Background: The quantitative assessment of neuroblastoma cell content in bone marrow aspirates for response evaluation has been introduced recently. Data on the concordance of interobserver reports are lacking so far. Methods: Investigators of seven European countries representing national reference or large oncological centres convened in 2016. They agreed to quantitatively assess routine bone marrow smears of the participating institutions and to discuss the discrepant results in joint meetings. Results From 2017 through 2019, three cytology rounds with 24, 28, and 28 bone marrow samples were run evaluating the representativity of the smears (yes/(restricted)/no) and the presence of tumors cells (yes/no and %). The comparison of the reports using κ (Fleiss) and α (Krippendorff) statistics demonstrated no robust reliabilities. The agreement on the representativity was moderate to poor, on the presence of tumor cells moderate to good and on the percentage of tumor cells slight to moderate. Though the unquestioned value of cytology to detect even tiny metastatic cells in bone marrow, the investigators unanimously agreed that a reliable quantification of the tumor cell content in bone marrow smears is unrealistic. For the key issue of representativity, a new practical definition was developed. Conclusion For any work with bone marrow aspirates the representativity of the material is of paramount importance. A practical definition is proposed. A reliable quantitative cytological assessment of tumor cell content in bone marrow aspirates is not feasible in metastatic neuroblastoma. Therefore its use as response criterion should be re-considered.

Bone marrow necrosis (BMN) is a rare pathologic finding, but when encountered is most often associated with malignancy. In adults its presence correlates with an inferior prognosis, however in children the prognostic implication is unclear. We performed a retrospective review of 3,760 bone marrow specimens in patients ≤ 18 years over a ten-year period. BMN was identified in less than 1% of specimens and only in patients with leukemia, lymphoma or neuroblastoma. BMN contributed to a delay in diagnosis; however, advanced medical imaging may serve as a tool to localize non-necrotic areas for bone marrow sampling, facilitating an expedited diagnosis.

