Introduction

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Oxysterol binding protein 3 (OSBPL3) is a protein involved in lipid binding and transport and is known to play an essential role in tumorigenesis. However, its expression and function in colorectal cancer (CRC) is unclear.

Aims & Methods

This study included patients who underwent CRC surgery at Gachon University Gil Medical Center between April 2010 and January 2013. We analyzed 448 patients with primary colorectal cancer (CRC) who underwent surgery and had preserved paraffin blocks. Using immunohistochemical staining, a clinically applicable, rapid, and highly accurate assay method, we aimed to detect OSBPL3 expression in CRC and correlate it with clinicopathologic characteristics, prognosis, and survival to identify novel patient-specific biomarkers.

Results

The 5-year event-free survival (EFS) and disease-specific survival (DSS) hazard ratios (HRs) of the OSBPL3^High subgroup were 1.65 (95% confidence interval (CI): 0.99-2.76, p = 0.05) and 1.49 (95% CI: 0.89-2.61, p = 0.20), respectively. When tumor node metastasis (TNM) staging and OSBPL3 expression were combined, the 5-year EFS and DSS HRs of patients with CRC with OSBPL3^High expression cancer at the same TNM stage (stage III/IV) were 4.06 (95% CI: 2.72-6.07, p = 0.001) and 4.41 (95% CI: 2.91-6.68, p = 0.001), respectively, compared to those with OSBPL3^Low expression cancer, indicating a poor prognosis. Therefore, OSBPL3^High expression is associated with poor prognosis and survival rate in CRC patients. Combining OSBPL3 expression with TNM staging can predict CRC prognosis and survival rate more accurately.

Conclusion

Our data show that increased expression of OSBPL3 is associated with poor prognosis and survival rate in CRC patients. By combining OSBPL3 expression with TNM staging, we can more accurately predict the prognosis of CRC.

Introduction

Cendakimab is a recombinant, humanized, high-affinity, neutralizing monoclonal antibody that binds to interleukin 13 (IL-13) and blocks interaction with both its receptors, IL-13Rα1 and IL-13Rα2. IL-13 is a cytokine implicated in the pathogenesis of atopic dermatitis (AD) and is thought to be a key driver of the complex pathophysiology of eosinophilic esophagitis (EoE). IL-13 signals through both IL-13Rα1 and IL-13Rα2 to regulate cellular and molecular pathways across a variety of cell types. The binding of IL-13 to IL-13Rα1 promotes a Type 2 immune response and eosinophil recruitment, whereas the binding of IL-13 to IL-13Rα2 is believed to play a role in fibrosis and epithelial tissue remodeling. Several biomarkers associated with Type 2 inflammatory diseases are known to be regulated by IL-13. Eotaxin-3, a key biomarker, plays a central role in attracting eosinophils to the site of inflammation. Periostin, an extracellular matrix protein linked to activated fibroblasts, is implicated in tissue remodeling and fibrosis. Another enzyme governed by IL-13 is matrix metalloproteinase-12 (MMP-12)—this enzyme contributes to tissue remodeling and breakdown of extracellular matrix components. Here, we evaluate the pharmacodynamic effects of IL-13 inhibition with cendakimab on the key serum biomarkers eotaxin-3, periostin, and MMP-12 in patients with AD, with a focus on exploring potential implications for EoE.

Aims & Methods

In this phase 2, multicenter, global, randomized, double-blinded, placebo-controlled, parallel-group study (NCT04800315), 220 adults with moderate-to-severe AD received cendakimab 360 mg Q2W, 720 mg QW, 720 mg Q2W, or placebo for 16 weeks. Blood samples were collected, and a panel of biomarkers were assessed. The current analysis focuses on the assessment of serum levels of eotaxin-3, periostin, and MMP-12 using Proximity Extension Assay pre- and post-treatment on day 1 (baseline), at week 1 and week 2, and then biweekly until week 16. The least square mean percent change from baseline at week 16 for each treatment group was evaluated.

Results

For all 3 doses of cendakimab, there was a significant decrease from baseline in the levels of eotaxin-3, periostin, and MMP-12 as early as week 1 post-treatment and continued through week 16 of cendakimab treatment (Table). Compared with placebo, cendakimab resulted in significantly greater reductions in these biomarker levels through week 16.

