An Exome Capture-Based RNA-Sequencing Assay for Genome-Wide Identification and Prioritization of Clinically Important Fusions in Pediatric Tumors.

This study reports the development of an exome capture-based RNA-sequencing assay to detect recurring and novel fusions in hematologic, solid, and central nervous system tumors. The assay used Twist Comprehensive Exome capture with either fresh or formalin-fixed samples and a bioinformatic platform that provides fusion detection, prioritization, and downstream curation. A minimum of 50 million uniquely mapped reads, a consensus read alignment/fusion calling approach using four callers (Arriba, FusionCatcher, STAR-Fusion, and Dragen), and custom software were used to integrate, annotate, and rank the candidate fusion calls. In an evaluation of 50 samples, the number of calls varied substantially by caller, from a mean of 24.8 with STAR-Fusion to 259.6 with FusionCatcher; only 1.1% of calls were made by all four callers. Therefore a filtering and ranking algorithm was developed based on multiple criteria, including number of supporting reads, calling consensus, genes involved, and cross-reference against databases of known cancer-associated or likely false-positive fusions. This approach was highly effective in pinpointing known clinically relevant fusions, ranking them first in 47 of 50 samples (94%). Detection of pathogenic gene fusions in three diagnostically challenging cases highlights the importance of a genome-wide and nontargeted method for fusion detection in pediatric cancer.

Survival outcomes and surgical morbidity based on surgical approach to pulmonary metastasectomy in pediatric, adolescent and young adult patients with osteosarcoma.

BACKGROUND: Thoracotomy is considered the standard surgical approach for the management of pulmonary metastases in osteosarcoma (OST). Several studies have identified the advantages of a thoracoscopic approach, however, the clinical significance of thoracotomy compared to thoracoscopy is yet to be evaluated in a randomized trial. AIMS: The primary aim was to determine the survival outcomes in OST patients based on surgical approach for pulmonary metastasectomy (PM) and secondary aim was to assess the post-operative morbidities of OST PM through various surgical approaches. MATERIALS AND METHODS: We conducted a single institution retrospective study to compare survival outcomes and surgical morbidity according to the surgical approach of the management of pulmonary metastases in patients with OST. RESULTS: Sixty-one patients with OST underwent PM. Twenty-one patients were metastatic at diagnosis and underwent PM during primary treatment; nine had thoracotomy, six thoracoscopy, and six combined thoracoscopy with thoracotomy (CTT). Forty-three patients with first pulmonary relapse or progression underwent PM; 18 had thoracotomy, 16 thoracoscopy and nine CTT. There was no difference in survival between surgical approaches. There were significantly more postoperative morbidities associated with thoracotomy for initial PM (pain and postoperative chest tube placement), and for PM at first relapse (pneumothoraces, pain, Foley catheter use and prolonged hospitalizations). CONCLUSION: Our study demonstrates that patients with OST pulmonary metastases have comparable poor outcomes despite varying surgical approaches for PM. There were significantly more postoperative morbidities associated with thoracotomy for PM. Surgical bias and other competing risks could not be assessed given the limitations of a retrospective study and may be addressed in a prospective trial evaluating surgical approach for PM in OST.

Phase I trial of Ganitumab plus Dasatinib to Cotarget the Insulin-Like Growth Factor 1 Receptor and Src Family Kinase YES in Rhabdomyosarcoma.

PURPOSE: Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701). PATIENTS AND METHODS: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT). RESULTS: Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response. CONCLUSIONS: The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months.

Combined low-pass whole genome and targeted sequencing in liquid biopsies for pediatric solid tumors.