To the Editor,We read the letter entitled “Acute lymphoblastic leukemia onset in a 3-year-old child with COVID-19 ” by Marcia et al . with great interest and we hereby suggest to start chemotherapy within the same timeline as for non-COVID-19 acute lymphoblastic leukemia (ALL) patients, following our experience managing a 3-year-old boy with concomitant diagnoses of precursor B-ALL and COVID-19. The patient was a previously healthy boy who presented to our hospital with a two-month history of intermittent fevers, night sweats, fatigue and cervical lymphadenopathies. His mother had been tested positive for COVID-19 three months earlier. He had been seen by his family physician by teleconference at the onset of his symptoms, at which point a COVID-19 infection was suspected but not confirmed. The persistence of symptoms and new onset of bone pain led his parents to reconsult at our hospital. At presentation, he had no respiratory symptoms. Physical examination was remarkable for fever, tachycardia and cervical lymphadenopathies. Bloodwork revealed pancytopenia and circulating peripheral blasts. Inflammatory markers were elevated (fibrinogen 7.08 g/L; C-reactive protein 255 mg/L; sedimentation rate 63 mm/h; ferritin 185 ug/L; D-dimers 0.51 ug/ml). Capillary gas, renal function, hepatic function, coagulation studies (INR/aPTT) and cardiac biomarkers (troponin and pro-BNP) were normal. Chest radiograph (CXR) was normal. COVID-19 testing by nasopharyngeal swab was positive. Bone marrow aspiration revealed 80% precursor B lymphoblasts of hyperdiploid subtype.Patient was admitted to a dedicated COVID-19 ward. Given the absence of SARS-CoV-2 infection’s severity criteria, no COVID-19-specific treatment was initiated. Chemotherapy was started promptly once the diagnostic work-up was completed, 6 days following the patient’s confirmed COVID-19 diagnosis. The patient was treated with a three-drug chemotherapy induction based on National Cancer Institute standard-risk criteria consisting of methylprednisolone, vincristine and asparaginase. Supportive treatment consisted of intravenous hydration and allopurinol for tumor lysis prevention, empirical antibiotics, blood transfusions and prophylactic low molecular weight heparin for COVID-19-associated thromboembolic complications. The patient’s clinical course was favorable; fevers, bone pains, peripheral blasts and inflammatory markers resolved quickly following the steroid prophase. Persistent and unexplained tachycardia led to extensive investigations given concerns for COVID-19-related thromboembolic complications. Troponins, pro-BNP, electrocardiogram, echocardiography, CXR and chest CT scan were unremarkable, and the tachycardia improved with packed red blood cell transfusion. The first negative COVID-19 test was obtained on day 4 of induction therapy but came back positive 48 hours later. The patient was discharged on day 13 of induction therapy. Three consecutive nasopharyngeal swabs were negative on days 21, 23 and 38 following COVID-19 diagnosis (Fig.1). End-induction bone marrow aspiration was consistent with morphologic remission and end-induction minimal residual disease by flow cytometry was positive at 0.025%.This case demonstrates the feasibility of treating children with newly diagnosed ALL who tested positive for COVID-19, without chemotherapy delay or modification, nor specific COVID-19 treatments, as done by Marcia et al . The province of Quebec constitutes the COVID-19 epicenter in Canada with half of all Canadian cases; the prevalence of COVID-19-positive cases was 3.3% among children under the age of 10, 5.3% between the age of 10-20 years and 49.2% for people aged 50 years and above.1 Importantly, no death has been reported among children in the province of Quebec, while 97.6% of COVID-related deaths were among individuals over the age of 60 years.1 Children appear to be less affected from COVID-19 infection and exhibit a milder disease course compared to adults, although the impact of COVID-19 infection among pediatric oncology patients remains unknown.2-4 Current published recommendations in the management of pediatric oncology patients during the COVID-19 pandemic emphasize on the importance of pursuing protocol-prescribed chemotherapy regimens based on the curable nature of most pediatric malignancies and the milder COVID-19 disease course observed in the pediatric population.4 However, case reports of severe COVID-19 disease in pediatric oncology patients start to emerge,5 and management of concomitant COVID-19 infection and newly diagnosed ALL can be challenging. First, our patient presented with a multisystem inflammatory syndrome which made it difficult to discern whether he was symptomatic from the COVID-19 infection versus the leukemia itself. Furthermore, we questioned whether the positive COVID-19 test by polymerase chain reaction (PCR) amplification in our patient truly reflects active infection since there was a nearly 3-month period between the first positive test in his family and when our patient was first tested positive. The positive PCR test could result from prolonged viral shedding in an immunocompromised patient affected by his leukemia onset. Alternatively, a positive test does not necessarily indicate the presence of viable virus as Wolfel and colleagues demonstrated that virus could not be grown from samples obtained from hospitalized patients beyond the eighth day of illness.6 Therefore, the general approach to await a negative result prior to begin chemotherapy might cause significant therapy delay and adversely impact outcomes in newly diagnosed ALL patients during the COVID-19 pandemic. Indeed, our patient took over 23 days to have 2 consecutive negative PCR tests 48 hours apart. Furthermore, the use of COVID-19-specific antiviral treatment in non-critically ill children is controversial given the lack of efficacy in this population.7Antiviral treatment may have significant drug interactions with chemotherapy and contribute to additive gastrointestinal and myelosuppressive toxicities. Nevertheless, the benefit of dexamethasone in COVID-19-positive patients requiring respiratory support in reducing early mortality8 and the exquisite sensitivity of lymphoblasts to corticosteroids could be an effective early strategy to safely initiate therapy in newly diagnosed ALL patients affected with COVID-19, particularly for those presenting with oncologic emergencies such as hyperleukocytosis or mediastinal mass. As the COVID-19 pandemic continues to evolve, pediatric oncologists will be confronted with the ongoing challenge to manage newly diagnosed cancer patients with concomitant COVID-19 infection. International COVID-19 registries in pediatric oncology are actively collecting clinical data to comprehensively assess the impact of COVID-19 within this patient population and to develop standardized management guidelines.9 As for now, an assessment of risks and benefits to initiate or delay cancer therapy will need to be carefully balanced on a case-by-case basis according to the patient’s clinical symptoms, type of malignancy, evidence-based treatment options, and emerging knowledge of COVID-19’s impact in our young cancer patients.CONFLICT OF INTEREST: The authors declare no conflict of interest.REFERENCES1. INSPQ. Données COVID-190 au Québec. 2020.2. Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020;382(17):1663-1665.3. Cruz AT, Zeichner SL. COVID-19 in Children: Initial Characterization of the Pediatric Disease. Pediatrics. 2020;145(6).4. Bouffet E, Challinor J, Sullivan M, Biondi A, Rodriguez-Galindo C, Pritchard-Jones K. Early advice on managing children with cancer during the COVID-19 pandemic and a call for sharing experiences. Pediatr Blood Cancer. 2020;67(7):e28327.5. Stokes CL, Patel PA, Sabnis HS, Mitchell SG, Yildirim IB, Pauly MG. Severe COVID-19 disease in two pediatric oncology patients.Pediatr Blood Cancer. 2020;67(9):e28432.6. Wolfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature.2020;581(7809):465-469.7. Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2. J Pediatric Infect Dis Soc. 2020.8. Group RC, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020.9. Sullivan M, Bouffet E, Rodriguez-Galindo C, et al. The COVID-19 pandemic: A rapid global response for children with cancer from SIOP, COG, SIOP-E, SIOP-PODC, IPSO, PROS, CCI, and St Jude Global.Pediatr Blood Cancer. 2020;67(7):e28409.Figure 1. Variation of C-reactive protein (CRP) throughout the hospitalization course (blue line). COVID-19 test results are identified in green when positive and red when negative. The day of ALL diagnosis, the day of chemotherapy start (black arrows), the duration of hospitalization (red box) and the duration of symptoms (green box) are indicated. Induction chemotherapy includes: Methylprednisone/prednisone (Day 1-32), Vincristine (Day 4, 11, 18, 25), PEG-Asparaginase (Day 7) and intrathecal cytarabine (Day 1 & 18).

