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Michelle Case,1 Sina Shirinpour,1 Huishi Zhang,1 Yvonne H Datta,2 Stephen C Nelson,3 Karim T Sadak,4 Kalpna Gupta,2 Bin He1,5 1Department of Biomedical Engineering, 2Department of Medicine, University of Minnesota, 3Pediatric Hematology-Oncology, Children’s Hospitals and Clinics of Minnesota, 4Pediatric Hematology-Oncology, University of Minnesota Masonic Children’s Hospital, 5Institute for Engineering in Medicine, University of Minnesota, Minneapolis, MN, USA Objective: Pain is a major issue in the care of patients with sickle cell disease (SCD). The mechanisms behind pain and the best way to treat it are not well understood. We studied how electroencephalography (EEG) is altered in SCD patients. Methods: We recruited 20 SCD patients and compared their resting state EEG to that of 14 healthy controls. EEG power was found across frequency bands using Welch’s method. Electrophysiological source imaging was assessed for each frequency band using the eLORETA algorithm. Results: SCD patients had increased theta power and decreased beta2 power compared to controls. Source localization revealed that areas of greater theta band activity were in areas related to pain processing. Imaging parameters were significantly correlated to emergency department visits, which indicate disease severity and chronic pain intensity. Conclusion: The present results support the pain mechanism referred to as thalamocortical dysrhythmia. This mechanism causes increased theta power in patients. Significance: Our findings show that EEG can be used to quantitatively evaluate differences between controls and SCD patients. Our results show the potential of EEG to differentiate between different levels of pain in an unbiased setting, where specific frequency bands could be used as biomarkers for chronic pain. Keywords: sickle cell disease, electroencephalography, chronic pain, electrophysiological source imaging, thalamocortical dysrhythmia

Background: The understanding of alterations within the immune system following doxorubicin (DOX) chemotherapy, and subsequent restoration, in childhood cancer survivors remains limited. This investigation endeavors to elucidate the immediate and delayed changes in thymic immune cell populations and their phenotypes in response to clinically relevant low doses of DOX in a juvenile mouse model., Methods: Male mice underwent a regimen of repeated low-dose DOX intraperitoneal injections at 4 mg/kg/week for three consecutive weeks. One week after the last dose of DOX, a subset of mice was euthanized to assess the immediate effects of DOX administration. A second subset of mice was euthanized five weeks after the last DOX dose to evaluate the delayed effects. Thymic samples were collected for multiparameter flow cytometry analysis to evaluate alterations in immune cell composition and phenotype. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to measure gene expression of- cytokines and senescence markers., Results: One week following DOX administration, DOX treatment resulted in significant decline in thymus weight, with notable alterations in immune cell subpopulations. Reduced frequencies of mature CD3+CD4+ and CD3+CD8+ T cells were observed, along with changes in proliferation and exhaustion markers. Gene expression analysis revealed upregulation of Foxn, Pax1, Ifnγ, and Il7 alongside decreased Il6 and Il17 expression. Furthermore, Cdkn1a (p21Cip1) expression was elevated, suggesting immunosenescence. Five weeks following DOX administration, delayed effects of DOX treatment manifested in rebound increase in thymus weight and altered frequencies of CD4+ and CD8+ T cell subsets, with distinct patterns of proliferation and exhaustion observed. Notably, central memory CD4+ T cells exhibited significant decrease in frequency, while naive and effector memory CD4+ T cells showed reduced proliferation (Ki67+) and PD1 expression. Similar trends were observed in CD8+ T cell subsets, indicating selective effects of DOX on T cell differentiation and function. Although expression of thymus-related genes was normalized, p21Cip1 gene expression remained elevated., Conclusion: DOX treatment elicits a multifaceted influence on immune cell subsets and thymic weight. Immediate effects included thymic atrophy and reductions in mature T cell populations, while delayed effects showed rebound thymic hyperplasia and selective changes in CD4+ and CD8+ T cell subsets. Notably, both central memory and effector memory T cells exhibited reduced proliferation and exhaustion, suggesting unique impacts of DOX on immune cell function. The enduring elevation in p21Cip1 gene expression 5 weeks after DOX treatment suggests an immunosenescent phenotype. These observations collectively illuminate the formidable task of preserving immune competence and overall well-being in childhood cancer survivors subjected to DOX therapy.

As childhood cancer treatments have improved to include new and innovative agents, the need for more advanced monitoring of their long-term effects and related research has increased. This has resulted in a need for evidence-based research methodologies for the longitudinal care of childhood cancer patients treated with targeted agents and immunotherapies. The rationale for this pilot study was to determine the feasibility and acceptability of a data capture methodology for pediatric, adolescent, and young adult cancer patients treated with targeted agents and immunotherapy as there is little research to inform this delivery of care. Data were collected from thirty-two patients and two providers for descriptive statistics and thematic analyses. Feasibility was characterized by expected participant attrition. Key drivers of acceptability were (1) providers' language and clarity of communication and (2) convenient participation requirements. Long-term follow-up research practices developed with input from key stakeholders, including patients, caregivers, and providers, can lead to acceptable and feasible research protocols that optimize successful participant recruitment. These evidence-based research practices can result in high participant satisfaction and can be implemented as program development initiatives across centers caring for childhood cancer survivors.

