Therapeutic Advances in Gastroenterology最新文献

Background: The current standard treatment paradigm for patients with unresectable and non-metastatic hepatocellular carcinoma (HCC) involves transarterial chemoembolization (TACE) as the primary local therapeutic modality, followed by systemic therapy upon disease progression. Emerging evidence suggests that the concurrent integration of immunotherapy and targeted therapy with TACE may yield synergistic therapeutic effects. Recent phase III trials-including EMERALD-1, LEAP-012, and TALENTACE-have provided important insights into the efficacy and safety of this multimodal approach.

Objectives: This meta-analysis aimed to quantitatively synthesize the efficacy and safety of first-line TACE combined with immunotherapy and targeted therapy versus TACE alone in patients with unresectable, non-metastatic HCC.

Design: Systematic review and meta-analysis of phase III randomized controlled trials (RCTs).

Data sources and methods: A systematic search of PubMed and major conference proceedings was conducted up to July 6, 2025. Three phase III trials (EMERALD-1, LEAP-012, TALENTACE) were included. Pooled hazard ratios (HRs) for progression-free survival (PFS), odds ratios (ORs) for objective response rate (ORR), and risk ratios (RRs) for adverse events (AEs) were calculated using fixed-effect or random-effects models.

Results: The combination of TACE with immunotherapy and targeted therapy demonstrated superior efficacy compared to TACE monotherapy. The pooled HR for PFS was 0.69 (95% confidence interval (CI): 0.60-0.79), indicating a significant delay in disease progression. The pooled OR for ORR was 1.83 (95% CI: 1.45-2.31), reflecting a markedly improved tumor response rate. However, overall survival (OS) data remain immature, and no statistically significant difference in OS was observed at this stage. In terms of safety, the combination therapy was associated with a higher incidence of AEs. Specifically, it significantly increased the risk of grade 3-5 AEs (RR: 1.88, 95% CI: 1.48-2.40) and serious AEs (RR: 1.65, 95% CI: 1.31-2.07).

Conclusion: First-line treatment with TACE combined with immunotherapy and targeted therapy significantly improves tumor response and prolongs PFS in patients with unresectable and non-metastatic HCC, albeit at the cost of increased toxicity. This combination strategy represents a promising advancement in the therapeutic landscape for HCC, offering meaningful improvements in oncologic outcomes while highlighting the need for careful toxicity management.

Trial registration: International Prospective Register of Systematic Reviews (PROSPERO; CRD420250652613).

Background: Unlike infliximab, ustekinumab (UST) has shown inconsistent associations between drug concentration and clinical efficacy across studies, with varying cutoff therapeutic trough levels (TLs) proposed.

Objectives: Given that patients have different histories of biologic use, we aimed to evaluate whether therapeutic TLs of ustekinumab require optimization in patients with Crohn's disease.

Design: Cohort study.

Methods: To assess whether ustekinumab has a potential therapeutic cutoff value, we evaluated and compared its 1-year TLs in 14 biologic-naïve patients and in 26 patients who were prescribed the drug after experiencing a loss of response to previous biologic therapies.

Results: The mean TL in the biologic-naïve patients was 3.41 µg/mL, which was significantly higher than that in the biologic-experienced patients (1.46 µg/mL; p = 0.007). The duration of prior biologic therapy and disease activity correlated with the ustekinumab TLs. With regard to the optimal cutoff value for predicting deep remission at 1 year, the threshold was 2.34 µg/mL for the biologic-naïve patients (area under the receiver operating characteristic curve (AUC) = 0.909, p < 0.001) and 1.18 µg/mL for the biologic-experienced patients (AUC = 0.892, p < 0.001).

Conclusion: Ustekinumab TLs in patients may differ according to their prior exposure to biologic agents and disease activity. Accordingly, rather than applying a uniform threshold, ustekinumab levels should be interpreted using individualized, patient-specific strategies in clinical practice.

Background: Intestinal fibrosis-associated stricture can lead to bowel complications and subsequent surgeries in patients with Crohn's disease (CD), but there are no widely accepted biomarkers for intestinal fibrostenosis.

Objectives: This study aims to investigate the value of interleukins (IL) in detecting CD-related intestinal fibrostenosis.

