Hemophagocytic lymphohistiocytosis (HLH) is an uncommon immunologic disorder associated with high rates of morbidity and mortality characterized by systemic inflammation and multiorgan dysfunction. The standard of care for primary treatment of HLH is chemotherapy (i.e. etoposide), but consideration of alternative therapies is warranted to support treatment goals for critically ill pediatric patients. We present the case of a 7-year-old male with trisomy 21, acute multiorgan failure secondary to infection, and subsequent HLH who was successfully treated with ruxolitinib. This represents the first use of ruxolitinib as a first-line agent for secondary HLH in a critically ill child with trisomy 21.

Background: V enetoclax is frequently used as salvage treatment in pediatric, adolescent, and young adult (AYA) patients with advanced hematologic malignancies. However, more robust data are needed from real-world studies to guide the safe and appropriate use of venetoclax in this population. Procedure: We retrospectively reviewed the medical records of all patients diagnosed with hematologic malignancies less than 30 years of age treated with venetoclax outside of clinical trials at the University of California San Francisco (UCSF) Benioff Children’s Hospitals from 2016 to 2022. Results: We identified 13 patients (AML , n= 8, B-ALL, n= 3, MDS, n= 2) aged 4 months to 27 years. A median of 3 prior lines of therapy were given (range 0 to 5). All patients received venetoclax in combination with either a hypomethylating agent or conventional chemotherapy. Three (23%) patients achieved a complete remission (CR); 2 (15%) achieved a partial remission (PR); 3 (23%) had stable disease (SD), and 5 (42%) had progressive disease. Median survival and time to progression from venetoclax initiation was 9 months (range 2.5 to 52 months), and 3 months (range 2 weeks to 7.5 months), respectively. Five patients (38%) developed life-threatening infections while receiving venetoclax, including bacteremia due to atypical organisms, invasive pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia, skin infections, encephalitis with bacterial brain abscesses. Conclusions: Venetoclax in combination with hypomethylating agents or cytotoxic chemotherapy was effective in a subset of pediatric/AYA patients with advanced hematologic malignancies, but was frequently associated with severe atypical infections, particularly in combination with cytotoxic chemotherapy.

Title: Symptomatic Hyperammonemia Secondary to Recombinant Erwinia AsparaginaseCatherine E. Martin, Pharm.D., Department of Pharmacy – Ambulatory Service, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAMira A. Kohorst, M.D., Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAAsmaa Ferdjallah, M.D., M.P.H, Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAJessica L. Kalmes, APRN, C.N.P., M.S.N, Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAHeather M. Johnson, APRN, C.N.P., M.S.N, Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAPaul J. Galardy, M.D., Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAShakila P. Khan, M.D., Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAAlexis K. Kuhn, Pharm.D., Department of Pharmacy – Ambulatory Service, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USACorresponding author: Catherine E. Martin; address: 200 First Street SW, Rochester, MN 55905; phone: 507-284-2695; fax: 507-266-4912; email: martin.catherine3@mayo.eduMain text word count: 967Number of tables, figures, and supporting information: NoneShort running title: Hyperammonemia after recombinant Erwinia asparaginaseKeywords: Asparaginase, hyperammonemia, pediatrics, Erwinia, leukemiaAbbreviations

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of peripheral T-cell lymphomas (PTCL) and is extremely uncommon in the pediatric population. We present a case of a 15-year-old girl with SPTCL and an unusual involvement of the breast. The FDG-PET/CT showed avid uptake of 18F-FDG in the breast predominantly involving the subcutaneous tissue that improves post treatment. To our knowledge, this is the first case of breast SPTCL reported in pediatric patient. A study published by Goto-et-al in 2019 [(1)](#ref-0001), found only 27 cases of SPTCL under 15 years, including four infants and none of them shown breast involvement.

A document by Fernanda Mota. Click on the document to view its contents.

