Introduction

Oncostatin M (OSM) is a pleiotropic cytokine belonging to the interleukin (IL)-6 family that acts on a large variety of cells involving two distinct heterodimeric receptor complexes: leukemia inhibitory factor receptor beta (LIFRβ) and OSM receptor beta (OSMRβ) that is the receptor able to mediate the most relevant biological effects of OSM in mice. OSM has been proposed to contribute to the progression of chronic liver diseases, hepatocellular carcinoma (HCC) development and metastasis. High levels of OSM were found in cirrhotic patients with different etiology carrying HCC. In particular we observed that OSM serum levels are significantly higher in patients carrying non-alcoholic steatohepatitis (NASH)-related HCC, as compared to those whit viral etiologies, and their increase paralleles the disease progression from simple steatosis to HCC. Noteworthy, OSM serum levels are significantly higher in patients with intermediate/advanced HCC and correlate with poor survival.

Aims & Methods

This work discusses the role of OSM in relation to the development of HCC in a NASH background. We investigated the role of OSM taking advantage of: a) cohort of NASH patients with HCC; b) human THP1 macrophage cell lines exposed to human recombinant OSM (hrOSM); c) Wild type (wt) mice fed with a control diet (CSAA) or a lipogenic diet (CDAA) for 24 weeks in order to reproduce the non-alcoholic fatty acid disease (NAFLD)/NASH pathogenic phenotype (CSAA-CDAA protocol); d) Wild type (wt) and OSMRβ knock out (OSMRβ^-/-) mice treated with a protocol of NASH-related liver carcinogenesis (DEN/CDAA protocol).

Results

In patients with NASH-related HCC, OSM is expressed in cancer cells and its expression increases with patient tumor grade. In in vitro experiments, conducted on human THP1 macrophages exposed to hrOSM, we found that OSM is able to promote an M2 pro-tumorigenic phenotype, which is due to the activation of STAT3 and PI-3K/Akt signaling pathways. Accordingly, OSM expression, which was found increased in NASH-related liver tumours of wt mice during the progression of NAFLD/NASH towards HCC, correlates with F4/80 gene expression. This data suggests an interplay between OSM and macrophages recruitment/functions in the tumor microenvironment. In particular, wt mice treated with the DEN-CDAA protocol show a stronger promotion of the M2 phenotype compared with the M1 and in these mice OSM transcript levels correlate better with M2 macrophage polarization markers. As OSMRβ is fundamental for the activation of the OSM-related STAT3 and PI-3K/Akt signaling pathways, the OSMRβ^-/- murine model was employed to exploit the role of OSM in this regard. In this respect, the data obtained in the OSMRβ^-/- murine models shows that the livers of these animals develop smaller tumours. This event appears to be due to: i) a decreased amount of M2 Tumor Associated Macrophages (TAMs) in the nodules as revealed by the reduction of transcription levels of CD163, PDL1, ARG1, CCL2 and CCR2 compared with wt mice; ii) a impairment of the angiogenic process as shown by lower transcript levels of VE-cadherin, VEGFR2 and CD105 compared with wt mice; iii) a reduction of tumor growth demonstrated by decreased levels of proliferation markers (PCNA, Ki67).

Conclusion

Experimental data highlight a pro-carcinogenic contribution for OSM in NASH, by promoting pro-tumorigenic inflammation, suggesting a possible role for the OSM/OSMRβ axis as therapeutic target for NASH-related HCC.

Introduction

Adenomas in the gastrointestinal tract are pre-malignant lesions that require complete excision for prevention of cancers. Conventional endoscopic techniques to remove these lesions involve either endoscopic mucosal resection or endoscopic submucosal dissection (1). Adenomas with submucosal fibrosis secondary to underlying tattoo, predisposing anatomical position and/or recurrence pose significant challenges in complete resection with higher rates of recurrent disease (1,2). With advances in third space endoscopic techniques, Hybrid approach involving combined EMR/ESD techniques or use of full-thickness resection devices have been described for en bloc resection of adenomas. However, especially in the West, there are times when piecemeal EMR is initiated and submucosal fibrosis is encountered prohibiting adequate snare engagement. We demonstrate five cases where this problem was overcome using submucosal incision and release using tip of the snare to perform salvage piecemeal EMR in the colon and duodenum.

Aims & Methods

In regards to the method, after the lesion with underlying submucosal fibrosis resistant to snare engagement has been identified, submucosal injection to areas surrounding the lesion using our standard polypectomy injectate was performed. Followed by mucosal incision to release and isolate the fibrotic areas using tip of the snare. After which we then employed standard polypectomy techniques to complete the EMR.

Results

The video showcases five cases of polyps in different regions of the colon that were treated with endoscopic mucosal resection (EMR) technique. The first case involved a transverse colonic polyp with an underlying tattoo that had fibrosis, making snare resection difficult. In the second case, a fibrotic polyp at the anal verge was resected by performing snare tip mucosal release to the anal margin on the lesion. In the third case, a recurrent polyp at the hepatic flexure had a fibrotic component that was resistant to submucosal lift. The fourth case involved an ascending colon polyp that had an area of submucosal fibrosis resistant to snare placement. The fifth case involved a large circumferential duodenal polyp that had fibrosis.

Conclusion

In conclusion Precut mucosal incision using snare-tip during piecemeal EMR when faced with resistant submucosal fibrosis is a cost effective and promising technique when standard approach is difficult. Further studies are required to compare its efficacy in regards to rate of adverse events and recurrence rates in comparison to other existing hybrid techniques. In our western practice, where ESD often is not the first-line option for adenoma resection, this technique allows clinicians to address the problem at hand without rescheduling or converting the procedure which has implications on timing, cost, and technical expertise of the endoscopy team.

References

1. Moss A, Bourke MJ, Tran K, Godfrey C, McKay G, Chandra AP, Sharma S. Lesion isolation by circumferential submucosal incision prior to endoscopic mucosal resection (CSI-EMR) substantially improves en bloc resection rates for 40-mm colonic lesions. Endoscopy. 2010 May;42(5):400-4.
2. Rashid MU, Alomari M, Afraz S, Erim T. EMR and ESD: Indications, techniques, and results. Surg Oncol. 2022 Aug;43:101742.