Lactate dehydrogenase reflects the status of ultra-high-risk neuroblastoma in a child under treatmentAkinori Yaguchi, Junya Fujimura, Ayane Yakabe, Megumi Fujiwara, Takeshi Ishibashi, Osamu Tomita, Toshiaki ShimizuDepartment of Pediatrics, Juntendo University Faculty of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

Background Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression. Procedure The Children’s Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug reinduction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m 2/dose) was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently combined with reinduction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) followed by an expansion pharmacokinetic (PK) cohort. Results Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m 2/dose orally for 21 days. No additional DLTs were observed in the dose determination or PK expansion cohorts and overall rates of grade 3/4 non-hematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. Conclusions Palbociclib in combination with reinduction chemotherapy was well tolerated with a RP2D of 50 mg/m 2/day for 21 days. Complete responses were observed among heavily pretreated patients.

Title : Cutaneous presentation of Candida krusei fungemia refractory to amphotericin BAuthors : Michelle Toker, BS1, Carson Kirkpatrick, MD1, Pooja Srivastava, MD1,2, Bijal Amin, MD1,2, Benedict Wu, DO, PhD1Affiliations :1- Division of Dermatology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA2- Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USACorresponding author :Michelle Toker, BSAlbert Einstein College of Medicine, Montefiore Medical Center1300 Morris Park Avenue, Bronx, New York, 10461Email: [email protected]: 516-946-4726Funding and support : NoneConflicts of Interest : NoneManuscript word count : 599Reference count : 5Figure count : 2Table count : 0Key words : disseminated fungemia, candida, oncology, leukemia, cutaneous fungal infection, rash, pathology, infectious disease

In low- and middle-income countries, malignancies remain underreported due to lack of quality data. This study outlines the histopathological pattern of pediatric solid malignancies in children aged 0-15yrs at the largest referral hospital in Ethiopia. 432 solid malignancies were evaluated. The most common malignancies were Lymphoma (21.8%), Retinoblastoma (19.4%), and Wilms tumor (13.9%). Burkitt lymphoma accounted for 2.1%, despite being the most reported pediatric malignancy in sub-Saharan Africa in published literature. Definitive diagnosis could not be made in 7% of cases, related to the lack of confirmatory testing. The study highlights the need for improvements in diagnostic capabilities in LMIC.

TITLE PAGETitle: Comment on: evaluating age and sex-specific rates of gall bladder disease in children with sickle cell diseaseArticle type: Letter to the editorCorrespondence : 1. Ifra Eeman Ahmed contact : 03335890003 Email : [email protected] : Federal medical & dental college,IslamabadAddress: House#2,Street#15g,Sector A,Bahria Enclave,IslamabadCo-author : 2. Satesh KumarContact: +92-3325252902 Email:Institute: Shaheed Mohtarma Benazir Bhutto Medical College Liyari, KarachiAddress: Parsa citi Garden east, KarachiWord count: 391Conflict of interest : NoneDeclaration : NoneAcknowledgment : None

Daratumumab induced Minimal Residual Disease Negative Remission in CD 38 (dim) Positive Pediatric Acute Myeloid LeukemiaPronamee Borah1, Dinah Ng1, Nitin Dayal2, Sangeeta Pathak3, Rahul Naithani11Hematology and Bone Marrow Transplant Division, Max Superspecialty Hospital, Delhi, India2Department of Lab Medicine, Max Superspecialty Hospital, Delhi, India3Department of Transfusion medicine, Max Superspecialty Hospital, Delhi, IndiaConflicts of interest: None to declare.No financial support was obtained in this study.Text word count 815Brief running title: Daratumumab in Pediatric AMLKey Words: Daratumumab, AML, ChildrenTables: 0; Figures: 0

