POLE codes for DNA polymerase epsilon (Pol ε) and variants of Pol ε catalytic subunit 1 can be pathogenic. We recently reported a novel POLE gene variant (p.[D1131fs];[T1891del]) which leads to bone marrow failure in two Japanese sisters. Here, we describe the successful course of hematopoietic stem cell transplantation of these two sisters. Both cases were born with congenital anemia and remained transfusion dependent. Their bone marrow showed gradually proceeding trilineage dysplasia. They both underwent HCT from an unrelated bone marrow donor and successfully achieved engraftment. Ten and eight years have passed respectively, and they are doing well without transfusion.

The AYA gap for rhabdomyosarcomaSimone Hettmer1 and Lars H. Lindner2Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.Department of Medicine III, LMU University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.To whom correspondence should be addressed. Email: [email protected]. Phone: +49 761 270-45140; Fax: +49 761 270-4518Cancer is the leading cause of death among adolescents and young adults (AYAs). Cancers diagnosed during the AYA period - defined by the National Cancer Institute as the age from 15 to 39 years - account for approximately 5% of all cancers [1]. As per the national report on the status of cancer (study period 2015-2019, [1]), 5-year relative survival rates for both children and AYAs suffering from cancer are high (85.1% for children and 85.8% for AYAs), and improvements in survival over time appear to be similar for both age groups [1]. Yet, the spectrum of cancer types diagnosed in AYAs varies widely. The most common malignancies are female breast cancer (15%), thyroid cancer (15%), testicular cancer (8%) and melanomas (7%) [1], but AYAs may also suffer from so-called pediatric cancers with peak incidence during childhood. When compared to their childhood counterparts, worse outcomes were reported for AYAs diagnosed with pediatric cancers, including but not limited to leukemias [2] and sarcomas [3]. This „AYA gap“ is of concern to both pediatric and adult oncologists.The accompanying paper by Harrison et al examines a cohort of 2151 patients with rhabdomyosarcomas (RMS) enrolled in consecutive Children’s Oncology Group (COG) trials, including 19% AYAs aged 15-39 years and 81% children aged 0-14 years [4]. Compared to children with RMS, AYAs experienced significantly lower 5-year event-free survival (EFS; 44% vs. 67%) and 5-year overall survival (OS; 52% vs. 78%). These observations are in line with a recent retrospective analysis of nearly 2000 patients treated on European paediatric Soft Tissue Sarcoma Group (EpSSG) protocols [3]. Importantly, relative survival of AYAs with RMS treated on EpSSG and COG protocols appears to be better [3, 4] than the survival observed in epidemiological studies such as EUROCARE-5 (39,6% 5-year relative survival among RMS patients aged 15–19 years, and 36·4% for those aged 20–39 years; study period 2000-2007 [5]). Survival benefits for AYA patients treated on pediatric RMS protocols are consistent with previous observations in AYAs receiving treatment according to pediatric acute lymphoblastic leukemia (ALL) protocols [2] or at pediatric cancer centers/ sites with pediatric oncology expertise [6]. AYA cancer patients appear to benefit from chemotherapy dose intensities higher than what is generally prescribed to older patients. They may also draw advantages from pediatric standards with respect to planning of multimodal treatment and cancer staging. For example, the bone marrow (rarely ever involved in adult-type soft tissue sarcomas (STS)) is the most frequent site of metastases in AYAs with RMS treated within the COG cohort reported by Harrison et al [4] and should always be considered when planning pre-treatment examinations of AYAs with RMS. All taken together, adult oncology providers of AYA patients with RMS are well advised to consult their pediatric oncology colleagues and/ or consider referral to an institution with pediatric oncology expertise.AYA cancer patients treated on pediatric protocols – including those suffering from RMS - still experience worse outcomes than their pediatric counterparts [2]. There is ample evidence to support higher risk biology, more aggressive clinical phenotypes and higher rates of early treatment failures in AYAs diagnosed with pediatric cancers – including leukemias andsarcomas- compared to children diagnosed with the same malignancies [2-4]. For RMS tumors, higher rates of alveolar histology tumors and metastatic disease in AYAs were observed in the COG cohort reported here [4], as well as in the EpSSG and other retrospective studies [3, 7]. In addition to higher-risk disease manifestation, more frequent treatment-related toxicities and higher rates of withdrawal from treatment contribute to worse outcomes of AYAs compared to children with cancer [2]. There is a direct association between age and treatment-related deaths for patients undergoing ALL treatment on pediatric protocols [2]. Harrison et al do not comment on differences in treatment-related toxicities between children and AYAs with RMS, but higher rates of vincristine neurotoxicity, nausea and pain were previously reported in older adolescents undergoing RMS treatment on pediatric protocols. Even in the absence of higher-grade toxicities, a high burden of low-grade adverse events can have a major impact on the ability to function in daily life, continue education, maintain employment or participate in social activities. Many AYAs with cancer need to rely more on their parents/ support persons, which threatens their age-appropriate strive for autonomy and may result in them rebelling against treatment recommendations or failing to self- manage complex medication plans [8]. Active involvement of AYAs in the development of a care plan, which considers dignity, normalcy and family/ social relationships may improve compliance and, ultimately, treatment success.RMS is the most common STS in children and adolescents and often referred to as a pediatric cancer. Nevertheless, it occurs at any age, and up to 40% of all cases are diagnosed in adults (including seniors) [9]. The molecular and histological heterogeneity of pediatric RMS was studied intensively in recent years [10]. However, the insights provided by Harrison et al [4] and Ferrrai et al [3] emphasize that the remarkable diversity apparent across the RMS spectrum is multidimensional. Distinct clinical and biological characteristics of RMS diagnosed in different age groups deserve further attention. The two main pediatric RMS subtypes are embryonal and alveolar RMS, whereas pleomorphic RMS and RMS not otherwise specified are predominant in older adults and considered fundamentally different cancers [9]. To obtain a better understanding of RMS diagnosed in AYAs, future study efforts should aim at investigating the full spectrum of the disease and differentially consider the molecular underpinnings and therapeutic requirements of RMS diagnosed at opposite ends of the AYA age range.

