Background: Hepatic metastasis from retinoblastoma (RB) is rare. We evaluated clinical features, imaging manifestations, treatment, and prognosis in these patients. Procedure: Clinical data of five patients diagnosed with hepatic metastases of RB at the Department of Pediatrics in Beijing Tongren Hospital between January 2009 and January 2019 were analyzed retrospectively. Results: Two patients had bilateral lesions, while three had unilateral lesions. Among the seven eyes with lesions, six and one were classified as stage E and C, respectively (International Integrated Reporting Council staging). On computed tomography (CT), low-density foci were observed (three, multiple foci and two, single foci). After chemotherapy, tumor regression was observed in four patients, while there was no response in one patient. Three patients who underwent enucleation were at high risk for extensive choroidal invasion. All patients had severe disease with multiple system involvement, including central nervous system (CNS) and bone metastases. Neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) levels were significantly elevated in all patients; after treatment, they decreased in four patients and remained unchanged in one patient with end-stage disease. Two patients died, with survival durations of 1 and 3 months following the diagnosis of hepatic metastasis. Three patients survived and continued treatment. Conclusion: Hepatic metastasis from RB is rare and usually occurs with CNS and bone metastases. On CT, hepatic foci could be indicated by low-density lesions with calcification. Chemotherapy could be effective for hepatic metastases. The prognosis of these patients is poor; however, hepatic metastasis is not a direct cause of death.

Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition.

Introduction: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond natural limits of the eye may lead to metastatic disease which is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. Method: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma group (EURbG) network. Extended information were gathered via personal Email communication. Results: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. Conclusion: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers.

