Introduction

Prior study demonstrates that Blink (first) impression has a high sensitivity amongst experienced endoscopists for polyp cancer (1-2). Discriminating between superficial and deep submucosally invasive polyp-cancer remains difficult even for experts (3-4). Both detection and depth stratification of cancer within polyps are critical for treatment stratification and optimal patient outcomes.

Aims & Methods

We aimed to determine whether identification of 6 endoscopic features of polyp cancer can increase sensitivity of cancer detection and endoscopist ability to discriminate depth of submucosal invasion (SMI).
An online survey was disseminated containing 20 overview images of colorectal polyps (1 image/polyp). Images (randomized) were shown before, and again after a 2-minute educational video (the intervention) which introduced six macroscopic (Blink) features of deep SMI - fold deformation, extra redness, depression, chicken skin mucosa, ulceration and spontaneous bleeding. Prior to the intervention participant Blink impression was elicited (cancer/no cancer). After the intervention the same question was asked, and participants were required to describe which of the six Blink features were present. Responses were analysed relative to histopathology (no vs superficial [<1000µm] vs deep [>1000µm] SMI).

Results

7/20 polyps shown contained cancer histologically (3 superficial, 4 deep SMI). 191 participants from 21 countries completed 3,755 observations.
The sensitivity of Blink impression (vs histopathology) increased after the educational intervention (0.67 [95%CI 0.65-0.70] pre vs 0.88 [95%CI 0.86-0.90] post [P<.001] but specificity decreased (0.69 [95%CI 0.670.71] pre vs 0.55 [95%CI 0.53-0.57] post [P<.001]). Trainees achieved the greatest gain in sensitivity after the intervention (+0.23, P<.001) (table 1).
Participant reported mean number of Blink features correlated significantly with expert opinion (correlation coefficient 0.73, p<.001), with the histological presence of cancer (no cancer=1.1 features vs cancer=2.2 features, p<.001) and with the histological depth of SMI (none=1.1 features, vs superficial SMI=2.0 [p=0.04], vs deep SMI=2.3 [p=0.003]). Per polyp, participants’ Blink impression (pre-education) was significantly associated with the number of reported features post intervention (P<.001-.012) in all except for 3 polyps which contained >3 features of SMI.

Conclusion

Significant improvement in the sensitivity of polyp cancer detection can be achieved amongst a varied population of endoscopists by the identification of 6 ‘Blink’ features. The number of features correlates with the presence of cancer and degree of SMI. This approach could minimise delays to correct treatment and remove the need for experience to rely upon Blink impression.

References

1. Debels L, Tate DJ. The Accuracy of Human Detection Of Submucosal Invasive Cancer - Analysis of 739 Individual Assessments of Large Non-Pedunculated Colorectal Polyps (LNPCPS) using a Novel Clinical Decision Support Tool. UEG Journal 2021; doi:10.1002/ueg2.121722.
2. Poortmans PJ, Debels L, Tate DJ. Endoscopic detection of cancer in colorectal polyps by young GI endoscopists: a pre- and post-intervention analysis of 680 individual responses. UEG Journal 2022; Vol.10.
3. Meulen LWT et al. Optical diagnosis of T1 CRCs and treatment consequences in the Dutch CRC screening programme. Gut 2020; 69: 2049-2051. doi:10.1136/gutjnl-2019-320403
4. Vleugels JLA et al. Suboptimal endoscopic cancer recognition in colorectal lesions in a national bowel screening programme. Gut 2020; 69: 977-980. doi:10.1136/gutjnl-2018-316882
5. Jang HW et al. Does magnifying narrow-band imaging or magnifying chromoendoscopy help experienced endoscopists assess invasion depth of large sessile and flat polyps? Dig Dis Sci 2014; 59: 1520-1528. doi:10.1007/s10620-014-3090-x
6. Horie H et al. Colonoscopic stigmata of 1 mm or deeper submucosal invasion in colorectal cancer. Dis Colon Rectum 2008; 51: 1529-1534. doi:10.1007/s10350-008-9263-y
7. Puig I et al. Accuracy of the Narrow-Band Imaging International Colorectal Endoscopic Classification System in Identification of Deep Invasion in Colorectal Polyps. Gastroenterology 2019; 156: 75-87. doi:10.1053/j.gastro.2018.10.004

Disclosure

David James Tate consulting fees and research support from Olympus Medical. The remaining authors have no competing interests to disclose.

