Introduction

New biologics such as vedolizumab (VDZ) and ustekinumab (UST) have expanded the therapeutic armamentarium for inflammatory bowel diseases (IBD) over the past decade. Head-to-head trials comparing safety to tumor necrosis factor alpha inhibitors (anti-TNF) are limited. Data on safety of biologic sequencing remains scarce.

Aims & Methods

Aim: To assess the impact of different biologics and previous treatments on the incidence of severe adverse events (SAE) in a real-world tertiary IBD patient cohort.
Methods: A retrospective monocentric study was performed at the Ghent University Hospital. Patients starting anti-TNF, VDZ or UST from January 2018 to June 2021 with follow-up until December 2021 were included. SAE were defined as intestinal resection (IR), IBD-inflammation related hospitalization (IBD-hosp), IBD-treatment related hospitalization (e.g. infections) (treat-hosp), malignancy and death. Cox regression analysis was used to explore risk factors (RF) of SAE.

Results

In total 267 patients were included: 84 on VDZ, 69 UST, 60 infliximab (IFX) and 54 adalimumab (ADM). At baseline a significant difference was found between biologic groups for age (younger in IFX and ADM - P=0.001), IBD type (Crohn’s disease (CD): VDZ 51.2%, UST 73.9%, IFX 70%, ADM 77.8% - P=0.003), CRP (in mg/L, med, IQR - VDZ: 5[1.6-12.4], UST: 8.5[2.8-19.3], IFX: 13 [1.87-31.8], ADM:3.2[1-8.1] - P<0.001) and calprotectin (in µg/g, med, IQR) (VDZ: 579 [175- 1801], UST: 707 [244-2889], IFX: 652 [65-2449], ADM 200 [43.7-789] - P=0.021)). Perianal CD rate was higher in anti-TNF and UST patients (P=0.003) and prior disease duration differed significantly (VDZ: 9years, UST10y, IFX 2y,ADM 3.5y - P<0.001)). Concomitant immunomodulator (IMM) use was higher in the IFX group (81.7% vs 25% for all other groups P<0.001)) and corticosteroid (CS) use differed among treatment groups (VDZ 78.6%, UST 68.1%, IFX 70%, ADM 55.6% (P=0.041)). Number of prior biologics was higher in the UST group (P<0.001).
No significant difference in SAE rate could be found between different biologics (UST 37.7%, IFX 33.3%, VDZ 23.8%, ADM 22.2% - P=0.148). Cox regression revealed age ≥60years (aHR 2.00, 95%CI 1.11-3.60, P=0.020) and higher number of previous biologics (aHR 1.29, 95%CI 1.03-1.60, P=0.024) as independent RF for SAE. Considering SAEs types, IR rate was not significantly different between biologic groups (VDZ 4.8%, UST 15.9%, IFX 8.3%, ADM 5.6% - P=0.096). Cox regression revealed previous IMM use as an independent RF for IR (aHR 4.26, 95%CI 1.62-11.19, P=0.003). No significant difference was found between biologics considering IBD-hosp (VDZ 15.5%, UST 30.4%, IFX 21.7%, ADM 14.8% – P=0.087). Higher number of previous biologics was an independent RF for IBD-hosp (aHR 1.32, 95%CI 1.02-1.71, P=0.036). Treat-hosp rate was not significantly different between biologic groups (VDZ 7.1%, UST 10.1%, IFX 6.7%, ADM 5.6% – P=0.811). Age ≥60years was found to be an independent RF of treat-hosp (aHR 4.93, 95%CI 1.91-12.76, P=0.001). Six patients developed malignancy (3 VDZ: colorectal carcinoma, melanoma, low grade appendix neoplasia; 2 IFX: cervix CIN3, gastric adenocarcinoma; 1 ADM: basal cell carcinoma). One patient died due to progressive melanoma while on VDZ.

Conclusion

In this tertiary real-world IBD patient cohort, no influence of type of biologic on the SAE rate could be found. Elderly age (≥60 years) and higher number of previous biologics were an independent RF for SAEs.

