Rare Tumors: Opportunities and challenges from the Children's Oncology Group perspective.

While all childhood cancers are rare, tumors that are particularly infrequent or underrepresented within pediatrics are studied under the umbrella of the Children's Oncology Group Rare Tumor committee, divided into the Retinoblastoma and Infrequent Tumor subcommittees. The Infrequent Tumor subcommittee has traditionally included an emphasis on globally rare tumors such as adrenocortical carcinoma, nasopharyngeal carcinoma, or those tumors that are rare in young children, despite being common in adolescents and young adults, such as colorectal carcinoma, thyroid carcinoma, and melanoma. Pleuropulmonary blastoma, gonadal stromal tumors, pancreatic tumors including pancreatoblastoma, gastrointestinal stromal tumor, nonmelanoma skin cancers, neuroendocrine tumors, and desmoplastic small round cell tumors, as well as other carcinomas are also included under the heading of the Children's Oncology Group Rare Tumor committee. While substantial challenges exist in rare cancers, inclusion and global collaboration remain key priorities to ensure high quality research to advance care.

Circulating tumor DNA sequencing of pediatric solid and brain tumor patients: An institutional feasibility study.

The potential of circulating tumor DNA (ctDNA) analysis to serve as a real-time "liquid biopsy" for children with central nervous system (CNS) and non-CNS solid tumors remains to be fully elucidated. We conducted a study to investigate the feasibility and potential clinical utility of ctDNA sequencing in pediatric patients enrolled on an institutional clinical genomics trial. A total of 240 patients had tumor DNA profiling performed during the study period. Plasma samples were collected at study enrollment from 217 patients and then longitudinally from a subset of patients. Successful cell-free DNA extraction and quantification occurred in 216 of 217 (99.5%) of these initial samples. Twenty-four patients were identified whose tumors harbored 30 unique variants that were potentially detectable on a commercially-available ctDNA panel. Twenty of these 30 mutations (67%) were successfully detected by next-generation sequencing in the ctDNA from at least one plasma sample. The rate of ctDNA mutation detection was higher in patients with non-CNS solid tumors (7/9, 78%) compared to those with CNS tumors (9/15, 60%). A higher ctDNA mutation detection rate was also observed in patients with metastatic disease (9/10, 90%) compared to non-metastatic disease (7/14, 50%), although tumor-specific variants were detected in a few patients in the absence of radiographic evidence of disease. This study illustrates the feasibility of incorporating longitudinal ctDNA analysis into the management of relapsed or refractory patients with childhood CNS or non-CNS solid tumors.

Clinical and molecular features of pediatric cancer patients with Lynch syndrome.

BACKGROUND: The association of childhood cancer with Lynch syndrome is not established compared with the significant pediatric cancer risk in recessive constitutional mismatch repair deficiency syndrome (CMMRD). PROCEDURE: We describe the clinical features, germline analysis, and tumor genomic profiling of patients with Lynch syndrome among patients enrolled in pediatric cancer genomic studies. RESULTS: There were six of 773 (0.8%) pediatric patients with solid tumors identified with Lynch syndrome, defined as a germline heterozygous pathogenic variant in one of the mismatch repair (MMR) genes (three with MSH6, two with MLH1, and one with MSH2). Tumor analysis demonstrated evidence for somatic second hits and/or increased tumor mutation burden in three of four patients with available tumor with potential implications for therapy and identification of at-risk family members. Only one patient met current guidelines for pediatric cancer genetics evaluation at the time of tumor diagnosis. CONCLUSION: Approximately 1% of children with cancer have Lynch syndrome, which is missed with current referral guidelines, suggesting the importance of adding MMR genes to tumor and hereditary pediatric cancer panels. Tumor analysis may provide the first suggestion of an underlying cancer predisposition syndrome and is useful in distinguishing between Lynch syndrome and CMMRD.

Integrated DNA and RNA sequencing reveals targetable alterations in metastatic pediatric papillary thyroid carcinoma.

