Introduction

Stereotactic Body Radiation Therapy (SBRT) has proven to be a safe and effective therapy for patients with deep abdominal malignancies who are ineligible/suboptimal candidates for surgery^1,2. SBRT’s effectiveness is dependent on precise targeting, achieved through both bone imaging and implantation of small markers (fiducials) that are visible during imaging which delineate margins of the target lesion³. Fusion of computed tomography (CT) and magnetic resonance imaging (MRI) can provide enhanced soft tissue contrast and improved delineation of the tumor⁴, and is the preferred choice at our institution. Fiducials have traditionally been made of gold due to its bioinertness and visibility on CT imaging, however gold is not accurately detected on MRI⁵. Platinum fiducials have recently emerged as an attractive alternative⁵, considering their improved detectability on MRI imaging. Endoscopic ultrasound (EUS)-guided implantation techniques have largely supplanted percutaneous methods for deep abdominal targeting, due to improved access and visualization⁶.

Aims & Methods

The objective of this case series was to describe our novel platinum seed (PS) fiducials developed in house for EUS-guided fiducial SBRT application. We reviewed the adequacy of fiducial placement, quality of pre-treatment imaging, and migration rates of our fiducials.This single-center case series included patients diagnosed with cancers of the abdomen, including pancreas, adrenal, and liver, who were scheduled to undergo SBRT requiring EUS-guided fiducial implantation between January 2011-February2024. The cohort was derived from a prospectively collected EUS database at The Ottawa Hospital in Ottawa, Canada. Patient demographics (sex and age), procedure details (tumor site, number of fiducials implanted, complications), and radiologist’s interpretation of MRI/CT imaging were assessed using hospital records. Approximately 70% of patients received antibiotics ((either IV x 1 does or oral antibiotics for 5 days post-procedure (eg. Ciprofloxacin, 500mg)). Our PS fiducials are made from 0.75mm wire cut into 3mm seeds which are then autoclaved in-house. Fiducials were implanted using a 19g FNA needle and advanced using an ERCP guidewire using EUS and fluoroscopic guidance.

Results

55 patients underwent EUS implantation for a total of 176 fiducials. Preplanning CT/MRI imaging identified 166/176 (94.3%) fiducial signal voids. When evaluating fiducial placement adequacy, 52 of 55 (94.5%) patients had adequate placement for SBRT. Two patients required a repeat procedure with additional fiducial implantation. One case was due to suspected migration, and the second case was due to fiducials being placed too closely preventing adequate delineation. In a third case, no signal voids were visualized for an unknown reason, however, no repeat procedure was required as spine tracking was used. None of the patients developed post-procedure infection or other adverse events (AEs) in this case series (follow up at 1 month). Cost analysis revealed the fiducials made in-house were ~20-fold less expensive compared to commercially available solid gold, gold coil, or solid platinum fiducials.

Conclusion

Our platinum seed fiducials made in-house appear to have similar adequacy and no increased risk of AEs for EUS-implantation when compared to commercially available fiducials^7,8. For centres using fused CT-MRI imaging for SBRT planning, PS fiducials are recommended. Moreover, significant cost-saving can be achieved through in-house production.

References

1. Rwigema JM, et al. Stereotactic body radiation therapy for abdominal and pelvic oligometastases: Dosimetric targets for safe and effective local control. Pract Radiat Oncol. 2015;5(3):e183-e191.
2. Almaghrabi MY, et al. Stereotactic body radiation therapy for abdominal oligometastases: a biological and clinical review. Radiat Oncol. Aug 01 2012;7:126. doi:10.1186/1748-717X-7-126
3. Moskalenko M, et al. Fiducial Markers Allow Accurate and Reproducible Delivery of Liver Stereotactic Body Radiation Therapy. Curr Oncol. May 16 2023;30(5):5054-5061.
4. Bryant JM, et al. Stereotactic Magnetic Resonance-Guided Adaptive and Non-Adaptive Radiotherapy on Combination MR-Linear Accelerators: Current Practice and Future Directions. Cancers (Basel). Mar 30 2023;15(7).
5. Nair VJ, et al. Feasibility, detectability and clinical experience with platinum fiducial seeds for MRI/CT fusion and real-time tumor tracking during CyberKnife. J Radiosurg SBRT. 2015;3(4):315-323.
6. Pishvaian AC, et al. EUS-guided fiducial placement for CyberKnife radiotherapy of mediastinal and abdominal malignancies. Gastrointest Endosc. Sep 2006;64(3):412-7.
7. Choi JH, et al. Fiducial placement for stereotactic body radiation therapy under only endoscopic ultrasonography guidance in pancreatic and hepatic malignancy: practical feasibility and safety. Gut Liver. 2014;8(1):88-93.
8. Kataki K, et al. Prospective Evaluation Fiducial Migration after Placement for Liver SBRT and Influence on Treatment Delivery. International Journ of Rad Onc. 2019;105(1):E222.

