Title PageManuscript TitleComment on: “A newborn with a large NTRK fusion positive infantile fibrosarcoma successfully treated with larotrectinib”Authors:Alana Slomovic, M.D., Pediatric Resident, Department of Pediatrics, Cohen Children’s Medical CenterTerry Amaral, M.D., Associate Chief - Division of Orthopedic Surgery, Long Island Jewish Medical Center, Assistant Professor, Zucker School of Medicine at Hofstra/NorthwellIgor Lobko, M.D., Chief – Division of Vascular/ Interventional Radiology, Long Island Jewish Medical Center, Assistant Professor, Zucker School of Medicine at Hofstra/NorthwellDavid Siegel, M.D., Executive Vice Chairman – Department of Radiology, Long Island Jewish Medical Center, Associate Professor, Zucker School of Medicine at Hofstra/ NorthwellRachelle Goldfisher, M.D., Division of Pediatric Radiology, Department of Pediatrics, Cohen Children’s Medical Center, Assistant Professor, Zucker School of Medicine at Hofstra/NorthwellRachel Kessel, M.D., Division of Pediatric Hematology/Oncology, Department of Pediatrics, Cohen Children’s Medical Center, Assistant Professor, Zucker School of Medicine at Hofstra/NorthwellCarolyn Fein Levy, M.D., Division of Pediatric Hematology/Oncology, Department of Pediatrics, Cohen Children’s Medical Center, Assistant Professor, Zucker School of Medicine at Hofstra/NorthwellCorresponding Author: Carolyn Fein Levy, M.D.269-01 76th Avenue, Suite 255New Hyde Park, NY 11040Phone: (718) 470 3460Fax: (718) 343 4642 email: firstname.lastname@example.orgMain text word count: 564 wordsNumber of figures: 1Short running title: Infantile fibrosarcoma treated with larotrectinibKey Words: Infantile fibrosarcoma, Larotrectinib, NTRK fusionAbbreviations Key:
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 80045720-777-6426David.email@example.comWord 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.
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.
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.
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: 425-205-0926Anish.Ray@CookChildrens.orgWord 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 . 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 . 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 . 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.
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.
Background: Sickle cell disease (SCD), the commonest monogenic disorder, affects more than 300,000 births annually, with 44,000 in India. While the clinical phenotype of SCD is considered to be milder in aboriginal populations in India, there is a paucity of data on outcomes. To determine the severity of SCD in this population, we studied mortality rates and causes of mortality in a longitudinal cohort of patients with SCD in a remote aboriginal community in India receiving community-based comprehensive care. Procedures: Causes of death in this cohort from January 2008 to December 2018 were analyzed. Details were collected from hospital records and in case of deaths at home, by utilizing the WHO verbal autopsy questionnaire. Results: The cohort consisted of 157 patients belonging to the Paniya, Betta Kurumba, Kattunyakan, and Mullu Kurumba tribes. During the study period, there were 22 deaths, all from the Paniya tribe. Twelve deaths (54.5%) occurred in the hospital and the remaining at home (45.5%) reflecting a crude mortality rate of 140 per 1000 population. 25% of deaths occurred in the 6-18 age group. There were no deaths in the 0-5 age group. The median age of death was 25 years, which was 20 years less than in the non-SCD aboriginal population. The leading causes of death were acute chest syndrome, anemia, and sepsis among the SCD patients and stroke and suicides in the non-SCD aboriginal population Conclusion: SCD is a severe disease among the Gudalur Valley’s aboriginal population with a significant risk of premature mortality.
BACKGROUND: Irinotecan is a drug active against pediatric sarcomas with a toxicity profile that theoretically allows for its association with more myelotoxic drugs. We examined the feasibility of a dose-density strategy integrating irinotecan in standard chemotherapy regimens for patients with high-risk sarcomas. METHODS: Between November 2013 and January 2020, 23 patients < 21 years old with metastatic (11 children) or recurrent (12 children) sarcomas were treated with 9 IrIVA/IrVAC cycles. All newly-diagnosed patients received IrIVA (ifosfamide 3g/m2 on days 1 and 2, vincristine 1.5 mg/m2 on day 1, actinomycin D 1.5 mg/m2 on day 1, irinotecan 20 mg/m2 for 5 consecutive days starting on day 8). Two relapsed patients received IrIVA and 10 IrVAC (cyclophosphamide 1.5 g/m2 on day 1 instead of ifosfamide). Feasibility was assessed in terms of toxicity and time to complete the treatment. RESULTS: 17 rhabdomyosarcomas, 4 Ewing sarcomas, 2 desmoplastic round cell tumors received a total of 181 cycles (range 2-10). Grade 4 neutropenia occurred in 62.4% of the cycles. 13 patients had febrile neutropenia. Diarrhea occurred in 14 cycles. The median time to complete the treatment was 195 days (range 170-231), 83.4% of cycles were administered on time or with a delay <1 week. With a median follow-up of 2.6 years (range 0.2-5.0), 12 patients are alive, 9 complete remissions, 3 with the disease. Conclusions: A dose density strategy combining irinotecan with standard chemotherapy is feasible. This approach will be investigated in the next trial coordinated by the European pediatric Soft tissue sarcoma Study Group.
Background: Childhood acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. The onset of obesity during childhood ALL has been well established and is associated with inferior survival rates and increased treatment-related toxicities. This pilot study sought to determine if a dietary intervention is feasible and minimizes weight gain during the initial phases of treatment for ALL. Methods: Participants were recruited from four institutions, fluent in English or Spanish, between 5-21 years old, and enrolled within three days of starting induction therapy. Participants were counseled for six months to follow a low glycemic diet. Dietary and anthropometric data were collected at baseline, end of induction, and end of month six (NCT03157323). Results: Twenty-three of 28 participants (82.1%) were evaluable and included in the analysis. Dietary intake of several nutrients targeted by the nutrition intervention declined (sugar, P = 0.003 and glycemic load, P = 0.053). We also observed a persistent increase in total vegetables across each timepoint (P = 0.015) and by the end of the intervention (P = 0.033). Importantly, we did not observe an increase in body mass index z-score during induction or over the six-month intervention period. Most families found the nutrition intervention easy to follow (60%) and affordable (95%) despite simultaneous initiation of treatment for ALL. Conclusions: A six-month nutrition intervention initiated during the initial phase of treatment for childhood ALL is feasible and may prevent weight gain. Our preliminary findings need to be confirmed in a larger clinical trial.