Introduction

Gastric cancer is one of the most common malignant tumors with high morbidity, and Helicobacter pylori (H. pylori) infection is the predominant risk factor for gastric cancer. In our previous study, we performed proteomic analysis and compared the differentially expressed RNA-binding proteins between the two groups after H. pylori infection, which led us to focus on Insulin-like growth factor-2 mRNA-binding protein1 (IGF2BP1). As an RNA-binding protein, IGF2BP1 plays an increasingly important role in tumorigenesis, but its mechanism in the pathogenesis of H. pylori infection remains unclear. Therefore, we investigated the role of IGF2BP1 in response to H. pylori infection and gastric tumorigenesis in this study.

Aims & Methods

In vitro cell culture, patient-derived organoids, and in vivo mouse models were used. RT-qPCR and Western blot were used to verify the phenomena in cellular level, mouse model and patient samples. Bioinformatics analyses of local and public databases were applied to analyze IGF2BP1 expression, signaling pathways, and clinical significance. The IGF2BP1 over-expressed stable cell line and stable knockout cell line were constructed by lentiviral infection. Cell proliferation was verified by CCK8 and cell apoptosis assay and the reactive oxygen species (ROS) production was detected by DCFH-DA probe assay. Further mechanisms were explored by RNA Immunoprecipitation (RIP) and RNA turnover experiments. Validated IGF2BP1 as a potential therapeutic target was accomplished by patient-derived organoids culture and xenograft in nude mice with intratumoral injection of BTYNB, a small molecule compound, which was identified as a potent and selective inhibitor of IMP1 binding to c-Myc mRNA.

Results

We found that the expression of IGF2BP1 was significantly up-regulated when H. pylori infected in cell lines, mouse model and patient samples. Cell proliferation induced by IGF2BP1 up-regulated was verified by CCK8 and cell apoptosis assay and ROS production was significantly inhibited after overexpression of IGF2BP1 and up-regulated after knockout of IGF2BP1, suggesting that IGF2BP1 promoted cell proliferation and inhibit ROS production and thus facilitated the survival of malignant cells. Further, transcriptome sequencing revealed that the relevant differentially expressed genes were mainly enriched in the endoplasmic reticulum stress-related pathway, suggesting that IGF2BP1 might influence the occurrence of oxidative stress via ferroptosis. Then we found that IGF2BP1 could inhibit ferroptosis by up-regulating the SLC7A11, which is an important molecule of ferroptosis pathway. Mechanismly, IGF2BP1 acted as an RNA m6A methylation reader to recognize and bind to SLC7A11 mRNA, and promoted the expression level of SLC7A11 after increasing its mRNA stability thereby inhibiting ferroptosis. Taken together, IGF2BP1 could inhibit ferroptosis and promote cell proliferation, thus promoting the development of gastritis and gastric cancer associated with H. pylori infection. Intratumoral injection of BTYNB into xenograft in nude mice significantly inhibited the proliferation of tumors with high IGF2BP1 expression, which indicated that IGF2BP1 was a potential therapeutic target in gastric cancer.The same result was likewise demonstrated in patient-derived organoids culture system.
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Conclusion

Our results clarified the important role of IGF2BP1 in gastric mucosal diseases associated with H. pylori infection, and identified IGF2BP1 was a potential therapeutic target in gastric mucosal diseases through cellular experiments, mouse model and clinical patient samples.

Introduction

Intragastric balloon (IGB) is a minimally invasive intervention used for obese patients who do not achieve adequate weight loss with standard medical therapy (SMT), which includes lifestyle interventions with or without pharmacological treatment. It is also an option for individuals who do not meet the criteria for bariatric surgery or choose not to undergo it. Despite its growing use, there is little data on the short and long-term effectiveness of IGB compared to SMT in randomized controlled trials (RCTs).

Aims & Methods

This systematic review and meta-analysis aimed to compare the efficacy of IGB therapy for at least six months versus SMT in the treatment of obesity, assessing outcomes at 6, 9, and 12 months. A comprehensive literature search was conducted in the MEDLINE, EMBASE, and Cochrane Library databases. The primary outcome was the percentage of excess weight loss (%EWL), while secondary outcomes included absolute weight loss (AWL), percentage of total weight loss (%TWL), and body mass index reduction (BMIR). We calculated mean differences (MD) with 95% confidence intervals (CI) for continuous outcomes. Meta-regression was performed using baseline body mass index (BMI) as a covariate, and subgroup analyses were conducted based on IGB type, baseline BMI, and pharmacological therapy in the SMT group.

