Purpose: Craniospinal irradiation (CSI) has historically treated the entire vertebral body (VB) in growing children. Vertebral body sparing proton craniospinal irradiation (VBSpCSI) is a technique which spares the majority of the VB from significant irradiation. This retrospective study reviews the acute toxicity of VBSpCSI compared to photon CSI. Methods: Pediatric CSI patients treated between 2008 and 2018 were evaluated. Patients were stratified to the VBSpCSI cohort or the photon cohort and analyzed for acute toxicity profile during treatment and disease-free survival (DFS). Statistical analysis was performed using Kaplan-Meier log rank analysis for DFS and Fisher’s exact test for toxicity. Results: Twenty-five patients received VBSpCSI and 13 patients received photon CSI. Mean patient age at treatment was 7.5y (range 2 to 16). The cohorts were well-matched with respect to gender, age, and CSI dose. Two-year DFS was similar between cohorts (81% VBSpCSI vs 61% photon, p=0.18). Patients receiving VBSpCSI had lower rates of grade 2+ GI toxicity (24% vs 76.5%, p=0.005), grade 2+ nausea (24% vs 61.5%, p=0.035), and any-grade esophagitis (0% vs 38%, p=0.0026). Patients treated with VBSpCSI had lower red blood cell transfusion rates (21.7% vs 60%, p=0.049) and grade 4+ lymphopenia (33.3% vs 77.8%, p=0.046). Conclusions: VBSpCSI in children is a volumetric de-escalation from traditional volumes which irradiate the entire vertebral body. Based on our results, VBSpCSI was associated with less acute gastrointestinal and hematologic toxicity. The study adds to the growing body of evidence supporting the use of protons over photons for pediatric CSI.

Background: Clear cell sarcoma (CCS), epithelioid sarcoma, and synovial sarcoma are rare tumors historically identified as high risk for lymph node metastasis. Nodal metastasis in adults with these subtypes has been described. This study investigates incident nodal metastasis and associated survival in children with these subtypes. Procedure: Using the National Cancer Database (2004-2015), we created a retrospective cohort of 1303 patients (aged ≤25 years) who underwent local control therapy for CCS, epithelioid sarcoma, and synovial sarcoma. Kaplan-Meier curves estimated overall survival (OS) by subtype. Stratifying on subtype, Cox regressions assessed OS by lymph node sampling status and nodal metastasis. Results: There were 103 (7.9%) patients with CCS, 221 (17.0%) with epithelioid sarcoma, and 979 (75.1%) with synovial sarcoma. Lymph node sampling was more frequent in patients with CCS (56.3%) and epithelioid sarcoma (52.5%) versus synovial sarcoma (20.5%, p<0.001). Synovial sarcoma metastasized to lymph nodes less frequently than CCS or epithelioid sarcoma (2.2% vs. 14.6% and 15.0%, p<0.001). Across all subtypes, lymph node metastasis was associated with inferior OS (HR 2.10, CI 1.44-3.07, p<0.001). Lymph node sampling was associated with improved OS in CCS (HR 0.35, CI 0.15-0.78, p=0.010), inferior OS in synovial sarcoma (HR 1.60, CI 1.13- 2.25, p=0.007), and no statistical association with OS in epithelioid sarcoma. Conclusions: Lymph node metastasis is rare in children with synovial sarcoma. Lymph node sampling procedures were not consistently performed for patients with CCS or epithelioid sarcoma, but improved OS supports routine lymph node sampling in children with CCS.

