Flavonoids and their derivatives are known for their diverse biological activities. This study aims to elucidate the structure-activity relationships (SARs) of flavonoids, including fisetin, luteolin, quercetin, and mono-methylated quercetins (MQs), with a focus on their potential as therapeutic agents for colorectal cancer (CRC). Using electrospray ionization tandem mass spectrometry (ESI-QTOF MS/MS) and retro Diels-Alder (rDA) analysis, we developed a novel analytical method to differentiate between MQs, despite their identical molecular weights, by analyzing their unique fragmentation patterns. Comparing the structures and activities of the tested flavonoids highlights the importance of the methylation and hydroxylation status at the carbon 3, 5, 7, 3', and 4' positions of quercetin for enhancing antiproliferative activity in human CRC cells. Specifically, 3-O-methylquercetin and 4'-O-methylquercetin were found to induce cell cycle arrest and apoptosis in CRC cells through mechanisms involving oxidative stress, mitochondrial dysfunction, and inactivation of the SRC/JAK2/STAT3 pathway, while exhibiting no cytotoxicity to normal human colon cells. These results suggest that MQs are promising therapeutic flavonoids for CRC treatment. This study underscores the importance of specific structural modifications in flavonoids to improve their anticancer efficacy, providing valuable insights for the development of targeted therapies for CRC.

Patients with long-standing inflammatory bowel disease (IBD) involving the colon are at higher risk of developing colorectal dysplastic or neoplastic lesions. While from sporadic colorectal cancer follows an "adenoma-carcinoma" sequence, IBD colitis-associated carcinogenesis is mainly related to an "inflammation-dysplasia-carcinoma" sequence. Currently, specific endoscopic surveillance strategies involving dye spray and virtual chromoendoscopy have been standardized, aiming for early CRC diagnosis. When detected, colitis-associated dysplasia should be classified according to standard classification, thus allowing for better treatment. Indeed, most IBD-associated dysplastic lesions can be treated with endoscopic resection, even though available procedures are usually more challenging than those in the general population. The higher frequency of severe submucosal fibrosis and the difficulty in the definition of lesions' margins account for this issue. Current endoscopic resection techniques include polypectomy, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). Recent evidence suggests the relevance of en bloc resection, as this may be associated with lower rates of recurrence. Therefore, particularly for larger (>20 mm) lesions, ESD should be preferred, even though it is considered the most difficult technique due to frequent severe submucosal fibrosis. Considering the growing number of new endoscopic resective techniques, including underwater EMR or ESD, which in the general population have been suggested to lower procedure-related risks and may also allow a larger spread of advanced endoscopic resection in IBD. However, additional data are needed to assess the medium- and long-term efficacy of endoscopic resection of visible dysplasia in IBD patients, which are burdened by a high risk of local and, more importantly, metachronous recurrence.

 Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal cancer. High-risk colorectal colitis-associated neoplasia (HR-CAN) can be difficult to treat using traditional endoscopic resection methods. This study evaluated the outcomes of endoscopic submucosal dissection (ESD) in patients with IBD and HR-CANs.

 This retrospective multicenter study consecutively included patients with IBD who were referred to expert Italian endoscopy centers for ESD or hybrid ESD (hESD) of HR-CANs. The main outcomes were rates of en bloc, R0, and curative resections, adverse events, local recurrence, metachronous lesions, and post-resection surgery. Kaplan-Meier method was used to analyze survival rates. Risk factors associated with the main outcomes were investigated by univariable analysis.

 91 patients with colonic IBD (disease duration 15.3 [SD 8.7] years, 82.4 % with ulcerative colitis) with 96 HR-CANs (mean size 34.8 [SD 16.2] mm, 53.1 % high grade dysplasia/adenocarcinoma) were included. ESD and hESD were performed in 82.3 % and 17.7 %, respectively. En bloc, R0, and curative resections were achieved in 95.8 % (95 %CI 89.6-98.8), 85.4 % (95 %CI 76.7-91.7), and 83.3 % (95 %CI 74.3-90.1). Adverse events occurred in 12.5 % (95 %CI 6.6-20.8), which were all conservatively managed. After a mean follow-up of 23.4 (SD 16.1) months, local recurrence and metachronous lesions each occurred in 3.1 %. Post-resection surgery was required in 11.5 %.

 ESD of HR-CANs showed favorable outcomes on the medium- and long-term course in patients with IBD.

Due to its rarity, there is limited information on the clinicopathologic features of dysplasia in pediatric patients with inflammatory bowel disease (IBD). The existing surveillance guidelines for these patients do not include dysplasia as a potential risk factor for colorectal cancer (CRC), and there is no clear guidance on the optimal strategy for detecting dysplasia. As such, we analyzed the clinicopathologic features of 20 IBD patients who developed at least one instance of dysplasia (n = 56) before the age of 21 years. The results were then compared with data from a previously published adult cohort, which included 315 dysplastic lesions from 167 consecutive adult IBD patients. The study group consisted of 11 males and 9 females, with a mean age of 11 years at the time of IBD diagnosis. The mean age at the time of the first dysplasia diagnosis was 18 years for the study group compared to 54 years for the adult group. The study group had a lower incidence of ulcerative colitis (65% vs. 92% in the adult group, p < 0.001), but the proportion of patients with concurrent primary sclerosing cholangitis (PSC) was nearly double that of the adult group (25% vs. 13%, p = 0.129). Dysplasia in the study group was more likely to be nonconventional (38%, p = 0.047) and invisible or flat (50%, p < 0.001) compared to the adult group (25% and 24%, respectively). High-risk nonconventional dysplastic subtypes, including crypt dysplasia (13%, p = 0.016), goblet cell-deficient dysplasia (11%, p = 0.010), and hypermucinous dysplasia (9%, p = 0.009), were more common in the study group compared to the adult group (4%, 3%, and 2%, respectively). The mean duration from IBD diagnosis to the first dysplasia diagnosis was significantly shorter in the study group (8 years) than in the adult group (16 years) (p = 0.005). While dysplastic lesions in the adult group were more likely to present as high-grade dysplasia (HGD) at initial diagnosis (17% vs. 4% in the study group, p = 0.008), the rate of advanced neoplasia (HGD or CRC) on follow-up was similar between the two groups (26% in the adult group vs. 22% in the study group, p = 1.000). In conclusion, dysplasia in pediatric IBD patients is often associated with nonconventional features (including the high-risk subtypes), an invisible/flat appearance, concurrent PSC, and early development (within 8 years of IBD diagnosis).

