Citations

Objective Cervical artery dissection (CeAD) may be limited to the extracranial extradural space or extend to the intradural space. Intradural extension can potentially increase the risk of stroke and subarachnoid hemorrhage. However, the factors associated with intradural extension and its impact on clinical outcome remain unclear. Methods This was a secondary analysis of the STOP‐CAD observational, multi‐center study. Patients with CeAD and intradural extension (CeADid) were compared with those with pure CeAD extradural dissections (CeADed) using multiple regression analyses. Results Of 4,023 patients with CeAD, 534 (13.3%) had CeADid. In comparison to patients with CeADed, those with CeADid more often had clinical overt stroke or transient ischemic attack (TIA) at presentation, acute infarcts on imaging, a vertebral artery affected, and severe stenosis of the involved vessel ( p < 0.001 for all). In contrast, carotid involvement and complete occlusions were more frequent in patients with CeADed ( p < 0.001 for both). CeADid was associated with a shift in the distribution of scores on the modified Rankin Scale (mRS) toward worse functional outcome (odds ratio [OR] = 0.76, 95% confidence interval [CI] = 0.62–0.92) but the odds for favorable outcomes (mRS = 0–2) did not differ between the groups after appropriate adjustments on multivariate analysis. CeADid was independently associated with higher mortality at 180 days on multivariate analysis (adjusted OR = 2.84, 95% CI = 1.50–5.38). Interpretation CeADid is associated with more severe clinical presentation, a shift toward less favorable outcomes, and higher mortality rates. These findings suggest that CeADid may represent a high‐risk type of CeAD. ANN NEUROL 2026;99:1189–1197

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.

Living donor liver transplantation (LDLT) is a life-saving procedure for patients with end-stage liver disease. As its use expands worldwide, ensuring the safety and well-being of live liver donors (LLD) is of paramount importance. Published evidence on early postoperative complications after living donor hepatectomy—those occurring within 90 days of surgery—is limited, and standardized postoperative care protocols are lacking. The International Liver Transplantation Society (ILTS) and the International Living Donor Liver Transplantation Group (iLDLT Group) convened a consensus conference in Toronto in March 2025 to develop guidelines for the safe care of the LLDs. This manuscript details the recommendations on early postoperative considerations for the safety of LLDs developed by Working Group III (WGIII) 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. WGIII addressed four key areas: (1) standardized postoperative care, (2) early biliary complications, (3) early postoperative liver dysfunction, and (4) early postdischarge follow-up. This report emphasizes the need for vigilant postoperative monitoring in specialized units, with access to experienced providers and defined clinical pathways. Structured clinical and psychosocial follow-up protocols, perioperative prophylaxis for surgical site infections and venous thromboembolism, and management of early biliary and vascular complications are discussed. These may help standardize care, reduce complications and improve short-term outcomes in LLDs.

Abstract Background: Despite recent therapeutic advances in AS cHL, PET-adaptive chemotherapy-based regimens remain a first-line treatment option, especially for patients (pts) without access to novel agents. Most PET-adaptive regiments start with either 2 cycles of escBEACOPP (escBEACOPP2) or ABVD (ABVD2) prior to interim PET assessment (iPET), followed by treatment de-escalation or intensification by iPET result. There have been no direct comparisons of escBEACOPP2 vs ABVD2 PET-adaptive regimens. Additionally, the AS-Hodgkin Lymphoma International Prognostication Index (A-HIPI) score (Rodday JCO 2023) has not been fully explored in escBEACOPP2 regimens. Therefore, we utilized multiple analytic approaches to compare outcomes of PET-adaptive escBEACOPP2 and ABVD2 regimens, while adjusting for and assessing the effect of the baseline A-HIPI score. Methods: Through the global HoLISTIC Consortium (www.hodgkinconsortium.com), we obtained individual patient data from 4 AS clinical trials of newly diagnosed cHL pts treated with PET-adaptive escBEACOPP2 (AHL2011) or ABVD2 (SWOG0816, RATHL, HD0607) regimens. Pts were restricted to age 18 to 65 years (y), stage IIB-IV, and PET-adapted treatment arms. Positive iPET was based on Deauville score &gt;3. Treatment effects of escBEACOPP2 vs ABVD2 (reference) on 5y progression-free survival (PFS) and overall survival (OS) were first evaluated using Cox