Let's TOC Fertility: A stepped wedge cluster randomized controlled trial of the Telehealth Oncofertility Care (TOC) intervention in children, adolescent and young adult cancer survivors.

INTRODUCTION: Children, adolescent, and young adult cancer survivors experience overall increased risks of infertility that are preventable through effective fertility preservation services prior to starting cancer treatment. Oncofertility care is the evidence-based practice of informing newly diagnosed cancer patients about their reproductive risks and supporting shared decision-making on fertility preservation services. Despite longstanding clinical guidelines, oncofertility care delivery continues to be limited and highly variable across adult and pediatric oncology settings. MATERIALS AND METHODS: We describe the design of a stepped wedge cluster randomized clinical trial to evaluate the effectiveness of the multi-component Telehealth Oncofertility Care (TOC) intervention conducted in 20 adult and pediatric oncology clinics across three health systems in Southern California. Intervention components are: 1) electronic health record-based oncofertility needs screen and referral pathway to a virtual oncofertility hub; 2) telehealth oncofertility counseling through the hub; and 3) telehealth oncofertility financial navigation through the hub. We hypothesize the intervention condition will be associated with increased proportions of patients who engage in goal-concordant oncofertility care (i.e., engagement in reproductive risk counseling and fertility preservation services that meet the patient's fertility goals) and improved patient-reported outcomes, compared to the usual care control condition. We will also evaluate intervention implementation in a mixed-methods study guided by implementation science frameworks. DISCUSSION: Our overall goal is to speed implementation of a scalable oncofertility care intervention at cancer diagnosis for children, adolescent and young adult cancer patients to improve their future fertility and quality of life. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05443737.

Social Determinants of Health and Informed Consent Comprehension for Pediatric Cancer Clinical Trials.

Importance: Ensuring valid informed consent (IC) prior to enrollment in clinical trials is a fundamental ethical right. Objective: To assess whether social determinants of health (SDOH) and related sociocontextual factors are associated with parental IC comprehension in therapeutic childhood cancer clinical trials. Design, Setting, and Participants: This cross-sectional study prospectively enrolled 223 parents of children with newly diagnosed cancer at Rady Children's Hospital San Diego, a large quaternary academic center in California, from October 1, 2014, to March 31, 2021. Linear mixed effects models were used to assess whether IC comprehension overall and by domain (purpose, procedures, and randomization; risks and benefits; alternatives; and voluntariness) were associated with SDOH and sociocontextual factors. Data were analyzed from January 1, 2022, to July 31, 2023. Exposures: Informed consent for a therapeutic childhood cancer clinical trial. Main Outcomes and Measures: The primary outcome of interest was IC comprehension and its associations with SDOH (marital status, language, educational attainment, employment, insurance type, socioeconomic status, and health literacy) and sociocontextual factors (ethnicity, satisfaction with informed consent, and cancer type). Results: Of 223 parents, 172 (77.1%) were aged 18 to 44 years, 111 (49.8%) were Hispanic, 152 (68.2%) were women, and 163 (73.1%) were married. In terms of race, 2 (0.9%) were American Indian or Alaska Native, 22 (9.9%) were Asian or Pacific Islander, 8 (3.6%) were Black, 149 (66.8%) were White, and 42 (18.8%) were more than 1 race. In multivariable linear mixed-effects analyses, limited vs adequate health literacy was associated with lower comprehension of informed consent overall (mean [SD], 68.28 [11.81] vs 79.24 [11.77]; ß estimate, -9.02 [95% CI, -12.0 to -6.07]; P < .001) and with lower comprehension of the purpose, procedures, and randomization (mean [SD], 65.00 [12.64] vs 76.14 [11.53]; ß estimate, -7.87 [95% CI, -10.9 to -4.85]; P < .001); risks and benefits (mean [SD], 62.84 [20.24] vs 73.14 [20.86]; ß estimate, -10.1 [95% CI, -15.6 to -4.59]; P < .001); alternatives (mean [SD], 54.27 [43.18] vs 82.98 [34.24]; ß estimate, -14.3 [95% CI, -26.1 to -2.62]; P .02); and voluntariness (mean [SD], 76.52 [24.33] vs 95.39 [13.89]; ß estimate, -9.14 [95% CI, -14.9 to -3.44]; P = .002) domains. Use of Spanish vs English language for medical communication was associated with lower comprehension overall (mean [SD], 66.45 [12.32] vs 77.25 [12.18]; ß estimate, -5.30 [95% CI, -9.27 to -1.34]; P = .01) and with lower comprehension of the purpose, procedures, and randomization (mean [SD], 63.33 [11.98] vs 74.07 [12.52]; ß estimate, -4.33 [95% CI, -8.43 to -0.23]; P = .04) and voluntariness (mean [SD], 70.83 [24.02] vs 92.54 [17.27]; ß estimate, -9.69 [95% CI, -16.8 to -2.56]; P = .009) domains. Conclusions and Relevance: In this cross-sectional study including parents of children with newly diagnosed cancer who provided IC for their child's participation in a therapeutic clinical trial, limited health literacy and use of Spanish language for medical communication were associated with lower comprehension of IC. These findings suggest that, in this setting, parents with limited health literacy or those who use Spanish language for medical communication may not fully comprehend IC and therefore may not make truly informed decisions. These findings support the investigation of interventions, across pediatric disciplines, tailored to the participant's language and health literacy level to improve IC comprehension, particularly in racial and ethnic minority populations.

