The genetic era of childhood cancer: Identification of high-risk patients and germline sequencing approaches.

Childhood cancer is a leading cause of death by disease in children ages 5-14, for which there are no preventive strategies. Due to early-age of diagnosis and short period of exposure to environmental factors, increasing evidence suggests childhood cancer could have strong association with germline alterations in predisposition cancer genes but, their frequency and distribution are largely unknown. Several efforts have been made to develop tools to identify children with increased risk of cancer who may benefit from genetic testing but their validation and application on a large scale is necessary. Research on genetic bases of childhood cancer is ongoing, in which several approaches for the identification of genetic variants related to cancer predisposition have been used. In this paper, we discuss the updated efforts, strategies, molecular mechanisms and clinical implications for germline predisposition gene alterations and the characterization of risk variants in childhood cancer.

Diffuse intrinsic pontine gliomas: First registry effort in Mexico.

INTRODUCTION: Brainstem tumors comprise 10.9% of all brain tumors, and pediatric diffuse intrinsic pontine gliomas (DIPG) have a fatal prognosis. Some countries have developed national and international register databases to characterize their populations to aid clinical and public policy decisions. This study provides information regarding the clinical characteristics of a retrospective cohort of children with DIPG in México from 2001 to 2021, and assesses the proposed prognostic factors previously described for survival outcome. METHODS: Health institutions from Mexico were invited to contribute to a retrospective electronic registry of patients with DIPG based on the International DIPG Registry. Fisher's exact test was used to compare long- and short-term survivors. Overall survival was estimated using the Kaplan-Meier method. Differences between survival curves were evaluated using the log-rank test and Cox proportional hazard regression analysis. RESULTS: Total 110 patients were included. The median age of the patients at diagnosis was 7 years. Sixty patients (54.5%) presented with symptoms in less than 6 months; the most frequent symptom was ataxia (56.4%). Ninety patients received treatment (81.8%), the overall survival at 4 years was 11.4%, and 16 patients (14.5%) were admitted for palliative end-of-life care. We found no significant survival differences for any of the prognostic factors. CONCLUSION: This study highlights the need to develop strategies to standardize healthcare processes and enhance the quality of care to improve clinical diagnosis in Mexico. We also observed a barrier to the acceptance of palliative end-of-life care in the family and medical teams.

High occurrence of CRLF2 abnormalities in Mexican children with B-cell acute lymphoblastic leukemia.

The P2RY8-CRLF2 and IGH-CRLF2 rearrangements induce the overexpression of cytokine receptor-like factor 2 (CRLF2) and have been associated with relapse and poor prognosis in B-cell acute lymphoblastic leukemia (B-ALL). Additionally, they are frequently documented in high-risk Hispanic populations. To better understand the potential causes of the adverse prognosis of childhood B-ALL in Mexico, we analyzed these rearrangements and the CRLF2 mRNA and protein levels in 133 Mexican children with B-ALL. We collected bone marrow samples at diagnosis and evaluated the CRLF2 gene expression by qRT-PCR and the total CRLF2 protein by flow cytometry. P2RY8-CRLF2 and IGH-CRLF2 were detected by RT-PCR and FISH, respectively. The median time of follow-up to determine the prognostic significance of the CRLF2 abnormalities was three years. In 82% of the participants, the mRNA levels correlated with the cell-surface and intracellular CRLF2 protein levels. The P2RY8-CRLF2 rearrangement was present in 31.5% (42/133) of the patients, while the IGH-CRLF2 rearrangement was detected in 13.5% (9/67) of patients with high expression of CRLF2 (6.8% of the total sample). CRLF2 copy number variations (gain) were also detected in 7.5% (5/67) of patients with high protein levels. The overall survival (OS) presented significantly lower rates in patients with high white blood cell count (≥50x109/L) regardless of CRLF2 expression, but high levels of CRLF2 gene expression appears to contribute to the reduction of OS within this group of patients. In conclusion, in our cohort, a high occurrence of CRLF2 abnormalities was documented, particularly the P2RY8-CRLF2 rearrangement, which might represent a characteristic of the Mexican population. Targeted therapy to treat this group of patients could improve OS.

Childhood acute lymphoblastic leukemia in Mexico: mortality trend analysis, 1998-2018.