The risk of developing advanced neoplasia (AN; colorectal cancer and/or high-grade dysplasia) in ulcerative colitis (UC) patients with a low-grade dysplasia (LGD) lesion is variable and difficult to predict. This is a major challenge for effective clinical management.

We aimed to provide accurate AN risk stratification in UC patients with LGD. We hypothesised that the pattern and burden of somatic genomic copy number alterations (CNAs) in LGD lesions could predict future AN risk.

We performed a retrospective multicentre validated case-control study using n=270 LGD samples from n=122 patients with UC. Patients were designated progressors (n=40) if they had a diagnosis of AN in the ~5 years following LGD diagnosis or non-progressors (n=82) if they remained AN-free during follow-up. DNA was extracted from the baseline LGD lesion, low-coverage whole genome sequencing performed and data processed to detect CNAs. Survival analysis was used to evaluate CNAs as predictors of future AN risk.

CNA burden was significantly higher in progressors than non-progressors (p=2×10-6 in discovery cohort) and was a very significant predictor of AN risk in univariate analysis (OR=36; p=9×10-7), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. Within-LGD lesion genetic heterogeneity did not confound risk prediction.

Measurement of CNAs in LGD is an accurate predictor of AN risk in inflammatory bowel disease and is likely to support clinical management.

Inflammatory bowel diseases (IBDs), encompassing Ulcerative Colitis (UC) and Crohn's Disease (CD), are chronic inflammatory disorders affecting the gastrointestinal tract. The association between IBD and colorectal cancer (CRC) is well-documented. Multiple factors have been identified as contributors to the risk of developing CRC in patients with IBD, including duration of disease, disease extension, family history of CRC, co-existance of primary sclerosing cholangitis (PSC), and potentially the presence of post-inflammatory polyps (PIPs). PIPs, often referred to as pseudopolyps, are polypoid structures that emerge as a result of severe mucosal inflammation. While their presence has been linked to greater disease severity, the role of PIPs in increasing CRC risk remains controversial. Increasing evidence suggests an association between post-inflammatory polyps (PIPs) and the risk of colorectal neoplasia, with PIPs potentially serving as an indicator of this risk through a history of enhanced inflammation. PIPs may also be linked to a distinct patient phenotype, including the presence of other known risk factors. More recent studies suggest that the risk burden (characterized by a high number or by large polyps) may be important. However, the evidence remains inconsistent, with some studies showing no clear association between PIPs and CRC risk after adjusting for other factors, including histological inflammation. In contrast, the data suggest a low rate of malignant transformation of the PIPs themselves. This narrative review aims to summarize the latest evidence regarding the relationship between PIPs and CRC in IBD, with a focus on UC. While some studies suggest that PIPs may serve as markers of higher disease severity and inflammation, their direct contribution to CRC risk remains unclear. Further research is needed to explore the inflammatory and carcinogenic pathways in patients with PIPs to better understand their role in colorectal cancer (CRC) development.

Patients with inflammatory bowel disease (IBD) have a higher risk of developing colorectal dysplasia and colorectal cancer compared to the general population. Although the use of surveillance protocols has improved the ability to detect dysplasia, some lesions are still missed at colonoscopy. This study aims to determine the rate of dysplastic lesions that are undetected at colonoscopies in IBD patients undergoing colectomy and to identify factors associated with missed dysplasia.

Patients who had received a total or subtotal colectomy at Mayo Clinic (Rochester, Minnesota), between January 2003 and December 2022, and had a complete colonoscopy within 5 years before surgery were retrospectively enrolled. Data abstracted included demographic information, disease-related data, colonoscopy and pathology reports, and surgery pathology reports. Colonoscopy and surgery findings were compared, and patients were divided into 3 groups: no dysplasia at both, detected dysplasia, and undetected dysplasia.

Among 1320 IBD patients undergoing colectomy, 5.4% had undetected dysplastic lesions identified only at surgery. Factors independently associated with dysplasia detection were endoscopic remission or mild endoscopic disease activity (odds ratio [OR], 2.326; P = .0081; 95% CI, 1.246-4.342), prior dysplasia detection (OR, 1.876; P = .0491; 95% CI, 1.002-3.511), colonoscopy performed for surveillance (OR, 2.380; P = .0048; 95% CI, 1.302-4.350), and longer disease duration at surgery (OR, 1.039; P = .0085; 95% CI, 1.010-1.070).

Clinicians should be aware of the risk of missing dysplastic lesions, especially when endoscopic disease activity is moderate/severe, and not only for longstanding disease. Efforts should be made to obtain endoscopic remission to make the "invisible" visible.

Chronic inflammation is a significant driver in the development of various diseases, including cancer. Colitis-associated colorectal cancer (CA-CRC) refers to the increased risk of colorectal cancer in individuals with chronic inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease.