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: The prognosis of metastatic hepatoblastoma remains poor; to improve it, pulmonary metastasis must be controlled. Indocyanine green (ICG) fluorescent imaging has been used recently for lung metastasectomy. The objective of our study was to clarify the usefulness of ICG imaging for lung metastasectomy of hepatoblastoma using detailed clinicopathological analysis. Procedure: Patients with hepatoblastoma who underwent resection of pulmonary metastases with ICG fluorescent imaging were studied using retrospective analysis of clinical information, a review of their surgical records, and a histological analysis of their metastatic nodules. Results: Sixteen patients were enrolled. In total, 61 ICG-imaging-guided pulmonary metastasectomies were performed, and 350 ICG-positive and 23 ICG-negative specimens were identified. Tumors were confirmed in 250 of the ICG-positive specimens, including eight nonpalpable nodules, on microscopic examination. One hundred ICG-positive specimens and histologically tumor-negative specimens showed histological changes suggesting the regression of a tumor or bloodstream disturbance. The palpable ICG-negative tumors showed more-severe atypia than the ICG-positive tumors. Conclusions: This study demonstrates the high sensitivity of ICG imaging in detecting metastatic lesions of hepatoblastoma. Histological examinations suggested that ICG imaging detects not only tumor cells, but also nontumorous pulmonary tissues affected by bloodstream disturbance. Because a number of false-positive specimens were detected, further optimization of the dose of ICG and the timing of its administration may be required for thorough metastasectomy. Several false-negative specimens were also detected, suggesting the presence of ICG-negative metastatic tumors. Palpation during operation and imaging studies remain essential for detecting metastatic lesions, even in the era of ICG imaging.

Background: While rare in children, chylothorax is a significant cause of respiratory morbidity and can lead to malnutrition and immunodeficiency. Historically, the traditional pharmacological treatment has been octreotide. There are several treatments that have been utilized in the past few years including sirolimus, however data regarding their efficacy and outcomes is limited. Furthermore, sirolimus has proven efficacy in complex vascular malformations, and hence, its utility/efficacy in pediatric chylous effusions warrants further investigation. Methods: In this retrospective study at Texas Children’s Hospital, data were extracted for all patients with chylothorax who were treated with sirolimus between 2009 and 2020. Details regarding underlying diagnosis, co-morbidities and number of days from sirolimus initiation to resolution of effusion were collected. Descriptive statistics were used to analyze the study cohort. Results: Initially a total of twelve infants were identified. Among them, seven patients had complete data and were included in the study. The mean duration of sirolimus treatment needed for chest tube removal was 16 days, with a median of 19 days and range of 7- 22 days. Chest tube output corresponded with sirolimus serum trough levels and trended down prior to chest tube removal. Conclusion: With close monitoring, sirolimus is a safe and effective therapy for pediatric lymphatic effusions even in critically-ill infants. The study also demonstrates shorter duration of chest tube requirement after initiation of sirolimus compared to previous studies. Our conclusion is based on a small case series due to the rare incidence of the condition.

Background Mature aggressive B-cell lymphoma are heterogenous malignancies that make up more than half of all diagnosed Non-Hodgkin lymphoma in children and adolescents. The overall survival rate increased over the last decades to 80–90%, due to fine tuning of polychemotherapy. However, new therapeutic implications are needed to further increase the overall survival. Current clinical trials analyze the therapeutic effect of rituximab in pediatric patients, while the mechanism of action in vivo is still not fully understood. Methods Effector molecules important for tumor defense were analyzed before and at day five after rituximab treatment via flow cytometry. Serum rituximab levels were measured with an ELISA. Results We evaluated patient parameters that may affect treatment response in relation to rituximab administration and serum rituximab levels. We indeed found a reduction of FcγRII levels after rituximab treatment in monocyte subtypes, while FcγRI expression was significantly increased, pointing to exhaustion of FcγRII mediated B cell depletion and compensation via FcγRI mediated trogocytosis. Serum levels of proinflammatory marker proteins S100A8/A9 and S100A12 significantly decreased after treatment to normal levels from an overall proinflammatory state before treatment. CD57, perforin and granzyme B expression decreased after treatment, probably due to exhaustion of NK cells. Conclusion The highlighted effects of rituximab treatment on patient’s immune response help understanding the biology behind tumor defense mechanisms and effector function. After subsequent studies, these novel insights might be translated into patient care and could contribute to improve treatment of pediatric patients with mature aggressive B-cell lymphoma.

