Citations

BACKGROUND: A preservation system, the Organ Care System (OCS; TransMedics) uses normothermic pulsatile perfusion during organ transport for heart transplantation. This system has demonstrated favorable outcomes in hearts recovered from extended-criteria donors after brain death (DBD) and donors after circulatory death (DCD). METHODS: The OCS Heart Perfusion Registry collects data on US heart transplantations using the OCS, static cold storage (SCS), or thoracoabdominal normothermic regional perfusion (NRP) and donor hearts recovered from DBD or DCD donors. We analyzed donor and recipient characteristics and posttransplantation outcomes in patients transplanted with OCS donor hearts (either DBD or DCD) compared with SCS hearts, and with OCS hearts from DCD donors compared with those recovered with NRP followed by SCS. Propensity score matching was used in survival analyses to adjust for differences among recipient characteristics. RESULTS: Between 2021 and 2023, 3225 consecutive heart transplantations enrolled from 56 centers were analyzed in the Heart Perfusion Registry. The OCS was used in 854 of 3225 heart transplantations (26.4%), among which 340 (39.8%) were DBD and 514 (60.2%) were DCD donors, whereas 2174 DBD donors were recovered with SCS and another 197 DCD donors with NRP techniques. The OCS-DBD group experienced a greater number of organ offer refusals before final acceptance (13 versus 6; Wilcoxon rank sum, P <0.001) and a longer transport distance (667 miles versus 232 miles; Wilcoxon rank sum, P <0.001) compared with SCS-DBD. Survival at 12 months was similar between the 2 groups (89.9% for OCS-DBD versus 90.6% for SCS-DBD; marginal Cox model, P =0.54). Among the OCS-DCD and SCS-DBD groups, survival at 12 months was also similar (91.0% versus 92.5%, respectively; marginal Cox model, P =0.32). The OCS-DCD and NRP-DCD groups demonstrated similar survival (91.0% versus 91.7%, respectively; log rank, P =0.63), although the transport distance was longer in OCS-DCD compared with DCD with NRP followed by SCS (400 miles versus 223 miles; Wilcoxon rank sum, P <0.001). By 2023, 90% of all OCS donor management and recovery was performed with dedicated organ recovery teams. CONCLUSIONS: We demonstrate that real-world implementation of the OCS for DBD donors (using predominantly a dedicated recovery team) is associated with expanded donor criteria, longer transport distance, and excellent posttransplantation outcomes. In OCS-DCD donors, outcomes parallel those of donors recovered with NRP-DCD and compare favorably with DBD donor organs.

770 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and limited treatment options. A 584 bp deletion in CTRB2 , which impairs chymotrypsin B2 function, has been linked to increased PDAC risk. This study investigates the impact of this deletion on progression and survival outcomes in patients with PDAC. Methods: There were 633 patients in whom CTRB2ex6 deletion was genotyped; 263 patients received chemotherapy and had time to progression (TTP) information. TTP was calculated from diagnosis date until earliest of 1) progression date (event), 2) surgery, death, or next chemotherapy date (competing risk), or 3) date last known to be alive (censor). Overall survival (OS) was calculated for the cohort from diagnosis until date of death (event) or date last known to be alive (censor). TTP was analyzed using cumulative incidence methods accounting for competing risks; OS was analyzed using Kaplan-Meier methods. Cox proportional hazard models adjusted for age and sex were used to test associations and compute hazard ratios (HR) and 95% confidence intervals (CI). Results: Median TTP in those with CTRB2ex6 deletion negative carrier status (n=209) was 1.3 years vs 5.9 years for those with positive carrier status (n=54). Estimated 3-year progression rates were 54.2% for patients with no CTRB2ex6 deletions, 43.7% for patients with one deletion (n=48), and 33.3% for patients with two CTRB2ex6 deletions (n=6). TTP was not associated with CTRB2 deletion carrier status (HR: 0.8, 95% CI: 0.6-1.3). Median OS for CTRB2ex6 deletion negative carriers (n=514) was 1.0 year vs 0.9 years for positive carriers (n=119); within deletion carriers, heterozygous carriers (n=110) had a median OS of 0.9 years, and homozygous carriers (n=9) had a median OS of 2.6 years. OS was not associated with CTRB2 deletion carrier status (HR: 1.0, 95% CI: 0.9-1.3). Conclusions: Although we did not detect statistically significant differences in TTP and OS by CTRB2ex6 deletion carrier status, there was an interesting trend toward longer TTP and OS in the small number of patients who carried homozygous CTRB2ex6 deletions. Larger studies are warranted to validate these findings.