Do we need more studies?Max M. van Noesel, MD, PhD, MSc1,2*Department of Solid Tumors, Princess Máxima Center for Pediatric Oncology, Utrecht, the NetherlandsDivision Imaging & Oncology, University Medical Center Utrecht, Utrecht, the Netherlands*Correspondance to: M.M van Noesel, MD, PhD, MSc, Department of Solid Tumors, Princess Máxima Center, Heidelberglaan 25, 3584 CS Utrechtc, Telephone: +31-6 5000 6581, Email: m.m.vannoesel@prinsesmaximacentrum.nl Text word count: 968 Abstract: - Short running title: Highlight PBC-22-1061 Tables: - Figures: - Abbreviations: -

INTRODUCTIONThe frequency of pediatric head and neck neoplasms ranges from approximately 2-15% of all pediatric cancers1. Skull base and calvarial neoplasms, including temporal bone and orbital masses are a subset of head and neck neoplasms occupying a number of neoplastic processes and categorically encompass several imaging patterns: singular dominant mass lesions with or without metastatic disease (e.g., rhabdomyosarcoma (RMS), chordoma), singular or multifocal metastatic disease (e.g., neuroblastoma), and multifocal disease due to systemic malignancy (e.g., leukemia, lymphoma, histiocytosis, etc.).While pathologies certainly vary between pediatric and adult patients, there remains significant overlap. As such, imaging protocols for skull base and calvarial neoplasms are similar in their general construct. However, optimized pediatric-specific protocols remain a must, as a retrofitted adult head and neck protocol is often ill equipped to offer quality, efficient and safe imaging (e.g., limiting radiation exposure) of the size-variable infant and pediatric patient. Moreover, sedation or general anesthesia is often required in the pediatric population in order to minimize motion artifact. Thus, optimization of imaging acquisition time is a very important technical consideration because it may decrease the necessity and duration of sedation/anesthesia and their potential risks in this vulnerable population. Standardized protocols for anatomic sub sites of the head and neck offer significant benefit in individual patient follow up on a local scale, and, on a broader scale, allow for collaborative understanding of imaging pathologies and innovative or benchmarked standardized treatment response assessment across institutions.In an effort to standardize protocols, this article offers minimum, pediatric specific anatomy-based initial and follow up imaging guidelines for pediatric malignancies of the orbits, calvarium, skull base and temporal bone. This manuscript was funded in part by the National Clinical Trials Network Operations Center Grant U10CA180886. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Background: Long-term oral dasatinib administration can induce pulmonary arterial hypertension (PAH) in pediatric patients with Philadelphia chromosome-positive (Ph +) acute lymphoblastic leukemia (ALL). We describe the findings in two pediatric cases involving Ph + ALL patients who developed cardiovascular events such as PAH after dasatinib treatment, and present a review of the related literature. Case presentation: Two pediatric patients diagnosed with B-cell ALL ( BCR-ABL P190 fusion gene positive) received conventional chemotherapy and imatinib simultaneously, which was then changed to dasatinib because of a partial response. The two patients developed PAH after 18 months and 6 years of dasatinib therapy. All signs and symptoms improved after immediate discontinuation of dasatinib and symptomatic treatment. Conclusions: Pediatric Ph + ALL patients receiving dasatinib should be carefully monitored for serious cardiopulmonary and vascular events such as PAH. Development of adverse reactions should be followed by immediate and permanent discontinuation of oral dasatinib. Dynamic monitoring by echocardiography is recommended when administering dasatinib for maintenance therapy.

Background: Chemotherapy induced nausea and vomiting (CINV) is a distressing adverse effect in children receiving cancer treatment. There are evidence-based pediatric clinical practice guidelines (CPG) on chemotherapy emetogenicity and acute CINV prevention, but adherence to these guidelines is low. Procedure: A quality improvement-based study was conducted at McMaster Children’s Hospital. The SMART aim was to increase adherence to guidelines on prevention of acute CINV in hospitalized patients receiving high (HEC) and moderately (MEC) emetogenic chemotherapy from baseline 25% to >70% by June 2021. Barriers were identified by process mapping and a series of interventions were implemented. Results: Guideline adherence (GA) was assessed in 270 inpatient chemotherapy administrations (HEC, MEC). Data was collected on 131 charts pre-interventions and 139 charts post-interventions. Interventions included education, addition of guideline recommended anti-emetics to the inpatient formulary and implementation of a standardized CPG tool. Initial rates of total CINV GA were 25%, which improved to 72% post-intervention (p <0.001). In subgroup analysis, GA in the MEC group improved from 13% to 34% (p=0.015), and in the HEC group from 32% to 93% (p<0.001). The most common reason for non-adherence in the HEC group was failure to use aprepitant as anti-emetic, and in MEC was option for ondansetron monotherapy prophylaxis. Conclusion: Using quality improvement methodology, barriers to guideline adherence were identified and interventions implemented. Guideline adherence for prevention of CINV improved, particularly in the HEC group but less for the MEC group. Future steps will include sustainability of interventions and addressing adherence in the MEC group.