This narrative review examines the link between chronic inflammation and CA-CRC. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science, focusing on studies published between 2000 and 2024. Studies were selected based on relevance to the role of inflammation in CA-CRC, specifically targeting molecular pathways and clinical implications. Both clinical and mechanistic studies were reviewed.

Sustained inflammation in the colon fosters a pro-tumorigenic environment, leading to the initiation and progression of CA-CRC. Prevention strategies must focus on controlling chronic inflammation, optimizing IBD management, and implementing regular screenings. Emerging therapies targeting key inflammatory pathways and immune responses, along with microbiome modulation, hold promise for reducing CA-CRC risk. Understanding these molecular mechanisms provides a path toward personalized treatment and better outcomes for patients with IBD at risk of colorectal cancer.

We herein present the case of a 30-year-old Japanese male patient with ulcerative colitis (UC) who was admitted to our hospital because of significant ascites. Upon evaluation, the patient was diagnosed with unresectable UC-associated cancer (UCAC), localized in the transverse colon. Using gene profiling of the tumor tissue, anti-epidermal growth factor receptor (EGFR) antibody combination chemotherapy was selected. Subsequently, the patient exhibited a temporary response to this regimen, with an enhancement in his quality of life and he was able to survive for 12 months. This case underscores the potential benefits of aggressive chemotherapy tailored to the gene profile in UCAC treatment, offering insights into potential avenues for improving the patient prognosis.

The significance of serrated epithelial change (SEC), defined as endoscopically invisible hyperplastic polyp (HP)-like mucosal change identified in patients with inflammatory bowel disease (IBD), remains unclear. Although some studies reported an increased risk of synchronous and/or metachronous colorectal neoplasia in patients with SEC, including advanced neoplasia (high-grade dysplasia or colorectal cancer), the development of SEC is not significantly associated with increased colonic inflammation. This contrasts with the reported positive correlation between increased colonic inflammation and the risk of colorectal neoplasia in ulcerative colitis, arguing against the notion that SEC may represent a form of dysplasia. As such, this study aimed to characterize the features of synchronous and metachronous dysplasia detected in patients with SEC to identify factors contributing to the increased risk of colorectal neoplasia, including advanced neoplasia, observed in a subset of these patients. Clinicopathologic features of 46 IBD patients with SEC (n=109) and synchronous and/or metachronous dysplasia (n=153) were analyzed. All dysplastic lesions were subtyped as either conventional or nonconventional dysplasia. As controls, 45 IBD patients with endoscopically visible or polypoid HP (n=75) and synchronous and/or metachronous dysplasia (n=87) were analyzed. The SEC group included 28 (61%) men and 18 (39%) women with a mean age of 58 years and a long history of IBD (mean duration: 23 years). The majority of patients (n=34; 74%) had ulcerative colitis, and 12 (26%) had Crohn's disease. Thirty-nine (85%) patients had a history of pancolitis, and 2 (4%) had concomitant primary sclerosing cholangitis. Twenty-seven (59%) patients had multifocal SEC. SEC was predominantly found in the left colon (n=52; 48%) and rectum (n=34; 31%). Dysplasia in the SEC group was often endoscopically invisible or flat (n=42; 27%) and demonstrated nonconventional dysplastic features (n=49; 32%). Six nonconventional subtypes were identified in the SEC group, including 17 (11%) dysplasia with increased Paneth cell differentiation, 12 (8%) hypermucinous dysplasia, 8 (5%) crypt cell dysplasia, 7 (5%) goblet cell deficient dysplasia, 3 (2%) sessile serrated lesion-like dysplasia, and 2 (1%) traditional serrated adenoma-like dysplasia. Advanced neoplasia was detected in 11 (24%) patients. The SEC group was more likely to have nonconventional dysplasia (32%, P <0.001), invisible/flat dysplasia (27%, P <0.001), and advanced neoplasia (24%, P <0.001) than the control group (7%, 2%, and 0%, respectively). High-risk nonconventional subtypes (ie, hypermucinous, crypt cell, and goblet cell deficient dysplasias) accounted for 18% of all dysplastic lesions in the SEC group, which were not seen in the control group ( P <0.001). The SEC group (n=35; 76%) also had a higher rate of concordance between the location of SEC and the area of synchronous/metachronous dysplasia than the control group (n=22; 49%) ( P =0.007). In conclusion, dysplasia detected in patients with SEC is often endoscopically invisible/flat (27%), nonconventional (32%, including the high-risk subtypes), and found in the same colonic segment as SEC (76%), which may in part explain why some patients with SEC are associated with an increased risk of colorectal neoplasia, including advanced neoplasia. The finding of SEC may warrant a careful follow-up colonoscopy with increased random biopsy sampling, especially in the segment of colon with SEC.

Screening colonoscopy and polypectomy are the cornerstone in decreasing the incidence and mortality of colorectal cancer. Despite the low incidence of colorectal cancer in India, there has been a rising trend in the incidence of colonic polyps and cancer over the last decade. It is, hence, imperative that we are well equipped in the management of colonic polyps. Adequate training in the detection and characterization of polyps to aid in their management is necessary. Detection of polyps can be increased by adhering to the standards of colonoscopy, including good bowel preparation, cecal intubation rate, adequate withdrawal time and use of distal attachment devices. A detected polyp needs optimal characterization to predict histology in real time and decide on the management strategies. Characterization of the polyps requires high-definition-white light endoscopy and/or image-enhanced endoscopy (dye based or digital). Various factors that help in predicting histology include size, location and morphology of the polyp and the pit pattern, vascular and surface pattern of the polyp. Polyps can be differentiated as neoplastic or non-neoplastic with reasonable accuracy with the above features. Prediction of advanced pathology including high-grade dysplasia and deep sub-mucosal invasion is essential, as it helps in deciding if the lesion is amenable to endotherapy and the technique of endoscopic resection. Adequate training in image-enhanced endoscopy is necessary to assess advanced pathology in polyps. Technology pertaining to image-enhanced endoscopy includes narrow banding imaging and blue laser imaging; newer variations are being introduced every few years making it necessary to be abreast with growing information. The recent advances in gastrointestinal (GI) endoscopy with the advent of endocytoscopy and artificial intelligence seem promising and are predicted to be the future of GI endoscopy.