3D bioprinted breast tumor-stroma models for pre-clinical drug testing.

The use of three-dimensional (3D) bioprinting has been proposed for the reproducible production of 3D disease models that can be used for high-throughput drug testing and personalized medicine. However, most such models insufficiently reproduce the features and environment of real tumors. We report the development of bioprinted in vitro 3D tumor models for breast cancer, which physically and biochemically mimic important aspects of the native tumor microenvironment, designed to study therapeutic efficacy. By combining a mix of breast decellularized extracellular matrix and methacrylated hyaluronic acid with tumor-derived cells and non-cancerous stromal cells of biological relevance to breast cancer, we show that biological signaling pathways involved in tumor progression can be replicated in a carefully designed tumor-stroma environment. Finally, we demonstrate proof-of-concept application of these models as a reproducible platform for investigating therapeutic responses to commonly used chemotherapeutic agents.

Childhood Leukemia Survival in the US-Mexico Border: Building Sustainable Leukemia Care Using Health Systems Strengthening Models.

PURPOSE: Pediatric leukemia outcomes are poor in most low- and middle-income countries (LMICs) and exacerbated by health care systems ill equipped to manage cancer. Effective leukemia management in LMICs involves curating epidemiologic data; providing health care workforce specialty training; developing evidence-based treatments and supportive care programs; safeguarding access to medications and equipment; providing patient and family psychosocial, financial, and nutritional support; partnering with nongovernmental organizations, and ensuring treatment adherence. METHODS: In 2013, through a partnership between North-American and Mexican institutions, we used the WHO Framework for Action, a health systems strengthening model to implement a leukemia care sustainable program aimed at improving acute lymphoblastic leukemia (ALL) outcomes at a public hospital in Mexico. We prospectively assessed clinical features, risk classification, and survival outcomes in children with ALL at Hospital General-Tijuana from 2008 to 2012 (preimplementation) and from 2013 to 2017 (postimplementation). We also evaluated program sustainability indicators. RESULTS: Our approach led to a fully-staffed leukemia service, sustainable training programs, evidence-based and data-driven projects to improve clinical outcomes, and funding for medications, supplies, and personnel through local partnerships. Preimplementation and postimplementation 5-year overall survival for the entire cohort of children with ALL, children with standard-risk ALL, and children with high-risk ALL improved from 59% to 65% (P = .023), 73% to 100% (P < .001), and 48% to 55% (P = .031), respectively. All sustainability indicators improved between 2013 and 2017. CONCLUSION: Using the health systems strengthening WHO Framework for Action model, we improved leukemia care and survival in a public hospital in Mexico across the US-Mexico border. We provide a model for the development of similar programs in LMICs to sustainably improve leukemia and other cancer outcomes.

Gene therapy preferences and informed decision-making: Results from a National Hemophilia Foundation Community Voices in research survey.