Jones et al. have given us an excellent guide for the management of symptomatic osteonecrosis in children and young adults with ALL. (1) I would like to present our 10 year retrospective concurrent control evaluation of pamidronate for reducing the incidence of symptomatic osteonecrosis which may be of interest.Patients aged 10-28 years at time of ALL diagnosis were given intravenous pamidronate (1 mg/kg IV over 2 hours) monthly for one year at the discretion of the primary oncologist, starting as early as possible after diagnosis.Concurrent controls age 10-28 did not receive pamidronate. All were treated according to the concurrent COG protocols with intermittent dexamethasone during delayed intensification.(2) Imaging was performed if osteonecrosis was suspected based on symptoms. Patients with BCR-ABL ALL were excluded, as dasatinib may increase the risk of osteonecrosis. (3,4)Patients were diagnosed between January 2010 and March 2018. They were censored at relapse (n=4; 2 controls) bone marrow transplant (n=4; 3 controls) or at last follow up. Data was analyzed 6/1/2020. The median follow up is 3.3 years from diagnosis to event or censoring. This retrospective study was approved by Children’s Minnesota IRB. Data was entered into excel and transferred to SPSS version 23 for analysis.There were 65 patients, 38 males, 27 females, of which 49 had B-lineage and 16 T-lineage ALL. Pamidronate was started during induction in 63% of patients, and before delayed intensification in 85%. The mean, median and interquartile range for the number of pamidronate doses was 11.6, 12, 10.8 to 12. Pamidronate was used in 26 patients, with four subsequently developing symptomatic osteonecrosis. There were 39 concurrent controls who did not receive pamidronate with 14 developing osteonecrosis. Five from this group have since received joint replacements. There were no short or long term side-effects from pamidronate infusions including osteonecrosis of the jaw or hypocalcemia.The incidence of symptomatic osteonecrosis by Kaplan-Meier analysis with was 16% with pamidronate vs. 39% in controls (figure 1). P-value is significant at 0.043 (Breslow Generalized Wilcoxan). There was no significant difference in the leukemia lineage, gender distribution or Body Mass Index (BMI) at diagnosis between groups. For all patients the mean, median, and interquartile range for BMI was 25.8; 22.0; 14.2 to 28.8 Kg/m2.The age at diagnosis was significantly greater in the pamidronate group with a mean, median and Interquartile range 18.4; 18.6; 13.8 to 23.4 years for pamidronate patients vs. 15.6; 15.7; 11.5 to 19.9 in concurrent controls (independent means t-test p = 0.01). Age was not significant for osteonecrosis in Cox Proportional Hazard analysis (p=0.10).Study limitations include small numbers of patients from a single institution and lack of a randomized control group. Strengths of the study are the long duration of followup, as most of the patients are beyond the peak risk time for osteonecrosis. We hope these results even with its limitations would spark interest in a randomized trial of pamidronate in patients at high risk of symptomatic osteonecrosis.Author Contributions and Disclosures: Bruce Bostrom was the sole contributor to this submission and has no conflict-of-interest to disclose. Jack Knutson assisted with data collection as part of a high school senior mentor connection project. Char Bostrom provided invaluable editorial assistance.Figure 1 legend : Incidence of symptomatic osteonecrosis from time of ALL diagnosis in patients who received prophylactic pamidronate and concurrent controls.

Introduction. Mutations of the APC (adenomatous polyposis coli) gene correlate mainly with familial adenomatous polyposis (FAP), but can occasionally be pathogenic for medulloblastoma (MBL) WNT subtype as well, the course of which has only recently been described. Methods. We retrospectively retrieved all patients with documented germline APC mutations and a centrally-reviewed diagnosis of MBL to examine the outcome of their MBL, late effects of its treatment, and further oncological events. Results. Between 2007-2016 we diagnosed and treated 6 patients, all with a pathogenic APC variant mutation, who all had MBL, classic histotype. None had metastatic disease. All patients were in complete remission a median 65 months after treatment with craniospinal irradiation at 23.4 Gy, plus a boost on the posterior fossa/tumor bed up to 54 Gy, followed by cisplatin/carboplatin, lomustine and vincristine for a maximum of 8 courses. Five of 6 diagnostic revised MRI were suggestive of the WNT molecular subgroup typical aspects. Four of 6 patients had a positive family history of FAP, while gastrointestinal symptoms prompted its identification in the other 2 cases. Four patients had developed other tumors (desmoid, MELTUMP, melanoma, pancreatoblastoma, thyroid Tir3) from 5 to 7 years after MBL. Discussion. Our data confirm a good prognosis for patients with MBL associated with FAP. Patients’ secondary tumors may or may not be related to their syndrome or treatment, but warrant adequate attention when planning shared guidelines for these patients.

