Comment on: Burden of central nervous system complications in sickle cell disease: A systematic review and meta-analysis R. Grant Steen, PhD103 Van Doren PlaceChapel Hill, NC [email protected] Editor;I read with interest a recent paper in Pediatric Blood & Cancer(1), about cognitive impairment in children with sickle cell disease (SCD). I’m always grateful to have my work cited, especially since our paper is almost 20 years old (2).However, it seems that Lee et al . have gone to great lengths to mischaracterize our work. They write (pg. 5) that, “SCI [silent cerebral infarct] and absence of SCI/CVA [cerebrovascular accident] were verified by review of brain MRIs in all studies except Ghafuri et al . and Steen et al . In these studies, absence of SCI/CVA was defined as no mention of cerebral infarcts in the subject’s medical records.” Also on pg. 5, they write that, “An alternative analysis was conducted excluding studies with insufficient definition of overt stroke and/or SCI based on clinical opinion (Ghafuriet al . and Steen et al .)”. I cannot speak for Ghafuriet al , but we did a careful review of MRI findings for every single patient in our study, as is necessary for a paper in theAmerican Journal of Neuroradiology . This should be pellucidly clear because the title of our paper is, “Cognitive Impairment in Children with Hemoglobin SS Sickle Cell Disease: Relationship to MR Imaging Findings and Hematocrit ”. All our SCD patients were evaluated by at least two neuroradiologists, and patients thought to be abnormal were evaluated by a third neuroradiologist blinded as to previous findings (2). One wonders what other errors may be present in Leeet al (1).Fortunately, this mischaracterization of our work did not lead to incorrect conclusions (1). A comparison of Table 1 to Supplementary Table 6, in which our paper and Ghafuri et al were deleted from analysis, shows that none of the major findings were changed much by deleting these papers (1). I agree with most conclusions in Lee et al .; in fact, I would go further. In uncited work from St. Jude Children’s Research Hospital, we found that children with SCD can suffer cognitive impairment even in the absence of MRI evidence of brain injury (3). We tested a hypothesis that children with SCD who are completely normal by MRI can still be cognitively impaired, as predicted by a model of diffuse brain injury. A total of 54 patients with hemoglobin SS (average age 10.9 years ± 2.9 years SD) were examined with the Wechsler Intelligence Scale for Children-III (WISC-III) and were randomly matched by age, race, and gender to healthy children from the Wechsler normative database. Patients were also imaged at 1.5 Tesla with standard imaging sequences. Among 30 patients judged normal by MRI, there were substantial deficits in Wechsler Full-Scale IQ, Verbal IQ, and Performance IQ (all P < 0.01), when compared to African-American controls. The patient Wechsler Full-Scale IQ was 12.9 points lower than that of matched controls and decreased as a function of age (P = 0.014). These findings strongly suggest that there is diffuse brain injury in SCD patients, perhaps associated with chronic hypoxia (3).

The ongoing COVID-19 pandemic strained medical systems worldwide. We report on the impact on pediatric oncology care in Latin American (LATAM) during its first year. Four cross-sectional surveys were electronically distributed among pediatric onco-hematologist in April/June/October 2020, and April/2021 through the Latin American Society of Pediatric Oncology (SLAOP) email list and St Jude Global regional partners. 453 pediatric onco-hematologists from 20 countries responded the first survey with subsequent surveys response rates above 85%. More than 95% of participants reported that treatment continued without interruption for new and active on-going patients, though with disruptions in treatment availability. During the first three surveys, respondents reported suspensions of outpatient procedures (54.2%), a decrease in oncologic surgeries (43.6%), radiotherapy (28.4%), stem cell transplants (SCT) (69.3%), and surveillance consultations (81.2%). Logistic regression analysis showed that at the beginning of the first wave, participants from countries with healthcare expenditure below 7% were more likely to report a decrease in outpatient procedures (OR:1.84, 95%C:1.19;2.8), surgeries (OR:3, 95%CI:1.9;4.6) and radiotherapy (OR:6, 95%CI:3.5;10.4). Suspension of surveillance consultations was higher in countries with COVID-19 case fatality rates above 2% (OR:3, 95%CI:1.4;6.2) and SCT suspensions in countries with COVID-19 incidence rate above 100 cases per 100,000 (OR:3.48, 95%CI:1.6;7.45). Paradoxically, at the beginning of the second wave with COVID-19 cases rising exponentially, most participants reported improvements in cancer services availability. Our data show the medium-term collateral effects of the pandemic on pediatric oncology care in LATAM, which might help delineate oncology care delivery amid current and future challenges posed by the pandemic.