Conclusion

Cendakimab decreased levels of key inflammatory and remodeling biomarkers over 16 weeks of treatment in patients with AD. These findings suggest that cendakimab modulates pathways of inflammation, fibrosis, and tissue remodeling in AD and add to the existing clinical evidence of its modulation in other Type 2 inflammatory diseases such as EoE.
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Table. Least square mean percent change from baseline in key serum biomarker levels at week 16 in patients with AD

Disclosure

ESD served as a consultant for Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/ Bristol Myers Squibb, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GlaxoSmithKline, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio, received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/ Bristol Myers Squibb, Regeneron, Revolo, Shire/Takeda, and received educational grant from Allakos, Aqilion, Holoclara, and Invea. JL, SH, LG, CDO, and CC are employees and stockholders of Bristol Myers Squibb. JS served as consultant for Abbvie, Alamar, Aldena, Amgen, AObiome, Apollo, Arcutis, Arena, Asana, Aslan, Attovia, BioMX, Biosion, Bodewell, Boehringer-Ingelheim, Bristol Myers Squibb, Cara, Castle Biosciences, Celgene, Connect Biopharma, Corevitas, Dermavant, Eli Lilly, FIDE, Galderma, GlaxoSmithKline, Incyte, Invea, Kiniksa, Leo Pharma, Merck, My-Or Diagnostics, Nektar, Novartis, Optum, Pfizer, RAPT, Recludix, Regeneron, Sandoz, Sanofi-Genzyme, Shaperon, TARGET-RWE, Teva, Union, UpToDate, participated on a data safety monitoring board or advisory board for Biosion and Sanofi, received grants or contracts from Galderma, Incyte, Pfizer, received honoraria from Abbvie, Eli Lilly, Leo Pharma, Pfizer, Regeneron, Sanofi-Genzyme.

Introduction

Lifestyle factors are significant contributors to fatigue, which affects approximately 45% of patients with Inflammatory Bowel Disease (IBD) in remission.

Aims & Methods

In this study, we evaluated the effect of a digital multimodal lifestyle intervention on fatigue in patients with IBD. Patients with IBD in biochemical remission (fecal calprotectin <150 mg/kg) were enrolled in a multicenter, non-randomized, controlled interventional study. The intervention group participated in a 12-month lifestyle program—provided by the non-profit organization Voeding Leeft—that included digital group meetings with a nutritionist and a lifestyle coach focusing on gradual and sustainable behavior change regarding nutrition, physical activity, sleep, and stress management. In addition, the program encouraged patients to exercise more self-control over their personal health. Following the initial six months, attendance at online sessions was not mandatory; however, patients could attend online sessions every six to 12 weeks to stay motivated and foster the lifestyle habits they acquired throughout the course. Patients in the control group received standard care that included an informational leaflet about the potential causes of fatigue in IBD, the leaflet also included basic lifestyle information and advice to exercise more, eat a healthier diet, stop smoking, reduce alcohol intake, improve sleeping habits, and manage stress. The allocation to a study group was determined by the availability within the group and participant’s ability to attend the scheduled intervention. Clinical data and patient-reported outcomes were collected. Fatigue was measured with the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); any increase in FACIT-F after six months was considered a positive response to the intervention. The Minimal Clinically Important Difference (MCID) for fatigue was at least a four-point increase in the FACIT-F score¹. Inverse probability treatment weighting was used to correct confounding by indication.

Results

Thirty-six patients in the intervention group and 32 in the control group were compared. After six months, more patients in the intervention group (82.1% of patients) than in the control group (54.2% of patients) experienced improvement in fatigue, P = 0.029. Likewise, significantly more patients in the intervention group (71.4% of patients) than the control group (33.3% of patients) achieved a MCID regarding fatigue; P = 0.006. The improvements in fatigue were sustained throughout the study period in the intervention group. Acceptance of the health status was a significant factor for improvement in fatigue (β 7.813, SE 1.908, P < 0.001). Compared to the control group, quality of life improved in the intervention group; these patients gained 0.05 more quality-adjusted life years throughout the study. Last but not least, significant improvements in dietary quality were observed as early as three months after the baseline in the intervention but not the control group; these improvements in the intervention group were sustained throughout the study period.

Conclusion

Multimodal lifestyle intervention improves fatigue, quality of life, and dietary quality in patients with IBD who are in remission. Acceptance of the health status appears essential for fatigue improvement; instruments evaluating acceptance could help to personalize treatment and maximize its effectiveness.

