Letter to the EditorCoronavirus disease COVID-19 has deeply modified national health services with a profound impact on hospital and in particular emergency and intensive care units (ICU) activities. As recently reported in Italy pediatric emergency accesses substantially decreased likely due to the instructions to prevent overcrowding in emergency rooms and spread of SARS-CoV-2 infection and to fear of the infection.1 At the Santobono-Pausilipon Hospital (Neaples), pediatric emergency accesses in March 2020 were only one fifth of those registered in 2019 in the same period. Likewhise a marked reduction of consultations occurred also in family pediatricians clinics.2We report here 3 children who arrived at hospital in life-threatening conditions at the onset of Acute Lymphoblastic Leukemia (ALL) between March 14 and April 10, 2020.First case: a 2-year-old-child arrived at the emergency department with a 15 days history of fatigue, pallor and dyspnea, in a comatose state, with severe anemia, respiratory distress, hematemesis and metabolic acidosis. Chest X-ray showed interstitial pneumonia. Blood tests showed: hemoglobin 2.7 gr/dL, WBC count 185.000/μl, platelets (PTL) 10.000/μl, LDH 3609 U/L. Peripheral blood was diagnostic for CD10, CD19 and CD58 positive ALL (B-lineage ALL). The patient, admitted at the ICU, intubated, transfused with RBC, PTL and plasma, died 12 hours after arrival at the hospital due to progressive worsening of clinical conditions. The nasal swab was negative for SARS-CoV-2 and positive for adenovirus.Second case: a 5-year-old-child arrived at the emergency department with a one month history of respiratory distress. Imaging showed a mediastinal mass compressing the brachiocephalic vein, the aorta, the pulmonary trunk and the left pulmonary artery, tracheal deviation, compression of the left main bronchus, left lung atelectasis and pleural effusion. Blood tests showed: hemoglobin 14.5 gr/dL, WBC count 37.000/μl, PTL 294.000/μl, LDH 6153 U/L, creatinine 1.9 mg/dl. Peripheral blood was diagnostic for CD5, CD7, CyCD3 and CD8 positive ALL (T-ALL). Steroid treatment was started. Clinical conditions deteriorated rapidly with cardiac and renal failure. The patient, admitted to ICU 2 hours after arrival at the hospital and intubated, died 24h later. The nasal swab was negative for SARS-CoV-2.Third Case: a 4-year-old child arrived at the hospital with one month history of fever, cough and shortness of breath treated at home with antibiotics and steroids without improvement. Imaging showed a mediastinal mass compressing the left brachiocephalic, azygos and superior cava veins, and right pulmonary artery and vein; mild tracheal deviation, compression of the left main bronchus; pericardial and pleural effusion; nephro-hepato-splenomegaly and ascites. Due to signs of cardiac tamponade, pericardiac and pleural drainage were placed and the patient was admitted at ICU and intubated. Blood tests showed: normal hemoglobin, WBC and PTL counts; LDH 2732 U/L, creatinine 2.98 mg/dl, K 8 mEq/L, Ca 5.4 mEq/L. Bone marrow was diagnostic for CD2, CD5, CD7, CD99 and CyCD3 positive ALL (T-ALL). Treatment with steroids was started. Due to progressive renal failure hemodialysis was performed for 9 days. Clinical conditions improved with rapid shrinking of mediastinal masses and resolution of pericardial and pleural effusion. The patient was thus extubated and treatment for ALL was instituted with good response to induction therapy. The nasal swab was negative for SARS-CoV-2.The 3 cases of ALL here described, 2 of them fatal, arrived at the hospital in critical conditions, most likely as a consequence of fear of COVID-19. Delay in diagnosis of neoplastic disease is a well-known problem in low-middle income countries (LMIC), but is quite rare in high-income countries (HIC). Actually, this combination of events never occurred in the past at the Santobono-Pausilipon Hospital, where, at the time of writing, no SARS-CoV-2 positive cases have been identified among children treated for cancer.Considering low prevalence of virus spreading in children and that SARS-CoV-2 positive children are generally asymptomatic or have a very mild course of the disease there is a substantial risk that collateral effects of COVID-19 pandemic, i.e. delays in diagnosis, chemotherapeutic treatments and treatment of chemotherapy complications, may be worse than those posed by the disease itself.3,4,7 Recently the major pediatric cancer scientific associations have expressed great concern on the risk that fear to access to medical care raised by Covid-19 may cause these delays not only in LMIC but also in HIC with dramatic consequences we are not used to face.5-6 Our experience confirms the occurrence of these collateral effects, indicating that there is a need of awareness of this risk and careful medical attention to assure timely diagnoses and adequate treatment adherence in childhood cancer.