Introduction

Hepatocellular carcinoma (HCC) is the most common primary malignant liver cancer globally and ranks as the third leading cause of cancer-related mortality. Treatment with immune checkpoint inhibitors (most commonly atezolizumab in combination with bevacizumab) is the most effective first-line systemic therapy for patients with advanced HCC. Since it is a new method of treatment, there is little clinical data on the use of this combination of drugs in practice (outside of prospective studies). This study aims to present the clinical outcomes of patients with HCC who underwent immunotherapy at our center over the past three years.

Aims & Methods

In this retrospective observational study, we included patients treated with the atezolizumab and bevacizumab combination between March 2020 and September 2023. Demographic information, general physical assesments, disease etiology, disease staging, liver cirrhosis status, portal hypertension and laboratory values (aminotransferases and total bilirubin) were collected. Adverse events were analyzed according to the Common Terminology Criteria (CTCAE). Descriptive statistics and survival analysis were performed using Statistical Package for the Social Sciences (SPSS) version 22.

Results

53 HCC patients received atezolizumab and bevacizumab in studied time period, 8 (15.1%) females and 45 (84.9%) males. The median age at the initiation of immunotherapy was 68 years (range 41 – 84 years). Thirteen patients (24.5%) had esophageal varices prior to immunotherapy, with three (5.6%) requiring ligation. The majority of patients had liver cirrhosis A 27 (50.9%) according to Child Pugh criteria, a minority B (9.4%), and 21 patients (39.6%) were without cirrhosis. The primary causes of the disease were alcohol (51.6%), metabolic dysfunction-associated steatotic liver disease (MASLD) (16.1%), hepatitis C virus (12.9%), hepatitis B virus (6.5%), and hemochromatosis (3.2%). Stage C HCC, according to The Barcelona Clinic Liver Cancer, World Health Organization (WHO) performance status 0, and absence of macrovascular invasion and extrahepatic spread were predominant at treatment initiation. Grade I or II adverse events occurred in almost all patients (98.1%). Severe adverse events were present in 36 patients (67.9%). Due to severe side effects, 8 (15.1%) patients discontinued treatment, 2 (3.8%) died due to treatment related complications (encephalitis and bleeding from esophageal varices). Treatment was modified in 21 (39.6%) patients due to adverse events. The estimated median survival was 15.7 months.

Conclusion

The majority of patients with unresectable HCC, treated with a combination of atezolizumab and bevacizumab immunotherapy, experienced adverse events, primarily grades I-II. The immunotherapy combination proved to be more effective in patients with viral etiology of liver cirrhosis. The estimated median survival was 15.7 months. This combination of immunotherapy has been demonstrated to be a safe and effective treatment method. Currently, there is limited data regarding the utilization of this treatment in standard clinical practice and our data aligns reasonably well with the findings of the registration study.

References

1. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of Hepatocellular Carcinoma. Hepatology. 2021 Jan;73 Suppl 1(Suppl 1):4–13.
2. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 2022 Mar;76(3):681–93.
3. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894–905.
4. Lee YC, Huang WT, Lee MY, Tsao CJ, Feng YH. Bevacizumab and Atezolizumab for Unresectable Hepatocellular Carcinoma: Real-world Data in Taiwan-Tainan Medical Oncology Group H01 Trial. In Vivo. 2023;37(1):454–60.
5. Himmelsbach V, Pinter M, Scheiner B, Venerito M, Sinner F, Zimpel C, et al. Efficacy and Safety of Atezolizumab and Bevacizumab in the Real-World Treatment of Advanced Hepatocellular Carcinoma: Experience from Four Tertiary Centers. Cancers (Basel). 2022 Mar 28;14(7):1722.
6. de Castro T, Jochheim LS, Bathon M, Welland S, Scheiner B, Shmanko K, et al. Atezolizumab and bevacizumab in patients with advanced hepatocellular carcinoma with impaired liver function and prior systemic therapy: a real-world experience. Ther Adv Med Oncol. 2022;14:17588359221080298.