We designed a liquid biopsy (LB) platform employing low-pass whole genome sequencing (LP-WGS) and targeted sequencing of cell-free (cf) DNA from plasma to detect genome-wide copy number alterations (CNAs) and gene fusions in pediatric solid tumors. A total of 143 plasma samples were analyzed from 19 controls and 73 patients, including 44 bone or soft-tissue sarcomas and 12 renal, 10 germ cell, five hepatic, and two thyroid tumors. cfDNA was isolated from plasma collected at diagnosis, during and after therapy, and/or at relapse. Twenty-six of 37 (70%) patients enrolled at diagnosis without prior therapy (radiation, surgery, or chemotherapy) had circulating tumor DNA (ctDNA), based on the detection of CNAs from LP-WGS, including 18 of 27 (67%) patients with localized disease and eight of 10 (80%) patients with metastatic disease. None of the controls had detectable somatic CNAs. There was a high concordance of CNAs identified by LP-WGS to CNAs detected by chromosomal microarray analysis in the matching tumors. Mutations identified in tumor samples with our next-generation sequencing (NGS) panel, OncoKids®, were also detected by LP-WGS of ctDNA in 14 of 26 plasma samples. Finally, we developed a hybridization-based capture panel to target EWSR1 and FOXO1 fusions from patients with Ewing sarcoma or alveolar rhabdomyosarcoma (ARMS), respectively. Fusions were detected in the plasma from 10 of 12 patients with Ewing sarcoma and in two of two patients with ARMS. Combined, these data demonstrate the clinical applicability of our LB platform to evaluate pediatric patients with a variety of solid tumors.

The Role of Pharmacotherapeutic Agents in Children with Desmoid Tumors.

Desmoid tumors (DT) are rare fibroblastic, soft-tissue tumors that do not metastasize but can aggressively infiltrate tissues causing significant chronic discomfort and/or functional impairment. In the pediatric population, the incidence of DT is greatest during infancy and adolescence but can occur at any age. Dysregulated ß-catenin, most commonly resulting from mutations in either CTNNB1 or germline APC (adenomatous polyposis coli) drives DT. Most cases are sporadic but some are associated with predisposition syndromes such as familial adenomatous polyposis (FAP). Historically, treatment has been surgery. However, the recurrence rate after surgery can be high. Various systemic cytotoxic chemotherapy regimens used in other soft-tissue sarcomas have been applied to DT with differing results. Given the chronic and rarely life-threatening nature of this disease and the potential short- and long-term toxicity of these regimens, especially in children, alternative non-cytotoxic interventions have been investigated. Molecularly targeted agents such as tyrosine kinase and gamma secretase inhibitors have shown activity against DT. Innovative local control therapies are being employed as alternatives to surgery and radiation. Periods of prolonged stability and spontaneous regression in the absence of therapy in some patients has prompted wider adoption of an upfront active surveillance approach in the appropriate setting. This review will briefly summarize the epidemiology, pathophysiology, and clinical presentation of DT in children, then focus on historical, current, and future pharmacotherapeutic management and finally, propose areas for future study.

Kaposiform hemangioendothelioma of the bone in children and adolescents.

Kaposiform hemangioendothelioma (KHE) is a rare, locally aggressive vascular tumor that mainly occurs during infancy or early childhood. Approximately 70% of cases are complicated by Kasabach-Merritt phenomenon. Although osseous extension of the primary lesion is relatively common, primary bone involvement by KHE is rare. Given the paucity of literature on primary KHE of the bone, we report a case series of primary KHE of the bone treated at our institution and describe the clinical presentation, radiologic and pathologic findings, management and outcomes.

Primary Adrenal Malignant Rhabdoid Tumor in a 14-Year-Old Female: A Case Report and Literature Review.

Malignant rhabdoid tumor (MRT) is a rare, SWItch/sucrose nonfermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1)-deficient, aggressive tumor, occurring predominantly in children below 3 years of age. Primary adrenal MRT is extremely rare, with only 3 cases reported in the literature. A previously healthy 14-year-old female presented with left upper quadrant/epigastric abdominal pain. Imaging studies revealed an 8.0 × 8.0 × 6.5 cm, heterogeneous, partially enhancing mass along the superior margin of the left kidney encasing the adrenal gland. Surgical resection of the tumor revealed a hypercellular heterogeneous neoplasm arising from the adrenal gland. It was composed predominantly of primitive small round blue cells with focal true rosettes and areas of vague glandular epithelial differentiation and chondroid differentiation. Classic rhabdoid-type cytoplasmic inclusions were focally present. Mitoses, tumor necrosis, and hemorrhage were readily seen. Tumor cells showed complete loss of SMARCB1 (INI1) nuclear staining, demonstrated strong, and diffuse positivity for glypican 3, patchy positivity for CD99, cytokeratin, Sal-like protein 4, Lin-28 homolog A, epithelial membrane antigen, and S100. Molecular studies revealed biallelic frameshift mutations in the SMARCB1 gene (c.673delG and c.683dupT) without pathogenic copy number aberrations. The histologic, immunohistochemical, and molecular findings support a diagnosis of MRT. The unusual age, location, and mutations of this case expand the clinicopathologic and molecular spectrum of MRT.

