Self‐Reported Quality of Life and Lived Experiences of Adolescent Cancer Survivors Aged 10–19 in Southwestern Uganda: A Mixed‐Methods Study in a Resource‐Limited Setting

ABSTRACT Background Cancer and its management affect the quality of life (QOL) and lived experiences of adolescent survivors. Aims We describe the QOL and document the lived experiences of adolescent cancer survivors at a tertiary hospital in southwestern Uganda. Methods and Results We conducted a mixed‐methods, cross‐sectional study using descriptive quantitative interviews using the summarized World Health Organization QOL questionnaire and qualitative in‐depth interviews with adolescent cancer survivors at Mbarara Regional Referral Hospital in southwestern Uganda in July and August 2023. We explored participants' perceptions of their health as a percentage of the overall QOL scores and evaluated their lived experiences using an inductive approach. The study obtained ethical approval from the Research and Ethics Committee of the Mbarara University of Science and Technology. A total of 42 adolescents with a mean age of 13.2 (SD ± 2.9) years participated in the study. Twenty‐three (55%) were males, and 24 (57%) had survived hematological malignancies. Participants reported very good ( n  = 12, 28.6%), good ( n  = 29, 69.1%), and poor ( n  = 1, 23%) QOL. Eleven (26.2%) and 30 (71.4%) participants reported they were very satisfied and satisfied with their health, respectively. Participants reported both positive and negative lived experiences. The positive experiences included persistent gratefulness, hope for a cure, and relationship restructuring. The negative experiences included concerns about body appearance, family separation, financial difficulties, and academic challenges. Conclusion The QOL of adolescent cancer survivors in our setting is generally good and is influenced by support from family and the healthcare system. Their lived experiences are varied. Psychosocial services and peer support could improve perceived negative experiences.

Arthur L. Prensky, 1930–2025

A Drug–Drug Interaction Study of Mobocertinib and Midazolam, a Cytochrome P450 3A Substrate, in Patients With Advanced Non–Small Cell Lung Cancer

Abstract Mobocertinib is a kinase inhibitor designed to selectively target epidermal growth factor receptor ( EGFR ) exon 20 insertion (ex20ins) mutations in non‐small cell lung cancer. This drug–drug interaction study assessed the effect of multiple‐dose administration of mobocertinib on the pharmacokinetics (PK) of midazolam, a sensitive cytochrome P450 3A substrate. Patients with locally advanced or metastatic non‐small cell lung cancer refractory/intolerant to standard available therapy were enrolled. In Cycle 1 (Part A; PK cycle), a single 3‐mg oral dose of midazolam was administered on Days 1 and 24, and a single 1‐mg intravenous dose of midazolam was administered on Days 2 and 25. Mobocertinib 160 mg once daily was administered orally on Days 3‐30. After Cycle 1, patients could continue receiving mobocertinib in 28‐day cycles in Part B of the study. The study objective was to characterize the effect of mobocertinib on the single oral‐ and intravenous‐dose PK of midazolam. Safety and exploratory efficacy were also assessed. Twenty‐six patients were enrolled, and 13 patients were PK‐evaluable. Safety findings were consistent with the known safety profile of mobocertinib, and diarrhea was the only Grade 3 or higher treatment‐related adverse event observed in more than 2 patients. Two of 16 patients with EGFR exon 20 insertion mutations were confirmed responders per investigator. Coadministration of mobocertinib decreased the area under the plasma concentration–time curve from time zero to infinity of oral and intravenous midazolam by approximately 32% and 16%, respectively (geometric least‐squares mean ratios of 0.676 and 0.837, respectively).

The Observation of Solvent Dependent 3 Intraligand and 3 Ligand‐to‐Ligand Charge Transfer Excited States in Au(III) Chromophores Containing Fluorene‐Diphenyl Amine Ligands

