Citations

Despite European colorectal liver metastases (CRLM) transplant trials having been performed entirely using deceased donor liver transplant (DDLT), there has been speculation about whether similar results can be achieved in the United States, given the lack of MELD score prioritization. A formal transplant protocol for unresectable CRLM was implemented in our center at the start of 2022 with the plan to utilize DDLT. Between 2022 and 2025, 86 patients with CRLM were referred to our program, and 19 patients underwent a formal transplant evaluation. Median time from listing until transplant was 31 days (range 3–115 d). Median allocation MELD was 8 (range 6–15). The donor livers were from DCDs, older donors, or National Share livers, which had been declined by all other centers. All but 2 of the cases underwent advanced perfusion. There were no cases of primary nonfunction, postreperfusion syndrome, acute kidney injury, hepatic artery thrombosis, or ischemic cholangiopathy. The length of stay for the median posttransplant was 5 days. Graft and patient survival were 100% at the time of maximal follow-up. Recurrence developed in 3 recipients (25.0%), 1 of whom was treated and has no evidence of disease. These findings support the viability of DDLT for CRLM using advanced perfusion, contingent on strict protocol adherence. Center-specific waitlist dynamics must inform the choice between DDLT and living donor liver transplant (LDLT).

Abstract Background & Aims Pregnancy can be a complex and risk-filled event for women with inflammatory bowel disease (IBD). High-quality studies in this population are lacking, with limited data on medications approved to treat IBD during pregnancy. For patients, limited knowledge surrounding pregnancy impacts pregnancy rates, medication adherence, and outcomes. Limited provider knowledge leads to highly varied practices in care affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike. The Global Consensus Consortium is a group of 39 IBD and content experts and 7 patient advocates from 6 continents who convened to review and assess current data and come to an agreement on best practices based on these data. Methods The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) process was used when sufficient published data were available and the RAND (Research and Development) process in those instances where expert opinion was needed to guide consistent practice. Recommendations were informed by the guiding principle that maternal health best supports infant health. Results The topics were divided into ten categories with 34 GRADE recommendations and 35 consensus statements. Conclusions Overall, the goal of the group was to provide data-driven and practical guidance to improve the care of women with IBD around the globe based on the best available research.

ABSTRACT Periprosthetic joint infection (PJI) is the most common and difficult to treat form of arthroplasty failure. While treatment with debridement, antibiotics, and implant retention (DAIR) is preferable to one- or two-stage implant exchange based on morbidity and cost, outcomes are not successful in all cases selected for this management strategy. DAIR is currently recommended when infection is perceived to be in an “acute” phase, based on symptom duration; despite this selection strategy, DAIR failure rates are high. A more objective means of predicting DAIR success could improve patient outcomes by limiting DAIR failures. To explore this possibility, advanced proteomic analysis of sonicate fluid samples from 95 subjects with PJI was performed using proximity extension assay (PEA), with 77 samples additionally undergoing complementary proteomics analysis with liquid chromatography with tandem mass spectrometry (LC-MS/MS). Sparse partial least squares differentiation analysis (sPLS-DA) separated samples from patients who underwent DAIR with known outcomes ( n = 19) into successful or unsuccessful groups, predicting DAIR surgical outcome (area under the curve [AUC]: 1; mean “leave one out” AUC: 0.6). Proteins predictive of DAIR surgical outcome were significantly enriched for the “protein repair” Gene Ontology (GO) pathway ( P -adj = 0.02). Additionally, proteomic signatures associated with symptom duration in PJI categorized samples into short and long symptom duration PJI. In summary, an investigation of 7,261 unique human proteins separated PJI-associated samples based on symptom duration and identified a proteomic profile predictive of DAIR success. IMPORTANCE Chronic infections are generally understood to last months to years, with acute infections lasting days to weeks. The transition from acute to chronic infection is, however, poorly understood. Periprosthetic joint infection (PJI) has been considered more challenging to treat when “chronic” than when “acute.” A surgery preferred for its recovery time and cost—debridement, antibiotics, and implant retention (DAIR)—is recommended for PJI management when symptom duration is short; yet, even in this select patient group, DAIR is associated with a high treatment failure rate. A means to better identify those predicted to have a successful outcome if they undergo DAIR is needed. Here, over 7,000 proteins from human clinical PJI samples were measured and shown to be able to separate samples based on symptom duration. Importantly, a proteomic profile predictive of DAIR success was identified.

