Introduction:Periodontitis prevalence is elevated in patients with inflammatory bowel diseases (IBD). Biological therapies targeting cytokines such as tumor necrosis factor (TNF) and interleukin-12/23 (IL-12/23) are central to IBD management, yet their impact on periodontal health remains unclear. Methods:In a cross-sectional, hypothesis-generating design, 45 patients with IBD were examined and stratified into three groups according to their biological therapy: anti-TNF therapy (n = 15), anti-IL-12/23 therapy (n = 15), and a control group not receiving these biologics (n = 15). Periodontal status was assessed using the Periodontal Screening Index (PSI; codes 0-4) across all sextants as a standardized screening measure. Medical history, oral hygiene behavior, and prior periodontal diagnoses were documented. To assess local immune activity, interleukin-6 (IL-6) concentrations in gingival crevicular fluid (GCF) were quantified by enzyme-linked immunosorbent assay (ELISA). Results:Overall, 16 patients exhibited either known or previously undiagnosed periodontitis, with interindividual variability in severity. Patients receiving anti-IL-12/23 therapy exhibited lower mean and maximal PSI scores compared with anti-TNF-treated patients, and no sextants with advanced periodontal inflammation (PSI 3-4) were detected in this group. In contrast, active or latent periodontitis was observed in both the anti-TNF and control cohorts. Concordantly, IL-6 levels in GCF were significantly reduced in patients undergoing IL-12/23 blockade compared with controls, indicating attenuated local inflammatory signaling at the periodontal interface. These findings were observed despite no statistically significant differences in clinical or endoscopic disease activity between groups. Conclusions:These exploratory findings suggest that systemic inhibition of the IL-12/23 axis in IBD is associated with reduced periodontal inflammatory burden and decreased local IL-6 activity, supporting a role for IL-23-dependent immune pathways in linking intestinal and oral mucosal inflammation. While causality cannot be inferred from this cross-sectional study, the data provide a mechanistic rationale for further longitudinal investigations into the impact of cytokine-targeted biologic therapy on the oral-gut immune axis.

OBJECTIVE:Augmented mucosal expression of the transcription factor GATA3 has been implicated in the pathogenesis of ulcerative colitis (UC). Here, we evaluated the efficacy and safety of SB012, an enema formulation of the DNAzyme hgd40 that specifically inactivates GATA3 messenger RNA, for induction therapy in patients with active UC. DESIGN:In this randomized, double-blind, placebo-controlled, multicenter, phase 2a study, patients with moderately-to-severely active UC were randomized to either receive SB012 enema (225 mg hgd40) or placebo once daily for 4 weeks. The primary endpoint was change in the Total Mayo Score at week 4 compared to baseline values in the SB012 versus placebo group. RESULTS:Patients were randomized 2:1 to the SB012 (n = 13) or placebo (n = 7) group. The treatment difference between the SB012 and placebo group was not statistically significant at week 4 (P = .286). In patients not treated with glucocorticoids, the Total Mayo score in the SB012 group improved on day 28 by -2.2 (P = .027; 95%CI: -4.1 to -0.3) compared to placebo, whereas no improvement was seen in patients using corticosteroids. Further, the median Total Mayo Score in the SB012 group dropped significantly from 9.0 (Q1-Q3 6.5-10) at baseline to 7.0 (4.0-8.5) at week 4 (P = .004), while there were no significant changes in the placebo group. Endoscopic improvement was reached by 17% (2/12) and 57% (4/7) in the SB012 and 17% (1/6) and 50% (3/6) in the placebo group at weeks 4 (P = 1.0) and 8 (P = 1.0), respectively. SB012 application was well tolerated. CONCLUSION:Overall, topical application of the GATA3-specific DNAzyme formulation SB012 was well tolerated, but did not reach the defined primary endpoint of treatment difference at week 4 between the SB012 and placebo group in active moderate-to-severe UC patients, unless confounding by glucocorticoids was taken into account.