Pediatric oncology is justifiably proud of its long tradition of multi-institutional collaboration in clinical research. Perhaps no other field of medicine has more effectively shown what can be achieved by pooling talent and resources to study challenging diseases. Historically, most collaborative projects were limited to a single country or continent. However, more progress comes from even broader international cooperation. With rare cancers, this may be the only way to gather sufficient patient numbers to address key questions. Sharing national experiences can also lead to a deeper understanding of the advantages and risks associated with different therapeutic approaches. The first steps to increased global cooperation, however, is agreeing on a common language to describe patient cohorts and consensus standards to guide diagnosis, evaluation, and treatment. Applying these lofting goals to pediatric soft tissue sarcomas, the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT) was born.From its initial formative meeting in May 2017, INSTRuCT has patterned its structure and purpose on the successful model of the International Neuroblastoma Risk Group (INRG).1,2 The membership of INSTRuCT is composed of three large cooperative clinical trials organizations: Children’s Oncology Group (COG), Cooperative Weichteilsarkom Studiengruppe (CWS), and European paediatric Soft tissue sarcoma Study Group (EpSSG). The first goal for INSTRuCT is to develop an international risk stratification system for rhabdomyosarcoma (RMS) to replace competing systems used in Europe and North America. A common RMS risk stratification system would facilitate the comparison of clinical trial results across cooperative groups. Before generating a RMS risk stratification system, INSTRuCT agreed upon a standard RMS data dictionary, leveraging the University of Chicago’s Pediatric Cancer Data Commons expertise in data standardization.3 The compilation of COG, CWS, and EpSSG data (and data from their legacy groups) from finished studies into a single INSTRuCT dataset is nearly complete, and will include more than 7000 patients enrolled on previous RMS clinical trials. Once the RMS risk stratification project is finished, INSTRuCT will mine its dataset for answers to questions that can only be addressed with large, well-annotated clinical data. Future work will also include expanding the RMS data dictionary and adding a non-RMS soft tissue sarcoma dataset, also drawn from COG, CWS, and EpSSG clinical trials.As the multi-disciplinary members of INSTRuCT were defining their RMS data dictionary, they realized they had the opportunity to develop international consensus statements on the diagnosis, evaluation, and management of pediatric soft tissue sarcomas. Clinical trial protocols include guidelines for pathologic diagnosis, imaging staging evaluation, and local control approaches with surgery and radiation therapy varied by primary anatomic site. INSTRuCT provided the forum for international discussion and consensus building, with the goal of publishing these expert opinions for broad dissemination and use by pediatric oncologists, surgeons, radiation oncologists, radiologists, and pathologists worldwide. In this issue of Pediatric Blood & Cancer, Morris et al. publish the one of first in a series of consensus statements from INSTRuCT, focusing on the surgical management in the diagnosis and local control of RMS arising in the extremity.4 Morris et al. outline recommended biopsy approaches, the rational for routine use of regional lymph node evaluation including the role of fluorodeoxyglucose positron emission tomography, and the decision-making behind up-front versus delayed primary excision. The recommendations are guided by the principles of maximizing oncologic outcome while maintaining extremity function. Given the rarity of extremity RMS and the absence of randomized trials comparing different management strategies, Morris et al. draw upon a combination of clinical data and expert opinion in their consensus guidelines, carefully documenting the level of evidence that supports each of their recommendations. Nonetheless, these guidelines represent the current state of the art for surgical management of extremity RMS and the basis for future clinical trial recommendations. A similar consensus statement on RMS of the female genital tract has also been published in Pediatric Blood & Cancer, by Lautz et al.5 With these two consensus statements, the INSTRuCTPediatric Blood & Cancer special series is off to an excellent start, with manuscripts on the surgical management for other primary sites and the pathologic evaluation of RMS to follow soon. As INSTRuCT co-chairs, we are pleased to introduce INSTRuCT to the global pediatric oncology community and look forward to many more contributions to come.

Ketamine is a dissociative anesthetic agent, with excellent analgesic properties and a favorable safety profile. Although it acts predominantly through NMDA receptor antagonism, numerous other molecular targets have been characterized, rendering anti-inflammatory, anti-depressant, and thus expanding its scope for new clinical applications. The noticeable safety of ketamine in children enables its widespread use in pediatric oncology, chiefly for procedural sedation. Its value for chronic pain management in children with cancer is being increasingly recognized but requires more evidence. The topical use of ketamine is largely in investigational stages.. Rational medical use of ketamine is largely free from significant long-term neurological side effects but may have some troublesome short-term effects such as vomiting, palpitations, urinary retention, and hallucinations. This review will provide a brief account of the pharmacology of ketamine and primarily focus on the relevant aspects of ketamine in pediatric oncology.

