Introduction

Treatment of IBD during pregnancy poses a clinical challenge. Myths and misconceptions abound. Numerous studies have shown active IBD is associated with adverse maternal and fetal outcomes. A growing field of new medication also creates challenges. We conducted a retrospective cohort study to report pregnancy outcomes and clinical practice in a large tertiary centre in the UK in 2023.

Aims & Methods

Tertiary care for pregnant patients with IBD is provided through a specialist joint gastroenterology-obstetrics service. Data was retrospectively extracted from the electronic health records of 50 women looked after between January 1st and July 1st 2023. We describe the patient population including IBD characteristics, treatments and disease activity during pregnancy and report obstetric outcomes.

Results

50 unique pregnant women were included; 30 (60.0%) had Crohn’s disease (CD) and 20 (60.0%) had Ulcerative Colitis (CD) with a median age of 34. Within the CD cohort, 4 (13.3%) had prior or active perianal disease. Vaginal delivery is relatively contraindicated in this cohort and all patients underwent C-section.  
Overall, 22/50 (44.0%) patients were taking biologics, 6/50 (12.0%) on thiopurines, 14/50 (28.0%) on mesalazine only and 14/50 (28%) were on no IBD medication at the time of conception. Of those taking biologics, 3/22 (13.6%) discontinued in the third trimester while 19/22 (86.4%) continued biologics throughout pregnancy. This reflects a recent change in practice; only patients in remission with low risk of flare stopped biologic medication during pregnancy. ¹
50% experienced an IBD flare during pregnancy. A flare was defined as a faecal calprotectin >250μg/g or exacerbation of symptoms requiring change in medical management.   
A significant proportion (20/50, 40.0%) developed anaemia during pregnancy (Hb <116g/L). 6 (12%) developed anaemia according to pregnancy parameters (Hb <106g/L. 21 (42.0%) received iron supplementation. 11 (52.4%) received it exclusively orally, 3 (14.3%) exclusively intravenously and 5 (23.8%) received both. Oral iron was tolerated poorly.  
 Regarding obstetric outcomes; 48 (96.0%) had live singleton births, with 1 (2.00%) miscarriage and 1 (2.00%) elective termination following an abnormal anomaly scan; found at post-mortem to have Turner’s syndrome. 35/48 (72.9%) women delivered in our hospital while 13/48 (18.1%) delivered in a local hospital.   
1/48 (3.9%) baby was born prematurely (<37 weeks). Median birthweight was 3235g (2410g – 4280g). 2/48 (4.2%) were born with low birth weight (<2.5Kg), and 4/48 (8.3%) had fetal macrosomia (>4.0Kg). Median birthweight was lower in mothers who experienced flare (3210g) compared to those with no flare (3310g).
Incidence of gestational diabetes mellitus (GDM) (25.7%) was higher compared with the national average of 5%. Antenatal steroid use is associated with hyperglycaemia and GDM. Steroids were required to control disease flares in 6/48 (12.5%) women; 3 had prednisolone, 2 had budesonide and 1 buccal hydrocortisone. Only 1/6 (16.7%) exposed to steroids developed GDM.

Conclusion

IBD flares were common in pregnancy, which may reflect the complexity of patients referred to the tertiary service. Most patients continued biologic medication during pregnancy including the third trimester. Obstetric and neonatal outcomes were similar to the general population. Anaemia was similar to and GDM was more common than the local population. Awareness and proactive management of these issues including continuing IBD medication is important to reduce the risk of associated complications.

References

1. Torres J, Chaparro M, Mette Julsgaard, Katsanos K, Zuzana Zelinkova, Agrawal M, et al. European Crohn’s and Colitis Guidelines on Sexuality, Fertility, Pregnancy, and Lactation. Journal of Crohn’s and Colitis [Internet]. 2022 Aug 25;17(1):1–27. Available from: https://academic.oup.com/ecco-jcc/article/17/1/1/6675338

Introduction

Immune checkpoint inhibitors (ICIs), alone or in combination with tyrosine-kinase inhibitors (TKIs), have changed the therapeutic landscape of several cancers, but response is still unsatisfactory in a considerable (>30%) rate of patients. Increasing evidence shows that gut microbiome composition associates with response to ICIs in patients with epithelial cancers. Preliminary evaluations also suggest that fecal microbiota transplantation (FMT) may enhance response to ICIs in patients with melanoma, but randomized studies to confirm these results, as well as findings from other epithelial cancers, are still unavailable.