Abstract Introduction The prevalence of periodontitis is elevated in patients with inflammatory bowel disease (IBD). The neutralisation of antibodies against the cytokines TNF and interleukin-12/23 (IL-12/23) is a fundamental component of the clinical management of IBD. However, the extent to which such cytokine blockade in IBD influences the clinical picture of periodontitis remains to be elucidated. Methods In this exploratory study, 45 patients suffering from IBD who were undergoing biological therapy with cytokine blockers were examined for the presence of periodontitis. The prospective study identified three distinct groups: anti-TNF therapy (n = 15), anti-IL-12/IL-23 therapy (n = 15), no anti-TNF or anti-IL-23 therapy (control group; n = 15). The depth of the gum pockets in all sextants was determined using the Periodontal Screening Index (PSI). Furthermore, a comprehensive medical history pertaining to IBD and oral hygiene was obtained. IL-6 levels were determined by ELISA in gingival crevicular fluid (GCF). Results Of the 45 patients with IBD, 14 had known or evidence of previously unknown periodontitis. The investigation revealed that the mean PSI index in the anti-IL-12/IL-23 group was significantly lower than in the other groups. Within the anti-IL-12/IL-23 group, two individuals with a history of periodontitis exhibited a PSI index of 0, while no subjects demonstrated indications of latent periodontitis. In contrast, three individuals in the anti-TNF group and six individuals in the control group had previously been diagnosed with periodontitis, and two and three additional individuals from these groups exhibited signs of previously unknown periodontitis. IL-6 levels in GCF were significantly lower in the anti-IL-12/IL-23 group as compared to the control group. Conclusion This exploratory study suggested that anti-IL-12/IL-23 therapy in IBD may have protective effects against periodontitis. Possible links between biologic therapy and periodontitis should be investigated prospectively in larger cohorts. Funding Source N/A Topic Categories Immune Mechanisms of Human Disease (HUM)

Extra-intestinal manifestations (EIMs) commonly occur in patients with inflammatory bowel diseases (IBD) and contribute significantly to morbidity and reduced quality of life. Their management remains challenging. Recently, the development of Janus Kinase (JAK) inhibitors has expanded the therapeutic options of luminal IBD, and three JAK inhibitors, tofacitinib, upadacitinib, and filgotinib, have been approved for IBD treatment, while a growing body of evidence suggests that JAK inhibitors may be a promising therapeutic option for the management of EIMs, particularly those affecting the joints and skin. In this comprehensive review, we aim to provide the available evidence concerning the impact of JAK inhibitors on EIMs treatment and analyze their underlying mechanisms of action.

Abstract Background Recently, autoantibodies directed against the epithelial adhesion protein integrin αVβ6 have been identified that strongly associate with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC) with potential disease-driving effects. The presence of anti-αVβ6 in PSC without IBD is under debate. Moreover, data on the effect of proctocolectomy on autoantibody levels remains scarce. Methods Anti-αVβ6-directed autoantibodies were detected by a commercial enzyme-linked immunosorbent assay in patient sera, including healthy controls (N = 62), ulcerative colitis (N = 36), Crohn’s disease (CD, N = 65), PSC with concomitant IBD (78 samples from N = 41 patients), PSC without clinically manifest IBD (41 samples from N = 18 patients). Additionally, sera after proctocolectomy were studied (44 samples / N= 10 patients: 5 with UC, 5 with PSC). Immunofluorescent analyses of the target autoantigen were performed in liver, large bile ducts from surgical resections and colon tissue samples of PSC patients and single-cell RNA seq datasets were studied. Results The target autoantigen is expressed in disease-associated epithelia in the colon, in cholangiocytes in fibrotic portal fields and periductular glands of the large bile ducts as detected in immunofluorescence and single-cell RNA sequencing datasets. Anti-αVβ6 antibodies occur in 74% of patients with PSC with IBD, but also in 39% of patients with PSC without manifest IBD with lower levels. Anti-αVβ6 levels correlate with intestinal disease activity in patients with primary sclerosing cholangitis. Interestingly, proctocolectomy reduces autoantibody levels more strongly in UC than in PSC patients. Conclusion Disease-associated anti-integrin αVβ6 autoantibodies are also present in PSC without IBD with lower levels, assay sensitivity being a crucial determinant of detection. Moreover, proctocolectomy more strongly reduced autoantibody levels in UC than in PSC. Preferential autoantibody persistence in PSC after proctocolectomy might explain the increased incidence of chronic pouchitis in PSC.