We report a case of a 34-month-old girl who has been followed up for 12 months after ingesting 105mg/kg of hydroxyurea (HU) and showed only transient mild bone marrow suppression. With anticipated increase in HU use among children with SCD in sub-Saharan Africa, the possibility of accidental ingestion should be envisaged and appropriate user-education and management guidelines established. Toxicity from accidental HU overdosage is generally mild and transient and should not constitute a barrier to its use in Nigerian children with SCD.

Abbreviations Full term COVID-19 coronavirus disease 2019 SARS-CoV-2 Severe acute respiratory syndrome corona virus 2

CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) is a rare entity recently described. Thirteen CNS HGNET-MN1 patients were identified using genome wide methylation arrays/RT-PCR across 7 institutions and were correlated with treatment and outcome. All patients had surgery (GTR:9/STR:4) as initial management followed by radiotherapy (focal:5/craniospinal:2/CyberKnife:1) and systemic chemotherapy in 3 patients. Seven patients relapsed; 5 local and 2 metastatic despite complete resection and radiotherapy. Three patients died due to their tumor relapse after 24 months despite upfront radiotherapy. Treatment of CNS HGNET-MN1 remains a major challenge with multiple failures, despite aggressive surgical resections and upfront radiotherapy.

Survivorship care is a major area of focus in the holistic management of childhood cancer with current knowledge and information almost exclusively from high-income countries. In this review, we summarize the state of scientific knowledge, service delivery, advocacy initiatives and research efforts in this field in India. 21 single centre studies published till date (20 in the last decade) confirm some of the well-documented issues in childhood cancer survivors and also highlight the high prevalence of hepatitis B and hepatitis C infection in our survivors. Heterogeneity in methodology, outcome metrics and quality precludes drawing further conclusions and the ongoing multicenter Indian Pediatric Oncology Group study would address this. Besides the usual model of follow-up clinics in hospital settings, innovative models of service delivery led by not-for-profit organisations are being developed. Advocacy initiatives driven by survivors and support groups are also underway. All of these portend a promising future.

The impact of wearing a mask on face-touching behavior is unknown. We conducted a brief survey and observational study to assess the perception and to quantify how masks affect face-touching behavior. Most felt that the mask would alter their face-touching behavior with only 18.3% feeling that masks would not affect it. During a total of 330 person-minutes of observation, overall face-touching rate was 15.1 face touches/hour (FT/hr), 6.4 FT/hr while wearing a mask and 20.1 FT/hr without a mask (p <0.01). Masks are an effective barrier and reduce face-touching behavior amongst healthcare professionals.

Background: Among pediatric hematopoietic stem cell transplant (HSCT) recipients, abnormal glycemic control is shown to be associated with increased risk of transplant-related mortality, death from any cause, risk of infection, increased hospitalized and intensive care days. Independent effects of higher glycemic variability, a component of glycemic control, have not been described. This study aimed to characterize risk factors for, and consequences of, higher glycemic variability in HSCT patients. Procedure: Medical records for a cohort of 344 patients, age 0-30 years, who underwent first HSCT from 2007–2016 at Children’s Hospital Colorado were retrospectively reviewed. Glucose coefficients of variation (CV) were analyzed for HSCT days -14 to 0 and 0-30, and patients were assessed for potential risk factors and outcomes. Results: Roughly one third of patients had pre-HSCT and day 0-30 glucose CV above the reported healthy adult range. Independent of HSCT type, doubling of pre-HSCT glucose CV was associated with a 4.91-fold (95% CI 1.40-17.24) increased hazard of infection, as well as increased risk for intensive care hospitalization for allogenic HSCT patients. Multivariable analysis demonstrated that allogeneic HSCT patients had a 1.40- and 1.38-fold (95% CI 0.98-1.99 and 1.00-1.91) increased hazard of death for every doubling of pre-HSCT and Day 0-30 glucose CV, respectively. Conclusions: Just as with higher mean glucose, higher glycemic variability in the pediatric HSCT population is independently associated with significantly increased morbidity. Additional research is required to evaluate the utility of glucose control to mitigate these relationships and improve HSCT outcomes.