Medical Marijuana in Pediatric Oncology: What Your Patients Are ThinkingDavid Brumbaugh, MD MSCS FAAPDepartment of Pediatrics, University of Colorado School of MedicineChildren’s Hospital Colorado13123 E. 16th Avenue, B290Aurora, CO [email protected] count: 837Short Running Title: Medical Marijuana in Pediatric OncologyKeywords: marijuana, cannabis, complementary, pediatricsAbbreviations:MM Medical MarijuanaAYA Adolescent/young adultTHC TetrahydrocannabinolUse of complementary therapies occurs by up to 40-80% of pediatric oncology patients.1,2 Although cannabis is hardly new to the scene as a complementary treatment, legalization of both medical and recreational marijuana in many states has made these products ubiquitous. Use of and interest in medical marijuana (MM) by hospitalized pediatric patients appears to be concentrated in oncology units for the purpose of relieving symptoms such as nausea, pain, and anorexia.3 Yet clinical practitioners are still limited by the absence of high-quality research in MM to guide them. FDA approval of Epidiolex™ for specific pediatric epilepsy syndromes was an important research milestone, but marijuana remains classified as a Drug Enforcement Administration Schedule I drug, imposing an enormous barrier for clinical researchers.So how should pediatric oncology programs approach the topic of MM? In this issue of Pediatric Blood and Cancer , Ananth and colleagues used a qualitative research design to characterize patient and family perception of MM from a single institution in a state with permissive rules towards both medical and recreational marijuana. The authors interviewed both parents of younger children as well as adolescent/young adult (AYA) patients. In this cohort of pediatric oncology patients/families, although the proportion of subjects using MM was only 27%, a higher proportion were interested in MM, though with concerns about safety and effectiveness.In the Ananth study, patients/families were primarily using or interested in MM for treatment of nausea, anorexia, and anxiety. A concerning number of families in this study expressed a hope that MM would be effective as anti-cancer therapy. With the absence of high-quality randomized controlled trials of MM for treatment of cancer or treatment-related symptoms in children to inform practitioners on safety, dosing, and toxicity, there is no evidence base for pediatric oncologists to base a recommendation of MM. But should we be dissuading interested families from using MM products because they are harmful?Regarding safety of MM use, most parents and nearly all AYA patients minimized risks. When expressed, safety concerns of MM were perceived as less than with alcohol, illicit drugs, or other prescribed medications. This is not surprising, as perceived risk of marijuana in AYA has been steadily failing over last five years in the National Survey on Drug Use and Health.4 Understandably, in this study safety concerns focused on the potential for addiction, which would be associated with MM products enriched in Tetrahydrocannabinol (THC), the principal psychoactive cannabinoid found in cannabis. However, cannabis is a complex plant with over 70 distinct cannabinoids, and the MM industry now contains a broad range of different types of products that have varying concentrations of THC and consequent psychoactive potential. Carver and colleagues noted in their study of 19 hospitalized patients actively using MM, the majority were using products enriched in Cannabidiol with low concentration of THC. One limitation of the study by Ananth, et al. is that there was no attempt to classify the type of MM either being actively used or of interest to patients and parents, so the appropriateness of the concern for addiction cannot be assessed. Absent in patients/families’ perception of risk was any potential for interaction with chemotherapeutics or other prescribed medications. Since both THC and Cannabidiol can impact drug bioactivation and metabolism through multiple pathways, this potential safety concern should be known to the patient and treatment team.Despite the high level of interest in MM in their study population, the minority of patients/families had discussed MM with their oncologist and in those cases, the patient/family initiated the conversation. Absent advice from their treatment team, there was reliance on friends, family, and the internet for more information. A majority of parents desired the involvement of their physician team in any consideration of MM, and previous research has shown a high level of willingness amongst pediatric oncology providers to consider MM use by their patients, particularly when patients are seriously ill, so what stands in the way of talking about it? Providers are concerned about the absence of good research and are less knowledgeable in the domain of rules/laws regulating access to MM, particularly at the state level where there has been so much change over the last decade.5 These gaps may explain why we don’t bring up the topic of MM with our patients and families as often as they would like.Institutions may consider designating a multidisciplinary team of providers to develop greater experience in the legal and pharmacologic aspects of MM use. This team can support providers in the shared decision-making process around MM. In some institutions, it may make sense to house this expertise within the pediatric palliative care program supporting oncology patients.In summary, MM presently is an important part of the complementary therapeutic options available to pediatric oncology patients and their families, who desire the involvement of their provider team in decision making around MM. Despite the lack of evidence supporting use of MM, many patients are using MM products or may in the future, so we should invite this discussion as this will strengthen our therapeutic partnership.1. Fernandez CV, Stutzer CA, MacWilliam L, Fryer C. Alternative and complementary therapy use in pediatric oncology patients in British Columbia: prevalence and reasons for use and nonuse. J Clin Oncol. 1998;16(4):1279-1286.2. Kelly KM, Jacobson JS, Kennedy DD, Braudt SM, Mallick M, Weiner MA. Use of unconventional therapies by children with cancer at an urban medical center. J Pediatr Hematol Oncol. 2000;22(5):412-416.3. Carver AE, Jorgensen J, Barberio MW, Lomuscio CE, Brumbaugh D. A Pediatric Hospital Policy for Medical Marijuana Use. Pediatrics.2020;146(2).4. Administration SAaMHS. 2019 NSDUH Detailed Tables. samhsa.gov/data/report/2019-nsduh-detailed-tables. Published 2019. Accessed.5. Ananth P, Ma C, Al-Sayegh H, et al. Provider Perspectives on Use of Medical Marijuana in Children With Cancer. Pediatrics.2018;141(1).

Emicizumab is a recombinant, humanized, and bispecific monoclonal antibody that bridges activated factor (F) IX and FX in place of FVIII to restore hemostasis in persons with hemophilia A (PHA). Data on the efficacy and safety of emicizumab in young children is limited. Immunologic naivety, physiologically decreased production of vitamin K dependent proteins, specifically FIX, and enhanced clearance of emicizumab in infants may support decreased emicizumab effectiveness. We report on the facilitation of care rendered by using emicizumab in young PHA with inhibitors and extend data on the efficacy and safety in PHA < 3 years.