OBJECTIVE: To determine the magnitude of mortality due to acute lymphoblastic leukemia (ALL) nationally and by age group, sex, state of residence and insurance status, as well as to evaluate time trends during the period 1998-2018 Materials and methods. We obtained ALL mortality data and estimated age-standardized national, state-level and health insurance mortality rates. We conducted a joinpoint regression analysis to describe mortality trends across the study period and estimate the average annual percent change (AAPC). RESULTS: In a 20-year period, age-standardized ALL mortality rates increased from 1.6 per 100 000 in 1998 to 1.7 in 2018. Nationally, a constant annual increase in mortality was observed for both sexes (1998-2002 AAPC 0.6 in boys, and 1998-2002 AAPC 0.3 in girls). We observed heteroge-neity in childhood ALL at a state level. CONCLUSION: Our results reflect the social, economic, geographic diversity of the country. Monitoring and surveillance of this disease is crucial to assess quality of care.

Characterization of Philadelphia-like Pre-B Acute Lymphoblastic Leukemia: Experiences in Mexican Pediatric Patients.

Ph-like subtypes with CRLF2 abnormalities are frequent among Hispano-Latino children with pre-B ALL. Therefore, there is solid ground to suggest that this subtype is frequent in Mexican patients. The genomic complexity of Ph-like subtype constitutes a challenge for diagnosis, as it requires diverse genomic methodologies that are not widely available in diagnostic centers in Mexico. Here, we propose a diagnostic strategy for Ph-like ALL in accordance with our local capacity. Pre-B ALL patients without recurrent gene fusions (104) were classified using a gene-expression profile based on Ph-like signature genes analyzed by qRT-PCR. The expressions of the CRLF2 transcript and protein were determined by qRT-PCR and flow cytometry. The P2RY8::CRLF2, IGH::CRLF2, ABL1/2 rearrangements, and Ik6 isoform were screened using RT-PCR and FISH. Surrogate markers of Jak2-Stat5/Abl/Ras pathways were analyzed by phosphoflow. Mutations in relevant kinases/transcription factors genes in Ph-like were assessed by target-specific NGS. A total of 40 patients (38.5%) were classified as Ph-like; of these, 36 had abnormalities associated with Jak2-Stat5 and 4 had Abl. The rearrangements IGH::CRLF2,P2RY8::CRLF2, and iAMP21 were particularly frequent. We propose a strategy for the detection of Ph-like patients, by analyzing the overexpression/genetic lesions of CRLF2, the Abl phosphorylation of surrogate markers confirmed by gene rearrangements, and Sanger sequencing.

Childhood Acute Leukemias in Developing Nations: Successes and Challenges.

PURPOSE OF REVIEW: Acute leukemias represent a tremendous threat to public health around the globe and the main cause of death due to disease in scholar age children from developing nations. Here, we review their current status in Mexico, as a paradigm of study, and the major challenges to control systemic diseases like childhood cancer. RECENT FINDINGS: A unique molecular epidemiology, late/low precision diagnosis, limited access to treatment, toxicity associated with therapy, continuous exposure to environmental risk factors, and the high frequency of early relapses are some of the factors cooperating to low rates of survival in low-to-medium-income countries. Deliberative dialogues and exhaustive programs have emerged as promising means of advancing evidence-informed policy, by providing a structured forum for key stakeholders to integrate scientific and pragmatic knowledge about complex health concerns. A system-wide strategy based on the comprehensive leukemia identity is essential for a meaningful decline in early childhood mortality.

Analysis of CYP450 gene allelic variants can predict ifosfamide toxicity in Mexican paediatric patients.

Context: Ifosfamide (IFA) is an effective antineoplastic for solid tumours in children, although it is associated with high levels of systemic toxicity and causes death in some cases. Objective: The aim of this study was to determine whether the presence of certain allelic variants of genes CYP2B6, CYP2C9, CYP3A4 and CYP3A5 increases the risk of toxicity in children with solid tumours treated with ifosfamide.Materials and methods: A total of 131 DNA samples were genotyped by real-time polymerase chain reaction (RT-PCR) using TaqMan probes. Toxicity was assessed using WHO criteria, and survival analysis was performed using Kaplan-Meier curves.Results: The rs3745274 allelic variant in CYP2B6 was associated with haematological toxicity, affecting neutrophils; CYP3A4 variant rs2740574 was also associated with toxicity, affecting both leukocytes and neutrophils. Additionally, the CYP3A5 gene variant rs776746 was found to affect haemoglobin.Conclusions: Our results show that allelic variants rs3745274 (CYP2B6), rs2740574 (CYP34) and rs776746 (CYP3A5) increase the risk for high haematological toxicity.Clinical trial registration: 068/2013.