Some colorectal cancer patients have experienced normal epithelial transformation into inflammatory and tumor states, but the molecular basis still needs to be further determined. The expression levels of SIX4 are gradually increased in dextran sodium sulfate (DSS) and azoxymethane (AOM)/DSS-induced colonic epithelial inflammation and tumors, respectively, in mice. Targeting SIX4 alleviates intestinal inflammation occurrence and reduces adenoma formation in mice. Clinical sample assays indicated that SIX4 is upregulated in inflammatory bowel disease (IBD) and colorectal cancer (CRC) tissues compared to normal colorectal tissues. In a subsequent study, we found that SIX4, transcriptionally activated by the proinflammatory IL-6/STAT3 signal, binds to c-Jun to transcribe IL-6, thus forming a positive IL-6/STAT3/SIX4/c-Jun feedback loop, which further induces intestinal inflammation occurrence. In addition, elevated SIX4 also induces the expression of DeltaNp63, rather than wild-type p63, by binding to its promoter and thus facilitates the activation of tumor stemness signals, which ultimately leads to the formation of colorectal cancer. Our study first observes that activated SIX4 in inflammation induction drives the transformation of colorectal epithelium into inflammation and tumor, which demonstrates SIX4 as a significant therapeutic target in IBD and colitis-associated colorectal cancer (CAC) and CRC pathogenesis.

Inflammatory bowel disease (IBD) is rapidly emerging in the Asia Pacific region. However, there are many challenges in the diagnosis and management of this condition. The Asian Pacific Association of Gastroenterology (APAGE) Working Group on IBD conducted a round table meeting to identify 10 common mistakes in the management of IBD in Asia. To summarize, many physicians still over rely on a definitive histological diagnosis before starting treatment and do not fully establish disease extent such as perianal and proximal gastrointestinal involvement in Crohn's disease (CD) or extent of involvement in ulcerative colitis (UC). It is also essential to actively look for evidence of extra-intestinal manifestations, which may influence choice of therapy. In terms of conventional therapy, underuse of topical 5 aminosalicylates (5-ASAs) in UC and inappropriate dosing of corticosteroids are also important considerations. Acute severe UC remains a life-threatening condition and delay in starting rescue therapy after inadequate response to intravenous steroids is still common. Anti-tumor necrosis factors should be considered first line in all cases of complex perianal fistulizing CD. Most patients with IBD are on potent immunosuppressive therapy and should be screened for latent infections and offered vaccinations according to guidelines. Under-recognition and management of significant complications such as anemia, osteoporosis, malnutrition, and thromboembolism should also be addressed. Colonoscopy is still not properly performed for dysplasia/cancer surveillance and for evaluating post-op recurrence of CD. Another common misstep is inappropriate withdrawal of medications during pregnancy leading to increased complications for the mother and the newborn.

Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC), and this risk increases dramatically in those who develop low-grade dysplasia (LGD). However, there is currently no accurate way to risk-stratify patients with LGD, leading to both over- and under-treatment of cancer risk. Here we show that the burden of somatic copy number alterations (CNAs) within resected LGD lesions strongly predicts future cancer development. We performed a retrospective multi-centre validated case-control study of n=122 patients (40 progressors, 82 non-progressors, 270 LGD regions). Low coverage whole genome sequencing revealed CNA burden was significantly higher in progressors than non-progressors (p=2×10-6 in discovery cohort) and was a very significant predictor of CRC risk in univariate analysis (odds ratio = 36; p=9×10-7), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. The measurement of CNAs in LGD lesions is a robust, low-cost and rapidly translatable predictor of CRC risk in IBD that can be used to direct management and so prevent CRC in high-risk individuals whilst sparing those at low-risk from unnecessary intervention.

Inflammatory bowel diseases (IBD) are associated with several well described neoplastic and structural complications. Increasing disease prevalence, healthcare barriers, and medication refractory phenotypes contribute to ongoing complications despite significant strides in medical management. Enhancements in endoscopic technology and techniques have allowed a minimally invasive approach for what has historically required surgery. In this article, we review the current and future landscape of endoscopic IBD intervention.

Endoscopic resection is the first line for managing conventional and complex colitis-associated dysplasia. Evidence supporting endoscopic submucosal dissection is mounting, yet there is a paucity of studies evaluating modified endoscopic mucosal resection techniques or hybrid endoscopic submucosal dissection. We also have more clarity in how best to approach fibrostenotic disease, as we learn how to position endoscopic stricturotomy and stenting, relative to balloon dilation. Finally, applications in managing penetrating and postsurgical complications have been described, but still require further study.

While important knowledge gaps still exist, the application of endoscopic therapies in IBD is more refined, especially within the management of colitis-associated dysplasia and strictures. The indications for endoscopy in perianal disease and other penetrating manifestations of Crohn's disease presents exciting opportunities for growth.

The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update (CPU) Commentary is to discuss the risks of various malignancies in patients with inflammatory bowel diseases (IBD) and the impact of the available medical therapies on these risks. The CPU will also guide the approach to the patient with IBD who develops a malignancy or the patient with a history of cancer in terms of IBD medication management.