Objective: To analyze the effect of a novel second-line escalating treatment strategy (high-dose dexamethasone (HDD), low-dose rituximab to eltrombopag) for children with severe chronic immune thrombocytopenia (SCITP). Materials and Methods: This study was a single-center, retrospective cohort study. The second-line escalating strategy included 3 steps: Step I (6 courses high-dose dexamethasone: HDD), Step II (HDD combined with low-dose rituximab), and Step III (eltrombopag). Results: A total of 30 cases (18 males and 12 females) were included; the median age was 8.83 (1.42-13.9) year-old, the duration time of ITP was 20.5 (12.0-96.0) months, and the platelet counts were 15 (3-29) ×109/L. After the median 14 (12-37) months’ treatment, the remission rate was 36.7% (11/30), and the sustained response (SR) rate was 68.2% (15/22). In eltrombopag (step III) cases, 47.5% (8/17) maintained platelet ≥50×109/L, 37.5% (3/8) dose tapering, and 25% (2/8) were successfully discontinued from medication. The number of patients at 12th, 24th, and 36th months was 30, 7, and 2, with the total response (TR) and remission rates of 80% (36.7%), 57.1% (28.6%), and 50% (50%), respectively. The total relapse rate was 26.7% (8/30)，three cases(75%, 3/4)from Step II and 5 cases (41.7% ,5/12)from Step III, none in Step I. Conclusion: The new second-line escalating strategy for children SCITP has an effective improving rate with 36.7% remission and 68.2% SR; 30% could benefit and retain stable response from HDD treatment. Combined treatment with eltrombopag can reduce the relapse rate of low-dose rituximab.

A document by Jonathan Marron. Click on the document to view its contents.

Sickle cell disease (SCD) patients are immunocompromised with multiple comorbidities and a hypercoagulation state. On the other hand COVID-19 is associated with cytokine storm and hypercoagulability. To find the susceptibility and the clinical course of COVID-19 in SCD patients we surveyed related published papers from USA, Europe, Middle East, few African patients and international SCD registry. The COVID-19 presentation was mild in children and moderate in many SCD adults. To explain these findings, possible benefits of high HbF level, and hydroxyurea therapy could be considered. The obtained results should be interpreted considering low cases from sub-Saharan people, younger age of SCD patients compared to general population, a bias toward registry of more severe form of the disease, the influence of preexisting comorbidities with multisystem organ damage in exacerbation of the COVID-19 and the fatality rate in SCD patients and the role of health socio-economic determinants.

Complex lymphatic anomalies are congenital diseases of the lymphatic circulation system that are associated with significant morbidity and early mortality. While guidelines for the comprehensive evaluation of the complex lymphatic anomalies were recently published, the diagnostic approach and medical management are not standardized. The current manuscript presents the clinical features of 4 complex lymphatic anomalies: Gorham-Stout disease, generalized lymphatic anomaly, kaposiform lymphangiomatosis, and central collecting lymphatic anomaly. We also offer three cases from the authors’ practice and our views on diagnostic testing and disease management including supportive care, medical therapies and other interventions.

BACKGROUND: Medulloblastoma (MB), the most malignant brain tumor of childhood has survival outcomes exceeding 80% for standard risk and 60% for high risk patients in high-income countries (HIC). These results have not been replicated in low-to-middle income countries (LMIC), where 80% of children with cancer live. METHODS: Retrospective review of 114 children (3-18 years) diagnosed with MB from 1997 to 2016 at INCA. Data on patients, disease characteristics and treatment information were retrieved from the charts and summarized descriptively. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier Method. RESULTS: The male/female ratio was 1.32 and the median age at diagnosis was 8.2 years. Headache (83%) and nausea/vomiting (78%) were the most common presenting symptoms. Overall survival (5y) was 59,1% and EFS (5y) was 58,4%. The OS for standard-risk patients was 69% and 53% for high-risk patients. Forty-five patients (35%) had metastatic disease at admission. Lower maternal education correlated with lower OS (71.3% versus 49% p=0.25). Patients who lived >40km from INCA fared better (OS= 68.2% versus 51.1% p=0.032). Almost 20% of families lived below the Brazilian minimum wage. CONCLUSIONS: The epidemiological characteristics of this series possibly explain the differences in survival that medulloblastoma patients have in Brazil. Issues related to limited health care resources, poverty, delayed diagnosis, treatment abandonment, and malnutrition are reflected in inferior survival outcomes when compared to high-income countries. Despite the difficulties encountered in an upper-middle income country, it was possible to deliver treatment with good results.

