Citations

INTRODUCTION: To assess strategies for optimizing participation of underserved minorities in a blood-based early colorectal cancer detection test study (PREEMPT CRC; NCT04369053) at a hospital serving primarily Black individuals. METHODS: Culturally sensitive, racially congruent research staff approached individuals undergoing average-risk screening colonoscopy. Consent/study procedures were synchronized with clinical appointments. Enrolled and not-enrolled patient characteristics were compared. Recruitment was compared with other study sites. RESULTS: In total, 247 of 509 eligible individuals were enrolled; most were identified as Black (88.7%). No baseline characteristics were associated with participation. Recruitment was high compared with other sites (11th centile). DISCUSSION: Recruitment barriers for Black individuals can be overcome when easy, culturally sensitive access is facilitated.

Background. Early allograft dysfunction (EAD) affects outcomes in liver transplantation (LT). Existing risk models developed for deceased-donor LT depend on posttransplant factors and fall short in living-donor LT (LDLT), where pretransplant evaluations are crucial for preventing EAD and justifying the donor’s risks. Methods. This retrospective study analyzed data from 2944 adult patients who underwent LDLT at 17 centers between 2016 and 2020. We developed a logistic regression model to predict EAD based on this development cohort. We used data from 1020 patients at the King Faisal Transplant Center for external validation. Results. In the development cohort, 321 patients (10.9%) experienced EAD. These patients had poorer health status, more liver decompensation, and higher requirements of hospitalization than those without EAD. Multivariable logistic regression identified independent pretransplant predictors of EAD: laboratory Model for End-Stage Liver Disease score (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.06-1.09), the necessity for hospitalization at the time of transplant (OR, 2.58; 95% CI, 2.00-3.30), and graft weight in kilogram (OR, 0.27; 95% CI, 0.17-0.45). Using these predictors, we developed the model for EAD after LDLT, which demonstrated strong discriminative ability in the development cohort with an area under the curve (AUC) of 0.71 (95% CI, 0.68-0.74). The model maintained high discrimination during internal validation (AUC, 0.70; 95% CI, 0.67-0.73) and showed a modest reduction in discriminative power in external validation (AUC, 0.65; 95% CI, 0.61-0.68). Conclusions. EAD post-LDLT is influenced by the recipient’s pretransplant health condition and the graft weight. Integrating the model for EAD after LDLT into the pretransplant process of pairing donors and recipients can enhance the safety and efficacy of LDLT.

826 Background: After initial response to first line therapy with imatinib, GISTs commonly progress due to secondary resistance mutations in KIT. As the KIT mutation targeting profiles of bezuclastinib (type I TKI) and sunitinib are distinct, when combined they inhibit a broad spectrum of secondary KIT mutations. Herein we report extended experience of patients treated with 2 nd line combination bezuclastinib and sunitinib, including response assessment and safety. Methods: Peak (NCT05208047), a global randomized Phase 3, open-label study, aims to evaluate efficacy and safety of bezuclastinib + sunitinib vs sunitinib in GIST pts with imatinib intolerance or resistance. In Part 1a of the 3-part study, the dose of an optimized formulation of bezuclastinib was escalated in serial cohorts to achieve a target exposure comparable to that achieved at the RP2D established in the prior Phase 1b/2a study. Part 1b evaluated the interaction between bezuclastinib + sunitinib. Key inclusion: adult with locally advanced, metastatic and/or unresectable GIST, ≥1 measurable lesion according to modified RECIST v1.1, and ECOG PS 0 to 2. Part 1 completed enrollment in Apr 2023. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was selected for Part 2. All Part 1 data reported herein are as of Aug 2023; updated safety and efficacy will be presented. Results: Part 1 has completed enrollment with 19 pts in Part 1a and 23 in 1b. In Part 1a, Cohort 1 included 5 pts starting at bezuclastinib 300 mg QD + sunitinib 37.5 mg QD; Cohort 2 included 14 pts at bezuclastinib 600 mg QD + sunitinib 37.5 mg QD. Pt characteristics in Part 1a+1b: median age - 60 yrs (range: 33-77); 81% men; 98% ECOG PS 0-1; 98% metastatic and 2% locally advanced. The majority of TEAEs were low grade and reversible with low rate (38%) of Grade 3+ events. There were limited (24%) dose reductions and infrequent (n=2) discontinuations due to TEAEs. Three pts experienced serious AEs possibly associated with study medications. In pts evaluable for response (received ≥1 cycle of study treatment and had assessments at baseline and post-baseline [n=40]), the objective response rate (ORR) was 20% (6 confirmed PRs, 2 unconfirmed PRs). Data remain immature to estimate median PFS for Part 1 pts. In a subset of pts with prior imatinib only (n=6), the closest approximation for pts enrolling in Part 2, the ORR was 33% (2 confirmed PRs). The majority of 2nd-line pts remain on treatment past 12 months. Conclusions: Data from Peak Part 1 show an encouraging safety and tolerability profile generally consistent with published sunitinib monotherapy experience. ORR in evaluable pts from Part 1 was 20%; ORR in 2 nd line pts was 33%. Part 2 of the Peak study is actively enrolling pts globally at the selected dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD versus sunitinib 37.5 mg QD. Clinical trial information: NCT05208047 .

Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer’s disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1–7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer’s disease cohort included 35 adults with sporadic Alzheimer’s disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting ‘pro-youthful’ levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer’s disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer’s disease and related dementias and warrant further investigation.