Objective (69) The occurrence of unpredictable pain crises are the principal determinant of the quality of life for patients with venous malformations (VM). A definite coagulation phenomenon, characterized by an increase in D-dimer levels and the presence of phleboliths within the malformation, has been previously reported. By applying Virchow’s triad and evaluating intralesional samples, our objective is to delineate the coagulation profile and the extent of endothelial dysfunction within the malformation. Methods (42) With the authorization of the Ethics Committee, a research project was undertaken on intralesional and extralesional blood samples from 30 pediatric patients afflicted with spongiform VM. Thromboelastometry analyses were performed using ROTEM ® Sigma, and the concentration of syndecan-1 was determined by ELISA. Results (80) In the ROTEM ® analyses, the A5, A10, and MCF values were below the established reference ranges in the intralesional samples in both the EXTEM and INTEM assays indicating that intralesional clots had significant instability. Furthermore, during the investigation of the delayed fibrinolysis phase using recombinant tissue plasminogen activator (rtPA) in EXTEM analysis, widespread hyperfibrinolysis was observed intralesional. Additionally, analysis of syndecan-1 showed significant differences between extralesional and intralesional levels (p<0.026) and controls (p<0.03), suggesting differences in the state of endothelium. Conclusions (39) For the first time, we developed a comprehensive understanding of the coagulopathic profile of VM and the role of endothelial dysfunction in its pathogenesis. These findings will enable the implementation of targeted therapies based on the individual coagulation profiles.