Comment on: 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.Chetan Dhamne MSc MD1, Tushar Vora MD1, Maya Prasad MD1, Nirmalya Roy Moulik MD PhD1, Badira C Parambil MD DM1, Akanksha Chichra MD1, Girish Chinnaswamy MD1, Shripad Banavali MD1, Gaurav Narula MD11 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India2. Homi Bhabha National Institute, Anushaktinagar, Mumbai, IndiaCorrespondence to:Gaurav Narula Pediatric Hematolymphoid Disease Management Group, Department of Medical Oncology, Tata Memorial Center, Parel Mumbai, 400012 Email: [email protected] word count: 576Brief running title: Letter to Editor (COVID-19) Global responseKeywords: COVID-19, SARS-CoV2, Pediatric Oncology, Children with cancerTables: 1Abbreviations

In the midst of a global public health crisis, medical providers find themselves on the frontline of unprecedented circumstances caring for patients as they fight the coronavirus disease 2019 (COVID-19) pandemic. Pediatricians are faced with the reality that COVID-19 positions marginalized groups of children and youths at an increased vulnerability to health care inequities. These at-risk groups include children and youth who are ethnic and racial minorities, immigrants, LGBTQ, homeless, in foster care, as well as those who have medically complex health conditions and/or mental health and substance use disorders (1, 2, 3). Now more than ever, health disparities have the potential to result in fatal health outcomes and healthcare professionals have the power to advocate for and protect their young patients. Given the urgent and pressing impacts of the current pandemic, Tsai and Kesselheim offer a timely and critical dialogue in this issue of Pediatric Blood & Cancer, focused on the effects of provider implicit bias that contribute to health disparities.Tsai and Kesselheim underscore the well documented literature on implicit bias in pediatric medical oncology and note the limited research in pediatric hematology-oncology, despite the complexities that exists in prognosis and treatment plans for this clinical population. Additionally, the case examples are thoughtful, transparent self-reflections from the authors personal clinical experiences with implicit bias in the field of pediatric hematology-oncology. The authors then outline a plan of action towards mitigating implicit bias in healthcare. They first emphasize the importance of acknowledging implicit bias, which is ubiquitous in human nature and exists under many circumstances. Subsequently, upon acknowledgment of existing implicit bias, providers should cultivate self-awareness via medical education in order to have the autonomy and ability to identify and detect implicit bias that negatively affect patient care. Moreover, the authors deduce that diversifying the medical team, both demographically and interprofessionally, can optimize detection of implicit bias. The authors go on to conclude that more research is needed in the specialty field of hematology-oncology to identify how implicit bias specifically affects provider’s ability to communicate complex diagnoses, prognoses, and treatment options.Derived from social psychology research, implicit bias refers to unconscious, unintentional, and automatic positively or negatively skewed classifications people make based on their own experiences and demographic background which then influences behavior and perceptions. The Institute of Medicine published a pivotal report illuminating how implicit bias can negatively influence patient care and may lead to health disparities (4). Examples of implicit bias affecting health outcomes include biases toward race, weight, sexual orientation, socioeconomic status, age, marital status and history of drug use (5, 6). There are two paths that may explain how implicit bias amongst medical providers may contribute to health disparities (5, See Figure 1). Path A suggests provider judgements and decisions regarding patient care can result in health disparities. Path B proposes that implicit bias amongst providers can lead to ineffective communication which affects the providers ability to cultivate a trusting relationship and environment. Patient’s distrust with their providers affects their willingness and ability to adhere to treatment recommendations which subsequently leads to health disparities. Moreover, this model also explains the conduit for interaction effects between path A and B. That is, compromised judgment leading to poor medical decisions may strengthen the probability of poor communication and distrust in the provider-patient relationship or the inverse. Also imperative to the discourse of health disparities and bias, not discussed by Tsai and Kesselheim, is the notion of “privilege” that, unlike minorities, many non-minorities may experience in their rise to becoming