Patient and health service factors associated with delays in cancer treatment for children without social security in Mexico.

BACKGROUND: The objective was to investigate factors associated with patient-related timing (PRT) to seek healthcare and health service-related timing (HSRT) to diagnose cancer and provide treatment to children without social security in Mexico. PROCEDURE: A cross-sectional survey was conducted in 13 Ministry of Health hospitals in the states of Chihuahua, Jalisco, Mexico City, Morelos, Oaxaca, Puebla, Queretaro, State of Mexico, and Tlaxcala. Study participants were parents of recently diagnosed pediatric cancer patients (≤ 17 years of age). Three groups of factors were investigated: (1) patients (child and parent characteristics); (2) healthcare providers (HCPs) (first-contact HCP, institution, perceptions of barriers to healthcare, etc.); and (3) disease factors (cancer type/site, stage/risk at diagnosis). PRT and HSRT-associated factors were identified using multiple negative binomial regressions. RESULTS: The study included 265 children; 49% sought care when symptoms first appeared. The median PRT was seven days, and the median HSRT was 40 days. Parents' perceptions of long wait times for appointments were associated with longer PRT and HSRT. Residing in the lowest or highest socioeconomic regions and persistent or worsening symptoms increased the probability of longer PRT. Older patient age, HCP requests for imaging tests or prescription for steroids, a higher number of doctors consulted, having a urinary tract cancer, and having an advanced stage or high-risk cancer increased the probability of longer HSRT. CONCLUSION: Strategies to shorten lag time from symptom onset to diagnosis and treatment are urgently needed for childhood cancers in Mexico.

Safety and efficacy of step-down to oral outpatient treatment versus inpatient antimicrobial treatment in pediatric cancer patients with febrile neutropenia: A noninferiority multicenter randomized clinical trial.

BACKGROUND: It has been suggested that low-risk febrile neutropenia (FN) episodes can be treated in a step-down manner in the outpatient setting. This recommendation has been limited to implementation in middle-income countries due to concerns about infrastructure and lack of trained personnel. We aimed to determine whether early step-down to oral antimicrobial outpatient treatment is not inferior in safety and efficacy to inpatient intravenous treatment in children with low-risk FN. PROCEDURE: A noninferiority randomized controlled clinical trial was conducted in three hospitals in Mexico City. Low-risk FN was identified in children younger than 18 years. After 48 to 72 hours of intravenous treatment, children were randomly allocated to receive outpatient oral treatment (experimental arm, cefixime) or to continue inpatient treatment (standard of care, cefepime). Daily monitoring was performed until neutropenia resolution. The presence of any unfavorable clinical outcome was the endpoint of interest. We performed a noninferiority test for comparison of proportions. RESULTS: We identified 1237 FN episodes; 117 cases were randomized: 60 to the outpatient group and 57 for continued inpatient treatment. Of the FN episodes, 100% in the outpatient group and 93% in the inpatient group had a favorable outcome (P < 0.001). The mean duration of antibiotics was 4.1 days (SD 2.5; 95% CI, 3.4-4.8 days) in the outpatient group and 4.4 days (SD 2.5; 95% CI, 3.7-5.0 days) in the inpatient group (P = 0.70). CONCLUSIONS: In our population, step-down oral outpatient treatment of low-risk FN was as safe and effective as inpatient intravenous treatment. Clinical Trials Identifier: NCT04000711.

Variants in ARID5B gene are associated with the development of acute lymphoblastic leukemia in Mexican children.