Clinical Case Summary

A 65-year-old man was admitted to our emergency department presenting with intermittent abdominal distension and difficulty in defecation for over a month, and absence of passage of stool and gas for 3 days. Soft tissue masses of sigmoid colon wrapping the left ureter on abdominal CT and a large nodular neoplasm in the sigmoid colon on colonoscopy were observed. Advanced colon cancer was highly suspected. However, we made sixes times biopsy totally and found no evidence of malignancy. Histopathology only showed moderate to severe chronic mucosal inflammation. We finally performed the subtotal colectomy and the histopathology of the excised colon showed us an unexpected finding: Schistosoma japonicum ova.
According to the data published by WHO in 2020, schistosomiasis has been reported in 78 countries worldwide, resulting in an estimated 240 million deaths¹. These highlight the significance of schistosomiasis eradication. Further history taking observed that the patient swam in the Baishui River, a tributary of Yangtze River, an endemic area of schistosomiasis, in recent four years of summer vacation.
During endoscopic examinations, patients may have characteristic scattered yellow nodules, while non-specific mucosal congestion, edema, thickening, ulcers, and polyps may be commonly observed. Therefore, misdiagnosis of intestinal schistosomiasis is common, with the rate of 30.3%^2,3. As we know, we made the first report of intestinal schistosomiasis infiltrating peritoneum and ureter, mimicking advanced colon cancer or Crohn’s disease. This highlights the importance of multi-site and deep biopsies or even surgery for the diagnosis of colonic neoplasm, especially when Schistosoma ova are distributed focally in submucosal area. Moreover, Schistosoma are far from eradication. Physicians should include schistosomiasis as a common differential diagnosis of colonic neoplasm. Detailed history taking of travel and migration is necessary in these patients.

References

(1) Díaz, A. V.; Walker, M.; Webster, J. P. Reaching the World Health Organization Elimination Targets for Schistosomiasis: The Importance of a One Health Perspective. Philos Trans R Soc Lond B Biol Sci 2023, 378 (1887), 20220274. https://doi.org/10.1098/rstb.2022.0274.
(2) Yang, Y.; Wang, X.-Y.; Duan, C.; Wang, Z.-J.; Sheng, H.-Y.; Xu, X.-L.; Wang, W.-J.; Yang, J.-H. Clinicopathological Characteristics and Its Association with Digestive System Tumors of 1111 Patients with Schistosomiasis Japonica. Sci Rep 2023, 13 (1), 15115. https://doi.org/10.1038/s41598-023-42456-9.
(3) Cai, L.; Chen, Y.; Xiao, S.-Y. Clinicopathologic Features of Chronic Intestinal Schistosomiasis and Its Distinction From Crohn Disease. Am J Surg Pathol 2021, 45 (3), 430–438. https://doi.org/10.1097/PAS.0000000000001594.

Introduction

H. pylori infection can remain after several eradication attempts. The objective of this study was to evaluate the effectiveness of the sixth-line rescue treatment in Europe.

Aims & Methods

Systematic and prospective registry on the clinical management of H. pylori infection. All cases with six eradication attempts registered in AEG-REDCap up to December 2022 were evaluated. The modified intention-to-treat (mITT) and per-protocol (PP) effectiveness was analysed.

