Marie-Luise Berres

Introduction: Multidisciplinary tumor boards (MTBs) are the standard for oncologic decision-making but require substantial time and personnel resources. Large language models (LLMs) may support MTBs by generating structured, guideline-based recommendations. We evaluated concordance between MTB decisions and LLM recommendations in newly diagnosed cholangiocellular adenocarcinoma (CCA) and hepatocellular carcinoma (HCC). Method: In this retrospective single-center study, MTB protocols from 2022–2023 were screened. After exclusions, 50 CCA and 50 HCC cases were analyzed. Institutional MTB recommendations were compared with outputs from ChatGPT and Claude using identical structured clinical summaries available at the time of MTB presentation. Agreement was assessed using Cohen’s kappa, and correlation using Spearman’s rank coefficient. Results: For CCA, exact concordance between MTB and ChatGPT was 80%, with substantial agreement (k = 0.688) and strong correlation (r = 0.725; both p < 0.001). Concordance with Claude was at 56%. For HCC, concordance between MTB and ChatGPT was 66%, with substantial agreement (k = 0.604) and moderate correlation (r = 0.484; both p < 0.001). Concordance with Claude was only 38%, with fair agreement (k = 0.314, p < 0.001) and weak correlation (r = 0.086, p = 0.551). Conclusions: LLM-derived recommendations varied markedly by model. ChatGPT demonstrated substantial concordance, whereas Claude showed limited agreement. MTBs appeared more individualized, while LLM outputs were more guideline-oriented. These findings highlight the potential role of LLMs as supportive tools for structured clinical reasoning and guideline adherence. Prospective multicenter studies should evaluate real-time LLM integration into MTB workflows, efficiency, decision quality, and patient outcomes safely.

Background and Aims: In the global, Phase 3 HIMALAYA study in unresectable hepatocellular carcinoma (HCC), STRIDE significantly improved overall survival (OS) versus sorafenib; durvalumab was noninferior to sorafenib. Immune checkpoint inhibitor studies have shown an association between the occurrence of immune-mediated adverse events (imAEs) and improved OS. We assessed potential associations between the occurrence of imAEs and OS, and temporal patterns of imAEs, in HIMALAYA. Approach and Results: OS in participants who did and did not experience imAEs and the frequency and timing of imAEs were assessed for STRIDE and durvalumab in the safety analysis set of HIMALAYA. imAEs occurred in 139/388 (35.8%) and 64/388 (16.5%) participants with STRIDE and durvalumab, respectively; most were low grade. OS hazard ratios (95% CI) in participants who experienced imAEs versus those who did not were 0.73 (0.56-0.95) for STRIDE and 1.14 (0.82-1.57) for durvalumab. The 36-month OS rate (95% CI) for STRIDE was 36.2% (28.1-46.7) and 27.7% (22.4-34.2) in participants who did and did not experience imAEs, respectively. The most common imAE category with STRIDE was endocrine events (16.5%). Most imAEs occurred ≤3 months after treatment initiation. Conclusions: Participants who experienced imAEs with STRIDE had a numerical improvement in OS versus those who did not, which was not observed for durvalumab. Long-term OS with STRIDE was observed regardless of imAEs. Most imAEs were low grade, manageable, and occurred in the first 3 months after treatment initiation. Results continue to support the benefits of STRIDE in a diverse population that reflects unresectable HCC globally. Export

Background/Objectives: Systemic treatment for unresectable hepatocellular carcinoma (HCC) has rapidly advanced, with immune checkpoint inhibitors now the preferred first-line option. However, with multiple agents available and no established treatment sequence, selecting the most suitable second-line (2L) therapy remains challenging. While sorafenib is frequently chosen for 2L treatment, comprehensive data supporting its use is limited. This study evaluates the effectiveness of sorafenib as 2L therapy and factors influencing outcomes following first-line treatment failure in advanced HCC patients. Methods: This is a retrospective, multicenter study, including 81 patients with unresectable HCC from 12 European centers who received sorafenib as 2L treatment. Median overall survival (mOS), median progression-free survival (mPFS), radiological response to treatment, and toxicity were evaluated. Univariable and multivariable analyses were performed to identify potential predictors of clinical benefit. Results: In this cohort, some patients were treated with 2L sorafenib mOS for 7.4 months (95% CI: 6.6–13.6) and other patients were treated with mPFS for 3.7 months (95% CI: 3.0–4.8). Multivariable analysis revealed the best median OS for patients with CP A and AFP levels < 400 ng/mL (15.5 months). Adverse events (AE) of grade ≥ 3 were reported in 59.4% of patients. Conclusions: In this real-world cohort of European patients with unresectable HCC, the outcome of sorafenib treatment in the 2L setting was comparable to that of the other established 2L treatment options in patients with preserved liver function and good performance status. This study contributes to the understanding of the role of sorafenib in the 2L setting and underscores the need for further research to identify predictive factors for response and survival in order to optimize treatment algorithms for advanced HCC.