Results

A total of 15 RCTs, including 1,961 patients, were included. Compared to SMT, IGB therapy resulted in significantly greater %EWL at 6 months (MD 16.80%; 95% CI [9.22%; 24.38%]), 9 months (MD 14.36%; 95% CI [7.67%; 21.04%]), and 12 months (MD 13.10%; 95% CI [10.43%; 15.77%]). IGB was also superior in AWL, %TWL, and BMIR across all time points (Table 1). Subgroup analyses revealed that results remained consistent regardless of pharmacological therapy use in the SMT group (p=0.77). The Orbera balloon showed superior %TWL at 6 months (p<0.01) and AWL at 6 months (test for subgroup differences with p=0.01), while the Spatz3 balloon demonstrated better %TWL at 9 months (p<0.01). Studies with a baseline BMI >40 kg/m² had significantly greater %TWL at 6 months (p=0.04) and AWL at 6 months (p<0.01) than those with BMI ≤40 kg/m². Meta-regression analysis indicated that higher baseline BMI was associated with greater AWL and BMIR at 6 months.

Conclusion

IGB therapy was significantly more effective than SMT, even when pharmacological therapy was included, leading to superior weight loss outcomes at 6, 9, and 12 months.

Table 1. Summary of findings.

References

1- Abu Dayyeh, Barham K, et al. Lancet. 2021.

2- Chan, Daniel L., et al. Obesity Surgery. 2021.

3- Coffin, B, et al. Obes Surg. 2017.

4- Courcoulas, et al. Int Journal of Obesity. 2017.

5- Farina, Maria Grazia, et al. Obes Surg. 2012.

6- Fuller, et al. Obes Bio and Int Physiology. 2013.

7- Gómez, V, et al. Obesity. 2016.

8- Hollenbach, M, et al. Digestion. 2024.

9- Kashani, et al. SN Comp Clinical Med. 2022.

10- Konopko-Zubrzycka, et al. J Clin Endoc Metab. 2009.

11- Lee, YM, et al. Gastrointest Endosc. 2012.

12- Mohammed, et al. Trends Med Res. 2014.

13- Ponce, J, et al. Surg Obes Relat Dis. 2015.

14- Sullivan, S, et al. Surg Obes Relat Dis. 2018.

15- Vicente, M, et al. Surgical Endoscopy. 2020.

Introduction

Upper gastrointestinal bleeding (UGIB) poses a significant threat in patients presenting to the emergency department, particularly in those with associated hemodynamic instability. Despite major advancements in medical and endoscopic therapeutic options, mortality rates have not shown a substantial decline over the years. This study aimed to assess clinical practice patterns in order to gain a clearer understanding of the pre-endoscopic assessment for patients with acute UGIB.

Aims & Methods

This study was an international online survey based on a prospective two-phase data collection approach, conducted between April 2023 and November 2023. The survey targeted practicing physicians actively involved in managing patients with UGIB. Data collection and management were performed through Research Electronic Data Capture (REDCap), an electronic data collection tool. The survey comprised four key domains: demographics and clinical practice, definitions of hemodynamic instability, pre-endoscopic assessment, and optimal timing of endoscopy, encompassing a total of 33 questions. The primary analysis provided a descriptive assessment of responses reported as proportions. Secondary analyses explored differences in responses based on years of clinical experience, practice setting, and the estimated annual number of UGIB cases encountered

Results

A total of 533 clinicians from 50 countries completed our survey. Among respondents, 54.6% work in university-based hospitals, and 67.7% reported managing over 100 UGIB patients annually. Regarding clinical experience, 55.7% have less than 10 years, with 44.3% with over 10 years of experience. Only 47.1% of respondents reported that their hospitals implement a triage system for UGIB patients. Additionally, 39.6% indicated that they do not use any risk stratification scores at the time of patient presentation. For initial fluid resuscitation, 0.9% saline (40.9%) and balanced crystalloid fluids (39.5%) were almost equally preferred. The rate of fluid resuscitation was reported to depend on the patient’s hemodynamic status by 40.2% of respondents. Most respondents indicated that hemodynamically unstable patients are primarily managed in the emergency department or intensive care unit. A total of 34.3% of respondents indicated that they do not routinely use prokinetics prior to endoscopy in UGIB patients, while 27.6% reported not commonly using them even in cases involving severe bleeding or known gastric emptying disorders. Proton pump inhibitors are administered prior to upper GI endoscopy in all cases by 70.4% of respondents, while vasoconstricting agents are used by 61% in cases of suspected variceal bleeding.

