BACKGROUND: Intercostal nerve cryoablation (INC) has shown promise as an adjunct method for analgesia in adults undergoing thoracotomy but has yet to be widely used in children for this indication. We hypothesize that INC decreases opioid utilization in children undergoing thoracotomy for cancer operations. METHODS: A retrospective review was performed of children who underwent thoracotomy for a cancer diagnosis at a freestanding children’s hospital from 2018-2023. Patient characteristics, intraoperative data, and data on clinical course were collected. Patients were divided into those who underwent INC and those who underwent routine care for comparison. RESULTS: Twenty-six patients underwent 38 procedures at a median age of 16 years (range 5-21 years). INC was performed in 23 cases over a median of 5 intercostal levels (range 2-7). Total oral morphine equivalents (OME) during inpatient admission were significantly lower in INC patients (137.6mg versus 514.5mg, p=0.002). Routine care patients were more likely to be discharged with an opioid prescription (30.4% versus 80.0%, p=0.008). Length of stay was similar between patients with INC and routine care (4 versus 5 days, p=0.15). There were no differences in rates of reoperation or 30-day readmission (emergency department (ED) or inpatient). CONCLUSTIONS: INC is a feasible and safe adjunct for children undergoing thoracotomy for cancer. INC is associated with reduced postoperative opioid utilization with respect to both inpatient use and outpatient prescriptions.

Background: Sickle cell disease (SCD) is characterized by vaso-occlusive crises (VOCs), that impair the health-related quality of life (HRQoL). The aim of this study is to evaluate the impact of hospitalization for VOCs on HRQoL in children with SCD over time. Methods: In this longitudinal cohort study, children aged 8-18 years diagnosed with SCD at the Amsterdam UMC were included between 2012 and 2021. HRQoL was annually measured as part of standard care using the Pediatric Quality of Life Inventory. The impact of hospitalization for VOC on HRQoL was evaluated using linear mixed models 3, 6, 9 and 12 months after hospitalization. The effect of frequency of hospitalization for VOC on HRQoL was evaluated over the last 12 months. Results: In total , 94 children with SCD were included with a median age of 11.8 years (IQR 9-14). Thirty-seven patients (39%) had been hospitalized for a VOC. Hospitalization for VOC led to a decrease of 3.2-4.8 points in total HRQoL compared to patients without hospitalization, most pronounced 3 months after hospitalization. Recurrent admission for VOC in the last 12 months was associated with a decrease of 2.3 points in total HRQoL (p=0.04). The most affected subscale was physical functioning. Conclusion: The adverse effects of hospitalization for VOC in children with SCD persist up to 12 months after hospitalization. After hospitalization for VOC, extra attention and support for its negative impact on HRQoL are recommended. This study also underlines the importance of systematically measuring HRQoL allowing clinicians to intervene accordingly.

Background: Multiple studies have now shown that a significant proportion of hemophilia carriers meet criteria for having hemophilia and/or report abnormal bleeding. However, to date, investigations of hemophilia carriers have almost exclusively involved women over 18 years of age. Little is known about factor activity levels and bleeding scores in carriers during childhood. We queried a large deidentified database of subjects with bleeding disorders residing in the United States to determine factor activity levels and bleeding scores. Procedures: The ATHNdataset was queried for hemophilia carriers under 18 years of age. Collected information included demographics, factor activity levels, bleeding scores. Results: Over 700 carriers in the pediatric age group were identified of which 626 submitted factor activity levels. Nearly half had factor activity levels less than 40 IU/dL, thereby meeting criteria for having hemophilia. Of those reporting bleeding scores, only 13.5% reported an abnormal bleeding score for age. The proportion reporting abnormal bleeding scores was higher in those with factor levels less than 40 IU/dL (23%) than those greater than 40 IU/dL (9.7%). Conclusions: The proportion of pediatric carriers with hemophilia was double of that previously reported for adults. Of those with hemophilia reporting a bleeding score, the majority (77%) did not report an abnormal bleeding score for age. However, nearly 10% of pediatric carriers not meeting criteria for having hemophilia reported abnormal bleeding scores for age. Similar results are reported in adults suggesting that factor activity levels may not be predictive of bleeding symptoms in carriers.

