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%.

Background – Loss of bone mineral is a common concomitant of the treatment of acute lymphoblastic leukemia (ALL) due mainly to chemotherapy, especially with corticosteroids. Osteopenia/osteoporosis may persist long into survivorship. Measurement of bone mineral density (BMD) by dual energy X-ray absorptiometry is limited to two-dimensionality and cannot distinguish trabecular from cortical bone. Methods – A sample of 74 subjects, more than 10 years from diagnosis, underwent peripheral quantitative computed tomography (pQCT) at metaphyseal (trabecular bone) and diaphyseal (cortical bone) sites in the radius and tibia. pQCT provides three-dimensional assessment of bone geometry, density and architecture. Results – Similarities of average values in multiple metrics with those in healthy subjects obscured deficits in both trabecular and cortical bone, as well as bone strength, revealed by Z scores using an ethnically comparable sample of healthy individuals. Connectivity, a measure of bone architecture and a surrogate measure of bone strength, was lower in females than males. Survivors of standard risk ALL had greater connectivity in and more compact trabecular bone than high risk survivors who had received more intensive osteotoxic chemotherapy. There were no statistically significant differences in any of the metrics at any of the sites between subjects who had or had not a history of fracture, cranial irradiation or use of a bisphosphonate. Conclusions – These long-term survivors of ALL have somehat compromised bone health, but data in comparable healthy populations are limited. Longitudinal studies in larger and more ethnically diverse cohorts will provide greater insight into bone health in this vulnerable population.

Title of the manuscriptComment on: Parents’ responses to prognostic disclosure at diagnosis of a child with a high-risk brain tumor: Analysis of clinician-parent interactions and implications for clinical practiceThe role of reflection in dealing with uncertainty

Background: Flow artifact, intrinsic to Magnetic Resonance Angiography (MRA), is dependent on technical parameters and can lead to overinterpretation of stenosis. Degree of cerebrovascular stenosis in pediatric patients with sickle cell anemia (SCA) informs need for chronic transfusion therapy, which may have significant risks. The primary objective of this study was to document any change in stroke prevention therapy that could be attributed to the implementation of a standardized MRA scanning protocol. Procedure: A standardized MRA scanning protocol with an echo time of <5 msec was implemented at Montefiore Medical Center in May 2016. Retrospective chart review identified 29 patients ≤ 21 years with SCA cerebral vasculopathy and an MRA head pre- and post-May 2016. Level of arterial stenosis on MRA, echo time, and treatment plans were documented both pre- and post-implementation. McNemar analysis determined the significance of change in treatment plans before and after implementation of the standardized scanning protocol. Results: Previously seen stenosis was re-classified to a lower degree in 12/29 patients (41%). Notably, 6 patients had a reclassification of vasculopathy leading to discontinuation of chronic transfusion therapy whereas 0 patients required escalation of therapy to chronic transfusions. McNemar analysis showed this difference to be statistically significant (p = 0.042). Conclusion: Minimizing flow artifact with echo time <5msec improves accurate interpretation of true cerebrovascular disease and ensures appropriate treatment plans are in place for stroke prevention. This is especially important when trying to implement “TCD With Transfusions Changing to Hydroxyurea (TWiTCH)” clinical trial results in the real-world setting.

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: [email protected] 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.

A document by Atish Bakane. Click on the document to view its contents.

Background and objectives: To investigate the feasibility and safety of ultrasound-guided totally implantable venous access ports (TIVAPs) via the right brachiocephalic vein (BCV) in pediatric patients. Methods: A single institutional retrospective review was performed on 35 pediatric patients with hematological malignancies who underwent TIVAPs implantation via ultrasound-guided right BCV approach from July 2018 to June 2021. Technical success rate, procedural information and TIVAP related complications were evaluated. Results: All the pediatric TIVAP devices were successfully implanted via right BCV access. Venous access was successful by first attempt in 32 children (91.42%); two cases (5.71%) required a second attempt; one patient (2.86%) required a third attempt. The mean procedural time was 44.63 ± 6.41 mins (range, 34-62 mins). No intraoperative complications occurred. The average TIVAP indwelling time was 563.51 ± 208.47 days (range, 193-1014 days) with a cumulative 19,723 catheter-days. The incidence of postoperative complications was 11.43% (4/35), corresponding to a rate of 0.20 complications per 1000 catheter-days. Two cases of local hematoma and two catheter dysfunctions occurred in three patients. No other complications such as wound dehiscence, delayed incision healing, catheter-related thrombosis (CRT), catheter malposition/fracture, surgical site infection, catheter-related bloodstream infection (CRBSI), pinch-off syndrome and drug extravasation were observed during follow-up. Conclusions: Ultrasound-guided right BCV access for TIVAPs placement in pediatric patients appears to be technically feasible, safe and effective. Further large-sample, prospective studies are warranted.

Objective: To evaluate group differences in social adjustment in survivors of pediatric ALL compared to survivor siblings, and controls; identify disease-related predictors of social adjustment in survivors; and explore whether executive functioning explained differences in social adjustment across groups and between disease-related predictors. Methods: Survivors of pediatric ALL (n=38, average age at diagnosis=4.27 years [SD=1.97]; average time off treatment=4.83 years [SD=1.52]), one sibling (if available, n=20), and one parent from each family were recruited from a long-term survivor clinic. Healthy age- and sex-matched controls (n=38) and one parent from each family were recruited from the community. Parents completed the Behavioral Assessment System for Children, Parent Rating Scale (BASC-3) Social Withdrawal subscale as a measure of social adjustment and the Behavior Rating Inventory of Executive Functions (BRIEF-2) as a measure of executive function for each of their children. Results: Parents reported that survivors had significantly worse social adjustment compared to controls (b=6.34, p=.004), but not survivor siblings. Among survivors, greater time off treatment (b=2.06, p=.058) and poorer executive functioning (b=0.42, p=.006) were associated with worse social adjustment. Executive function did not mediate differences in social withdrawal between survivors and controls or the relationship between time off treatment and social withdrawal among survivors. Conclusions: Survivors of pediatric ALL presenting to follow-up programs should be screened for difficulties with social adjustment. Future research should examine treatment- and non-treatment-related factors contributing to poorer social outcomes.