BACKGROUND Despite improvements in overall survival for pediatric cancers, treatment disparities remain for racial/ethnic minorities compared to non-Hispanic white; however, the impact of race on treatment outcomes for pediatric brain and central nervous system (CNS) tumors in the United States is not well known. METHODS We included 8713 children aged 0 – 19 years with newly diagnosed primary brain and CNS tumors between 2000 – 2015 from the Census Tract-level SES and Rurality Database developed by Surveillance, Epidemiology and End Results Program. We used Chi-square tests to assess differences in sociodemographic, cancer, and treatment characteristics by race/ethnicity and Kaplan–Meier curves and Cox proportional hazards models to examine differences in 10-year survival, adjusting for these characteristics. RESULTS Among 8,713 patients, 56.75% were non-Hispanic white, 9.59% non-Hispanic black, 25.46% Hispanic, and 8.19% from “other” racial/ethnic groups. Median unadjusted survival for all pediatric brain tumors was 53 months but varied significantly by race/ethnicity with a median survival of 62 months for Non-Hispanic whites, 41 months for Non-Hispanic blacks, and 40 months for Hispanic and Other. Multivariable analyses demonstrated minority racial groups still had significantly higher hazard of death than non-Hispanic whites; Hispanic [aHR 1.25 (1.18 - 1.31)]; non-Hispanic black [aHR 1.12(1.04 - 1.21)]; Other [aHR 1.22(1.12 - 1.32)]. Results were consistent when stratified by tumor histology. CONCLUSION We identified disparities in survival among racial/ethnic minorities with pediatric brain and CNS tumors, with Hispanic patients having the highest risk of mortality. Eliminating these disparities requires commitment towards promoting heath equity and personalized cancer treatment.

A document by Denis Cozzi. Click on the document to view its contents.

Background. Adolescents/young adults (AYAs) with acute lymphoblastic leukemia (ALL) are more likely to have chemotherapy-related complications than children. In addition, several reports have shown that infections account for most of the therapy-related mortality during cancer treatment in AYAs. Thus, we hypothesized that chemotherapy-induced myelosuppression is more severe in AYAs than in children, and the state of neutropenia was compared between children and AYAs using the D-index, a numerical value calculated from the duration and depth of neutropenia. Procedure. This study retrospectively analyzed 95 patients newly diagnosed with ALL at our institution between 2007 and 2019. Of these, 81 were children (< 15 years old) and 14 were AYAs (≥ 15 years old). The D-index and duration of neutropenia during induction chemotherapy for ALL were compared between children and AYAs. Results. The median D-index of children was significantly higher than that of AYAs (8,187 vs. 6,446, respectively, P = 0.017). Moreover, the median duration of neutropenia was also significantly longer in children than in AYAs (24.0 days vs. 11.5 days, respectively, P = 0.007). Conclusion. Contrary to our expectations, myelosuppressive toxicity during induction chemotherapy for ALL was more severe in children than in AYAs.

Langerhans Cell Histiocytosis (LCH) is characterized by activating variants of the MAPK pathway. Inhibition of the MAPK pathway with trametinib (MEK inhibitor) has been shown to induce responses in LCH patients. Two adolescent males with LCH driven by BRAF p.N486_P490del have received trametinib for >1 year with no reactivation in one and partial response in another (including stable lung disease). A third male with neonatal LCH and MAP2K1 p.K57_G61del had a complete response to trametinib with no active disease after 22 months. All patients continue on trametinib monotherapy with tolerable skin and CPK toxicity.

Background: The prognosis of children with acute myeloid leukemia (AML) has improved with the efficacy of hematopoietic cell transplantation as a second-line therapy and improvements in supportive care following anthracycline- and cytarabine-based chemotherapy; however, the outcomes of children with relapsed AML still remain unsatisfactory. Procedure: In order to identify prognostic factors and improve their prognosis, we analyzed 111 patients who relapsed after treatment with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol and who were registered in the retrospective JPLSG AML-05R study. Results: The 5-year overall survival rate was 36.1%. The major determinant of survival was duration from the diagnosis to relapse. The mean duration in the non-surviving group (10.1 ± 4.1 months) was shorter than that in the surviving group (16.3 ± 8.3 months) (p<0.01). Moreover, achieving a second complete remission (CR2) prior to hematopoietic cell transplantation was associated with a good prognosis (p<0.01). Etoposide, cytarabine and mitoxantrone (ECM)- or fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG)-based regimens were therefore recommended for reinduction therapy (p<0.01). A genetic analysis also revealed the prognostic significance of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication as a poor prognostic marker (p=0.04) and core binding factor-AML, t(8;21) and inv(16), as good prognostic markers (p<0.01). Conclusions: Achieving a CR2 prior to HCT is important in order to improve the prognosis of relapsed pediatric AML. Recent molecular targeted therapies, such as FLT3 inhibitors, may contribute to overcome their prognoses. Larger prospective investigations are necessary to establish individualized treatment strategies for patients with relapsed childhood AML.