Purpose/Objectives: To evaluate dosimetric differences between auto-planned Volumetric Modulated Arc Therapy (VMAT) Total Body Irradiation (TBI) technique and 2D AP/PA TBI technique. Methods: Ten pediatric patients treated with VMAT-TBI on Varian c-arm linac were included in this study. VMAT-TBI plans were generated using our in-house developed and publicly shared auto-planning scripts. For each VMAT-TBI plan, a 2D AP/PA plan was created replicating the institution’s clinical setup with the patient positioned at extended SSD with a compensator to account for differences in patient thickness, 50%-transmission daily lung blocks and electron chest-wall boosts prescribed to 50% of the photon prescription. Clinically relevant metrics were analyzed and compared between the VMAT and 2D plans. Results: All VMAT-TBI plans achieved PTV D90%≥100% of prescription. VMAT-TBI PTV D90% significantly increased (6.2%±2.4%, p<0.001) compared to the 2D technique, whereas no differences were observed in global Dmax (p<0.2) and PTV V110% (p<0.4). Compared to the 2D plans, significant decreases in the Dmean to the lungs (-25.6%±11.5%, p<0.001) and lungs-1cm (-34.1%±10.1%, p<0.001) were observed with the VMAT plans. The VMAT technique also provided additional sparing to other organs: for 12Gy prescription, kidneys Dmean of 64.7%±3.3%; for 2Gy prescription, testes/ovaries (Dmean of 31.6%±10.7%), brain (Dmean of 74.8%±1.6%) and thyroid (Dmean of 72.5±3.5%). Conclusions: Superior lung sparing with improved target coverage and similar global Dmax were observed with the VMAT plans as compared to 2D plans. In addition, VMAT-TBI plans provided greater dose reductions in gonads, kidneys, brain, and thyroid.

A document by Clifford Takemoto. Click on the document to view its contents.

A unique case of hybrid SEF-LGFMS with a EWSR1-CREB3L1 Fusion and robotic-assisted bronchoscopy in an 11-year-old Authors: Leore Lavin, MS1*, Nithya Krishnamurthy, BA1*, Chantal Spencer Grant, MD2, Kayleen Bailey, MD3Affiliations : 1Icahn School of Medicine at Mount Sinai, 2Mount Sinai Hospital Department of Pediatric Pulmonology, 3Mount Sinai Hospital Department of Pediatric Hematology-Oncology* Both authors contributed equally to this workCorresponding author: Leore Lavin,[email protected] East 98th St. New York, NY 10029. 646-709-8909.Running title: Rare pediatric SEF-LGFMS with EWSR1-CREB3L1 FusionKeywords: Robotic Bronchoscopy, Pediatric Oncology, SEF, LGFMS, EWSR1, CREB3L1Abbreviations:

Mixed Phenotype Acute Leukemia with BCL11B Copy Gain: What is the Best Strategy? Keri Toner MD1, 2, Reuven Schore MD1,2 and Jinjun Cheng MD PhD1,3,4*Center for Cancer and Blood Disorders, Children’s National Hospital, Washington, DCDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USADivision of Pathology and Laboratory Medicine, Children’s National Hospital, Washington, DCDepartments of Pathology and Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA

Background: Characterize indications for pediatric palliative-intent proton radiation therapy (PIPRT). Procedure: We retrospectively reviewed patients ≤21 years who received PIPRT. We defined PIPRT as radiotherapy (RT) aimed to improve cancer related symptoms/provide durable local control in the non-curative setting. Mixed proton/photon plans were included. Adjacent reirradiation (reRT) was defined as a reRT volume within the incidental dose cloud of a prior RT target, whereas direct reRT was defined as in-field overlap with prior RT target. Acute toxicity during RT until first inspection visit was graded according to the Common Terminology Criteria for Adverse Events. The Kaplan-Meier method, measured from last PIPRT fraction, was used to assess progression free survival (PFS) and overall survival (OS). Results: 18 patients underwent PIPRT between 2014-2020. Median age at treatment start was 10 years (2-21). Median follow up was 8.2 months (0-48). Treatment sites included: brain/spine (10), abdomen/pelvis (3), thorax (3) and head/neck (2). Indications for palliation included: durable tumor control (18), neurologic symptoms (4), pain (3), airway compromise (2), and great vessel compression (1). Indications for protons included: reRT (15) (4 adjacent, 11 direct), craniospinal irradiation (4), reduction of dose to normal tissues (3). 16 experienced grade (G) 1-2 toxicity; 2 G3. There were no reports of radionecrosis. Median PFS was 5.3 months (95% CI 2.7-16.3). Median OS was 8.3 months (95% CI 5.5-26.3). Conclusions: The most common indication for PIPRT was reRT to provide durable tumor control. PIPRT appears to be safe, with no cases of high grade toxicity.