Type of manuscript : CorrespondenceTitle : Stomatocytes - a whistleblower for future familial cardiovascular events- unraveling the diagnosis of Sitosterolemia in an Indian family. Running title : Hemolytic manifestation of sitosterolemia in an Indian familyAuthors : Richa Chauhan¹, Manas Kalra², Surbhi Singh ¹*, Anupam Sachdev², Jyoti Kotwal¹Affiliation : Departments of Hematology¹ and Pediatric hemato-oncology2, Sir Gangaram Hospital, New DelhiAuthor’s contribution: The manuscript is original and all authors have contributed equally to manuscript preparation.Text word count : 1091Number of Figures : 01Keywords : macrothrombocytopenia, stomatocytosis, sitosterolsDisclosure statement : NoneFunding : NilConflicts of interest : There is no conflicts of interest.

Background: Radiation therapy normal tissue dose constraints are critical when treating pediatric patients. However, there is limited evidence supporting proposed constraints which has led to variations in constraints over the years. In this study we identify these variations in dose constraints within pediatric trials both in the United States (US) and in Europe used in the past 30 years. Procedure: All pediatric trials from the Children’s Oncology Group website were queried from inception until January 2022 and a sampling of European studies was included. Dose constraints were identified and built into an organ-based interactive web application with filters to display data by organs-at-risk (OARs), protocol, start date, dose, volume, and fractionation scheme. Dose constraints were evaluated for consistency over time and compared between pediatric US trials and European trials Results: One hundred and five closed trials were included—93 US trials and 12 European trials. Thirty-eight separate OARs were found with high dose constraint variability. Across all trials, nine organs had greater than 10 different constraints (median 16, range 11-26), including serial organs. When comparing US versus European dose tolerances, US constraints were higher for seven OARs, lower for one, and identical for five. No OARs had constraints change systematically over the last 30 years. Conclusion: Review of pediatric dose-volume constraints in clinical trials showed substantial variability for all OARs. Continued efforts focused on standardization of OAR dose constraints and risk profiles are essential to increase consistency of protocol outcomes and ultimately to reduce radiation toxicities in the pediatric population.

Comment on: Effects of COVID-19 vaccination on platelet counts and bleeding in children, adolescents, and young adults with immune thrombocytopenia

Background Progressive transformation of germinal centers (PTGC) is a rare diagnosis characterized by asymptomatic lymph node enlargement. It has previously been associated with lymphoma, autoimmune conditions, and lymphoproliferative diseases in small pediatric case series. Procedures We conducted a single-center retrospective review of pediatric cases of PTGC diagnosed at our institution by hematopathologists from 2000 - 2020. Results We identified 57 primary cases and 3 recurrent cases of PTGC. There was a male predominance in cases (32/57), with median age at diagnosis of 11 years. Head and neck lymph nodes were the most commonly involved and biopsied sites. Laboratory and imaging evaluations were obtained inconsistently. Only 16% of patients saw a pediatric hematology/oncology (PHO) specialist prior to diagnosis and 37% had follow-up with PHO after diagnosis. Six patients (10%) had a preceding or concurrent diagnosis of lymphoma and 5% of patients returned with recurrent PTGC. Conclusions Patients with PTGC had similar characteristics to those from previous case series. Fewer patients underwent recurrent lymph node biopsy than previously described. PTGC has been linked to certain types of lymphoma, although never definitively associated with lymphoma. Follow-up with a PHO provider is indicated to ensure that close surveillance is performed.

L-asparaginase (L-ASNase) is an essential component of chemotherapy schemes due to its differential action over normal and leukemic cells. Recently, concerns on the performance of commercial formulations administered in developing countries have been reported. To address this problem, we developed a cell-based protocol to compare the activity of different L-ASNase formulations used in Colombia. We found three statistically different groups, ranging from full to no activity on leukemic cells using 0.05, 0.5 and 5.0 IU/mL concentrations. According to our results, we advise a preclinical evaluation for formulations of L-ASNase distributed in developing countries which could impact the outcome of patients.