Background/Purpose Stage at diagnosis is an important metric in treatment and prognosis of cancer, and also in planning and evaluation of cancer control. In sub-Saharan Africa (SSA), for the latter, the only data source is the population-based cancer registry (PBCR). For childhood cancers, the “Toronto Staging Guidelines” have been developed to facilitate abstraction of stage by cancer registry personnel. Although the feasibility of staging using this system has been shown, there is limited information on the accuracy of staging. Methods A panel of case records of 6 common childhood cancers was established. 51 cancer registrars from 20 SSA countries staged these records, using Tier 1 of the Toronto guidelines. The stage that they assigned was compared with that decided by two expert clinicians. Results The registrars assigned the correct stage for 53-83% of cases (71% overall), with the lowest values for acute lymphocytic leukaemia (ALL), retinoblastoma and non Hodgkin lymphoma (NHL), and the highest for osteosarcoma (81%) and Wilms tumour (83%). For ALL and NHL, many unstageable cases were mis-staged, probably due to confusion over the rules for dealing with missing data; for the cases with adequate information, accuracy was 72-73%. Some confusion was observed over the precise definition of three stage levels of retinoblastomas. Conclusions A single training in staging resulted in an accuracy, for solid tumours, that was not much inferior to what has been observed in high income settings. Nevertheless, some lessons were learned on how to improve both the guidelines, and the training course.

A 19 year-old adolescent girl with Dravet syndrome, characterized by complex seizure disorder and global developmental delay, presented with B-cell acute lymphoblastic leukemia. The genetic basis for her Dravet syndrome was a pathogenic variant in SCN1A, a sodium channel subunit. SCN1A is chiefly expressed in neuronal tissue, but bioinformatic analysis demonstrated its presence in B cell lineage. One estimate suggested that 10% of children with pediatric cancer have a germline predisposition involving proto-oncogenes or tumor suppressors. This number might be even higher should non-classical genetic variants, such as that encoding a sodium channel subunit, be considered.

Background While racial disparities in the clinical outcomes of hematopoietic stem cell transplant (HSCT) patients have been explored, racial disparities in quality of life (QoL) during the readjustment phase after transplant has yet to be investigated in pediatric patients. The objective of this study was to examine the role of patient race in QoL at least two years after pediatric HSCT. Procedure We conducted a retrospective chart review of patients under 21 years of age at diagnosis that received an allogeneic transplant at our institution between January 2007 and December 2017. Patient QoL was assessed using the PedsQL TM 4.0 at least two years post-transplant. Patient demographic, treatment, and transplant outcome data were obtained for subsequent analysis, where patient race was categorized as either Black, White, Hispanic, or Native American. Results Data were collected on 86 pediatric patients who underwent HSCT. Forty patients (46.5%) were non-Hispanic White, 29 (33.7%) Hispanic, 10 (11.6%) Black, and 7 (8.1%) Native American. Where preliminary analyses indicated a difference in QoL by patient race, there were no significant differences in physical, emotional, social, and school functioning by patient race after adjusting for transplant characteristics (age at transplant, sex, diagnosis, donor type and conditioning regimen) and determinants of socioeconomic status (insurance type, estimated household income). Conclusions Pediatric patients had comparable QoL, regardless of race, at a median of three years after HSCT in our study cohort.

Background Based on previous reports of disparities in financial burden following cancer, this study aims to characterize mechanisms of disparities experienced by caregivers of children with cancer, including the impact of work flexibility and social support. Methods Cross-sectional survey (in English or Spanish) of caregivers of children with cancer that assessed household material hardship (HMH), financial toxicity and income change. Results Of 156 caregivers surveyed, 32% were Hispanic and 32% were low income. Hispanic caregivers were more likely to report HMH and financial toxicity compared to non-Hispanic White and Asian (HMH 57% v. 21% v. 19%, p<0.001; financial toxicity 73% v. 52% v. 53%, p=0.07). Low and middle income caregivers were more likely to experience HMH and financial toxicity compared to high income (HMH: 68% low v. 38% middle v 8.7% high, p<0.001; financial toxicity: 81% v. 68% v. 44%, p<0.001). All income categories demonstrated significant increases in HMH one year after diagnosis. Seventeen percent reported >40% income loss, more of whom were low income than high income (27% v. 12%, p=0.20). Work flexibility and social support were associated with income and financial toxicity. Conclusion HMH, financial toxicity, and income loss are prevalent after a child’s cancer diagnosis, suggesting that screening should be incorporated into routine care. This financial burden disproportionately affects low income and Hispanic caregivers. Further research is underway to understand how safety net services are utilized by families, how best to support families with HMH, and how the financial burden of cancer has been impacted by COVID-19.