The COVID-19 pandemic paved the way for the widespread use of virtual care for childhood cancer survivors (CCSs). CCSs were virtual recipients of diverse care, including long-term follow-up (LTFU), primary care, mental health care, and several others. Virtual care comes with well-documented benefits and challenges. These are further magnified for CCSs living in rural or non-metropolitan areas. Here, we describe the virtual care of CCSs from two Upper Midwest cities with well-established childhood cancer survivor programs within large comprehensive cancer centers in the United States. CCSs from non-metropolitan areas, especially CCSs with two or more late effects, used virtual care more often during the COVID-19 pandemic compared to CCSs from metropolitan areas. A review of the related literature is also included and the identified challenges in providing virtual care, such as privacy concerns, technology-connectivity constraints, and medical license restrictions. Despite these limitations, the care of CCSs has evolved to leverage virtual care and its ability to increase access for patients and promote continuity of care for CCSs living in rural areas.

Background: Barriers to cervical cancer screening in young adults include a lack of knowledge and negative perceptions of testing. Evidence shows that mobile technology reduces these barriers; thus, we developed a web app, Game-based Learning Avatar-navigated mobile (GLAm), to educate and motivate cervical cancer screening using the Fogg Behavioral Model as a theoretic guide. Users create avatars to navigate the app, answer short quizzes with education about cervical cancer and screening, watch videos of the screening process, and earn digital trophies., Objective: We tested ease of use, usefulness, and satisfaction with the GLAm app among young adults., Methods: This mixed methods study comprised a qualitative think-aloud play interview session and a quantitative survey study. Participants were cervical cancer screening-eligible US residents aged 21 to 29 years recruited through social media. Qualitative study participants explored the app in a think-aloud play session conducted through videoconference. Data were analyzed using directed content analysis to identify themes of ease of use, usefulness, and content satisfaction. Qualitative study participants and additional participants then used the app independently for 1 week and completed a web-based survey (the quantitative study). Ease of use, usefulness, and satisfaction were assessed using the validated Technology Acceptance Model and Computer System Usability Questionnaire adapted to use of an app. Mean (SD) scores (range 1-7) are presented., Results: A total of 23 individuals participated in one or both study components. The mean age was 25.6 years. A majority were cisgender women (21/23, 91%) and White (18/23, 78%), and 83% (19/23) had at least some secondary education. Nine participants completed the think-aloud play session. Direct content analysis showed desire for content that is concise, eases anxiety around screenings, and uses game features (avatars and rewards). Twenty-three individuals completed the quantitative survey study. Mean scores showed the app was perceived to be easy to use (mean score 6.17, SD 0.27) and moderately useful to increase cervical cancer screening knowledge and uptake (mean score 4.94, SD 0.27). Participants were highly satisfied with the app (mean score 6.21, SD 1.20)., Conclusions: Survey results showed participants were satisfied with the app format and found it easy to use. The app was perceived to be moderately useful to inform and motivate cervical cancer screening; notably, the screening reminder function was not tested in this study. Qualitative study results demonstrated the app's ability to ease anxiety about screening through demonstration of the screening process, and brevity of app components was favored. Interpretation of results is limited by the predominantly cisgender, White, and educated study population; additional testing in populations which historically have lower cervical cancer screening uptake is needed. A modified version of the app is undergoing efficacy testing in a randomized clinical trial., (©Lindsey J Wanberg, Angela Kim, Rachel I Vogel, Karim Thomas Sadak, Deanna Teoh. Originally published in JMIR Formative Research (https://formative.jmir.org), 08.08.2023.)

Pediatric, adolescent and young adult patients undergoing cancer treatment and/or hematopoietic stem cell transplant are at increased risk for developing a secondary human papillomavirus (HPV)-associated malignancy. The objective of this study was to determine HPV vaccination coverage among individuals participating in a childhood cancer survivor program (CCSP). A retrospective cohort study was conducted among CCSP patients age 11-26 years attending a CCSP visit between 2014 and 2019. Survivors were age-, sex-, and race-matched 1:2 with controls without cancer. Data were abstracted from the electronic health record and state-based vaccination registry. Analysis was limited to Minnesota residents to minimize missing vaccination data. Survivorship care plans (SCPs) were reviewed for vaccine recommendations. 592 patients were included in the analyses (200 CCSP patients; 392 controls). By study design, mean age (18.4 years), race (72 % white), and sex (49 % female) were similar in the two groups. Among CCSP patients 22 % resided in a rural area compared to 3.8 % of controls. Vaccination coverage among CCSP patients was not statistically significantly different from controls [60.0 % vs 66.3 %, OR = 0.82, 95 % CI: (0.55, 1.23), p = 0.35]. Completion of 3 doses was not different between groups even though 3 doses is recommended for all CCSP patients regardless of age at initiation (28.5 % vs 30.1 %, p = 0.09). Only 8.0 % of SCPs recommended HPV vaccination. Although patients participating in a CCSP did not have significantly different HPV vaccination coverage compared to controls, HPV vaccination initiation and 3-dose series completion are still suboptimal in a patient population at high-risk of a secondary HPV-associated cancer., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Cancer therapy duration is variable and may take years, adding a new challenge of maintaining the best life quality for cancer survivors. In cancer patients, late-onset toxicities have been reported with monoclonal antibodies and may involve several body organs or systems. They are defined as an autoimmune illnesses that can happen months to years after treatment discontinuation. Late-onset toxicities have become a focus of clinical care and related research. After cancer therapy is completed, the patient should receive longitudinal follow-up to detect these late effects as early as possible. The current review summarizes the recently reported late-onset toxicities of four classes of monoclonal antibodies (anti-CD52, anti-CTLA-4, anti-PD-1 and anti-CD20) with guidance for the diagnostic tools, appropriate management and treatment.