A high impact of ARID5B SNPs on acute lymphoblastic leukemia (ALL) susceptibility has been described in Hispanic children; therefore, it is relevant to know if they influence the high incidence of childhood-ALL in Mexicans. Seven SNPs (rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, rs4948488) of ARID5B were analyzed in 384 controls and 298 ALL children using genomic DNA and TaqMan probes. The SNPs were analyzed for deviation of Hardy-Weinberg equilibrium; Fisher's exact test was used to compare the genotypic and allelic frequencies between controls and patients. The association between SNPs and ALL susceptibility was calculated, and haplotype and ancestry analyses were conducted. All SNPs were associated with ALL, pre-B ALL, and hyperdiploid-ALL susceptibility (p < 0.05). No association with T-ALL and gene fusions was found (p > 0.05). The seven SNPs were associated with risk of pre-B ALL in younger children; however, rs2393732, rs2393782, rs2893881, and rs4948488 were not associated with susceptibility in older children and adolescents. The CAG haplotype (rs10821936, rs10994982, rs7089424) was strongly associated with ALL risk in our population (p < 0.00001). The frequency of all risk alleles in our ALL, pre-B, and hyperdiploid-ALL patients was higher than that in Hispanic children reported. This is the first report showing the association between rs2393732, rs2393782, and rs4948488 with pre-B hyperdiploid-ALL children. The G allele at rs2893881 confers major risk for pre-B hyperdiploid-ALL in Mexican (OR, 2.29) than in Hispanic children (OR, 1.71). The genetic background of our population could influence the susceptibility to ALL and explain its high incidence in Mexico.

Expression of YY1 in Wilms tumors with favorable histology is a risk factor for adverse outcomes.

AIM: To investigate the role of the transcription factor YY1 in Wilms tumor (WT). PATIENTS & METHODS: We measured YY1 expression using tissue microarray from patients with pediatric renal tumors, mainly WT and evaluated correlations with the predicted clinical evolution. YY1 expression was measured using immunohistochemical and protein expression was determined by digital pathology. RESULTS & CONCLUSION: YY1 significantly increased in WT patients. In addition, an increase in YY1 expression had a greater risk of adverse outcomes in WT patients with favorable histology. YY1 expression was higher in the blastemal component of tumors, and high nuclear expression positively correlated with metastasis. YY1 may be considered as a metastasis risk factor in WT.

The burden of childhood cancer in Mexico: Implications for low- and middle-income countries.

In Mexico, childhood cancer incidence and mortality have increased in the last decade. Through government actions since 2005, the Popular Medical Insurance (PMI) program for childhood cancer was created. The objective of PMI was to offer early cancer diagnosis, standardized treatment regimens, and numerous pediatric oncology residency programs. It has also accredited 55 national hospitals for the care of these children. Current problems still present under the PMI include shortage of pediatric oncologists and nurses and high rate of abandonment of treatment. Our aim is to describe the current scenario of childhood cancer care in Mexico, especially from the perspective of the PMI and how it has impacted human resources, infrastructure, and medical education.

Current outlook of childhood cancer epidemiology in a middle-income country under a public health insurance program.

In Mexico, childhood cancer (0-18 years) is treated in a multidisciplinary way while providing care for more than half of the affected children through a public medical insurance. This insurance is given to all children who do not have any health care coverage in Mexico. This program is offered to the poorest of all Mexicans. All the children with this disease are submitted to pathology diagnosis and treatment according to national treatment protocols from 57 accredited medical institutions. From 2007 to 2015, a total of 24,039 children with cancer have been registered; the male gender predominates by 55%. The highest incidence was in the group aged between 0 and 4 years. Every year, there has been an increment in registration. In 2015, there were 3,433 new patients with an incidence of 150.1/million. In the same year, the incidence for all types of leukemia increased to 89.5/million. But for acute lymphoblastic leukemia, the incidence was found to be 79.8/million, which is extremely high. The mortality rate for all these patients in 2015 was 5.3/100,000. However, with regard to children aged between 15 and 18 years, the mortality rate was 8.5/100,000. Abandonment rate was 10%, and there were nine state institutions that had a mortality rate between 25% and 50% among their patients. Coincidentally, as per the Human Development Index, the parameters for education, health, and income were low for those nine institutions. The purpose of this work is to show the epidemiology and the burden we are facing due to this disease.

Descriptive Epidemiology in Mexican children with cancer under an open national public health insurance program.