BACKGROUND: Pediatric papillary thyroid carcinoma (PTC) is clinically and biologically distinct from adult PTC. We sequenced a cohort of clinically annotated pediatric PTC cases enriched for high-risk tumors to identify genetic alterations of relevance for diagnosis and therapy. METHODS: Tumor DNA and RNA were extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation using a custom 124-gene hybridization capture panel and the 75-gene Archer Oncology Research Panel, respectively. NGS libraries were sequenced on an Illumina MiSeq. RESULTS: Thirty-six pediatric PTC cases were analyzed. Metastases were frequently observed to cervical lymph nodes (29/36, 81%), with pulmonary metastases less commonly found (10/36, 28%). Relapsed or refractory disease occurred in 18 patients (18/36, 50%). DNA sequencing revealed targetable mutations in 8 of 31 tumors tested (26%), most commonly BRAF p.V600E (n = 6). RNA sequencing identified targetable fusions in 13 of 25 tumors tested (52%): RET (n = 8), NTRK3 (n = 4), and BRAF. Mutually exclusive targetable alterations were discovered in 15 of the 20 tumors (75%) with both DNA and RNA analyzed. Fusion-positive PTC was associated with multifocal disease, higher tumor staging, and higher American Thyroid Association risk levels. Both BRAF V600E mutations and gene fusions were correlated with the presence of cervical metastases. CONCLUSIONS: Targetable alterations were identified in 75% of pediatric PTC cases with both DNA and RNA evaluated. Inclusion of RNA sequencing for detection of fusion genes is critical for evaluation of these tumors. Patients with fusion-positive tumors were more likely to have features of high-risk disease.

Challenges and solutions to the study of rare childhood tumors.

PURPOSE OF REVIEW: The majority of progress made in pediatric oncology over the past 50 years has been achieved in the most common cancers. Rare pediatric cancers, which collectively comprise more than 10% of all pediatric cancers, pose multiple challenges to researchers and clinicians, all which stem from the infrequency of these cancers. There has been a tremendous increase in focus on rare pediatric cancers by international consortia and registries, disease-specific clinics, and divisions of academic children's hospitals in the last 10 years. This focus, along with the progress made in cancer genomics, has changed the landscape for the study and treatment of rare pediatric cancers. This review focuses on the past, present, and future of the study and treatment of rare pediatric cancers. RECENT FINDINGS: Cancer genomics is changing the way some cancers are being diagnosed, categorized, and treated. Rare pediatric cancers potentially stand to greatly benefit from advances in precision diagnosis and treatment. SUMMARY: The challenges of studying rare pediatric cancers are well known. By utilizing similar techniques that allowed for progress in the common pediatric malignancies, namely collaboration, increased focus, greater funding, and utilization of cancer genomics, progress in the study and treatment of rare pediatric cancers is promising.

Agenesis of the corpus callosum and hepatoblastoma.

Agenesis of the corpus callosum is a congenital brain malformation that can occur in isolation or as a component of a congenital syndrome. Hepatoblastoma (HB) is a rare tumor that comprises two thirds of primary hepatic neoplasms in children and adolescents. Up to 20% of children with HB have associated congenital anomalies. In addition to defined genetic syndromes such as Familial Adenomatous Polyposis, Beckwith-Wiedemann syndrome, Trisomy 13, and Trisomy 18, HB is significantly associated with kidney/bladder abnormalities. We present two children with multiple congenital anomalies, including agenesis of the corpus callosum, who were subsequently diagnosed with HB. Review of the literature revealed two patients with clinically-diagnosed Aicardi syndrome and HB. Due to the rarity of both agenesis of the corpus callosum and HB, this is likely a true association. Further investigation into the underlying genetic and molecular basis of this probable association is warranted.

Pediatric Bronchial Carcinoid Tumors: A Case Series and Review of the Literature.

Bronchial carcinoid tumor, while rare, remains the most common primary malignant lung tumor in children. We present a retrospective analysis of 7 patients with typical bronchial carcinoid tumors diagnosed at 2 pediatric tertiary care referral centers between 1990 and 2014. The most common presenting symptom was pneumonia, followed by respiratory distress. Somatostatin scans were performed in selected patients. All patients had negative resection margin following surgery and were alive without disease at last follow-up. Typical carcinoid tumors have a good prognosis following definitive surgical resection. A review of published literature on pediatric bronchial carcinoid tumors is provided.

Therapeutic response of metastatic angiomatoid fibrous histiocytoma carrying EWSR1-CREB1 fusion to the interleukin-6 receptor antibody tocilizumab.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that has been associated with EWSR1-CREB1 gene fusion. Outcome in patients with unresectable distant metastases is generally fatal. Interleukin-6 (IL-6) secretion has been described in tumors with EWSR1-CREB1 fusion, and may promote tumor growth due to autocrine stimulation. Tocilizumab is an IL-6 receptor antibody that has potential benefit as a targeted therapy in refractory neoplasms with IL-6 secretion. We describe a child with metastatic AFH with EWSR1-CREB1 fusion and elevated IL-6 whose disease progressed during treatment with traditional chemotherapeutic agents, but improved after targeted therapy with tocilizumab.

