. CONCLUSION: The presence of SCU histology in HB does not appear to adversely affect outcome. Future studies should be able to treat patients with SCU HB according to risk stratification without regard to the presence of SCU histology.

BACKGROUND: 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 AND METHODS: Patients on the Childrens Oncology Group non randomized, multicenter phase III study, AHEP0731, were stratified based on Evans 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. RESULTS: 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%. CONCLUSION: 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. LEVEL OF EVIDENCE: Prognosis study, Level I evidence.

Purpose: Pediatric CNS tumors are increasingly a priority, particularly with the WHO designation of low-grade glioma (LGG) as one of six index childhood cancers. There are currently limited data on outcomes of pediatric patients with LGGs in low- and middle-income countries (LMICs). Methods: To better understand the outcomes of LGGs in LMICs, this systematic review interrogated nine literature databases. Results: The search identified 14,977 publications. Sixteen studies from 19 countries met the selection criteria and were included for data abstraction and analysis. Eleven studies (69%) were retrospective reviews from single institutions, and one (6%) captured institutional data prospectively. The studies captured a total of 957 patients with a median of 49 patients per study. Seven (44%) of the studies described the treatment modalities used. Of 373 patients for whom there was information, 173 (46%) had a gross total or near total resection, 109 (29%) had a subtotal resection, and 91 (24%) had only a biopsy performed. Seven studies, with a total of 476 patients, described the frequency of use of radiotherapy and/or chemotherapy in the cohorts: 83 of these patients received radiotherapy and 76 received chemotherapy. The 5-year overall survival ranged from 69.2% to 93.5%, although lower survival rates were reported at earlier time points. We identified limitations in the published studies with respect to the cohort sizes and methodologies. Conclusion: The included studies reported survival rates frequently exceeding 80%, although the ultimate number of studies was limited, pointing to the paucity of studies describing the outcomes of children with LGGs in LMICs. This study underscores the need for more robust data on outcomes in pediatric LGG.

Objective: To evaluate the prognostic impact of gastrointestinal involvement on the survival of children with Langerhans cell histiocytosis (GI-LCH) registered with the international clinical trials of the Histiocyte Society. Study design: This was a retrospective analysis of 2414 pediatric patients registered onto the consecutive trials DAL-HX 83, DAL-HX 90, LCH-I, LCH-II, and LCH-III. Results: Among the 1289 patients with single-system LCH, there was no single case confined to the GI tract; 114 of 1125 (10%) patients with multisystem LCH (MS-LCH) had GI-LCH at initial presentation. GI-LCH was significantly more common in children aged <2 years at diagnosis (13% vs 6% in those aged >2 years; P < .001) and in those with risk organ involvement (15% vs 6% in those without risk organ involvement; P < .001). The 5-year overall survival (OS) in patients without risk organ involvement was excellent irrespective of GI disease (98% vs 97% in patients with GI-LCH; P = .789). In patients with risk organ involvement, the 5-year OS was 51% in 70 patients with GI-LCH vs 72% in 394 patients without GI-LCH (P < .001). Conclusions: GI-LCH has an additive unfavorable prognostic impact in children with MS-LCH and risk organ involvement. The emerding need for more intensive or alternative treatments mandates prospective evaluation.

The COVID-19 pandemic is one of the most serious global challenges to delivering affordable and equitable treatment to children with cancer we have witnessed in the last few decades. This Special Report aims to summarize general principles for continuing multidisciplinary care during the SARS-CoV-2 (COVID-19) pandemic. With contributions from the leadership of the International Society for Pediatric Oncology (SIOP), Children's Oncology Group (COG), St Jude Global program, and Childhood Cancer International, we have sought to provide a framework for healthcare teams caring for children with cancer during the pandemic. We anticipate the burden will fall particularly heavily on children, their families, and cancer services in low- and middle-income countries. Therefore, we have brought together the relevant clinical leads from SIOP Europe, COG, and SIOP-PODC (Pediatric Oncology in Developing Countries) to focus on the six most curable cancers that are part of the WHO Global Initiative in Childhood Cancer. We provide some practical advice for adapting diagnostic and treatment protocols for children with cancer during the pandemic, the measures taken to contain it (e.g., extreme social distancing), and how to prepare for the anticipated recovery period.

