Citations

Abstract Dementia caregivers are at heightened risk for developing mental and physical health problems. Interventions designed to protect caregiver health often create additional demands on time and energy (e.g., exercise programs). Technology-based interventions (e.g., remote monitoring) can be effective, scalable, and do not add greatly to caregiver burden. Through a collaboration with a local technology company, Care Daily, we conducted two randomized controlled trials to evaluate People Power Caregiver (PPCg), a system of sensors in the home connected to cloud-based AI that alerts caregivers about worrisome deviations from normal patterns (e.g., care-recipient’s falls, wandering). Across two studies (study 1: 9-month duration with professional installation of PPCg; study 2: 6-month duration with caregiver self-installing the PPCg using remote tech support), 284 caregivers were recruited; 261 completed initial study deployment (e.g., system installation); and 235 completed the entire study protocol. Use of PPCg was associated with (a) reduced caregiver anxiety in study 1; (b) greater protection from declines in sleep efficiency in studies 1 and 2. These findings underscore the promise of technology-based intervention to mitigate health problems in dementia caregivers. However, challenges and complexities in recruitment (e.g., remote consenting both caregivers and care recipients), retention (e.g., due to changes in home environment or caregiving status), system installation (e.g., working with caregivers with less experience using technology), data quality assurance (e.g., invalid sensor data) as well as our efforts to overcome these challenges have been instructive. Lessons learned from these studies can provide useful guidance for future large-scale, technology-based interventions for dementia caregivers.

Abstract The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell‐mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune‐related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. Highlights The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid‐beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system.

Background and Objectives: Faculty members who are underrepresented in medicine (URM) may benefit from mentorship that is designed specifically to meet their unique needs and is focused on improving their career pathways in academic medicine. The Underrepresented in Medicine Mentorship Program (URM-MP) is an academic society-based mentorship program that pairs early career URM faculty with mid- to late-career faculty specifically trained to address URM issues. Methods: During the first 3 years of the program, mentors received web-based training on addressing oppression and marginalization of URM faculty in academic medicine. Mentor and mentee pairs met monthly for 1 year and received support from program leaders through web-based check-in meetings twice per year. Pre- and postassessment data were collected from mentees to help identify their needs and evaluate their experiences. Check-in meetings provided feedback about the program. Results: Fifty-seven URM faculty participated in years 1, 2, and 3. Results of pre- and postsurveys showed that mentees significantly improved their self-perceived effectiveness to enhance their careers, to find resources to perform their jobs, and to navigate the challenges of advancing in academic medicine. Qualitative analyses revealed themes of appreciation for mentors supporting their unique experiences as URM faculty. Check-in feedback further reinforced the relationship aspects of the mentorship as a significant benefit of this program. Conclusions: Society-based mentorship that involves specific training for mentors and fosters trusting mentor-mentee relationships can improve URM faculty’s confidence regarding their ability to succeed in academic medicine.

Adolescents and young adults living with advanced cancer must often discover new rules for living during cancer treatment. Such experiences may lead them to emerge to higher levels of consciousness and find personal meaning in these experiences. Newman’s theory of health as expanding consciousness was this qualitative research study’s framework examining hope’s role for adolescents and young adults living with advanced cancer. Fifteen participants aged 12-21 years created written narratives and illustrations to describe their experiences with hope. We propose an updated theoretical model in which hope facilitates expanding consciousness in adolescents and young adults living with advanced cancer.