Background and Aims: Intracranial germ cell tumor (iGCT) survivors have multiple risk factors for growth hormone (GH) deficiency, a commonly reported late effect in childhood cancer survivors. The objective of this study is to examine the prevalence of GH deficiency among childhood iGCT survivors., Methods: Participants were previously enrolled in the Germ Cell Tumor Epidemiology Study (GaMETES), a case parent triad study conducted using the Children's Oncology Group registry protocols, including 216 cases with iGCTs. Data on late effects and outcomes are available for 129 iGCT cases who consented for a follow-up study including a self-administered questionnaire and medical record retrieval. GH deficiency was identified via self-report and validated through medical record review. Chi-squared and Fisher's exact tests were used to examine cases with GH deficiency predating iGCT detection. Logistic regression was used to identify predictors of GH deficiency as a late effect., Results: Of 129 iGCT cases who participated in the late effects study, 45% had GH deficiency; 18% had GH deficiency predating the iGCT and 27% developed GH deficiency within a median of 19 months after diagnosis. Younger age at diagnosis, suprasellar location, and higher radiation doses were associated with GH deficiency as a late effect., Conclusions: GH deficiency is highly prevalent as an early clinical sign for iGCT and frequently arises as an early late effect after treatment. Additional investigation is needed to address earlier detection and treatment for this highly prevalent late effect in iGCT survivors., Competing Interests: Financial Disclosures/Conflict of interest: Bradley S Miller is a consultant for Ascendis, BioMarin, Novo Nordisk, Pfizer, Sandoz, Tolmar and Vertice. His affiliations did not have any impact on his participation in this study as this was a retrospective clinical study. The other authors have no relevant financial or non-financial interests to disclose.

Background: Survivor-focused care for adolescent and young adult (AYA) childhood cancer survivors (CCS) often involves their parents. Recognizing the importance of parents in the ongoing care of CCS, our study sought to identify key aspects of a successful transition for CCS from pediatric- to adult-centered care from the parent perspective., Methods: We conducted qualitative interviews with 26 parents of CCS who were receiving care in the long-term follow-up (LTFU) clinic at a single institution. We used a semi-structured interview protocol with the parents and conducted a thematic content analysis., Results: Using a constant comparison approach, data revealed three primary themes regarding parents' perspectives toward ensuring a seamless transition from pediatric- to adult-centered follow-up care: (1) the transition needs to include seamless communication between all involved parties, (2) survivors need to demonstrate sufficient health care self-efficacy in order to achieve a successful transition, and (3) the survivor-focused care should include support for survivors' overall well-being, including financial and health insurance literacy., Conclusions: For parents of AYA CCS, the optimal pediatric to adult care transition model should include mechanisms that facilitate communication between parents, CCS, and survivor-focused providers while also supporting self-efficacy and financial literacy as it relates to health insurance., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Childhood cancer survivors undergo serial echocardiograms to screen for cardiotoxicity. It is not clear whether small longitudinal changes in functional or structural parameters over time have clinical significance., Objectives: To assess the timing of changes in serial echocardiographic parameters in pediatric age childhood cancer survivors and to evaluate their associations with cardiomyopathy development., Methods: We performed a multi-center retrospective case-control study of ≥1-year survivors following the end of cancer therapy. Cardiomyopathy cases (fractional shortening (FS) ≤28% or ejection fraction (EF) ≤50% on ≥2 occasions) were matched to controls (FS ≥30%, EF ≥55%, not on cardiac medications) by cumulative anthracycline and chest radiation dose, follow-up duration, and age at diagnosis. Digitally archived clinical surveillance echocardiograms were quantified in a central core lab, blinded to patient characteristics. Using mixed models with interaction terms between time and case status, we estimated the least square mean differences of 2D, M-mode, pulsed wave Doppler and tissue Doppler imaging derived parameters across time between cases and controls., Results: We identified 50 matched case-control pairs from 5 centers. Analysis of 412 echocardiograms (cases, n=181; controls, n=231) determined that indices of LV systolic function (FS, biplane EF), diastolic function (mitral E/A ratio), and LV size (end diastolic dimension z-scores) were significantly different between cases and controls, even four years prior to the development of cardiomyopathy., Conclusions: Longitudinal changes in cardiac functional parameters can occur relatively early in pediatric age childhood cancer survivors and are associated with the development of cardiomyopathy.