models. Importantly, baseline disease risk was adjusted for using the 5y PFS or OS A-HIPI score (including stage, sex, age, bulk, lymphocyte count, albumin, white blood cell count), where higher scores indicate higher predicted risk (scale 1-100). The A-HIPI was modeled per 1 standard deviation (SD) increase. Our multistate model (MSM) comprised 4 health states: diagnosis, sustained remission at 1yr, treatment failure, and death from any cause. Pts all started in the diagnosis state and transitioned to other states without return to prior states. We assessed the impact of treatment on transitions (except binary sustained remission at 1y) that involved ≥5 pts per treatment group, adjusting for A-HIPI for all transitions. All effects are reported as adjusted hazard ratios (aHRs) with 95% confidence intervals (CI). Results: 2,381 AS cHL pts were included (n=372 for escBEACOPP2, n=2009 for ABVD2). For escBEACOPP2 and ABVD2 groups (median follow-up 60 and 56 months), respectively, the mean baseline A-HIPI scores (i.e., predicted 5y PFS event rate) were 25.1 (SD=6.3) and 22.9 (SD=6.5), the rates of positive iPET were 11.3% and 17.0%, 5y PFS was 87.0% and 79.5%, and 5y OS was 96.3% and 94.6%. In Cox models, escBEACOPP2 was associated with significantly improved PFS compared to ABVD2 (aHR=0.54, 95% CI=0.39-0.73); the aHR for OS was 0.67 (95% CI=0.37-1.19). Notably, higher risk A-HIPI score was associated with significantly worse PFS (aHR=1.42, 95% CI=1.31-1.54) and OS (aHR=1.60, 95% CI=1.47-1.76), independent of treatment. In the MSM, the effect of escBEACOPP2 compared to ABVD2 regimens was modeled in 3 transitions with adjustment for A-HIPI score: those treated with escBEACOPP2 had lower likelihood of treatment failure with (aHR=0.38, 95% CI=0.22-0.66) or without (aHR=0.61, 95% CI=0.40-0.92) sustained remission at 1y; the aHR for treatment failure to death was 0.55 (95% CI=0.25-1.22). Higher risk baseline A-HIPI score was associated with higher likelihood of treatment failure and death without sustained remission at 1y (aHR=1.43, 95% CI=1.28-1.61 and aHR=2.50, 95% CI=1.80-3.49, respectively). Furthermore, higher risk baseline A-HIPI score was associated with higher likelihood of treatment failure after achieving sustained remission at 1y (aHR=1.29, 95% CI=1.12-1.48) as well as death after treatment failure (aHR=1.54, 95% CI=1.27-1.86). Conclusions: Comparing newly diagnosed adult AS cHL PET-adaptive regimens with adjustment for baseline A-HIPI score, we found pts treated with escBEACOPP2 on AHL2011 had improved PFS versus pooled pt data from 3 ABVD2 trials. Using MSM, we further demonstrated that escBEACOPP2 was associated with a lower likelihood of treatment failure with or without achieving sustained remission at 1yr. In addition, baseline A-HIPI score was associated with PFS and OS, which was independent of treatment. Finally, higher baseline A-HIPI scores maintained prognostic impact throughout the disease course, including increased risk of treatment failure for pts in remission at 1yr and death after treatment failure.

Abstract Background: Although progression-free survival (PFS) in early-stage (ES) classic Hodgkin Lymphoma (cHL) is high, there remains a subset of patients (pts) at higher risk of worse outcomes, particularly in those with unfavorable risk disease. Leveraging pt-level data from within the HoLISTIC (Hodgkin Lymphoma International STudy for Individual Care) Consortium, the E-HIPI was developed in clinical trial pts and validated in real-world registry pts to predict 2-year (y) PFS (Rodday. NEJM Evidence 2025). Continuous, objective, and readily measurable pre-treatment variables were considered, with sex, maximum tumor diameter, albumin, and hemoglobin included as significant predictors. Using the E-HIPI, interactive calculators for pt risk, comparison, and stratification were created (https://rtools.mayo.edu/holistic_ehipi/). Although the E-HIPI was developed and validated in both unfavorable and favorable ES cHL pts, the clinical predictors are primarily markers of unfavorable disease. In the development and initial validation cohorts, 2y PFS was 93.7% and 90.3%, respectively, the C-statistic was 0.63 in both cohorts, calibration was strong with slight underprediction of events in the validation cohort, and the E-HIPI outperformed the historic binary classification of patients as favorable or unfavorable using EORTC criteria. However, since pts in the original E-HIPI development and validation were primarily treated with ABVD chemotherapy protocols, additional validation is needed, particularly among pts with unfavorable ES cHL who were treated initially with more intensive chemotherapeutic platforms (e.g., BEACOPP-based). Thus, we conducted an external validation of the E-HIPI in