Cytotoxic agents are the major part of current therapeutic arsenal in pediatric oncology. Recently, small molecules have been combined in the standard regimen for targeted cancer therapy. Both drugs provoke adverse effects on the living cells via the specific and non-specific actions to neoplastic cells. Considering genetic and epigenetic events, the late effect rather than acute toxicity is a matter of concern for healthy subjects at risk of exposure to anticancer drugs. To reduce the risk, a list of hazardous drugs (HDs) has been updated by the National Institute for Occupational Safety and Health (NIOSH) including commonly used cytotoxic agents. HDs are defined by their association with genotoxicity, carcinogenicity, teratogenicity, impaired fertility, reproductive toxicity, and/or serious organ toxicity even at a lower dose.1 The American Society of Clinical Oncology (ASCO) standard promotes the safety of professional staff of pharmacists, physicians, nurses, and other collaborators in oncology care.2 It recommends the preventive measures to avoid the toxic products, incorporating the latest evidence of the deleterious late effects after exposure, and the benefits of control measures, along with expert consensus. United States Pharmacopeia Chapter <800> requires an appropriate list of HDs in healthcare settings, providing concrete information regarding the articles of personal protective equipment, as well as where and how they should be donned, used, and removed is prescribed.3Several guidelines for the occupational exposure to HDs have been established for the health of hospital workers,1-5 but not the family members of childhood cancer. We thus investigated the exposure of caregiver and medical staff to anticancer drugs and the environmental contamination. Fifteen inpatients with pediatric cancer were recruited who received high-dose cyclophosphamide (CPM) from 2017 to 2018. Seven infants and 8 adolescents had 4 leukemias and 11 solid tumors. The median age at the time of this study was 78 months ranging from 13 to 200 months. The infants and adolescents received CPM of 1g /m2 or more; median 640 (range 620~1300) mg, and 1230 (range 780~1230) mg, respectively. Six hours after the first administration, the concentration of CPM was measured in the urine and saliva from attending mothers, nurses, doctors, nursery teachers, child-life specialists, and housekeeping staff members in the ward, using the liquid chromatography/mass spectrometry method (Shionogi Analysis Centre Co., Ltd., Osaka, Japan)6. Safe handling and closed-system-drug-transfer devices (JMS Co. Ltd., Hiroshima, Japan) are the standard of our center to minimize the technical exposure.7 This study was approved by the institutional review board of Kyushu University. Five of 7 (71%) infant’s and 2 of 8 (25%) adolescent’s mothers showed increased urine levels of CPM. The median value of infant’s mothers (192 ng/10 mL, range 0~1,510) was significantly higher than that of adolescent’s mothers (0 ng/10 mL, 0~58.4) (p =0.005). CPM was detected in the saliva samples of two mothers caring infants, but not in the urine or saliva of any medical staff (Figure ). The environmental contamination in a room of the infant whose mother showed the highest concentrations was assessed by the modified method.6 High levels of CPM were determined in the monitoring samples from a 17-year-old boy; toilet floor (1020 times of the detection limit), toilet seat (167 times), wash basin (45.6 times), a 13-year-boy; underwear (735 times) bed sheets (224 times), bed fence (34.8 times), bedside floor (20.9 times), exhaust vent (13.1 times), bedside table (7.4 times), door knob (4.9 times), curtain (4.7 times), and a 2-year-boy; bathing hot water (205 times) at 24 hours after the first administration, respectively. No staff having detectable CPM levels represented the control of HDs exposure in our hospital. In contrast, the exposure was frequently found in attending mothers caring infants. The higher levels of CPM in infants’ mothers than in adolescents’ mothers are explained by the closer contact for care. The environmental contamination has occurred from the body fluid of patients but not the drug delivery.The latest systems and guidelines have effectively controlled the accidental exposures of drugs to medical staff, as shown in the present results, throughout the process from the formulation in the pharmacy department, transportation, and administration to bed-side patients. The mother’s exposure is categorized as an intermediate risk. It may occur in case of high-dose therapy with limited duration. However, the metabolites of CPM including 4-hydroxycyclophosphamide show cytotoxicity.9 The mixture of selected cytostatic drugs has an augmented cytotoxicity leading to the late effects on genome even at low concentrations.10 During the long-term intense chemotherapy for pediatric cancer, the preliminary results may raise the need for preventive measures for caregivers according to the equivalent levels to medical staffs.

