Knowledge of Required Medical Surveillance Among Adolescent and Young Adult Survivors of Childhood Cancer.

PURPOSE: Adolescent and young adult (AYA) cancer survivors experience treatment-related late effects so guidelines recommend providing a treatment summary, yearly follow-up, and risk-adapted testing. AYA survivors' knowledge of surveillance follow-up was studied. RESULTS: Survey responses for 73 AYAs were stratified: low (0 to 1 correct; n=18; 24.7%) versus high knowledge (2 to 4 correct; n=55; 75.3%) of their required testing. Patient-reported Outcomes Measurement Information System (PROMIS) scores fell within average ranges for participant age ( T -scores: 52.4 for physical function, 49.3 for anxiety, 46.3 for depression, and 44.7 for fatigue). Younger age at survivorship visit was a significant predictors of improved knowledge scores. CONCLUSION: Despite attendance at a survivorship clinic, minority of participants (9.5%) demonstrated complete knowledge of surveillance testing needs. Most survivors are aware of some of their surveillance needs. PROMIS scores were not associated with surveillance knowledge.

Pulmonary Toxicities Associated With the Use of Immune Checkpoint Inhibitors: An Update From the Immuno-Oncology Subgroup of the Neutropenia, Infection & Myelosuppression Study Group of the Multinational Association for Supportive Care in Cancer.

The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, with agents such as nivolumab, pembrolizumab, and cemiplimab targeting programmed cell death protein-1 (PD-1) and durvalumab, avelumab, and atezolizumab targeting PD-ligand 1 (PD-L1). Ipilimumab targets cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). These inhibitors have shown remarkable efficacy in melanoma, lung cancer, urothelial cancer, and a variety of solid tumors, either as single agents or in combination with other anticancer modalities. Additional indications are continuing to evolve. Checkpoint inhibitors are associated with less toxicity when compared to chemotherapy. These agents enhance the antitumor immune response and produce side- effects known as immune-related adverse events (irAEs). Although the incidence of immune checkpoint inhibitor pneumonitis (ICI-Pneumonitis) is relatively low, this complication is likely to cause the delay or cessation of immunotherapy and, in severe cases, may be associated with treatment-related mortality. The primary mechanism of ICI-Pneumonitis remains unclear, but it is believed to be associated with the immune dysregulation caused by ICIs. The development of irAEs may be related to increased T cell activity against cross-antigens expressed in tumor and normal tissues. Treatment with ICIs is associated with an increased number of activated alveolar T cells and reduced activity of the anti-inflammatory Treg phenotype, leading to dysregulation of T cell activity. This review discusses the pathogenesis of alveolar pneumonitis and the incidence, diagnosis, and clinical management of pulmonary toxicity, as well as the pulmonary complications of ICIs, either as monotherapy or in combination with other anticancer modalities, such as thoracic radiotherapy.

Patient-Reported and Parent Proxy-Reported Outcomes in Pediatric Medical Specialty Clinical Settings: A Systematic Review of Implementation.

OBJECTIVE: Youth with chronic illness are at higher risk for psychosocial difficulties, leading to a call for screening via patient-reported outcomes (PROs). The purpose of the current review is to summarize PRO implementation in pediatric medical specialty settings. A literature review of PRO implementation in these settings, conceptual issues, value and approach, legal and ethical concerns, as well as a case example of PROA in type 1 diabetes are presented. METHODS: A systematic review was conducted to identify relevant articles published since the most recent Journal of Pediatric Psychology Special Issue on Evidence-Based Assessment in Pediatric Psychology (2008). RESULTS: Thirty-two articles were identified and reviewed. The majority of studies reported that PROA was feasible, did not disrupt clinic flow, identified psychosocial issues warranting intervention, and was acceptable to families and providers. Response to elevated scores and impact on behavioral health referrals varied. CONCLUSION: While many evidenced-based assessment measures are well-validated within pediatric chronic illness groups, the literature regarding implementation of PROs is still emerging. Research findings are promising, with PROs being feasible, acceptable, and leading to increased discussion of psychosocial issues when integrated into pediatric medical settings. Additional research is needed to evaluate the longitudinal impact of PROs and the optimal manner of responding to assessment data, particularly when clinically-elevated. Ultimately, identifying psychosocial issues in pediatric medical settings can promote optimal health and well-being of youth with chronic illness and their families.

