Daria Salyakina

Pediatric cancers are fundamentally different from those in adults, with lower frequency of genetic mutations and fewer options for targeted therapies. The implementation of functional precision medicine (FPM) - the integration of ex vivo drug screening and mutation profiling- can, therefore, provide better treatment options for pediatric tumor patients. In this study, we investigated the feasibility and clinical utility of FPM in the management of pediatric patients with recurrent and/or refractory cancers. We use a functional ex vivo drug screening test (DST) panel encompassed 40 formulary drugs frequently used at Nicklaus Children’s hospital and 47 non-formulary drugs approved by FDA for cancer treatment, as well as drugs from phase III and IV clinical trials. Drug sensitivity scores (DSS) were calculated for each drug based on cancer cells’ responses. DST results were then combined with results from targeted mutation profiles to match actionable mutations with selective targeted therapies. We have recruited a total of 21 patients into this ongoing clinical trial (number NCT03860376) and were able to perform drug testing and mutation profiling on 17 patients. We optimized and successfully performed DST on at least 13 different tumor types including acute myeloid leukemia, chronic lymphoblastic leukemia, ependymoma, osteosarcoma, Ewing’s sarcoma, rhabdomyosarcoma, glioblastoma, medulloblastoma, astrocytoma, neuroblastoma, rhabdoid, lung, and liver tumors. Our feasibility study, so far, has demonstrated that ex vivo DST can be performed within a clinically actionable time frame (median: 7 days). Ex vivo DST returned between 10 and 30 treatment options for each patient. These patients showed different responses to the 103 FDA-approved compounds used in the screen. More than half of the evaluated compounds were not active in any of the patients. Remarkably, DST provided valuable information to the oncologists on drug dosing and treatments that may not be effective and should be avoided. DSS synergizes with genomic data to further refine treatment recommendations. FPM-guided treatment regimens resulted in encouraging partial and complete responses as compared to progressive disease in prior regimens and physician choice regimens. Thus, our study shows technical feasibility of integrating functional precision medicine approaches for patients with refractory/relapsed pediatric cancers. Routine clinical integration of FPM for treatment selection is technically feasible and has led to improved treatment of pediatric cancer patients with refractory malignancies in an initial patient cohort, warranting further investigation. Citation Format: Arlet Maria Acanda de la Rocha, Maggie Fader, Ebony Coats, Joseph Dunn, Leat Perez, Cima Saghira, Ileana Sotto, Ziad Khatib, Ossama Maher, Haneen Abdella, Cristina M. Andrade-Feraud, Alexa Jacome, Lilliam Rimblas, Paula S. Espinal, Tomás R. Guilarte, Jennifer McCafferty-Fernandez, Daria Salyakina, Diana J. Azzam. Feasibility and efficacy of a functional precision medicine approach in the management of relapsed/refractory childhood cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4103.

There is an increasing demand for supporting the adoption of rapid whole-genome sequencing (rWGS) by demonstrating its real-world value. We aimed to assess the cost-effectiveness of rWGS in critically ill pediatric patients with diseases of unknown cause. Data were collected prospectively of patients admitted to the Nicklaus Children’s Hospital’s intensive care units from March 2018 to September 2020, with rWGS (N = 65). Comparative data were collected in a matched retrospective cohort with standard diagnostic genetic testing. We determined total costs, diagnostic yield (DY), and incremental cost-effectiveness ratio (ICER) adjusted for selection bias and right censoring. Sensitivity analyses explored the robustness of ICER through bootstrapping. rWGS resulted in a diagnosis in 39.8% while standard testing in 13.5% (p = 0.026). rWGS resulted in a mean saving per person of $100,440 (SE = 26,497, p < 0.001) and a total of $6.53 M for 65 patients. rWGS in critically ill pediatric patients is cost-effective, cost-saving, shortens diagnostic odyssey, and triples the DY of traditional approaches.