INTRODUCTION: To inform education and treatment discussions, it is important to understand how persons with haemophilia prefer to learn about and discuss new therapies and to identify variables that influence decision-making. AIM: The aim of this study was to evaluate preferences and variables which influence decision-making related to gene therapy and other novel haemophilia therapies. METHODS: An online survey was sent to men with severe haemophilia enrolled in the National Hemophilia Foundation Community Voices in Research online platform for patient-powered research. RESULTS: One hundred four men completed the survey including 33% Hispanics, 96 who had had not gene therapy and 71/96 (74%) who were on prophylaxis. Ninety-five percent were somewhat or very familiar with gene therapy. Men with haemophilia obtain information about new therapies from several sources, most commonly their haemophilia treatment team, patient advocacy groups and self-study. Participants identified safety and efficacy as well as other educational needs to inform decision-making. Of those without prior gene therapy, 73% indicated a high likelihood of considering gene therapy. Hispanic ethnicity and government-issued insurance were associated with a higher likelihood of considering gene therapy as a treatment option. CONCLUSION: Haemophilia Treatment Centers and patient advocacy groups must be able to educate persons with haemophilia about aspects of novel therapies which are important to the individual, especially short- and long-term safety and efficacy. Further research is needed to determine how patient activation and health literacy influence decision-making and how to achieve equitable access and valid informed consent for novel therapies.

Single-agent Bevacizumab in the Treatment of Symptomatic Newly Diagnosed and Recurrent/Refractory Pediatric Cervicomedullary Brainstem Low-grade Gliomas: A Single Institutional Experience.

Bevacizumab-based therapies have been utilized as single or combination therapy of refractory/recurrent pediatric low-grade gliomas. Its efficacy for symptomatic cervicomedullary low-grade gliomas (cmLGGs) in the upfront and the recurrent setting is less known. We report our retrospective single institutional experience from 2015 to 2021 with single-agent bevacizumab for symptomatic cmLGG. Six consecutive patients (4 female, ages 2 to 12 y) with newly diagnosed (n=3) and recurrent/refractory (n=3) symptomatic nondisseminated cmLGG (5/6 biopsy-proven, 2 BRAFV600E, 2 BRAF-KIAA1549) were treated with single-agent bevacizumab. All demonstrated radiographic response most pronounced on post-gadolinium T1-weighted magnetic resonance imaging (2 complete, 4 partial) at a median of 8 weeks (range: 2 to 12 wk). Clinical response was seen in all patients with improvement in cranial nerve abnormalities (3 recurrent/refractory, 1 newly diagnosed), strength (2 recurrent/refractory, 2 newly diagnosed), pain (2 recurrent/refractory), and anorexia (1 newly diagnosed). Four patients (2 recurrent/refractory, 2 newly diagnosed) experienced disease progression on subsequent adjunct therapies, 2 of which (the 2 newly diagnosed patients) are currently being rechallenged. At a mean follow-up of 7 months, all patients are clinically stable without disease progression. Single-agent bevacizumab may be effective in the management of symptomatic newly diagnosed and recurrent/refractory cmLGG and warrants further evaluation in a clinical trial setting.

A Multicomponent Telehealth Intervention to Improve Oncofertility Care Delivery Among Young Cancer Patients: A Pilot Study.

Purpose: Oncofertility care for pediatric, adolescent, and young adult cancer patients remains under-implemented across adult and pediatric oncology settings. We pilot tested an electronic health record (EHR)-enabled multicomponent oncofertility intervention (including screening, referral, and fertility consult) in an adult academic oncology program and systematically assessed intervention fit to pediatric and community oncology programs. Methods: Using surveys (n = 33), audits (n = 143), and interviews (n = 21) guided by implementation science frameworks, we pilot tested the EHR-enabled intervention for oncofertility care in young cancer patients at an adult oncology program and evaluated implementation outcomes. We interviewed health care providers from seven regional oncology and fertility programs about intervention fit to their clinical contexts. Results: We recruited 33 health care providers from an adult oncology setting and 15 health care providers from seven additional oncology and fertility settings. At the adult oncology setting, the intervention was found to be appropriate, acceptable, and feasible and improved the screening of fertility needs (from 30% pre- to 51% post-intervention); yet, some patients did not receive appropriate referrals to fertility consults. Providers across all settings suggested content and context modifications, such as adding options to the intervention or allowing the screening component to pop up at a second visit, to improve and adapt the intervention to better fit their clinical care contexts. Conclusions: We found that the EHR-enabled intervention increased the rate of goal-concordant oncofertility care delivery at an adult oncology program. We also identified facilitators, barriers, and needed adaptations to the intervention required for implementation and scaling-up across diverse oncology settings.