Renal cell carcinoma harboring somatic TSC2 mutations in a child with methylmalonic acidemia.

Pediatric renal cell carcinoma (RCC) is a rare cancer that can be associated with inherited diseases including tuberous sclerosis complex (TSC) caused by germline mutations in TSC1 or TSC2. Somatic mutations in TSC1 and TSC2 have also been reported in adult RCC, which predict response to mTOR inhibitors. Here, we present the first case of RCC in a child with methylmalonic acidemia (MMA). Clinical whole exome sequencing of blood and tumor samples confirmed the diagnosis of MMA and revealed two somatic inactivating mutations in TSC2, suggesting the potential consideration of an mTOR inhibitor in the event of tumor recurrence.

Phase 2 clinical trial of intrathecal topotecan in children with refractory leptomeningeal leukemia: a Children's Oncology Group trial (P9962).

PURPOSE: We performed a phase 2 study in children with recurrent or refractory leptomeningeal leukemia to determine the objective response rate after treatment with intrathecal (IT) topotecan. PATIENTS AND METHODS: Patients received age-adjusted IT topotecan (0.4 mg/dose for patients >3 years of age) administered twice weekly (every 3-4 days) for 6 weeks during induction, weekly for 4 weeks during consolidation, and twice monthly for 4 months and then monthly thereafter during maintenance. RESULTS: Twenty-two patients enrolled in the study, of whom 20 were eligible and assessable for toxicity and 16 were assessable for response. Of 16 patients, 6 (38%) had a complete response, 8 (50%) had stable disease, and 2 (13%) had progressive disease. The median event-free survival time (95% CI) was 3.1 (1.6-10.3) months and the median overall survival time (95% CI) was 18.0 (7.3-38.3) months. Eight patients (40%) experienced grade 3 or 4 adverse events. There were no grade 4 neurological events (Table III). Four patients experienced a total of 6 grade 3 neurological events including an olfactory seizure, a headache, transient grade 3 speech impairment, muscle weakness, motor neuropathy, and ataxia. Headache was the most common grade ≤2 neurologic event and two patients developed grade ≤2 arachnoiditis. CONCLUSION: IT administration of topotecan was tolerable on this dose and schedule. The majority of adverse events were mild to moderate, reversible side effects. Complete central nervous system remissions were achieved in a subset of children with recurrent or refractory central nervous system leukemia.

Detection of hypertrophic cardiomyopathy is improved when using advanced rather than strictly conventional 12-lead electrocardiogram.

INTRODUCTION: Twelve-lead electrocardiogram (ECG) is used to screen for hypertrophic cardiomyopathy (HCM), but up to 25% of HCM patients do not have distinctly abnormal ECGs, whereas up to 5% to 15% of healthy athletes do. We hypothesized that an approximately 5-minute resting advanced 12-lead ECG test ("A-ECG score") could detect HCM with greater sensitivity than pooled conventional ECG criteria and distinguish healthy athletes from HCM with greater specificity. MATERIALS AND METHODS: Five-minute 12-lead ECGs were obtained from 56 HCM patients, 56 age/sex-matched healthy controls, and 69 younger endurance-trained athletes. Electrocardiograms were analyzed using recently suggested pooled conventional ECG criteria and also A-ECG scoring techniques that considered results from multiple advanced and conventional ECG parameters. RESULTS: Compared with pooled criteria from the strictly conventional ECG, an A-ECG logistic score incorporating results from just 3 advanced ECG parameters (spatial QRS-T angle, unexplained portion of QT variability, and T-wave principal component analysis ratio) increased the sensitivity of ECG for identifying HCM from 89% (78%-96%) to 98% (89%-100%; P = .025), while increasing specificity from 90% (83%-94%) to 95% (92%-99%; P = .020). CONCLUSIONS: Resting 12-lead A-ECG scores that are simultaneously more sensitive than pooled conventional ECG criteria for detecting HCM and more specific for distinguishing healthy athletes and other healthy controls from HCM can be constructed. Pending further prospective validation, such scores may lead to improved ECG-based screening for HCM.