Obituary PBC Dr Pat Morris JonesDr Morris Jones who was President of SIOP in 1980/81 died on March 16 2020 at the age of 87. She was one of the first doctors in the UK to specialise in the care of children with cancer and over her 40 year career from 1953 to 1993 she saw survival rates improve from cancer being mainly a fatal disease to one where there was a real chance of cure with more than half of children surviving. She was an only child ,born in Oswestry ,close to the border with Wales. She trained in medicine at the Royal Free Medical School in London and found her way to Manchester to specialise in paediatrics. There she came under the influence of Basil Marsden, a paediatric pathologist and Dr Dorothy Pearson a radiotherapist. In 1954 Marsden had established the world’s first population based children’s malignant disease registry which became a prototype for registries all over the world. Dr Pearson was a founding member of SIOP and its second president. In the late 50s and early 60s the only real treatments available were surgery and radiotherapy but the emerging success of chemotherapy pioneered in the US, France and Germany led to a need for paediatricians to sub specialise in paediatric oncology. By the time Pat became involved the antagonism towards giving children chemotherapy had largely dissipated but how to use it to best advantage remained to be determined. She took up this challenge and built up one of the largest units in the UK. For many years she was single handed and absolutely dedicated to the care of children. She rarely took a day off. . Before people were talking about evidence based medicine she was adamant that treatment should be given in trials where we could learn what was best for the future. She was especially interested in Wilms’ tumour and very involved in the Medical Research Council embryonal tumour group and in the MRC UKALL trials. In 1977 she helped found the UK Children’s Cancer Study Group (UKCCSG) which eventually ensured that all children in the UK with cancer had access to the most up to date treatment. The early involvement of Manchester in the pre chemotherapy era using radiotherapy, and the registry, led her to take a real interest in the late effects of treatment. She had a collection of slides which she used to illustrate the late effects of radiotherapy when given to young children. Failure of skeletal growth could ensue from radiotherapy to growing bones and second malignancies occurred within radiation fields. She became heavily involved with Anna Meadows in Philadelphia in setting up the Late Effects Study Group which received substantial funding from NIH. This work was extended and has been perpetuated by Les Robison and his colleagues and has hugely influenced the design of clinical treatment protocols in recent years. She wrote an influential paper in 1990 entitled Childhood Cancer; Cure at what cost? In which she described the evolution of treatment for childhood cancer from one of cure at any cost to cure at least cost. Her fervent hope was that we would eventually get to a stage of cure at no cost. Pat was an inspirational teacher and leader and many of the young aspiring paediatric oncologists in the 70s turned to her for career advice and then once appointed to a post used her as a source of support and advice on patient management. She was most people’s “phone a friend”.The psychosocial problems faced by both children and parents became much more obvious once potentially curative treatments were being used. Paradoxically parents seemed to be able to cope better with the near certainty of death of their child than with the possibility, but by no means certainty, of long term survival. She worked closely with Peter McGuire, a psychiatrist, and with social workers to define the problems faced by children and their families and devised interventions to try and help. It was clear from the early leukaemia trials, which involved cranial irradiation and brain tumours that endocrine insufficiency was a real problem and she worked closely with Professor Steve Shalet, a paediatric endocrinologist, to not only define what these problems were but also how to follow up and screen survivors. She was always much in demand for conferences once causing consternation in Bruges when, invited to take a shot at the men only archery club she hit the bull’s eye first time. The local tradition was that anyone who did this was invited to become a member.Her retirement at the age of 60 was marked by an enormous party in Manchester Town Hall attended by many of the patients whom she had successfully treated and the parents of many of those who had died. She remembered all of their names. She was short in stature but big in personality, loved clothes and is remembered for her leather skirts and red shoes. In later years her hair was often a shade of blue and always well coiffeured . She was always a straight talker and had lots to say in meetings. She was direct and always had strong opinions. She was once quoted in a national newspaper that money was being wasted on sending children to Disneyland.Throughout her career she loved foreign travel which was often associated with scientific meetings. She built up a wide circle of friends including Anna Meadows, Dan D’Angio, Mark Nesbit and Audrey Evans whom she would call upon to offer training places to her aspiring young colleaguesWhen she retired from clinical work in 1993 she decided to move to London. “As a single lady why would I want to move into a country cottage? Soon after her move to central London she met and married her Italian hairdresser, Alfonso Cassarini, and enjoyed 20 blissful years travelling widely and exploring the capital’s culture.Pat Morris Jones was a forceful and formidable pioneer who always had the best interests of children and their families at the forefront of everything that she did. The incredible survival rates for children with cancer in the present era using treatments which are designed to minimise late effects are built on the shoulders of giants like her who dared to try.Alan CraftTim Eden

The coagulopathy of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well documented in adults, with increases in D-dimer and prothrombin time strong predictors of mortality and anticoagulation shown to decrease this mortality. Viscoelastic parameters such as elevations in maximum clot firmness (MCF) on rotational thromboelastometry (ROTEM) have correlated with a hypercoagulable state in adults with SARS-CoV-2. We report our experience in children infected with SARS-CoV-2, with noted elevations in D-dimer and MCF on ROTEM (indicating hypercoagulability). Exploration of viscoelastic testing to provide additional laboratory-based evidence for pediatric-specific risk-assessment for thromboprophylaxis in SARS-CoV-2 is warranted.