BACKGROUND: All the children registered at the National Council for the Prevention and Treatment of Childhood Cancer were analyzed. The rationale for this Federal Government Council is to financially support the treatment of all children registered into this system. All patients are within a network of 55 public certified hospitals nationwide. METHODS: In the current study, data from 2007 to 2012 are presented for all patients (0-18 years) with a pathological diagnosis of leukemia, lymphoma and solid tumors. The parameters analyzed were prevalence, incidence, mortality, and abandonment rate. RESULTS: A diagnosis of cancer was documented in 14,178 children. The incidence was of 156.9/million/year (2012). The median age was 4.9. The most common childhood cancer is leukemia, which occurs in 49.8% of patients (2007-2012); and has an incidence rate of 78.1/million/year (2012). The national mortality rate was 5.3/100,000 in 2012, however in the group between 15 to 18 years it reaches a level of 8.6. CONCLUSIONS: The study demonstrates that there is a high incidence of childhood cancer in Mexico. In particular, the results reveal an elevated incidence and prevalence of leukemia especially from 0 to 4 years. Only 4.7% of these patients abandoned treatment. The clinical outcome for all of the children studied improved since the establishment of this national program.

Immunotherapy for Pediatric Gliomas: CAR-T Cells Against B7H3: A Review of the Literature.

BACKGROUND: B7H3 is a co-stimulatory molecule for immune reactions found on the surface of tumor cells in a wide variety of tumors. Preclinical and clinical studies have reported it as a tumor target towards which various immunotherapy modalities could be directed. So far, good results have been obtained in hematological neoplasms; however, a contrasting situation is evident in solid tumors, including those of the CNS, which show high refractoriness to current treatments. The appearance of cellular immunotherapies has transformed oncology due to the reinforcement of the immune response that is compromised in people with cancer. OBJECTIVE: This article aims to review the literature to describe the advancement in knowledge on B7H3 as a target of CAR-T cells in pediatric gliomas to consider them as an alternative in the treatment of these patients. RESULTS: Although B7H3 is considered a suitable candidate as a target agent for various immunotherapy techniques, there are still limitations in using CAR-T cells to achieve the desired success. CONCLUSION: Results obtained with CAR-T cells can be further improved by the suggested proposals; therefore, more clinical trials are needed to study this new therapy in children with gliomas.

Germline mutations in pediatric cancer cohort with mixed-ancestry Mexicans.

BACKGROUND: Childhood cancer is one of the primary causes of disease-related death in 5- to 14-year-old children and currently no prevention strategies exist to reduce the incidence of this disease. Childhood cancer has a larger hereditary component compared with cancer in adults. Few genetic studies have been conducted on children with cancer. Additionally, Latin American populations are underrepresented in genomic studies compared with other populations. Therefore, the aim of this study is to analyze germline mutations in a group of mixed-ancestry Mexican pediatric patients with solid and hematological cancers. METHODS: We analyzed genetic variants from 40 Mexican childhood cancer patients and their relatives. DNA from saliva or blood samples was used for whole-exome sequencing. All variants were identified following GATK best practices. RESULTS: We found that six patients (15%) were carriers of germline mutations in CDKN2A, CHEK2, DICER1, FANCA, MSH6, MUTYH, NF1, and SBDS cancer predisposition genes, and additional new variants predicted to be deleterious by in silico algorithms. A population genetics analysis detected five components consistent with the demographic models assumed for modern mixed-ancestry Mexicans. CONCLUSIONS: This report identifies potential genetic risk factors and provides a better understanding of the underlying mechanisms of childhood cancer in this population.

Challenges in Treating Pediatric Cancer Patients during the COVID-19 Pandemic: Balancing Risks and Care.

The COVID-19 pandemic has resulted in millions of fatalities worldwide. The case of pediatric cancer patients stands out since, despite being considered a population at risk, few studies have been carried out concerning symptom detection or the description of the mechanisms capable of modifying the course of the COVID-19 disease, such as the interaction and response between the virus and the treatment given to cancer patients. By synthesizing existing studies, this paper aims to expose the treatment challenges for pediatric patients with COVID-19 in an oncology context. Additionally, this updated review includes studies that utilized the antiviral agents Remdesivir and PaxlovidTM in pediatric cancer patients. There is no specific treatment designed exclusively for pediatric cancer patients dealing with COVID-19, and it is advisable to avoid self-medication to prevent potential side effects. Managing COVID-19 in pediatric cancer patients is indeed a substantial challenge. New strategies, such as chemotherapy application rooms, have been implemented for children with cancer who were positive for COVID-19 but asymptomatic since the risk of disease progression is greater than the risk of complications from SARS-CoV-2.