Background:Immunotherapy-based combinations are currently the standard of care in the systemic treatment of patients with HCC. Recent studies have reported unexpectedly long survival with lenvatinib (LEN), supporting its use in first-line treatment for HCC. This study aims to compare the real-world effectiveness of LEN to atezolizumab/bevacizumab (AZ/BV).Methods:A retrospective analysis was conducted to evaluate the effectiveness and safety of frontline AZ/BV or LEN therapy in patients with advanced HCC across 18 university hospitals in Europe.Results:The study included 412 patients (AZ/BV: n=207; LEN: n=205). Baseline characteristics were comparable between the 2 treatment groups. However, patients treated with AZ/BV had a significantly longer median progression-free survival compared to those receiving LEN. The risk of hepatic decompensation was significantly higher in patients with impaired baseline liver function (albumin-bilirubin [ALBI] grade 2) treated with AZ/BV compared to those with preserved liver function. Patients with alcohol-associated liver disease had poorer baseline liver function compared to other etiologies and exhibited a worse outcome under AZ/BV.Conclusions:In this real-world cohort, survival rates were similar between patients treated with LEN and those treated with AZ/BV, confirming that both are viable first-line options for HCC. The increased risk of hepatic decompensation in patients treated with AZ/BV who have impaired baseline liver function underscores the need for careful monitoring. Future trials should aim to distinguish more clearly between metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease.

BACKGROUND & AIMS: T cells are crucial for the antitumor response against colorectal cancer (CRC). T-cell reactivity to CRC is nevertheless limited by T-cell exhaustion. However, molecular mechanisms regulating T-cell exhaustion are only poorly understood. METHODS: We investigated the functional role of cycl in -dependent kinase 1a (Cdkn1a or p21) in cluster of differentiation (CD) 4+ T cells using murine CRC models. Furthermore, we evaluated the expression of p21 in patients with stage I to IV CRC. In vitro coculture models were used to understand the effector function of p21-deficient CD4+ T cells. RESULTS: We observed that the activation of cell cycle regulator p21 is crucial for CD4+ T-cell cytotoxic function and that p21 deficiency in type 1 helper T cells (Th1) leads to increased tumor growth in murine CRC. Similarly, low p21 expression in CD4+ T cells infiltrated into tumors of CRC patients is associated with reduced cancer-related survival. In mouse models of CRC, p21-deficient Th1 cells show signs of exhaustion, where an accumulation of effector/effector memory T cells and CD27/CD28 loss are predominant. Immune reconstitution of tumor-bearing Rag1-/- mice using ex vivo-treated p21-deficient T cells with palbociclib, an inhibitor of cyclin-dependent kinase 4/6, restored cytotoxic function and prevented exhaustion of p21-deficient CD4+ T cells as a possible concept for future immunotherapy of human disease. CONCLUSIONS: Our data reveal the importance of p21 in controlling the cell cycle and preventing exhaustion of Th1 cells. Furthermore, we unveil the therapeutic potential of cyclin-dependent kinase inhibitors such as palbociclib to reduce T-cell exhaustion for future treatment of patients with colorectal cancer.

Background Recently, autoantibodies directed against the epithelial adhesion protein integrin alpha V beta 6 have been identified that are strongly associated with ulcerative colitis (UC). We aimed to elucidate whether anti-integrin alpha V beta 6 (anti-alpha V beta 6) is present in primary sclerosing cholangitis (PSC), its associated inflammatory bowel disease, or other cholestatic liver diseases and their persistence after proctocolectomy.Methods We detected anti-alpha V beta 6 by an enzyme-linked immunosorbent assay in sera collected at 2 German tertiary centers, including healthy controls (N = 62), UC (N = 36), Crohn's disease (CD, N = 65), PSC-inflammatory bowel diseases (IBD) (78 samples from N = 41 patients), PSC without IBD (PSC, 41 samples from N = 18 patients), primary biliary cholangitis (PBC, N = 24), autoimmune hepatitis (AIH, N = 32), secondary sclerosing cholangitis (SSC, N = 12), and metabolic dysfunction-associated steatotic liver disease (MASLD, N = 24). In addition, sera after proctocolectomy were studied (44 samples/N = 10 patients). Immunofluorescent analyses were performed in tissue samples from liver, large bile duct from surgical resections, and colon of PSC patients.Results Anti-alpha V beta 6 occurred in 91% of UC, 17% of CD, 73% of PSC-IBD, 39% of PSC, 4% of PBC, 14% of AIH, and 0% of healthy controls, SSC, or MASLD. Integrin alpha V beta 6 is selectively expressed in disease-associated epithelia of both bile duct and colon. Anti-alpha V beta 6 levels correlate moderately with intestinal disease activity in PSC-IBD, but only weakly with biliary disease.Conclusions Anti-alpha V beta 6 frequently occurs in patients suffering from PSC, especially in PSC-IBD. Anti-alpha V beta 6 levels positively correlate to IBD activity in PSC-IBD, but may also occur in the absence of clinically manifest IBD in PSC. Graphical Abstract

