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Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. The combination of tremelimumab and durvalumab is now a standard treatment option for advanced HCC., Objective: To study immune responses in HCC patients treated with tremelimumab and durvalumab., Design: We treated 28 HCC patients with durvalumab, tremelimumab and locoregional therapies. We performed a high-dimensional multiomics analysis including whole exome sequencing, single-cell RNA seq, CO-Detection by indEXing, flow cytometry and multiplex cytokine/chemokine analysis of patients' blood and tumour samples and integrated this data to elucidate immune correlatives and response mechanisms. Mice with syngeneic HCC were treated with anti-PD-L1 plus anti-CTLA4 for hepatic lymphocytes, tumour-infiltrating lymphocytes and peripheral blood mononuclear cell analysis., Results: The median overall survival was 19.2 months. Tumour tissue analysis revealed enhanced interferon responses, with stronger effects in responders. Gene set variation analysis indicated enhanced antigen presentation in responders. Spatial analysis revealed that non-responder tumours had higher numbers of Tregs located in neighbourhoods enriched with immune cells and expressed higher levels of ICOS and PD-1. Conversely, non-responder PD1+CD8+T in these Treg-enriched neighbourhoods expressed lower ICOS. Cell-communication analysis demonstrated that Treg-CD8+T interaction was enhanced in non-responder tissue. Peripheral blood analysis showed increased classical monocytes in responders and Tregs in non-responders. Treg-CD8+T interaction was confirmed in preclinical models. Finally, single-patient computational analysis from the all-across analysis was performed on 860 features, which led to the identification of multiomics feature sets including Treg features., Conclusion: Our study provides a blueprint for in-depth analysis of immune correlates in immunotherapy studies and demonstrates the importance of Treg distribution in HCC., Trial Registration Numbers: NCT02821754 and the EudraCT identifier: 2019-002767-98., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: The major breakthrough in cancer therapy with immune checkpoint inhibitors (ICIs) has highlighted the important role of immune checkpoints in antitumoral immunity. However, most patients do not achieve durable responses, making biomarker research in this setting essential. CD27 is a well known costimulatory molecule, however the impact of its soluble form in ICI is poorly investigated. Therefore, we aimed at testing circulating concentrations of soluble CD27 (sCD27) and CD27 bound to extracellular vesicles (EVs) as potential biomarkers to predict response and overall survival (OS) in patients undergoing ICI., Methods: Serum and plasma levels of sCD27 were assessed by immunoassay in three patient cohorts (n = 187) with advanced solid malignancies including longitudinal samples (n = 126): a training (n = 84, 210 specimens, Aachen ICI) and validation cohort (n = 70, 70 specimens, Hamburg ICI), both treated with ICI therapy, and a second independent validation cohort (n = 33, 33 specimens, Hamburg non-ICI) undergoing systemic therapy without any ICI. In a subset (n = 36, 36 baseline and 108 longitudinal specimens), EV-bound CD27 from serum was measured, while EV characterization studies were conducted on a fourth cohort (n = 45)., Results: In the Aachen and Hamburg ICI cohorts, patients with lower circulating sCD27 levels before and during ICI therapy had a significantly longer progression-free survival (PFS) and OS compared to patients with higher levels, a finding that was confirmed by multivariate analysis (MVA) (Aachen ICI: p PFS  = 0.012, p OS  = 0.001; Hamburg ICI: p PFS  = 0.040, p OS  = 0.004) and after randomly splitting both cohorts into training and validation. This phenomenon was not observed in the Hamburg non-ICI cohort, providing a rationale for the predictive biomarker role of sCD27 in immune checkpoint blockade. Remarkably, EV-bound CD27 baseline levels and dynamics during ICI therapy also emerged as potent predictive biomarkers, acting however antagonistically to soluble sCD27, i.e. higher levels were associated with PFS and OS benefit. Combining both molecules ("multi-CD27" score) enhanced the predictive ability (HR PFS : 17.21 with p < 0.001, HR OS : 6.47 with p = 0.011)., Conclusion: Soluble and EV-bound CD27 appear to have opposing immunomodulatory functions and may represent easily measurable, non-invasive prognostic markers to predict response and survival in patients undergoing ICI therapy., (© 2024. The Author(s).)