A PRIMARILY CLINICIAN’S RESPONSIBILITY

Mixed phenotype acute leukemia (MPAL) is a relatively rare and heterogeneous group of diseases, which account for 2-5% of leukemia. So far, no optimal treatment regimens have been established for MPAL patients. CD19 chimeric antigen receptor T (CAR T) therapy have shown remarkable efficacy in B-ALL patients. In this study, 5 MPAL patients received CD19 CAR T cell infusion and 3 out of 5 patients (60%) achieved complete response (CR). 2 of 5 patients had only mild cytokine release syndrome (CRS). Neurotoxicity was not observed. Our data indicate that CD19 CAR T therapy is safe and effective for majority refractory/relapsed (r/r) MPAL patients.

Letter to the Editor: Interesting clinical observationTitle: Acute Exacerbation of Graft-versus-Host Disease following SARS-CoV2 infection after Hematopoietic Stem Cell Transplant in Two Pediatric PatientsRunning Title: Graft-versus-Host Disease and SARS-CoV2 infectionAuthors: Michelle Choe1,2* Caridad Martinez1,2, Robert Krance1,2, Erin Doherty1,2ORCID:Michelle Choe: 0000-0001-9850-9435Institutional Affiliation:1 Hematology and Cancer Center, Texas Children’s Hospital, Houston, Texas2 Department of Pediatrics, Baylor College of Medicine, Houston, Texas*Corresponding Author:Michelle Choe, MD6701 Fannin St. Ste. 1510Houston, TX 77030P: 832-822-4242F: 832-825-1453Abbreviations key:

Introduction: Hematologic complications of SARS-CoV-2 infection are well described in hospitalized adults with correlation to adverse outcomes. Information published in children has been limited. Methods: An international multi-centered retrospective registry was established to collect data on the clinical manifestations of SARS-CoV-2 or multisystem inflammatory syndrome (MIS-C) in hospitalized children between February 1, 2020 – May 31, 2021. This sub-study focused on hematologic manifestations. Study variables included patient demographics, comorbidities, clinical presentation, course, laboratory parameters, management, and outcomes. Results: Nine hundred and eighty-five children were enrolled and 915 (93%) had clinical information available; 385 (42%) had symptomatic SARS-CoV-2 infection upon admission, 288 had MIS-C (31.4%) and 242 (26.4%) had alternate diagnosis with SARS-CoV-2 identified incidentally. During hospitalization, 10 children (1%) experienced a thrombotic event, 16 (1.7%) had hemorrhage and 2 (0.2%) had both thrombotic and hemorrhagic episodes. Significant prothrombotic comorbidities included congenital heart disease (p-value = 0.007), central venous catheter (p = 0.04) in children with primary SARS-CoV-2 infection; and obesity (p-value= 0.002), cytokine storm (p= 0.012) in those with MIS-C. Significant pro- hemorrhagic conditions included age > 10 years (p = 0.04), CVC (p= 0.03) in children with primary SARS-CoV-2infection; and thrombocytopenia (0.001), cytokine storm (0.02) in those with MIS-C. Eleven patients died (1.2 %) with no deaths attributed to thrombosis or hemorrhage Conclusion: Thrombotic and hemorrhagic complications are uncommon in children with SARS-CoV-2 infection and observed with underlying co-morbid conditions. Understanding the complete spectrum of hematologic complications in children with SARS-CoV-2 infection or MIS-C requires ongoing multi-center studies.