This CPU was commissioned and approved by the AGA Institute CPU committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPU committee and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. This communication incorporates important and recently published studies in the field, and it reflects the experiences of the authors who are experts in the diagnosis and management of IBD.

Little is known about the molecular features of visible polyps with low-grade intestinal-type dysplasia in patients with inflammatory bowel disease (IBD). To better understand their origins and biological potential, we sought to genomically profile these lesions and compare them with invisible low-grade dysplasia and sporadic adenomas from non-IBD patients.

22 polyps within areas of colitis, 13 polyps outside areas of colitis, 10 foci of invisible dysplasia from patients with IBD and 6 sporadic tubular adenomas from non-IBD patients were analysed using the OncoPanel assay.

Polyps arising in areas of colitis showed a greater spectrum of mutations, including APC, KRAS, FBXW7, TP53, ARID1A and TCF7L2. Polyps outside colitis and non-IBD sporadic adenomas showed a limited mutational profile, with APC and CTNNB1 mutations. Invisible dysplasia was characterised by TP53, CTNNB1 and KRAS alterations. Compared with dysplastic polyps, none of the invisible dysplastic foci showed APC alterations (73%-within colitis; p=0.0001, 92%-outside colitis; p<0.0001, 83%-sporadic adenomas; p=0.001). TP53 mutations were significantly higher in invisible dysplasia (50%) compared with polyps within colitis (9%; p=0.02) and outside colitis (8%; p=0.03).

Molecular alterations in visible low-grade dysplastic polyps with conventional intestinal-type dysplasia from patients with IBD and sporadic adenomas from non-IBD patients overlap significantly. APC alterations appear to play a major role in the development of visible low-grade dysplastic lesions in patients with IBD, regardless of background colitis. As with IBD-associated colorectal cancers, TP53 mutations are an early event in the development of invisible, low-grade conventional intestinal-type dysplasia in patients with IBD.

Ulcerative colitis (UC) is characterized by an abnormal immune response, and the pathogenesis lacks clear understanding. The cGAS-STING pathway is an innate immune signaling pathway that plays a significant role in various pathophysiological processes. However, the role of the cGAS-STING pathway in UC remains largely unclear. In this study, we obtained transcriptome sequencing data from multiple publicly available databases. cGAS-STING related genes were obtained through literature search, and differentially expressed genes (DEGs) were analyzed using R package limma. Hub genes were identified through protein-protein interaction (PPI) network analysis and module construction. The ConsensuClusterPlus package was utilized to identify molecular subtypes based on hub genes. The therapeutic response, immune microenvironment, and biological pathways of subtypes were further investigated. A total of 18 DEGs were found in UC patients. We further identified IFI16, MB21D1 (CGAS), TMEM173 (STING) and TBK1 as the hub genes. These genes are highly expressed in UC. IFI16 exhibited the highest diagnostic value and predictive value for response to anti-TNF therapy. The expression level of IFI16 was higher in non-responders to anti-TNF therapy. Furthermore, a cluster analysis based on genes related to the cGAS-STING pathway revealed that patients with higher gene expression exhibited elevated immune burden and inflammation levels. This study is a pioneering analysis of cGAS-STING pathway-related genes in UC. These findings provide new insights for the diagnosis of UC and the prediction of therapeutic response.

Treatment of ulcerative colitis (UC) has been revolutionized by the arrival of biotherapies and technical progress in interventional endoscopy and surgery. (Sub)total emergency colectomy is required in the event of complicated severe acute colitis: colectasis, perforation, hemorrhage, organ failure. Corticosteroid therapy is the reference treatment for uncomplicated severe acute colitis, while infliximab and ciclosporin are 2nd-line treatments. At each step, before and after each line of treatment failure, surgery should be considered as an option. In cases refractory to medical treatment, the choice between surgery and change in medication must weigh the chronic symptoms associated with the disease against the risks of postoperative complications and functional sequelae inherent to surgery. Detection of dysplastic lesions necessitates chromoendoscopic imaging with multiple biopsies and anatomopathological verification. Endoscopic treatment of these lesions remains reserved for selected patients. These different indications call for multidisciplinary medical-surgical discussion. Total coloproctectomy with ileo-anal anastomosis (TCP-IAA) is the standard surgery, and it holds out hope for healing. Modalities depend on patient characteristics, previous emergency colectomy, and presence of dysplasia. It may be carried out in one, in two modified, or in three phases. The main complications are anastomotic fistula, short-term pouch-related fistula, ileo-anal pouch syndrome, pouchitis and long-term digestive and sexual disorders. For selected cases, an alternative can consist in total colectomy with ileo-rectal anastomosis or permanent terminal ileostomy. The objective of this update is to clarify the indications, modalities, and results of surgical treatment of ulcerative colitis in accordance with the most recent data in the literature.

Colitis-associated intestinal cancer (CAC) can develop in patients with inflammatory bowel disease; however, the malignant grade of CAC may differ from that of sporadic colorectal cancer (CRC). Therefore, we compared histological findings distinct from cancer stage between CAC and sporadic CRC to evaluate the features of CAC.

We reviewed the clinical and histological data collected from a nationwide database in Japan between 1983 and 2020. Patient characteristics were compared to distinguish ulcerative colitis (UC), Crohn's disease (CD), and sporadic CRC. Comparisons were performed by using all collected data and propensity score-matched data.

A total of 1077 patients with UC-CAC, 297 with CD-CAC, and 136 927 with sporadic CRC were included. Although the prevalence of well or moderately differentiated adenocarcinoma (Tub1 and Tub2) decreased according to tumor progression for all diseases (P < 0.01), the prevalence of other histological findings, including signet ring cell carcinoma, mucinous carcinoma, poorly differentiated adenocarcinoma, or squamous cell carcinoma, was significantly higher in CAC than in sporadic CRC. Based on propensity score-matched data for 982 patients with UC and 268 with CD, the prevalence of histological findings other than Tub1 and Tub2 was also significantly higher in those with CAC. At pT4, mucinous carcinoma occurred at a significantly higher rate in patients with CD (45/86 [52.3%]) than in those with sporadic CRC (13/88 [14.8%]) (P < 0.01).

