Introduction

Colorectal serrated lesions (SLs) include hyperplastic polyp (HP), traditional serrated adenoma (TSA) and sessile serrated lesion (SSL). Aberrant DNA methylation is prevalent in colorectal SLs. We previously reported that SMOC1 (SPARC-related molecular calcium-binding 1) was frequently methylated and silenced in TSAs as well as in high-grade adenomas and colorectal cancers (CRCs) but was rarely methylated and silenced in SSLs. [1] However, the expression of SMOC1 in colorectal lesions, including SLs, has not yet been studied in detail.

Aims & Methods

To evaluate the potential of SMOC1 as a biomarker for diagnosis of SLs and risk prediction in colorectal tumors, we aimed to characterize the expression of SMOC1 in colorectal lesions. Specimens of colorectal lesions (n = 199) and adjacent normal colorectal tissues (n = 112) were collected from 173 patients who underwent endoscopic or surgical resection. Colorectal lesions were randomly divided into two groups: a training set and a validation set. SMOC1 expression was analyzed by immunohistochemistry. A rabbit anti-SMOC1 polyclonal antibody (1:1000 dilution, C-20; Sigma-Aldrich) was used for immunohistochemical staining. The intensity of SMOC1 staining was graded as strong (3), moderate (2), weak (1) or negative (0). The proportions of positively stained tumor cells were assigned a value of 0 to 10. Because neoplasm heterogeneity caused varying degrees of immunoreactivity in the slides, we used the sum of each intensity × proportion as an immunohistochemistry (IHC) score (e.g., intensity × proportion = (3) × 5 + (2) × 3 + (1) × 1 + (0) × 1 = IHC score 22; maximum score = 30) to improve accuracy. When TSAs had both flat and protruding components, SMOC1 expression was evaluated in the protruding component. Thereafter, levels of SMOC1 expression were compared between flat and protruding components in order to evaluate its involvement in the progression of TSAs. All slides were independently evaluated by gastrointestinal pathologists who were blinded to the clinical data.

Results

Histology of the 199 colorectal lesions was as follows: HP, n = 26; SSL, n = 50; SSL with dysplasia (SSLD)/SSL with early invasive cancer (EIC), n = 14; TSA, n = 51; TSA with high grade dysplasia (HGD)/EIC, n = 3; low grade adenoma, n = 17; high grade adenoma, n = 14; HGD, n = 16; EIC, n = 8. Mean IHC scores in normal colonic tissues and colorectal lesions in the training set were as follows: normal colon, 24.2; HP, 21.6; SSL, 24.8; SSLD/SSL with EIC, 17.5; TSA, 7.3; low grade adenoma, 21.4; high grade adenoma, 11.7; HGD, 12.1; EIC, 10.9. These results suggest that SMOC1 is abundantly expressed in normal colon, HPs, SSLs and low grade adenomas, whereas it is significantly downregulated in TSAs, high grade adenomas, HGDs and EICs (p < 0.05). Mean IHC scores for colorectal lesions in the validation set were as follows: HP, 17.7; SSL, 22.8; SSLD/SSL with EIC, 11.5; TSA, 3.1; TSA with HGD/EIC, 4.7. Again, we observed abundant expression of SMOC1 in HPs and SSLs, whereas it was significantly downregulated in TSAs and TSAs with HGD/EIC (p < 0.05). Among TSAs that contained both flat and protruding components, levels of SMOC1 expression were significantly lower in the protruding components both the training set (p < 0.001) and the validation set (p < 0.05).

Conclusion

Our results suggest that reduced expression of SMOC1 is associated with progression of TSAs and conventional adenomas and that SMOC1 may be a diagnostic marker of SLs as well as a predictive marker of colorectal tumors at high risk of developing into cancer.

References

[1] Aoki H, Yamamoto E, Takasawa A, Niinuma T, Yamano HO et al. Epigenetic silencing of SMOC1 in traditional serrated adenoma and colorectal cancer. Oncotarget. 2018

Introduction

Piecemeal endoscopic mucosal resection (pEMR) is the preferred treatment for large non-pedunculated colorectal polyps (LNPCPs)[1,2]. A major limitation of pEMR is residual or recurrent adenoma (RRA), which was reported to in 15%-30% of cases at first surveillance colonoscopy (SC1)[3], performed 3-6 months after the index procedure, but is reduced to the range of 3%-5% by applying ablative measures to the post-EMR resection margin[4].

Aims & Methods

This study aimed to evaluate the effects of late SC1 on RRA.
This is an analysis of a prospectively collected cohort of adult patients referred for pEMR at two academic centers in Israel, from 2016 to 2023. We included all patients who underwent pEMR of LNCPCs and completed SC1.
We compared outcomes between patients who completed early SC1 at 3-6 months following the index procedure with patients who completed late SC1 later than 6 months. All procedures and surveillance colonoscopies were performed by experienced endoscopists trained in pEMR using high-definition scopes. EMR was followed by thermal ablation of the entire mucosal defect margin with snare soft tip coagulation, as previously described[4].
Scar evaluation at SC1 was performed with high-definition white light and chromoendoscopy. Our primary endpoint was RRA at SC1.
Analyses were performed per lesion. We compared baseline parameters and outcome rates between groups, and performed multivariate analysis to assess the adjusted association of months to SC1 with RRA.