Aims & Methods

Our aim is to investigate, by a randomized, double-blind, placebo-controlled trial (TACITO trial - NCT04758507), whether targeted FMT (from donors who respond to ICIs) is effective in improving response to combined ICIs/TKIs first-line therapy in patients with advanced renal cell carcinoma (aRCC).
Fifty patients with aRCC, who were starting, or have started no earlier than 8 weeks, treatment with axitinib+pembrolizumab as first-line therapy, were randomized 1:1 to receive donor FMT (d-FMT) or placebo FMT (p-FMT) for three times in six months. Both groups underwent the first procedure by colonoscopy, followed by capsulized FMT after 90 and 180 days, respectively. Patients in the d-FMT arm received feces from a patient with mRCC who had achieved a complete and long-lasting response to ICIs, selected by following protocols recommended by international guidelines.
Patients were followed up 7, 15, 30, 90, 180, 270, and 360 days after randomization for clinical evaluation and collection of biological samples. The primary endpoint was the progression-free survival (PFS) at 12 months. Secondary endpoints were: median PFS, overall survival (OS), objective response rate (ORR), adverse events after FMT, microbiome changes after FMT.
Sample size calculation was based on the hypothesis that FMT can provide a 20% improvement of the 12-month PFS rate when associated to standard of care (SOC) - from 60%, that is the reported 12-month PFS for SOC- to 80%.

Results

Fifty patients were randomized to d-FMT (International mRCC Database Consortium[IMDC] risk: 28% favorable, 72% intermediate-poor) or p-FMT (32% favorable, 68% intermediate-poor). At August 2024, 44 of them completed the follow-up and were evaluated for the primary endpoint (24 in the d-FMT arm and 20 in the p-FMT arm). The 12-month PFS rate was 66.7% in the d-FMT arm vs. 35.0% in the p-FMT arm (p=0.036). In the overall population, after a median follow-up of 28.0 months, the median PFS was 14.2 months (95%CI, 0.9–27.6) in the d-FMT arm vs. 9.2 months (95% CI, 3.0–15.4) in the p-FMT arm, and the median OS were not reached vs. 25.3 (95%CI, 17.1–33.6) months with d-FMT and p-FMT, respectively. The ORR was 54% in the d-FMT arm vs. 28% in the p-FMT arm. Stable disease (SD) was found in 38% of the d-FMT arm vs. 44% of the p-FMT arm. Disease progression (PD) was observed in 8% of the d-FMT arm vs. 28% of the p-FMT arm. Only one patient in the p-FMT arm reported a procedure-related adverse event (grade 3 oral mucositis) and discontinued capsules assumption.

Conclusion

The preliminary results of this unprecedented randomized controlled trial suggest that responder-derived FMT may improve the efficacy of ICIs+TKIs in patients with aRCC.

Supplementary Infographic ↗

Introduction

Mirikizumab, an anti-IL-23p19 antibody, has demonstrated efficacy and safety in moderately-to-severely active ulcerative colitis (UC) Phase 3 trials (LUCENT-1 and -2; NCT03518086, NCT03524092). A treatment goal for patients with UC is corticosteroid (CS)-free remission. We assessed the CS-sparing effect of mirikizumab among the extended induction patient population receiving CS at induction baseline.

Aims & Methods

In LUCENT-1, patients in the modified intention to treat mirikizumab group (n=868) received mirikizumab 300 mg intravenously (IV) at Week (W)0, W4, and W8. Patients receiving mirikizumab on CS at baseline (n=351) remained on their stable baseline dose (prednisone ≤20 mg/day or equivalent, budesonide MMX 9 mg/day, or beclomethasone 5 mg/day) during induction (W0 to W12). Patients not achieving clinical response (≥2-point and ≥30% decrease in Modified Mayo Score from baseline; and rectal bleeding=0 or 1, or ≥1-point decrease from baseline) at W12 (n=272) entered LUCENT-2 open label (OL) extended induction and received 300 mg mirikizumab IV at W12, W16, and W20. Extended induction responders at W24 (n=144) entered OL maintenance and received 200mg mirikizumab subcutaneously (SC) Q4W until W52. CS taper was initiated if clinical response was achieved at W24 or earlier based on investigator discretion if symptomatic improvement was evident. Patients who discontinued CS and remained off throughout the study were considered “discontinued.” Descriptive statistics for efficacy outcomes were summarized. Missing data were imputed as non-response.