Regression of kaposiform lymphangiomatosis and chronic disseminated intravascular coagulation after inhaled budesonide-formoterol treatmentMasaru Imamura1, Chansu Shin1, Akihiko Saitoh1, Michio Ozeki 2, Kentaro Matsuoka3 Chihaya Imai11Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan2Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan3Department of Pathology, Tokyo Metropolitan Children’s Medical Center, Tokyo, JapanCorresponding author: Masaru Imamura, Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuou-ku, Niigata City, Niigata 951-8510, Japan.Phone +81-25-227-2222FAX +81-25-227-0778Email: [email protected] Count for Main Text: 701 wordsNumber of Tables: 0Number of Figures: 2Running title: KLA IMPROVED AFTER INHALED STEROIDKeywords: kaposiform lymphangiomatosis, lymphatic malformation, inhaled corticosteroid, rare disease, progressive diseaseAbbreviations:

Adeeb Oweidat MD, DESAIC, EDRA

Treatment for childhood solid tumors may lead to an increased risk for gonadal dysfunction/infertility. Discussion of risk should occur at diagnosis, any changes in therapy, and during survivorship. Gonadotoxic therapies were abstracted from 32 Children’s Oncology Group (COG) phase III, frontline solid tumor protocols, in use from 2000-2022. Risk for gonadal dysfunction/infertility was assessed based on gonadotoxic therapies, sex, and pubertal status and assigned as minimal, significant, and high following the Oncofertility Consortium Pediatric Initiative Network (PIN) risk stratification. Most protocols (65.6%, 21/32) contained at least one therapeutic arm with a high level of increased risk. Solid tumor therapies present challenges in risk stratification due to response-adjusted therapy and the need to account for radiation field in the risk assessment. This guide hopes to serve as a tool to assist in standardizing gonadotoxic risk assessments across disciplines and improve referral for fertility services and reproductive health counseling for patients receiving COG based solid tumor therapy.

Background: There remains limited knowledge about the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-COV2) vaccination in pediatric oncology patients, which is essential to provide counseling and risk adaptation in this vulnerable population. The goal of this study was to understand immunogenicity after vaccination in pediatric oncology patients and determine if certain clinical factors impacted response. Methods: Patients 0-25 years of age with a diagnosis of cancer and actively receiving therapy were enrolled on study. We excluded patients who were completely vaccinated prior to their cancer diagnosis. Blood samples were collected pre-vaccination, as well as 2, 4-6, and 8-12 weeks after vaccination. Healthy children who were fully vaccinated enrolled as controls. Clinical data and complete blood counts around time of vaccination were collected. To study B and T cell immunity, we measured neutralizing antibodies by enzyme-linked immunoassay and interferon gamma secretion by enzyme-linked immunospot, respectively. Results: 26 patients enrolled on study, for which 11 were evaluable oncology patients and 7 were healthy controls. Adequate B cell response was seen in 36.4% of patients and adequate T cell response in 77.8% of patients. Numbers were too small to detect differences based on malignancy type. There was no differences in immunity based on absolute lymphocyte count (ALC) or intensity of therapy. Conclusion: Pediatric oncology patients have a suboptimal immune response to SARS-COV2 vaccination. Booster doses will be imperative to provide optimal protection against COVID-19, however blood counts may not be a useful guide to optimize the time of administration.

Background and Objectives: Initially developed as immunosuppressive agents, mTOR inhibitors are currently used widely in the management of vascular malformations and tumors. The incidence of infectious complications in the vascular anomalies (VA) population is not well defined. The goal of this systematic review was to better define the types and severity of reported infectious complications in patients with VAs treated with mTOR inhibition. Methods: This was a systematic review conducted following PRISMA guidelines evaluating all research articles focused on infectious complications in patients with VAs treated with sirolimus or everolimus. Thirty articles including 1181 total patients and 315 infections (in 290 unique patients) were ultimately included. Results: The majority of infections were viral upper respiratory (n=137, 54%), followed by pneumonia (n=52, 20%), and cutaneous infections (n=20, 8%). There were 6 total infection-related fatalities, which all occurred in patients younger than 2 years. Only 1 case of Pneumocystis jirovecii pneumonia (PJP) was reported. This was in an infant with KHE who was also treated with steroids and did not receive PJP prophylaxis. Almost 1/3 (n=95, 32%) of infectious complications were graded 3 to 4 according to CTCAE criteria. Details of patient age, subtype of VA, and timing of infection were lacking from many reports. Conclusions: Most infectious complications reported in patients with VA on mTOR inhibitors were viral respiratory infections and non-severe. Bacteremia, infectious fatalities, and PJP are exceedingly rare. Future studies are needed to clarify the spectrum of infectious risks in VA patients and to provide guidance for infection prevention.