a medical professional as well as their medical decision making (7). Such privilege can inadvertently bias providers to behave in ways that illuminate implicit bias. Therefore, the ability to acknowledge privilege is essential to increasing one’s proclivity to recognize their implicit biases. The authors provide vignettes that pointedly describe the importance of self-awareness. Practicing self-awareness promotes the ability to detect implicit biases that may affect patient care and result in unintentional health disparities. Moreover, central to the author’s argument, it is fundamentally important to identify and implement practical steps to address provider implicit bias.The use of research to inform best clinical practice by implementing skills training is key in addressing health disparities related to provider implicit bias. A potential barrier to successful training and education on provider implicit bias is limited support from institutional leadership (8). Committed leadership on curricula related to implicit bias at an institutional level is likely to reflect long-term systemic change (9, 10). Furthermore, providing a nonjudgmental and safe environment for providers to address difficult content is also key in fostering self-awareness that is more likely to result in long-term change (10). Considering the role of power dynamics in practice and training is also fundamental for cultivating a safe environment for self-disclosure and self-awareness and bringing about systemic long-standing modifications. Tsai and Kesselheim highlight the importance of building demographically diverse and interdisciplinary medical teams. Purposeful team development can also reveal and mitigate any systemic workforce and recruitment biases (11). Having various perspectives while discussing a treatment plan can combat implicit bias. For example, if a complex case is presented at morning rounds with a team that is homogeneous in background and trainings there is potential for groupthink that is anchored in one or two individuals’ implicit biases. Specific to complex cases in pediatric hematology-oncology this can be critical especially during a pandemic that is particularly impacting vulnerable populations, who are often less likely to be represented among medical decision makers. A diverse team can provide insight for culturally competent care as well as provide important perspectives that could optimize diagnostic and treatment outcomes.As a clinician, it is not an easy task to be open to becoming vulnerable to exploring self-awareness as it relates to implicit bias. It is also our ethical duty to do no harm. Acknowledging implicit bias as a catalyst to health disparities while implementing effective skills training to address implicit bias is crucial to protecting our most vulnerable pediatric patients.ReferencesSilliman Cohen RI, Adlin Bosk E. Vulnerable youth and the COVID-19 pandemic. Pediatrics . 2020; doi: 10.1542/peds.2020-1306Cholera R, Falusi OO, Linton JM. Sheltering in place in a xenophobic climate: 12 COVID-19 and children in immigrant families. Pediatrics. 2020; doi: 10.1542/peds.2020-1094Wong CA, Ming D, Maslow G, Gifford EJ. Mitigating the impacts of the COVID-19 pandemic response on at-risk children. Pediatrics . 2020; doi: 10.1542/peds.2020-0973Smedley BD, Stith SY, Nelson AR, Smedley BD, Stith SY, Nelson AR, editors. Unequal treatment: confronting racial and ethnic disparities in health care. Institute of Medicine. National Academies Press; Washington, D.C: 2002. doi.org/10.17226/12875Zestcott C, Blair I, Stone J. Examining the presence, consequences, and reduction of implicit bias in health care: A narrative review. Group Processes & Intergroup Relations . 2016;19(4):528-542. doi:10.1177/1368430216642029DelFattore J. Death by Stereotype? Cancer Treatment in Unmarried Patients. New England Journal of Medicine . 2019;381(10):982-985. doi:10.1056/nejmms1902657Hall J, Carlson K. Marginalization. Advances in Nursing Science . 2016;39(3):200-215. doi:10.1097/ans.0000000000000123Dehon E, Weiss N, Jones J, Faulconer W, Hinton E, Sterling S. A Systematic Review of the Impact of Physician Implicit Racial Bias on Clinical Decision Making. Academic Emergency Medicine. 2017;24(8):895-904. doi:10.1111/acem.13214Pereda B, Montoya M. Addressing Implicit Bias to Improve Cross-cultural Care. Clin Obstet Gynecol . 2018;61(1):2-9. doi:10.1097/grf.0000000000000341Sherman M, Ricco J, Nelson S, Nezhad S, Prasad S. Implicit Bias Training in Residency Program: Aiming for Enduring Effects. Fam Med. 2019;51(8):677-681. doi:10.22454/fammed.2019.947255Hall W, Chapman M, Lee K et al. Implicit Racial/Ethnic Bias Among Health Care Professionals and Its Influence on Health Care Outcomes: A Systematic Review. Am J Public Health. 2015;105(12):2588-2588. doi:10.2105/ajph.2015.302903a

