Using the Power Wheel as a transformative tool to promote equity through spaces and places of patient engagement.

BACKGROUND: Patient engagement is the active collaboration between patient partners and health system partners towards a goal of making decisions that centre patient needs-thus improving experiences of care, and overall effectiveness of health services in alignment with the Quintuple Aim. An important but challenging aspect of patient engagement is including diverse perspectives particularly those experiencing health inequities. When such populations are excluded from decision-making in health policy, practice and research, we risk creating a healthcare ecosystem that reinforces structural marginalisation and perpetuates health inequities. APPROACH: Despite the growing body of literature on knowledge coproduction, few have addressed the role of power relations in patient engagement and offered actionable steps for engaging diverse patients in an inclusive way with a goal of improving health equity. To fill this knowledge gap, we draw on theoretical concepts of power, our own experience codesigning a novel model of patient engagement that is equity promoting, Equity Mobilizing Partnerships in Community, and extensive experience as patient partners engaged across the healthcare ecosystem. We introduce readers to a new conceptual tool, the Power Wheel, that can be used to analyse the interspersion of power in the places and spaces of patient engagement. CONCLUSION: As a tool for ongoing praxis (reflection +action), the Power Wheel can be used to report, reflect and resolve power asymmetries in patient-partnered projects, thereby increasing transparency and illuminating opportunities for equitable transformation and social inclusion so that health services can meet the needs and priorities of all people.

Internet-Delivered Cognitive Behavioral Treatment for Chronic Pain in Adolescent Survivors of Childhood Cancer: Protocol for a Single-Group Feasibility Trial.

BACKGROUND: There are over 500,000 survivors of childhood cancer in North America alone. One in 4 survivors experiences chronic pain after treatment has been completed. Youths with chronic pain report increased anxiety, depression, activity limitations, and sleep disturbances. An 8-week web-based cognitive behavioral treatment for chronic pain (Web-Based Management of Adolescent Pain [WebMAP]) has demonstrated a reduction in pain in youths but has not yet been explored in survivors. OBJECTIVE: The objectives of this study are to (1) test the feasibility and acceptability of WebMAP for a sample of survivors with chronic pain and their parents; (2) assess the acceptability of WebMAP using qualitative interviews; (3) assess WebMAP's effect on activity limitations, pain intensity, depression and anxiety symptoms, and sleep disturbances; and (4) assess WebMAP's effect on parent pain catastrophizing and parental response to their child's pain. METHODS: A single-arm mixed methods pre-post intervention study design will be used. Participants will be 34 survivors and at least one of their parents or caregivers. Inclusion criteria are (1) a cancer history, (2) current age of 10-17 years, (3) >2 years post treatment or >5 years post diagnosis, (4) pain present over prior 3 months impairing >1 area of daily life and occurring >1 time per month, and (5) computer access with broadband internet. Survivors will complete a pretreatment questionnaire, which will include the following: the Child Activity Limitations Interview, the pain intensity Numerical Rating Scale, Patient-Reported Outcomes Measurement Information System (PROMIS)-Pain Interference, Anxiety, Depression, Insomnia Severity Index, and Adolescent Sleep Wake Scale. Parents will complete the Pain Catastrophizing Scale-Parent Version and the Adult Responses to Child Symptoms. Upon completion of pretreatment questionnaires (T0), survivors will begin WebMAP. After the 8-week intervention, survivors will complete the same measures (T1), and at 3-month follow-up (T2). Posttreatment interviews will be conducted to determine acceptability. Feasibility will be assessed via recruitment and retention rates. Treatment engagement will be measured by number of modules completed. Pre-post outcome data will be assessed using linear mixed models. Qualitative data will be analyzed using thematic analysis. Patient partners will be involved in study design, recruitment, interpretation of results, and knowledge translation. RESULTS: This study has been funded in January 2022. Data collection started in May 2022 and is projected to end in August 2023. We have enrolled 10 participants as of December 2022. CONCLUSIONS: Investigating whether WebMAP is useful to survivors will be an important step in improving pain management in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05241717; https://clinicaltrials.gov/ct2/show/NCT05241717. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45804.

The Impact of the Early COVID-19 Global Pandemic on Children Undergoing Active Cancer Treatment and Their Parents.