Letter to the editor

Background: We aimed to retrospectively investigate the role of neoadjuvant chemotherapy in low-risk patients with hepatoblastoma (HB) who underwent curative resection between February 2009 and December 2017. We also verified the feasibility of the risk stratification system to select the optimal patients for upfront resection. Procedure: We compared 5-year overall survival (OS) and event-free survival (EFS) between the upfront surgery (US) (n=26) and neoadjuvant chemotherapy (NC) (n=104) groups at three oncology centers in Beijing, China. To reduce the effect of covariate imbalances, propensity score matching (PSM) was used. We explored whether preoperative chemotherapy affected surgical outcomes and identified the risk factors for events and death, including resection margin status, PRETreatment EXTent of disease stages, age, sex, pathology classification, and α-fetoprotein levels. Results: The median follow-up period was 64 months (interquartile range 60–72). After PSM, 22 pairs of patients were identified and the patient characteristics were similar for all variables included in propensity score matching. In the US group, the 5-year EFS and OS rates were 81.8% and 86.3%, respectively. In the NC group, 5-year EFS and OS rates were 81.8% and 90.9%, respectively. No significant differences in EFS or OS were observed between the groups. Pathological classification was the only risk factor for death and disease progression, tumor recurrence, diagnosis of other malignant neoplasms, and death from any cause ( p=0.007 and p=0.032, respectively). Conclusion: Upfront resection can achieve long-term disease control in low-risk patients with resectable HB, thus reducing the cumulative toxicity of platinum-based chemotherapy drugs.

A document by Evan Cantor. Click on the document to view its contents.

Background: Clinical informatics tools to integrate data from multiple sources have the potential to catalyze population health management of childhood cancer survivors at high risk for late heart failure through the implementation of previously validated risk calculators. Methods: The Oklahoma cohort (n=365) harnessed data elements from Passport for Care (PFC) and the Duke cohort (n=274) integrated cancer registry and electronic health record data, using standard query language, to automatically extract chemotherapy exposures for survivors <18 years old at diagnosis. The Childhood Cancer Survivor Study (CCSS) late cardiovascular risk calculator was implemented and risk groups for heart failure were compared to the Children’s Oncology Group (COG) Long-Term Follow-up Guidelines. Results: The Oklahoma and Duke cohorts both observed good overall concordance between the CCSS and COG risk groups for late heart failure with weighted Kappa statistics of 0.70 and 0.75, respectively. Low-risk groups showed excellent concordance (Kappa >0.9). Moderate and high-risk groups showed moderate concordance (Kappa 0.44-0.60 across both cohorts). In the Oklahoma cohort, adolescents at diagnosis were significantly less likely to receive guideline-adherent care for echocardiogram surveillance compared with survivors <13 years old at diagnosis (OR 0.22; 95% CI 0.10-0.49). Conclusions: Clinical informatics tools represent a feasible approach to leverage discrete data elements regarding key treatment exposures from PFC or the EHR to successfully implement previously validated late cardiovascular risk prediction models on a population health level. Real-world evidence on the concordance of CCSS, COG, and IGHG risk groups promises to refine current guidelines and identify inequities in guideline-adherent care.

Objectives This systematic review provides an overview of the effect of malnutrition on the pharmacokinetics of chemotherapy in children with cancer. Methods PubMed, Embase and Cochrane were searched to identify eligible studies. Malnutrition was referred to as undernutrition, as defined by the World Health Organisation and the Gomez Criteria. Results Four studies with a total of 668 children with cancer were included and n=121 (18%) were malnourished. In vincristine, the differences in pharmacokinetic parameters were statistically significant where clearance rates were commonly lower and area under the curve was increased in malnourished children. Conclusion The results are suggestive for pharmacokinetic alterations of chemotherapy in malnourished children with cancer. However, the data is scarce, groups are small, and most studies have been performed in high-income countries. Pharmacokinetic research among (severely) malnourished children with cancer is needed in order to improve their outcome, directed by sub-group and ultimately individualized drug dosing.

A document by Laila Alkhouli. Click on the document to view its contents.

Disseminated Fungal Disease Caused by Magnusiomyces clavatus in a Pediatric Cancer Patient: First Case Report in North America and Review of the LiteraturePaul G. Mitchell MD 1, Bill H. Chang MD, PhD2, Lorne W. Walker MD, PhD3

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.