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.

Two pediatric oncologic cases of hypereosinophilic syndrome and review of the literature.

BACKGROUND: Persistent peripheral blood hypereosinophilia may cause tissue damage, leading to hypereosinophilic syndrome (HES) with end-organ dysfunction. Here we discuss two unique pediatric cases of primary hypereosinophilic syndrome with oncologic etiologies to highlight the importance of early recognition, workup and treatment of HES. CASE 1: A previously healthy 7-year-old male presented with acute myocardial infarction and transient ischemic attack and found to have significant hyperleukocytosis with a total white blood count of 131 000 and hypereosinophilia with an absolute eosinophil count of 99 560. He was ultimately diagnosed with precursor B-cell acute lymphoblastic leukemia with immunoglobulin heavy chain gene rearrangement. He completed standard treatment without significant complications and remains in remission at about 2 years off therapy. He is in overall good health and has normal cardiac function. CASE 2: A 13-year-old female was referred for iron deficiency and reported a history of severe anxiety, shortness of breath and anorexia. She had experienced fatigue and dizziness associated with frequent panic attacks and shortness of breath with strenuous activity since the age of five. Serial laboratory investigations revealed persistent hypereosinophilia (AEC 4000-6000/µl). Additional workup revealed elevated vitamin B12 (>2000 pg/ml; normal range: 243-894) and tryptase (16.4 ng/ml; normal range: ≤10.9). The FIP1L1-PDGFRA gene fusion was detected by fluorescence in situ hybridization (FISH) on peripheral blood, diagnostic for myeloid/lymphoid neoplasm with eosinophilia. Evaluation for end-organ damage associated with persistent hypereosinophilia included an echocardiogram which revealed severe restrictive cardiomyopathy with pulmonary hypertension. Monotherapy with imatinib was initiated, after which she achieved a rapid hematologic response and remains in molecular remission, though she continues to have persistent asymptomatic severe pulmonary hypertension in the setting of severe diastolic dysfunction. CONCLUSION: Persistent hyperosinophilia can be a silent cause of significant and often irreversible tissue damage and should therefore always prompt workup for both primary and secondary causes.

A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group.

BACKGROUND: To estimate the response rate and therapy related toxicities of the anti-CD20 monoclonal antibody rituximab when combined with chemotherapy including ifosfamide, carboplatin, and etoposide (ICE) in patients with relapsed and refractory B-cell non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia (B-ALL). METHODS: Patients received rituximab and ICE for 1-3 cycles, depending upon response. Rituximab (375 mg/m(2)) was given on day 1 and 3 of each cycle (day 1 only for cycle 3), with ifosfamide (3,000 mg/m(2)) and etoposide (100 mg/m(2)) given on days 3, 4, and 5 and carboplatin (635 mg/m(2)) given on day 3 only. RESULTS: Twenty-one patients were enrolled, of whom 20 were eligible and evaluable. Although hematologic toxicities were common, only one patient was removed from study due to prolonged myelosuppression. Toxicities related to infusions of rituximab were frequent but manageable. Of the six eligible patients with diffuse large B-cell lymphoma, three achieved complete remission (CR), one had stable disease (SD), and two had progressive disease (PD). Of the 14 eligible patients with Burkitt lymphoma and B-ALL, there were four complete responses (CR), five partial responses (PR), one SD, and four with PD. Thus, the CR/PR rate for the entire group was 12/20 (60%). Following completion of protocol therapy six patients were able to proceed to consolidation with high-dose therapy and stem cell rescue. CONCLUSIONS: The combination of rituximab and ICE chemotherapy was associated with an encouraging objective response (OR) rate and an acceptable toxicity profile.

A case series of pediatric primary central nervous system lymphoma: favorable outcome without cranial irradiation.

PURPOSE: To describe the outcome of childhood primary central nervous system lymphoma (PCNSL) treated with chemotherapy alone or with chemotherapy plus cranial radiotherapy (CRT). METHODS: Retrospective chart review of children with PCNSL at six tertiary care pediatric centers. RESULTS: Eight immunocompetent and four immunocompromised children were included. Ten children received chemotherapy alone without CRT, with most receiving high-dose methotrexate and high-dose cytarabine. Five year event-free survival (EFS) in this group was 70.0 +/- 14.5%. Two children received chemotherapy plus CRT; one relapsed and died while the other is alive in remission. Three children died, including two from relapsed disease. The other child with human immunodeficiency virus infection died of an opportunistic infection while in remission following chemotherapy alone. CONCLUSIONS: Most children with PCNSL can achieve long-term remissions with chemotherapy alone without CRT. Multi-center prospective studies are needed to confirm or refute these results in a larger number of patients.

A survey of clinical productivity and current procedural terminology (CPT) coding patterns of pediatric hematologist/oncologists.

BACKGROUND: Subspecialty-specific normative values for clinical productivity of practicing pediatric hematologist/oncologists have not been well established. This information could be a useful adjunct in administrative decision-making in areas such as necessary levels of physician staffing and development of compensation plans. METHODS: Current procedural terminology (CPT) coding information was obtained from 27 pediatric hematology/oncology groups. Clinical productivity was assessed by overall number of patient encounters and the total number of physician work relative value units (RVU) as defined by the resource-based relative value scale. The average physician productivity within each individual program was calculated. To determine uniformity of CPT coding, an additional survey solicited mock patient encounter documentation and CPT coding for a simple clinical vignette. RESULTS: A broad range of clinical productivity was observed for both numbers of patient encounters and RVU. Evaluation of the CPT coding data of the surveyed groups revealed differences in usage of certain evaluation and management (E/M) codes and procedural and specimen interpretation codes. Within individual categories of E/M service codes, a wide variation in assigned CPT code levels was also observed. This observation was supported by differences in the E/M coding for the clinical vignette. CONCLUSIONS: Assessment and tracking of physician productivity can provide useful information for the administrative management of pediatric hematology/oncology programs. Caution must be exercised, however, when making productivity comparisons with other subspecialties or even between pediatric hematology/oncology programs. Such comparisons should take into account the number of patient encounters, characteristics of E/M coding patterns, the use of physician extenders, as well as overall RVU production.