Targeted Therapies in Pediatric Acute Myeloid Leukemia - Evolving Therapeutic Landscape.

Acute myeloid leukemia (AML) accounts for 25% of all leukemia diagnosis and is characterized by distinct cytogenetic and molecular profile. Advances in the understanding of the causative driver mutations, risk-based therapy and better supportive care have led to an overall improvement in survival with frontline therapy. Despite these improvements, a significant number fail either because of primary refractory disease to the conventional 7+3 combination of anthracyclines and cytosine arabinoside (Cytarabine; Ara-C) or experience relapse post remission. Salvage therapy is complicated by the cardiotoxicity driven limitations on the reuse of anthracyclines and development of resistance to cytarabine. In this chapter authors will review the recent studies with targeted agents for refractory AML including targets for immunotherapeutic strategies.

Checkpoint Immunotherapy in Pediatric Oncology: Will We Say Checkmate Soon?

Immune checkpoint inhibitors (ICIs) are a relatively new class of immunotherapy which bolsters the host immune system by "turning off the brakes" of effector cells (e.g., CTLA-4, PD-1, PD-L1). Although their success in treating adult malignancy is well documented, their utility in pediatric cancer has not yet been shown to be as fruitful. We review ICIs, their use in pediatric malignancies, and active pediatric clinical trials, exemplifying some of adult efforts that could be related to pediatric future trials and complications of ICI therapy. Through our review, we propose the consideration of ICI as standard therapy in lymphoma and various solid tumor types, especially in relapsed or refractory (R/R) disease. However, further studies are needed to demonstrate ICI effectiveness in pediatric leukemia.

Curing childhood cancer the "Natural" Way: Nature as the source of chemotherapy agents.

For many centuries, products of natural origin from plants, marine, microbes and soil micro-organisms have been studied by numerous researchers across the world to yield many of the chemotherapeutic agents we use in this modern era. There has been a tremendous gain in knowledge from various screening and separating techniques which led to the discovery of biologically active small molecules from natural products. Preclinical studies testing the antitumor activities of these agents against tumor cell lines and xenograft animal models were the gateway to the clinical trials in humans leading to the approval of these agents that are in clinical use today. This review summarizes how various chemotherapeutic agents were discovered from products of natural origin, their preclinical development, and their indications in both pediatric and adult oncology. Many of these natural products have contributed to the very high cure rates of both pediatric leukemias and solid tumors.

The Impact of COVID-19 on Pediatric Malignancy Diagnosis and Treatment: Never the Same but Lessons Learned.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic affected the pediatric oncology population globally. Over the course of 2 years, increasing reports have been made to better understand this entity and its pathologic complications on these patients. The pandemic has allowed healthcare providers, hospital systems, and leading oncologic societies to quickly adapt and formulate new guidelines for the effective understanding, management, and treatment of patients with pediatric malignancy.

Pineal Parenchymal Tumor of Intermediate Differentiation and DICER1 Syndrome: A Case Report.

DICER1 syndrome is a rare inherited tumor predisposition syndrome associated with an increased risk for several malignant and benign tumors. We present a patient with pineal parenchymal tumor of intermediate differentiation who was found to have a germline pathogenic variant in DICER1 gene. Pineoblastoma is a known DICER1-related tumor; however, the association between pineal parenchymal tumor of intermediate differentiation and DICER1 mutation is rare with only 1 recent large molecular study that has reported this association. This report adds to the evolving tumor spectrum of DICER1 and highlights the importance of molecular evaluation of pediatric brain tumors, for both therapeutic decisions and long-term surveillance.

The paradox of Myeloid Leukemia associated with Down syndrome.