References

1. Cella D, Yount S, Sorensen M, et al. Validation of the Functional Assessment of Chronic Illness Therapy Fatigue Scale relative to other instrumentation in patients with rheumatoid arthritis. J Rheumatol 2005;32:811-9.

Disclosure

AEvdMdJ received unrestricted research grants from Galapagos, Norgine, Vedanta, Nestle, including speaker’s fees from Galapagos, Tramedico, Takeda, Ferring, and Janssen Pharmaceuticals. PWV has received speaker fee from Galapagos and Takeda and served on the advisory board of Lilly, Galapagos, Janssen, BMS, Takeda, and Abbvie. RL has received travel expenses from Galapagos and Cablon Medical and served on the advisory board at Cablon Medical. NW and MJHB are employed by the non-profit organization Voeding Leeft and were a part of the team that guided participants in the intervention group. All other authors have no conflicts of interest to declare.

Introduction

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor symptoms, such as gastrointestinal symptoms. Emerging evidence suggests that gut permeability and inflammation play a role in PD pathophysiology via the gut-brain axis. According to Braak’s theory, the pathological degeneration associated with PD may originate from the gut and subsequently develop in the brain through the vagus nerve.

Aims & Methods

The aims were to assess the relationship between gut permeability and neuroinflammation in a cohort of patients with PD and REM behavior disorder (RBD), a condition that often precedes the onset of PD. The study prospectively included 28 PD patients and 18 RBD patients both complaining of GI symptoms. No serious organic diseases or therapies potentially affecting GI motility were reported. Relevant demographic and clinical data were collected for all patients. There was the inclusion of 14 healthy controls (HCs). A serum ELISA assay of tumor necrosis factor (TNF), caspase-1, and lipopolysaccharide-binding protein (LBP) was performed in all participants to investigate systemic inflammatory status and gut permeability, respectively. In a total of 10 PD patients, 4 RBD patients and 9 HCs, multiple colic biopsies were obtained to assay tissue expression of inflammation markers by both western blot (WB) (i.e. caspase-1 and procaspase-1) and immunofluorescence (IF) (i.e. ASC and CD68). Data were expressed as mean ± SD, and ANOVA and Dunnett's tests were used to compare the three groups.

Results

All three groups were comparable in age and sex. Serum assays showed significantly increased LBP, in patients with PD (35.0 ± 0.25; p = 0.002) and RBD (32.2 ± 1.1; p = 0.009) compared with HCs. TNF (0.1 ± 0.02; p = 0.03) and caspase-1 (16.9 ± 9.4; p = 0.04) were significantly raised only in the PD group in comparison with HCs (Table 1). WB analysis showed significant differences in the expression of procaspase-1 (157.3 ± 17.8; p = 0.02) and caspase-1 (168.3 ± 23.3; p = 0.03) only in PD patients compared with HCs. IF showed a qualitative increase in both CD68+ macrophage infiltration and ASC expression in PD and RBD groups compared with HCs.

	PD	RBD	HCs	P-value
LBP (ng/ml)	35.0 ± 0.25	32.2 ± 1.1	23.1 ± 2.1	0.009 (RBD vs HCs) 0.002 (PD vs HCs)
Caspasi-1 (ng/ml)	16.9 ± 9.4	11.4 ± 2.1	9.9 ± 2.7	0.04 (PD vs HCs)
TNF (pg/ml)	0.1 ± 0.02	0.05 ± 0.02	0.04 ± 0.02	0.03 (PD vs HCs)

Conclusion

Our results show a bowel activation of NLRP3 inflammasome in PD, as demonstrated both by the levels of procaspase-1 and caspase-1 on WB analysis and by the increase of CD68+ macrophages and ASC in the lamina propria of colonic mucosa. Only a qualitative increase in NLRP3 activation at IF could be observed in RBD patients. However, findings from colonic biopsies, if related to elevated serum levels of TNF and caspase-1 in PD patients, and LBP in PD and RBD patients, suggest that bowel inflammation, sustained by increased gut permeability, may represent an early stage in the develop of RBD and PD.

Introduction

The detection of cancer within large non-pedunculated colorectal polyps (LNPCPs) is suboptimal in non-expert settings. Identification of 6 macroscopic (Blink) features (6BF) of deep submucosal invasive cancer (SMI) has shown significant improvement in the sensitivity of cancer detection by inexperienced endoscopists at the expense of decreased specificity. This study investigates the impact of endoscopic resection scars, which can resemble deep SMI, on the accuracy of non-expert endoscopists using the 6BF evaluation system known as Blink Impression.