Results

Of the 272 mirikizumab patients in the extended induction population, 118 received CS at induction baseline. The mean prednisone equivalent dose was 15mg. At W24, among the 62/118 (52.5%) who achieved clinical response and continued with maintenance, 8 (12.9%) discontinued CS, 2 (3.2%) achieved clinical remission off CS, and 8 (12.9%) achieved symptomatic remission off CS. At W52, 43/62 (69.4%) of the extended induction responders discontinued CS, 18 (29.0%) achieved clinical remission off CS, and 37 (59.7%) achieved symptomatic remission off CS. Among patients with non-missing data who completed W52 of mirikizumab treatment, 89.6% had discontinued CS (Table).
Table. Corticosteroid-Sparing Effect of Mirikizumab in Extended Induction Population Receiving Corticosteroids at Induction Baseline

Conclusion

Nearly 70% of extended induction responders discontinued CS by W52. CS-sparing effect of mirikizumab in patients with moderately-to-severely active UC is clinically meaningful and aligns with the treatment goal of CS discontinuation.

Disclosure

DL declares counseling, boards, transports or fees from Abbvie, Biogaran, Biogen, Ferring, HAC-pharma, Janssen, MSD, Novartis, Pfizer, Prometheus, Roche, Takeda, Theradiag, Tillots.
CS reports advisory board and consultant fees for Abbvie, BMS, Lilly, Janssen, Pfizer, Prometheus, Takeda and Trellus Health; speaker for CME activities for Abbvie, Janssen, Pfizer and Takeda; received grant support from Abbvie, Janssen, Pfizer and Takeda; intellectual property for a “System and Method of Communicating Predicted Medical Outcomes”; co-founder of MiTest Health, LLC (software company) that has technology (PROSPECT/CDPATH) that has been licensed to Takeda.
PD reports consulting fees from Johnson and Johnson, Gilead, Lilly, BMS, Novartis, Pfizer, and Takeda; financial support for research from Takeda and Pfizer; stock options for DigbiHealth; and licensing royalties from PreciDiag.
KM has received speaker fees and research grants from AbbVie, EA Pharma, Mochida, Mitsubishi-Tanabe, ZERIA, Nippon Kayaku, and JIMRO; speaker fees from Takeda, Janssen, Pfizer, Kyorin, Kissei, Gilead, Eli Lilly, and Celltrion Healthcare.
JPG has served as speaker, consultant, and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos, Lilly, Ferring, Faes Farma, Shire Pharmaceuticals, Dr Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine and Vifor Pharma.
KHS, IR,SB are employees and minor shareholders of Eli Lilly and Company
JP is an employee of Syneos Health and contractor for Eli Lilly and Company
VJ has received consulting/advisory board fees from AbbVie, Alimentiv Inc. (formerly Robarts Clinical Trials), Arena Pharmaceuticals, Asieris, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Reistone Biopharma, Roche, Sandoz, Takeda and TopiVert, and speaker’s fees from AbbVie, Ferring, Galapagos, Janssen, Pfizer, Shire and Takeda.

Introduction

Current surveillance for low-risk Barrett's Esophagus (BE) patients is burdensome, cost-ineffective and dependent on subjective histological assessment of dysplasia with high inter-observer variability. This study aims to identify genomic features that can be identified in a clinically translatable targeted sequencing panel, enhancing the stratification of low-risk BE patients and enabling personalized surveillance strategies.

Aims & Methods

BE patients identified as progressors to early esophageal adenocarcinoma or non-progressors from a large community-based cohort, were matched for age, sex and BE segment length. DNA from baseline and prior non-dysplastic biopsies was sequenced using a targeted capture-based panel designed to detect mutations and copy number changes (CNV). Detected mutations, homozygous deletions, and high-level amplifications were filtered for likely pathogenic events. We performed logistic regression, covariate analysis, and penalized mixed-effect models. A joint model for survival and mixed effects was implemented to analyze the data distributed over space and time.