Background: Outcome of children with bladder-prostate rhabdomyosarcoma has improved with multimodal therapies, including surgery and/or radiotherapy for local treatment. Our aim was to report the long-term urological complications after a conservative approach combining conservative surgery and brachytherapy. Patients and methods: Eighty-six patients, free of disease, were retrospectively reviewed. Symptoms related to urinary tract obstruction, incontinence, infection and lithiasis were reported and graded according to CTCAE classification. Only symptomatic patients underwent urodynamic studies. Risk factors for complications were analyzed. Results: There were 76 males and 10 females. The median follow-up was 6.3 years (18 months-24 years). Complications occurred after a median follow up 5 years (0-21). Twenty-two patients had long-term urological complications. Urinary tract obstruction was found in 15 patients, urinary incontinence in 14 patients. Recurrent urinary tract infection and urinary lithiasis were found in 5 patients respectively. Beyond symptom, 3 etiologies were identified: bladder dysfunction in 15 patients, urethral stenosis in 6 and uretero-vesical junction stenosis in 5. Posterior bladder wall dissection used in large prostatic tumors, operation at age less than 2 years and partial prostatectomy were identified as risk factors for these complications. Conclusion: The conservative surgical approach combined with brachytherapy for BPRMS leads to long-term urological complications in 22% of patients free of their disease. Optimizing brachytherapy doses for young children and establishing a clear and long term follow-up protocol, could help to reduce these complications.

Supraclavicular Lymphadenopathy after COVID-19 vaccinationKelsey Larkin 1, Archana Sharma DO2, Richard Drachtman MD,2, Gratian Salaru , MD31 Robert Wood Johnson Medical School2Division of Pediatric Hematology, Rutgers Cancer Institute, Robert Wood Johnson Medical School3Department of Pathology, Robert Wood Johnson Medical SchoolCorrespondence to Archana Sharma, DO, Rutgers Cancer Institute of NJ, 195 Little Albany Street, Room 3507, New Brunswick, NJ 08901.Telephone: 732-235-8864Sharmaar@cinj.rutgers.eduText Word Count: 974Brief running title: Lymphadenopathy after COVID-19 vaccination.Key words: lymphadenopathy, COVID-19, vaccine,Images: 2

TITLE PAGEManuscript title: Isolated neutropenia preceding acute lymphoblastic leukemia in children

LETTER TO THE EDITOR

OBJECTIVE  To determine the overall survival (OS) and prognostic factors influencing outcomes in children and adolescents with malignant extracranial germ cell tumours (MEGCTs) in preparation for the development of a harmonised national treatment protocol.METHODS A retrospective folder review was undertaken at nine South African paediatric oncology units to document patient profiles, tumour and treatment-related data and outcomes for all children with biopsy proven MEGCTs from birth up to and including 16 years of age. RESULTS Between 1 January 2000 and 31 December 2015, 218 patients were diagnosed with MEGCTs. Female sex (HR 0.284 p=0.037) and higher socio-economic status (SES) (HR 0.071; p=0.039) were associated with a significantly lower risk of death. Advanced clinical stage at diagnosis significantly affected 5-year OS: stage I -96%; stage II - 94.3%; stage III -75.5%; (p=0.017) and stage IV (60.1%; p<0.001). There was a significant association between earlier stage at presentation and higher SES (p=0.03). Patients with a serum AFP level of more than 33,000 ng/ml at diagnosis had significantly poorer outcomes (p=0.002). The use of chemotherapy significantly improved survival, irrespective of the regimen used (p<0.001). CONCLUSIONS The cohort demonstrated a 5-year OS of 80.3% with an EFS of 75.3%. Stage, the use of chemotherapy and an elevated serum AFP level of more than 33,000ng/ml were independently predictive of outcome. The relationship between SES and outcome is important as the implementation of the new national protocol hopes to standardise care across the socio-economic divide. 