Aims & Methods

An online survey was disseminated containing 20 overview images of LNPCPs (1 image/polyp). Images (randomized) were shown before, and after a 2-minute educational video (the intervention) introducing the 6BF - fold deformation, extra redness, depression, chicken skin mucosa, ulceration and spontaneous bleeding. Before and after the intervention participant Blink Impression was elicited (cancer/no cancer) and only after, the presence of the 6BF. Responses were analysed relative to histopathology (no vs superficial vs deep SMI) and expert opinion on the presence of the 6BF and endoscopic resection scars.

Results

7/20 LNPCPs contained cancer (3 superficial, 4 deep SMI), 3 contained scars. 191 participants from 21 countries completed 3,755 observations. 129/191 (67.5%) participants were inexperienced. Expert-identified scarred LNPCPs contained median 1.0 (IQR 2.0) BF vs 1.0 (IQR 2.0) for no cancer, 2.0 (IQR 2.0) for superficial SMI and 3.0 (IQR 2.0) for deep SMI (all P<.001). Presence of ≥2 BF therefore reliably identifies cancer within LNPCPs but not scars. Fold deformation was the only BF identified more commonly amongst scarred LNPCPs (44.6%) vs no cancer (22.5%, P<.001) and vs superficial SMI (33.0%, P<.001), but similar to deep SMI (44.6%, P=1.000). Depression, chicken skin mucosa and spontaneous bleeding were less commonly identified in scarred polyps (12.3%, 7.6% and 1.8%) than both no cancer (33.1%, 14.4% and 8.6%, all P<.001), superficially invasive (68.6%, 14.3% and 5.8%, all P<.001) or deeply invasive polyps (45.9%, 19.6% and 40.5%, all P<.001). Extra redness and ulceration were identified with similar frequency to no cancer in scars (26.4% vs 26.8%, P=0.891 and 10.2% vs 9%, P=0.441 respectively), but less commonly than superficial (64.2%, P<.001 and 15.7%, P<.001) or deep SMI (60.2%, P<.001 and 24.7%, P<.001) (Table 1).

Conclusion

The presence of ≥2BF reliably discriminates LNPCPs with cancer from non-cancer even in the presence of scarred lesions amongst non-expert endoscopists. Scarred LNPCPs exhibit fold deformation at a similar rate to LNPCPs with deep SMI but other BF are not present.

References

Debels LK, Smeets S, Poortmans PJ, Argenziano ME, Desomer L, Anderson J, Valori R, David J Tate. Identification of 6 key features of colorectal polyps increases the sensitivity of cancer detection and ability to discriminate deep submucosal invasion The basis of the Blink (first) impression? United European Gastroenterology Journal 2023; Vol.11

Introduction

Ulcerative colitis, a type of inflammatory bowel disease, is characterised by chronic colonic inflammation often resulting in uncontrolled crypt lengthening and the development of colitis-associated colorectal cancer (CA-CRC). Orally administered Emu Oil, derived from Emu adipose tissue, has demonstrated protective and reparative properties in preclinical models of bowel disease, including CA-CRC. However, its long-term potential to reduce colonocyte proliferation and inhibit CA-CRC progression remains undetermined. Protein Ki-67 has been used widely as a proliferation marker for human tumour cells and may serve as a potential predictive biomarker for cancer progression.

Aims & Methods

We hypothesized that orally administered Emu Oil would reduce colonocyte proliferation, evidenced by decreased Ki-67 expression, in a mouse model of CA-CRC. Female C57BL/6 mice were injected with saline or azoxymethane (7.4mg/kg; intraperitoneal), followed by ad libitum access to either water or three dextran sulphate sodium (DSS)/water cycles (each cycle comprising seven days DSS [2%w/v] and 14 days water). Mice (n=9/group) were orally administered either water (80μL) or Emu Oil (low 80μL or high 160μL dose) thrice weekly for nine weeks. Proximal and distal colonic sections were stained with haematoxylin and eosin for crypt depth, cell count and size measurements and stained immunohistochemically to detect and quantify the proliferation marker Ki-67 in upper and lower colonocyte crypt zones. p<0.05 was considered statistically significant.