Results

331 baseline samples and 214 temporal samples, accounting for 105 progressors who progressed after a median 4 (IQR 2.4-7.2) years, and 115 non-progressors who had a median progression-free follow-up of 6 (IQR 4.3-7.3) years, were analyzed. TP53 mutations strongly predict risk (p < 0.0001, Hazard Ratio (HR) = 3.84, 95% confidence interval (CI) 2.89-5.67) as does CNV 17p loss (p < 0.0001, HR = 4.41, 95% CI 2.29-8.52). While there is significant overlap between TP53 mutations and 17p loss, patients with both trended to progress faster. Chromosomal arm CNVs (p = 0.0012, HR = 1.32, 95% CI 1.14-1.52), amplifications (p < 0.001, HR = 2.89, 95% CI 1.57-5.31) and mutational burden (p<0.0001, HR = 1.30, 95% CI 1.21-1.40) were also associated with progression risk. A combined model incorporating: —TP53 mutations, 17p loss, and mutational burden—demonstrated a 57% sensitivity and 84% specificity and an AUC of 0.758. This model identified 60 of 105 progressors in non-dysplastic BE patients.

Conclusion

As expected, TP53 was a pivotal risk factor in this spatial and time-dependent cohort, even in the absence of dysplasia. Two hits in TP53 (mutation with 17p loss) suggested a trend toward near term progression, suggesting the possibility of more refined stratification. Prior studies focused on either mutations or CNVs for risk stratification. We show the combination of both, detected in a clinically translatable assay, improves prognostic value, effectively identifying the majority of progressors among non-dysplastic BE patients while maintaining an acceptable false-positive rate. This approach has the potential to dramatically impact risk stratification and surveillance strategies in non-dysplastic BE patients.

Supplementary Infographic ↗

Introduction

Obesity is a chronic relapsing multifactorial disease. As such, a “one and done” strategy may not lead to satisfying results in the long term for both surgical and endoscopic procedures. Endoscopic Sleeve Gastroplasty (ESG) is an effective, safe and repeatable bariatric procedure. As loss of satiety with weight regain or insufficient weight loss may occur after a primary ESG, re-ESG may play a role in such patients to improve weight loss. In this case series, we evaluate the short and medium-term outcomes of the re-ESG.

Aims & Methods

A retrospective analysis was performed on a prospective database including patients who underwent ESG between March 2017 and September 2022; patients who received a re-ESG because of progressive loss of satiety, insufficient weight loss and weight regain ≥ 50% after primary ESG were included in the analysis. %EWL, %TBWL, and the Bariatric Analysis and Reporting Outcome System (BAROS) questionnaire were assessed during follow-up. Weight loss parameters were calculated both after re-ESG and overall.

Results

Of 406 patients that underwent ESG, twenty-seven required a re-ESG (6.7%). The mean time between the primary ESG and the re-ESG was 20 months (range 7-42). Re-ESG was technically feasible in all patients and no periprocedural adverse events occurred. The adherence to follow-up was 22/27 (81.5%) at 1 month, 17/26 (65.4%) at 3 months, 15/23 (60.9%) at 6 months and 13/19 (68.4%) at 12 months.
The mean BMI was 38.4 ± 6.5 kg/m² and 35.5 ± 6.0 kg/m² at primary ESG and re-ESG, respectively. The overall mean %TBWL was 18.2% ± 8.1 and 18.7% ± 6.2 at 6 and 12 months, respectively. The mean %TBWL after re-ESG was 10.3% ± 6 at 1 month, 13.2% ± 6.4 at 3 months, 13.6% ± 7.7 at 6 months, 14.1% ± 7.5 at 12 months. BAROS questionnaire mean score was 4.2 ± 2.0 and 4.1 ± 1.8 at 6 and 12 months, respectively. More details are summarized in Table 1. All patients reported a proper sense of satiety and substantial improvement in quality of life after the re-ESG.

Conclusion

According to our experience, re-ESG has satisfying short and medium-term outcomes in terms of satiety, weight loss and quality of life. As such, repeating ESG should not be seen as a failure, but a further step in the endoscopic approach to obesity.

Disclosure

Ivo Boskoski is a consultant for Apollo Endosurgery, Cook Medical, BostonScientific, and Nitinotes.