Citations

The 2025 Annual Congress of the International Liver Transplantation Society (ILTS), themed “ Advancing Liver Transplantation: Embracing Innovation for the Future ,” was held from May 28 to 31 in Singapore. The meeting offered a comprehensive scientific program, featuring 92 sessions and 7 pre-congress workshops spanning living donor liver transplantation, advanced surgery, anesthesia and critical care, transplant oncology and immunology, basic science, pediatrics, and more. The program emphasized collaboration and innovation to advance patient outcomes in liver transplantation. In this report, the ILTS Vanguard Committee summarizes the key proceedings of the congress.

The success of living donor liver transplantation (LDLT) has bridged the growing gap between organ demand and availability in patients with liver failure or liver cancer. Safety of the living liver donor (LLD) is paramount, and astute intraoperative management plays a critical role in ensuring optimal outcomes for them. Given that intraoperative surgical and anesthesia practices vary widely across centers, the International Liver Transplantation Society (ILTS) and the International Living Donor Liver Transplantation Group (iLDLT Group) convened a global consensus conference in Toronto in March 2025 to develop guidelines for intraoperative management of the LLD. This manuscript details the recommendations on intraoperative considerations for the safety of LLD developed by Working Group II of the Consensus Scientific Committee, using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for assessment of recommendations, and the Danish model of consensus. Working Group II focused on intraoperative monitoring, fluid and ventilation strategies, surgical techniques for vascular and biliary division, surgeon and center-specific experience, and intraoperative crises planning. These guidelines aim to support both established and emerging LDLT teams to ensure high-quality and safe intraoperative care for the LLD.

Abstract BTK degraders promote proteasomal degradation of BTK and can overcome resistance to covalent and noncovalent BTK inhibitors in patients with relapsed CLL. Currently the molecular basis for BTK degrader resistance is unknown. We therefore set out to understand BTK degrader resistance based on observations from the phase 1 trial of zelebrudomide (NX-2127) (NCT04830137), the first BTK degrader to enter clinical studies. Targeted 500-gene sequencing was performed on blood and/or tissue from four CLL patients treated with zelebrudomide. In one patient previously treated with chemoimmunotherapy, ibrutinib, venetoclax, and pirtobrutinib, BTK A428D was detected in the baseline blood sample with variant allele frequency (VAF) of <2%, along with BTK V416L (13%) and mutations in TP53 (60%) and SF3B1 (37%). Following daily treatment with 100mg zelebrudomide and subsequent dose escalation to 200mg, at 6 months the VAF of all four mutations increased, with BTK A428D VAF increasing to 6% in the blood and 29% in a lymph node. BTK A428D was detected at baseline but not at progression in a second patient. To evaluate the impact of BTK A428D on drug response, we transduced BTK-dependent TMD8 cells with BTK WT, C481S, L528W, and A428D, and found that BTK A428D uniquely conferred resistance to all FDA-approved BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib) as well as three BTK degraders under clinical evaluation (zelebrudomide, bexobrutideg, BGB-16673). To model the subclonal nature of BTK A428D we conducted a competition assay in which TMD8 cells expressing GFP + BTK A428D (5%) were mixed with TMD8 cells expressing mCherry + BTK WT (95%); over 9 days the GFP + BTK A428D expanded from 5% to 88-97% with all four BTKi and all three BTK degraders. In vitro kinase assays revealed that the BTK A428D mutant protein lacks kinase activity yet facilitates calcium flux and ERK/AKT signaling upon B-cell receptor activation, suggesting a scaffolding effect similar to other kinase deficient BTK mutations. To determine whether BTK A428D affects BTK degradation, we developed a reporter that fuses the BTK kinase domain to GFP. BTK A428D showed minimal degradation following 20 hours of treatment with a titration of all three BTK degraders. Similarly, we knocked BTK A428D into the endogenous BTK locus of HBL1 cells and confirmed a lack of degradation at doses up to 1 µM of all 3 degraders. Consistent with these findings, surface plasmon resonance revealed that the FDA-approved BTK inhibitors as well as zelebrudomide, bexobrutideg, BGB-16673, and AbbVie-1 (Compound 1 from WO 2023183811) are unable to bind to BTK A428D. Additionally, an in-cell NanoBRET assay demonstrated that zelebrudomide was unable to mediate the interaction between cereblon and BTK A428D. Strikingly, NanoBRET also demonstrated that a panel of promiscuous kinase-binding compounds was unable to bind to BTK A428D. The lack of binding of both selective and promiscuous kinase binders to BTK A428D led us to speculate that the mutation disrupted the ATP binding pocket to an unusual degree. We therefore solved the crystal structure of apo BTK A428D and found that, in addition to its predicted steric clash with ligand binding in the hinge region, the mutation led the protein to crystallize with its activation loop occupying the catalytic cleft, rendering it inaccessible. This is the first apo BTK structure observed in this autoinhibited conformation, and explains the observed binding profile. We hypothesized that the addition of a second targeted agent such as venetoclax might mitigate expansion of the A428D subclone. To test this, we introduced the BTK A428D mutation into the endogenous BTK gene in 3% of TMD8 cells and then exposed them to 0.1µM of zelebrudomide, bexobrutideg, or BGB-16673 +/- venetoclax 0.1µM. Combining the BTK degraders with venetoclax slowed the emergence of the BTK A428D resistant population and, in the case of zelebrudomide, eradicated both the wild-type and A428D clones. In summary, we identified and validated BTK A428D as a clinically relevant acquired pan-resistance mutation that confers resistance by blocking access to the ATP binding pocket. This mechanism differs from other kinase dead BTK mutations in which the kinase's enzymatic pocket remained accessible.These data also provide rationale for combining BTK degraders with BCL2 inhibitors, particularly in patients with BTK A428D mutations, or high-risk mutations such as in TP53.