CAC, including early-stage CAC, has a higher malignant grade than sporadic CRC, and this difference increases in significance with tumor progression.

In this meta-analysis, we studied the safety and efficacy of endoscopic submucosal dissection (ESD) for colorectal dysplasia in patients with inflammatory bowel disease (IBD).

Multiple databases were searched, and studies were retrieved based on pre-specified criteria until October 2022. The outcomes assessed were resection rates, procedural complications, local recurrence, metachronous tumors, and the need for surgery after ESD in IBD. Standard meta-analysis methods were followed using the random-effects model, and I2% was used to assess heterogeneity.

Twelve studies comprising 291 dysplastic lesions in 274 patients were included with a median follow-up of 25 months. The pooled en-bloc resection, R0 resection, and curative resection rates were 92.5% (95% confidence interval [CI], 87.9%-95.4%; I2=0%), 81.5% (95% CI, 72.5%-88%; I2=43%), and 48.9% (95% CI, 32.1%-65.9%; I2=87%), respectively. The local recurrence rate was 3.9% (95% CI, 2%-7.5%; I2=0%). The pooled rates of bleeding and perforation were 7.7% (95% CI, 4.5%-13%; I2=10%) and 5.3% (95% CI, 3.1%-8.9%; I2=0%), respectively. The rates of metachronous recurrence and additional surgery following ESD were 10% (95% CI, 5.2%-18.2%; I2=55%) and 13% (95% CI, 8.5%-19.3%; I2=54%), respectively.

ESD is safe and effective for the resection of dysplastic lesions in IBD with an excellent pooled rate of en-bloc and R0 resection.

Colonoscopy withdrawal time (CWT) of at least 6-9 minutes is the minimum time needed for adequate adenoma detection in the general population. The ideal CWT in patients with inflammatory bowel disease (IBD) has not been determined. We aimed to identify the optimal CWT associated with the detection of visible dysplasia in patients with IBD.

This is a retrospective study from 1/1/2017 to 9/1/2022 of adult patients with IBD in endoscopic healing undergoing surveillance via high-definition white light colonoscopy. The primary outcome was the association of CWT with visible dysplasia detection.

A total of 259 patients (mean age 56 ± 14.8 years; 51.3% female, 68% with ulcerative colitis; 8.9% with primary sclerosing cholangitis) underwent 330 colonoscopies. Patients with visible dysplasia were more likely to be older (P < .001) and have a personal history of visible dysplasia (P < .001) and invisible dysplasia (P = .023). The mean CWT was significantly longer in the visible dysplasia group at 26 minutes (interquartile range [IQR] 20-38.5) vs. 21 minutes (IQR 15-28) in procedures without visible dysplasia (P < .001). On multivariable analysis, increased age (P < .001), increased CWT (P = .001), and personal history of visible dysplasia (P = .013) were independently associated with the detection of visible dysplasia. A CWT of ≥15 minutes (odds ratio [OR] 2.71; 95% confidence interval [CI], 1.11-6.6; P = .02] and not ≥9 minutes (OR 2.57; 95% CI, 0.33-20.2; P = .35) is significantly associated with detection of visible dysplasia.

For patients with IBD undergoing surveillance via high-definition white light colonoscopy, the mean CWT was independently associated with the detection of visible dysplasia.

Patients with a long history of ulcerative colitis (UC) are at risk of developing a significant complication known as UC-associated neoplasia (UCAN). To reduce the risk of UCAN and the associated mortality, the current guidelines recommend initiating surveillance colonoscopy 8-10 years after confirmation of UC diagnosis. In recent years, advancements in endoscopic diagnostic technologies, including magnifying and image-enhancing techniques, have allowed for the production of high-contrast images that emphasize mucosal structures, vascular patterns, and color tones. Recently, image-enhanced endoscopy technologies have become available and offer the potential to improve the qualitative endoscopic assessment of UCAN. The use of high-definition chromoendoscopy enables the evaluation of subtle mucosal patterns in the colon. Magnifying narrow-band imaging facilitates the visualization of mucosal vascular structures. Texture and color enhancement imaging processes structure, color tone, and brightness aspects more appropriately, whereas linked color imaging optimizes the emphasis on mucosal and vascular redness. Both techniques are expected to excel in the depiction of subtle color variations and mucosal changes characteristic of UCAN. This article provides an overview of the current status and future challenges regarding the use of various image-enhanced endoscopy techniques in the diagnosis of UCAN.

It has been claimed that Dendrobium officinale polysaccharides (PSs) can degrade into oligosaccharide and then transform into short-chain fatty acids in the intestine after oral administration, and play an anti-colitis-associated cancer (CAC) effect by inhibiting intestinal inflammation. However, the material basis and core chemical structure underlying the anti-colon cancer properties of PSs have not yet been elucidated. In this study, PSs were degraded into enzymatic oligosaccharides (OSs) using β-mannanase. The results of in vivo experiments revealed that PSs and OSs administered by gastric lavage had similar antitumor effects in CAC mice. OS-1 (Oligosaccharide compounds 1) and OS-2 (Oligosaccharide compounds 2) were further purified and characterized from OSs, and it was found that OS-1, OS-2, OSs, and PSs had similar and consistent anti-inflammatory activities in vitro. Chemical structure comparison and evaluation revealed that the chemical structure of β-D-Manp-(1 → 4)-β-D-Glcp corresponding to OS-1 was the least common PS structure with anti-colitic activity. Therefore, our findings suggest that OSs are the material basis for PSs to exert anti-CAC activity and that the chemical structure of β-D-Manp-(1 → 4)-β-D-Glcp corresponding to OS-1 is the core chemical structure of PSs against CAC.