Biologicals have dominated the therapeutic scenery in inflammatory bowel diseases (IBDs), namely ulcerative colitis (UC) and Crohn's disease (CD), for the past 20 years. The development of tofacitinib was the starting point for an era of small molecules after the era of biologicals. These new agents may challenge the use of biological agents in the future. They share properties that appeal to both patients and physicians. Low production costs, a lack of immunogenicity, and ease of use are only some of their benefits. On the other hand, patients and their physicians must manage the potential side effects of small molecules such as JAK inhibitors or S1P1R modulators. Here, we present agents that have already entered the clinical routine and those that are still being investigated in clinical trials.

Introduction: In the REFLECT trial, lenvatinib was found to be non-inferior compared to sorafenib in terms of Overall Survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world, and to identify clinical factors that could be significantly associated with survival outcomes. Methods: The study population derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included Western and Eastern populations from 23 centres in five countries. Results: We included 1325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3 and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH related aetiology was independently associated with good prognosis. Median progression free survival was 6.3 months. Multivariate analysis for Progression Free survival revealed that NAFLD/NASH, BCLC, NLR and AST as independent prognostic factors for progression free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited that the appearance of decreased appetite Grade ≥ 2 versus Grade 0-1 as an independent prognostic factor for worse Progression Free Survival. 924 patients on 1325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over two-months from the beginning of second line treatment. From first line therapy the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months) and best supportive care (10.8 months). Conclusions: Our study confirms in a large and global population of patients with advanced HCC not candidate to locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.

Background Lenvatinib is approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). The efficacy of lenvatinib in Caucasian real-world patients is insufficiently defined. The purpose of this study was to evaluate the efficacy of lenvatinib in a multi-center cohort (ELEVATOR) from Germany and Austria. Methods A retrospective data analysis of 205 patients treated with first-line systemic lenvatinib at 14 different sites was conducted. Overall survival, progression free survival, overall response rate and adverse event rates were assessed and analyzed. Results Patients receiving lenvatinib in the real-world setting reached a median overall survival of 12.8 months, which was comparable to the results reported from the REFLECT study. Median overall survival (mOS) and progression free survival (mPFS) was superior in those patients who met the inclusion criteria of the REFLECT study compared to patients who failed to meet the inclusion criteria (mOS 15.6 vs 10.2 months, HR 0.55, 95% CI 0.38-0.81, p=0.002; mPFS 8.1 vs 4.8 months HR 0.65, 95% CI 0.46-0.91, p=0.0015). For patients with an impaired liver function according to the Albumin-Bilirubin (ALBI) grade, or reduced ECOG performance status ≥2, survival was significantly shorter compared to patients with sustained liver function (ALBI grade 1) and good performance status (ECOG performance status 0), respectively (HR 1.69, 95% CI 1.07-2.66, p=0.023; HR 2.25, 95% CI 1.19-4.23, p=0.012). Additionally, macrovascular invasion (HR 1.55, 95% CI 1.02-2.37, p=0.041) and an AFP ≥200 ng/mL (HR 1.56, 95% CI 1.03-2.34, p=0.034) were confirmed as independent negative prognostic factors in our cohort of patients with advanced HCC. Conclusion Overall, our data confirm the efficacy of lenvatinib as first-line treatment and did not reveal new or unexpected side effects in a large retrospective Caucasian real-world cohort, supporting the use of lenvatinib as meaningful alternative for patients that cannot be treated with IO-based combinations in first-line HCC.