Background/Objectives: Little information has been published on patients diagnosed with brain metastasis secondary to lung cancer. Correlating outcome patterns (hospice care, lost to follow-up, death before hospice care or treatment) and specific characteristics of treated and untreated patients may identify subsets of patients who may benefit from treatment. Methods: We evaluated data from the Kentucky Cancer Registry and identified 284 cases who were diagnosed with brain metastasis secondary to non-small cell lung cancer (NSCLC) between 1 August 2016, and 31 December 2019. We evaluated type and timing of treatment received, as well as focused on those patients who did not receive treatment. For those patients who did not receive treatment, various characteristics that may have impacted their decision or ability to undergo follow-up were also evaluated. This included social history, disease burden, as well as oncology treatment timelines. Lastly, due to the high smoking rate in Kentucky, we conducted an analysis of patient tobacco use. Results: Our results show that 61 cases (21.8%) never received treatment for lung cancer with brain metastasis. Further analysis of the non-treated cases demonstrated that 19 cases (31.1%) never met with an oncology team while in the hospital or after discharge; 14 of the 61 cases (23.0%) were too sick to receive treatment and died prior to having the option of treatment; and 47 of the 61 cases (77.0%) may have had the option of treatment but declined. Conclusions: Historically, patients with brain metastases have faced poor prognoses and limited treatment options. However, advancements in systemic chemoimmunotherapy and targeted therapies have introduced new treatment possibilities, offering improved symptom control and the potential for prolonged survival. This analysis is crucial for identifying potential barriers to care, optimizing resource allocation, and guiding future research.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

AbstractBackgroundGrowth Differentiation Factor 15 (GDF15) is a TGF‐beta superfamily protein upregulated during immune‐mediated stress responses. Peripheral GDF15 is linked to adverse aging across organ systems including the brain. Immune dysregulation is implicated in frontotemporal dementia (FTD) pathogenesis. We examined how plasma GDF15 levels associated with longitudinal cognitive and neurofilament light chain (NfL) trajectories in adults with FTD and controls. Furthermore, we tested the utility of GDF15 as a prognostic biomarker against common inflammatory proteins (CRP and IL6).Method231 adults with FTD (24.35% sporadic FTD syndromes; 19.19% MAPT; 19.56% GRN; 22.14% C9orf72 pathogenic carriers) and 40 normal controls from the ALLFTD Consortium completed longitudinal neuropsychological testing and a blood draw with plasma analyzed on SomaScan V4.0 (baseline only: GDF15, CRP, and IL6) and Simoa (longitudinal: NfL). CRP and IL6 were selected as control markers to test the specificity of GDF15. Linear mixed effects models separately examined longitudinal cognition (global, executive functioning, memory, and language z‐scores) and plasma NfL levels as a function of baseline plasma GDF15, time, and their interaction, controlling for baseline age, sex, and education. Parallel models were conducted for CRP and IL6.ResultIn the whole cohort, higher baseline plasma GDF15 levels associated with steeper global cognitive decline (b = ‐3.91, p = 0.0092) and NfL accumulation (b = 3.88, p = 0.00088) over time. When examining cognitive domains, we found GDF15 only associated with worse executive functioning trajectories (b = ‐3.19, p = 0.0021). In contrast, baseline levels of CRP and IL6 did not display statistically significant relationships with cognitive or NfL trajectories. Prognostic effects of GDF15 remained statistically significant when restricting analyses to those with FTD pathogenic variants (b = ‐2.98, p = 0.0054 [global cognition], b = 2.69, p = 0.0098 [NfL]).ConclusionAdults with FTD and higher baseline peripheral GDF15 levels exhibit accelerated cognitive decline and neurodegeneration. Our results support GDF15 as a potential prognosticator of adverse clinical outcomes in FTD and highlight the relevance of GDF15‐specific pathways in FTD progression. Plasma GDF15 may provide utility over commonly examined inflammatory proteins and further work to explore its clinical value is indicated.

AbstractBackgroundEffect and Safety of Electroconvulsive Therapy plus Usual Care for the Acute Management of Severe Agitation in Dementia (ECT‐AD) is a multi‐site NIA‐funded FDA‐regulated pioneering clinical trial to investigate the effectiveness of electroconvulsive therapy (ECT) in treating severe and treatment‐refractory agitation and aggression among individuals with advanced dementia, a condition that has a profound negative impact on patient quality of life and caregiver burden. Here we present baseline demographics of the patient population in this ongoing trial.MethodTo date we have enrolled 18 participants, with a mean age of 74.1 years, where majority are male (61.1%). The racial composition is predominantly White (94.4%), with Asian representation (5.6%, 1/18), and with 11.1% (2/18) identifying as Hispanic or Latino. Dementia subtypes in our cohort include Alzheimer’s disease (AD, 77.8%), vascular dementia (VaD, 16.7%, 3/18), and frontotemporal dementia (FTD, 5.6%, 1/18).ResultBaseline assessments reveal severe cognitive and functional impairment, as indicated by a mean Mini‐Mental State Examination (MMSE) score of 4.0, Barthel Index (BI) score of 52.2, and SIB‐8 score of 2.9, all consistent with advanced stages of dementia. High mean total scores on the Cohen‐Mansfield Agitation Inventory (CMAI, 75.8), Neuropsychiatric Inventory (NPI) agitation (15.1) and aggression (9.2) scales, and Pittsburgh Agitation Scale (PAS, 7.8), reflect the severe levels of agitation and aggression in our participants.ConclusionThese baseline demographic and clinical data underscore the profound impact of advanced dementia, highlighting the need for innovative treatment approaches like ECT. The ECT‐AD trial offers a critical step towards understanding and improving the management of agitation in dementia, with implications that could enhance current clinical care practices.