Virtual reality as a non-medical tool in the treatment of anxiety, pain, and perception of time in children in the maintenance phase of acute lymphoblastic leukemia treatment.

Introduction: Management of pediatric cancer patients involves invasive procedures such as punctures, injections, catheter placements, and chemotherapy which can generate fatigue, nausea, vomiting, anxiety, and pain. Virtual Reality (VR) is a nonpharmacological intervention classified as a cognitive-behavioral method to relieve symptoms. Methods: We designed a crossover protocol and included 20 patients between 9 and 12 years old; ten were male. All patients had acute lymphoblastic leukemia diagnosis and were treatedwith St. Jude's XV protocol in the maintenance phase. Pain and anxiety were measured with validated scales in the pediatric population. Results: Although we used a small group of patients, we found statistical difference in the reduction of anxiety and perception of time. Discussion: These results open a window to non-pharmacological treatments and show a strategy to improve quality of life in children inside the hospital.

Not only a therapeutic target; mTOR in Hodgkin lymphoma and acute lymphoblastic leukemia.

Introduction: The mechanistic/mammalian target of rapamycin (mTOR) is a serine/threonine kinase, which is downregulated or upregulated and is implicated in different types of cancer including hematologic neoplasms, skin prostate, and head and neck cancer. Aim: The aim of this study was to explore the current knowledge of mTOR signaling in acute lymphoblastic leukemia and Hodgkin lymphoma. Methods: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching PubMed, Discovery Service for National Autonomous University of Mexico, Registro Nacional de Instituciones y Empresas Científicas y Tecnológicas (RENIECYT), and Scientific Electronic Library Online (SciELO) from 1994 to 2023. A total of 269 papers were identified for acute lymphoblastic leukemia, but based on specific criteria, 15 were included; for Hodgkin lymphoma, 110 papers were identified, but 5 were included after manual searching. Results: A total of 20 papers were evaluated, where mTOR activity is increased in patients with Hodgkin lymphoma and acute lymphoblastic leukemia by different molecular mechanisms. Conclusions: mTOR activity is increased in patients with both hematologic neoplasms and NOTCH; interleukin 4, 7, and 9, and nuclear proteins have been studied for their role in the activation of mTOR signaling.

Addressing the unmet needs of women with breast cancer in Mexico: a non-randomised pilot study of the digital ePRO intervention.

OBJECTIVES: This study aimed to explore the acceptability, feasibility, usability, and preliminary effect of an electronic patient-reported outcome (ePRO) intervention for patients with breast cancer in Mexico. DESIGN: We conducted a multimethod non-randomised pilot study. We used a pre-test/post-test design for quantitative assessment of the intervention's effect on patients' supportive care needs and quality of life. We conducted in-depth interviews (IDIs) with participants and healthcare workers to explore the intervention's benefits and barriers and understand its feasibility. PARTICIPANTS: 50 women aged 20-75 diagnosed with stage I-III breast cancer were enrolled within 2 weeks of starting neoadjuvant or adjuvant treatment with chemotherapy or radiotherapy. We excluded illiterate women and those with visual impairment, cognitive disability or severe depression. IDIs were conducted with 18 participants and 10 healthcare providers. SETTING: Oncology services in three public hospitals of the Mexican Social Security Institute. INTERVENTION: The ePRO intervention consisted of a responsive web application for weekly symptom reporting combined with proactive follow-up by nurses guided by predefined clinical algorithms for 6 weeks. RESULTS: 50 women were enrolled out of 66 eligible patients approached (75.8%). All 50 completed the 4-week follow-up assessment (100% retention). Completion of the symptom registry declined from 100% in week 1 to 66% in week 6. Participants experienced decreases in supportive care needs and increased quality of life. The ePRO application was rated highly usable. Participants and health professionals both perceived intervention benefits. Drawbacks included poor fit for women receiving radiotherapy and challenges using the application for women with low digital literacy or experiencing severe symptoms. CONCLUSIONS: This pilot study provided evidence of the high usability and potential efficacy of a web-based ePRO intervention. We revised recruitment during the pilot to include multiple facilities, and we will further revise for the randomised trial to address barriers to successful ePRO implementation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID: NCT05925257.