As we celebrate 2020 as the Year of the Nurse and the Midwife and recognize the Global Initiative for Childhood Cancer, members of the International Society of Pediatric Oncology (SIOP) Baseline Nursing Standards Taskforce would like to highlight advocacy efforts promoting the baseline nursing standards.1, 2 Your published article, An ethical imperative: safety and specialization as nursing priorities of WHO Global Initiative for Childhood Cancer(Pergert and colleagues) reveals the importance of ongoing efforts to support implementation of the Baseline Nursing Standards.3 Given that the majority of hospitals are not meeting the standards in low- and middle-income countries (LMIC), as well as some high-income countries (HIC),4, 5 advocacy initiatives are required to raise awareness of the need to meet these standards. During the COVID-19 pandemic, health facilities face new challenges in meeting the standards. To achieve the WHO global initiative’s goal to save one million children’s lives by 2030, it is important to continue efforts to address baseline nursing standards.Pediatric oncology as a subspecialty requires a nursing workforce with specialized education and clinical skills to achieve optimal patient outcomes. Knowledge itself is not enough if nurses lack the resources and support to practice or implement appropriate nursing care in their work settings. The six Baseline Nursing Standards focus on key elements essential to delivering quality and safe care (Table 1). Collectively, they serve as a framework and foundation for positive pediatric oncology nursing practice environments internationally.Advocacy efforts to disseminate the baseline standards are well established. To date, fourteen organizations have endorsed the Standards. Members of the SIOP PODC Nursing Working Group hosted a “Leadership and Advocacy Workshop: Disseminating the Baseline Nursing Standards” prior to the SIOP Conference in October 2017. Twenty-two pediatric hematology/oncology nurse leaders and four stakeholder-group representatives (parent, physicians, advocates) from 14 countries met and established goals and strategic priorities for advocacy of the standards. As a result, the Baseline Nursing Standards Advocacy Toolkit was developed and can be found on the SIOP Nursing Website https://siop-online.org/baseline-nursing-standards-advocacy-toolkit. The toolkit contains practical advocacy resources, including a PowerPoint presentation, an endorsement letter template, publications, podcasts, a social media campaign and examples of elevator speeches for each standard. Furthermore, the Standards have been featured in international presentations, such as a keynote presentation (S. Day) in SIOP Lyon, an award session and nursing abstract presentations at SIOP congresses and continental meetings.To reach the WHO target of doubling the global childhood cancer survival rate to 60%, achievement of baseline nursing standards for pediatric oncology must be prioritized and appropriately resourced by hospital administrators, governments and other stakeholders. Amid a global pandemic where nursing resources are stretched, creative ways to support and advocate for implementation of the standards is needed. In recognition of the recent publication by the Nurse Specialists of the Global Initiative for Childhood Cancer noting the baseline standards, now is the time to act and improve childhood and adolescent cancer outcomes through raising the standard of pediatric oncology nursing practice around the world.Linda Abramovitz, Rehana Punjwani, Glenn M. Afungchwi and Courtney Sullivan and the SIOP PODC Baseline Standards Nursing Task Force.A special thank you to Rachel Hollis for her commitment and ongoing advocacy efforts focused on the baseline nursing standards.ReferencesDay S, Hollis R, Challinor J, Bevilacqua G, Bosomprah E, SIOP PODC Nursing Working Group. Baseline standards for paediatric oncology nursing care in low to middle income countries: position statement of the SIOP PODC Nursing Working Group. Lancet Oncol. 2014; 15(7):681-682 PMID: 24872097.Day S, Challinor J, Hollis R, Abramovitz L, Hanaratri Y, Punjwani R. Paediatric Oncology nursing care in low-and middle-income countries: a need for baseline standards. Cancer Control. 2015;2015:111-116Pergert P, Sullivan CE, Adde M, et al. An ethical imperative: Safety and specialization as nursing priorities of WHO Global Initiative for Childhood Cancer. Pediatr Blood Cancer. 2019;e28143. https://doi.org/ 10.1002/pbc.28143Morrissey L, Lurvey M, Sullivan C, et al. Disparities in the delivery of pediatric oncology nursing care by country income classification: international survey results. Pediatr Blood Cancer. 2019;66(6):e27663.Sullivan CE, Morrissey L, Day SW, Chen Y, Shirey M, Landier W. Predictors of Hospitals’ Nonachievement of Baseline Nursing Standards for Pediatric Oncology. Cancer Nurs. 2019 Mar 29;

As the effects of cancer and its treatment have long-lasting negative impacts on the health and quality of life of survivors, there is a need to explore new avenues to optimize long-term patient outcomes in pediatric oncology. Therefore, this scoping review aims to report on the state of the evidence on the use and effects of behavioural interventions targeting physical activity and diet behaviours in pediatric oncology. Fourteen quantitative studies were included. Studies evaluated a combination of two or three different modalities, including education (n=11), physical activity (n=6), psychosocial support or training (n=6), reward system (n=2) and adventure-based activities (n=1).  Overall, behavioural interventions in pediatric oncology appear beneficial; however, no conclusive evidence favouring specific interventions were identified.

There are no proven safe and effective therapies for children who develop life-threatening complications of SARS-CoV-2. Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2 but has theoretical risks. We report on the first use of CP in children with life-threatening COVID-19, providing data on four pediatric patients with acute respiratory distress syndrome. We measured donor antibody levels and recipient antibody response prior to and following CP infusion. Infusion of CP was not associated with antibody-dependent enhancement (ADE) and did not suppress endogenous antibody response. We found CP was safe and possibly efficacious. Randomized pediatric trials are needed.