Improved Outcome in Children With Newly Diagnosed High-Risk Neuroblastoma Treated With Chemoimmunotherapy: Updated Results of a Phase II Study Using hu14.18K322A.

PURPOSE: We evaluated whether combining a humanized antidisialoganglioside monoclonal antibody (hu14.18K322A) throughout therapy improves early response and outcomes in children with newly diagnosed high-risk neuroblastoma. PATIENTS AND METHODS: We conducted a prospective, single-arm, three-stage, phase II clinical trial. Six cycles of induction chemotherapy were coadministered with hu14.18K322A, granulocyte-macrophage colony-stimulating factor (GM-CSF), and low-dose interleukin-2 (IL-2). The consolidation regimen included busulfan and melphalan. When available, an additional cycle of parent-derived natural killer cells with hu14.18K322A was administered during consolidation (n = 31). Radiation therapy was administered at the end of consolidation. Postconsolidation treatment included hu14.18K322A, GM-CSF, IL-2, and isotretinoin. Early response was assessed after the first two cycles of induction therapy. End-of-induction response, event-free survival (EFS), and overall survival (OS) were evaluated. RESULTS: Sixty-four patients received hu14.18K322A with induction chemotherapy. This regimen was well tolerated, with continuous infusion narcotics. Partial responses (PRs) or better after the first two chemoimmunotherapy cycles occurred in 42 of 63 evaluable patients (66.7%; 95% CI, 55.0 to 78.3). Primary tumor volume decreased by a median of 75% (range, 100% [complete disappearance]-5% growth). Median peak hu14.18K322A serum levels in cycle one correlated with early response to therapy (P = .0154, one-sided t-test). Sixty of 62 patients (97%) had an end-of-induction partial response or better. No patients experienced progressive disease during induction. The 3-year EFS was 73.7% (95% CI, 60.0 to 83.4), and the OS was 86.0% (95% CI, 73.8 to 92.8), respectively. CONCLUSION: Adding hu14.18K322A to induction chemotherapy improved early objective responses, significantly reduced tumor volumes in most patients, improved end-of-induction response rates, and yielded an encouraging 3-year EFS. These results, if validated in a larger study, may be practice changing.

Charting a path for prioritization of novel agents for clinical trials in osteosarcoma: A report from the Children's Oncology Group New Agents for Osteosarcoma Task Force.

Osteosarcoma is the most common bone tumor in children and young adults. Metastatic and relapsed disease confer poor prognosis, and there have been no improvements in outcomes for several decades. The disease's biological complexity, lack of drugs developed specifically for osteosarcoma, imperfect preclinical models, and limits of existing clinical trial designs have contributed to lack of progress. The Children's Oncology Group Bone Tumor Committee established the New Agents for Osteosarcoma Task Force to identify and prioritize agents for inclusion in clinical trials. The group identified multitargeted tyrosine kinase inhibitors, immunotherapies targeting B7-H3, CD47-SIRPα inhibitors, telaglenastat, and epigenetic modifiers as the top agents of interest. Only multitargeted tyrosine kinase inhibitors met all criteria for frontline evaluation and have already been incorporated into an upcoming phase III study concept. The task force will continue to reassess identified agents of interest as new data become available and evaluate novel agents using this method.

Rationale for the use of tyrosine kinase inhibitors in the treatment of paediatric desmoid-type fibromatosis.