Primary central nervous system tumors survival in children in ten Colombian cities: a VIGICANCER report.

Purpose: Primary central nervous system (CNS) tumors are the second most common cancer in children and adolescents, leading to premature death and disability. Population-based survival estimates aid decision-making in cancer control, however data on survival for primary CNS tumors in Latin America is lacking. We describe survival rates for children with primary CNS tumors treated in ten Colombian cities. Methods: We analyzed data from children and adolescents newly diagnosed with cancer between 2012 and 2021, participating in the Childhood Cancer Clinical Outcomes Surveillance System (VIGICANCER) in ten cities in Colombia. VIGICANCER collects information on clinical outcomes from twenty-seven pediatric oncology units and conducts active follow-up every three months. VIGICANCER does not register craniopharyngiomas; we excluded intracranial germ cell tumors for this report. We used the Kaplan-Meier method to estimate the overall survival probability, stratified by sociodemographic variables, topography, WHO grading, receipt of radiation therapy, and type of surgical resection. We analyzed the prognostic capacity of variables using multivariate proportional Cox's regression, stratified by city and year of diagnosis. Results: During the study period, VIGICANCER included 989 primary CNS tumors in 879 children and 110 adolescents. The cohort median age was 9 years; 53% of patients were males, and 8% were Afro-descendants. Most common tumors were supratentorial astrocytomas (47%), astrocytic tumors (35%), medulloblastomas (20%), ependymomas (11%), and mixed and unspecified gliomas (10%). Five-year overall survival of the entire cohort was 54% (95% CI, 51-58); for supratentorial gliomas, WHO grade I was 77%, II was 62%, III-IV was 27%, respectively, and for medulloblastoma was 61%. The adjusted hazard rate ratio for patients with WHO grade III and IV, for those with subtotal resection, for brainstem location, and for those not receiving radiation therapy was 7.4 (95% CI, 4.7-11.8), 6.4 (95% CI, 4.2-9.8), 2.8 (95% 2.1-3.8), 2.0 (95% CI, 1.3-2.8) and 2.3 (95% CI, 1.7-3.0), respectively. Conclusion: We found that half of Colombia's children and adolescents with primary CNS tumors survive five years, compared to 70% to 80% in high-income countries. In addition to tumor biology and location, gross total resection was crucial for improved survival in this cohort. Systematic monitoring of survival and its determinants provides empirical data for guiding cancer control policies.

Protocols for the Evaluation of Neurodevelopmental Alterations in Rabbit Models In Vitro and In Vivo.

The rabbit model is gaining importance in the field of neurodevelopmental evaluation due to its higher similarity to humans in terms of brain development and maturation than rodents. In this publication, we detailed 14 protocols covering toxicological relevant endpoints for the assessment of neurodevelopmental adverse effects in the rabbit species. These protocols include both in vitro and in vivo techniques, which also cover different evaluation time-points, the neonatal period, and long-term examinations at postnatal days (PNDs) 50-70. Specifically, the protocols (P) included are as follows: neurosphere preparation (GD30/PND0; P2) and neurosphere assay (P3), behavioral ontogeny (PND1; P4), brain obtaining and brain weight measurement at two different ages: PND1 (P5) and PND70 (P12), neurohistopathological evaluations after immersion fixation for neurons, astrocytes, oligodendrocytes and microglia (PND1; P6-9) or perfusion fixation (PND70; P12), motor activity (P11, open field), memory and sensory function (P11, object recognition test), learning (P10, Skinner box), and histological evaluation of plasticity (P13 and P14) through dendritic spines and perineuronal nets. The expected control values and their variabilities are presented together with the information on how to troubleshoot the most common issues related to each protocol. To sum up, this publication offers a comprehensive compilation of reliable protocols adapted to the rabbit model for neurodevelopmental assessment in toxicology.