While the survival of children with cancer has improved over time, infection remains a major morbidity and mortality risk. We conducted a systematic literature review to determine the unmet needs in diagnosing infection in immunocompromised children with cancer. The comprehensive search strategy followed the guidelines established by the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement and spanned multiple bibliographic databases and other public sources from January 1, 2012–June 23, 2022. From 5,188 records, 34 unique pediatric-focused studies met inclusion criteria. This review highlights the lack of published data on infectious disease testing in pediatric oncology patients and the need for well-designed clinical impact and cost-effectiveness studies of both existing and novel diagnostic platforms. Such studies are necessary to optimize diagnostic and antimicrobial stewardship, leading to improvement in patient outcomes.

Rhabdomyosarcoma (RMS) is a highly aggressive pediatric cancer known for its therapeutic challenges, particularly when it becomes metastatic or recurrent. Traditional treatment approaches have shown limited success, prompting a growing interest in targeted therapies. The emergence of next-generation sequencing (NGS) has revolutionized our ability to identify actionable mutations in RMS, offering the promise of personalized treatments and improved patient outcomes. A recent case involving a 3-year-old child diagnosed with embryonal RMS highlighted the potential of next-generation sequencing (NGS) in clinical practice. Despite receiving initial chemotherapy, the patient’s tumor showed progressive growth. What made this case particularly intriguing was the discovery of co-occurring somatic mutations in the RAS/MAPK pathway, specifically in BRAF and HRAS genes, which are traditionally believed to be mutually exclusive. Notably, the BRAF mutation identified in this case, N581I, is a non-classical (Class III) hotspot mutation that had not been previously reported in embryonal RMS. This novel finding underscores the critical importance of comprehensive genetic profiling in pediatric cancers and suggests the existence of potential therapeutic avenues that target BRAF alterations. In conclusion, the integration of NGS technologies in clinical practice holds great promise for identifying previously unrecognized mutations in pediatric cancers like RMS. These findings have the potential to open up new treatment options and improve outcomes for young patients facing this aggressive disease.

Monolobated Megakaryocytes in Diamond Blackfan Anemia withRPL5 Mutation at Disease Presentation Mimicking Myelodysplastic Syndrome

In March 2023, over 800 researchers, clinicians, patients, survivors, and advocates from the pediatric oncology community met to discuss the progress, plans, and future priorities of the National Cancer Institute’s Childhood Cancer Data Initiative. We present here the status of the initiative’s efforts in building its data ecosystem to provide access to childhood cancer data; updates on the Molecular Characterization Initiative; plans for implementing a Coordinated National Initiative for Rare Cancers in Children and Young Adults; and efforts to establish a framework for computable consent.

Background and Objectives: Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumors in children historically associated with significant morbidity and mortality. This study was conducted to determine first line therapy in the absence of available prospective clinical trials. Methods: Patients from 17 institutions diagnosed with KHE/TA between 2005-2020 with > 6 months follow-up were included. Response rates to sirolimus and vincristine were compared at 3 and 6 months. Durability of response and response to other treatment modalities were also evaluated. Results: Of 159 unique KHE/TA subjects, Kasabach-Merritt phenomenon (KMP) was present in 64 (40.3%) and only 2 patients were deceased (1.3%). Over 60% (n=96) demonstrated treatment response at 3 months and >70% (n=114) by 6 months (no significant difference across groups). The vincristine group had higher radiologic response at 3 months compared to sirolimus (72.7% vs 20%, p=0.03) but there was no differences between these groups at 6 months. There were no differences in rates of recurrent or progressive disease between vincristine and sirolimus. Conclusions: In this large, multicenter cohort of 159 patients with KHE/TA, rates of KMP were consistent with historical literature but the mortality rate (1.3%) was much lower. Overall treatment response rates were high (>70%) and there were no significant difference in treatment response or durability of disease comparing sirolimus to vincristine. Our results support individualized treatment decision plans depending on clinical scenario and patient/physician preferences. Response criteria and response rates reported here will be useful for guiding future treatment protocols for vascular tumors.