Abstract Introduction Survival following allogeneic hematopoietic cell transplantation (allo-HCT) has improved over the last several decades. Implementation of reduced-intensity conditioning and improvement in graft selection, graft vs. host disease (GVHD) prophylaxis and treatment, and infection disease management, among others, have contributed to reducing non-relapse mortality (NRM). The use of post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis, in particular, has been associated with reduced incidence of acute and chronic GVHD in both HLA-matched related and matched unrelated donor allografts. In this study, we aim to determine prognostic factors for NRM (including early NRM defined as within 100 days post-transplantation), disease-related mortality (DRM), and overall survival (OS) in a large cohort of patients following allo-HCT. Methods Patients who received consecutive allo-HCT at our institution from 2009-2023 were included. Clinical data were collected from retrospective reviews of the electronic medical records. Patient- and transplant-related variables were compared between patients who died and those who were alive at 100 days post allo-HCT. Univariate and multivariate Cox proportional hazard models were used to identify prognostic associations between risk factors and OS. Kaplan-Meier method was used to evaluate OS. Log-rank test was used to compare OS between groups. Statistical significance was set to < 0.05. Results A total of 536 patients (male=285, 53%) were included. Median age at time of allo-HCT was 59 (range, 19-75) years. Most patients were White/Caucasian (n=232, 86%). The most common diagnoses included acute myeloid leukemia (AML) (n=110, 41%), myelodysplastic syndrome (n=52, 19.2%), myelofibrosis (n=23, 9%), B-cell acute lymphoblastic leukemia (B-ALL) (n=22, 8.1%), non-Hodgkin lymphoma (n=21, 8%), and chronic myeloid leukemia (n=10, 4%). The median follow-up for survivors was 4.2 (range, 1.1-14.4) years. A total of 80 (14.9%) patients died within 100 days with most deaths attributed to NRM (n=61, 76%). Specific causes of death included infection/sepsis in 22 (27.5%) patients, GVHD in 10 (12.5%), respiratory failure in 9 (11.2%), multiorgan failure in 5 (6.3%), graft failure in 5 (6.3%), and other causes in 10 (12.5%). Progressive disease was the cause of death in 19 (23.8%) patients. Male gender (HR=1.92; p= 0.006), remission status other than CR1 or CR2 for acute leukemia patients (HR=8.44; p<0.0001), non- PTCy strategies (HR=2.4; p= 0.0006), and earlier year of transplantation (HR=1.12; p=< 0.001) were associated with increased risk of mortality at 100 days on univariate analysis. Only use of TBI (HR=2.56, p=0.048) and earlier year of transplantation (HR=1.2; p=0.001) were associated with increased risk of DRM at 100 days post-allografting on univariate analysis. Pertaining to risk of NRM at 100 days, male gender (HR=1.89; p=0.02), diagnosis other than acute leukemia (HR=2.27; p=0.004), non-PTCy strategies (HR=2.44; p=0.003), and earlier year of transplantation (HR=1.1; p=0.004) were adversely associated with NRM. On multivariate analysis, only earlier year of transplantation was found to be associated with increased risk of DRM at 100 days (HR 1.15; p=0.049). Male gender (HR=1.78; p=0.035), diagnosis other than acute leukemia (HR=2.38; p=0.003), and non-PTCy strategies (HR=2.2; p=0.032), were associated with increased risk of NRM at 100 days. Conclusion Non-relapse mortality (NRM) accounted for most deaths within the first 100 days of allo-HCT, primarily due to infection/sepsis and GVHD. Factors associated with increased NRM included male gender and diagnoses other than acute leukemia. Significantly, post-transplantation cyclophosphamide (PTCy) was the only treatment strategy modification that decreased 100-day NRM and improved survival, independent of the transplantation year.