pts treated on recent unfavorable ES cHL GHSG trials. Methods: The validation cohort included 2367 adults (ages 18 to 60y) with newly-diagnosed unfavorable cHL from randomized phase 3 trials conducted by the GHSG (HD14 von Tresckow. JCO 2012; and HD17 Borchmann. Lancet 2021). We calculated the predicted probability of 2y PFS events based on the E-HIPI model equation (scale 1-100%). Model performance was assessed using discrimination and calibration. Discrimination, which is the model's ability to separate high and low risk pts, was assessed using Harrell's C-statistic. Calibration, which is the model's ability to accurately predict absolute risk, was assessed by comparing observed and predicted probabilities of 2y PFS events within quintiles of predicted probabilities and estimating calibration-in-the-large (predicted minus observed event rate) and the calibration slope. Results: For pts treated on unfavorable GHSG trials, mean age was 33y, 95% had stage II disease, mean baseline E-HIPI score (i.e., predicted 2y PFS event rate) was 6.0% (SD=2.3%), and the observed 2y PFS rate was 96.2% (95%CI: 95.4-97.0%). The C-statistic was 0.65 (95% CI: 0.59-0.70), calibration-in-the-large was 0.02, and the calibration slope was 1.08 (95% CI: 0.52, 1.64). Within the lowest risk E-HIPI quintile, the observed 2y PFS event rate was 1.6%, compared with 6.1% in the highest risk quintile. Conclusions: In external validation of the recently published E-HIPI in pts with cHL treated on unfavorable GHSG trials using more intensive BEACOPP-based protocols, discrimination was similar to the original development and validation cohorts. Collectively, the E-HIPI is a treatment-agnostic prediction tool across varied treatment regimens for unfavorable ES cHL pts. Better 2y PFS in the GHSG trials than in the E-HIPI development and initial validation cohorts may have contributed to mild misclassification, likely reflecting differences in treatment regimens. This may be resolved with recalibration or incorporating granular treatment variables into future models. Additional research is needed to understand E-HIPI performance in pts with favorable disease who have even lower event rates as well as to more fully predict individualized pt outcomes across varied chemotherapy platforms and radiation received for all ES cHL pts.

Abstract Description CD8 T cell programming creates a pool of naïve, effector, memory, or exhausted subsets, however the regulation of these trajectories is not expansively elucidated and has serious implications for cancer immunity and immune checkpoint inhibitor (ICI) therapy. We found a significant decrease of Dual Specificity Phosphatase 2 (DUSP2) in CX3CR1+ CD8s, a highly resilient subset, from ICI responders. Thus, we hypothesized that DUSP2 negatively regulates CD8 T cells in responses to ICI therapy. DUSP2 knockdown (KD) statistically improved CD8 cytotoxicity and expression of NKG7, a vital effector molecule. DUSP2 KD also increased SMARCA4 expression, a BRG/BRM-associated factor (BAF) complex ATPase, and increased open chromatin regions of BAF components. BAF complexes are chromatin remodelers implicated in CD8 differentiation pathways. In line with this, we found CD8s from DUSP2 conditional knockout (cKO) mice demonstrated a trend in defective memory generation. DUSP2 cKO CD8s also trended towards decreased PD-1 and increased CX3CR1 expression, demonstrating a more effector like phenotype. DUSP2 cKO mice did not show a significant difference in tumor protection in-vivo, presumably due to skewing of CD8 fates via BAF. Promisingly, DUSP2 KD increased ex-vivo cytotoxic functionality in about 50 percent of tested cancer patient PBMCs. Adjuvant BAF inhibition with DUSP2 KO versus KD in a specific CD8 subset may enhance responses further, providing a novel avenue for improving ICI efficacy. Funding Sources Supported by NCI 1F31CA287495-01 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Abstract Description A durable T cell immunity against cancer is dependent on a continually refilling of effector CD8+ T cells. Thymic output has been correlated with favorable prognosis in cancer patients of advanced ages, suggesting thymus is an important source for refilling T cells that are capable of controlling cancer progression in the periphery. However, it remains unclear how PD-1 signals regulate the cytotoxic potential of CD8+ T cells in thymus before they egress to the periphery to establish durable anti-tumor immunity. Here we report PD-1 signaling prelimits thymic single positive (SP) CD8+ T cells to acquire cytotoxic potential by downregulating Gzmb and Nkg7, which are required for CD8+ T cell-mediated cytotoxicity. Unexpectedly, we found the absence of Pdcd1 also led to upregulation of Tox and