Trends in Tissue Bioprinting, Cell-Laden Bioink Formulation, and Cell Tracking.

Use of three-dimensional bioprinting for the in vitro engineering of tissues has boomed during the past five years. An increasing number of commercial bioinks are available, with suitable mechanical and rheological characteristics and excellent biocompatibility. However, cell-laden bioinks based on a single polymer do not properly mimic the complex extracellular environment needed to tune cell behavior, as required for tissue and organ formation. Processes such as cell aggregation, migration, and tissue patterning should be dynamically monitored, and progress is being made in these areas, most prominently derived from nanoscience. We review recent developments in tissue bioprinting, cellularized bioink formulation, and cell tracking, from both chemistry and cell biology perspectives. We conclude that an interdisciplinary approach including expertise in polymer science, nanoscience, and cell biology/tissue engineering is required to drive further advancements in this field toward clinical application.

Docosahexaenoic Acid and Melatonin Prevent Impaired Oligodendrogenesis Induced by Intrauterine Growth Restriction (IUGR).

In this study, our aims were to characterize oligodendrogenesis alterations in fetuses with intrauterine growth restriction (IUGR) and to find therapeutic strategies to prevent/treat them using a novel rabbit in vitro neurosphere culture. IUGR was surgically induced in one uterine horn of pregnant rabbits, while the contralateral horn served as a control. Neural progenitor cells (NPCs) were obtained from pup's whole brain and cultured as neurospheres mimicking the basic processes of brain development including migration and cell differentiation. Five substances, chosen based on evidence provided in the literature, were screened in vitro in neurospheres from untreated rabbits: Docosahexaenoic acid (DHA), melatonin (MEL), zinc, 3,3',5-Triiodo-L-thyronine (T3), and lactoferrin (LF) or its metabolite sialic acid (SA). DHA, MEL and LF were further selected for in vivo administration and subsequent evaluation in the Neurosphere Assay. In the IUGR culture, we observed a significantly reduced percentage of oligodendrocytes (OLs) which correlated with clinical findings indicating white matter injury in IUGR infants. We identified DHA and MEL as the most effective therapies. In all cases, our in vitro rabbit neurosphere assay predicted the outcome of the in vivo administration of the therapies and confirmed the reliability of the model, making it a powerful and consistent tool to select new neuroprotective therapies.

Improving vitamin D testing and supplementation in children with newly diagnosed cancer: A quality improvement initiative at Rady Children's Hospital San Diego.

BACKGROUND: Vitamin D deficiency and insufficiency have been associated with poorer health outcomes. Children with cancer are at high risk for vitamin D deficiency and insufficiency. At our institution, we identified high variability in vitamin D testing and supplementation in this population. Of those tested, 65% were vitamin D deficient/insufficient. We conducted a quality improvement (QI) initiative with aim to improve vitamin D testing and supplementation among children aged 2-18 years with newly diagnosed cancer to ≥80% over 6 months. METHODS: An inter-professional team reviewed baseline data, then developed and implemented interventions using Plan-Do-Study-Act (PDSA) cycles. Barriers were identified using QI tools, including lack of automated triggers for testing and inconsistent supplementation criteria and follow-up testing post supplementation. Interventions included an institutional vitamin D guideline, clinical decision-making tree for vitamin D deficiency, insufficiency and sufficiency, electronic medical record triggers, and automated testing options. RESULTS: Baseline: N = 26 patients, four (15%) had baseline vitamin D testing; two (8%) received appropriate supplementation. Postintervention: N = 33 patients; 32 (97%) had baseline vitamin D testing; 33 (100%) received appropriate supplementation and completed follow-up testing timely (6-8 weeks post supplementation). Change was sustained over 24 months. CONCLUSIONS: We achieved and sustained our aim for vitamin D testing and supplementation in children with newly diagnosed cancer through inter-professional collaboration of hematology/oncology, endocrinology, hospital medicine, pharmacy, nursing, and information technology. Future PDSA cycles will address patient compliance with vitamin D supplementation and impact on patients' vitamin D levels.

Disparities in Pediatric Oncology: The 21st Century Opportunity to Improve Outcomes for Children and Adolescents With Cancer.

