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: 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.
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.
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.
Shwachman–Diamond syndrome with Shwachman–Bodian–Diamond syndrome (SBDS) biallelic variants is a rare disorder that predisposes the carrier to malignant hemopathies but solid-cancer predisposition is poorly known. Among 155 cases entered in the French Severe Chronic Neutropenia Registry, three were identified original with malignant solid tumors (ovary, breast and esophagus). All cancers occurred in the fifth decade and, despite being at localized stages at diagnosis, they were rapidly fatal thereafter. No cancer was observed in the 14 HSCT survivors post transplantation. Based on our experience and the literature, age >40 years was the only apparent risk factor.
BACKGROUND The aim of this study was to investigate the progress made with pediatric oncology care in Cameroon from 2000 to 2020. METHOD A literature search was conducted for published articles on childhood cancer in Cameroon and relevant documents and conference abstracts were reviewed. The articles were analysed under eight themes: covering detection, diagnosis, management and program development. RESULTS Forty publications were analysed. Cancer diagnosis was achieved with cytology, histology and simple imaging. Management for common and curable cancers was with use of modified treatment regimens for low- and middle- income settings. There was good collaboration between the pediatric oncology professionals nationally and international partners. Advocacy led to the support of the Ministry of Health with pediatric oncology specific priority actions in the latest national cancer control plan. CONCLUSION Commitment of childhood cancer specialists, non-governmental organizations, and the government can lead to successful childhood cancer management in a low-income country.
Population-based data on survival from childhood cancers in sub-Saharan Africa is sparse. We report data for nine childhood cancers in the population of Kampala Uganda. Survival for eight out of nine cancers was below the WHO’s global target of 60% (the exception was Hodgkin lymphoma (86% at 3 years)). There was significant (p<0.05) decline in survival between 1 and 3 years for Wilms tumour and Kaposi sarcoma (30% and 34% at 3-years respectively). Survival from Burkitt lymphoma, Wilms tumour and Kaposi sarcoma has not changed since 2005.
Data for visual acuity (VA) after treatment of neurofibromatosis type 1-associated optic pathway gliomas (NF1-OPGs) is limited. We retrospectively collected VA, converted to logMAR, before and after targeted therapy with everolimus for NF1-OPG, and compared to radiologic outcomes (14/18 with NF1-OPG, 25 eyes [3 without quantifiable vision]). Upon completion of treatment, VA was stable in 19 eyes, improved in 4 eyes, and worse in 2 eyes; visual and radiologic outcome were discordant. In summary, the majority of children with NF1-OPG exhibited stabilization of their VA after everolimus treatment. A larger, prospective study will help delineate visual outcomes after targeted therapy.
Background Disruption of critical cell cycle regulators is a potential therapeutic target for brain tumors in children and adolescents. The aim of this study was to determine the maximum tolerated dose (MTD) and describe toxicities related to palbociclib, a selective cyclin dependent kinase 4/6 (CDK4/6) inhibitor in pediatric patients with progressive/refractory brain tumors with intact retinoblastoma protein. Methods Palbociclib was administered orally starting at 50 mg/m2 daily for the first 21 days of a 28 day course. Dose escalation was according to the Rolling-6 statistical design in less heavily (Stratum I) and heavily pretreated (Stratum II) patients, and MTD was determined separately for each group. Pharmacokinetic studies were performed during the first course, and pharmacodynamic studies were conducted to evaluate relationships between drug levels and toxicities. Pharmacogenetic analyses were based on pre-treatment samples. Results A total of 21 patients were enrolled on Stratum I and 14 patients on Stratum II. The MTD for both strata was 75 mg/m2. Palbociclib absorption (mean Tmax between 4.9 and 6.6 h) and elimination (mean half-life between 11.3 and 19.5 h) were assessed. The most common toxicity was myelosuppression. Higher palbociclib exposure was associated with grade 3/4 neutropenia and leukopenia. No patients had an objective response to palbociclib therapy. Conclusions Palbociclib was safely administered to children and adolescents at a dosage of 75 mg/m2 for 21 consecutive days followed by 7 days of rest in both strata. Future studies will be required to establish its optimal utilization in pediatric patients with brain tumors.