Tim3 in thymic SP CD8+ T cells, thereby pre-programming these cells for exhaustion within the tumor. Thus, the absence of PD-1 signals in CD8+ T cells only partially delayed tumor growth in peripheral tissues. To improve therapeutic effects of PD-1 inhibition, we observed that tumor growth in CD8-specific Pdcd1 conditional knockout mice was further suppressed by treatment with a PD-L1 antibody that blocks PD-L1 and CD80 interaction. Our results imply that PD-1 inhibition promotes the expansion of effector cytotoxic CD8+ T cells but also retains T cell exhaustion potential, which can be mitigated by PD-L1 blockade that allows more CD80 to provide costimulatory signals to T cells via CD28. Funding Sources NCI R01CA256927 NCI R01CA261932 NCI P30CA15083 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Description The efficacy of ICI and T cell-based therapies is dependent on sufficient killing of tumor cells by T cells. Thus, it’s critical for effector T cells to maintain their function and overcome metabolic stress within the tumor microenvironment. Our previous work in human resilient CD8+ T cells identified malic enzyme 1 (ME1) as a key enzyme that augments effector CD8+ T cells’ metabolic and functional fitness via increased ATP production and curbed ROS production. To further study ME1’s role in promoting CD8+ T cell resilience in vivo, we produced CD8-specific ME1 conditional knockout and transgenic (ME1 Tg) mouse models. In MC38, ME1 was upregulated in CD8+ T cells in TILs compared to those in spleen and ME1 loss in CD8+ T cells abrogated tumor responses to ICI. In ME1 Tg mice, MC38 had reduced tumor growth, while B16F10 tumors were sensitized to ICI. We observed lower ROS and increased lipid content in CD8+ T cells in the TILs of ME1 Tg mice, underscoring ME1’s role in activating alternative metabolic pathways to fuel mitochondrial respiration while keeping ROS in check. The association of ME1 with 6PGD, a key enzyme in the pentose phosphate pathway (PPP), implies its regulation of redox homeostasis in CD8+ T cells. Importantly, ME1 overexpression in TILs dramatically improved the efficacy of TIL therapy in treatment of established tumors. Overall, ME1 upholds T cell resilience in tumor tissues and provides a new therapeutic target to improve the efficacy of TIL therapy. Funding Sources This work was supported by the Mayo Clinic Center for Biomedical Discovery (to H.D.); the Mayo Clinic Cancer Center’s David F. and Margaret T. Grohne Cancer Immunology and Immunotherapy program (to H.D.); R01 AI095239 (to H.D.), R01 CA200551 (to H.D. and S.S.P.), and R01 CA256927 (to H.D.). Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Importance Total pancreatectomy (TP) is indicated for advanced pancreatic cancer or multifocal tumors. Furthermore, TP may be performed to avoid the risk of pancreatic fistula in selected patients to improve the perioperative risk profile. Objective To define reference values for TP based on a low-risk cohort treated at expert centers. Design, Setting, and Participants This multicenter study analyzed outcomes from patients undergoing primary TP for malignant or benign lesions from 25 international expert centers from January 2017 to November 2023. Low-risk patients undergoing TP (LR-TP) were without vascular resections or significant comorbidities. Exposures TP. Main Outcomes and Measures Twenty reference values were derived from the 75th or the 25th percentile of the median values of all centers. Outcomes of LR-TP were compared with a cohort of TP with vascular resection, TP due to high-risk pancreatic anastomosis, and the benchmark values for low-risk pancreatoduodenectomy. Results Of 994 patients, 333 (33.5%; median [IQR] age, 66 [58-72] years; 171 male [51.4%]) qualified as the LR-TP cohort. Reference values included blood loss (≤1000 mL), major complications (≤37%), 3-month postoperative mortality (&amp;lt;6%), and retrieved lymph nodes (≥29). Compared with TP with vascular resections, reference cutoffs were not met for major complications (51% vs LR-TP ≤37%) and 90-day mortality (11% vs LR-TP ≤6%). For TP due to high-risk anastomosis, failure to rescue rate (38% vs ≤6%) and 90-day mortality (11% vs LR-TP ≤6%) were not met. Compared with pancreatoduodenectomy, reference values for postoperative mortality were 3 times higher for LR-TP (≤2% vs ≤6%) and less for resected lymph nodes (≥16 vs ≥29). Conclusions and Relevance This case-control study provided global reference values for TP, indicating significantly higher postoperative morbidity and mortality compared with pancreatoduodenectomy. Perioperative morbidity of TP was especially increased in patients with vascular resections. These reference values can serve for quality control of pancreatic surgery.