Monoclonal antibodies (mAbs) targeting disialoganglioside 2 (GD2) are an important treatment advance for high-risk neuroblastoma, including in patients with refractory or relapsed disease. Dinutuximab and dinutuximab beta are administered for ≥8 hours (and up to 10 days for dinutuximab beta), whereas naxitamab is administered over 0.5 to 2 hours as tolerated. As acute pain is a class effect of anti-GD2 mAbs, effective pain management is crucial to successful treatment. Here, we provide an overview of current pain-management strategies for anti-GD2 mAb infusions, including discussion of opioid analgesics, ketamine, gabapentin, and other similar agents, and non-pharmacologic approaches. Potential future pain management options are also discussed, in addition to the use of sedatives to reduce the anxiety that may be associated with infusion-related pain. Specific guidance for pain management during naxitamab infusions is provided, as these infusions are administered over 0.5 to 2 hours and may not need overnight hospitalization based on the physician’s assessment, and require rapid-onset analgesia options suitable for potential outpatient administration.

Title: Vaccine Preventable Illness After Blinatumomab Therapy: A Case ReportAuthors: Katie Voelz MD1,2, Anthony Salvatore DO1, Sudarshawn Damodharan DO1,2 & Cathy Lee-Miller MD1,21Department of Pediatrics, University of Wisconsin School of Medicine & Public Health, Madison, WI, USA2Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, University of Wisconsin School of Medicine & Public Health, Madison, WI, USACorrespondence:Cathy Lee-MillerUniversity of Wisconsin School of Medicine & Public Health1111 Highland Ave, WIMR 4105Madison, WI 53705Email: calee4@wisc.eduWord Count: Main Text: 848Manuscript contains 1 TableShort running Title: Vaccine-preventable, ALL, immunotherapyKeywords: Blinatumomab, ALL, vaccination, pediatrics