The arylgold(III) complex Au(III)‐DPA and its alkynyl analog Au(III)‐ADPA are synthesized and characterized using steady‐state and time‐resolved optical spectroscopy and density functional theory calculations. Both complexes embed the fluorenyl moiety with substitution at the 2,7‐positions, and both carry diphenylamine (DPA) substituents. The photophysical properties of the molecules are examined in toluene and tetrahydrofuran (THF) solutions. Both complexes possess similar ground‐state absorption spectra, which are a combination of ligand centered π ‐ π * transitions and metal‐perturbed π ‐ π * transitions. The excited‐state luminescent properties of the molecules are solvent dependent. In toluene, Au(III)‐DPA displays featureless phosphorescence, and Au(III)‐ADPA exhibits structured phosphorescence both ascribed to a metal‐perturbed triplet intraligand ( 3 IL) π ‐ π * state. In THF, however, both Au(III)‐DPA and Au(III)‐ADPA exhibit broad, red‐shifted phosphorescence indicative of a solvent stabilized triplet ligand‐to‐ligand charge transfer ( 3 LLCT) state. The intersystem crossing efficiencies of both complexes are also investigated. Pulsed laser experiments reveal high intersystem crossing values (>0.79) for both complexes in both solvents, indicating that intersystem crossing is the dominant pathway for singlet excited‐state decay. Density functional theory calculations indicate frontier orbitals centered on the substituted fluorenyl ligands highest occupied molecular orbital (HOMO) and the cyclometalating ligand lowest unoccupied molecular orbital (LUMO), supporting the assignment of 3 LLCT excited states in more polar solvents.

A DNA Scaffold Approach Facilitates 5′ Labeling of the SARS‐CoV‐2 RNA Pseudoknot for Single‐Molecule Förster Resonance Energy Transfer Investigation

Single‐molecule Förster resonance energy transfer (smFRET) studies of highly structured RNA molecules are often frustrated by issues with efficient dye conjugation. Here, a DNA scaffold‐based labeling strategy is developed, and applied to the frameshift‐stimulating RNA pseudoknot from the SARS‐CoV‐2 genome. FRET‐active reporters were prepared containing both Cy3 (donor) and Cy5 (acceptor) molecules and measurements conducted on freely‐diffusing single molecules, enabling the evaluation of conformational heterogeneity via smFRET population distributions. Freely diffusing pseudoknots, modified at the base of stem 1, display a broad range of NaCl‐dependent FRET states in solution, consistent with conformational freedom that extends beyond the static X‐ray and cryo‐EM structures. This work is a proof‐of‐principle demonstration of the feasibility of our DNA scaffold approach in enabling smFRET studies on this important class of biomolecule. Together, this work outlines new biochemical and biophysical approaches toward the study of RNA conformational dynamics in pseudoknots, riboswitches, and other structured RNA elements.

Donor–Acceptor Interactions of C 60 F 18 with Polycyclic Aromatic Hydrocarbons: Size Effects in Bulk Crystallization and Surface Constraints

An in‐depth study of donor–acceptor (D/A) interactions between the high‐dipole acceptor C 60 F 18 (A) and polycyclic aromatic hydrocarbon (PAH) donors—pyrene, perylene, and coronene—reveals a surprisingly strong PAH size influence on the D/A complex stoichiometry and ordering in co‐crystals. The crystallographic study shows the tendency of D/A mixtures to form stacked layered structures for the larger PAHs, perylene and coronene, while the role of aromatic π–π interactions diminishes, in contrast to the smaller pyrene/C 60 F 18 system. The behavior of the layered‐D/A assemblies is investigated by utilizing sequential deposition and co‐evaporation of C 60 F 18 and coronene on Au(111) surfaces. Scanning tunneling microscopy shows that the flat lying configuration adopted by coronene on the metal, which forms highly ordered close‐packed monolayers stabilized by the interaction between their π electrons and the high density of gold surface states, hinders the formation of the ordered assemblies of the corresponding co‐crystal. The influence of the substrate plus the critical role played by electronic and steric effects in the co‐crystal formation are believed to cause the lack of viability. However, it is remarkable that, on the surface, adsorbed single C 60 F 18 molecules are well centered on top of one coronene molecule, facilitating charge transfer between D and A molecules.

Regulatory Pathways for Qualification and Acceptance of Digital Health Technology‐Derived Clinical Trial Endpoints: Considerations for Sponsors

Despite widespread interest and substantial investment in the adoption of sensor‐based digital health technologies (sDHTs) for remote data capture in drug development trials, no drug has been approved based on an sDHT‐derived primary endpoint in the United States (US). One reason for this lack of advancement is the complexity of obtaining regulatory endorsement for those endpoints within current US regulatory pathways. The goal of our review is to describe the two choices currently available to pharmaceutical study Sponsors: (i) they may navigate the traditional route of compiling the evidence to support the sDHT‐derived endpoint in their investigational new drug (IND) application, requiring specific expertise and substantial resources; or (ii) they may navigate the drug development tool (DDT) pathway with the goal of qualifying their sDHT‐derived endpoint as a biomarker or clinical outcome assessment applicable to a broader context of use (COU), either alone or as part of a partnership or consortium. We describe the nuances of each pathway; the evidentiary requirements for supporting an sDHT‐derived endpoint and the technology used to capture it; and the impact that an sDHT's regulatory status may have on a Sponsor's decision to use it for data capture. By systematically comparing the IND and DDT pathways, our over‐arching goals are to support the increasing deployment of sDHTs within the clinical research setting and help advance regulatory science in the field of digital medicine.