Conclusion

Our survey found considerable variability among respondents regarding the pre-endoscopic management of patients presenting with upper gastrointestinal hemorrhage. The overall adherence to international guidelines was low, which can potentially result in a significant negative impact on patient outcomes.

Introduction

Mirikizumab, a p19-directed interleukin-23 monoclonal antibody, is efficacious in inducing clinical response at Week(W) 12 and maintaining clinical remission through W52 in patients with moderately-to-severely active Crohn’s disease (CD) as shown in the phase 3 treat-through trial VIVID-1 (NCT03926130).¹ Here, we present analysis of maintenance outcomes through W52 for Patient-Reported Outcome (PRO) clinical responders and nonresponders at W12.

Aims & Methods

The analysis set includes patients randomized to mirikizumab at baseline, who did or did not achieve PRO clinical response at W12 after intravenous (IV) induction treatment (900 mg mirikizumab IV every 4 weeks [Q4W]) before entering subcutaneous (SC) maintenance treatment (300 mg mirikizumab SC Q4W). Descriptive statistics are used to summarize the data, applying nonresponder imputation for missing binary endpoints. As a treat-through study, no rerandomization was applied.

Results

From a total of 551 patients who entered SC maintenance treatment, baseline characteristics of age, duration of CD, and baseline Crohn’s Disease Activity Index (CDAI) were similar between W12 PRO responders (n=402, 73.0%) and W12 PRO nonresponders (n=149, 27.0%). PRO responders at W12 had a higher objective inflammatory burden at baseline (faecal calprotectin, c-reactive protein, and Simple Endoscopic Score-CD), whereas concomitant or prior medication usage was similar between the groups. For W12 PRO responders, SC mirikizumab treatment from W12 to W52 resulted in an increase in CDAI clinical remission from 52.2% to 65.4%, PRO clinical remission from 53.2% to 65.4%, and endoscopic response from 35.1% to 54.7%, respectively (Table 1). Among W12 PRO nonresponders, PRO response was achieved by 39.6% at W16, 45.6% at W20, 44.3% at W24, and 56.4% at W52 with continued mirikizumab SC treatment, while CDAI clinical remission and PRO clinical remission were achieved by 33.6% and 31.5% at W52, respectively. Endoscopic response increased from 30.2% at W12 to 40.3% at W52 among W12 PRO nonresponders (Table 1).

Conclusion

Subcutaneous mirikizumab maintenance treatment over 40 weeks leads to incremental and sustained improvements in rates of clinical and endoscopic response regardless of PRO clinical response status after induction. A substantial proportion of clinical nonresponders at W12 improved early during maintenance treatment suggesting continued treatment with mirikizumab can be beneficial and lead to long-term response.

References

1. Ferrante, Marc et al. Efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn's disease: a phase 3, multicentre, randomised, double-blind, placebo-controlled and active-controlled, treat-through study. Lancet. 2024;404(10470):2423-2436. doi:10.1016/S0140-6736(24)01762-8

Introduction

While three JAK inhibitors are now available in Ulcerative Colitis (UC), no direct comparison exists between these drugs making difficult the hierarchization of these therapeutic options.

Aims & Methods

We performed a systematic review and network meta-analysis to compare the short and long-term efficacy of the three available JAK inhibitors (JAKi) (Tofacitinib/TOFA, filgotinib/FILGO, upadacitinib/UPA) in patients with moderat-to-severe UC.
We performed a systematic review and network meta-analysis (PRISMAguidelines) of randomized controlled trials (including post-hoc analyses) conducted in adults, evaluating the efficacy of JAKi in moderate-to-severe UC.
The outcome mesures were 1) steroid-free clinical remission (CFREM) after induction therapy (partial Mayo score ≤ 2), 2) CFREM with endoscopic improvement (endoscopic Mayo score ≤ 1) after induction therapy, 3) CFREM at one year among induction-responders, 4) CFREM at one year among patients in clinical remission after induction.
The network meta-analysis was carried out according to a random effects model. The results are presented as relative risk (RR) with 95% confidence interval. The risk of bias of the studies was assessed according to the Cochrane risk-of-bias tool for randomized trials and overall statistical heterogeneity between studies was assessed using τ .
The SUCRA ranking method (surface under the cumulative ranking) was used to rank the treatments.