Timely diagnosis and effective management of colorectal dysplasia play a vital role in preventing mortality from colorectal cancer in patients with chronic inflammatory bowel disease. This review provides a contemporary overview of the pathologic and endoscopic classification of dysplasia in inflammatory bowel disease, their roles in determining surveillance and management algorithms, and emerging diagnostic and therapeutic approaches that might further enhance patient management.

Patients with inflammatory bowel disease have an increased risk of developing colorectal cancer as compared with the general population. Endoscopic surveillance to detect early dysplastic changes is advised by several published clinical guidelines, which provide recommendations as to the timing and performance of surveillance procedures. There is a paucity of data as to adherence with these guidelines in clinical practice.

A longitudinal inception cohort study of all new patients diagnosed with inflammatory bowel disease across a service network of Australian hospitals between January 2005 and June 2014, with continuous follow-up in a gastroenterology clinic until December 31, 2022. Patients were included if they warranted surveillance according to the Australian guidelines. Adherence to guidelines and technical and quality measures were reported.

A total of 136 patients were included, and a total of 263 surveillance procedures were performed. Ninety-five patients (70%) had their first surveillance colonoscopy within the correct time interval. Fifty patients (37%) were completely adherent to guidelines with respect to timing of all surveillance procedure. The overall dysplasia detection rate for surveillance procedures was 10%. Chromoendoscopy was only performed in 16% of procedures.

Adherence to endoscopic surveillance guidelines with regard to timing of procedures and the utilization of chromoendoscopy is poor. Further clinician education, promotion of the surveillance guidelines and incorporation of chromoendoscopy training as part of the national colonoscopy training program may improve adherence to guidelines.

Due to their increased cancer risk, patients with longstanding inflammatory bowel disease are offered endoscopic surveillance with concomitant histopathologic assessments, aimed at identifying dysplasia as a precursor lesion of colitis-associated colorectal cancer. However, this strategy is beset with difficulties and limitations. Recently, a novel classification criterion for colitis-associated low-grade dysplasia has been proposed, and an association between nonconventional dysplasia and progression was reported, suggesting the possibility of histology-based stratification of patients with colitis-associated lesions. Here, a cohort of colitis-associated lesions was assessed by a panel of 6 experienced pathologists to test the applicability of the published classification criteria and try and validate the association between nonconventional dysplasia and progression. While confirming the presence of different morphologic patterns of colitis-associated dysplasia, the study demonstrated difficulties concerning diagnostic reproducibility between pathologists and was unable to validate the association of nonconventional dysplasia with cancer progression. Our study highlights the overall difficulty of using histologic assessment of precursor lesions for cancer risk prediction in inflammatory bowel disease patients and suggests the need for a different diagnostic strategy that can objectively identify high-risk phenotypes.

The landscape of ulcerative colitis has changed in the last two decades. Advancements in pharmacotherapeutics have heralded the introduction of new treatment options, with many agents in development. Better clinical outcomes are seen with tighter disease control, made possible with greater understanding of inflammatory pathways and their blockade with drugs. There has been a resultant shift in treatment targets, beyond symptoms to endoscopic and histological healing. Controlling the burden of disease activity also lowers the risk of developing colorectal cancer. Colorectal cancer screening now requires the use of dye-based agents and high-definition colonoscopy to improve the detection of colonic neoplasms.

Surveillance colonoscopies are crucial for high-risk patients with inflammatory bowel diseases (IBD) to detect colorectal carcinoma (CRC). However, there is no established quality metric for dysplasia detection rate (DDR) in IBD surveillance. This study assessed the DDR in a dedicated surveillance program at a tertiary referral center for IBD.

Consecutive patients with quiescent colitis were enrolled in a cross-sectional study evaluating DDR. High-definition colonoscopy with dye chromoendoscopy (DCE) was performed by a specialized operator. Advanced dysplasia (AD) was defined as low-grade dysplasia ≥ 10 mm, high-grade dysplasia, or colorectal cancer. Risk factors for dysplasia detection were analyzed.

In total, 119 patients underwent 151 procedures, identifying 206 lesions, of which 40 dysplastic with seven AD . Per-lesion and per-procedure DDR were 19.4 % and 20.5 %, respectively. The per-procedure AD detection rate (ADDR) was 4.6 %. A Kudo pit pattern of II-V had a sensitivity of 92.5 % for dysplasia detection but a false positive rate of 64.8 % (p < 0.001). Age at diagnosis and at index colonoscopy and past or indefinite dysplasia were associated with per-procedure dysplasia detection.

In a real-world setting, a dedicated surveillance program achieved a high DDR. We suggest that optimal DDR in high-risk IBD patients be defined and implemented as a standardized quality measure for surveillance programs.

Longstanding inflammatory bowel disease (especially in patients with severely active disease or primary sclerosing cholangitis) is associated with an increased risk of developing dysplasia and adenocarcinoma. This review covers critical clinical aspects, such as risk factors and screening endoscopy basics, emphasising the SCENIC (Surveillance for Colorectal Endoscopic Neoplasia Detection in Inflammatory Bowel Disease International Consensus) guidelines. The histopathological and molecular features of both conventional (adenomatous) dysplasia and the non-conventional subtypes (hypermucinous dysplasia, goblet cell-deficient dysplasia, crypt cell dysplasia, serrated dysplasias) are discussed with an emphasis on challenging diagnostic areas and helpful tips to allow correct categorisation by the practising pathologist.