Results

In the proximal colon, numbers of Ki-67-positive cells in the upper and lower crypt regions of CA-CRC mice were increased by up to 100% compared with normal controls; low dose Emu Oil significantly decreased numbers of Ki-67-positive cells by 47% (p<0.05) compared with CA-CRC controls. Numbers of Ki-67-positive cells in the distal colon increased only in the upper crypt region in CA-CRC controls compared with normal mice (157%), with no further impact following Emu Oil administration (p>0.05). The overall percentage of Ki-67-positive cells remained unchanged in proximal and distal colonic crypts across treatment groups (p>0.05). Proximal and distal colonic crypt depth increased in mice with CA-CRC (20% and 37%, respectively; p<0.01), with greater distal colonocyte count, compared with normal controls (37%; p<0.05). Emu Oil did not impact proximal and distal colonic crypt depth nor cell counts in normal or CA-CRC mice (p>0.05). Furthermore, proximal colonocyte count, proximal and distal colonic cell diameter, and number of cells per 100μm remained unchanged among treatment groups (p>0.05).

Conclusion

Crypt lengthening in CA-CRC was primarily attributed to crypt cell hyperplasia, determined by increased cell numbers with no change in cell size. Low-dose Emu Oil administration in mice with CA-CRC resulted in attenuation of proximal colonic crypt cell proliferation, with no impact on crypt depth or cell size. Importantly, crypt depth and proliferation in normal mice remained unchanged following Emu Oil treatment, supporting its safety for long-term use to treat intestinal disorders. Future studies would benefit from an assessment of Emu Oil and its impact on expression of the oncogene Kras, tumour suppressor genes p53 and Apc, and inflammatory cytokines, including interleukin- 6, tumor necrosis factor-alpha and interferon-gamma, which are implicated in colorectal cancer progression.

Introduction

Peroxisome proliferator-activated receptor delta (PPARδ) agonists, such as seladelpar, emerged as potential therapies for PBC and other cholestatic diseases. PPARδs are nuclear receptors widely expressed in hepatocytes, cholangiocytes, Kupffer cells, and hepatic stellate cells. Activation of this receptor may modify the progression of PBC, particularly through its bile acid retention mechanism and antifibrotic and anti-inflammatory effects, inducing biochemical and clinical improvement in PBC patients.

Aims & Methods

We aimed to compare the efficacy and safety of seladelpar vs placebo for treating patients with primary biliary cholangitis (PBC) and inadequate response or intolerance to ursodeoxycholic acid (UDCA). We systematically searched MEDLINE, Embase, and Cochrane databases from inception to March 12, 2024. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were employed for dichotomous and continuous outcomes, respectively, using a random-effects model. We used Review Manager 5.4.1 for statistical analyses.

Results

We included 3 randomized clinical trials (395 patients). The results of the pooled analyses are shown in Table 1. Compared with placebo, seladelpar increased the probability of achieving composite biochemical response both at week 4 (RR 6.7; 95% CI 4.0 to 11.1) and at week 12 (RR 6.1; 95% CI 3.7 to 9.9), decreased alkaline phosphatase levels both at week 4 (MD -34.3%; 95% CI -39.6 to -29.0%) and at week 12 (MD -40.8%; 95% CI -47.9 to -33.6), increased the probability of achieving alkaline phosphatase normalization at week 12 (RR 18.6; 95% CI 3.8 to 90.4), and decreased pruritus scores at week 12 in both the overall population (MD -0.6; 95% CI -1.1 to -0.2) and the population with baseline pruritus score ≥4 (MD -1.2; 95% CI -2.0 to -0.4). Additionally, there was a non-significant difference between seladelpar and placebo in the risk of any adverse event (RR 1.0; 95% CI 0.9 to 1.1), any serious adverse event (RR 0.9; 95% CI 0.3 to 2.4), or any adverse event leading to treatment discontinuation (RR 0.7; 95% CI 0.2 to 2.0).

Table 1. Results from the pooled analyses

Conclusion

Seladelpar may be an effective and safe treatment option for patients with PBC and inadequate response or intolerance to UDCA. However, new large RCTs assessing long-term efficacy and safety outcomes are necessary to better evaluate its place in PBC management.

References

1. Hirschfield GM, Shiffman ML, Gulamhusein A, et al. Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study. Hepatology 2023;78:397–415.
2. Hirschfield GM, Bowlus CL, Mayo MJ, et al. A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis. N Engl J Med 2024;390:783–794.
3. Jones D, Boudes PF, Swain MG, et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. The Lancet Gastroenterology & Hepatology 2017;2:716–726.

Disclosure

The authors have no ​conflict of interest