Malignant glioma is considered invariably recalcitrant, thus necessitating development of new therapeutic approaches. Spontaneously arising canine glioma exhibits important molecular and pathological similarities to malignant pediatric glioma, making it an invaluable model for testing novel therapies. We evaluated safety and activity of RNA lipid particle aggregates (LPAs) designed to provoke cancer immunogenicity in 10 dogs with histologically confirmed glioma. Vaccine manufacturing was feasible in all subjects and generally well tolerated. Median survival time was 123 and 155 days in dogs receiving three (Group A) or four (Group B) vaccines, respectively; this was increased from historical reporting of subjects receiving palliative care. Responding animals had a robust cytokine response following infusions. In animals receiving non-specific RNA-LPAs, there was localization of messenger RNA (mRNA) payloads to the brain tumor microenvironment and a rapid shift in immunologic gene signatures consistent with a viral response. These data demonstrate the ability to induce rapid viremic response in the tumor microenvironment following a single peripherally administered mRNA vaccine. Since RNA-LPAs are amenable to repeat boosts, these formulations may overcome challenges of tumor immunosuppression and therapeutic access and are currently under evaluation in first-in-human trials ( NCT04573140 , NCT06389591 ).

Abstract INTRODUCTION Glioblastoma (GBM) contains metabolically distinct cell lineages: treatment-sensitive cells (TSCs) dependent on glycolysis and treatment-resistant persister cells (TRPCs) reliant on lipid metabolism. Our integrative systems biology approach, combining spatial multi-omics and targeted analyses, uncovers lipid acquisition in TRPCs as a pivotal driver of GBM progression which is supported by a retrospective study of statin-treated patients, providing clinical evidence for the therapeutic potential of targeting lipid metabolism in GBM patients stratified based on high TRPC signatures. METHODS We applied spatial transcriptomics and proteomics combined with 3D reconstruction of the tumor microenvironment to map TRPC- and TSC-enriched regions. Immunohistochemically stained tissues were analyzed using CellProfiler and our custom SNAQ algorithm for single-cell neighborhood analysis. Lipid transfer from Tumor-Associated Myeloid Cells (TAMCs) to TRPCs was tracked via flow cytometry, holotomography, and time-lapse imaging. Genetic and pharmacological targeting of CCR2, CSF1R, and FABP3 was performed in vitro and in vivo. Finally, a retrospective analysis of 4,085 GBM patients assessed the impact of statin treatment in relation to TRPC signatures. RESULTS TRPCs exploit recruited TAMCs to acquire lipids, supporting their survival and immune evasion. These interactions are mediated by CCL2/7–CCR2 and CSF1–CSF1R signaling. Disruption of TRPC-TAM lipid homeostasis significantly remodeled the immune microenvironment, reduced tumor growth, and extended survival in preclinical models. Patients with high TRPC signatures typically had poor outcomes; however, retrospective analysis revealed that statin treatment was associated with improved survival in this subgroup. These findings position lipid trafficking as a metabolic vulnerability in GBM and highlight the therapeutic relevance of targeting TRPC–TAMC interactions. CONCLUSION Our study reveals lipid trafficking to TRPCs as a key mechanism driving GBM progression. Targeting TAMC-mediated lipid transfer disrupts immune suppression and tumor growth. Transcriptomic profiling may guide patient stratification, identifying those likely to benefit from lipid metabolism-targeted therapies such as statins.