Tissue inhibitor of metalloproteinases-1 (TIMP-1), an important regulator of matrix metalloproteinases (MMPs), has recently been shown to interact with CD74, a receptor for macrophage migration inhibitory factor (MIF). However, the biological effects mediated by TIMP-1 through CD74 remain largely unexplored. Using sequence alignment and in silico protein–protein docking analysis, we demonstrated that TIMP-1 shares residues with both MIF and MIF-2, crucial for CD74 binding, but not for CXCR4. Subcellular colocalization, immunoprecipitation, and internalization experiments supported these findings, demonstrating that TIMP-1 interacts with surface-expressed CD74, resulting in its internalization in a dose-dependent manner, as well as with a soluble CD74 ectodomain fragment (sCD74). This prompted us to study the effects of the TIMP-1–CD74 axis on monocytes and vascular smooth muscle cells (VSCMs) to assess its impact on vascular inflammation. A phospho-kinase array revealed the activation of serine/threonine kinases by TIMP-1 in THP-1 pre-monocytes, in particular AKT. Similarly, TIMP-1 dose-dependently triggered the phosphorylation of AKT and ERK1/2 in primary human monocytes. Importantly, Transwell migration, 3D-based Chemotaxis, and flow adhesion assays demonstrated that TIMP-1 engagement of CD74 strongly promotes the recruitment response of primary human monocytes, while live cell imaging studies revealed a profound activating effect on VSMC proliferation. Finally, re-analysis of scRNA-seq data highlighted the expression patterns of TIMP-1 and CD74 in human atherosclerotic lesions, thus, together with our experimental data, indicating a role for the TIMP-1–CD74 axis in vascular inflammation and atherosclerosis.

Hepatocellular carcinoma (HCC) constitutes a devastating health burden. Recently, tumor microenvironment-directed interventions have profoundly changed the landscape of HCC therapy. In the present study, the function of the chemokine CXCL10 during fibrosis-associated hepatocarcinogenesis was analyzed with specific focus on its impact in shaping the tumor microenvironment. C57BL/6J wild type (WT) and Cxcl10 knockout mice (Cxcl10^−/−) were treated with diethylnitrosamine (DEN) and tetrachloromethane (CCl₄) to induce fibrosis-associated HCCs. Cxcl10 deficiency attenuated hepatocarcinogenesis by decreasing tumor cell proliferation as well as tumor vascularization and modulated tumor-associated extracellular matrix composition. Furthermore, the genetic inactivation of Cxcl10 mediated an alteration of the tumor-associated immune response and modified chemokine/chemokine receptor networks. The DEN/CCl₄-treated Cxcl10^−/− mice presented with a pro-inflammatory tumor microenvironment and an accumulation of anti-tumoral immune cells in the tissue. The most striking alteration in the Cxcl10^−/− tumor immune microenvironment was a vast accumulation of anti-tumoral T cells in the invasive tumor margin. In summary, our results demonstrate that CXCL10 exerts a non-redundant impact on several hallmarks of the tumor microenvironment and especially modulates the infiltration of anti-tumorigenic immune cells in HCC. In the era of microenvironment-targeted HCC therapies, interfering with CXCL10 defines a novel asset for further improvement of therapeutic strategies.

Background and Aims: Leukocyte infiltration is a hallmark of hepatic inflammation. The Junctional Adhesion Molecule A (JAM‐A) is a crucial regulator of leukocyte extravasation and is upregulated in human viral fibrosis. Reduced shear stress within hepatic sinusoids and the specific phenotype of liver sinusoidal endothelial cells (LSEC) cumulate in differing adhesion characteristics during liver fibrosis. The aim of this study was to define the functional role of cell‐specific adhesion molecule JAM‐A during hepatic fibrogenesis.Methods: Complete, conditional (intestinal epithelial; endothelial) and bone marrow chimeric Jam‐a knockout animals and corresponding C57Bl/6 wild‐type animals were treated with carbon tetrachloride (CCl₄, 6 weeks). For functional analyses of JAM‐A, comprehensive in vivo studies, co‐culture models and flow‐based adhesion assays were performed.Results: Complete and bone marrow‐derived Jam‐a^−/− animals showed aggravated fibrosis with increased non‐sinusoidal, perivascular accumulation of CD11b⁺F4/80⁺ monocyte‐derived macrophages in contrast to wild‐type mice. Despite being associated with disturbed epithelial barrier function, an intestinal epithelial Jam‐a knockout did not affect fibrogenesis. In endothelial‐specific Jam‐a^−/− animals, liver fibrosis was aggravated alongside sinusoid capillarization and hepatic stellate cell (HSC) activation. HSC activation is induced via Jam‐a^−/− LSEC‐derived secretion of soluble factors. Sinusoid CD31 expression and hedgehog gene signalling were increased, but leukocyte infiltration and adhesion to LSECs remained unaffected.Conclusions: Our models decipher cell‐specific JAM‐A to exert crucial functions during hepatic fibrogenesis. JAM‐A on bone marrow‐derived cells regulates non‐sinusoidal vascular immune cell recruitment, while endothelial JAM‐A controls liver sinusoid capillarization and HSC quiescence.