Children with Down syndrome constitute a distinct genetic population who has a greater risk of developing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) compared to their non-Down syndrome counterparts. The risk for developing solid tumors is also distinct from the non-Down syndrome population. In the case of myeloid leukemias, the process of leukemogenesis in Trisomy 21 begins in early fetal life where genetic drivers including GATA1 mutations lead to the development of the preleukemic condition, transient abnormal myelopoiesis (TAM). Various other mutations in genes encoding cohesin, epigenetic regulators and RAS pathway can result in subsequent progression to Myeloid Leukemia associated with Down Syndrome (ML-DS). The striking paradoxical feature in the Down syndrome population is that even though there is a higher predisposition to developing AML, they are also very sensitive to chemotherapy agents, particularly cytarabine, thus accounting for the very high cure rates for ML-DS compared to AML in children without Down syndrome. Current clinical trials for ML-DS attempt to balance effective curative therapies while trying to reduce treatment-associated toxicities including infections by de-intensifying chemotherapy doses, if possible. The small proportion of patients with relapsed ML-DS have an extremely poor prognosis and require the development of new therapies.

Juvenile Xanthogranuloma of the Pancreas in a Pediatric Patient Mimicking Pancreatic Neoplasm With High CA 19-9: Case Report and Literature Review.

Juvenile xanthogranuloma (JXG) is a rare, non-Langerhans cell histiocytosis. It is usually a benign and self-limiting condition. The most common sites are skin and soft tissue. Pancreatic involvement is extremely rare. We present an unusual case of a 13-month-old female child with JXG of the pancreas and elevated cancer antigen 19-9. JXG should always be considered as a differential diagnosis for pediatric patients presenting with a pancreatic mass, solid and/or cystic in nature. Therefore, avoiding unnecessary invasive diagnostic procedures.

Higher daily doses of caffeine lowered the incidence of moderate to severe neurodevelopmental disabilities in very low birth weight infants.

AIM: We determined the influence of cumulative dosing of caffeine citrate on the neurodevelopmental outcomes of low birth weight (VLBW) infants at 18-22 months of postmenstrual age. METHODS: This retrospective chart analysis was conducted at Detroit Medical Center, Michigan, USA. The 181 infants we included were born between January 2006 and December 2016, were less than 32 weeks of gestational age and weighed less than 1500 grams. Data on their perinatal and postnatal characteristics were retrieved from their medical records and they were assessed using the Bayley Scales of Infant Development - Third Edition. RESULTS: The 64 infants with no neurodevelopmental disability or a mild disability received a significantly higher average daily dose (mg/kg/day) of caffeine citrate with a median of 7.58 (range 2.7-12.2) mg/kg/day, than the 79 infants with a moderate to severe disability, who received a median of 6.47 (range 3.1-12.5, p = 0.01). The total cumulative dose had no effect on bronchopulmonary dysplasia or neurodevelopmental outcomes. CONCLUSION: A higher average daily dose of caffeine citrate was associated with better neurodevelopmental outcomes of VLBW infants. However, the cumulative dose did not have an impact on their short-term or long-term outcomes. Further research is needed to confirm our findings.

Effect of early caffeine on neurodevelopmental outcome of very low-birth weight newborns.

OBJECTIVES: The objective of this study is to evaluate the effect of early caffeine therapy started within the first 48 h of life on neurodevelopmental outcome in very low birth weight (VLBW) newborns. STUDY DESIGN: VLBW newborns received either caffeine therapy within first 48 h of life (Early group), after 3rd day of life (Late group) or no caffeine during first month of life as per clinical team. A cohort of these newborns (n = 160) who survived were evaluated using Bayley Scale of Infant Development III (BSID III) developmental testing between 18 and 22 months of corrected age. RESULTS: VLBW newborns in the "Early group" had significantly better composite, cognitive, language and motor BSID III scores as compared to those in "Late group" and no caffeine group. Composite BSID III scores were unchanged in the presence or absence of chorioamnionitis for "Early group", while the BSID III scores were significantly lower in the presence of acute chorioamnionitis in "Late group" and no caffeine group. CONCLUSIONS: Early caffeine therapy was associated with better BSID III scores in a cohort of VLBW newborns. Newborns with acute chorioamnionitis benefited from early caffeine therapy.