Cytopenias are common among neonates in neonatal intensive care units (NICU). Although, bone marrow aspirations (BMA) are often performed as part of diagnostic work up but trephine marrow biopsies (BMB) have not been reported from living neonates. BMB is indispensable to accurately assess the cellularity and architecture. There is paucity of literature regarding the technique of BMB in neonates. In this report, for the first time, we describe trephine BMB from Posterior superior iliac crest (PSIC) using 18 guage BMA needle in six living neonates admitted to NICU where bone marrow biopsy findings helped in understanding the underlying mechanism and diagnosis of cytopenias.

Background A diagnosis of childhood cancer results in new parent-child communication challenges. Little is known about how communication changes over time after diagnosis or relapse. The objective of this study was to determine the effect of time since diagnosis and relapse on quality of parent-child communication. We hypothesized that there would be a positive correlation between time and quality of parent-child communication. Methods Cross-sectional study in children (7 to 17 years) with relapsed/refractory cancer and their caregivers, who spoke English, were not cognitively impaired, and had internet access. Parents were recruited through Facebook ads. Parents and children completed the Parent-Adolescent Communication Scale (PACS), a 20-item measure of communication quality, with openness and problem subscales. Spearman’s Rho coefficients assessed correlations between PACS scores and time since diagnosis/relapse. Results There was a statistically significant negative correlation between parent PACS scores and time since child’s cancer diagnosis (Spearman’s Rho = - 0.21, p = 0.02), indicating a tendency for overall worsening communication as time since diagnosis increased. There was a positive correlation between the parent PACS problem scores and time since diagnosis (Spearman’s Rho = + 0.22, p = 0.01), indicating more problematic communication as time since diagnosis increased. Correlations of time since relapse and PACS scores were small and not statistically significant. Conclusion Parent-child communication worsens over time following a child’s cancer diagnosis with more communication problems, contrary to our hypothesis. Future studies are needed to evaluate intervention timing to best support parent-child communication beyond the new diagnosis period.

Emicizumab is a prophylaxis for patients with severe haemophilia A with inhibitor. Despite the daily prophylaxis, coagulation states stay below normal value and cannot be assessed by standard hemostasis techniques. In our two patients, we use thrombin generation assay (endogenous thrombin potential (ETP) and Peak) to monitor the patient’s clotting status. Under emicizumab, it is needed to add by-passing agent such as FVIIa (Novoseven®) to avoid bleeding before surgery. By-passing agent dose was chosen with the help of thrombin generation assay and after collegial concertation.