Abstract Background and Aims In the VICTOR trial (NCT05093933), vericiguat was neutral for the primary composite endpoint of cardiovascular death or hospitalization for heart failure (HF). VICTOR was powered to independently assess cardiovascular death. This study reports detailed analysis on the effects of vericiguat on mortality. Methods VICTOR, a double-blind, placebo-controlled, randomized trial, enrolled 6105 ambulatory patients with HF and reduced ejection fraction (HFrEF) without recent worsening and randomized them to vericiguat or placebo. The main outcome for this analysis was the pre-specified secondary endpoint of cardiovascular death. All-cause death, sudden cardiac death, and death related to HF were also assessed. Results Over a median of 19.7 months (inter-quartile range 14.6–25.4), cardiovascular deaths occurred in 292 patients (5.7 deaths per 100 patient-years) and 346 patients (6.8 deaths per 100 patient-years) in the vericiguat and placebo groups, respectively (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.71–0.97; P = .020). Risk of death from any cause was lower with vericiguat vs placebo (377 [7.3 deaths per 100 patient-years] vs 440 [8.6 deaths per 100 patient-years]; HR 0.84, 95% CI 0.74–0.97; P = .015). Sudden cardiac death and HF-related deaths were lower with vericiguat vs placebo (1.6 vs 2.2 events per 100 patient-years; HR 0.75, 95% CI 0.56–0.99; P = .042 and 1.7 vs 2.4 events per 100 patient-years; HR 0.71, 95% CI 0.54–0.94; P = .016, respectively). Lower mortality rates were consistent across subgroups including baseline therapy. Consistent cardiovascular and all-cause mortality benefit was seen across baseline N-terminal pro-B-type natriuretic peptide levels. Conclusions In ambulatory well-treated participants with HFrEF, vericiguat was associated with clinically meaningful reductions in the key secondary outcome of cardiovascular death, as well as all-cause mortality.

Abstract Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8⁺ T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor β (ERβ)—a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8⁺ T cell function, and depletion of CD8⁺ T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

Blood iron levels are related to many health conditions, affecting hundreds of millions of individuals worldwide. To aid in the prevention and treatment of iron-related disorders, previous research has developed a low-cost, accurate, point-of-care method for measuring iron from a single finger-prick blood sample. This study builds upon that work by introducing an improved imaging method that accurately reads sensor images irrespective of variations in environmental illumination and camera quality. Smartphone cameras were used as analytical tools, demonstrating an average coefficient of variation of 5.13% across different phone models, and absorbance results were found to be improved by 8.80% compared to the method in a previous study. The proposed method successfully enhances iron detection accuracy under diverse lighting conditions, paving the way for smartphone-based sensing of other colorimetric reactions involving various analytes.

Abstract Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle. The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins. Clonally expanded and highly differentiated CD8 + T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. However, the target antigens mediating T cell activation have remained elusive. Here, we investigate whether the de novo proteins induced by aberrant cryptic splicing due to TDP-43 nuclear loss can act as neo-antigens. We detect the HDGFL2 cryptic peptide and multiple other TDP-43 cryptic exons in IBM skeletal muscle, where their presence correlates with enrichment of T cells and class I antigen presentation pathways. Furthermore, we identify epitopes deriving from HDGFL2 and IGLON5 cryptic peptides which are recognized by clonally expanded and functionally differentiated populations of CD8 + T cells in ALS and IBM Patients. Finally, we demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic peptide derived epitopes (cryptic epitopes) and are able to kill TDP-43 deficient astrocytes. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.