Kaposi’s sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (Pα(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected Pα(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected Pα(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis. Identification of the KS progenitor cell creates the possibility of studying viral oncogenesis and its determinants from its initial steps as a continuum. It also increases our understanding of pathogenic mechanisms and disease preferential tropism. Hereby we identify Pα(+)S-MSCs as KS progenitors, in which KSHV infection has oncogenic consequences; only when these cells are in a pro-angiogenic environment in which PDGFRA activation enables an oncogenic de-repressed KSHV epigenome. These results identify a KS-progenitor population in the Pα(+)S-MSCs and point to pro-angiogenic environmental conditions as essential for oncogenic viral gene expression and transformation. We designed a novel model of KSHV oncogenesis, creating a very robust platform to identify KSHV oncogenic pathways and their relationship with cellular lineages and extracellular growth environments.

BACKGROUND: The Choosing Wisely^® Campaign (CWC) was launched in 2012. Five recommendations to reduce the use of “low‐value” services in hospitalized children were published in 2013.OBJECTIVES: The aim of this study was to estimate the frequency and trends of utilization of these services in tertiary children's hospitals five years before and after the publication of the recommendations.METHODS: We conducted a retrospective, longitudinal analysis of hospitalizations to 36 children's hospitals from 2008 to 2017. The “low‐value” services included (1) chest radiograph (CXR) for asthma, (2) CXR for bronchiolitis, (3) relievers for bronchiolitis, (4) systemic steroids for lower respiratory tract infection (LRTI), and (5) acid suppressor therapy for uncomplicated gastroesophageal reflux (GER). We estimated the annual percentages of the use of these services after risk adjustment, followed by an interrupted time series (ITS) analysis to compare trends before and after the publication of the recommendations.RESULTS: The absolute decreases in utilization were 36.6% in relievers and 31.5% in CXR for bronchiolitis, 24.1% in acid suppressors for GER, 20.8% in CXR for asthma, and 2.9% in steroids for LRTI. Trend analysis showed that one “low‐value” service declined significantly immediately (use of CXR for asthma), and another decreased significantly over time (relievers for bronchiolitis) after the CWC.CONCLUSIONS: There was some decrease in the utilization of “low‐value” services from 2008 to 2017. Limited changes in trends occurred after the publication of the recommendations. These findings suggest a limited impact of the CWC on clinical practice in these areas. Additional interventions are required for a more effective dissemination of the CWC recommendations for hospitalized children.

Background: This study focuses on the implementation of CYP2D6 genetic test profiling and the challenges associated with using standard pharmacogenetics panels in a diverse South Florida population.Methods: A total of 413 participants were recruited to participate in this study through Nicklaus Children's Hospital. Buccal swabs were collected and tested using an extended CYP2D6 panel including 22 alleles. Phenotype, genotype, and allelic frequencies were compared among different racial and ethnic groups.Results: The majority of participants (75.0%) self‐identified as Hispanics. Four alleles, CYP2D6*4, *17, *41, and *2A, showed a statistically significant difference between White Hispanics and Black Non‐Hispanics. Aggregate frequency of all alleles with decreased function varied between 2.8% and 50.0% in different racial and ethnic groups. Additionally, rare allele combinations were observed in this South Florida cohort.Conclusions: The heterogeneity among Hispanic groups demonstrated in previous literature and by this study reflects the complexity of ethnicity and suggests that a more granular categorization is needed, one based on ancestry and migration history rather than primary language. Overall, we have determined that there are statistically significant differences in CYP2D6 allele frequencies in the distinct racial and ethnic populations of South Florida, demonstrating a unique genetic makeup within South Florida. However, overall, the frequencies of Poor Metabolizer, Normal Metabolizer, Intermediate Metabolizer, and Ultrarapid Metabolizer did not differ between racial and ethnic groups at a statistically significant level.