Adult cancer disparities have been documented for decades and continue to persist despite clinical advancements in cancer prevention, detection, and treatment. Pediatric cancer survival has improved significantly in the United States for the past 5 decades to over 80%; however, disparate outcomes among children and adolescents with cancer still affect many populations in the United States and globally, including racial and ethnic minorities, populations with low socioeconomic status, and residents of underserved areas. To achieve equitable outcomes for all children and adolescents with cancer, it is imperative that concerted multilevel approaches be carried out to understand and address health disparities and to ensure access to high-quality cancer care. Addressing social determinants of health, such as removing barriers to health care access and ensuring access to social supports, can reduce pediatric cancer disparities. Nevertheless, public health policy, health system interventions, and innovative delivery of evidence-based services are critically needed. Partnerships among patients, caregivers, and health care providers, and among health care, academic, and governmental institutions, have a pivotal role in reducing cancer disparities and improving outcomes in the 21st century.

Assessment of Factors Associated With Parental Perceptions of Voluntary Decisions About Child Participation in Leukemia Clinical Trials.

Importance: Obtaining voluntary informed consent prior to enrollment in clinical trials is a fundamental ethical requirement. Objective: To assess whether health literacy, contextual factors, or sociodemographic characteristics are associated with perception of voluntariness among parents who had consented for their child's participation in a leukemia therapeutic clinical trial. Design, Setting, and Participants: This cross-sectional study prospectively enrolled 97 parents of children diagnosed as having leukemia at Rady Children's Hospital San Diego, a large tertiary academic center in California, from 2014 to 2017. Health literacy, contextual factors (acculturation, decisional regret, and satisfaction with informed consent), sociodemographic characteristics, and perception of voluntariness after consenting for a therapeutic clinical trial were measured. Univariable and multivariable regression were used to determine significant associations. The analyses for the present study were conducted from May 2019 to May 2020. Exposures: Informed consent for a therapeutic leukemia clinical trial. Main Outcomes and Measures: The primary outcome of interest was perception of voluntariness and its associations with health literacy and other contextual factors (acculturation, decisional regret, and satisfaction with informed consent) and sociodemographic characteristics, including age, race/ethnicity, parental language, educational level, insurance type, marital status, and socioeconomic status. Results: Of 97 parents included, the majority were women (65 [67%]), married (71 [73%]), and of self-reported Hispanic ethnicity (50 [52%]). Lower perception of voluntariness was significantly associated with lower health literacy (r = 0.30; 95% CI, 0.11-0.47; P = .004), Spanish language (x̅ = -4.50, P = .05), lower acculturation if of Hispanic ethnicity (r = 0.30; 95% CI, 0.02-0.54; P = .05), greater decisional regret (r = -0.54; 95% CI, -0.67 to -0.38; P < .001), and lower satisfaction with informed consent (r = 0.39; 95% CI, 0.21-0.54; P < .001) in univariable analysis. Lower health literacy remained significantly associated with lower perception of voluntariness in multivariable analysis after adjustment for contextual factors and sociodemographic characteristics (ß = 4.06; 95% CI, 1.60-6.53; P = .001). Lower health literacy was significantly associated with Hispanic ethnicity (mean, 4.16; 95% CI, 3.75-4.57; P < .001), Spanish language spoken at home (mean, 3.17; 95% CI, 1.94-4.40; P < .001), high school or less educational level (mean, 3.41; 95% CI, 2.83-3.99; P < .001), public insurance (mean, 4.00; 95% CI, 3.55-4.45; P < .001), and unmarried status (mean, 3.71; 95% CI, 2.91-4.51; P = .03). Conclusions and Relevance: Among parents of children with newly diagnosed leukemia who had consented for their child's participation in a therapeutic clinical trial, lower perception of voluntariness was significantly associated with lower health literacy. These results suggest that parents with low health literacy may perceive external influences in their decision for their child's participation in clinical trials. This finding highlights the potential role of recruitment interventions tailored to the participant's health literacy level to improve voluntary informed consent in underserved populations.

The Golden Hour: Sustainability and Clinical Outcomes of Adequate Time to Antibiotic Administration in Children with Cancer and Febrile Neutropenia in Northwestern Mexico.