PurposeTo investigate relapse detection methods among children and adolescents with nongerminomatous malignant germ cell tumors (MGCTs) and to determine whether tumor markers alone might be sufficient for surveillance.MethodsWe retrospectively reviewed all patients enrolled in a phase III, single-arm trial for low-risk and intermediate-risk MGCTs. The method used to detect relapse was assessed based on case report forms, tumor markers, imaging, and pathology reports. Relapses were classified into one of two categories on the basis of whether they were (1) detectable by tumor marker elevation or (2) not detectable by tumor markers.ResultsA total of 302 patients were enrolled, and 284 patients had complete data for review. Seven patients had normal tumor markers at initial diagnosis, and none experienced a relapse. At a median follow-up of 5.3 years, 48 patients (16.9%) had experienced a relapse. After central review, 47 of 48 relapses (98%) were detected by tumor marker elevation. Of the 47 patients, 16 (33.3%) had abnormal tumor markers with normal/unknown imaging, 31 patients (64.6%) had abnormal tumor markers with abnormal imaging, and one patient (2.1%) had abnormal imaging with unknown marker levels at relapse.ConclusionTumor marker elevation is a highly sensitive method of relapse surveillance, at least among children and adolescents with tumor marker elevation at initial diagnosis. Eliminating exposure to imaging with ionizing radiation may enhance the safety of relapse surveillance in patients treated for MGCT.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.

BackgroundCentral nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH.MethodsCerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease.ResultsOsteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement.ConclusionIn LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.

In this report, we characterize the timing and behavior of malignant ovarian germ cell tumors (GCTs) in pediatric patients with dysgenetic gonads compared to those with normal gonadal development. Patients from the Children's Oncology Group AGCT0132 with malignant ovarian GCTs were included. Within this population, we sought to identify patients with gonadoblastoma, streak ovaries, or other evidence of gonadal dysgenesis (GD). Patients with malignant GCTs containing one or more of the following histologies-yolk sac tumor, embryonal carcinoma, or choriocarcinoma-were included. Patients were compared with respect to event-free survival (EFS) and overall survival (OS). Nine patients with GD, including seven with gonadoblastoma (mean age, 9.3 years), were compared to 100 non-GD patients (mean age, 12.1 years). The estimated 3-year EFS for patients with GD was 66.7% (95% CI 28.2-87.8%) and for non-GD patients was 88.8% (95% CI 80.2-93.8%). The estimated 3-year OS for patients with GD was 87.5% (95% CI 38.7-98.1%) and for non-GD patients was 97.6% (95% CI of 90.6-99.4%). Patients presenting with nongerminomatous malignant ovarian GCTs in the context of GD have a higher rate of events and death than counterparts with normal gonads. These findings emphasize the importance of noting a contralateral streak ovary or gonadoblastoma at histology for any ovarian GCT and support the recommendation for early bilateral gonadectomy in patients known to have GD with Y chromosome material. In contrast to those with pure dysgerminoma, these patients may represent a high-risk group that requires a more aggressive chemotherapy regimen.

