Making sense of artificial intelligence and large language models-including ChatGPT-in pediatric hematology/oncology.

ChatGPT and other artificial intelligence (AI) systems have captivated the attention of healthcare providers and researchers for their potential to improve care processes and outcomes. While these technologies hold promise to automate processes, increase efficiency, and reduce cognitive burden, their use also carries risks. In this commentary, we review basic concepts of AI, outline some of the capabilities and limitations of currently available tools, discuss current and future applications in pediatric hematology/oncology, and provide an evaluation and implementation framework that can be used by pediatric hematologist/oncologists considering the use of AI in clinical practice.

Advancing clinical and translational research in germ cell tumours (GCT): recommendations from the Malignant Germ Cell International Consortium.

Germ cell tumours (GCTs) are a heterogeneous group of rare neoplasms that present in different anatomical sites and across a wide spectrum of patient ages from birth through to adulthood. Once these strata are applied, cohort numbers become modest, hindering inferences regarding management and therapeutic advances. Moreover, patients with GCTs are treated by different medical professionals including paediatric oncologists, neuro-oncologists, medical oncologists, neurosurgeons, gynaecological oncologists, surgeons, and urologists. Silos of care have thus formed, further hampering knowledge dissemination between specialists. Dedicated biobank specimen collection is therefore critical to foster continuous growth in our understanding of similarities and differences by age, gender, and site, particularly for rare cancers such as GCTs. Here, the Malignant Germ Cell International Consortium provides a framework to create a sustainable, global research infrastructure that facilitates acquisition of tissue and liquid biopsies together with matched clinical data sets that reflect the diversity of GCTs. Such an effort would create an invaluable repository of clinical and biological data which can underpin international collaborations that span professional boundaries, translate into clinical practice, and ultimately impact patient outcomes.

Creating a data commons: The INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT).

In this article, we will discuss the genesis, evolution, and progress of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT), which aims to foster international research and collaboration focused on pediatric soft tissue sarcoma. We will begin by highlighting the current state of clinical research for pediatric soft tissue sarcomas, including rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma. We will then explore challenges and research priorities, describe the development of INSTRuCT, and discuss how the consortium aims to address key research priorities.

Pharmacogenomic genotypes define genetic ancestry in patients and enable population-specific genomic implementation.

The importance of genetic ancestry characterization is increasing in genomic implementation efforts, and clinical pharmacogenomic guidelines are being published that include population-specific recommendations. Our aim was to test the ability of focused clinical pharmacogenomic SNP panels to estimate individual genetic ancestry (IGA) and implement population-specific pharmacogenomic clinical decision-support (CDS) tools. Principle components and STRUCTURE were utilized to assess differences in genetic composition and estimate IGA among 1572 individuals from 1000 Genomes, two independent cohorts of Caucasians and African Americans (AAs), plus a real-world validation population of patients undergoing pharmacogenomic genotyping. We found that clinical pharmacogenomic SNP panels accurately estimate IGA compared to genome-wide genotyping and identify AAs with ≥70 African ancestry (sensitivity >82%, specificity >80%, PPV >95%, NPV >47%). We also validated a new AA-specific warfarin dosing algorithm for patients with ≥70% African ancestry and implemented it at our institution as a novel CDS tool. Consideration of IGA to develop an institutional CDS tool was accomplished to enable population-specific pharmacogenomic guidance at the point-of-care. These capabilities were immediately applied for guidance of warfarin dosing in AAs versus Caucasians, but also provide a real-world model that can be extended to other populations and drugs as actionable genomic evidence accumulates.

Simplifying the use of pharmacogenomics in clinical practice: Building the genomic prescribing system.

BACKGROUND: A barrier to the use of genomic information during prescribing is the limited number of software solutions that combine a user-friendly interface with complex medical data. We built and designed an online, secure, electronic custom interface termed the Genomic Prescribing System (GPS). METHODS: Actionable pharmacogenomic (PGx) information was reviewed, collected, and stored in the back-end of GPS to enable creation of customized drug- and variant-specific clinical decision support (CDS) summaries. The database architecture utilized the star schema to store information. Patient raw genomic data underwent transformation via custom-designed algorithms to enable gene and phenotype-level associations. Multiple external data sets (PubMed, The Systematized Nomenclature of Medicine (SNOMED), National Drug File - Reference Terminology (ND-FRT), and a publically-available PGx knowledgebase) were integrated to facilitate the delivery of patient, drug, disease, and genomic information. Institutional security infrastructure was leveraged to securely store patient genomic and clinical data on a HIPAA-compliant server farm. RESULTS: As of May 17, 2016, the GPS back-end housed 257 CDS encompassing 112 genetic variants, 42 genes, and 46 PGx-actionable drugs. The GPS user interface presented patient-specific CDS alongside a recognizable traffic light symbol (green/yellow/red), denoting PGx risk for each genomic result. The number of traffic lights per visit increased with the corresponding increase in the number of available PGx-annotated drugs over time. An integrated drug and disease search functionality, links to primary literature sources, and potential alternative PGx drugs were indicated. The system, which was initially used as stand-alone CDS software within our clinical environment, was then integrated with the institutional electronic medical record for enhanced usability. There have been nearly 2000 logins in 43months since inception, with usage exceeding 56 logins per month and system up-times of 99.99%. For all patient-provider visits encompassing >3years of implementation, unique alert click-through rates corresponded to genomic risk: red lights clicked 100%, yellow lights 79%, green lights 43%. CONCLUSIONS: Successful deployment of GPS by combining complex data and recognizable iconography led to a tool that enabled point-of-care genomic delivery with high usability. Continued scalability and incorporation of additional clinical elements to be considered alongside PGx information could expand future impact.