Results

Overall, 81 patients were included, mainly from Spain (44% of cases), Italy (26%) and the United Kingdom (17%). The mean age was 52 years, with 52% women and 1.2% of patients allergic to penicillin. Culture was performed in 26 cases (32%), of which: 13 (50%) had bacterial antibiotic resistance to clarithromycin, 12 (46%) to nitroimidazole, and 8 (31%) to quinolones. In addition, 8 (35%) patients had dual resistance (both to clarithromycin and metronidazole) and 7 (27%) triple resistance (also to levofloxacin). Twenty-two different therapeutic combinations were used, most of them prescribed for 14 days (57%) and with low doses (39%) of PPIs. The most frequent treatments were: quadruple bismuth-tetracycline-metronidazole prescribed as three-in-one single-capsule (17%), triple amoxicillin-rifabutin (15%), quadruple bismuth-furazolidone-amoxicillin (11%), triple amoxicillin-levofloxacin (7.4%), and classical quadruple bismuth-tetracycline-metronidazole (6.2%). The highest eradication rates (mITT) were achieved with the single-capsule (77%) and with the quadruple therapy with bismuth-furazolidone-amoxicillin (67%). Overall effectiveness was 53%, both by mITT and PP analyses. Additional information on effectiveness, tolerability, compliance, and prior therapies is shown in the table.

Conclusion

Sixth-line eradication treatments in Europe obtain suboptimal eradication rates. The only therapies that reach acceptable outcomes are the bismuth quadruple therapies with either tetracycline-metronidazole (single-capsule) or with furazolidone-amoxicillin.

Disclosure

Olga P. Nyssen received research funding from Mayoly and Allergan.
Javier P. Gisbert served as speaker, consultant, and advisory member for or received research funding from Mayoly, Allergan, Diasorin, Gebro Pharma, and Richen.

Clinical Case Summary

Introduction: Kaposi sarcoma is the most common digestive malignancy in Human Immunodeficiency Virus (HIV)-positive patients, but it can also occur in HIV-negative individuals. It is a low-grade vascular tumor associated with Human Herpes Virus-8 (HHV-8) and can appear in immunosuppressed patients. Lesions can develop on the skin, but they could also be found in internal organs and lymph nodes.
Case-report: A 61-year-old Caucasian female with alcoholic liver cirrhosis and diabetes mellitus presented in the Dermatology Department with multiple painless red-to-purple papular nodules across the thorax, cervical area, limbs, and face. Skin biopsies from the posterior cervical area and internal part of the right foot revealed a well-defined nodular dermal tumor with submucosal vascular spindle cells forming slits containing red blood cells and low mitotic activity. Immunohistochemistry confirmed CD34, CD31, HHV-8, and Ki67>30% expression, indicative of cutaneous Kaposi sarcoma. HIV serological tests were negative. Further assessments performed in the Gastroenterology Department established decompensated liver cirrhosis. Moreover, upper digestive endoscopy revealed esophageal varices, portal hypertension gastropathy, along with multiple umbilicated nodules with central ulcerations in the gastric fundus and body. Biopsy samples from these lesions described histopathological findings suggestive of Kaposi sarcoma, while immunostaining for HHV-8 and CD31 was positive. Proposed systemic chemotherapy was declined by the patient. Tumors of the gut with spindle-shaped cells such as leiomyomas, rhabdomyosarcomas, or gastrointestinal stromal tumors must be considered in the differential diagnosis of Kaposi sarcoma.
Conclusion: Kaposi sarcoma can develop in HIV-negative immunosuppressed patients, with conditions such as liver cirrhosis and HHV-8 infections, potentially affecting the digestive tract.

References

1. Xu H, Edwards JR, Espinosa O, Banerji S, Jackson DG, Athanasou NA. Expression of a lymphatic endothelial cell marker in benign and malignant vascular tumors. Hum Pathol 2004;35:857–861.
2. Rossi S, Orvieto E, Furlanetto A, Laurino L, Ninfo V, Dei Tos AP. Utility of the immunohistochemical detection of FLI-1 expression in round cell and vascular neoplasm using a monoclonal antibody. Mod Pathol 2004;17:547–552.
3. Antman K, Chang Y. Kaposi's sarcoma. N Engl J Med. 2000;342:1027–1038.
4. Huang WY, Pantanowitz L, Dezube BJ. Unusual sites of malignancies: CASE 3. AIDS-related Kaposi's sarcoma of the gastrointestinal tract. J Clin Oncol. 2005;23:2098–2099.
5. Arora M, Goldberg EM. Kaposi sarcoma involving the gastrointestinal tract. Gastroenterol Hepatol (N Y). 2010 Jul;6(7):459-62. PMID: 20827371; PMCID: PMC2933764.