(1) Background: The COVID-19 global pandemic has impacted people worldwide with unique implications for vulnerable groups. In this cross-sectional study, we examined the impact of the early pandemic on children undergoing active cancer treatment and their parents. (2) Methods: In May 2020, 30 parents of children undergoing active cancer treatment completed an online survey regarding the impact of COVID-19 on their child's cancer care, perceived utility of telemedicine, and child and parent mental health status. (3) Results: Most participants (87%) reported that they did not experience any changes to major cancer treatments. Among those who reported using telemedicine, 78% reported this to be beneficial. Over half of the participants reported that their child's mental health status was worse now than prior to the COVID-19 global pandemic. Parent-reported child anxiety scores were significantly higher for those who reported changes to mental health care for their child compared to those who did not report the same, t(25.99) = -3.04, p = 0.005. (4) Conclusion: Child and parent mental health status were affected when compared to pre-pandemic. Telemedicine appears to be a promising complement to face-to-face meetings for some families and warrants further exploration.

Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset.

PURPOSE: Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD. PATIENTS AND METHODS: We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation. RESULTS: Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10-12), immunohistochemistry (86%, P = 4.6 × 10-3), or tumor mutational burden (80%, P = 9.1 × 10-4). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA (P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD (P = 2.2 × 10-5). CONCLUSION: LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.

The Perceived Impact of COVID-19 on the Mental Health Status of Adolescent and Young Adult Survivors of Childhood Cancer and the Development of a Knowledge Translation Tool to Support Their Information Needs.

Background: Adolescent and young adult (AYA; 13 to 39 years) survivors of childhood cancer may be especially vulnerable to physical health and mental health concerns during the pandemic. We investigated the impact of COVID-19 on the mental health status of AYA survivors (Aim 1) and shared tailored, evidence-based health-related information on COVID-19 (Aim 2). Methods: Between May and June 2020, participants completed a cross-sectional online survey assessing their cancer history, current mental health status, and their COVID-19 information needs. Results: Ninety-four participants (78 females, 13 males, 2 non-binary) with a mean age of 26.9 years (SD = 6.2) were included in the final sample. Participants reported residing from 10 countries and 94% identified as White. Nearly half of the participants (49%) described their mental health status as worse now than before the pandemic. Thirty-nine participants (41%) that indicated their current mental health status was tied to fears/worries about their past cancer and treatment experienced a higher level of anxiety and PTSS than those who did not report the same. Most participants (77%) had not received any information related to the potential risks of COVID-19 and expressed an interest in receiving this information. In response, an infographic detailing recommended strategies for coping with mental health problems in the pandemic, along with preliminary study findings, was developed. Discussion: AYA survivors reporting their mental health status was linked to their past cancer experienced poorer mental health. There is a value to educating survivors on their potential health risks, but accounting for their perceived mental health vulnerabilities should be considered when disseminating knowledge. The use of an infographic is a unique contribution towards the development of innovative and personalized means of sharing health education to this vulnerable yet resilient group. This research on the mental health status of AYA survivors very early in the pandemic informs continued initiatives investigating the rapidly changing nature of how COVID-19 may impact AYA survivors today and in the future.

Characterizing pain in long-term survivors of childhood cancer.

