A document by Peter Shaw. Click on the document to view its contents.

Abstract Background: Location of cancer care (LOC: pediatric versus adult center) impacts outcomes in adolescents and young adults (AYA) with some cancer types. Data on impact of LOC on survival in AYA with osteogenic sarcoma (OGS) and Ewing sarcoma (EWS) are limited. Objectives: To compare differences in demographics, disease/treatment characteristics, and survival in a population-based cohort of AYA with OGS or EWS treated at pediatric versus adult centers Methods: The IMPACT Cohort captured demographic, disease, and treatment data for all AYA (15-21 years old) diagnosed with OGS and EWS in Ontario, Canada between 1992-2012. Patients were linked to provincial administrative healthcare databases. Outcomes were compared between patients treated in pediatric versus adult centers using appropriate statistical methods. Results: 137 AYA were diagnosed with OGS (LOC: 47 pediatric, 90 adult) and 84 with EWS (LOC: 38 pediatric, 46 adult). AYA treated at pediatric centers were more likely to be enrolled in a clinical trial (OGS 55% vs 1%, [p<0.001]; EWS 53% vs 2%, [p<0.001]) and received higher cumulative chemotherapy doses. Five-year event-free survival (EFS ± Standard Error) in OGS and EWS were 47% ± 4 and 43% ± 5, respectively. In multivariable analysis, the impact of LOC (pediatric vs adult center) on EFS in OGS (adjusted hazard ratio [HR] 1.15, 95% CI 0.58-2.27, P=0.69) and EWS (adjusted HR 1.82, 95% CI 0.97-3.43, P=0.06) were not statistically significant. Conclusion: Outcomes did not differ by LOC suggesting that AYA with bone tumors can be treated at either pediatric or adult centers.

Title: The Practical Matters of Including Patient Reported Outcomes in Pediatric Oncology Clinical CareEmily L Mueller, MD MSc1,2Center for Pediatric and Adolescent Comparative Effectiveness Research, Indiana University, Indianapolis, IN 46202Section of Pediatric Hematology Oncology, Department of Pediatrics, Indiana University, Indianapolis, IN 46202Correspondence:Emily L Mueller, MD, MSc705 Riley Hospital Dr, ROC 4340Indianapolis, IN 46202Cell: 312-399-0245 Fax: [email protected] word count: 0Main text word count: 6654Number of tables: 0Number of figures: 0Short Title: Practicalities of PRO in Clinical CareAbbreviations:

INTRODUCTION Home-based treatment of low-risk febrile neutropenia (FN) in children with cancer with oral or intravenous antibiotics is safe and effective. There are limited data on the economic impact of this model of care. We evaluated the cost-effectiveness of implementing a low-risk FN program, incorporating home-based intravenous antibiotics, in a tertiary pediatric hospital. METHODS A decision analytic model was constructed to compare costs and outcomes of the low-risk FN program, with usual in-hospital treatment with intravenous antibiotics. The program included a clinical decision rule to identify patients at low-risk for severe infection and home-based eligibility criteria using disease, chemotherapy and patient-level factors. Health outcomes (quality-of-life) and probabilities of FN risk classification and home-based eligibility were based on prospectively collected data. Patient-level costs were extracted from hospital records. Cost-effectiveness was expressed as the incremental cost per quality-adjusted life year (QALY). FINDINGS The mean healthcare cost of home-based FN treatment in low-risk patients was A$7,765 per patient compared to A$20,396 for in-hospital treatment (mean difference A$12,632 (95% CI,12,496-12,767)). Overall, the low-risk FN program was the dominant strategy, being more effective (0.0011 QALY (95% CI,0.0011-0.0012)) and less costly. Results of the model were most sensitive to proportion of children eligible for home-based care program. CONCLUSION Compared to in-hospital FN care, the low-risk FN program is cost-effective, with savings arising from cheaper cost of caring for children at home. These savings could increase as more patients eligible for home-based care are included in the program.