Design: This is an observational study.

Methods: Transcriptomic profiling was performed from paired CD surgical resections containing non-involved and fibrostenotic segments. Data were integrated with a public dataset and a Luminex-based serum assay to identify fibrosis-related interleukins, which were further validated at mRNA and protein levels. Correlations with clinical indicators and surgical outcome were analyzed. Lastly, an in vitro assay was used to evaluate the pro-fibrotic effect of the candidate interleukin.

Results: Bulk RNA-sequencing and public dataset revealed increased expression of IL11 in the fibrostenotic intestinal segments of CD patients, which was further validated by real-time polymerase chain reaction and immunohistochemistry. The serum Luminex assay showed that serum IL11 is significantly increased in stricturing CD patients compared to that in non-stricturing CD patients. Clinically, serum IL11 was correlated with disease behavior (r = 0.343, p = 0.006), and increased IL11 expression was linked to a higher risk of subsequent surgery (log-rank p = 0.0055). Furthermore, single-cell RNA sequencing revealed that IL11 and its receptor IL11RA were mainly expressed by fibroblasts. In vitro, IL11 functionally promoted intestinal fibrosis.

Conclusion: IL11, mainly derived from fibroblasts, is enriched in fibrostenotic tissue of CD and promotes intestinal fibrosis. IL11 may serve as a potential biomarker for CD fibrostenosis.

Background: Potassium-competitive acid blocker-based regimens, such as tegoprazan, have demonstrated promising efficacy for Helicobacter pylori eradication. In regions with high antibiotic resistance, such as Gansu Province, bismuth-containing quadruple therapy (BQT) remains the recommended first-line treatment. However, evidence on the efficacy and safety of high-dose tegoprazan-amoxicillin dual therapy (TA) remains limited.

Objectives: To compare the eradication rates and safety profiles of TA and BQT.

Design: Prospective, multicentre, randomised controlled trial.

Methods: Patients were enrolled from 10 centres across Gansu Province, China, between September and December 2024. Participants were randomised 1:1 to receive either BQT (esomeprazole 20 mg twice daily + bismuth potassium citrate 600 mg twice daily + amoxicillin 1000 mg twice daily + metronidazole 400 mg four times daily) or TA (tegoprazan 50 mg twice daily + amoxicillin 750 mg four times daily) for 14 days. The primary outcome was eradication rate. Secondary outcomes included adverse event (AE) rates, treatment compliance and cost-effectiveness.

Results: A total of 288 patients were randomised, with baseline characteristics well balanced between the TA and BQT groups (p > 0.05). Eradication rates for TA versus BQT were 68.06% (98/144) versus 81.25% (117/144) (difference, -13.19%; 95% confidence interval (CI): -22.95 to -3.43; p = 0.009; non-inferiority p = 0.736) in the intention-to-treat analysis; 69.01% (98/142) versus 81.82% (117/143; difference, -12.81%; 95% CI: -22.70 to -2.90; p = 0.011; non-inferiority p = 0.711) in the modified intention-to-treat analysis; and 72.59% (98/135) versus 89.31% (117/131; difference, -16.72%; 95% CI: -26.01 to -7.43; p < 0.001; non-inferiority p = 0.924) in the per-protocol analysis. AEs were less frequent with TA (8.30% vs 25.70%, p < 0.0001), with similar compliance rates (95.07% vs 91.61%, p = 0.241). Multivariate analysis indicated that long-term residence in the southern region of Gansu Province (including Longnan City and Tianshui) was significantly associated with higher eradication rates compared with the Hexi region (adjusted odds ratio = 5.46, p = 0.04), suggesting that geographical factors independently influenced treatment outcomes.

Conclusion: TA did not achieve non-inferiority to BQT and yielded significantly lower eradication rates. The inferior eradication efficacy of TA precludes its recommendation as a first-line therapy in high-resistance settings, such as Gansu.

Trial registration: This trial was registered on the Chinese Clinical Trial Registry with the registration number ChiCTR2400081873.

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.