Our pediatric hematology/oncology fellowship program set out to create a case-based learning curriculum for common hematologic malignancies that would apply principles of adult learning theory and improve fellows’ retention of information in a supportive, goal-oriented learning environment. A framework we employed in developing this curriculum is that of “flow theory,” which parallels many of the tenets of adult learning theory. After implementing this curriculum, which we call “the unknown case,” the percentage of fellows correctly identifying common hematopathologic diagnoses improved from 50% to 85%.

Coronavirus disease 2019 (COVID-19) was first described in December 2019 in Wuhan, the capital of China’s Hubei province. 1,2. On March 11, 2020, WHO declared COVID-19 as a pandemic3. The first confirmed case of COVID-19 in Egypt was reported on February 14, 2020. As of May 10, 2020, there have been 8,964 confirmed cases, 2,002 recovered and 514 deaths4.

COVID-19 in a child with severe aplastic anemiaYunus Murat Akçabelen1, Ayça Koca Yozgat1, Aslı Nur Parlakay2, Nese Yarali11 Department of Pediatric Hematology, Ankara City Hospital Children’s Hospital, Turkiye2 Department of Pediatric Infectious Disease, Ankara City Hospital Children’s Hospital, TurkiyeArticle type: Letter to the editörRunning Title: COVID-19 in pediatric aplastic anemiaKey words: COVID-19, children, aplastic anemiaDisclosures: noneWord counts: 625

The 2019 novel coronavirus disease (COVID-19) has affected all aspects of life globally and care of children with malignancies is no exception. We are part of a large tertiary care 2000 bedded university hospital in North India. Approximately 450 new malignancies are diagnosed annually, translating to 10 patients per week. About 200 children attend the clinics every week. Additionally, 15-20 walk-in patients are evaluated daily in the daycare. Patients travel from distances as far as 500 km to reach our center.  Merely 20% live within 50 km of the hospital, and approximately 35% reside at a distance exceeding 200 km. Two-third of the patients hail from urban areas and one third belong to rural areas. The majority of families stay in a patient hostel in the hospital premises, and a few rent a flat in the city for the 4-9 months duration of intensive phase of therapy. The Government of India mandated a lockdown on the 24th March 2020 in response to the coronavirus pandemic and the outpatient services of the hospital were closed. The borders with the neighboring states were sealed & vehicular movement curtailed with barring of public transport & suspension of all interstate and intercity travel. The citizens were advised to maintain social distancing. The unit was faced with the formidable challenge of ensuring the well-being of children under our care from a wide geographical spread with minimal access to Pediatric Oncology services in their   hometowns. How did we manage our patients?

Abbreviations key:

A diverse panel of pediatric cancer advocates and experts, whose collective experience spans the continuum of international academic medicine, industry, federal research, and cancer advocacy, recently discussed challenges for pediatric cancer research in the context of Coronavirus Disease 2019 (COVID-19). Specifically, this special report addresses the following focus areas: (1) the critical role that translational research has played in transforming pediatric cancer outcomes; (2) the current and potential future impact of COVID-19 on pediatric cancer research; (3) target areas of COVID-19 research that may have application in immunity, oncogenesis and therapeutic discovery; and (4) future considerations and directions in maintaining pediatric cancer research during and after COVID-19.

Monocyte subset analysis by flow cytometry has been shown to be a useful diagnostic tool in chronic myelomonocytic leukemia in adults. An increase in the classical monocyte fraction (CD14++/CD16-) greater than 94.0% of total monocytes is considered highly sensitive and specific in distinguishing CMML from other myeloproliferative disorders. In a pilot study of juvenile myelomonocytic leukemia cases, we noted that CD14++/CD16- monocyte fraction was >95% in de novo JMML with somatic PTPN11 mutations but normal in those with monosomy 7 or Noonan syndrome. Monocyte subgroup profiling by itself is not diagnostic of JMML but may distinguish molecular subgroups within JMML.