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

Background: Maintaining dose-dense, interval-compressed chemotherapy improves survival in Ewing sarcoma patients but is limited by myelosuppression. Romiplostim is a thrombopoietin receptor agonist that may be useful in the treatment of chemotherapy-induced thrombocytopenia (CIT). Methods: Patients aged between 3 and 33 years with Ewing sarcoma from 2010-2020 were reviewed. CIT was defined as a failure to achieve 75,000 platelets per microliter by day 21 after the start of any chemotherapy cycle. Fisher exact test was used for univariate analysis and Pearson’s correlation coefficient was used for the association between continuous variables. Results: 27 out of 42 patients (64%) developed isolated CIT, delaying one to four chemotherapy cycles per patient. CIT occurred during consolidation therapy in 24/27(88.9%) and with ifosfamide/etoposide cycles in 24/27 (88.9%). Univariate analysis failed to identify risk factors for CIT. The use of radiation approached significant (p value=0.056). Ten patients received romiplostim. The median starting dose was 3 (range 1-5) mcg/kg. Doses were escalated weekly by 1-2 mcg/kg to 4-10 mcg/kg and continued throughout chemotherapy. A higher romiplostim dose was associated with a higher change in average platelet counts from baseline r= 0.73 (p=0.04). No romiplostim-related adverse events were identified aside from mild headache. Conclusions: CIT is the primary reason for the inability to maintain treatment intensity in Ewing sarcoma. The concurrent use of romiplostim with chemotherapy is safe and feasible, and efficacy was associated with higher romiplostim doses.

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.

Background: Childhood acute lymphoblastic leukemia (ALL) treatment requires numerous lumbar punctures (LPs) with intrathecal (IT) chemotherapy to prevent and treat central nervous system disease. Historically, LPs in this setting are performed using propofol sedation. At our institution, LPs are often alternatively performed under nitrous oxide (N2O). To date, there have been no large scale assessments comparing these sedation methods for this purpose. Procedures: Retrospective cohort study of patients aged 0-31 years with ALL treated between 1/1/2013-12/31/2018 at the Children’s Minnesota Cancer and Blood Disorders Center, including all therapeutic LPs performed in the clinic setting under either propofol or N2O. Results: Among 215 patients and 2677 therapeutic LPs, 56.6% (n = 1515) occurred under N2O with 43.3% (n = 93) of patients using exclusively N2O with all LPs. The incidence of traumatic LPs (RBC ≥ 10 cells/µL) were similar between both treatments (27.3% vs 30.2). Successful IT chemotherapy delivery (99.7% N2O vs 99.8% propofol) did not differ between sedation types. Experiencing a traumatic LP under N2O was associated with a sedation switch for the subsequent LP (aOR 2.40, p=0.002) while older age (aOR 1.08, p<0.0001) and higher BMI percentile (aOR 1.01, p=0.009) were associated with increased likelihood for undergoing a traumatic LP. Conclusion: N2O is an effective sedation option for therapeutic LPs in children with ALL with noninferiority to propofol in terms of IT chemotherapy administration and traumatic LP incidence. For many patients, N2O can effectively replace propofol during LP procedures, which has important safety and quality-of-life implications.