Background: Pediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes. Procedure: Survivors who underwent PRT (n=38) or XRT (n=20) participated in a neurocognitive evaluation >1 year post-radiotherapy. Group differences in cognitive and social functioning were assessed using ANCOVA. Regression analyses examined predictors of peer relations and social skills. Results: Age at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p>0.05). However, XRT participants were younger at diagnosis (XRT M=5.0 years, PRT M=7.6 years) and further out from radiotherapy (XRT M=8.7 years, PRT M=4.6 years). The XRT group performed worse than the PRT group on measures of processing speed (p=0.01) and verbal memory (p<0.01); however, social outcomes did not differ by radiation type. The proportion of survivors with impairment in peer relations and social skills exceeded expectation (2(1)=38.67, p<0.001; 2(1)=5.63, p<0.05), and verbal memory approached significance as a unique predictor of peer relations (t=-2.01, p=0.05). Total tumor RT dose significantly predicted social skills (t=-2.23, p<0.05). Conclusions: Regardless of radiation modality, survivors are at risk for social challenges, with one-quarter being socially excluded or undervalued. Deficits in verbal memory may place survivors at particular risk. Results support monitoring of cognitive and social functioning throughout survivorship.

Purpose: The aim of this study was to evaluate the diagnostic accuracy of 18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) and positron emission tomography/computed tomography (PET/CT) in imaging primary and metastatic lesions in Ewing sarcoma (ES). Methods: PubMed, Cochrane, Scopus, and Web of Science were searched for relevant studies. Data concerning 18F-FDG-PET/CT diagnostic accuracy were extracted and then analysed using Open Meta-analyst software. Reported diagnostic accuracy outcomes included sensitivity, specificity, negative likelihood ratio (NLR), positive likelihood ratio (PLR), and diagnostic odds ratio. Results: 31 studies with a total of 735 patients were included in this meta-analysis. The sensitivity and specificity of 18F-FDG PET/CT were: 92.6% and 74.1% for total ES lesions, 96.7% and 68.3% for ES primary lesions, 76.1% and 92.4% for lung metastasis, 83.9% and 93.2% for bone metastasis and 89.9% and 92.6% for ES recurrence respectively. Conclusion: 18F-FDG PET/CT is sensitive and accurate in diagnosing, staging, and detecting the recurrence of ES compared to non-PET imaging. It has high specificity for diagnosing recurrence of ES as well as lung and bone metastases.

A document by Daiane Cecconello. Click on the document to view its contents.

Title Successful treatment with haploidentical PBSCT with post-transplant cyclophosphamide in a child with relapsed neuroblastoma after autologous PBSCT

Objectives. Neuroblastoma is the most common extracranial tumour in children, and prognosis for refractory and relapsed disease is still poor. Early Phase clinical trials play a pivotal role in the development of novel drugs. Ensuring adequate recruitment is crucial. The primary aim was to determine the rate of participation trials for children with refractory/relapsed neuroblastoma in two of the largest Drug Development European institutions. Methods. Data from patients diagnosed with refractory/relapsed neuroblastoma between January 2012 and December 2018 at the two institutions were collected and analysed. Results. Overall, 48 patients were included. A total of 31 (65%) refractory/relapsed cases were enrolled in early Phase trials. The main reasons for not participating in clinical trials included: not fulfilling eligibility criteria prior to consent (12/17, 70%) and screening failure (2/17, 12%). Median time on trial was 4.3 months (range 0.6-13.4). Most common cause for trial discontinuation was disease progression (67.7%). Median overall survival was longer in refractory (28 months, 95% CI, 20.9-40.2) than in relapsed patients (14 months, 95% CI, 8.1-20.1)) [p=0,034]. Conclusions. Although two thirds of children with refractory/relapsed neuroblastoma were enrolled in early Phase trials, recruitment rates can still be improved. The main cause for not participating on trials was not fulfilling eligibility criteria prior to consent, mainly due to performance status and short life expectancy. This study highlights the hurdles to access to innovative therapies for children with relapsed/refractory neuroblastomas and identifies key areas of development to improve recruitment to early phase trials.

Objective: To compare outcomes data of obese and non-obese pediatric patients with acute promyelocytic leukemia from the Cancer and Leukemia Group B trial C9710 and the Children’s Oncology Group trial AAML0631. Methods: Data including demographics, adverse events, overall survival and event free survival was analyzed, with a focus on mortality in obese patients. Results: The incidence of obesity was 34% on C9710 and 35% on AAML0631. There was significantly lower overall survival in the obese population on AAML0631. Thirteen patients died during therapy or in follow up; seven of these occurred during induction. Conclusion: The incidence of obesity is higher in patients with APL compared to the general population. The presence and degree of obesity can influence OS on the most current treatment regimen. This implies the need for close management of obese patients at diagnosis as well as reinforces the need for further research on obesity driven APL