Disclosure

No conflict of interest.

Introduction

Response rates to the Low FODMAP Diet (LFD) in IBS vary and predictors of benefit remain poorly defined. While several studies from Western populations have identified microbial signatures linked to response, data from Asian cohorts remain limited.

Aims & Methods

This study aims to identify microbial predictors and longitudinal microbiome shifts in Asian IBS-D patients consuming a LFD. We recruited 20 adult Asian patients with IBS-D diagnosed according to the ROME-IV criteria. All subjects received LFD dietary advice from a dietitian at initiation and were followed-up for a total of 28-days. Clinical response was assessed by a ≥50-point improvement in the IBS Symptom Severity Score (IBS-SSS) from Day 0 (baseline) as compared to follow-up at Day 28. Stool samples were collected at baseline, Day 14, and Day 28. Microbial DNA was extracted using bead-beating and Qiagen PowerFecal kits, and the V3–V4 region of the 16S rRNA gene was amplified and sequenced on the Illumina MiSeq platform. Bioinformatic processing included denoising with DADA2, taxonomic assignment using the SILVA 138 database, and rarefaction to even sequencing depth. Microbiome metrics included alpha diversity (Shannon and Simpson), beta diversity (Bray-Curtis PCoA with PERMANOVA), and differential abundance testing with DESeq2.

Results

By Day 28, 11 of 20 patients (55%) achieved clinical response, with a median IBS-SSS reduction of 172 points (IQR: 88–248), compared to 24 points in non-responders (IQR: −11 to 55; p=0.003). Alpha diversity was not significantly different between groups, but responders exhibited a trend toward higher Shannon and Simpson diversity at baseline. Beta diversity analysis using Bray-Curtis dissimilarity revealed partial clustering by responder status (PERMANOVA p=0.06), and PCoA plots showed individual-specific shifts in community structure across time, indicating that the LFD induces personalized microbiome trajectories.
At baseline, responders had significantly higher relative abundances of butyrate-producing and anti-inflammatory genera, including Ruminococcus, Blautia, Eubacterium siraeum, and Bifidobacterium bifidum (adjusted p<0.05). These findings are consistent with prior reports, including Bennet et al. (2018) and Vervier et al. (2022), where such taxa were part of a “health-like” IBS-P (pathogen-enriched) to IBS-H (health-like) axis. The enrichment of Blautia and Ruminococcus is particularly noteworthy as these are established butyrate producers involved in maintaining colonic barrier function and reducing visceral hypersensitivity. By Day 28, differential abundance analysis revealed that responders exhibited increases in Ruminococcus bicirculans, Parabacteroides gordonii, and Weissella cibaria. In contrast, non-responders showed persistence or increases in taxa such as Tyzzerella and Olsenella, which have been associated with inflammation or IBS severity in prior studies (Chuah et al., 2024).

Conclusion

This study provides novel microbiome insights from an underrepresented Asian IBS population consuming a LFD. Despite dietary and baseline microbiota differences from Western populations, we observed remarkably consistent microbiome predictors of response, including higher baseline levels of butyrate-producing taxa and favorable microbial restructuring during the intervention. These results reinforce the reproducibility and functional relevance of microbiome predictors in IBS dietary therapy, and support microbiome profiling as a potential tool for personalized dietary guidance across a diverse global population.

References

Bennet SMP et al. Multivariate modelling of faecal bacterial profiles of patients with IBS predicts responsiveness to a diet low in FODMAPs. Gut. 2018 May;67(5):872-881.
Vervier K et al. Two microbiota subtypes identified in irritable bowel syndrome with distinct responses to the low FODMAP diet. Gut. 2022 Sep;71(9):1821-1830.
Chuah KH, Mahadeva S. Can we predict who will respond to a low-FODMAP diet in irritable bowel syndrome? J Gastroenterol Hepatol. 2024 Feb;39(2):217-218. ​