Feasibility of functional precision medicine for guiding treatment of relapsed or refractory pediatric cancers.

Children with rare, relapsed or refractory cancers often face limited treatment options, and few predictive biomarkers are available that can enable personalized treatment recommendations. The implementation of functional precision medicine (FPM), which combines genomic profiling with drug sensitivity testing (DST) of patient-derived tumor cells, has potential to identify treatment options when standard-of-care is exhausted. The goal of this prospective observational study was to generate FPM data for pediatric patients with relapsed or refractory cancer. The primary objective was to determine the feasibility of returning FPM-based treatment recommendations in real time to the FPM tumor board (FPMTB) within a clinically actionable timeframe (<4 weeks). The secondary objective was to assess clinical outcomes from patients enrolled in the study. Twenty-five patients with relapsed or refractory solid and hematological cancers were enrolled; 21 patients underwent DST and 20 also completed genomic profiling. Median turnaround times for DST and genomics were within 10 days and 27 days, respectively. Treatment recommendations were made for 19 patients (76%), of whom 14 received therapeutic interventions. Six patients received subsequent FPM-guided treatments. Among these patients, five (83%) experienced a greater than 1.3-fold improvement in progression-free survival associated with their FPM-guided therapy relative to their previous therapy, and demonstrated a significant increase in progression-free survival and objective response rate compared to those of eight non-guided patients. The findings from our proof-of-principle study illustrate the potential for FPM to positively impact clinical care for pediatric and adolescent patients with relapsed or refractory cancers and warrant further validation in large prospective studies. ClinicalTrials.gov registration: NCT03860376 .

Real-world economic evaluation of prospective rapid whole-genome sequencing compared to a matched retrospective cohort of critically ill pediatric patients in the United States.

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.

Cost-effectiveness of exome and genome sequencing for children with rare and undiagnosed conditions.

PURPOSE: This study aimed to estimate the cost-effectiveness of exome sequencing (ES) and genome sequencing (GS) for children. METHODS: We modeled costs, diagnoses, and quality-adjusted life years (QALYs) for diagnostic strategies for critically ill infants (aged <1 year) and children (aged <18 years) with suspected genetic conditions: (1) standard of care (SOC) testing, (2) ES, (3) GS, (4) SOC followed by ES, (5) SOC followed by GS, (6) ES followed by GS, and (7) SOC followed by ES followed by GS. We calculated the 10-year incremental cost per additional diagnosis, and lifetime incremental cost per QALY gained, from a health care perspective. RESULTS: First-line GS costs $15,048 per diagnosis vs SOC for infants and $27,349 per diagnosis for children. If GS is unavailable, ES represents the next most efficient option compared with SOC ($15,543 per diagnosis for infants and $28,822 per diagnosis for children). Other strategies provided the same or fewer diagnoses at a higher incremental cost per diagnosis. Lifetime results depend on the patient's assumed long-term prognosis after diagnosis. For infants, GS ranged from cost-saving (vs all alternatives) to $18,877 per QALY (vs SOC). For children, GS (vs SOC) ranged from $119,705 to $490,047 per QALY. CONCLUSION: First-line GS may be the most cost-effective strategy for diagnosing infants with suspected genetic conditions. For all children, GS may be cost-effective under certain assumptions. ES is nearly as efficient as GS and hence is a viable option when GS is unavailable.

Readiness and barriers to adopt evidence-based practices for substance abuse treatment in Mexico / Disponibilidad y barreras a la adopción de prácticas basadas en la evidencia para el tratamiento del uso de sustancias en México

ABSTRACT: Introduction: Evidence shows a lag in adoption of evidence-based practices (EBPs) for substance abuse treatment and supports the need for studying the factors involved in this worldwide problem. Objective: This study aimed to assess the readiness and barriers to adopt EBPs for substance abuse in a sample of outpatient treatment centers of a newly created Mexican Clinical Trials Network. Method: An online survey was administered to directors (n = 8) and clinicians (n = 40) from seven outpatient treatment centers in Mexico. Questions were obtained from two surveys that had been implemented in the US to assess the same objectives. Results: Respondents reported being more ready to adopt Cognitive Behavioral Therapy (CBT, 83.3%) and Motivational Enhancement Therapy (MET, 79.1%), compared to 12 step facilitation (58.3%), couples therapy (56.2%), Brief Strategic Family Therapy (BSFT, 66.6%), and motivational incentives (60.4%). Directors had lower mean resistance to EBPs (11.8 vs. 17.4; p = 0.01) than clinicians. The biggest barriers identified by directors to EBP adoption were not having enough clinical staff, being unable to afford well-trained staff, not enough psychiatric and medical support. Discussion and conclusion: CBT and MET emerged as the most frequently used evidence based practices in the sites that are part of the Mexican Clinical Trials Network. Staff positive attitudes towards EBPs are critical for adoption.

RESUMEN: Introducción: La literatura demuestra una demora en la adopción de las practicas basadas en la evidencia (PBEs) para el tratamiento del abuso de sustancias y apoya la necesidad de estudiar los factores involucrados en este problema mundial. Objetivo: Este estudio evaluó la disponiblildad y las barreras de la adopción de PBE para el abuso de sustancias en una muestra de centros pertenencientes a la nueva Red Mexicana de Ensayos Clinicos. Método: Se administró una encuesta online a directores (n = 8) y a clinicos (n = 40) de siete centros de tratamiento ambulatorio para el tratamiento de las adicciones en México. Las preguntas se obtuvieron de dos encuestas que se administraron en los Estados Unidos con los mismos objetivos. Resultados: Los encuestados reportaron estar más dispuestos a la adopción de la Terapia Cognitivo Conductual (CBT,83.3%) y Terapia de Incremento Motivacional (MET, 79.1%),comparado con la facilitación de los 12 pasos (58.3%),terapia de pareja (56.2%), Terapia Familiar Breve y Estratégica (BSFT, 66.6%),e incentivos para la motivación (60.4%). Los directores tuvieron menor promedio de Resistencia a las PBEs (11.8 vs. 17.4; p = 0.01) que los clinicos. Las principales barreras identificadas por los directores fueron no tener suficiente personal clínico, no poder costear personal altamente entrenado, apoyo psiquiátrico y médico insuficiente. Discusión y conclusión: La CBT y la MET emergieron como las PBEs usadas con mayor frecuencia en centros que son parte de la Red Mexicana de Ensayos Clínicos. Las actitudes positivas del personal hacia las PBEs son críticas para la adopción.