Background: Postoperative hypocalcemia is a frequent complication after thyroid surgery. Hypoparathyroidism may develop as transient (TtHP), with normalization within six months from surgery, or permanent (PtHP) if the patient requires replacement therapy. The present study analyzes rates and factors associated with the development of TtHP or PtHP following thyroid surgery in a pediatric population. Procedure: A retrospective multicenter study analyzing 363 patients was carried out. We recorded gender, age, tumor size, type of surgery, lymph node dissection, histology. Calcium levels were acquired daily for 72 hours after discharge. Subsequent sample collection was customized on the patient’s hypocalcemia severity. Results: We analyzed 363 patients aged ≤18 years (mean age 14.2 years) who underwent thyroid surgery clustered into age groups (≤15 or >15). Patients mean follow-up was 5.8 years (1-11yrs). At histology 310 (85%) were papillary carcinoma, 32 (9%) were follicular carcinoma, 6 (2%) presented diffuse sclerosing variant of papillary thyroid carcinoma whilst 15 (4%) had familial medullary carcinoma. TtHP developed in 36 (9,9%), PtHP in 20 (5.5%) cases. TtHP was more frequent in younger patients (p=0,009). Both PtHP and TtHP were increased in case of larger tumors (≥2 cm) (p=0,001). All TtHP and PtHP were in TT group. PtHP rate was increased if lymph node dissection was carried out (p<0.001). Conclusions: The risk of hypoparathyroidism is related to younger age, tumor size, TT and lymph node dissection therefore surgeons should tailor surgery as much as possible to avert such complication.

While treatment protocols for Hodgkin Lymphoma (HL) are well established, there is no literature available to guide therapy or estimate prognosis for patients with Fontan physiology who develop HL. The physiology of a Fontan procedure can result in the inability to tolerate chemotherapy toxicities, supportive care and infection. We present a series of 3 patients with Fontan physiology who were treated for HL and discuss their clinical course and treatment.

Title PageComment on ” Ototoxicity in Pediatric Hematopoietic Stem Cell Transplantation with High-Dose Carboplatin: Identifying Modifiable Risk Factors through the Inclusion of Younger Patients” Authors:Rachana Mehta, MSc 1 1 Clinical Microbiology, RDC, Manav Rachna International Institute of Research and Studies, Faridabad, Haryana 121004, India. Email: rachanamehta0909@gmail.comRanjana Sah, MD 2,32 Department of Paediatrics, Dr. D. Y. Patil Medical College Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth (Deemed-to-be-University), Pimpri, Pune – 411018, Maharashtra, India.3 Department of Public Health Dentistry, Dr. D. Y. Patil Dental College Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth (Deemed-to-be-University), Pimpri, Pune – 411018, Maharashtra, India. Email: ranjanasah384@gmail.com*Corresponding Author: Rachana Mehta, MScClinical Microbiology, RDC, Manav Rachna International Institute of Research and Studies, Faridabad, Haryana 121004, India Email:  rachana.mehta0909@gmail.comKey words: Ototoxicity, Pediatric HSCT, Carboplatin, Furosemide, Modifiable Risk FactorsWord count: 415Reference count: 4Tables and figure count: 0Statements and Declarations:Declaration of Funding:  No funding was received for this study.Declaration of Financial Interests:  The authors declare no financial interests relevant to this study.Declaration of Non-Financial Interests:  The authors declare no non-financial interests relevant to this study.Ethical Approval:  Not required.Clinical Trial Registration Details/Number:  Not applicable, as this study does not report a clinical trial.Research Registry Number:  Not applicable.Human Ethics and Consent to Participate Declarations:  Not applicable as no patient data were collected or analyzed in this commentary.Generative AI Use Statement:  Generative AI tools, including Paperpal and ChatGPT-4o, were utilized solely for language refinement, grammar enhancement, and stylistic refinement. These tools had no role in the conceptualization, data analysis, interpretation of results, or substantive content development of this manuscript. All intellectual contributions, data analysis, and scientific interpretations remain the sole work of the authors. The final content was critically reviewed and edited to ensure accuracy and originality. The authors take full responsibility for the accuracy, originality, and integrity of the work presented.Data Availability Statement:  Not applicable as no data was generated or analyzed in this study.CRediT Author Statement:Rachana Mehta:  Conceptualization, Methodology, Writing—Original Draft, Writing—Review & Editing.Ranjana Sah: Validation, Supervision, Project Administration, Writing—Original Draft, Writing—Review & Editing.Manuscript