Youth with sickle cell disease (SCD) and their caregivers are susceptible to stress and depression, perhaps exacerbated by pandemic-associated health and economic concerns. Most of the 50 youth-caregiver dyads enrolled in the multi-site HABIT trial took an on-line survey of self-reported mental health symptoms and food insecurity during the 2020 COVID-19 pandemic. Compared to largely pre-pandemic results, prevalence of mental health symptoms in dyad members appeared to have shifted: fewer youth and more caregivers were affected during the pandemic; many of both groups lacked optimism. Pandemic screening of youth with SCD for mental health symptoms and food insecurity appears warranted.

Among all pediatric hematologist-oncologists (PHOs) certificated by the Japanese Society of Pediatric Hematology/Oncology (JSPHO), 215 PHOs (70.0%) received $908,900 personal payments from 54 pharmaceutical companies between 2016 and 2019. Four-year combined average payments per author was $2,961 (standard deviation: $6,299). While the prevalence of physicians with payments was relatively stable during the study period with 40.4% and 44.6% in 2016 and 2019, the average annual personal payments increased nearly double from $559 in 2016 to $1,096 in 2019, respectively. Payments from the top five companies with the largest total payments accounted for 48.8% of total monetary values.

Because they can experience neutropenia due to bone marrow failure, patients with Shwachman-Diamond syndrome (SDS) carry increased risk for serious infections compared to the general population; however, it has been unknown whether this predisposes them to COVID-19 infection or more significant complications. We compiled results from a survey distributed to participants in the Shwachman-Diamond Syndrome Registry between May and June 2021. In this report we describe the characteristics and outcomes of patients with SDS who had COVID-19. Patients reported a short clinical course without significant complications or severe cytopenias. Additionally, COVID-19 vaccines were well tolerated with only minor side effects.

Background It is unclear how intensity-modulated radiation therapy (IMRT) impacts long-term risk of second malignant neoplasms (SMNs) in childhood cancer patients. Procedure Patients aged 10 years, many solid SMNs after IMRT in childhood cancer survivors develop in the high dose region. These data serve as a foundation for comparison with other modalities of radiation treatment (e.g., proton therapy).

Objective: To synthesise existing qualitative research exploring the experiences of parents caring for children with cancer during the end-of-life phase, and the factors that influence parental decision making when choosing the location of end-of-life care and death for their child. Results: This review included 15 studies involving 460 parents of 333 children and adolescents who died from progressive cancer. Where reported, the majority (58%) of children died at home or in a hospital (39%), with only a small fraction dying in a hospice. Factors impacting decision-making for location of care included the quality of communication and the quality of care available. Themes related to choosing home for end-of-life care and death included: honouring the child’s wishes, familiarity of home, and parents’ desire to be their child’s primary carer. Preference for location of death in hospital included trust in hospital staff, practical logistics and the safety of the hospital environment.

We report the first case series of 14 children with intracranial germ cell tumour (iGCT) and concomitant central diabetes insipidus (DI), who developed hyponatremia secondary to renal salt wasting syndrome (RSWS) following the administration of carboplatin. Clinicians prescribing platinum-based chemotherapy for this group of patients should be alert to the risk of RSWS. Regular monitoring should be performed as hyponatraemia can be asymptomatic until it is severe.

Background: Cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is an option in advanced peritoneal sarcomatosis. Nevertheless, CRS and HIPEC are not successful in all patients. An enhancement of HIPEC using photodynamic therapy might be beneficial. Therefore, a combination of the photosensitizer Hypericin (HYP) with HIPEC was evaluated in an animal model. Procedure: An established HIPEC animal model for rhabdomyosarcoma (NOD/LtSz-scid IL2Rγnullmice, n=80) was used. All groups received HYP (100 µg/200 µl) intraperitoneally with and without cisplatin-based (30 or 60 mg/m2) HIPEC (37 or 42 °C, for 60 min) (five groups, each n=16). Tumor dissemination was documented visually and by using HYP-based fluorescence guidance. HYP-based photodynamic therapy (PDT) of the tumor was performed. Finally, tissue samples were evaluated regarding proliferation (Ki-67) and apoptosis (TUNEL). Results: HYP uptake even in smallest tumor nodes (< 1 mm) was found. HYP-based fluorescence guidance allowed a better tumor detection in comparison to visual inspection. Immunohistochemistry revealed HYP penetration across the tumor surface. HYP-based PDT without HIPEC induced marginal apoptotic effects at the tumor surface. Combining HYP with HIPEC revealed cisplatin concentration dependent decrease in proliferation capacity and induction of apoptosis across determined cell layers of the tumor surfaces. Conclusion: HYP as fluorescent photosensitizer offers an intraoperative diagnostic advantage detecting intraperitoneal tumor dissemination. The combination of HYP and cisplatin-based HIPEC was feasible in vivo showing enhanced effects on tumor proliferation and apoptosis induction across the tumor surface. Further studies combining HYP and HIPEC will follow to establish a clinical application.