Background: Splenic marginal zone lymphoma (SMZL) is a rare indolent disease with a median overall survival (OS) of more than 10 years, although a proportion of patients may develop aggressive histology transformation. In a previous report from this large, international dataset, the 10-year cumulative incidence of transformation was 17% (95% 13-21) and in another study of 186 patients, the 10-year cumulative incidence was 14%Click or tap here to enter text.. In this report, we focus on risk factors for transformation as well as clinical characteristics and outcomes of transformed SMZL (tSMZL). Patients and methods: Adults diagnosed with SMZL in 2000-2018 were identified through regional or nationwide population-based registries or from hospital registries. Only patients likely to have SMZL as defined by Matutes et al. were included. Those with discordant lymphoma and/or transformation at diagnosis were excluded. Medical records were reviewed by local clinicians with experience in hematology/oncology, and detailed information on clinical characteristics, treatment lines, and outcomes was collected. Only histologically confirmed high-grade transformations (HT) were included. OS was defined as the time from transformation to death or censoring at last follow-up. Additional analyses stratified by treatment exposure prior to HT and treatment of HT were conducted. Multivariable Cox analyses were performed to determine clinicopathological features associated with transformation and OS. Results: Out of 940 patients with SMZL, 111 developed HT during a median follow-up of 9.1 years. The median time from diagnosis to HT was 3.4 years with an interquartile range of 1.6-7.4 years. Median age at HT was 71 years. Patients with HT shared similar baseline characteristics to those without in terms of age at diagnosis (66.4 vs 67.6), f:m ratio (1.5 vs 1.1) and ECOG ³2 (7.2% vs 7.4%). The 5-yr OS from the time of HT was 42% (CI 95%, 32-54). Of the 111 patients with tSMZL, a complete treatment history from SMZL diagnosis until HT was available for 88 included in the following analyses. By the time of HT, 46 had not received any prior systemic therapy (37 only splenectomy, 9 no therapy), 6 patients had received rituximab alone or combined with splenectomy, and 36 patients had received chemotherapy alone or as part of combined modality treatment. In a uni- and multivariable models for HT, we assessed age, treatment at diagnosis, sex, extra-hilar lymphadenopathy, and extranodal involvement. In both the uni- and multivariable model, age >70 (HR 1.9, 95% CI: 1.1-3.4), immediate treatment including splenectomy (HR 2.0, 95% CI: 1.05-3.6), and extra-hilar lymphadenopathy (HR 1.9, 95% CI: 1.1-3.3) were associated with higher HT hazard, while extranodal involvement (HR 0.23, 95% CI: 0.06-0.84) was associated with a lower HT hazard. At the time of first-line treatment, multivariable analysis revealed similar results and with no association between risk of transformation and treatment strategy (i.e splenectomy alone, rituximab monotherapy or chemotherapy with /without rituximab or splenectomy, and other). At the time of HT, patients who had been previously treated with chemotherapy had an inferior 5-year OS of 24% (95%CI: 13-44%) versus 54% (95%CI: 41-71%) for those who had not received chemotherapy prior to HT. In contrast, there was no difference in the survival of patients that transformed less than or more than 24 months from diagnosis with 5-year OS after HT of 35% (95%CI 20-60%) and 45% (95%CI, 33-61%) respectively. In a multivariable Cox regression analyses of age at time of HT, sex, time since last treatment <24 months, chemo-exposure in previous treatment lines and anthracycline-containing therapy (+/-R) at the time of HT, only prior chemo-exposure was borderline associated with poorer OS (HR 1.8, 95%CI: 0.9-3.5). Conclusion: Patients with SMZL face a notable risk of developing tSMZL over time. Patients in need of immediate treatment at first SMZL diagnosis, age >70 and extrahilar lymphadenopathy had a higher risk of tSMZL and outcomes at the time of HT were poor if patients had been exposed to prior chemotherapy after adjustment for age, sex, and time since last treatment.