Rotational thromboelastometry (ROTEM) has been shown to reduce the need for transfused blood products in adult and pediatric cardiac surgery patients. However, similar evidence in newborns, neonates, and young infants is lacking. We quantified ROTEM value changes in pediatric patients on cardiopulmonary bypass (CPB) before, during and after blood product transfusion. Each surgery had at least four interventions: initiating CPB; platelet administration during rewarming phase; post-CPB and following protamine and human fibrinogen concentrate (HFC) administration; and further component therapy if bleeding persisted and ROTEM indicated a deficiency. ROTEM assays were performed prior to surgery commencement, on CPB prior to platelet administration and following 38 mL/kg platelets, and post-CPB after protamine and HFC administration. ROTEM assays were also performed in the post-CPB period after further blood component therapy administration. Data from 161 patients were analyzed. Regression models suggested significant changes in HEPTEM clotting time after all interventions. PLT administration during CPB improved HEPTEM α by 22.1° (p < 0.001) and FIBTEM maximum clot firmness (MCF) by 2.9 mm (p < 0.001). HFC administration after CPB termination significantly improved FIBTEM MCF by 2.6 mm (p < 0.001). HEPTEM MCF significantly increased after 3/4 interventions. HEPTEM α significantly decreased after two interventions and significantly increased after two interventions. Greatest perturbances in coagulation parameters occurred in patients ≤90 days of age. CPB induced profound perturbations in ROTEM values in pediatric cardiac surgery patients. ROTEM values improved following PLT and HFC administration. This study provides important clinical insights into ROTEM changes in pediatric patients after distinct interventions.

Children may visit the emergency department (ED) regularly in part because they and their caregivers may be experiencing barriers to appropriate and timely pediatric care. However, assessing the wide range of potential barriers to access to care that children and their caregivers may experience is often a challenge. The objective of this study was to assess the barriers to pediatric health care reported by caregivers and to examine the association between those reported barriers to care with the frequency of children's ED visits in the past 12 months. Assessment of ED utilization and access to care barriers was made through a telephone interview survey conducted as part of a broader Community Health Needs Assessment in 2015. A weighted community sample of adult caregivers (N = 1057) of children between the ages of 0–17 residing in Miami-Dade, Broward, and Palm Beach counties, Florida were contacted. This study found that multiple ED visits (≥2 vs. 0) in the past 12 months by a child were most strongly associated with access to care barriers attributed to language and culture (relative risk [RR] = 2.51), trouble finding a doctor (RR = 1.86), scheduling an appointment (RR = 1.68), and transportation access (RR = 1.73). These findings suggest that access to care barriers experienced by households may exacerbate the risk of a child experiencing repeated visits to the ED in a year. Findings are discussed further in the context of actionable population health management strategies to reduce risk of frequent ED utilization by children.

Currently, Community Health Needs Assessment (CHNA) reports lack a standard structure, making it difficult to derive meaningful information. However, they have the potential to be a useful tool for analyzing pediatric outcomes, guiding resource allocation, and linking to Patient-Centered Outcomes Research Institute priorities. The objective was to evaluate the utility of CHNA for informing future pediatric, patient-centered outcomes research. The authors analyzed CHNA documents, published before July 1, 2016 by 61 nonprofit hospitals, focusing on 4 metropolitan areas in Florida: Miami, Orlando, Tampa, and Jacksonville. Out of 18 health priorities identified, access to care and obesity were universally recognized as the most urgent pediatric health needs across all hospital types and metropolitan regions. This analysis also yielded insights into key regional differences. The authors advocate that a major change in the CHNA format be implemented using a common set of domains to produce meaningful, interpretable, and comparable results that inform and guide patient-centered health outcomes research.

This study evaluated whether rotational thromboelastometry (ROTEM; Tem International GmbH, Munich, Germany) FIBTEM maximum clot firmness (MCF) can be used to predict plasma fibrinogen level in pediatric patients undergoing cardiac surgery. Linear regression was conducted to predict plasma fibrinogen level using FIBTEM MCF (0.05 level of significance). Scatter plot with the regression line for the model fit was created. Fifty charts were retrospectively reviewed, and 87 independent measurements of FIBTEM MCF paired with plasma fibrinogen levels were identified for analysis. Linear regression analysis suggested a significant positive linear relationship (P < .0001) between plasma fibrinogen levels and MCF. Both MCF intercept and slope were significantly correlated with fibrinogen level (P < .0001). The estimated regression equation (predicted fibrinogen = 78.6 + 12.4 × MCF) indicates that a 1-mm increase in MCF raises plasma fibrinogen level by an average of 12.4 mg/dL. The statistically significant positive linear relationship observed between MCF and fibrinogen levels (P < .001) suggests that MCF can be used as a surrogate for fibrinogen level. This relationship is of clinical relevance in the calculation of patient-specific dosing of fibrinogen supplementation in this setting.