Symptom distress and decreased quality of life (QOL) among children with cancer are well documented. Research is emerging on the child’s voice in QOL-symptom reports, but existing QOL questionnaires are burdensome and objective biologic markers are lacking. We examined children’s symptoms and QOL from parent and child perspectives and compared the results to one biologic marker (body posture). A cross-sectional secondary analysis of prospective data from children receiving creative arts therapy explored potential associations among demographics with and between QOL measures (PedsQL, Faces Scale, posture). Children (n = 98) ranged in age from 3-17 years (M = 7.8) and were in the first year of cancer treatment. No significant associations were found among the child’s sex, race/ethnicity, socioeconomic status (SES), or distance from hospital and total PedsQL. Older age was associated with worse total PedsQL, pain, nausea, worry, and posture (all ps < .05). Greater worry (β = 0.51) and worse posture (β = 0.41) were the QOL variables most strongly correlated with older age. Poorer posture was associated with worse child PedsQL (total score, nausea, treatment anxiety, cognitive) and parent PedsQL (pain, nausea). Worse scores on the Faces Scale, PedsQL, and posture were all correlated (rs = .21 - .39, all ps < .05). Interventions to improve QOL could target nausea, worry, and older patients. Accuracy and interpretation of symptom distress in children is problematic. The Faces Scale and posture may be suitable, readily obtained measures of QOL in pediatric oncology that hold promise.

A document by Cecilia Ugaz. Click on the document to view its contents.

Pyruvate kinase (PK) deficiency is an important cause of hereditary non-spherocytic hemolytic anemia caused by a defect in the glycolytic pathway in red blood cells. PK deficient erythrocytes have impaired ATP production and resultant difficulty maintaining normal cell integrity and function, leading to mild to severe anemia due to increased extravascular hemolysis and splenic destruction. Sequelae of chronic hemolysis can result in severe and occasionally life-threatening complications such as hepatobiliary disease, iron overload, bone and cardiopulmonary disease, as well as often markedly impaired quality of life. While the mainstay of management of PK deficiency involves supportive care, comprehensive screening recommendations and disease modifying therapies in development are likely to significantly improve the management of patients. Here, we provide a case-based comprehensive review of the diagnostic evaluation, complications, monitoring recommendations and management of PK deficiency in children.

Dinutuximab, an immune-mediated therapy used in the treatment of high-risk neuroblastoma targets the protein disialoganglioside (GD2) present on neuroblastoma cells, neurons, and peripheral nerve fibers. Off target effects could lead to severe nerve pain. Pain regimens including continuous infusion opioids are required during the first treatment course. Our institution utilizes a combination of intravenous (IV) lidocaine infusions and morphine for the treatment of dinutuximab-associated neuropathic pain. The primary outcome of this study was to compare morphine equivalents for cycle one of dinutuximab at an institution that uses IV lidocaine (primary) versus those that do not (comparison). Secondary outcomes included both dinutuximab infusion time and safety of IV lidocaine. A retrospective, multi-centered, electronic chart review was performed at three tertiary academic medical centers. Patients between 0-18 years of age during their first course of dinutuximab were included to evaluate the primary outcome of adjuvant morphine equivalents needed. Total morphine equivalents at the primary institution were 1.87 mg/kg vs 1.79 mg/kg at the comparison institutions (p=0.413). Dinutuximab infusion time was significantly lower at the primary institution: 610.5 minutes vs 676.23 minutes (p=0.046). Only one patient at the primary institution experienced nausea, vomiting and paresthesias. This study did not find a statistically significant difference in morphine equivalents between patients who received IV lidocaine and those who did not. However, we did find that use of IV lidocaine resulted in a statistically significant lower dinutuximab infusion time and that it is a safe adjuvant medication in the treatment of dinutuximab-associated neuropathic pain.