Many long-term survivors of childhood cancer (LTSCC), individuals at least 5 years post-diagnosis or 2 years post-treatment, experience late- and long-term effects from their treatments, including pain. Yet, pain is poorly understood among LTSCC. The current study aimed to (1a) describe rates and multiple dimensions of pain; (1b) identify patterns of chronic pain; and (2) test correlates of chronic pain in LTSCC. Survivors (n = 140; 48.6% male, Mage = 17.3 years (range = 8-25)) were recruited from across Canada. Between 2017 and 2019, participants completed the Pain Questionnaire, Pain Catastrophizing Scale, Pediatric Quality of Life Inventory, Patient-Reported Outcome Measurement Information System (PROMIS)-Pain Interference, Anxiety, and Depression scales, Child Posttraumatic Stress Scale, the Posttraumatic Stress Disorder Checklist for the DSM-V, and the Cancer Worry Scale. RESULTS: Twenty-six percent of LTSCC reported experiencing chronic pain. Exploratory cluster analysis showed 20% of survivors had moderate to severe chronic pain based on measures of pain intensity and interference. The combination of higher posttraumatic stress symptoms, older current age, more pain catastrophizing, and sex (being female) significantly predicted the presence of chronic pain in logistic regression, χ2 (4, N = 107) = 28.10, p < .001. Higher pain catastrophizing (OR = 1.09; 95% CI = 1.02-1.16), older current age (OR = 1.20; 95% CI = 1.07-1.34), and higher posttraumatic stress (OR = 1.92; 95% CI = 1.01-3.63) were significant predictors of chronic pain. LTSCC should be screened for the presence and magnitude of chronic pain during long-term follow-up visits so appropriate interventions can be offered and implemented. Future research should investigate pain interventions tailored for this population. RELEVANCE: Findings support regular screening for the presence and magnitude of chronic pain in survivors of childhood cancer in long-term follow-up care.

Establishing best practices in cancer online support groups: protocol for a realist review.

INTRODUCTION: Considerable observational evidence suggests that cancer online support groups reduce feelings of isolation, depression and anxiety, enhance coping and self-management, and lead to better informed patients. Other studies indicate that cancer online support groups can increase distress. Yet no studies theorise the complex, context-dependent mechanisms by which cancer online support groups generate their-sometimes contrasting-outcomes. METHODS AND ANALYSIS: Guided by an integrated knowledge translation approach and the strategy for patient-oriented research, we will conduct a realist review of cancer online support groups in partnership with stakeholders. We will follow Pawson's five steps and existing quality standards to develop a program theory that explains how cancer online support groups work, for whom and in what circumstances. The specific research questions will be: what positive and negative outcomes have been reported on cancer online support groups? What are the mechanisms that are associated with these outcomes, in which contexts and for whom? Through a rigorous review of relevant scientific and grey literature, as well as ongoing dialogue with stakeholders, a program theory will be developed to explain who benefits from cancer online support groups and who does not, what benefits they derive (or do not), and the factors that affect these outcomes. ETHICS AND DISSEMINATION: The use of secondary data for this review precludes the need for ethical approval. Dissemination will be informed by the knowledge-to-action framework and will consist of tailored knowledge products that are conceived of collaboratively with stakeholders. These will include peer-reviewed publications on how cancer online support groups can be optimised and best practice recommendations to maximise the benefits experienced by people with cancer. These traditional scientific outputs, along with their respective evidence summaries, will be amplified through strategic social media events hosted and promoted by knowledge users. PROSPERO REGISTRATION NUMBER: CRD42021250046.

Readdressing the Needs of Cancer Survivors During COVID-19: A Path Forward.

The growing number of cancer survivors and the high prevalence of cancer-related physical and psychosocial effects pose important and pressing challenges to health systems. The coronavirus disease 2019 (COVID-19) pandemic has led to further stressors on cancer survivors and health care systems. As the pandemic continues to have substantial impact on the world, it is critical to focus attention on the health care needs of cancer survivors. In this commentary, we propose an adoption of essential steps that should be part of a continuous adaptive approach to promote effective cancer survivorship care during ongoing COVID-19 waves and beyond.

DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.This article is highlighted in the In This Issue feature, p. 995.

Cancers from Novel Pole-Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade.

POLE mutations are a major cause of hypermutant cancers, yet questions remain regarding mechanisms of tumorigenesis, genotype-phenotype correlation, and therapeutic considerations. In this study, we establish mouse models harboring cancer-associated POLE mutations P286R and S459F, which cause rapid albeit distinct time to cancer initiation in vivo, independent of their exonuclease activity. Mouse and human correlates enabled novel stratification of POLE mutations into three groups based on clinical phenotype and mutagenicity. Cancers driven by these mutations displayed striking resemblance to the human ultrahypermutation and specific signatures. Furthermore, Pole-driven cancers exhibited a continuous and stochastic mutagenesis mechanism, resulting in intertumoral and intratumoral heterogeneity. Checkpoint blockade did not prevent Pole lymphomas, but rather likely promoted lymphomagenesis as observed in humans. These observations provide insights into the carcinogenesis of POLE-driven tumors and valuable information for genetic counseling, surveillance, and immunotherapy for patients. SIGNIFICANCE: Two mouse models of polymerase exonuclease deficiency shed light on mechanisms of mutation accumulation and considerations for immunotherapy.See related commentary by Wisdom and Kirsch p. 5459.