Background: Combined Immuno-chemotherapy consisting of gemcitabine, cisplatin and the programmed death-ligand one inhibitor durvalumab (GCD) is the new standard of care for patients with biliary tract cancers (BTC) based on positive results of the TOPAZ-1 study., Objective: We here evaluated the efficacy and safety of GCD for BTC in a German multicenter real-world patient cohort., Methods: Patients with BTC treated with GCD from 9 German centers were included. Clinicopathological baseline parameters, overall survival (OS), response rate and adverse events (AEs) were retrospectively analyzed. The prognostic impact was determined by Kaplan-Meier analyses and Cox regression models., Results: A total of 165 patients treated with GCD between 2021 and 2024 were included in the study. Median OS and median progression-free survival were 14 months (95% CI 10.3-17.7) and 8 months (95% CI 6.8-9.2), respectively. The best overall response rate was 28.5% and disease control rate was 65.5%. While extrahepatic and intrahepatic BTC showed similar outcomes, mOS was significantly shorter in patients with gall bladder cancer (GB-CA) with 9 months (95% CI 5.5-12.4; p = 0.02). In univariate analyses age ≥70 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥1, status post cholecystectomy, GB-CA and high baseline CRP values were significantly associated with OS. ECOG PS ≥ 1 and GB-CA remained independent prognostic factors for OS in multivariable cox regression analysis. AEs have been reported in 130 patients (78.8%), including 149 grade 3-4 AEs (25.5%). One patient died of severe infectious pneumonia. Immune-related (ir)AEs occurred in 17 patients (10.3%), including 9 grade 3-4 irAEs (2.2%), which led to treatment interruption in 4 patients., Conclusions: Immuno-chemotherapy in patients with BTC was feasible, effective and safe in a real-life scenario. Our results were comparable to the phase 3 clinical trial results (TOPAZ-1). Reduced efficacy was noted in patients with GB-CA and/or a reduced performance status that warrants further investigation., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Introduction and Objectives: Autoimmune liver diseases (AILD) are rare causes hepatocellular carcinoma (HCC), and data on the efficacy and tolerability of anti-tumor therapies are scarce. This pan-European study aimed to assess outcomes in AILD-HCC patients treated with tyrosine kinase inhibitors (TKIs) or transarterial chemoembolization (TACE) compared with patients with more common HCC etiologies, including viral, alcoholic or non-alcoholic fatty liver disease., Materials and Methods: 107 patients with HCC-AILD (AIH:55; PBC:52) treated at 13 European centres between 1996 and 2020 were included. 65 received TACE and 28 received TKI therapy. 43 (66 %) were female (median age 73 years) with HCC tumor stage BCLC A (34 %), B (46 %), C (9 %) or D (11 %). For each treatment type, propensity score matching was used to match AILD to non-AILD-HCC on a 1:1 basis, yielding in a final cohort of 130 TACE and 56 TKI patients for comparative analyses of median overall survival (mOS) and treatment tolerability., Results: HCC-AILD patients showed comparable mOS to controls for both TACE (19.5 vs. 22.1 months, p = 0.9) and TKI (15.4 vs. 15.1 months, p = 0.5). Adverse events were less frequent in AILD-HCC patients than controls (33 % % vs. 62 %, p = 0.003). For TKIs, there were no significant differences in adverse events (73% vs. 86%, p = 0.2) or interruption rates (44% vs. 36 %, p = 0.7)., Conclusions: In summary, this study demonstrates comparable mOS for AILD-HCC patients undergoing local and systemic treatments, with better tolerability than HCC of other causes. TKIs remain important therapeutic options for AILD-HCC patients, particularly given their exclusion from recent immunotherapy trials., Competing Interests: Conflicts of interest A.L. reports receiving consulting fees from Advanz Pharma, AlfaSigma, Takeda, and Albireo Pharma, and speaker fees from Gilead, Abbvie, MSD, Intercept Pharma, AlfaSigma, GSK, and Incyte. BS received grant support from AstraZeneca and Eisai; speaker honoraria from Eisai; and travel support from AbbVie, AstraZeneca, Ipsen, and Gilead. MP received travel support from Bayer, BMS, Ipsen, Lilly, MSD, and Roche; he is a consultant for AstraZeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; and he received travel support from Bayer, BMS, Ipsen, and Roche. HW received consulting and speaker fees from Roche, AstraZeneca, Eisai, and Ipsen., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. All rights reserved.)