LETTER TO THE EDITOR

Title: Emerging Therapeutic Options for Sickle Cell Anemia: Enhancing the Current Predominant Treatment

Comment on: Viral infections in pediatric brain tumor patients treated with targeted therapiesAimen Waqar KhanDepartment of Medicine, Jinnah Sindh Medical University, Karachi, PakistanDear Dr. Newburger,We have read with great enthusiasm the article titled Viral infections in pediatric brain tumor patients treated with targeted therapies by Lisa Mayr et al [1]. We commend the authors’ efforts in collating epidemiologic data and investigating infectious outcomes between pediatric patients being treated with targeted therapy versus conventional therapies. It was a pleasure to read such a well-written paper. We concur with the conclusion that patients receiving targeted therapies are made more susceptible to developing viral infections than those receiving conventional treatment. However, we would like to draw attention to some key points regarding the study following a thorough appraisal.To begin with, the retrospective nature of the study adds several unavoidable biases such as recollection bias and incorrect data retrieval, which may have been mitigated had the investigators included current cases at the time. The study is also limited in its single-centered scope making it difficult to generalize the findings to this particular pediatric demographic. Moreover, the comparison between the two subsets of brain tumor patients is also subject to several partialities. For instance, it is noted that those receiving targeted therapies were managed in an outpatient setting and by extension, exposed to greater environmental stressors than those being managed on conventional chemotherapy. As a result, a greater proportion of virological infections were reported in children receiving targeted therapy than those being managed conventionally. Further, due to the lack of available data correlating disease severity with treatment option, the possibility that patients receiving conventional chemotherapy simply had a lower disease grade than those on targeted therapies and vice versa exists. Knowing this is pertinent as the body’s ability to fight off infections is greatly influenced by the grade of cancer and hence degree of inflammation [2]. Next, it remains to be seen what the baseline nutritional status of the participants was as nutrition and metabolism are known to have a bearing on immune status and hence infectious susceptibility [3]. Finally, the deduction that patients treated with bevacizumab or mTOR (mechanistic target of rapamycin) inhibitors suffered more infections than those treated with other targeted therapeutic drugs cannot be made with certainty as not enough patients were treated with drugs other than bevacizumab or mTOR inhibitors for a fair and accurate comparison.In conclusion, multi-centered prospective studies are required to better lay claims regarding infectious outcomes and attention to potential influencers of immunity must be given to minimize bias in future studies.

Calcineurin inhibitors (CNI), cyclosporine and tacrolimus, are commonly used for pharmacotherapeutic prophylaxis of Graft-vs.-Host disease after hematopoietic cell transplantation (HCT). Unfortunately, their use is associated with significant toxicities. While intolerance to CNI is well defined, there is very little data on how they impact outcomes after HCT in children. Our retrospective study in a cohort of 82 children, shows a high intolerance rate of 39% in this population associated with lower event free survival and a higher transplant-related mortality.