Preferences for cancer survivorship care among adolescents and young adults who experienced healthcare transitions and their parents.

PURPOSE: This study aimed to elucidate experiences and preferences for survivorship care delivery among adolescent and young adult (AYA) childhood cancer survivors who experienced healthcare transitions. METHODS: Eight focus groups were conducted with two groups of AYA survivors and their parents: (1) those who recently completed cancer treatment and are beginning follow-up care and (2) those who disengaged in follow-up care after the transition from pediatric to adult survivorship clinics. Interviewers used a structured interview guide that contained questions about perceptions and preferences for survivorship care models, resources, and tools (e.g., a survivorship care plan). We employed directed content analysis techniques to identify and organize relevant themes. RESULTS: Results of this study support six primary themes for optimizing survivorship care models for AYA: (1) improve knowledge of late effects and need for LTFU; (2) provide supportive services that help to address fear and uncertainty about health; (3) adapt survivorship care to be consistent with AYA developmental factors; (4) increase support surrounding healthcare transitions; (5) improve survivorship care communication and coordination between patients and families, and between providers; and (6) incorporate digital health tools. CONCLUSIONS: These groups represent vulnerable patient populations in AYA survivorship care and their perspectives highlight potential clinical and research priorities for enhancing long-term care models. IMPLICATIONS FOR CANCER SURVIVORS: Elucidating AYA and parent recommendations for survivorship care delivery can help to promote continuous engagement in care, target unmet needs, and promote health through survivorship models that are deemed acceptable to both patients and families.

Bone marrow adipocytes resist lipolysis and remodeling in response to ß-adrenergic stimulation.

Bone marrow adipose tissue (BMAT) is preserved or increased in states of caloric restriction. Similarly, we found that BMAT in the tail vertebrae, but not the red marrow in the tibia, resists loss of neutral lipid with acute, 48-hour fasting in rats. The mechanisms underlying this phenomenon and its seemingly distinct regulation from peripheral white adipose tissue (WAT) remain unknown. To test the role of ß-adrenergic stimulation, a major regulator of adipose tissue lipolysis, we examined the responses of BMAT to ß-adrenergic agonists. Relative to inguinal WAT, BMAT had reduced phosphorylation of hormone sensitive lipase (HSL) after treatment with pan-ß-adrenergic agonist isoproterenol. Phosphorylation of HSL in response to ß3-adrenergic agonist CL316,243 was decreased by an additional ~90% (distal tibia BMAT) or could not be detected (tail vertebrae). Ex vivo, adrenergic stimulation of lipolysis in purified BMAT adipocytes was also substantially less than iWAT adipocytes and had site-specific properties. Specifically, regulated bone marrow adipocytes (rBMAs) from proximal tibia and femur underwent lipolysis in response to both CL316,243 and forskolin, while constitutive BMAs from the tail responded only to forskolin. This occurred independently of changes in gene expression of ß-adrenergic receptors, which were similar between adipocytes from iWAT and BMAT, and could not be explained by defective coupling of ß-adrenergic receptors to lipolytic machinery through caveolin 1. Specifically, we found that whereas caveolin 1 was necessary to mediate maximal stimulation of lipolysis in iWAT, overexpression of caveolin 1 was insufficient to rescue impaired BMAT signaling. Lastly, we tested the ability of BMAT to respond to 72-hour treatment with CL316,243 in vivo. This was sufficient to cause beiging of iWAT adipocytes and a decrease in iWAT adipocyte cell size. By contrast, adipocyte size in the tail BMAT and distal tibia remained unchanged. However, within the distal femur, we identified a subpopulation of BMAT adipocytes that underwent lipid droplet remodeling. This response was more pronounced in females than in males and resembled lipolysis-induced lipid partitioning rather than traditional beiging. In summary, BMAT has the capacity to respond to ß-adrenergic stimuli, however, its responses are muted and BMAT generally resists lipid hydrolysis and remodeling relative to iWAT. This resistance is more pronounced in distal regions of the skeleton where the BMAT adipocytes are larger with little intervening hematopoiesis, suggesting that there may be a role for both cell-autonomous and microenvironmental determinants. Resistance to ß-adrenergic stimuli further separates BMAT from known regulators of energy partitioning and contributes to our understanding of why BMAT is preserved in states of fasting and caloric restriction.