Purpose: Listeria monocytogenes causes severe bacterial infections with the highest mortality rate among foodborne pathogens in Europe. Combination treatment with ampicillin and gentamicin is recommended for invasive manifestations. However, evidence to support this treatment approach remains limited due to a lack of randomised controlled trials. To explore this critical issue further, we conducted this retrospective, single-center study., Methods: We identified all patients hospitalized with invasive listeriosis at the University Medical Center Hamburg-Eppendorf between 2009 and 2020 and analyzed the effect of gentamicin combination treatment versus monotherapy on 90-day mortality., Results: In total, 36 patients with invasive listeriosis were included, of which 21 patients received gentamicin combination treatment and 15 received monotherapy. The mean age-adjusted Charlson Comorbidity Index (aaCCI) value was lower in the gentamicin combination treatment group (5.4 vs. 7.4). Neurolisteriosis was more common in the gentamicin group (81% vs. 20%). The 90-day mortality was with significantly lower in the gentamicin combination treatment group (10%) compared to the monotherapy group (60%). Multivariable cox regression analysis, adjusted for a propensity score computed based on neurolisteriosis, aaCCI and sex, revealed a significantly reduced hazard ratio of 0.07 (95% CI: 0.01-0.53, p = 0.01) for 90-day mortality for the gentamicin combination treatment., Conclusion: This retrospective study highlights the benefit of gentamicin combination treatment in reducing the 90-day mortality rate among patients with invasive listeriosis. The high prevalence of monotherapy in this study cohort raises concerns about the adequacy of antibiotic therapy in clinical practice., (© 2024. The Author(s).)

Introduction: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many malignancies in recent years. However, immune-related adverse events (irAE) are a frequent concern in clinical practice. The safety profile of ICI for the treatment of malignancies in patients diagnosed with autoimmune and cholestatic liver disease (AILD) remains unclear. Due to this uncertainty, these patients were excluded from ICI clinical trials and ICI are withheld from this patient group. In this retrospective multicenter study, we assessed the safety of ICI in patients with AILD., Methods: We contacted tertiary referral hospitals for the identification of AILD patients under ICI treatment in Europe via the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Fourteen centers contributed data on AILD patients with malignancies being treated with ICI, another three centers did not treat these patients with ICI due to fear of irAEs., Results: In this study, 22 AILD patients under ICI treatment could be identified. Among these patients, 12 had primary biliary cholangitis (PBC), five had primary sclerosing cholangitis (PSC), four had autoimmune hepatitis (AIH), and one patient had an AIH-PSC variant syndrome. Eleven patients had hepatobiliary cancers and the other 11 patients presented with non-hepatic tumors. The applied ICIs were atezolizumab (n=7), durvalumab (n=5), pembrolizumab (n=4), nivolumab (n=4), spartalizumab (n=1), and in one case combined immunotherapy with nivolumab plus ipilimumab. Among eight patients who presented with grade 1 or 2 irAEs, three demonstrated liver irAEs. Cases with grades ≥ 3 irAEs were not reported. No significant changes in liver tests were observed during the first year after the start of ICI., Discussion: This European multicenter study demonstrates that PD-1/PD-L1 inhibitors appear to be safe in patients with AILD. Further studies on the safety of more potent dual immune checkpoint therapy are needed. We conclude that immunotherapy should not categorically be withheld from patients with AILD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kocheise, Piseddu, Vonderlin, Tjwa, Buescher, Meunier, Goeggelmann, Fianchi, Dumortier, Riveiro Barciela, Gevers, Terziroli Beretta-Piccoli, Londoño, Frankova, Roesner, Joerg, Schmidt, Glaser, Sutter, Fründt, Lohse, Huber, von Felden, Sebode and Schulze.)