A document by Thangaraj Abiramalatha. Click on the document to view its contents.

Tristan Boam1, Bethan G Rogoyski2, Melissa Gabriel3, Paul D Losty4Department of Paediatric Surgery, Leicester Royal Infirmary, Leicester, UKLeicester School of Allied Health Sciences, De Montfort University, Leicester, UKDepartment of Urology, Norfolk and Norwich Hospital, Norwich, UKAlder Hey Children’s Hospital NHS Foundation Trust, School of Health and Life Science, University of Liverpool, UK

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors in childhood. Cancer predisposition syndromes (CPS) are increasingly recognized as the underlying cause for a number of pediatric malignancies and up to 40% of PPGL are currently thought to be associated with a hereditary predisposition1,2. With the increasingly widespread availability of functional molecular imaging techniques, nuclear medicine imaging modalities such as 18F-FDG-PET/CT, 123I-MIBG SPECT/CT, and 68Ga-DOTATATE PET/CT now play an essential role in the staging, response assessment and determination of suitability for targeted radiotherapy in patients with PPGL. Each of these imaging modalities targets a different cellular characteristic, such as glucose metabolism (FDG), norepinephrine transporter expression (MIBG), or somatostatin receptor expression (DOTATATE), and therefore can be complementary to anatomic imaging and to each other. Given the recent FDA approval3 and increasing use of 68Ga-DOTATATE for imaging in children4, the purpose of this article is to use a case-based approach to highlight both the advantages and limitations of DOTATATE imaging as it compares to current radiologic imaging techniques in the staging and response assessment of pediatric PPGL, and to offer a decision algorithm for the use of functional imaging that can be applied to PPGL, as well as other neuroendocrine malignancies.

BACKGROUND/OBJECTIVES: Survivors of pediatric brain tumors (BT) are at increased risk for difficulties with social competence, including poor social information processing (SIP) and peer relationships. Due to improved survival rates among BT, there is a need to better understand these challenges and if they are specific to BT versus other survivors of childhood cancer. METHODS: 51 BT and 34 survivors of pediatric solid tumors (ST) completed evaluations of SIP and peer relationship quality within 6 months of completing treatment and at one year follow-up. Caregivers also completed a measure of social skills. Linear mixed models evaluated (1) differences between BT and ST on SIP and social skills and (2) how indices of SIP were associated with peer relationships over time for ST and BT. RESULTS: BT did not differ from ST on indices of SIP or social skills over time. There was a three-way interaction between measures of SIP, group, and time to predict peer relationships. ST showed a positive association between baseline social skills and theory of mind and peer relationships over time, whereas BT showed an inverse association between baseline social skills and theory of mind and peer relationships over time. CONCLUSION: Baseline SIP and social skills affected the trajectory of BT peer relationships. BT social functioning should be monitored regularly after the completion of treatment to determine if and when intervention services would be beneficial.

The mRNA COVID-19 vaccine and COVID-19 infection caused by the SARS-CoV-2 virus may be immunologic triggers for the development of thrombotic thrombocytopenic purpura (TTP). There is not yet literature that discusses TTP induced by COVID-19 vaccination or infection in pediatric or adolescent patients. We describe 4 adolescents presenting with TTP (both de novo and relapsed disease) following administration of the Pfizer COVID-19 vaccine or after COVID-19 infection. Our observations demonstrate that the Pfizer-BioNTech mRNA vaccine and COVID-19 infection can act as triggers for the development/relapse of both congenital and acquired TTP.