BACKGROUND:About 1 year ago a novel virus - SARS-CoV-2 - began to spread around the world. It can lead to the disease COVID-19, which has caused more than 1 million deaths already.SUMMARY:While it was first recognized as a disease leading to pneumonia and lung failure, we know by now that COVID-19 is more complex. COVID-19 is a systemic hyperinflammatory disease affecting not only the lungs, but also many other organs. Especially the gastrointestinal (GI) tract is often involved in COVID-19.KEY MESSAGES:This review provides an overview of the different affected organs of the GI tract and offers information on how gastroenterologists should take care of their patients with different GI disorders.

Background: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. Patients and methods: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. Results: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). Conclusion: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

Gastrointestinal (GI) cancers such as colorectal cancer (CRC), gastric cancer (GC), esophageal cancer (EG), pancreatic duct adenocarcinoma (PDAC) or hepatocellular cancer (HCC) belong to the most commonly diagnosed types of cancer and are among the most frequent causes of cancer related death worldwide. Most types of GI cancer develop in a stepwise fashion with the occurrence of various driver mutations during tumor progression. Understanding the precise function of mutations driving GI cancer development has been regarded as a prerequisite for an improved clinical management of GI malignancies. During recent years, CRISPR/Cas9 has developed into a powerful tool for genome editing in cancer research by knocking in and knocking out even multiple genes at the same time. Within this review, we discuss recent applications for CRISPR/Cas9-based genome editing in GI cancer research including CRC, GC, EG, PDAC and HCC. These applications include functional studies of candidate genes in cancer cell lines or organoids in vitro as well as in murine cancer models in vivo, library screening for the identification of previously unknown driver mutations and even gene therapy of GI cancers.

The systemic treatment of unresectable hepatocellular carcinoma (HCC) has been improved throughout the past years. Different tyrosine kinase inhibitors (TKI) and checkpoint inhibitors have approval for first- and second-line treatment. Still, data are missing about the choice for the right agent and senseful therapy sequences. Between 2017 and 2019 we treated 149 HCC patients. From those, we identified the patients, who received lenvatinib either as a first-line treatment or in a later treatment line. We investigated seven patients retrospectively, who received lenvatinib in second, third, or fourth treatment line regarding efficacy and safety. Besides that, we compared those patients with 13 patients, who received lenvatinib as a first-line treatment regarding duration of therapy, overall survivial (OS), side effects and best response to treatment. We discovered remission (PR) showed 4/7, stable disease (SD) 2/7 and 1/7 mixed response with an overall tolerable safety profile in patients with a later line lenvatinib treatment. The duration and overall survival for therapy is similar in first- and later treatment lines with comparable results. Most side effects are moderate in each treatment line. Remarkably, on patient diagnoses with HCC (the Barcelona Clinic Liver Cancer C algorithm), who received lenvatinib in fourth line reached 67 months OD since diagnosis. We conclude, that lenvatinib could be considered as a treatment option of HCC for later treatment lines.

The human abdomen harbors organs that the host's immune system can attack easily. This immunological storm front leads to diseases like Crohn's Disease, Ulcerative Colitis or Autoimmune Hepatitis. Serious symptoms like pain, diarrhea, fatigue, or malnutrition accompany these diseases. Moreover, many patients have an increased risk for developing special kind of malignancies and some autoimmune disease can show a high mortality. The key to treat them consists of a deep understanding of their pathophysiology. In vitro and especially in vivo basic research laid the foundation for our increasing knowledge about it during the past years. This enabled the development of new therapeutic approaches that interact directly with cytokines or immune cells instead of building the treatment on a total immunosuppression. Different kind of antibodies, kinase inhibitors, and regulatory T cells build the base for these approaches. This review shows new therapeutical approaches in gastrointestinal autoimmune diseases in context to their pathophysiological basis.

Hintergrund Patienten, die an einer chronisch-entzündlichen Darmerkrankung (CED) wie Colitis ulcerosa (CU) oder Morbus Crohn leiden, haben ein erhöhtes Risiko an einer bestimmten Unterart des colorektalen Carzinoms (CRC), dem sogenannte Colitis-assoziierte Carzinom (CAC) zu erkranken.