Background: Patient-reported outcomes (PROs) that assess health-related quality of life (HRQoL) are increasingly important components of cancer care and research that have been infrequently used in sub-Saharan Africa (SSA). We aimed to longitudinally measure HRQoL among pediatric lymphoma patients in Malawi. Methods: We administered the Chichewa Pediatric Patient-Reported Outcome Measurement Information System Pediatric (PROMIS)-25 at diagnosis, active treatment, and follow-up among pediatric lymphoma patients in Lilongwe, Malawi. Mean scores were calculated for the six PROMIS-25 HRQoL domains (Mobility, Anxiety, Depressive Symptoms, Fatigue, Peer Relationships, and Pain Interference) using the PROMIS scoring manual. Results: Seventy-five children completed PROMIS-25 surveys at diagnosis, 35 (47%) during active treatment, and 24 (32%) at follow-up. The majority of patients died (n= 37, 49%) or were lost-to-follow-up (n=8, 11%). Most (n=51, 68%) were male, median age was 10 (IQR 8-12), 48 (66%) presented with advanced Stage III/IV, 61 (81%) were diagnosed with Burkitt lymphoma and 14 (19%) had Hodgkin lymphoma. At diagnosis, HRQoL was poor across all domains, except for Peer Relationships. Improvements in HRQoL during active treatment and follow-up exceeded the minimally important difference. Poor Lanksy performance status ≤ 70 and Pain Intensity = 10 at diagnosis were associated with increased mortality risk and worse survival. Conclusions: Our experience suggests incorporating assessments of HRQoL via PROs in oncology care is feasible in SSA, can provide prognostic information, and generates clinically meaningful data to inform supportive care interventions. Further, PROs offer an opportunity to include patient voices and prioritize holistic patient-centered care even in low-resource settings.

Comment on: The use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis1Paige Vicenzi, OMS-IV, 2Zahra Jiwani, DO, 3Ricardo Guirola, MD,1,4Tyler Hamby, PhD, 5Anish Ray, MD1Texas College of Osteopathic Medicine, University of North Texas Health Science Center2Department of Pediatrics, Children’s Hospital of Michigan3Department of Pediatric Rheumatology, Cook Children’s Health Care System4Department of Research Operations, Cook Children’s Health Care System5Department of Pediatric Hematology/Oncology, Cook Children’s Health Care SystemCorresponding Author:Anish Ray, MD1500 Cooper St., 5th floor,Fort Worth, TX 76104Phone: [email protected] Count: 497Number of Tables: 0Number of Figures: 1Running Title: Anakinra in Secondary HLHKeywords: hemophagocytic lymphohistiocytosis, anakinra, pediatricThe authors have no financial support or conflicts of interest.Hemophagocytic lymphohistiocytosis (HLH) is a rare yet potentially fatal systemic disease arising from uncontrolled activation of the immune system. According to the Histiocyte Society’s 2004 guidelines, patients must meet five of eight criteria to be diagnosed with HLH [1]. HLH may be classified into primary and secondary. Primary, or familial, HLH is attributed to underlying defects in genes that control natural killer (NK) and cytotoxic T-lymphocyte (CTL) cell degranulation. Secondary HLH, in contrast, may occur in the context of triggers, such as malignancy, rheumatologic disease, or infection. Systemic-onset juvenile idiopathic arthritis (SoJIA) is a well-recognized trigger of HLH and both share overlapping features (e.g. fever and elevated ferritin). Management of SoJIA includes the immunomodulator Anakinra, an interleukin 1 (IL-1) receptor antagonist hypothesized to dampen an overactive immune system. Three patients treated for HLH with concomitant SoJIA diagnosis at Cook Children’s Medical Center between 2014 and 2019 are described below in order to examine the role of immunomodulators in their clinical course and outcome.Three Hispanic patients (aged 8-15) presented with a constellation of systemic symptoms, including fever, generalized rash, fatigue, and weight loss. Upon fulfilment of necessary criteria and subsequent diagnosis of HLH, they were treated accordingly with HLH-2004 protocol. Case 3, whose HLH was suspected to be secondary to Epstein-Barr Virus (EBV) infection, rapidly responded to treatment and, therefore, briefly discontinued Etoposide; however, she tolerated this poorly and resumed treatment after a six-week hiatus with the addition of weekly Rituximab to mitigate rising EBV titers. All patients achieved remission.Past medical history for case 3 included autoimmune disorders such as celiac disease, type 1 diabetes and suspected idiopathic juvenile arthritis for which she did not require ongoing care prior to presenting with features of secondary HLH. Cases 1 and 2 were diagnosed with SoJIA following their HLH diagnosis. Cases 1 and 3 relapsed with HLH within months of their initial encounter. Due to their concurrent diagnosis of SoJIA, both received daily Anakinra. Case 3 experienced rapid resolution of symptoms. In contrast, Case 1 had unsatisfactory response of musculoskeletal manifestations prompting switch from Anakinra to weekly Tocilizumab—another biologic that antagonizes IL-6 receptor—with favorable response. Case 2 was started on daily Anakinra immediately following his diagnosis of SoJIA and has yet to relapse. In summary, all cases have yet to experience an additional relapse following introduction of Anakinra or Tocilizumab. Figure 1 provides the treatment timelines for Cases 1-3 who had 5.37, 2.87, and 4.62 years of follow up, respectively.Though traditional therapy for HLH includes intensive courses of etoposide and corticosteroids with substantial risk for morbidity and mortality, biologics represent a newer class of medications highly effective in treating diseases with inflammatory or immune-mediated components [2]. In a reimaging of the HLH treatment algorithm, a recent study proposes Anakinra as initial treatment with sequential escalation of immunosuppression to mitigate adverse effects [3]. This case series reinforces that immunomodulators, such as Anakinra, are safe and promising treatment options in pediatric patients with secondary HLH.