In children with desmoid-type fibromatosis (DTF) in whom disease progression occurs after an initial watch-and-wait strategy, prolonged low-dose chemotherapy using vinblastine and methotrexate (VBL-MTX) is currently the standard of care. These conventional drugs have been prospectively evaluated but their efficacy and safety profiles are limited, and alternative therapeutic options are therefore essential. Based on the results of clinical trials, the use of tyrosine kinase inhibitors (TKIs) in the treatment of DTF is currently considered only in adult patients. TKIs such as imatinib show superior therapeutic efficacy to VBL-MTX and tolerable short-term side effects for the treatment of adult DFT, supporting the concept of the use of TKIs for the treatment of paediatric DFT. Moreover, new-generation TKIs, such as pazopanib and sorafenib, have shown improved therapeutic efficacy compared to imatinib in adult non-comparative studies. A tolerable safety profile of TKI therapy in children with disease entities other than DTF, such as leukaemia, has been reported. However, the efficacy and, in particular, the long-term safety of TKIs, including childhood-specific aspects such as growth and fertility, for the treatment of children with DTF should be investigated prospectively, as DFT therapy requires long-term drug exposure.

A multidisciplinary approach to management of abdominal lymphatic malformations.

BACKGROUND/PURPOSE: Abdominal lymphatic malformations (LM) are a rare subset of vascular anomaly caused by abnormal development of the lymphatic system. They are classified as macrocystic, microcystic or combination macrocystic and microcystic. Surgical resection, percutaneous sclerotherapy, and medical therapy are all employed to treat these complex and often symptomatic lesions. No standardized treatment algorithm exists currently. The purpose of this study was to establish a multidisciplinary treatment approach to abdominal LMs. METHODS: A retrospective observational study was conducted from 2013 to 2019 on patients with abdominal LMs at a single tertiary children's hospital vascular anomalies center. Demographics, imaging, and treatment modality were recorded. Clinical and/or radiographic response to the primary treatment modality as well as complications was the outcomes measured. RESULTS: Nineteen patients (12 macrocystic, 5 microcystic and 2 combined) were identified, with a median age at diagnosis of 2.2 years (range 0.1-20.8 years). Sclerotherapy was the most common primary treatment, followed by surgical resection and sirolimus. No difference in clinical response (p = 0.58) or complications (p = 0.31) was observed based on primary treatment or subtypes. CONCLUSIONS: Based on our institutional experience, we propose an LM subtype-based treatment algorithm for abdominal LMs. It employs a multidisciplinary approach, and results in satisfactory patient outcomes with minimal complications. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Custom Pediatric Oncology Next-Generation Sequencing Panel Identifies Somatic Mosaicism in Archival Tissue and Enhances Targeted Clinical Care.

BACKGROUND: Disorders in the PIK3CA-related overgrowth spectrum because of somatic mosaicism are associated with segmental overgrowth of the body in conjunction with vascular, skeletal, and brain malformations such as hemimegalencephaly. A pathogenic variant may only be detectable in affected tissue and not in peripheral blood or saliva samples; therefore archival tissue may be the only relevant available specimen for testing. Although this is a common approach for cancer testing, it is not typically used for constitutional genetic disorders. METHODS: PIK3CA mosaicism was assessed with a custom pediatric oncology next-generation sequencing panel (OncoKids) designed to capture somatic mutations in pediatric malignancies. The panel covers a wide range of targets including PIK3CA and AKT1 hotspots. We used OncoKids on archival formalin-fixed, paraffin-embedded or frozen samples from seven patients with facial hemihypertrophy and lipomas, hemimegalencephaly, or hemihypertrophy with a lymphovascular malformation. The age of the archival tissue examined by next-generation sequencing ranged from two to 13 years (median 5 years). Every patient had clinical manifestations within the PIK3CA-related overgrowth spectrum and had a sample of an affected tissue available for testing from a prior surgical intervention. RESULTS: PIK3CA mosaicism was detected in all seven patients and the mutant allele fraction was lower in the lymphovascular malformation tissues (8% to 11%) than in brain (20% to 32%) and lipomatous (16% to 23%) tissues. CONCLUSIONS: Our study highlights the clinical utility of using a robust, oncology-focused next-generation sequencing assay to identify PIK3CA mosaicism in noncancer cases. It is feasible to use archival samples that are more than a decade old to obtain a molecular diagnosis, which can then be used to improve health care management.