Iterative Development of a Tailored mHealth Intervention for Adolescent and Young Adult Survivors of Childhood Cancer.

Objectives: Methods for developing mobile health (mHealth) interventions are not well described. To guide the development of future mHealth interventions, we describe the application of the agile science framework to iteratively develop a mHealth intervention for adolescent and young adult (AYA) survivors of childhood cancer. Methods: We created the AYA STEPS mobile app (AYA Self-management via Texting, Education, and Plans for Survivorship) by modifying and integrating two existing programs: an online survivorship care plan (SCP) generator and a text messaging self-management intervention for AYA off treatment. The iterative development process involved three stages of agile science: 1) Formative work, 2) Obtaining feedback about the first AYA STEPS prototype, and 3) Pilot testing and finalization of a prototype. We determined preferences of AYA stakeholders as well as discovered and addressed technology problems prior to beginning a subsequent randomized controlled trial. Results: AYA survivors reported that the app and the embedded tailored messages related to their health and SCP, were easy to use and generally satisfying and beneficial. Usage data supported that AYA were engaged in the app. Technology glitches were discovered in the pilot and addressed. Conclusions: The iterative development of AYA STEPS was essential for creating a consistent and acceptable end user experience. This study serves as one example of how behavioral scientists may apply agile science to their own mHealth research.

Mobile health intervention for youth with sickle cell disease: Impact on adherence, disease knowledge, and quality of life.

BACKGROUND: Adherence to illness self-management among youth with sickle cell disease (SCD) positively impacts health outcomes and decreases overall healthcare costs. Despite this, children with SCD face several barriers to adherence, with adherence rates that remain moderate to low. The current feasibility study examined the Intensive Training Program (ITP), a mobile health (mHealth) intervention for youth with SCD designed to promote disease knowledge, adherence, and patient-provider communication. PROCEDURE: Youth with SCD prescribed hydroxyurea between ages 7-18 completed baseline disease knowledge and psychosocial assessments and then were provided with the ITP app. Youth participated in the 90-day ITP, during which they completed three education modules, tracked adherence through daily self-recorded videos on the app, and received video messages from providers. Participants completed poststudy knowledge, psychosocial, and feasibility questionnaires. Medication possession ratio (MPR) was obtained via pharmacy-refill rates. RESULTS: Thirty-two youths (mean age = 13.0 years) participated, with an average adherence tracking rate of 0.6 (standard deviation = 0.34). All participants demonstrated increased MPR (0.57-0.74, P < 0.001, d = 0.75) and disease knowledge (59.6-88.6%, P < 0.001). There was variable engagement in the ITP; completers demonstrated significantly better SCD-related functioning (P < 0.05), higher parent-reported treatment functioning (P < 0.05), and lower pain impact than noncompleters of the ITP (P < 0.05). CONCLUSIONS: Results support the ITP can feasibly be implemented to promote adherence among youth with SCD. All participants demonstrated increased adherence and disease knowledge. However, there was variable engagement and only intervention completers showed improvements in psychosocial outcomes. Further research is needed to evaluate long-term outcomes and ways to promote engagement in mHealth interventions among the youth.

Utilizing a Novel Mobile Health "Selfie" Application to Improve Compliance to Iron Chelation in Pediatric Patients Receiving Chronic Transfusions.