PURPOSE: Time to antibiotic administration (TTA) is a commonly used standard of care in pediatric cancer settings in high-income countries. Effective interventions to improve outcomes in cancer patients with febrile neutropenia (FN) often address timely and appropriate antibiotic administration. We assessed the effectiveness of a locally adapted multimodal strategy in decreasing TTA in a resource-constrained pediatric cancer center in Mexico. METHODS: We conducted a prospective observational study between January 2014 and April 2019. A three-phase (phase I: execution, phase II: consolidation, phase III: sustainability) multimodal improvement strategy that combined system change, FN guideline development, education, auditing and monitoring, mentoring, and dissemination was implemented to decrease TTA in inpatient and ambulatory areas. Sustainability factors were measured by using a validated tool during phases I and III. RESULTS: Our population included 105 children with cancer with 204 FN events. The baseline assessment revealed that only 50% of patients received antibiotics within 60 minutes of prescription (median time: inpatient, 75 minutes; ambulatory, 65 minutes). After implementing our improvement strategy, the percentage of patients receiving antibiotics within 60 minutes of prescription increased to 88%. We significantly decreased median TTA in both clinical areas during the three phases of the study. In phase III (sustainability), the median TTA was 40 minutes (P = .023) in the inpatient area and 30 minutes (P = .012) in the ambulatory area. The proportion of patients with sepsis decreased from 30% (baseline) to 5% (phase III) (P = .001). CONCLUSION: Our results demonstrate that locally adapted multimodal interventions can reduce TTA in resource-constrained settings. Mentoring and dissemination were novel components of the multimodal strategy to improve FN-associated clinical outcomes. Improving local infrastructure, ongoing monitoring systems, and leadership engagement have been key factors to achieving sustainability during the 5-year period.

Theory-Guided Development of Fertility Care Implementation Strategies for Adolescent and Young Adult Cancer Survivors.

Purpose: Oncofertility care at cancer diagnosis remains underimplemented across oncology and fertility care settings, with limited tools to scale up effective implementation strategies. Using implementation science theory, we systematically assessed factors that influence oncofertility care implementation and mapped scalable strategies, particularly electronic health record (EHR)-enabled ones, that fit adult and pediatric oncology care contexts. Methods: Using purposeful sampling, we recruited health care providers and female, reproductive-aged survivors of adolescent and young adult (AYA) cancers (AYA survivors) from a comprehensive cancer center and a freestanding children's hospital to semistructured interviews and focus groups. Using thematic analysis combining inductive codes with deductive codes using the Consolidated Framework for Implementation Research (CFIR), we characterized barriers and facilitators to care and designed responsive strategies. Two coders independently coded each transcript. Results: We recruited 19 oncology and fertility providers and 9 cancer survivors. We identified barriers and facilitators to oncofertility care in the CFIR domains of individual, inner setting, outer setting, and process, allowing us to conceptualize oncofertility care to encompass three core components (screening, referral, and fertility preservation counseling) and map five strategies to these components that fit an adult and a children's context and bridge oncology and fertility practices. The strategies were screening using a best practice advisory, referral order, telehealth fertility counseling, provider audit and feedback, and provider education. All but provider education were EHR tools with embedded efficiencies. Conclusion: An implementation science approach systematically assessed oncofertility care and mapped strategies to provide a theory-based approach and scalable EHR tools to support wider dissemination.

Improving Pediatric Neuro-Oncology Survival Disparities in the United States-Mexico Border Region: A Cross-Border Initiative Between San Diego, California, and Tijuana, Mexico.