Background: Conservative-surgery (CS) brachytherapy (BT) techniques for local therapy in bladder-prostate rhabdomyosarcoma (BP-RMS) seeks to retain organ function. We report bladder function after high-dose-rate (HDR) BT combined with targeted CS for any vesical component of BP-RMS. Procedure: Prospective cohort of all BP-RMS patients between 2014-19 receiving HDR-BT (Iridium-192, 27.5Gy in 5 fractions) with/without percutaneous endoscopic-polypectomy (PEP) or partial cystectomy (PC). Functional assessment included frequency-volume-chart, voided volumes, post-void residual, flow studies, continence status and ultrasound scanning; abnormalities triggered video-urodynamics. Results: Thirteen patients (10 male), aged 9 months to 4 years (median 23 months), presented with localised fusion-negative embryonal BP-RMS measuring 23-140mm (median 43mm) in cranio-caudal extent. After induction chemotherapy, local treatment consisted of PC+BT in three, PEP+BT in four and BT alone in six. At a median 3½ years (range 1¾-7 years) follow up, all were alive without relapse. At a median age of 6 years (4-9 years), the median bladder capacity was 86% (47%-144%) of that expected for age, including 75% (74-114%) after PC. There was no relation to radiation dose to the bladder. Complications occurred in two: one urethral stricture and one vesical decompensation in a patient with pre-existing high-grade VUR. The remaining patients are dry by day; five with anticholinergic medication for urinary urgency. Three patients are enuretic. Conclusions: Day-time dryness at a median 3½ years after CS-HDR-BT was achieved in 92%, with 85% voiding urethrally, and 62% attaining day-and-night continence aged 4-9 years. We report reduced open surgery, with minimally-invasive percutaneous surgery with HDR-BT or brachytherapy alone being suitable for many.

Background: Sedation for lumbar punctures (LPs) in pediatric acute lymphoblastic leukemia (ALL) patients has been the standard for decades to reduce pain and anxiety. Recent studies on the potential long-term neurocognitive effects of cumulative propofol exposure has raised concerns about this practice. The recent pandemic introduced additional burdens to patients, with the requirement of a negative COVID-19 test prior to each sedated procedure. Procedure: These factors prompted a quality improvement intervention at our institution where we aimed to reduce post-Induction sedated lumbar punctures (LPs) by 50%. Our intervention included patient and family education followed by a simulation of the procedure for selected patients. Those converted to unsedated LPs were queried for their preference. Comparative cost, clinical time and LP success rates were collected for sedated and unsedated LPs. Results: Following the intervention, the percentage of LPs performed with sedation dropped from 100% to 48.1%. All LPs were successful using both techniques. Most patients who experienced the unsedated LP technique, and their guardians, strongly preferred this approach. Unsedated LPs significantly reduced clinical time (169 vs 83 minutes) for families, decreased expenditures ($5,736.16 reduction per procedure) and improved institutional opportunity cost due to a decrease in last-minute cancellations. Conclusion: We have shown that it is feasible to significantly reduce the use of sedation for LPs in patients with ALL, which has the potential to improve health and patient experience at a lower cost.

Vaccination is a critical tool in the prevention of COVID-19 infection for individuals and for communities. The mRNA vaccines contain polyethylene glycol (PEG) as a stabilizer. Currently in North America only the BNT162b2 (Pfizer-BioNTech) mRNA vaccine is approved individuals 12 to 17 years of age. Most patients treated with contemporary regimens for acute lymphoblastic leukemia receive Peg-asparaginase and 10-30% will develop allergic reactions. Optimizing access and safety for vaccine administration for these patients critical. This report describes a process developed to support COVID vaccination in a cohort of adolescents and young adults with a history of PEG-asparaginase allergy.

Objective: To evaluate group differences in social adjustment in survivors of pediatric ALL compared to survivor siblings, and controls; identify disease-related predictors of social adjustment in survivors; and explore whether executive functioning explained differences in social adjustment across groups and between disease-related predictors. Methods: Survivors of pediatric ALL (n=38, average age at diagnosis=4.27 years [SD=1.97]; average time off treatment=4.83 years [SD=1.52]), one sibling (if available, n=20), and one parent from each family were recruited from a long-term survivor clinic. Healthy age- and sex-matched controls (n=38) and one parent from each family were recruited from the community. Parents completed the Behavioral Assessment System for Children, Parent Rating Scale (BASC-3) Social Withdrawal subscale as a measure of social adjustment and the Behavior Rating Inventory of Executive Functions (BRIEF-2) as a measure of executive function for each of their children. Results: Parents reported that survivors had significantly worse social adjustment compared to controls (b=6.34, p=.004), but not survivor siblings. Among survivors, greater time off treatment (b=2.06, p=.058) and poorer executive functioning (b=0.42, p=.006) were associated with worse social adjustment. Executive function did not mediate differences in social withdrawal between survivors and controls or the relationship between time off treatment and social withdrawal among survivors. Conclusions: Survivors of pediatric ALL presenting to follow-up programs should be screened for difficulties with social adjustment. Future research should examine treatment- and non-treatment-related factors contributing to poorer social outcomes.