In memoriam: Dr. Audrey E. EvansJohn M. Maris, MDDr. Audrey E. Evans, emeritus Professor of Pediatrics at the University of Pennsylvania and the first Chief of the Division of Oncology at the Children’s Hospital of Philadelphia (CHOP), died peacefully at her home on September 29, 2022, surrounded by loved ones at the age of 97. She will be remembered for her groundbreaking leadership in developing new treatments for children with cancer and for establishing the Philadelphia Ronald McDonald House as a home away from home for families whose children are being treated for serious illnesses. The original House in Philadelphia has served as the model for the now 375 Homes around the world today.Audrey E. Evans was born March 6, 1925, in York, England, the second of three children. Audrey developed a passion for horses and equestrian pursuits early in life that she carried with her well into her seventies. After receiving her medical training at the University of Edinburgh in Scotland, she came to the U.S. in the early 1950’s on a Fulbright scholarship. She trained with Dr. Sydney Farber and was on the frontline of the first successful treatments of human cancer with chemotherapy. During these early years in Boston, Baltimore and Chicago, Dr. Evans, formed her lifelong commitment to the problem of childhood cancer, and dedicated her career to not only improving cure rates, but also to do so with a focus on quality of life during and after treatment. She was a trailblazer and serves as a role model for several generations of pediatric oncologists. Her holistic view of how serious illness impacts not just the patient, but the entire family has influenced the approach to children with cancer of countless childhood cancer health care professionals. “A sick child is a sick family”, she would often say.Dr. Evans was recruited to the Children’s Hospital of Philadelphia (CHOP) in 1969 by future Surgeon General C. Everett Koop to be the first Director and Chief of the Division of Oncology. This was immediately followed by a dizzying array of seminal achievements. She was the first to develop a neuroblastoma staging system, and the fundamental aspects of the system remain in clinical use today. She was the first to describe, along with late husband Dr. Giulio (Dan) D’Angio, the amazing phenomena of spontaneous regression of widely disseminated neuroblastoma that she dubbed “4S disease” (S = special). Dr. Evans organized and chaired the inaugural Advances in Neuroblastoma Research (ANR) Meeting in a small conference room at CHOP in May of 1975. This meeting has grown into a major international conference attended by hundreds of physicians and scientists focused understanding neuroblastoma and improving patient outcomes.She oversaw enormous growth of the Division of Oncology at CHOP, and trained dozens of eventual leaders in the field. During this time, Dr. Evans was key to the formation of the first childhood cancer cooperative groups and led many of the early seminal studies. These efforts led to dramatically increased cure rates in a variety of childhood cancer, as well as establishing the infrastructure for all of the advancements made since. Her legacy in the field of pediatric oncology is unparalleled.Dr. Evans was one of the first to recognize the importance of the nursing, psychology, and social work disciplines to the care of children with cancer. She recruited individuals in these fields well before her peers, and current rich collaborative programs with these disciplines in oncology are due to Dr. Evans’ pioneering efforts.Faced with the problems associated with a growing cancer program at CHOP, namely, how to care for the child and their families, in 1974 Dr. Evans co-founded with Philadelphia Eagles General Manager Jimmy Murray the original Ronald McDonald House on Chestnut Street in Philadelphia, a short walk from CHOP. There are now McDonald Houses across the globe, all enabled by Dr. Evans’ vision. Dr. Evans was also instrumental to the start of the Ronald McDonald Camps for children with cancer and survivors, establishing the program in 1987.Dr. Evans has received essentially every honor possible in the field of pediatric oncology. These include, but are not limited to, the Janeway Award, the American Society of Pediatric Hematology/Oncology Distinguished Career Award, an award from the American Cancer Society, the Spectrum Award of the American Red Cross, the Alpha Delta Kappa International Woman of the Year Award, the Osler Award from the University of Pennsylvania, the Lifetime Achievement Award from the International Society of Paediatric Oncology (with her husband), and most recently, an honorary Fellowship of the Royal College of Physicians of Edinburgh, her Alma Mater.Audrey married Dan D’Angio just before her 80thbirthday in a humble ceremony followed by a cup of tea and then return to work at CHOP. A true Renaissance woman, Audrey will be remembered not only for her groundbreaking work in pediatric oncology, but also for passion for dressage, scuba diving, and her annual early spring trips to Scotland to assist in birthing lambs. After retiring at in 2009, she focused on establishing and nourishing the St. James School for at-risk children in North Philadelphia with Dan’s able assistance. Audrey and Dan spent many wonderful years together on Rittenhouse Square in Philadelphia until his death in their home on September 14, 2018. She died peacefully in the same place with the singular goal of joining him again.

Purpose : To determine whether extent of surgical resection of the primary tumour correlates with survival in patients with International Neuroblastoma Staging System (INSS) stage 4, high-risk neuroblastoma. Methods : Data were extracted for patients with newly diagnosed INSS stage 4, high-risk neuroblastoma between 2001-2019 from the national Cancer in Young People in Canada (CYPC) database. Complete resection was defined as gross total resection of primary tumour based on operative reports. Primary endpoints were 3 and 5-year event-free (EFS) and overall survival (OS). Survival analyses were completed using log-rank test and Cox proportional hazards regression including covariates of age, sex, decade of treatment (2001-2009 vs. 2010-2019), immunotherapy, and tandem stem-cell transplant (SCT). Results : One-hundred and forty patients with complete surgical data were included. On univariate analysis, 3-year EFS and OS for patients that had complete vs. incomplete resection was 71% (95% CI 57-80%) vs. 48% (36-60%) and 86% (75-93%) vs. 64% (51-74%), p=0.008 and p=0.002, respectively. 5-year EFS and OS for patients with complete resection also demonstrated significantly improved survival. On Cox Proportional Hazards models adjusted for age, immunotherapy, tandem SCT and surgical resection, only complete resection was associated with statistically significant improved 3 yr EFS and OS, HR=0.48 (0.29-0.81; p=0.006) and HR=0.42 (0.24-0.73; p=0.002). Conclusions : In a large Canadian INSS stage 4 high-risk neuroblastoma cohort, complete surgical resection was associated with increased EFS and OS. Within the constraints of a retrospective study, these results suggest that the ability to achieve primary tumor complete resection in patients with metastatic high-risk disease is associated with improved survival.