A method for whole protein isolation from human cranial bone.

The presence of the dense hydroxyapatite matrix within human bone limits the applicability of conventional protocols for protein extraction. This has hindered the complete and accurate characterization of the human bone proteome thus far, leaving many bone-related disorders poorly understood. We sought to refine an existing method of protein extraction from mouse bone to extract whole proteins of varying molecular weights from human cranial bone. Whole protein was extracted from human cranial suture by mechanically processing samples using a method that limits protein degradation by minimizing heat introduction to proteins. The presence of whole protein was confirmed by western blotting. Mass spectrometry was used to sequence peptides and identify isolated proteins. The data have been deposited to the ProteomeXchange with identifier PXD003215. Extracted proteins were characterized as both intra- and extracellular and had molecular weights ranging from 9.4 to 629 kDa. High correlation scores among suture protein spectral counts support the reproducibility of the method. Ontology analytics revealed proteins of myriad functions including mediators of metabolic processes and cell organelles. These results demonstrate a reproducible method for isolation of whole protein from human cranial bone, representing a large range of molecular weights, origins and functions.

A Phase I New Approaches to Neuroblastoma Therapy Study of Buthionine Sulfoximine and Melphalan With Autologous Stem Cells for Recurrent/Refractory High-Risk Neuroblastoma.

BACKGROUND: Myeloablative therapy for high-risk neuroblastoma commonly includes melphalan. Increased cellular glutathione (GSH) can mediate melphalan resistance. Buthionine sulfoximine (BSO), a GSH synthesis inhibitor, enhances melphalan activity against neuroblastoma cell lines, providing the rationale for a Phase 1 trial of BSO-melphalan. PROCEDURES: Patients with recurrent/resistant high-risk neuroblastoma received BSO (3 gram/m(2) bolus, then 24 grams/m(2) /day infusion days -4 to -2), with escalating doses of intravenous melphalan (20-125 mg/m(2) ) days -3 and -2, and autologous stem cells day 0 using 3 + 3 dose escalation. RESULTS: Among 28 patients evaluable for dose escalation, one dose-limiting toxicity occurred at 20 mg/m(2) melphalan (grade 3 aspartate aminotransferase/alanine aminotransferase) and one at 80 mg/m(2) (streptococcal bacteremia, grade 4 hypotension/pulmonary/hypocalcemia) without sequelae. Among 25 patients evaluable for response, there was one partial response (PR) and two mixed responses (MRs) among eight patients with prior melphalan exposure; one PR and three MRs among 16 patients without prior melphalan; one stable disease with unknown melphalan history. Melphalan pharmacokinetics with BSO were similar to reports for melphalan alone. Melphalan Cmax for most patients was below the 10 µM concentration that showed neuroblastoma preclinical activity with BSO. CONCLUSIONS: BSO (75 gram/m(2) ) with melphalan (125 mg/m(2) ) is tolerable with stem cell support and active in recurrent/refractory neuroblastoma. Further dose escalation is feasible and may increase responses.

An Approach to Acquiring, Normalizing, and Managing EHR Data From a Clinical Data Repository for Studying Pressure Ulcer Outcomes.

Changes in the methods that individual facilities follow to collect and store data related to hospital-acquired pressure ulcer (HAPU) occurrences are essential for improving patient outcomes and advancing our understanding the science behind this clinically relevant issue. Using an established electronic health record system at a large, urban, tertiary-care academic medical center, we investigated the process required for taking raw data of HAPU outcomes and submitting these data to a normalization process. We extracted data from 1.5 million patient shifts and filtered observations to those with a Braden score and linked tables in the electronic health record, including (1) Braden scale scores, (2) laboratory outcomes data, (3) surgical time, (4) provider orders, (5) medications, and (6) discharge diagnoses. Braden scores are important measures specific to HAPUs since these scores clarify the daily risk of a hospitalized patient for developing a pressure ulcer. The other more common measures that may be associated with HAPU outcomes are important to organize in a single data frame with Braden scores according to each patient. Primary keys were assigned to each table, and the data were processed through 3 normalization steps and 1 denormalization step. These processes created 8 tables that can be stored efficiently in a clinical database of HAPU outcomes. As hospitals focus on organizing data for review of HAPUs and other types of hospital-acquired conditions, the normalization process we describe in this article offers directions for collaboration between providers and informatics teams using a common language and structure.

N-linked glycan profiling in neuroblastoma cell lines.

Although MYCN amplification has been associated with aggressive neuroblastoma, the molecular mechanisms that differentiate low-risk, MYCN-nonamplified neuroblastoma from high-risk, MYCN-amplified disease are largely unknown. Genomic and proteomic studies have been limited in discerning differences in signaling pathways that account for this heterogeneity. N-Linked glycosylation is a common protein modification resulting from the attachment of sugars to protein residues and is important in cell signaling and immune response. Aberrant N-linked glycosylation has been routinely linked to various cancers. In particular, glycomic markers have often proven to be useful in distinguishing cancers from precancerous conditions. Here, we perform a systematic comparison of N-linked glycomic variation between MYCN-nonamplified SY5Y and MYCN-amplified NLF cell lines with the aim of identifying changes in sugar abundance linked to high-risk neuroblastoma. Through a combination of liquid chromatography-mass spectrometry and bioinformatics analysis, we identified 16 glycans that show a statistically significant change in abundance between NLF and SY5Y samples. Closer examination revealed the preference for larger (in terms of total monosaccharide count) and more sialylated glycan structures in the MYCN-amplified samples in comparison to smaller, nonsialylated glycans that are more dominant in the MYCN-nonamplified samples. These results offer clues for deriving marker candidates for accurate neuroblastoma risk diagnosis.