Background: Recurrent Clostridioides difficile infection (rCDI) disrupts health-related quality of life (HRQoL), often causing debilitating symptoms, emotional distress, and social withdrawal. Fecal microbiota, live-jslm (RBL; REBYOTA^®) is approved by the FDA to reduce CDI recurrence. While the burden of rCDI is well established, less is known about the patient experience after RBL treatment and its impact on HRQoL.

Objectives: To explore the burden of rCDI on HRQoL, and any improvements in symptoms and impacts after RBL administration by colonoscopy.

Design: A qualitative sub-study embedded in the CDI-SCOPE phase IIIb clinical trial (NCT05831189).

Methods: Qualitative interviews were conducted with 30 trial participants approximately 8 weeks after RBL treatment. Interviews were conducted using a semi-structured discussion guide; they were audio-recorded, transcribed verbatim, and thematically analyzed.

Results: Thirty of 41 trial participants (73%) took part in the qualitative interviews (July 2023-September 2024). Participants (mean age 59 years; 87% female) had experienced multiple prior rCDI episodes. Before RBL treatment, participants reported severe symptoms, including diarrhea (30/30; 100%), abdominal pain (21/30; 70%), and fatigue (14/30; 47%), which negatively affected daily life, social interactions, and emotional health. Eight weeks after RBL treatment, no participants reported a recurrence. Diarrhea symptoms resolved (17/30; 57%) or improved (13/30; 43%) for all participants, typically within 1 month. Average severity scores for diarrhea declined markedly (from 8.9 to 1.3). Every participant (100%) reported improved ability to engage in daily activities; nearly all (29/30; 97%) described positive changes to social life/relationships, and 77% (23/30) reported improved emotional well-being.

Conclusion: RBL administered via colonoscopy provided rapid, meaningful relief from rCDI symptoms, and due to symptom improvements, many participants reported that they were able to resume daily life. These findings highlight the broader value of RBL in restoring HRQoL and overall well-being.

Trial registration: ClinicalTrials.gov: NCT05831189.

Background: Crohn's disease (CD) involves chronic intestinal inflammation, frequently requiring surgical intervention. CD patients undergoing surgery often undergo increased psychological stress. One of the outcomes of persistent stress is post-traumatic stress (PTS), a mental health concern associated with immune dysregulation and disease progression. However, research on PTS in CD patients following surgery is limited.

Objectives: This study aims to explore the incidence and associated factors of PTS in CD patients after surgery.

Design: A retrospective cross-sectional study.

Methods: This retrospective cross-sectional study investigated 124 patients with CD who underwent surgery between September 2015 and July 2023. Online questionnaires, including the PTSD checklist, 5th edition (PCL-5), Crohn's and Colitis Knowledge Score, and Short Generic Patient Experience Questionnaire, were employed. The potential risk factors for PTS were evaluated through univariate and multivariate analyses.

Results: Among sampled individuals, 44 patients (35.5%) were classified into the PTS group. The patients in the PTS group had a significant lower monthly income (27.3% vs 8.8%, p = 0.006), higher Harvey-Bradshaw Index score (3.82 ± 3.25 vs 2.31 ± 2.50, p = 0.009), more occurrence of perianal lesions (36.4% vs 20%, p = 0.047), higher ostomy (36.4% vs 20%, p = 0.047), and laparotomy rates (31.8% vs 15%, p = 0.028). Through logistic regression analysis, we identified postoperative complications and a history of multiple surgeries as independent risk factors for PTS (p = 0.002 and p = 0.019, respectively).

Conclusion: PTS is common in CD patients requiring bowel resection and multiple surgeries, as well as other postoperative related factors, can invoke psychological and mental stress. These findings provide insights for formulating medical service strategies that prioritize patient mental health.

Background: Fecal microbiota, live-jslm (RBL) is approved in the United States and Canada for prevention of recurrent Clostridioides difficile infection (rCDI) in adults following standard-of-care (SOC) antibiotic treatment.

Objectives: Provide an updated integrated safety analysis, incorporating final safety data from Punch CD3-OLS.

Design: Safety data were combined from five RBL trials: three phase II and two phase III trials.

Methods: Adult participants had documented rCDI and completed SOC therapy before receiving one or two doses of RBL or placebo, rectally administered as one treatment course. Treatment-emergent adverse events (TEAEs) were recorded for ⩽6 months.