A Phase 1 and pharmacokinetic study evaluating daily or weekly schedules of the humanized anti-GD2 antibody hu14.18K322A in recurrent/refractory solid tumors.

Hu14.18K322A is a humanized anti-GD2 monoclonal antibody with a single point mutation that reduces complement-mediated cytotoxicity, with a maximum tolerated dose (MTD) of 60 mg/m2 daily for 4 days in children with recurrent/refractory neuroblastoma. We report additional results of a Phase 1 trial to determine the MTD and safety profile of hu14.18K322A in patients with osteosarcoma, and of an alternative schedule of weekly hu14.18K322A administration in patients with neuroblastoma or osteosarcoma. Eligible patients with recurrent/refractory osteosarcoma received hu14.13K22A daily x4 every 28 days in a Phase 1 traditional 3 + 3 dose escalation design. Additional patients with osteosarcoma were then enrolled to receive hu14.18K322A once weekly for 4 weeks per course. Patients with recurrent/refractory neuroblastoma were also enrolled on the weekly schedule at 50 mg/m2/dose. Six patients with osteosarcoma treated on the daily schedule received a median of 2 (range 1-6) courses; the recommended daily dose was established as 60 mg/m2. Three patients had stable disease (SD) as best overall response. Five patients (3 neuroblastoma, 2 osteosarcoma) enrolled on the weekly schedule received a median of 1 (1-3) course; 2 achieved SD as best overall response. Pain, fever, hematologic toxicities, hyponatremia, and ocular/visual abnormalities were common toxicities among both schedules. Dose-limiting toxicities attributed to hu14.18K322A included anorexia and fatigue (n = 1). Pharmacokinetic profiles were similar between daily and weekly schedules. The recommended dose for patients with osteosarcoma receiving daily hu14.18K322A x4 is 60 mg/m2. Patients receiving the weekly schedule experienced similar pharmacokinetics and toxicity profile as the daily schedule.

Phase I expansion cohort to evaluate the combination of bevacizumab, sorafenib and low-dose cyclophosphamide in children and young adults with refractory or recurrent solid tumours.

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.

Pre-existing antitherapeutic antibodies against the Fc region of the hu14.18K322A mAb are associated with outcome in patients with relapsed neuroblastoma.

PURPOSE: Patients with cancer receiving tumor-reactive humanized monoclonal antibody (mAb) therapy can develop a human antihuman antibody (HAHA) response against the therapeutic mAb. We evaluated for HAHA in patients with neuroblastoma treated in a phase I study of humanized anti-GD2 mAb (immunoglobulin (Ig)G1 isotype), hu14.18K322A (NCT00743496). The pretreatment sera (collected prior to mAb treatment) from 9 of 38 patients contained antitherapeutic antibodies, even though they had no prior mAb exposure. We sought to characterize these pre-existing antitherapeutic antibodies (PATA). EXPERIMENTAL DESIGN: The PATA+ pretreatment samples were characterized via ELISA; clinical associations with PATA status were evaluated. RESULTS: Pretreatment sera from eight of nine PATA+ patients also bound rituximab and demonstrated preferential ELISA reactivity against the Fc portions of hu14.18K322A and rituximab as compared with the Fab portions of these mAbs. These PATA+ sera also recognized dinutuximab (human IgG1 isotype) and mouse IgG2a isotype mAbs, but not a mouse IgG1 isotype or the fully human panitumumab (IgG2 isotype) mAb. Of the 38 treated patients, only 4 patients (all in the PATA+ cohort) demonstrated no disease progression for >2.5 years without receiving further therapy (p=0.002). CONCLUSIONS: This study demonstrates an association between clinical outcome and the presence of PATA against determinant(s) on the Fc component of the therapeutic mAb, suggesting that the PATA may be playing a role in augmenting mAb-based antitumor effects. Further analyses for the presence of PATA in a larger cohort of patients with relapsed neuroblastoma, analyses of their clinical correlates, identification of their immunological targets, and potential antitumor mechanisms are warranted.