Background Consultation of specialty palliative care remains uncommon in pediatric stem cell transplant (SCT) despite growing evidence that early integration of palliative care improves outcomes in patients with advanced cancers or undergoing SCT. Little is known about how multidisciplinary pediatric SCT teams perceive palliative care and its role in SCT. Procedure We conducted semi-structured interviews of members of a multi-disciplinary SCT team to understand their perceptions of palliative care, how specialty palliative care is integrated into SCT, and to identify barriers to increased integration. Eligible participants included physicians, nurses, nurse practitioners, social workers, and child life specialists. Data was analyzed using thematic analysis. Results Four major themes were identified. First, SCT team members held a favorable perception of the palliative care team. Second, participants desired increased palliative care integration in SCT. Third, participants believed that the palliative care team had insufficient resources to care for the large number of SCT patients which led to the SCT team limiting palliative care consultation. And, finally, the lack of a standardized palliative care consultation process prevented greater integration of palliative care in SCT. Conclusions SCT team members held a favorable perception of palliative care and saw a role for greater palliative care integration throughout the SCT course. We identified modifiable barriers to greater palliative care integration. SCT teams who desire greater palliative care integration may adapt and implement an existing model of palliative care integration in order to improve standardization and increase integration of specialty palliative care in SCT.

Pyruvate kinase (PK) deficiency is an important cause of hereditary non-spherocytic hemolytic anemia caused by a defect in the glycolytic pathway in red blood cells. PK deficient erythrocytes have impaired ATP production and resultant difficulty maintaining normal cell integrity and function, leading to mild to severe anemia due to increased extravascular hemolysis and splenic destruction. Sequelae of chronic hemolysis can result in severe and occasionally life-threatening complications such as hepatobiliary disease, iron overload, bone and cardiopulmonary disease, as well as often markedly impaired quality of life. While the mainstay of management of PK deficiency involves supportive care, comprehensive screening recommendations and disease modifying therapies in development are likely to significantly improve the management of patients. Here, we provide a case-based comprehensive review of the diagnostic evaluation, complications, monitoring recommendations and management of PK deficiency in children.

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.

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

A document by Bilawal Nadeem. Click on the document to view its contents.

Objective: To compare outcomes data of obese and non-obese pediatric patients with acute promyelocytic leukemia from the Cancer and Leukemia Group B trial C9710 and the Children’s Oncology Group trial AAML0631. Methods: Data including demographics, adverse events, overall survival and event free survival was analyzed, with a focus on mortality in obese patients. Results: The incidence of obesity was 34% on C9710 and 35% on AAML0631. There was significantly lower overall survival in the obese population on AAML0631. Thirteen patients died during therapy or in follow up; seven of these occurred during induction. Conclusion: The incidence of obesity is higher in patients with APL compared to the general population. The presence and degree of obesity can influence OS on the most current treatment regimen. This implies the need for close management of obese patients at diagnosis as well as reinforces the need for further research on obesity driven APL

Concurrence of a Kinase-dead BRAF and an OncogenicKRAS Gain-of-function Mutation in Juvenile Xanthogranuloma

Severe autoimmune lymphoproliferative syndrome phenotype in a pediatric patient with a germline FAS gene variant Authors: Alexandra Dreyzin MD MS1; Jinjun Cheng MD PhD2, David Leitenberg MD PhD3, and Yaser Diab MBBS1Center for Cancer and Blood Disorders, Children’s National Hospital, Washington, DCDivision of Pathology and Laboratory Medicine, Children’s National Hospital, Washington, DCDepartment of Microbiology, Immunology and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.

Background: Vitamin D deficiency and insufficiency have been associated with poorer health outcomes. Children with cancer are at high risk for Vitamin D deficiency and insufficiency. At our institution, we identified high variability in Vitamin D testing and supplementation in this population. Of those tested, 65% were Vitamin D deficient/insufficient. We conducted a quality improvement (QI) initiative with aim to improve Vitamin D testing and supplementation among children aged 2-18 years old with newly-diagnosed cancer to ≥ 80% over 6 months. Methods: An inter-professional team reviewed baseline data, then developed and implemented interventions using Plan-Do-Study-Act (PDSA) cycles. Barriers were identified using QI tools, including lack of automated triggers for testing and inconsistent supplementation criteria and follow-up testing post-supplementation. Interventions included an institutional Vitamin D guideline, clinical decision-making tree for Vitamin D deficiency, insufficiency and sufficiency, electronic medical record triggers, and automated testing options. Results: Pre-intervention: N=26 patients, four (15%) had baseline Vitamin D testing; two (8%) received appropriate supplementation. Post-intervention: N=33 patients; 32 (97%) had baseline Vitamin D testing; 33 (100%) received appropriate supplementation and completed follow-up testing timely (6-8 weeks post-supplementation). Change was sustained over 24 months. Conclusions: We achieved and sustained our aim for Vitamin D testing and supplementation in children with newly-diagnosed cancer through inter-professional collaboration of hematology/oncology, endocrinology, hospital medicine, pharmacy, nursing, and information technology. Future PDSA cycles will address patient compliance with Vitamin D supplementation and impact on patients’ Vitamin D levels.