Introduction

Inflammatory bowel disease (IBD), consisting of Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic inflammation of the intestines. This is accompanied by oxidative stress, which plays an important role in the pathophysiology of IBD. Oxidative stress-related biomarkers can serve as potential biomarkers for disease activity monitoring. Systemic free thiols (FT) are found to accurately reflect oxidative stress brought on by inflammation and have shown promise as a biomarker for inflammatory disease activity in IBD. However, the clinical significance of this marker warrants validation. This prospective diagnostic study aimed to compare FT to other validated biomarkers and investigate the link between FT and endoscopic disease activity in patients with IBD.

Aims & Methods

An interim analysis was conducted in 52 patients. FT were measured using a colorimetric detection method. Clinical disease activity was quantified by the Harvey-Bradshaw Index (HBI) for CD and Simple Clinical Colitis Activity Index (SCCAI) for UC. Biochemical disease activity was determined by measuring blood C-reactive protein [CRP] and fecal calprotectin [fCal] levels. Endoscopic disease activity was quantified with the Mayo endoscopic sub score for UC and the Simple Endoscopic Score (SES-CD) for CD. Serum FT levels were assessed for correlations with disease activity parameters using linear and logistic regression analyses. Discriminative capacity of FT as biomarker was assessed by calculating receiver operating characteristics (ROC) statistics.

Results

Serum FT levels demonstrated a significant inverse correlation with clinical parameters, such as the HBI (r=-0.53, p<0.05). Additionally, other inflammatory biomarkers, including CRP, exhibited a negative correlation with serum FT levels (r=-0.43, p<0.05), which were decreased in patients with active IBD . Discrimination between clinically quiescent (HBI<5) and active disease based on serum FT levels was accurate (AUC=0.80, p=0.02) with a value numerically higher than that of fCal (AUC=0.55, p=0.83). Serum FT levels did not significantly differ between biochemically quiescent and active disease based on CRP (AUC=0.69, p=0.20). Both endoscopic scores demonstrated a tendency toward negative associations with serum FT levels. Patients with moderate and severe disease activity had lower FT levels compared to those with mild disease activity (estimated marginal means [EMM] 497.2 vs 529.5 µM, p=0.43) and 447.1 vs 529.5µM , p=0.06, respectively).

Conclusion

The interim analysis of this study indicates that plasma FT levels inversely correlate with IBD activity and may surpass traditional markers like fCal in detecting disease states. Plasma FT demonstrates potential as a sensitive biomarker for both clinical and endoscopic disease activity in IBD. Further patient inclusion and longitudinal data are essential to validate FT's utility fully. Continued research could establish FT as a key tool for personalized treatment strategies, improving patient outcomes in IBD management.

Disclosure

S. Geertsema, A.R. Bourgonje., H. van Goor, G. Dijkstra, and K.N. Faber are supported by a research grant from Janssen Research & Development LLC. A.R. Bourgonje received speaker fees from AbbVie. G. Dijkstra received research grants from Royal DSM, Takeda, and Janssen Pharmaceuticals and speaker fees from AbbVie, Pfizer, Takeda, and Janssen Pharmaceuticals.

Introduction

Patients with inflammatory bowel diseases (IBD) exhibit distinct shifts in circulating metabolite levels that have been associated with clinical disease activity and disease phenotype. However, there are limited data on the impact of metabolomic changes on disease progression in IBD. In this study, we aimed to understand the association of circulating metabolite levels and related pathways with the risk of disease progression in patients with IBD. Furthermore, we aimed to predict disease progression in these patients using both clinical and metabolomic features.

Aims & Methods

We conducted an observational cohort study using the Mount Sinai Crohn’s and Colitis Registry (MSCCR). Patients were prospectively enrolled with baseline questionnaires and biospecimens that were then linked to longitudinal electronic health record data. A total of 1,456 serum metabolites were measured in 277 patients with UC and 375 patients with CD using untargeted metabolomics. Disease progression was defined as any new steroid or biological prescriptions, IBD-related hospitalizations, or surgery. Multivariable Cox proportional hazards regression (CoxPH) models, adjusted for age, sex, smoking, biologic use, and surgery were used to explore metabolite associations with risk of disease progression. Metabolite set enrichment analysis (MSEA) was performed to identify underlying metabolic pathways associated with disease progression. Prediction analyses were performed using L1-regularized CoxPH models with Random Survival Forests (RSF), and applied using different preceding feature selection approaches. Clinical parameters and metabolites were used as input features individually and in combination. Models were evaluated using Harrell’s C-index, the Brier Score, and the area under the curve (AUC) at 3-years follow-up time.