Introduction: Phase I trials are designed to evaluate the safety and tolerability of new treatments. Review of adverse events (AEs) experienced by trial participants is a critical aspect of these early phase trials. Current practice for safety and tolerability data collection is for clinicians to evaluate AEs using the Common Terminology Criteria for Adverse Events (CTCAE). Past work has demonstrated that clinicians may miss or underreport symptomatic AEs. The Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE) is an item library of questions for patients to self-report symptomatic AEs in clinical trials that is complementary to the CTCAE. PRO-CTCAE offers a patient-centric method for capturing symptomatic AEs, which may be missed or underreported by clinicians. The PRO-CTCAE library includes questions using patient friendly terms to assess frequency, severity, and interference of symptomatic AEs on 0-4 verbal descriptor scales (e.g., severity is rated by patients as none, mild, moderate, severe, or very severe). The goal of the current work was to demonstrate how to incorporate AE information from PRO-CTCAE and CTCAE into a Phase I dose review report. Methods: We used data from a Phase I clinical trial of patients with relapsed or refractory acute myeloid leukemia. Therapy was administered on 28-day cycles. Patients completed questionnaires on an electronic device on days 1, 8, 15, and 22 of the first cycle of treatment. Through iterative feedback from clinicians and statisticians, we developed an example dose review report. The report summarized data for one dose level in which 4 patients were treated. These 4 patients comprised the first patient cohort enrolled in the available Phase I clinical trial. The report was intended to be representative of the type of report that would be reviewed to make a decision about the next dose level for a new cohort of patients. Results: The final dose review report included narratives for each patient generated by the statistical team based on patient-reported and physician-graded AEs in cycle 1, tabular summaries integrating CTCAE and PRO-CTCAE, and novel graphical presentation of PRO-CTCAE and CTCAE, including swimmer plots and butterfly plots for symptoms listed as dose limiting toxicity criteria. In this cohort, 3/4 (75%) patients had at least one grade 3+ AE, as assessed by CTCAE, and 4/4 (100%) patients had at least one score 3 symptomatic AE, as assessed by PRO-CTCAE. All 4/4 (100%) patients had at least one reported symptom on the PRO-CTCAE that was not captured by CTCAE or was reported at a lower grade by CTCAE. Multiple versions of the example dose review report were presented to the study team and iterative feedback was solicited from clinicians and statisticians. Feedback highlighted the usefulness of narratives and patient-level graphical displays. Narratives within the dose review report were refined to focus on treatment emergent AEs, minimizing text and succinctly presenting baseline symptoms where relevant. Symptom-level graphics of combined PRO-CTCAE scores and CTCAE grades were preferred over graphics consolidating data for multiple symptoms. Final graphics and report will be presented. Conclusions: We demonstrated that PRO-CTCAE, which captures patient-reported symptoms, complements traditional AE reporting and that reporting PRO-CTCAE and CTCAE jointly in a Phase I dose level report can provide a more complete picture of safety and tolerability in the Phase I setting.

Background New therapies for myelofibrosis (MF) are being developed but how these compare with current therapies is limited to analyzing single outcome measures such as spleen volume reduction or quality-of-life (QoL). However, these outcome trajectories might diverge and some endpoints may not be clinically relevant. To remedy this an ELN (European LeukemiaNet) taskforce developed a composite endpoint using the Desirability-Of-Outcome-Ranking (DOOR) method which allows multiple outcomes to be simultaneously considered and therapies achieving diverging endpoints compared. Methods An Expert Panel used DOOR to divide outcome relevancy into 8 dimensions: clinical meaningfulness, modifiability, reliability, feasibility, decisional value, acceptability, frequency, and cost. Next, a weight was assigned to each dimension using the mean Likert score assigned by the panelists. Next, the panel validated which dimensions were met by each of 30 outcomes most frequently listed by clinical trials. A weighted score (WS) for each outcome was calculated based on weights assigned to a dimension and accomplishment rates assigned to outcomes. Outcomes were then distributed into quartiles. Next, operational definitions of outcomes were tested in Delphi consensus method requiring > 75% agreement. Last, a literature review indicated correlations of the outcomes ranked in the 1st 2 quartiles with survival. Results Three composite endpoints were developed and named DEMYOs (DEsirability-of-MYelofibrosis-Outcomes). DEMYO-1, the proportion of people alive and free of severe vascular events, blast transformation, severe anaemia and thrombocytopenia and very-severe symptom burden, encompassed outcomes in the 1st quartile (WS > 29.5) and is the proposed composite endpoint for trials of people with advanced JAK-inhibitor refractory MF. DEMYO-2, defined as the proportion of people alive and free of accelerated or blast phase, severe or worsening anaemia, severe and major vascular events, severe or symptomatic splenomegaly, severe or worsening symptoms and any emergent adverse genetic abnormality, included the outcomes ranked in the 1st 2 quartiles (WS > 26.5) and is proposed for trials of people with a sub-optimal response to JAK-inhibitors. DEMYO-3, defined as the proportion of people alive and free of blast transformation, vascular events, severe, symptomatic or worsening clinical features and of worsening prognostic co-variates, included outcomes in the 1st 3 quartiles (WS > 23.5) and is proposed for trials of people not yet receiving JAK-inhibitors. Interpretation DEMYO composite endpoints capture relevant clinical features of MF and represent endpoints important to patients, physicians and other stakeholders. DEMYO validation is feasible by available trial data and, once validated, the composite endpoints can be endorsed by medicines regulatory agencies. DOOR proved feasible and robust in this 1st-in-haematology application and we encourage further use. No funding