Purpose To determine whether the pattern of lung nodules in children with metastatic hepatoblastoma (HB) correlates with outcome. Methods Thirty-two patients with metastatic HB were enrolled on Children's Oncology Group Protocol AHEP0731 and treated with vincristine and irinotecan (VI). Responders to VI received two additional cycles of VI intermixed with six cycles of cisplatin/fluorouracil/vincristine/doxorubicin (C5VD), and nonresponders received six cycles of C5VD alone. Patients were imaged after every two cycles and at the conclusion of therapy. All computed tomography scans and pathology reports were centrally reviewed, and information was collected regarding lung nodule number, size, laterality, timing of resolution, and pulmonary surgery. Results Among the 29 evaluable patients, only 31% met Response Evaluation Criteria in Solid Tumors (RECIST) for measurable metastatic disease. The presence of measurable disease by RECIST, the sum of nodule diameters greater than or equal to the cumulative cohort median size, bilateral disease, and ≥ 10 nodules were each associated with an increased risk for an event-free survival event ( P = .48, P = .08, P = .065, P = .03, respectively), with nodule number meeting statistical significance. Ten patients underwent pulmonary resection/metastasectomy at various time points, the benefit of which could not be determined because of small patient numbers. Conclusion Children with metastatic HB have a poor prognosis. Overall tumor burden may be an important prognostic factor for these patients. Lesions that fail to meet RECIST size criteria (ie, those < 10 mm) at diagnosis may contain viable tumor, whereas residual lesions at the end of therapy may constitute eradicated tumor/scar tissue. Patients may benefit from risk stratification on the basis of the burden of lung metastatic disease at diagnosis.

Purpose To investigate whether event-free survival (EFS) can be maintained among children and adolescents with intermediate-risk (IR) malignant germ cell tumors (MGCT) if the administration of cisplatin, etoposide, and bleomycin (PEb) is reduced from four to three cycles and compressed from 5 to 3 days per cycle. Patients and Methods In a phase 3, single-arm trial, patients with IR MGCT (stage II-IV testicular, II-III ovarian, I-II extragonadal, or stage I gonadal tumors with subsequent recurrence) received three cycles of PEb. A parametric comparator model specified that the observed EFS rate should not be significantly < 92%. As recommended for trials that test a reduction of therapy, a one-sided P value ≤ .10 was used to indicate statistical significance. In a post hoc analysis, we also compared results to the EFS rate of comparable patients treated with four cycles of PEb in two prior studies. Results Among 210 eligible patients enrolled from 2003 to 2011, 4-year EFS (EFS4) rate was 89% (95% confidence interval, 83% to 92%), which was significantly lower than the 92% threshold of the comparison model ( P = .08). Among 181 newly diagnosed patients, the EFS4 rate was 87%, compared with 92% for 92 comparable children in the historical cohort ( P = .15). The EFS4 rate was significantly associated with stage (stage I, 100%; stage II, 92%; stage III, 85%; and stage IV, 54%; P < .001). Conclusion The EFS rate for children with IR MGCT observed after three cycles of PEb was less than that of a prespecified parametric model, particularly for patients with higher-stage tumors. These data do not support a reduction in the number of cycles of PEb from four to three. However, further investigation of a reduction in the number of cycles for patients with lower-stage tumors is warranted.

Purpose To determine whether the pattern of lung nodules in children with metastatic hepatoblastoma (HB) correlates with outcome. Methods Thirty-two patients with metastatic HB were enrolled on Childrens Oncology Group Protocol AHEP0731 and treated with vincristine and irinotecan (VI). Responders to VI received two additional cycles of VI intermixed with six cycles of cisplatin/fluorouracil/vincristine/doxorubicin (C5VD), and nonresponders received six cycles of C5VD alone. Patients were imaged after every two cycles and at the conclusion of therapy. All computed tomography scans and pathology reports were centrally reviewed, and information was collected regarding lung nodule number, size, laterality, timing of resolution, and pulmonary surgery. Results Among the 29 evaluable patients, only 31% met Response Evaluation Criteria in Solid Tumors (RECIST) for measurable metastatic disease. The presence of measurable disease by RECIST, the sum of nodule diameters greater than or equal to the cumulative cohort median size, bilateral disease, and ≥ 10 nodules were each associated with an increased risk for an event-free survival event ( P = .48, P = .08, P = .065, P = .03, respectively), with nodule number meeting statistical significance. Ten patients underwent pulmonary resection/metastasectomy at various time points, the benefit of which could not be determined because of small patient numbers. Conclusion Children with metastatic HB have a poor prognosis. Overall tumor burden may be an important prognostic factor for these patients. Lesions that fail to meet RECIST size criteria (ie, those < 10 mm) at diagnosis may contain viable tumor, whereas residual lesions at the end of therapy may constitute eradicated tumor/scar tissue. Patients may benefit from risk stratification on the basis of the burden of lung metastatic disease at diagnosis.