Results

During a median of 2-year follow-up (IQR 0.3-5.1 years), 375 patients (57.5%) had a disease progression event. Among CD, 151 metabolites significantly correlated with the composite outcome (FDR<0.1). Of these, 81 (53.6%) were linked to higher risk, mainly enriched in amino acids, purine, and pyrimidine metabolism, fibrinogen cleavage peptides, and bile acid pathways. Additionally, 70 (46.4%) metabolites associated with lower risk with enrichment in fatty acid metabolism, steroid biosynthesis, histidine, tryptophan, and antioxidant pathways. In CD, aspartate metabolism was most significantly associated with increased risk and linoleic metabolism with decreased risk. In UC, 84 metabolites were significantly associated with disease progression (FDR<0.1), with 29 (34.5%) associated with increased and 55 (65.5%) with decreased risk. Metabolic pathways linked to higher risk were sphingolipid, benzoate, hydrogen sulfide, polyamine, and tyrosine metabolism, while protective metabolites were enriched in branched-chain amino acid (BCAA), steroid biosynthesis, histidine, and phenylalanine pathways. In UC, sphingolipid metabolism was prominently associated with increased risk and BCAA metabolism with decreased risk. The combination of metabolomic and clinical features best predicted disease progression in both CD and UC, with 20 and 25 features robustly selected, respectively.

Conclusion

Specific metabolites and metabolic pathways are associated with risk of disease progression in patients with IBD, highlighting potential prognostic metabolite biomarkers and pathways that may be important in modulating risk of disease progression. ​Metabolomic features improve overall model performance ​when predicting disease progression in IBD, with distinct metabolites showing high predictive value.

Introduction

Potential therapeutic effects of natural compounds, such as grape polyphenols, have been suggested in the prevention and treatment of mucositis induced by radiotherapy or bacterial infections. Lipopolysaccharide (LPS) significantly increases the paracellular permeability of gut epithelium downregulating the expression of tight junctions. In this study, the protective effect of proanthocyanidin-rich grape seed extract (GSE) was investigated on epithelial barrier damage and ROS production induced by LPS and ionizing radiations in an in vitro model.

Aims & Methods

GSE chemical analysis was performed by high-performance liquid chromatography (HPLC-DAD) and nuclear magnetic resonance (NMR).
Human intestinal epithelial cell line Caco-2, previously treated with LPS [10 µg/m] (pathogenic strain of Escherichia Coli 0111:B4) [1], GSE [6,25 mg/ml] and LPS + GSE, were irradiated with 10 Gy subdivided in 5 daily fractions using TrueBeam™ radiotherapy system by Varian Medical System. Epithelial barrier integrity was investigated measuring the paracellular flux of fluorescein isothiocyanate-dextran (FD-4) [1] and ROS production was assessed by adding 2′,7′-dichlorodihydrofluorescein diacetate (H2-DCF-DA) [3] using a multiplate reader (Tecan). Each experiment was performed twice in triplicates with independent controls among the three conditions.

Results

HPLC-DAD and NMR revealed a 70% content of total procyanidins in both the extract obtained from the virgin hydroalcoholic mixture and quantify 24 metabolites classified as amino acids, organic acids, classified as amino acids, organic acids, carbohydrates and miscellaneous molecules. Among them, it is interesting the presence of ascorbate, procyanidin B1 and polymeric procyanidins.
Our in vitro experiments showed a significant increased permeability was observed in LPS-treated cells over time compared to control (5.215 vs 0.3418; p<0.05), which is prevented by co-treatment with GSE (5.215 vs 0.3407; p<0.05). Irradiation significantly increased intestinal permeability over time and in a dose dependent manner compared to control both in Caco2 cells without LPS treatment (at day 5 with maximal dose of 10 Gy: 3.64 vs 0.441; p<0.05) and in LPS-treated cells (25.5 vs 2.42; p<0.05). GSE treatment significantly reduced this damage in both conditions (25.5 vs 2.04; p<0.05 and 38.87 vs 2.675; p<0.05 respectively). Moreover, LPS significantly increased ROS production in Caco2 cells (12,9 vs 104; p<0.0001) and GSE treatment significantly prevented this damage (104 vs 11.3; p<0.0001). Irradiation increased ROS production in LPS-treated cells (3056 vs 362; p<0.0001) and also in this case GSE treatment was able to reduce ROS production due to irradiation (502 vs 357; p<0.0001). this beneficial effect was observed also in LPS treated cells and then exposed to irradiation (3056 vs 681; p<0.0001).

Conclusion

In an in vitro model, GSE is able to prevent the intestinal epithelium permeability damage and ROS production induced by LPS and by ionizing radiations suggesting a potential therapeutic effect. Further studies are needed to better understand the mechanism underlying radiation-induced mucositis and the antioxidant effect of GSE in its prevention and management.

References

[1] Gori M, Altomare A, Cocca S, Solida E, Ribolsi M, Carotti S, Rainer A, Francesconi M, Morini S, Cicala M, Guarino MPL. Palmitic Acid Affects Intestinal Epithelial Barrier Integrity and Permeability In Vitro. Antioxidants (Basel). 2020 May 13;9(5):417
[2] Calabriso N, Massaro M, Scoditti E, Verri T, Barca A, Gerardi C, Giovinazzo G, Carluccio MA. Grape Pomace Extract Attenuates Inflammatory Response in Intestinal Epithelial and Endothelial Cells: Potential Health-Promoting Properties in Bowel Inflammation. Nutrients. 2022 Mar 11;14(6):1175