Results: TEAEs were reported in 70.9% (845/1192) of RBL recipients; most TEAEs were mild to moderate and gastrointestinal in nature. Most serious TEAEs were related to preexisting conditions or CDI. There was no clustering of serious TEAEs. Most TEAEs leading to death were related to preexisting conditions.

Conclusion: Overall, data demonstrate RBL has a favorable 6-month safety profile.

Trial registration: ClinicalTrials.gov: NCT01925417; NCT02299570; NCT02589847; NCT03244644; NCT03931941.

Background: Mirikizumab is a first-in-class IL-23p19 inhibitor, which is approved for the treatment of adults with moderate to severe ulcerative colitis (UC).

Objectives: We aimed to assess the effectiveness and safety of mirikizumab in moderate to severe UC in a real-world cohort from two inflammatory bowel disease referral centers.

Design: This was a two-center international retrospective observational cohort study.

Methods: This study aimed to assess the effectiveness and safety of mirikizumab for 12 weeks of induction. Clinical response and remission were defined as a reduction in the Simple Clinical Colitis Activity Index (SCCAI) of ⩾3 points, and SCCAI ⩽ 2, respectively. The primary outcome was the clinical remission rates after 12 weeks of induction.

Results: We included 74 adult patients (58.1% female, 56.8% pan-colitis extent). Most patients (69/74, 93%) were previously exposed to a biological or a small-molecule therapy, and 39 (52.7%) started mirikizumab while on corticosteroids. By the end of induction, 8.1% discontinued therapy due to either lack of efficacy or an adverse event. Overall, clinical response, clinical remission, and corticosteroid-free-remission were 70.3%, 17.6%, and 16%, respectively. Week-12 clinical response and clinical remission rates were comparable between exposed and naïve patients for anti-tumor necrosis factor agents, ustekinumab, vedolizumab, and Janus-kinase inhibitors.

Conclusion: Mirikizumab was effective for inducing clinical response and well-tolerated in a substantial cohort of treatment-experienced patients with UC. This positions mirikizumab as a valuable option to the expanding therapeutic armamentarium for UC.

Background: Fecal microbiota, live-jslm (RBL) is a microbiota-based product for the prevention of recurrent Clostridioides difficile infection (rCDI) in adults following antibiotic treatment. The safety and clinical effectiveness of RBL administered via colonoscopy in adults with rCDI were evaluated in CDI-SCOPE. An 8-week analysis showed 9.8% of participants had RBL-related treatment-emergent adverse events (TEAEs; primary endpoint) and 95.1% experienced treatment success (no CDI recurrence).

Objectives: To evaluate long-term safety and clinical effectiveness of RBL through 6 months of follow-up in CDI-SCOPE.

Design: Single-arm exploratory phase IIIb trial conducted at 12 sites in the United States.

Methods: Eligible adults with rCDI received a single 150-mL dose of RBL to the right colon via colonoscopy. The primary endpoint was RBL-related TEAEs through 8 weeks after RBL administration or confirmed treatment failure. Secondary endpoints included safety up to 6 months after RBL administration. Exploratory analyses included assessment of further CDI episodes.

Results: Of the 41 participants enrolled, 39 completed trial assessments through 6 months. From 8 weeks through 6 months after RBL administration, 36 TEAEs in 15 participants (36.6%) were reported, one of which (irritable bowel syndrome) was RBL-related; most TEAEs (97.2%) were of mild or moderate severity. Over the 6-month trial period, 23 participants (56.1%) experienced 69 TEAEs; 94.2% were of mild or moderate severity. Serious TEAEs occurred in three participants (7.3%), none of which were related to RBL or its administration, and no TEAEs led to discontinuation or death. Overall, 38 participants (92.7%) did not experience further CDI episodes, 1 (2.4%) did between 8 weeks and 6 months, and 2 (4.9%) had an indeterminate outcome due to trial withdrawal before 8 weeks.

Conclusion: RBL administered via colonoscopy was safe and effective for preventing CDI recurrence in adults with rCDI in CDI-SCOPE.

Trial registration: ClinicalTrials.gov: NCT05831189.