Rearrangements of the KMT2A gene are characteristic of infantile acute lymphoblastic leukemia (ALL) and are associated with increased lineage plasticity and resistance to therapy. Here, we describe the case of a 9-month-old infant with infantile ALL who experienced multiple immunophenotypic switches in her leukemia throughout therapy and ultimately achieved remission with the combination of CPX-351 and Inotuzumab. This case highlights the unique clinical challenges infantile ALL poses on monitoring therapeutic response with current methods of measuring minimal residual disease as well as the challenges in treating infantile B-ALL.

A document by Paul Meyers. Click on the document to view its contents.

Introduction: The risk of relapse in retinoblastoma is currently determined by the presence of high-risk histopathologic factors in the enucleated eye. However, the probability of developing metastatic disease is heterogeneous among these patients. Evaluating a biological marker to identify high-risk patients could be useful in clinical setting. This study aims to evaluate whether the expression of TFF1, a surrogate for subtype 2 retinoblastoma, is a prognostic marker for relapse and death. Methods: This multicenter cohort study included 273 patients, 48 of whom had extraocular disease. Immunohistochemical staining were performed for CRX, ARR3, TFF1 and Ki67. Tumors were classified as histological subtype 1 (HS1) if they had low or no expression of TFF1 (quick score (QS) ≤ 50) and as histological subtype 2 (HS2) if they expressed TFF1 diffusely (QS > 50). We studied the association between HS classification and outcome. Results: Of 273 patients, 35.9% were classified as HS1, 59.3% as HS2 and 4.8% were not evaluable. In multivariate analysis, patients with HS2 tumors had a higher probability of relapse and death than those with HS1 ( P < 0.0001 and P = 0.00020, respectively). We identified a higher-risk subgroup among HS2 tumors, presenting non-mutually exclusive expression of ARR3 and TFF1 and had an increased risk of relapse and death compared to tumors that displayed mutually exclusive expression ( P = 0.012 and P = 0.027, respectively). Conclusions: Expression of TFF1, especially when it is not-mutually exclusive with ARR3, is an independent prognostic marker of poor outcome in retinoblastoma.

Standard management of pediatric Non-Hodgkin’s Lymphoma (NHL) patients have included an initial assessment of the disease at presentation to establish it’s extent. This “staging” process has historically assigned patients using traditional classifications which were established decades ago when, like other pediatric malignancies, the more extensive involvement of the cancer for a patient directly correlated with the patient’s long term survival[[1]](#ref-0001). Advances in radiologic technology have evolved in the way the disease extent was evaluated, moving from conventional radiographs, to computerized tomography (CT) to magnetic resonance imaging (MRI) to most recently positron emission tomography (PET)[[2]](#ref-0002). Despite the development and use of PET scans for decades for various cancer diagnoses, the role of PET scans for NHL remains unclear[[3]](#ref-0003). Indeed, its value for many conditions is its ability to assess the response to initial therapy and establish the patient’s risk stratification guiding the remaining treatment plan[[4]](#ref-0004). Such efforts have not occurred in clinical trials of NHL and thus we are left to examine case series and try to discern its value for this disease.

Purpose Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma. Methods Oral cabozantinib (25mg/m 2) was administered daily for 21 (dose level 1) or 14 (dose level -1B) days. Topotecan (0.75mg/m 2) and cyclophosphamide (250mg/m 2) were administered IV on days 1-5. A modified 3+3 design based upon first cycle dose-limiting toxicities (DLT) was used for dose escalation. Results Twelve patients with a median age of 15 (12.9-33.2) years were enrolled (7 with Ewing sarcoma; 5 with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis; grade 3 transaminitis; prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level -1B (interrupted cabozantinib, given days 8-21), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease. Conclusions The recommended phase 2 doses and schedules for this combination are topotecan 0.75mg/m 2 IV days 1-5, cyclophosphamide 250mg/m 2 IV days 1-5, and cabozantinib 25mg/m 2 days 8-21. Non-concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity while allowing for potential disease control.