Introduction

In Nonalcoholic steatohepatitis (NASH), several pathogenetic mechanisms occur as explained by the “multiple hit pathogenesis”. However, the characteristic inflammation of NASH is orchestrated by the innate immunity, since Kupffer cells are triggered by PAMPs and DAMPs, and recruit monocytes (Mo), which repopulate the liver with new macrophages, perpetuating inflammation.
The recent promising field of immunometabolism showed that myeloid cells undergo a metabolic reprogramming to sustain the pro-inflammatory activity, suggesting novel immunosuppressive approaches by targeting cellular metabolism. However, immune cell bioenergetic alterations in chronic diseases such as NASH, are substantially unexplored.

Aims & Methods

Here, we questioned whether circulating Mo in NASH presented immunometabolic alterations. 20 NASH patients (histologically determined) and 10 healthy controls were enrolled for isolation of circulating CD14+ Mo from peripheral blood. Mo were used for analysis of bioenergetics and mitochondrial function, and RNA/protein isolation. To do this, glycolysis and mitochondrial respiration (MR) were quantified with extracellular acidification rate and oxygen consumption rate, respectively, by using a Seahorse HS Mini analyser (Agilent). Respiratory chain (RC) complexes enzymatic activities and H₂O₂ production rate were analysed. In a second step, the effect of succinate dehydrogenase (SDH) inhibition was investigated in vitro by exposing patient Mo to dimethyl malonate (DMM), and in vivo by using a preclinical model of NASH. In particular, wild-type (C57BL/6) mice were fed with high-fat and high-cholesterol (HF-HC) diet for 8 weeks. From week 6 to week 8 mice were i.p. injected with DMM (160 mg/kg), or vehicle (PBS) every second day.

Results

NASH Mo presented a peculiar bioenergetic profile characterized by a significant increase of both glycolysis and MR compared to controls, with a preponderant change of glycolysis. Basal and maximal respirations were higher in NASH Mo, although this resulted not only in more ATP production, but also in a very high proton leak. In accordance with this, we found that NASH Mo showed a higher enzymatic activity of RC complex I and complex II. However, using pyruvate/malate and succinate as substrates we observed that complex I and II activities produced high levels of H₂O₂ with consequent mitochondrial oxidative stress. Taken together these results highlighted that Mo in NASH have a bioenergetic reprogramming with increase of glycolysis and mitochondrial dysfunction. The mRNA expression of 78 targets, included in the PrimePCR^TM array “mitochondria energy metabolism plus”, showed the significant down-regulation of 7 genes, while 32 genes resulted up-regulated. Most of these genes encoded for RC complex subunits, and in particular, 3 out of 4 SDH subunits resulted more expressed. SDH is an enzyme complex also known as RC complex II, and its role in driving the metabolic rewiring of macrophages has been recently demonstrated. Therefore, considering the higher activity and expression of RC complexes, and in particular the SDH, we tried to expose NASH Mo to DMM, a SDH inhibitor with demonstrated immunomodulatory properties. Interestingly, DMM normalized glycolysis and MR levels, abrogating Il-1β and TNF-α expression. Moreover, HF-HC fed mice were treated with DMM, improving steatohepatitis in terms of liver injury, steatosis and inflammation. The macrophage amount in the liver was reduced and the expression of M2 markers such as arginase1 and CD163 was partially restored by DMM.

Conclusion

Mo immunometabolism might be targeted in NASH.