Hepatocellular carcinoma (HCC) has high recurrence rates exceeding 50% despite curative resection. The serum biomarker alpha-fetoprotein (AFP) is a well-known prognostic marker for HCC. EpCAM-positive circulating tumor cells (CTC) have a high predictive value for early HCC recurrence after curatively intended resection, most likely indicating micro-metastases at the time of resection. However, sensitivity remains low. The objective of this study was to evaluate a composite test comprising both CTC and AFP to identify patients at high risk for early HCC recurrence. We prospectively enrolled 58 patients undergoing curative intended resection for HCC at a tertiary referral center. Blood specimens were obtained prior to resection and analyzed for EpCAM-positive CTC and serum AFP levels. A positive result was defined as either detection of CTC or AFP levels ≥ 400 ng/ml. Eight patients tested positive for CTC, seven for AFP, and two for both markers. A positive composite test was significantly associated with shorter early recurrence-free survival (5 vs. 16 months, p = 0.005), time to recurrence (5 vs. 16 months, p = 0.011), and overall survival (37 vs. not reached, p = 0.034). Combining CTC and AFP identified patients with poor outcome after surgical resection, for whom adjuvant or neoadjuvant therapies may be particularly desirable., (© 2023. The Author(s).)

Background: Mentoring is important for a successful career in academic medicine. In online matching processes, profile texts are decisive for the mentor-selection. We aimed to qualitatively characterize mentoring-profile-texts, identify differences in form and content and thus elements that promote selection., Methods: In a mixed method study first, quality of texts in 150 selected mentoring profiles was evaluated (10-point Likert scale; 1 = insufficient to 10 = very good). Second, based on a thematic and content analysis approach of profile texts, categories and subcategories were defined. We compared the presence of the assigned categories between the 25% highest ranked profiles with the 25% lowest ranked ones. Finally, additional predefined categories (hot topics) were labelled on the selected texts and their impact on student evaluation was statistically examined., Results: Students rated the quality of texts with a mean of 5.89 ± 1.45. 5 main thematic categories, 21 categories and a total of 74 subcategories were identified. Ten subcategories were significantly associated with high- and four with low-rated profiles. The presence of three or more hot topics in texts significantly correlated with a positive evaluation., Conclusion: The introduced classification system helps to understand how mentoring profile texts are composed and which aspects are important for choosing a suited mentor., (© 2023. The Author(s).)