Abstract INTRODUCTION Glioblastoma (GBM) is a brain cancer known for its complex tumor microenvironment and ability to reprogram glucose metabolism and evade host immune responses. CAR-T cell therapy has attracted considerable attention due to its potential for high specificity and efficacy across various cancer types. However, its success in GBM has been limited due to the unique and hostile metabolic landscape of the tumor microenvironment. GBM tumor cells exhibit enhanced aerobic glycolysis, resulting in elevated glucose consumption. This restricts glucose availability for T cells, impairing activation and anti-tumor response. In our study, we enhanced the tumoricidal activity of CD70 CAR T-cells by overexpressing the glucose transporters GLUT1 and GLUT3, thereby improving their metabolic fitness and enabling them to overcome tumor-induced glucose deprivation. METHODS The CD70 CAR T-cell glucose metabolic pathway was modulated via glucose transporter overexpression. The efficacy and safety of metabolically modified CD70 CAR T-cells was investigated in in vitro and in vivo platforms. RESULTS GLUTs overexpression does not negatively affect T-cell differentiation and function but improves glucose consumption and intra-tumoral T-cell trafficking. We then used CD70 CAR-T platform and overexpress GLUT1 and GLUT3 to engineer T-cells. GLUT overexpression provided metabolic advantage to CD70CAR T-cells, which showed enhanced activation and cell avidity when co-cultured with GBM cells in both glucose enriched and restricted conditions. The metabolic modifications regulate CAR T-cell efficacy by enhancing intra-tumoral trafficking and persistence, followed by improved anti-tumor response and survival in mice. The lack of significant alterations in body weight and organ morphology in mice receiving GLUT-overexpressing CD70 CAR T-cells suggests that the adoptive transfer of these metabolically enhanced T cells does not elicit toxicity, thereby demonstrating a favorable safety profile during treatment. CONCLUSION Our study demonstrates development of immunotherapeutic strategies by incorporating core principles of tumor and immune cell metabolism, thus providing evidence that targeting immune-metabolic pathways is a potential approach to treat brain tumor.

Abstract Immune checkpoint inhibitors (ICIs) have limited benefit in recurrent high-grade astrocytoma (rHGA), largely because the blood–brain barrier and a profoundly immunosuppressive tumor microenvironment prevent T cells from infiltrating. Laser interstitial thermal therapy (LITT) is a minimally invasive, cytoreductive procedure that can “heat up” these otherwise “cold” tumors and sensitize them to ICIs. In this tri-institutional Phase 1/randomized Phase 2 trial (NCT02311582), bevacizumab- and immunotherapy-naïve rHGA patients were initially randomized 1:1 to either LITT followed by pembrolizumab (LITT+PEM) or non-LITT surgery (biopsy or resection) followed by pembrolizumab (NLS+PEM). Phase 2 participants enrolled at a second recurrence—with several already at a third recurrence—underscoring the advanced disease stage of this cohort. After 21 patients, randomization was halted when contemporaneous evidence showed limited benefit from adjuvant ICIs alone, and the remaining 24 patients received only LITT+PEM. In the 21-patient intent-to-treat cohort, LITT+PEM extended median OS to 21.3 months with 54% alive at 18 months (OS18) versus 6.7 months with 12.5% OS18 with NLS+PEM (HR 0.29; 95% CI, 0.01–0.88; p=0.021). Median PFS was 7.8 versus 2.2 months (HR 0.3; 95% CI, 0.10–0.87; p=0.020). Among 39 per-protocol patients, LITT+PEM yielded a median OS of 11.8 months with 42% OS18 versus 5.2 months with 0% OS18 for NLS+PEM (HR 0.17; 95% CI, 0.06–0.49; p=0.0002), and a median PFS of 4.5 versus 1.6 months (HR 0.21; 95% CI, 0.08–0.56; p=0.0006). The combination was well tolerated. Immune profiling revealed that LITT triggers early activation of non-classical monocytes—a change associated with improved survival—while subsequent pembrolizumab unleashes robust CD8⁺ T cell proliferation and clonal expansion. Long-term LITT+PEM survivors developed coordinated memory T-cell responses, whereas shorter-surviving patients exhibited stagnant memory pools and exhausted phenotypes. Together, these results demonstrate that LITT plus pembrolizumab is safe, overcomes rHGA’s immunosuppressive barrier, and mobilizes robust anti-tumor immunity.

Abstract INTRODUCTION The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site‐level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. Highlights The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi‐etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).