Comment on: Langerhans cell histiocytosis with BRAF p.N486_P490del or MAP2K1 p.K57_G61del treated by the MEK inhibitor trametinib1Paige Vicenzi, OMS-IV, 2Anish Ray, MD1Texas College of Osteopathic Medicine, University of North Texas Health Science Center2Department 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: 513Number of Tables: 0Number of Figures: 0Running Title: Langerhans cell histiocytosis treated by trametinibKeywords: Langerhans cell histiocytosis, MAP2K1, trametinib, pediatricThe authors have no financial support or conflicts of interest.Langerhans cell histiocytosis (LCH) is a rare but heterogenous myeloid malignancy. The discovery of mitogen-activated protein kinase (MAPK) pathway activating mutations as key oncogenic drivers offered only equivocal implications at best; the promise of targeted therapy was often eclipsed by a more severe clinical course, risk organ involvement, poorer response to standard therapy, and higher risk of relapse.1 There is, however, mounting evidence in support of MAPK pathway inhibition for patients with BRAF V600E mutations. A recent report outlines rapid and durable response of relapsed, multisystemic LCH with either BRAF p.N486_P490 or MAP2K1 p.K57_G61 deletion to MEK inhibitor trametinib.2 Two of the three patients achieved nonactive disease, including a 2-year-old male with MAP2K1 deletion who, despite reports attributing trametinib resistance to MAP2K1 mutations3, continues to thrive. We take this opportunity to describe an analogous experience treating a relapsed LCH patient with trametinib at Cook Children’s Medical Center from early 2020 to present.Our patient is a 4-year-old male who presented in March 2017 with new onset central diabetes insipidus (DI) and skin rash; skin biopsy provided diagnosis of LCH, but skeletal survey was negative for bone involvement. He was treated with twelve cycles of cytarabine (100 milligram (mg)/m2 intravenous daily for five days, every four weeks) and DDAVP for DI. At the completion of cytarabine, a second skin biopsy revealed recurrence of LCH, which warranted treatment with hydroxyurea (20 mg/kilogram (Kg) daily) and methotrexate (2.5 mg at 0.12 mg/Kg twice a week). This was continued for 52 weeks despite a brief interruption of methotrexate due to dermatitis. Three months following completion of this therapy, brain MRI revealed a 7 mm lesion of the skull. Curettage by neurosurgery confirmed relapse of LCH in January 2020. Genetic testing of this sample was negative forBRAF mutation, but positive for a mutation in the MAP2K1 gene, specifically a point mutation resulting in a substitution of Q56P. Shortly after his biopsy, the patient developed a soft tissue swelling on his skull. Due to these results and his multiple relapses, the patient was started on trametinib (2.5 mg daily) in February 2020 with rapid resolution of skull swelling and transient but dramatic reduction of his desmopressin dose from 3.2 mg twice a day to 0.2 mg twice a day. He has not experienced toxicity and continues to tolerate the drug well.Though trametinib presents a promising treatment for high-risk, relapsed LCH, it is not without limitations. In 2020, we also treated a 15-year-old male with relapsed LCH and BRAF V600E with trametinib monotherapy. Due to skin rash (Grade II), the patient became noncompliant. Despite stopping altogether after a month of treatment, he has yet to experience disease recurrence. But as stated in the aforementioned report, sufficient dose and treatment length to attain MAPK pathway suppression merits further investigation. In our similar experience treating a young child with multisystemic LCH and MAP2K1 mutation, we remain encouraged that MEK inhibition via trametinib monotherapy is a viable treatment option. In the context of genomic landscaping, we hope to incite further exploration of targeted therapy, and consequently, greater consensus on LCH management.