Results

Nine studies were included in this network meta-analysis, including a total of 2015 patients.
TOFA 10mg bid, FILGO 200 mg qd and UPA 45mg qd were more effective than placebo to induce CFREM and CFREM with endoscopic improvement. Side-by-side comparisons between JAKi found a higher efficacy of UPA 45 mg qd versus FILGO 200 mg qd (RR=0.22[0.10; 0.45]) for induction but no other significant difference between JAKi. SUCRA ranking hierarchizes induction therapies as following : UPA 45 mg qd (0.99), TOFA 10mg bid (0.75), FILGO 200 mg qd (0.27) and placebo (0.01).
Among induction-responders, all JAKi maintenance regimen (TOFA 10mg bid, TOFA 5mg, bid, FILGO 200mg qd, FILGO 100 mg qd, UPA 30 mg qd, UPA 15 mg qd) were more effective than placebo to achieve CFREM at one year with the following SUCRA ranking : UPA 30mg qd (0.85), TOFA 10mg bid (0.80), FILGO 200 mg qd (0.64), TOFA 5mg bid (0.56), UPA 15 mg (0.44), and placebo (0.01).
Among patients in CFREM after induction phase, all JAKi maintenance regimen (TOFA 10mg bid, TOFA 5mg, bid, FILGO 200mg qd, FILGO 100 mg qd, UPA 30 mg qd, UPA 15 mg qd) were more effective than placebo to achieve CFREM at one year with a different ranking (SUCRA) : TOFA 10 mg bid (0.84), FILGO 200 mg bid (0.74), TOFA (5mg bid) (0 .66), UPA 30mg qd (0.63), UPA 15 mg (0.44) and placebo (0.09).

Conclusion

While this network meta-analysis confirms the efficacy of JAKi to induce and maintain CFREM in moderate-to-severe UC, UPA seems to be the most effective JAKi to induce and maintain CFREM. However, once CFREM achieved after induction, continuing the same dose than during induction such as TOFA (10mg bid) or FILGO 200 mg seems to be more effective than reducing the dose (UPA 30 mg or UPA 15 mg) to maintain remission highlighting the dose-efficacy relationship of JAKi.

Disclosure

Consulting fees from: Abbvie, Amgen, Arena, Biocon, Biogen, Celltrion Healthcare, CTMA, Ferring, Galapagos/AlfaSigma, GutyCare/Resilience Janssen, Lilly, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda et Tillotts
Lecture fees from: Abbvie, Amgen, Biogen, Celltrion Healthcare Galapagos/AlfaSigma, Ferring, Janssen, Lilly, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma
Research grants/fundings from: Abbvie, Celltrion Healthcare, Janssen, Lessaffre, Lilly, Pfizer, Sandoz and Takeda

Introduction

Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis. Indeed, several risk stratification scores have been developed to anticipate early detection in order to better codify their management, including the Toronto Hepatocellular Carcinoma Risk Index (THRI). It is a simple and validated tool that has been developed to predict the risk of HCC in patients with cirrhosis and is mainly based on the following parameters: etiology, age, sex and platelet count.
The objective of this study was to evaluate the reliability of the THRI score in predicting the occurrence of hepatocellular carcinoma.

Aims & Methods

We conducted a monocentric retrospective study collecting all cirrhotic patients over an 8-year period [2008-2015]. Clinico-biological data, disease severity, and long-term outcomes were collected.
THRI was calculated for all patients, and were classified according to HCC risk into three levels : low HCC risk (<120), intermediate HCC risk (between 120 and 240), and those with high HCC risk (>240).
A statistical study using the SPSS tool was carried out. The performance of this score was evaluated with the area under the receiver operating characteristics curve (AUROC).

Results

We included 120 cirrhotic patients with an M/F sex ratio equal to 0.5. The mean age was 57 years [14-85]. The most frequent aetiology of cirrhosis were viral C (49%) and viral B (31%). The mean overall survival was approximately 6 years after diagnosis.
Twenty-five patients developed HCC during follow-up (20.8%). Patients who developed HCC had a higher THRI score than those who did not develop HCC : 264.8 ± 48.6 versus 232.3 ± 64.8, respectively with p-value = 0.008
Patients with a low risk of HCC were 5 (4.2%), none of whom had developed HCC. Fifty-eight patients (48.3%) were at intermediate risk, 12% of them (N=7) had developed HCC. The remaining 57 patients (47.5%) were at a high risk and 31.6% of them (N=18) developed HCC during their follow-up.
The AUROC for the THRI to predict HCC was 0.649 ([95% CI 0.533–0.765]. The cutoff THRI value in predicting the occurrence of HCC was 235.5 with a sensitivity of 72% and a specificity of 50%.

Conclusion

According to our study, the THRI score appears to be an effective tool for predicting the occurrence of HCC in cirrhotic patients. Its good sensitivity allows to identify the high-risk HCC population for early screening.