e18064 Background: Cell-free circulating tumor DNA (ctDNA)-based test has emerged as a promising tool in informing treatment modification in solid tumors. The clinical applications of ctDNA in head and neck squamous cell carcinoma (HNSCC) has been explored and here we report the clinical utilities of ctDNA in disease monitoring in HNSCC. Methods: HNSCC patients treated at our institution with available ctDNA test (Signatera) results between 2022 and 2024 were identified. Clinical information including disease site, stage and imaging results were collected and analyzed. Results: A total of 59 patients were identified. 21 (36%) patients had P16 + oropharyngeal cancer, 16 (27%) had oral cavity cancer, 9 (15%) patients had laryngeal cancer, 7 (12%) had P16-oropharyngeal cancer, 6 (10%) had perinasal sinus, hypopharyngeal or nasopharyngeal cancers. At the time of ctDNA test, 22 (36%) patients completed curative-intent treatment and had no radiographic evidence of disease (NED), 16 (26%) patients were treatment-naïve and had local/regional (LR) disease only, and 22 (36%) patients completed definitive treatment and developed radiographic evidence of LR recurrence or distant (D) metastatic disease. ctDNA was detectable in less than half (44%) of the treatment-naïve patients and the detection rate was even lower (14%) in the subgroup of p16+ oropharyngeal cancer. However, among patients with LR recurrent and distant metastatic disease, majority (77%) had positive ctDNA. ctDNA was undetectable in most of the patients (80%) who completed definitive treatment and were NED radiographically. Among the 3 patients who had detectable ctDNA, 2 were subsequently found to have recurrent disease on images and 1 is still on surveillance (table). Conclusions: Positive ctDNA was detected in most of the HNSCC with LR recurrent or distant metastatic disease, supporting its potential role in treatment response monitoring in this group of patients. Detectable ctDNA preceded radiographic evidence of recurrent disease in a small number of patients, suggesting the possibility of minimal residual disease detection using ctDNA in a subgroup of patients. Treatment history S/P definitive treatment Treatment naive S/P definitive treatment Radiographic evidence of disease (patient number) No (21) Yes (16; LR only) Yes (21; LR only: 10, distant: 11) ctDNA negative 18 9 4 ctDNA positive 3 (recurrence confirmed on subsequent imaging in 2 patients) 7 17

e21573 Background: In melanoma, biomarkers such as lactate dehydrogenase (LDH), circulating tumor DNA (ctDNA), and the neutrophil-lymphocyte ratio (NLR) have been linked to disease progression. This study aims to compare survival outcomes in melanoma patients based on high versus low levels of these biomarkers, assessing their impact on survival within their respective groups. By evaluating these biomarkers, we hope to identify potential prognostic indicators that could guide treatment decisions and improve personalized care in melanoma management. Methods: We conducted a retrospective survival analysis of 43 melanoma patients, excluding 16 due to incomplete data at Dignity Health Cancer Institute in Phoenix, Arizona. Kaplan-Meier survival analysis was used to compare survival between groups with high vs low levels of biomarkers. Patients were stratified by median values for LDH, NLR, and the presence of detectable ctDNA. Patients included in the analysis were treated systemically with pembrolizumab, encorafenib/binimetinib, nivolumab, or ipilimumab/nivolumab. Survival curves were generated, and statistical significance was assessed using log-rank tests. Data was sourced from our electronic medical record and Signatera™ assay to obtain the primary endpoints. Specimens were standardized in accordance with Natera’s™ specifications. All analyses were executed in GraphPad Prism software. Results: When stratifying by ctDNA, 18 patients had undetectable ctDNA, while 9 had detectable ctDNA with an average level of 1330 (SD = 2067). The median survival for the high ctDNA group was 220 days, whereas the low ctDNA group had significantly longer survival, with only two deaths observed (p = 0.006) within the time period. For LDH, using a cutoff of 204 (IQR = 90.5), patients with high LDH had a median survival of 220 days, while those with low LDH had a significantly longer survival (p = 0.004). When comparing NLR with a cutoff at 2.94 (IQR = 3.7), no significant difference in survival was found between high and low NLR groups (p = 0.72). Conclusions: Our findings show that patients with higher levels of ctDNA and LDH have significantly shorter survival compared to those with low levels of these biomarkers. While NLR did not show a significant survival difference, the study suggests that higher ctDNA and LDH could be important markers for identifying patients at greater risk of poor outcomes. These results underscore the potential value of monitoring these biomarkers to assess disease progression and survival in melanoma patients. Further studies with larger cohorts are needed to validate these findings and refine melanoma prognostic models.