Should nitrous oxide ever be used in oncology patients receiving methotrexate therapy?

Nitrous oxide (N2 O) is frequently used for short anesthesia/analgesia in children undergoing painful or repetitive procedures. Children with acute lymphoblastic leukemia (ALL) require repeated lumbar punctures with direct instillation of intrathecal chemotherapy, usually the anti-folate agent methotrexate, during their treatment. These procedures are frequently performed under anesthesia. Concerns have been intermittently raised about a drug interaction between methotrexate and N2 O that may potentiate the undesirable side effects of methotrexate, including neurotoxicity. However, the clinical evidence consists mainly of isolated case reports leading to a lack of consensus among pediatric anesthetists about the relative risk benefits of using N2 O in children with ALL. In this article, we review the biochemical basis and scientific observations that suggest a significant interaction between N2 O and methotrexate due to their dual inhibition of the key enzyme methionine synthase. The possible role of this interaction in potentiating neurotoxicity in children with cancer is discussed, and arguments and counterarguments about the clinical significance of this largely theoretical relationship are explored. Following comprehensive review of all the available data, we make the case for the circumstantial evidence being sufficiently compelling to prompt a review of practice by pediatric anesthetists and call for a precautionary approach by avoiding the use of N2 O in children receiving concurrent methotrexate.

The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation.

Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML.

Effect of methotrexate/vitamin B12 on DNA methylation as a potential factor in leukemia treatment-related neurotoxicity.

Methotrexate (MTX) is administered to treat childhood acute lymphoblastic leukemia (ALL). It acts by inhibiting dihydrofolate reductase which reduces methyltetrahydrofolate, a key component in one carbon metabolism, thus reducing cell proliferation. Further perturbations to one carbon metabolism, such as reduced vitamin B12 levels via the use of nitrous oxide for sedation during childhood ALL treatment, may increase neurotoxicity risk. With B12 as an enzymatic cofactor, methyltetrahydrofolate is essential to produce methionine, which is critical for DNA methylation. We investigated global and gene specific DNA methylation in neuronal cell lines in response to MTX treatment and vitamin B12 concentration individually, and in combination. RESULTS: MTX treatment alone significantly increased LINE-1 methylation in SH-SY5Y (p = 0.040) and DAOY (p < 0.001), and increased FKBP5 methylation in MO3.13 cells (p = 0.009). CONCLUSION: We conclude that altered DNA methylation of brain/central nervous system cells could be one mechanism involved in MTX treatment-related neurotoxicities and neurocognitive late effects in ALL survivors.

Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients.

PURPOSE: Methotrexate administration is associated with frequent adverse neurological events during treatment for childhood acute lymphoblastic leukemia. Here, we present evidence to support the role of common drug interactions and low vitamin B12 levels in potentiating methotrexate neurotoxicity. METHODS: We review the published evidence and highlight key potential drug interactions as well as present clinical evidence of severe methotrexate neurotoxicity in conjunction with nitrous oxide anesthesia and measurements of vitamin B12 levels among pediatric leukemia patients during therapy. RESULTS: We describe a very plausible mechanism for methotrexate neurotoxicity in pediatric leukemia patients involving reduction in methionine and consequential disruption of myelin production. We provide evidence that a number of commonly prescribed drugs in pediatric leukemia management interact with the same folate biosynthetic pathways and/or reduce functional vitamin B12 levels and hence are likely to increase the toxicity of methotrexate in these patients. We also present a brief case study supporting out hypothesis that nitrous oxide contributes to methotrexate neurotoxicity and a nutritional study, showing that vitamin B12 deficiency is common in pediatric leukemia patients. CONCLUSIONS: Use of nitrous oxide in pediatric leukemia patients at the same time as methotrexate use should be avoided especially as many suitable alternative anesthetic agents exist. Clinicians should consider monitoring levels of vitamin B12 in patients suspected of having methotrexate-induced neurotoxic effects.