A Phase II Trial of Hu14.18K322A in Combination with Induction Chemotherapy in Children with Newly Diagnosed High-Risk Neuroblastoma.

PURPOSE: We sought to evaluate whether combining a humanized antidisialoganglioside mAb (hu14.18K322A) with induction chemotherapy improves early responses and outcomes in children with newly diagnosed high-risk neuroblastoma. PATIENTS AND METHODS: We conducted a prospective nonrandomized, single-arm, two-stage, phase II clinical trial. Six courses of induction chemotherapy were coadministered with hu14.18K322A and followed with granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose IL2. Consolidation was performed with a busulfan/melphalan preparative regimen. An additional course of hu14.18K322A was administered with parent-derived natural killer cells, when available, during consolidation. Hu14.18K322A, GM-CSF, IL2, and isotretinoin were then administered. Secondary outcomes included reduced tumor volume and semiquantitative 123I-metaiodobenzylguanidine scoring [i.e., Curie scores (CS)] at the end of induction. RESULTS: Forty-two patients received hu14.18K322A and induction chemotherapy. This regimen was well tolerated, with continuous-infusion narcotics adjusted to patient tolerance. Partial responses (PR) or better after the first two chemoimmunotherapy courses occurred in 32 patients [76.2%; 95% confidence interval (CI), 60.6-88.0]. This was accompanied by primary tumor volume reductions (median, -76%; range, -100% to 5%). Of 35 patients with stage IV disease who completed induction, 31 had end-of-induction CSs of 2 or less. No patients experienced progression during induction. Two-year event-free survival (EFS) was 85.7% (95% CI, 70.9-93.3). CONCLUSIONS: Adding hu14.18K322A to induction chemotherapy produced early PR or better in most patients, reduced tumor volumes, improved CSs at the end of induction, and yielded an encouraging 2-year EFS. These results, if validated in a larger study, may change the standard of care for children with high-risk neuroblastoma.

Sorafenib Population Pharmacokinetics and Skin Toxicities in Children and Adolescents with Refractory/Relapsed Leukemia or Solid Tumor Malignancies.

PURPOSE: To determine the pharmacokinetics and skin toxicity profile of sorafenib in children with refractory/relapsed malignancies. PATIENTS AND METHODS: Sorafenib was administered concurrently or sequentially with clofarabine and cytarabine to patients with leukemia or with bevacizumab and cyclophosphamide to patients with solid tumor malignancies. The population pharmacokinetics (PPK) of sorafenib and its metabolites and skin toxicities were evaluated. RESULTS: In PPK analysis, older age, bevacizumab and cyclophosphamide regimen, and higher creatinine were associated with decreased sorafenib apparent clearance (CL/f; P < 0.0001 for all), and concurrent clofarabine and cytarabine administration was associated with decreased sorafenib N-oxide CL/f (P = 7e-4). Higher bilirubin was associated with decreased sorafenib N-oxide and glucuronide CL/f (P = 1e-4). Concurrent use of organic anion-transporting polypeptide 1B1 inhibitors was associated with increased sorafenib and decreased sorafenib glucuronide CL/f (P < 0.003). In exposure-toxicity analysis, a shorter time to development of grade 2-3 hand-foot skin reaction (HFSR) was associated with concurrent (P = 0.0015) but not with sequential (P = 0.59) clofarabine and cytarabine administration, compared with bevacizumab and cyclophosphamide, and with higher steady-state concentrations of sorafenib (P = 0.0004) and sorafenib N-oxide (P = 0.0275). In the Bayes information criterion model selection, concurrent clofarabine and cytarabine administration, higher sorafenib steady-state concentrations, larger body surface area, and previous occurrence of rash appeared in the four best two-predictor models of HFSR. Pharmacokinetic simulations showed that once-daily and every-other-day sorafenib schedules would minimize exposure to sorafenib steady-state concentrations associated with HFSR. CONCLUSIONS: Sorafenib skin toxicities can be affected by concurrent medications and sorafenib steady-state concentrations. The described PPK model can be used to refine exposure-response relations for alternative dosing strategies to minimize skin toxicity.