Purpose To determine whether the pattern of lung nodules in children with metastatic hepatoblastoma (HB) correlates with outcome. Methods Thirty-two patients with metastatic HB were enrolled on Children's Oncology Group Protocol AHEP0731 and treated with vincristine and irinotecan (VI). Responders to VI received two additional cycles of VI intermixed with six cycles of cisplatin/fluorouracil/vincristine/doxorubicin (C5VD), and nonresponders received six cycles of C5VD alone. Patients were imaged after every two cycles and at the conclusion of therapy. All computed tomography scans and pathology reports were centrally reviewed, and information was collected regarding lung nodule number, size, laterality, timing of resolution, and pulmonary surgery. Results Among the 29 evaluable patients, only 31% met Response Evaluation Criteria in Solid Tumors (RECIST) for measurable metastatic disease. The presence of measurable disease by RECIST, the sum of nodule diameters greater than or equal to the cumulative cohort median size, bilateral disease, and ≥ 10 nodules were each associated with an increased risk for an event-free survival event ( P = .48, P = .08, P = .065, P = .03, respectively), with nodule number meeting statistical significance. Ten patients underwent pulmonary resection/metastasectomy at various time points, the benefit of which could not be determined because of small patient numbers. Conclusion Children with metastatic HB have a poor prognosis. Overall tumor burden may be an important prognostic factor for these patients. Lesions that fail to meet RECIST size criteria (ie, those < 10 mm) at diagnosis may contain viable tumor, whereas residual lesions at the end of therapy may constitute eradicated tumor/scar tissue. Patients may benefit from risk stratification on the basis of the burden of lung metastatic disease at diagnosis.

PurposeTo determine whether overall survival (OS) can be preserved for patients with stage I pediatric malignant ovarian germ cell tumor (MOGCT) with an initial strategy of surveillance after surgical resection.Patients and methodsBetween November 2003 and July 2011, girls age 0 to 16 years with stage I MOGCT were enrolled onto Children's Oncology Group study AGCT0132. Required histology included yolk sac, embryonal carcinoma, or choriocarcinoma. Surveillance included measurement of serum tumor markers and radiologic imaging at defined intervals. In those with residual or recurrent disease, chemotherapy with compressed PEB (cisplatin, etoposide, and bleomycin) was initiated every 3 weeks for three cycles (cisplatin 33 mg/m(2) on days 1 to 3, etoposide 167 mg/m(2) on days 1 to 3, bleomycin 15 U/m(2) on day 1). Survivor functions for event-free survival (EFS) and OS were estimated using the Kaplan-Meier method.ResultsTwenty-five girls (median age, 12 years) with stage I MOGCT were enrolled onto AGCT0132. Twenty-three patients had elevated alpha-fetoprotein (AFP) at diagnosis. Predominant histology was yolk sac. After a median follow-up of 42 months, 12 patients had evidence of persistent or recurrent disease (4-year EFS, 52%; 95% CI, 31% to 69%). Median time to recurrence was 2 months. All patients had elevated AFP at recurrence; six had localized disease, two had metastatic disease, and four had tumor marker elevation only. Eleven of 12 patients experiencing relapse received successful salvage chemotherapy (4-year OS, 96%; 95% CI, 74% to 99%).ConclusionFifty percent of patients with stage I pediatric MOGCT can be spared chemotherapy; treatment for those who experience recurrence preserves OS. Further study is needed to identify the factors that predict recurrence and whether this strategy can be extended successfully to older adolescents and young adults.