Colitis associated colorectal cancer is a disease with a high incidence and complex course that develops from chronic inflammation and deteriorates after various immune responses and inflammation-induced attacks. Colitis associated colorectal cancer has the characteristics of both immune diseases and cancer, and the similarity of treatment models contributes to the similar treatment dilemma. Immunometabolism contributes to the basis of life and is the core of many immune diseases. Manipulating metabolic signal transduction can be an effective way to control the immune process, which is expected to become a new target for colitis associated colorectal cancer therapy. Immune cells participate in the whole process of colitis associated colorectal cancer development by transforming their functional condition via changing their metabolic ways, such as glucose, lipid, and amino acid metabolism. The same immune and metabolic processes may play different roles in inflammation, dysplasia, and carcinoma, so anti-inflammation agents, immunomodulators, and agents targeting special metabolism should be used in combination to prevent and inhibit the development of colitis associated colorectal cancer.

Given the chronic nature of mucosal inflammation present in patients with inflammatory bowel disease (IBD), there is a high risk of dysplastic lesions progressing to cancer, in addition to a high risk of synchronous and/or metachronous cancers developing in those diagnosed with dysplasia. Due to this, consensus guidelines recommend regular surveillance. When visible dysplasia is encountered, options include endoscopic or surgical resection depending on characteristics of the lesion. Advancements in endoscopic tools increasingly allow for endoscopic removal when appropriate. Invisible dysplasia discovered on random biopsy should prompt referral to physicians who specialize in IBD. While surgical resection with proctocolectomy significantly decreases the risk of colorectal cancer, the risk must be balanced against the morbidity of surgery and quality-of-life concerns. Management of dysplasia in IBD patients requires complex decision-making that requires balance of patient values and goals of care with cancer-related risk factors.

Primary sclerosing cholangitis (PSC) was declared one of the biggest unmet needs in hepatology during International Liver Congress 2016 in Berlin. Since then, not much has changed unfortunately, largely due to the still elusive pathophysiology of the disease. One of the most striking features of PSC is its association with inflammatory bowel disease (IBD), with the majority of patients with PSC being diagnosed with extensive colitis. This review describes the epidemiology of IBD in PSC, its specific phenotype, complications and potential pathophysiological mechanisms connecting the two diseases. Whether PSC is merely an extra-intestinal manifestation of IBD or if PSC and IBD are two distinct diseases that happen to share a common susceptibility that leads to a dual phenotype is debated. Implications for the management of the two diseases together are also discussed. Overall, this review summarises the available data in PSC-IBD and discusses whether PSC and IBD are one or two disease(s).

Inflammatory bowel disease (IBD) increases the risk of dysplasia and colorectal cancer (CRC). Moreover, colitis-associated CRC is responsible for a disproportionate number of CRC-related mortality. For this reason, societies recommend screening and surveillance colonoscopy as the standard of care for patients with ulcerative colitis and Crohn's colitis. Nonetheless, interval cancer defined as CRC detected within the appropriate surveillance interval might still occur despite following guideline recommendations. Even though there is limited data on risk factors associated with interval CRC in IBD, patient and disease-associated factors and technical aspects of the surveillance might play a role. This review aims to provide information on the epidemiology of interval CRC in IBD, the factors that might be associated with its occurrence, and the challenges of CRC screening and dysplasia management in patients with IBD.

Patients suffering from inflammatory bowel disease (IBD) face a two to three-fold higher risk of developing colorectal cancer (CRC) compared to the general population. In recent years, significant progress has been made in comprehending the natural history of IBD-associated CRC (IBD-CRC) and refining its treatment strategies. The decreased incidence of IBD-CRC can be attributed to improved therapeutic management of inflammation, advancements in endoscopy, and early detection of precancerous lesions via surveillance programs. Advanced imaging technologies have made previously undetectable dysplasia visible in most cases, allowing for a much more precise and detailed examination of the mucosa. Additionally, new tools have facilitated the endoscopic resection (ER) of visible lesions in IBD. Particularly, the key to effectively manage colitis-associated colorectal neoplasia (CAN) is to first identify it and subsequently guarantee a complete ER in order to avoid surgery and opt for continuing surveillance. Advanced ER techniques for CAN include endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and hybrid ESD-EMR (h-ESD). This narrative review aims to consolidate the current literature on IBD-CRC, providing an overview of advanced techniques for ER of CAN in IBD, with a particular emphasis on the impact of ESD on the long-term outcomes of IBD patients.

Given the need to improve the sensitivity of non-invasive methods to detect colorectal neoplasia, particularly adenomas, we compared a fecal test using a monoclonal antibody (Mab) raised against constituents of colonic adenomas designated Adnab-9 (Adenoma Antibody 9), recognizing an N-linked 87 kDa glycoprotein, to gFOBT, which is shown to reduce CRC mortality. p87 immunohistochemistry testing is significantly more sensitive (OR 3.64[CI 2.37-5.58]) than gFOBT (guaiac-based fecal occult blood test) for adenomas (<3 in number), advanced adenomas (OR 4.21[CI 2.47-7.15]), or a combination of the two (OR 3.35[CI 2.47-4.53]). p87 immunohistochemistry shows regional Paneth cell (PC) expression mainly in the right-sided colon and is significantly reduced in the ceca of African Americans (p < 0.0001). In a subset of patients, we obtained other body fluids such as urine, colonic effluent, and saliva. Urine tests (organ-specific neoantigen) showed a significant difference for advanced adenomas (p < 0.047). We conclude that fecal p87 testing is more sensitive than gFOBT and Adnab-9 and could be used to better direct the colonoscopy screening effort.