Iron chelation therapy can prevent iron overload for pediatric patients with sickle cell disease and ß-thalassemia major; however, adherence is suboptimal. Therefore, we developed an intensive training program (ITP), to improve medication management and disease knowledge. The objectives were to determine feasibility of the ITP and its preliminary impact on adherence, disease knowledge, and health outcomes. Pediatric patients were recruited to participate in the ITP over a 90-day period and were followed for 6 months. The ITP consisted of 3 components: (1) provider-led education modules; (2) patient recording daily videos of at-home medication administration; and (3) provider feedback through video messages through the ITP app. Eleven patients participated (mean=12.4 y). Initially, patients endorsed high satisfaction and ease of use and tracked their medication usage 81% (24 out of 30) of days. At 90 days, adherence rates remained consistent (80%) and disease knowledge retention was high (96%). At 6 months, participants exhibited a clinically relevant decrease in serum ferritin, which trended toward statistical significance (P=0.068). Medication possession ratio did not significantly increase (0.65 to 0.72; not significant). The mobile ITP was feasibly implemented in a clinical setting; in addition, high levels of compliance, disease knowledge retention, and acceptance encourage larger studies evaluating mobile health technology to improve child health parameters.

Fatigue in Children With Sickle Cell Disease: Association With Neurocognitive and Social-Emotional Functioning and Quality of Life.

Children with sickle cell disease (SCD) report fatigue in addition to acute and chronic pain, which can decrease overall health-related quality of life (HRQL). The primary objective of the current study was to investigate the relationship between fatigue and HRQL. Given limited prior research, secondary objectives included investigation of associations between fatigue and functional outcomes, including child neurocognitive and social-emotional functioning. Children aged 8 to 16 years (N=32) and a caregiver completed measures of fatigue, HRQL, pain, and neurocognitive and social-emotional functioning. Controlling for pain and number of SCD-related hospitalizations, hierarchical linear regression models were used to determine the impact of child-reported and parent-reported fatigue on child HRQL. Correlational analyses were used to explore the relationship between fatigue and additional child outcomes. Data indicated that children with SCD experience clinically relevant levels of fatigue, which independently predicts lower HRQL. Fatigue was also associated with lower working memory, executive functioning, and higher levels of internalizing symptoms. Given its observed impact on HRQL and relationship to functional outcomes, fatigue may be an important target of clinical, home, or school interventions. This practice may attenuate the burden of fatigue in these patients, and in turn, help improve the quality of life of children living with SCD.

FhCaBP4: a Fasciola hepatica calcium-binding protein with EF-hand and dynein light chain domains.

In trematodes, there is a family of proteins which combine EF-hand-containing domains with dynein light chain (DLC)-like domains. A member of this family from the liver fluke, Fasciola hepatica-FhCaBP4-has been identified and characterised biochemically. FhCaBP4 has an N-terminal domain containing two imperfect EF-hand sequences and a C-terminal dynein light chain-like domain. Molecular modelling predicted that the two domains are joined by a flexible linker. Native gel electrophoresis demonstrated that FhCaBP4 binds to calcium, manganese, barium and strontium ions, but not to magnesium or zinc ions. The hydrophobic, fluorescent probe 8-anilinonaphthalene-1-sulphonate bound more tightly to FhCaBP4 in the presence of calcium ions. This suggests that the protein undergoes a conformational change on ion binding which increases the number of non-polar residues on the surface. FhCaBP4 was protected from limited proteolysis by the calmodulin antagonist W7, but not by trifluoperazine or praziquantel. Protein-protein cross-linking experiments showed that FhCaBP4 underwent calcium ion-dependent dimerisation. Since DLCs are commonly dimeric, it is likely that FhCaBP4 dimerises through this domain. The molecular model reveals that the calcium ion-binding site is located close to a key sequence in the DLC-like domain, suggesting a plausible mechanism for calcium-dependent dimerisation.