e16368 Background: Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second cause of cancer death in the US by 2040. For the minority of patients who are candidates for curative-intent surgical resection, a neoadjuvant approach with chemotherapy or chemotherapy followed by chemoradiotherapy (chemoRT) has become the standard of care. The tumor microenvironment (TME) has been recognized as a key factor in therapeutic resistance and disease progression. This study aims to explore the prognostic value of human-interpretable machine learning image features (HIFs) derived from whole-slide H&E images. Methods: Consecutive PDAC patients who underwent neoadjuvant therapy followed by surgical resection were studied in this single-institution retrospective study. Clinical variables collected include tumor site (head/body/tail), surgery extent, histology, sex, age at diagnosis, grade, treatment response (4-point scale), LVI, PNI, resection margin status, pathological TNM staging, number of lymph nodes removed/positive, neoadjuvant strategy (chemotherapy vs chemoRT), and number of neoadjuvant chemo cycles. These factors were analyzed with a multivariable Cox proportional hazards model for disease-free survival (DFS) after surgery. Additionally, 420 human-interpretable image features (HIFs) derived from a commercial machine learning software were analyzed with a univariable Cox model on a binary outcome of 1-yr DFS, applying a Bonferroni correction for multiple comparisons to identify significant predictors. Results: Increased neoadjuvant chemotherapy cycles (HR = 0.62, p = 0.001, [median: 8, IQR: 6-12]) and receipt of combination neoadjuvant therapy (HR = 0.15, p = 0.020, [29% chemo, 71% +chemoRT]) exhibited a protective effect in the multivariable DFS model. 3 HIFs quantifying immune cells and macrophages within the cancerous tissue and its stroma were associated with an improved probability of 1-year DFS. Conclusions: In addition to clinical factors, HIFs may offer valuable insights into the tumor microenvironment's influence on PDAC progression, paving the way for improved prognostic models and therapeutic strategies. Future work will integrate clinical predictors with HIFs in a combined model.

AbstractIn response to the evolving treatment landscape for new‐onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy‐seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second‐line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second‐line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1–1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3–2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second‐line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3–8.9)—particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3–21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5–20.1)—than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second‐line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes.

Abstract Febrile infection‐related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non‐FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non‐FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non‐FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non‐infection‐related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein‐1 alpha (MIP‐1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non‐FIRES NORSE are very similar conditions.