Background: Since the introduction of the combination treatment of anti-programmed death-ligand 1 antibody atezolizumab and anti-VEGF antibody bevacizumab (AB), median overall survival in HCC has drastically improved. However, evidence on the efficacy and safety of the novel treatment standard in patients with prior exposure to systemic treatment is scarce. The aim of this global, multicenter, observational study was to evaluate the efficacy and safety of AB in patients after previous systemic therapy., Methods: We screened our global, multicenter, prospectively maintained registry database for patients who received any systemic therapy before AB. The primary end point was overall survival; secondary end points were time-to-progression, progression-free survival, objective response rate, and safety (rate and severity of adverse events)., Results: Among 493 patients who received AB for unresectable HCC, 61 patients received prior systemic therapy and were included in this analysis. The median age of the study population was 66 years, with 91.8% males. Predominant risk factors for HCC were viral hepatitis (59%) and alcohol (23%). Overall survival for AB was 16.2 (95% CI, 14.5-17.9) months, time-to-progression and progression-free survival were 4.1 (95% CI, 1.5-6.6) and 3.1 (95% CI, 1.1-5.1) months, respectively. The objective response rate was 38.2% (7.3% with complete and 30.9% with partial response). Overall survival was not influenced by treatment line (2nd vs. >2nd) or previous systemic treatment modality (tyrosine kinase inhibitors vs. immune checkpoint inhibitors). Treatment-related adverse events of all grades according to Common Terminology Criteria for Adverse Events were documented in 42.6% of patients, with only 13.1% of grade ≥3, including one death., Conclusion: In this observational study, AB emerges as a safe and efficacious treatment option in patients with HCC previously treated with other systemic therapy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Background: The immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown., Methods: We used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages., Results: Our data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice., Conclusions: We here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Giannou, Kempski, Zhang, Lücke, Shiri, Zazara, Belios, Machicote, Seeger, Agalioti, Tintelnot, Sagebiel, Tomczak, Bauditz, Bedke, Kocheise, Mercanoglu, Fard-Aghaie, Giorgakis, Lykoudis, Pikouli, Grass, Wahib, Bardenhagen, Brunswig, Heumann, Ghadban, Duprée, Tachezy, Melling, Arck, Stringa, Gentilini, Gondolesi, Nakano, Thomson, Perez, Li, Mann, Izbicki, Gagliani, Maroulis and Huber.)

Cytoplasmic double-stranded RNA is sensed by RIG-I-like receptors (RLRs), leading to induction of type I interferons (IFN-Is), proinflammatory cytokines, and apoptosis. Here, we elucidate signaling mechanisms that lead to cytokine secretion and cell death induction upon stimulation with the bona fide RIG-I ligand 5'-triphosphate RNA (3p-RNA) in tumor cells. We show that both outcomes are mediated by dsRNA-receptor families with RLR being essential for cytokine production and IFN-I-mediated priming of effector pathways but not for apoptosis. Affinity purification followed by mass spectrometry and subsequent functional analysis revealed that 3p-RNA bound and activated oligoadenylate synthetase 1 and RNase L. RNase L-deficient cells were profoundly impaired in their ability to undergo apoptosis. Mechanistically, the concerted action of translational arrest triggered by RNase L and up-regulation of NOXA was needed to deplete the antiapoptotic MCL-1 to cause intrinsic apoptosis. Thus, 3p-RNA-induced apoptosis is a two-step process consisting of RIG-I-dependent priming and an RNase L-dependent effector phase., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic immune receptor sensing viral RNA. It triggers the release of type I interferons (IFN) and proinflammatory cytokines inducing an adaptive cellular immune response. We investigated the therapeutic potential of systemic RIG-I activation by short 5'-triphosphate-modified RNA (ppp-RNA) for the treatment of acute myeloid leukemia (AML) in the syngeneic murine C1498 AML tumor model. ppp-RNA treatment significantly reduced tumor burden, delayed disease onset and led to complete remission including immunological memory formation in a substantial proportion of animals. Therapy-induced tumor rejection was dependent on CD4 + and CD8 + T cells, but not on NK or B cells, and relied on intact IFN and mitochondrial antiviral signaling protein (MAVS) signaling in the host. Interestingly, ppp-RNA treatment induced programmed death ligand 1 (PD-L1) expression on AML cells and established therapeutic sensitivity to anti-PD-1 checkpoint blockade in vivo. In immune-reconstituted humanized mice, ppp-RNA treatment reduced the number of patient-derived xenografted (PDX) AML cells in blood and bone marrow while concomitantly enhancing CD3 + T cell counts in the respective tissues. Due to its ability to establish a state of full remission and immunological memory, our findings show that ppp-RNA treatment is a promising strategy for the immunotherapy of AML.