Childhood cancer survivors are at increased risk for treatment-related late effects; data are lacking on how COVID-19 infection impacts this cohort. We assessed COVID-19-related symptoms; SARS-CoV-2 IgG seroprevalence; and rate of COVID-19-related hospitalization among 321 asymptomatic survivors of childhood cancer or transplantation seen for routine long-term follow-up between May-September 2020 in a New York City tertiary cancer center. While 11% (n=35) reported possible COVID-19-related symptoms, 7.8% (n=20) of those tested had positive SARS-CoV-2 IgG, and only 1 patient (0.3%) required COVID-19 related hospitalization. This report suggests that childhood cancer survivors are at low risk for COVID-19 complications.

Background: This retrospective study harnessed an institutional cancer registry to construct a childhood cancer survivorship cohort, integrate electronic health record (EHR) and geospatial data to risk stratify patients for serious adverse health outcomes, analyze follow-up care patterns, and determine factors associated with suboptimal follow-up care. Procedure: The survivorship cohort included patients ≤18 years of age with a diagnosis of a malignancy reported to the institutional cancer registry between January 1, 1994 and November 30, 2012. ICD-O-3 coding and treatment exposures facilitated risk stratification of survivors. All follow-up visits were extracted from the EHR through linkage to the cancer registry based on medical record number (MRN). Results: Eight-hundred-and-sixty-five survivors were included in the final analytic cohort, of whom 191, 496, and 158 were considered low, intermediate, and high risk survivors, respectively. Two-hundred-and-eight-two survivors (32.6%) were not seen in any oncology-related subspecialty clinic at Duke five to seven years after initial diagnosis. Factors associated with a clinic visit included younger age (p=0.008), acute lymphoblastic leukemia (ALL) as the primary diagnosis (p<0.001), race/ethnicity (p=0.010), risk strata (p=0.001), distance to treatment center (p<0.0001), and lower ADI (p=0.011). Multivariable logistic modeling with adjustment for diagnosis of ALL, gender, age at diagnosis, and race/ethnicity attenuated the association between follow-up care and risk strata (p=0.17) Conclusions: Nearly a third of survivors received suboptimal follow-up care. This study provides a reproducible model to integrate cancer registry and EHR data to construct risk-stratified survivorship cohorts to assess follow-up care.

The care of patients with vascular anomalies is quickly becoming a complex field requiring high quality, coordinated multidisciplinary care. In this article, we review the history of multidisciplinary care in this field, discuss the benefits of this model of care, and outline some of the essential components and structure of a successful vascular anomalies team. We provide an overview of two example programs and a roadmap for other centers to develop their own multidisciplinary vascular anomalies teams.