Background: Telehealth use was previously limited by strict regulations and financial constraints. However, the pandemic prompted some countries to ease their telehealth laws. Thus, we conducted a bibliometric analysis and network visualization to gauge changes in tele-neuropsychology (Tele-NP) and tele-mental Health (Tele-MH) trends with the onset of the COVID-19 pandemic. Materials and methods: The authors conducted a literature search on SCOPUS and included relevant articles pertaining to Tele-NP and Tele-MH, which were published before the COVID-19 pandemic (2017–2019) and during the COVID-19 pandemic (2020–2022). The authors presented publication patterns on psychiatric disorders, mode of administration, journals, active countries, authors, affiliations, funding sponsors, keywords, publication, and citation output. Results: Three hundred forty-one articles were included in our study with 80 articles before the pandemic and 261 during the pandemic. Our analysis revealed the greatest increase in publications and citations output was from the year 2020 to 2021. A greater number of journals published tele-NP and tele-MH-related research, with higher frequency, during the COVID-19 pandemic with Telemedicine and E-health leading the way. WHO regional analysis revealed that the Region of the Americas (AMRO) was the leading contributor in terms of publications. Harvard Medical Center remained the number one contributor both before and during the COVID-19- pandemic. Publications by funding sponsors, particularly by those that were US-based, increased twice as much during the pandemic. Conclusion: The increase in research output following the COVID-19 outbreak reflects the growing interest and relevance of telemedicine for the delivery of mental health services.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second cause of cancer death in the US by 2040. Five-year overall survival is only ~12% despite decades of research. The mainstay of treatment remains chemotherapy in the absence of highly recurrent, therapeutically actionable, genetic targets. For the minority of patients (~15-20%) who are candidates for curative-intent surgical resection, six months of intensive neoadjuvant chemotherapy with/without chemoradiation has become standard-of-care. However, despite evidence of radiographic, metabolic, and biochemical responses, significant viable residual disease on pathologic analysis is almost universally observed with approximately 40-60% risk of disease recurrence. Thus, there is a critical need to better understand why PDAC remains recalcitrant to current therapeutic modalities. Pathologic evaluation of PDAC reveals a complex microenvironment consisting of neoplastic cells dynamically interacting with both “normal” cellular (e.g. mesenchymal, immune) and non-cellular (e.g. collagen) stromal elements. While biologically important, experimental models and small-scale efforts to dissect the PDAC ecosystem are limited by focus on individual tumor compartments and generation of conflicting results. Consequently, there is a need for a more comprehensive understanding of the structure and dynamics of the PDAC TME through the theoretical lens of evolutionary ecology. Current therapies are not focused on the PDAC ecosystem. We hypothesize that cell-cell interactions of PDAC cells with its local niche are important for conferring treatment resistance. Thus, better understanding of said interactions could yield novel ecologically-informed therapies. Consequently, we developed a digital pathology library of approximately 1000 PDAC resection cases (whole-slide H&E images) performed at Mayo Clinic between 2013-2021. Approximately 400 cases are treatment naive while about 600 were treated with neoadjuvant therapy. While some qualitative features of pathologic analysis have prognostic value (e.g., pathologic treatment response, presence of perineural or lymphovascular invasion, extent of desmoplasia), we aim to identify prognostic spatial relationships using tools from landscape ecology. We utilized the HoVer-Net model for nuclei segmentation and classification and spatial statistics methods and landscape fragmentation analysis to understand the spatial organization within the PDAC tumor ecology. With these methodologies, we can assess the spatial context of cell interactions, habitat/niche/microenvironment formation, ecological relationships between cell populations, and the different tissue components. The different spatial statistics/metrics are used to quantify levels of immune cell infiltration, mixing, as well as the complexity and diversity of microenvironment phenotypes leading to high levels of tumor heterogeneity. Such measurements can help predict the likelihood of a PDAC tumor adaptive potential that could lead to fast evolutionary responses to therapy, progression, and poor prognosis. Citation Format: Merih D. Toruner, Luis Cisneros, Zafar Siddiqui, Chady Meroueh, Ritambhara Singh, Carlo Maley, Martin E. Fernandez-Zapico, Ryan M. Carr. Dissecting the pancreatic cancer microenvironment using landscape ecology [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B026.

Abstract Background EuroQoL EQ-5D-5L is a commonly used measure of health-related quality of life in clinical trials given the use of its index score as a measure of health utilities. It is unclear whether EQ-5D-5L is sensitive to changes in neurocognitive function and progression that occur following brain radiation. This study sought to evaluate the sensitivity of EQ-5D-5L in reflecting these changes. Methods A secondary analysis of NRG Oncology CC001 was performed. Mean EQ-5D-5L index and visual analog scale (VAS) score changes from baseline between groups of patients stratified by neurocognitive function and intracranial progression status were assessed. MD Anderson Symptom Inventory for brain tumor (MDASI-BT) symptom and interference items were also analyzed between groups. Results EQ-5D-5L mean index and VAS score changes between patients who had cognitive failure and those who had preserved cognition showed no statistically significant differences at any timepoint. In contrast, VAS changes at 4 months (1.61 vs -5.13, P = .05) and 6 months (8.17 vs −0.14, P = .04) were significantly improved in the patients who survived without intracranial progression. MDASI-BT cognitive factor scores were improved in the cohort of patients with preserved neurocognitive function at 2 months (1.68 vs 2.08, P = .05) and 4 months (1.35 vs 1.83, P = .04). MDASI-BT symptom interference was significantly associated with intracranial progression at 4 months, but not with neurocognitive status. Conclusion EQ-5D-5L index and VAS scores were not sensitive to neurocognitive changes that patients experienced, but VAS scores were sensitive to progression. This study challenges the routine use of EQ-5D as a quality of life metric in brain metastases clinical trials that are focused on preventing neurocognitive dysfunction. Trial Registration NCT# 02360215.