Background: Methotrexate is widely recommended as a first-line treatment for the intensive systemic and consolidation phases of childhood acute lymphoblastic leukemia. However, methotrexate-induced nephrotoxicity is a severe adverse reaction, of which the mechanism remains unclear. Methods: An untargeted metabolomics analysis of serum from childhood acute lymphoblastic leukemia with delayed methotrexate excretion with or without acute kidney injury was performed to identify altered metabolites and metabolic pathways. An independent external validation cohort and in vitro assays further confirmed the candidate metabolites and the mechanisms underlying the nephrotoxicity of methotrexate. Results: Four metabolites showed significant differences between normal excretion and delayed excretion, seven metabolites reflected the differences between groups with or without acute kidney injury, and six pathways were finally enriched. In particular, oxidized glutathione is confirmed as an candidate metabolite involved in the toxicity of methotrexate. Based on the depletion of glutathione mediated cell death, it was found that methotrexate overload significantly reduced cell viability, triggered reactive oxygen species and intracellular Fe 2+ accumulation, and altered the expression of ferroptosis-related proteins in HK-2 cells. These methotrexate-induced changes were alleviated or reversed by the administration of a ferroptosis inhibitor, further suggesting that ferroptosis promoted methotrexate-induced cytotoxicity in HK-2 cells. Conclusions: Our findings revealed complex metabolomic profiles and provided novel insights into the mechanism by which ferroptosis contributes to the nephrotoxic effects of methotrexate.

Gorham-Stout disease (GSD) and generalized lymphatic anomaly (GLA) are subtypes of complex lymphatic malformations (CLMs) with osseous involvement that cause significant complications in children, including pain and pathologic fractures. Mutations in cellular growth pathways are common, and the mTOR inhibitor sirolimus alleviates symptoms in some, but not all, patients. We describe two patients, one with GSD and one with GLA, who were found to have EML4::ALK fusions. This report of a targetable, oncogenic fusion in vascular malformations expands our understanding of the genetic basis for CLMs and suggesting additional targeted therapies could be effective.

In optic pathway glioma (OPG), bevacizumab-based therapy (BBT) has promising effects on radiographic tumor burden, but impact on vision is less clear. This single-institution study characterized visual acuity (VA) and visual field (VF) outcomes in 17 pediatric OPG patients treated with BBT. VA was stable or improved in 14 patients. Nine patients had evaluable VF data, 6 of whom experienced stability or improvement. Among 6 patients with vision deterioration as a treatment indication, stable or improved was observed for both VA and VF in 5 patients. In summary, BBT was associated with favorable visual outcomes in most patients with OPG.

Stroke in Sickle Cell Revascularization Surgery Retrospective Study (SiSCRS) in this issue reports retrospective data from 15 medical centers to examine the benefit of cerebral revascularization surgery (CRS) in children with sickle cell disease (SCD) who also have Moyamoya Syndrome (SCD-MMS). The American Society of Hematology guidelines “suggests evaluation for revascularization surgery in addition to regular blood transfusion” for treating SCD-MMS combined with a history of stroke or transient ischemic attack but categorizes this as a “conditional recommendation based on very low certainty in the evidence about effects”. The research presented in this article is aimed at reducing the uncertainty surrounding revascularization surgery as a treatment using retrospective data from 15 medical centers with expertise in CRS for SCD-MMS. Even with the 78 children with CRS (Surgery group) and 63 children in the non-surgery (Conservative group), the differences between the two groups had mixed statistical significance in multivariate analyses. SiSCRS is an important retrospective analysis but must be interpreted with caution. The benefit of CRS attains statistical significance only in some of the comparisons. The rate of stroke in pediatric SCD decreases with age, creating a bias in favor of the older group (i.e., the Surgery Group) to have fewer CVEs, The additional role of aspirin and the bias of patient selection for surgery also weaken the ability to make definitive statements. The SiSCRS results suggest a likely retrospective benefit of CRS, but the benefit must be demonstrated with more rigorous studies in the future.

Lactate dehydrogenase reflects the status of ultra-high-risk neuroblastoma in a child under treatmentAkinori Yaguchi, Junya Fujimura, Ayane Yakabe, Megumi Fujiwara, Takeshi Ishibashi, Osamu Tomita, Toshiaki ShimizuDepartment of Pediatrics, Juntendo University Faculty of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

Background Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression. Procedure The Children’s Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug reinduction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m 2/dose) was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently combined with reinduction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) followed by an expansion pharmacokinetic (PK) cohort. Results Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m 2/dose orally for 21 days. No additional DLTs were observed in the dose determination or PK expansion cohorts and overall rates of grade 3/4 non-hematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. Conclusions Palbociclib in combination with reinduction chemotherapy was well tolerated with a RP2D of 50 mg/m 2/day for 21 days. Complete responses were observed among heavily pretreated patients.