PURPOSE: Treatment of children with CNS tumors (CNSTs) demands a complex, interdisciplinary approach that is rarely available in low- and middle-income countries. We established the Cross-Border Neuro-Oncology Program (CBNP) between Rady Children's Hospital, San Diego (RCHSD), and Hospital General, Tijuana (HGT), Mexico, to provide access to neuro-oncology care, including neurosurgic services, for children with CNSTs diagnosed at HGT. Our purpose was to assess the feasibility of the CBNP across the United States-Mexico border and improve survival for children with CNSTs at HGT by implementing the CBNP. PATIENTS AND METHODS: We prospectively assessed clinicopathologic profiles, the extent of resection, progression-free survival, and overall survival (OS) in children with CNSTs at HGT from 2010 to 2017. RESULTS: Sixty patients with CNSTs participated in the CBNP during the study period. The most common diagnoses were low-grade glioma (24.5%) and medulloblastoma (22.4%). Of patients who were eligible for surgery, 49 underwent resection at RCHSD and returned to HGT for collaborative management. Gross total resection was achieved in 78% of cases at RCHSD compared with 0% at HGT (P < .001) and was a predictor of 5-year OS (hazard ratio, 0.250; 95% CI, 0.067 to 0.934; P = .024). Five-year OS improved from 0% before 2010 to 52% in 2017. CONCLUSION: The CBNP facilitated access to complex neuro-oncology care for underserved children in Mexico through binational exchanges of resources and expertise. Survival for patients in the CBNP dramatically improved. Gross total resection at RCHSD was associated with higher OS, highlighting the critical role of experienced neurosurgeons in the treatment of CNSTs. The CBNP model offers an attractive alternative for children with CNSTs in low- and middle-income countries who require complex neuro-oncology care, particularly those in close proximity to institutions in high-income countries with extensive neuro-oncology expertise.

Effect of a Daily Text Messaging and Directly Supervised Therapy Intervention on Oral Mercaptopurine Adherence in Children With Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.

Importance: Suboptimal adherence to oral mercaptopurine treatment in children with acute lymphoblastic leukemia (ALL) increases the risk of relapse. A frequently expressed barrier to adherence is forgetfulness, which is often overcome by parental vigilance. Objective: To determine whether a multicomponent intervention, compared with education alone, will result in a higher proportion of patients with ALL who have mercaptopurine adherence rates 95% or higher, for all study participants and among patients younger than 12 years and vs those aged 12 years and older. Design, Setting, and Participants: The adherence intervention trial was an investigator-initiated, multi-institutional, parallel-group, unblinded, randomized clinical trial conducted between July 16, 2012, and August 8, 2018, at 59 Children's Oncology Group institutions in the US, enrolling patients with ALL diagnosed through age 21 years and receiving mercaptopurine for maintenance. The date of final follow-up was January 2, 2019. Data analysis was performed from February to October 2019. Interventions: Patients were randomized 1:1 to education alone or the intervention package, which consisted of education and personalized text message reminders daily to prompt directly supervised therapy. Four weeks of baseline adherence monitoring were followed with a 16-week intervention. Main Outcomes and Measures: The primary end point was the proportion of patients with adherence rates 95% or higher over the duration of the intervention for all study participants, and for those younger than 12 years vs those aged 12 years and older. Results: There were 444 evaluable patients (median age, 8.1 years; interquartile range, 5.3-14.3 years), including 230 in the intervention group and 214 in the education group. Three hundred two patients (68.0%) were boys, 180 (40.5%) were non-Hispanic White, 170 (38.3%) were Hispanic, 43 (9.7%) were African American, and 51 (11.5%) were Asian or of mixed race/ethnicity. The proportion of patients with adherence rates 95% or higher did not differ between the intervention vs education groups (65% vs 59%; odds ratio, 1.33; 95% CI, 1.0-2.0; P = .08). Exploratory analyses showed that among patients aged 12 years and older, those in the intervention group had higher mean (SE) adherence rates than those in the education group (93.1% [1.1%] vs 90.0% [1.3%]; difference, 3.1%; 95% CI, 0.1%-6.0%; P = .04). In particular, among patients aged 12 years and older with baseline adherence less than 90%, those in the intervention group had higher mean (SE) adherence rates than those in the education group (83.4% [2.5%] vs 74.6% [3.4%]; difference, 8.8%; 95% CI, 2.2%-15.4%; P = .008). No safety concerns were identified. Conclusions and Relevance: Although this multicomponent intervention did not result in an increase in the proportion of patients with ALL who had mercaptopurine adherence rates 95% or higher, it did identify a high-risk subpopulation to target for future adherence intervention strategies: adolescents with low baseline adherence. Trial Registration: ClinicalTrials.gov Identifier: NCT01503632.