Embryonal rhabdomyosarcoma in a patient with a germline CBL pathogenic variant.

Germline pathogenic variants in CBL are associated with an autosomal dominant RASopathy and an increased risk for malignancies, particularly juvenile myelomonocytic leukemia. Herein, we describe a patient with clinical features of a Noonan-spectrum disorder who developed embryonal rhabdomyosarcoma of the bladder at age two years. Tumor analysis using the OncoKids® cancer panel revealed a CBL pathogenic variant: NM_005188.3:c.1100A>C (p.Gln367Pro). Sanger sequencing of peripheral blood DNA confirmed a de novo heterozygous germline variant. This is the first report of embryonal rhabdomyosarcoma in association with a germline CBL pathogenic variant, further broadening the CBL cancer predisposition spectrum.

Integrated analysis of long-term growth and bone development in pediatric and adolescent patients receiving bevacizumab.

BACKGROUND: We conducted an integrated analysis of clinical data to describe long-term effects of bevacizumab on growth and bone development in pediatric and adolescent patients with solid tumors. PROCEDURE: Clinical data were pooled from five phase I/II trials of bevacizumab versus chemotherapy: BERNIE, HERBY, and AVF4117s enrolled newly diagnosed patients, AVF3842s and AVF2771s enrolled patients with relapsed/refractory disease. Height, weight, body mass index (BMI), and bone-age data were pooled by treatment group. Growth charts were used to track and monitor growth in relation to a reference population of healthy children. Bone age was measured based on X-ray of the left hand and wrist. Analyses were exploratory/descriptive. RESULTS: Overall, 268 patients received bevacizumab ± chemotherapy and 135 received chemotherapy alone. Baseline characteristics were generally balanced. Median duration of long-term follow-up was 41.8 months (range, 2.4-75.1) with bevacizumab and 22.9 months (range, 2.8-69.2) with chemotherapy alone. Patients had age-appropriate baseline height and weight. Mean height and weight percentiles decreased over time in both treatment groups, but remained within the normal range (height: mean standard deviation score [SDS] range -2 to +3; weight: mean SDS range -2 to +1). Similar trends were seen in BMI. A tendency for reduced growth velocity relative to the reference population was observed at 6 months and 1 year in both groups, but there was no additional decrease for patients receiving bevacizumab. CONCLUSION: Bevacizumab did not appear to have additional negative effects on growth or development of pediatric and adolescent patients with solid tumors.

Health-Related Quality of Life and Survival Outcomes of Pediatric Patients With Nonmetastatic Osteosarcoma Treated in Countries With Different Resources.

PURPOSE: Health-related quality of life (HRQOL) improves throughout treatment of patients with nonmetastatic osteosarcoma. We compared HRQOL for patients in the United States and Chile treated on an international trial (OS99) with polychemotherapy and surgery, and we assessed the relationships among HRQOL measures, event-free survival (EFS), and overall survival (OS). MATERIALS AND METHODS: Patients with newly diagnosed, localized osteosarcoma and their parents completed three HRQOL instruments (PedsQL v.4, PedsQL Cancer v.3, and Symptom Distress Scale [SDS]). Data were collected at four time points throughout therapy. Repeated measures models were used to investigate the effect of treatment site on instrument scores. The log-rank test examined the impact of treatment site on survival outcomes, and Cox proportional hazards regression models evaluated baseline HRQOL measures as predictors of EFS and OS. RESULTS: Of 71 eligible patients, 66 (93%) participated in the HRQOL studies in the United States (n = 44) and Chile (n = 22). The median age was 13.4 years (range, 5 to 23 years). Clinical characteristics were similar between treatment sites. US patients reported better scores for physical ( P = .030), emotional ( P = .027), and school functioning ( P < .001). Chilean patients reported poorer scores for worry ( P < .001) and nausea ( P = .007). Patient and parent nausea scores were similar between patients treated in the United States and Chile by the end of therapy. Differences in symptom distress were not observed between the countries. Neither HRQOL measures nor treatment site were associated with EFS or OS. CONCLUSION: Although significant differences in HRQOL were observed between countries, outcomes were similar, and HRQOL measures were not associated with prognosis.