Background Intrahepatic cholangiocarcinoma (ICC) is a highly malignant and progressive cancer that ranks the second most common liver cancer. To further understand molecular mechanisms of rise and progression of cholangiocarcinoma animal models are needed. Next to carcinogen-induced ICC-models or genetically engineered models, there are only few allograft or xenograft transplant models that claim challenging operative techniques or longer time periods for tumor development. Method Hep55.1C cells were injected in the liver of 6-8 weeks old C57/B6 male mice. Tumor growth was followed by weekly ultrasound. After two or four weeks respectively mice were sacrificed. ICC and the tumor microenvironment were characterized via qRT-PCR, histological characterization/ multiplex imaging, flow cytometry and RNAseq. Murine data were comprehensively correlated with human data. Results Tumor size was 0.6cm² or 1cm² on average after two or four weeks after transplantation with a prevalence 100%. Tumor tissue in comparison to surrounding tissue showed high expression of cholangiocyte markers but not hepatocyte markers or markers for hepatocellular carcinoma. Immunohistological staining revealed a strong and ubiquitous signal for Pan-Cytokeratin within the tumor but not the surrounding tissue in contrast to HNF4α that was upregulated in the surrounding tissue. The analysis of the tumor microenvironment revealed a strong human homology regarding proliferation, gene expression pattern, tumor-associated immune response and stromal composition. Conclusion We here present a new intrahepatic cholangiocarinoma mouse model with human homology. Tumor induction shows a 100% success rate with macroscopic tumor growth within few weeks. Our model is therefore most suitable to evaluate interventional therapies. Publication Date: 26 January 2022 (online) © 2022. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

Liver cirrhosis poses a major risk for the development of hepatocellular carcinoma (HCC). This retrospective study investigated to what extent radiomic features allow the prediction of emerging HCC in patients with cirrhosis in contrast-enhanced computed tomography (CECT). A total of 51 patients with liver cirrhosis and newly detected HCC lesions (n = 82) during follow-up (FU-CT) after local tumor therapy were included. These lesions were not to have been detected by the radiologist in the chronologically prior CECT (PRE-CT). For training purposes, segmentations of 22 patients with liver cirrhosis but without HCC-recurrence were added. A total of 186 areas (82 HCCs and 104 cirrhotic liver areas without HCC) were analyzed. Using univariate analysis, four independent features were identified, and a multivariate logistic regression model was trained to classify the outlined regions as “HCC probable” or “HCC improbable”. In total, 60/82 (73%) of segmentations with later detected HCC and 84/104 (81%) segmentations without HCC were classified correctly (AUC of 81%, 95% CI 74–87%), yielding a sensitivity of 72% (95% CI 57–83%) and a specificity of 86% (95% CI 76–96%). In conclusion, the model predicted the occurrence of new HCCs within segmented areas with an acceptable sensitivity and specificity in cirrhotic liver tissue in CECT.

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with anti-fibrotic properties in toxic liver injury models and anti-steatotic functions in non-alcoholic fatty liver disease (NAFLD) attributed to the CD74/AMPK signaling pathway. As NAFLD progression is associated with fibrosis, we studied MIF function during NAFLD-associated liver fibrogenesis in mice and men by molecular, histological and immunological methods in vitro and in vivo. After NASH diet feeding, hepatic Mif expression was strongly induced, an effect which was absent in Mif^∆hep mice. In contrast to hepatotoxic fibrosis models, NASH diet-induced fibrogenesis was significantly abrogated in Mif^−/− and Mif^∆hep mice associated with a reduced accumulation of the pro-fibrotic type-I NKT cell subpopulation. In vitro, MIF skewed the differentiation of NKT cells towards the type-I subtype. In line with the murine results, expression of fibrosis markers strongly correlated with MIF, its receptors, and markers of NKT type-I cells in NASH patients. We conclude that MIF expression is induced during chronic metabolic injury in mice and men with hepatocytes representing the major source. In NAFLD progression, MIF contributes to liver fibrogenesis skewing NKT cell polarization toward a pro-fibrotic phenotype highlighting the complex, context-dependent role of MIF during chronic liver injury.