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening hematological disorder affecting approximately 24 people per million in the United States (US). Iptacopan, the first orally administered monotherapy for PNH, received US Food and Drug Administration approval in December 2023. APPRISE-PNH (A Patient Platform for Real-world data on Iptacopan in the United StatEs for patients with PNH) is a data platform designed to capture comprehensive real-world information on patients with PNH treated with iptacopan in the US. This interim analysis aims to provide early insights into the characteristics and treatment patterns of patients enrolled in APPRISE-PNH to date. Methods: APPRISE-PNH is a retrospective, longitudinal, data platform including adult patients (age ≥18 years) with PNH treated with iptacopan in the US real-world setting. Consenting patients in the US are recruited through the iptacopan distribution network. The present analysis includes data from patients enrolled between July 2 and July 26, 2024, with additional data collection expected through the remainder of 2024 and 2025. Patient characteristics and treatment patterns were evaluated descriptively. Duration of therapy was measured from the date of iptacopan initiation until the date of iptacopan discontinuation or data cut-off, whichever occurred first. Treatment adherence was measured using both the medication possession ratio (MPR), calculated as the ratio of the total days supply to days covered, and the proportion of days covered (PDC), calculated as the ratio of days with supply to days covered. Results: As of July 26th, 2024, nine patients with PNH have enrolled in the APPRISE-PNH data platform. The median age at the start of iptacopan therapy was 44 years (interquartile range [IQR] 40-73 years), seven (78%) patients were female, and four (44%) were covered by commercial insurance. Overall, two (22%) patients were treatment-naïve at the start of iptacopan therapy, while seven (78%) patients had received prior complement-inhibitor (CI) therapy for PNH (44% ravulizumab, 44% eculizumab, 33% pegcetacoplan). The median duration of iptacopan therapy was 2.0 months (IQR 1.5-2.9 months). All patients received iptacopan 200 mg twice daily (as per the product label) and the median number of fills was 2.0 (IQR 1.0-3.0). At the time of data cut-off, no patients had discontinued iptacopan therapy. The MPR in this group of patients was 136% (IQR 114%-150%) and PDC was 100% (IQR 100%-100%). Conclusions: These are the first data from the APPRISE-PNH data platform and represent the first insights into real-world use of iptacopan in the US. Many patients enrolled in APPRISE-PNH had previously received CI therapy for PNH. Treatment adherence, as indicated by both the MPR and PDC, was high across iptacopan-treated patients. Enrollment into the APPRISE-PNH data platform is currently ongoing; data from additional patients, additional laboratory and clinical outcomes, and longer follow-up data are expected to be available at the time of presentation.

Background: Adolescents and young adults (AYAs) living with advanced cancer may experience a heightened risk for existential distress. Addressing AYAs’ hopes can stimulate a dialogue about their concerns, values, and goals, provide a path to holistically support their existential needs, and potentially alleviate their distress. This study aimed to evaluate hope's role in a sample of AYAs living with advanced cancer. Method: This study used a Husserlian phenomenology-informed descriptive qualitative research design to elicit AYAs’ experiences with hope while living with advanced cancer. Participants were virtually recruited from an academic medical center and an online non-profit organization. Thematic analyses were performed across the data set to identify final themes. Results: Fifteen AYAs aged 12–21 years diagnosed with advanced hematological (80%) or solid (20%) malignancies participated in this study. A main theme of Simple Supports of Hope with a subtheme of Diversion was identified. Participants described music as a form of diversion, which supported their hope. Participants found listening to music calming and comforting and helped them cope with their distress. Performing music provided a creative outlet for negative feelings associated with cancer treatment. Participants reported creating music transformed and deintensified the treatment environment and helped spread hope to healthcare staff. Discussion: AYAs may intentionally use music to improve emotional expression, empowerment, connection, and coping strategies throughout the treatment process for cancer. Additional research needs to be conducted exploring the use of music interventions such as therapeutic songwriting or compositional music therapy to assist AYAs with building coping strategies during treatment for cancer.