Narrow Therapeutic Index Drugs: FDA Experience, Views, and Operations

The U.S. Food and Drug Administration (FDA) has defined narrow therapeutic index (NTI) drugs as “those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life‐threatening or result in persistent or significant disability or incapacity.” FDA has undertaken efforts to develop NTI assessment criteria and enhance public confidence in generic NTI drugs through public workshops, research, and post‐marketing surveillance. In 2015, FDA formed the NTI Drug Working Group to develop a consistent approach to identify NTI drugs and resolve NTI‐related scientific and regulatory issues in a transparent and collaborative manner. One key objective of the NTI Drug Working Group is to evaluate potential NTI drugs based on five general characteristics of NTI drugs as highlighted in the case example for theophylline drug products. As of January 5, 2024, there are 33 drug products, with 14 distinct active ingredients, specified as NTI drugs in their respective product‐specific guidances (PSGs) for generic drug development. Future collaborative efforts with other agencies to harmonize the terms and definitions for NTI drugs may help enhance clarity and consistency during the drug development and the regulatory review process.

Urinary Kidney Injury Biomarker Profiles in Healthy Individuals and After Nephrotoxic and Ischemic Injury

Two observational studies were conducted to support an initiative to qualify translational kidney safety biomarkers as clinical drug development tools that identify tubular injury prior to changes in estimated glomerular filtration rate (eGFR). Normal healthy volunteers provided three morning spot urine collections over 4 weeks. Patients undergoing surgical resection and intrathoracic cisplatin for malignant pleural mesothelioma provided urine samples pre‐ and postoperatively at 4, 8, and 12 hours and daily for 6 days. Using receiver‐operating characteristics curves, “statistically significant thresholds” established peak longitudinal changes for 8 biomarkers to differentiate mesothelioma patients who developed acute kidney injury (AKI) from normal healthy volunteers. We also assessed “medically significant thresholds” to differentiate mesothelioma patients who did vs. did not develop AKI. Statistically and medically significant thresholds for a fold‐change from baseline of urine creatinine (UCr)‐normalized values were established for 6 biomarkers: clusterin (2.2, 5.1); osteopontin (3.1, 7.1); N ‐acetyl‐ ß ‐ D ‐glucosaminidase (2.7, 8.1); kidney injury molecule‐1 (4.3, 7.5); cystatin C (1.8, 4.5); neutrophil gelatinase‐associated lipocalin (2.9, 7.8). For urine albumin and total protein, thresholds were established based on UCr‐normalized absolute values: (> upper limit normal, > 10× upper limit normal). Statistically significant thresholds for all biomarkers outperformed eGFR at discriminating mesothelioma subjects exposed to cisplatin from healthy volunteers, demonstrating their utility for enhancing safe drug development. Medically significant thresholds provide perspective on when patients begin to exhibit AKI. These studies have established guideposts for confirmatory studies with additional cohorts and nephrotoxicants to formally qualify the selected biomarkers with worldwide regulatory authorities.

Return of Clinically Actionable Pharmacogenetic Results From Molecular Tumor Board DNA Sequencing Data: Workflow and Estimated Costs

Pharmacogenetic testing can prevent severe toxicities from several oncology drug therapies; it also has the potential to improve the outcomes from supportive care drugs. Paired tumor and germline sequencing is increasingly common in oncology practice; these include sequencing of pharmacogenes, but the germline pharmacogenetic variants are rarely included in the clinical reports, despite many being clinically actionable. We established an informatics workflow to evaluate the clinical sequencing results for pharmacogenetic variants. We used the Aldy computational tool, which we have previously shown to determine the variant alleles in 14 pharmacogenes in clinical sequencing data with >99% accuracy, to identify pharmacogenetic variants in the clinical whole exome sequencing from our molecular tumor board. Patients with genetic variants that are clinically actionable for their individual therapy programs, including both treatment and supportive care, are referred to a clinical pharmacogenetics testing laboratory for confirmation. Through an evaluation of our weekly informatics workflow, we determined it took approximately 3.25 hours to complete the analysis of the sequencing data from approximately 20 patients. Using a United States pharmacist's median salary, we estimated the incremental added cost of the process to be only ~$15 per patient. This adds only a minor increase to the patient's cost of testing and has the potential to improve the safety and efficacy of their treatment.