Results

We analyzed 516 lesions that underwent index pEMR resection and subsequent SC1. Baseline parameters and recurrence rates are presented in Table 1. The early SC1 group (n=371) underwent SC1 at a mean of 5.1 months versus a mean of 11.1 months in the late SC1 group (p<0.01; Table 1). Polyp size in the early SC1 group was significantly larger than that in the late SC1 group (mean size 35.9 mm [SD 13.9] vs. 32.1 mm [SD 12.4], p<0.01; Table 1). The distribution of lesion location, granularity differed between the groups (Table 1). However, there were no significant differences in lesion Paris classification or rates of high grade dysplasia (Table 1).
We found no statistically significant difference in the rate of recurrence at SC1 between the two groups (6.3% in the standard group versus 4.8% in the delayed group, p=0.64). Additionally, a sub-analysis comparing the early SC1 group to patients with very late SC1 (>12 months – mean time to SC1 17.9 (SD [5.4] months) and did not reveal significant difference in recurrence at SC1 (6.2% in the early SC1 vs 6.3% in the very late group, p=1).
Multivariate analysis, adjusted for lesion size, location, and high-grade dysplasia, showed that time to SC1 was not significantly associated with RRA (odds ratio 1.05, 95% confidence interval 0.98-1.13).

TABLE 1. Comparison of baseline variables and outcome between the early and late SC1.

Conclusion

Late SC1 is not associated with an increased RRA. Hence, we suggest that high-quality pEMR with margin ablation may alleviate the need for early SC1, thereby reducing healthcare and patient burdens. Further interventional studies are required.

References

[1] Ferlitsch M, Moss A, Hassan C, et al. Colorectal polypectomy and endoscopic mucosal resection (EMR): European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy 2017; 49: 270–297. doi:10.1055/S-0043-102569/ID/JR15335-1/BIB
[2] Shaukat A, Kaltenbach T, Dominitz JA, et al. Endoscopic Recognition and Management Strategies for Malignant Colorectal Polyps: Recommendations of the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2020; 159: 1916-1934.e2. doi:10.1053/j.gastro.2020.08.050
[3] Belderbos TDG, Leenders M, Moons LMG, et al. Local recurrence after endoscopic mucosal resection of nonpedunculated colorectal lesions: Systematic review and meta-analysis. Endoscopy 2014; 46: 388–400. doi:10.1055/S-0034-1364970/ID/JR910-7/BIB
[4] Klein A, Tate DJ, Jayasekeran V, et al. Thermal Ablation of Mucosal Defect Margins Reduces Adenoma Recurrence After Colonic Endoscopic Mucosal Resection. Gastroenterology 2019; 156: 604-613.e3. doi:10.1053/j.gastro.2018.10.003

Disclosure

The authors report no conflict of interests

Introduction

Patients with Serrated polyps are at increased risk for colorectal cancer (CRC) compared to those without polyps at screening colonoscopy. However, the burden of the serrated pathway by subtypes of serrated polyps (hyperplastic polyps, Sessile serrated lesions/traditional serrated adenomas) to long-term CRC mortality in screening patients is not well understood.

Aims & Methods

We conducted a retrospective cohort study where we included screening participants of the Austrian Quality Certificate for Screening Colonoscopy between 2010-2020. Data on CRC deaths by primary tumor location in the cohort was obtained by database linkage to the Austrian Death registry. We assessed cumulative incidence of CRC deaths after the diagnosis of SSL/TSA, HP and conventional adenomas with deaths from other causes as competing risk. Whether polyp size in HP, SSL/TSA, adjusted for polyp location, sex and age was associated with CRC death was assessed by Cox regression.

Results

321,964 participants were included in the final analysis. 10-year Cumulative incidence of CRC death was 0.13% (95% CI 0.12-0.14%) for participants with HP, 0.16% (95% CI 0.16-0.16%) for participants with SSL/TSA and 0.25% (95% CI 0.23-0.27%) after the diagnosis of conventional adenomas. 1,271 (95% CI 2.71%) HP were ≥10 mm, as compared to 1,354 (95% CI 18.65%) SSL/TSA and 9,576 (95% CI 13.26%) conventional adenomas. When adjusted for polyp location, the association of polyp size ≥10 mm with CRC death was of similar magnitude in participants with conventional adenomas (HR 3.69, 95% CI 2.45 - 5.55), SSL/TSA (HR 3.24, 95% CI 1.35 - 7.79) and HP (HR 5.08, 95% CI 2.42 - 10.65). Participants who had hyperplastic polyps at screening mostly died of cancers located in the distal colon (62.1%, n = 18), while only 10.3% (n = 3) of CRC deaths after the detection of hyperplastic polyps were of proximal tumors. In participants with SSL/TSA, 42.9% (n = 3) of deaths were from proximal tumors, only 14.3% (n = 1) were located in the sigmoid colon or rectum.

Conclusion

Across all histologic types, participants with a polyp sized ≥10 mm have higher hazards for CRC death after screening colonoscopy compared to polyps <10 mm. Although only few participants had large HP detected at screening, polyp size is associated with CRC mortality in participants with HP, when adjusting for of polyp location.

Introduction

The standard treatment for pT1 colorectal cancer classified as high risk (poor differentiation, deep submucosal invasion, intense tumor budding, resection margins that are positive or lymphovascular invasion) is surgery [1]. However, some studies have revealed that patients who undergo surgery and endoscopic treatment have similar disease progression outcomes, and it is also controversial which histological factors influence disease progression [2,3].

Aims & Methods

The aim of this study was to analyze the characteristics and evolution of patients undergoing surgery or endoscopic treatment after the resection of pT1 colorectal adenocarcinoma with histological findings considered high risk for lymph node metastasis.
We conducted an observational study of historical cohorts. We included patients with pT1 Adenocarcinoma and histological criteria of poor prognosis with at least six months of follow-up, and who were diagnosed between 2018 and 2024. The therapeutic approach was determined by a multidisciplinary committee.

Results

We included 54 patients (74.1% male) with a mean age of 65.3 years and mean follow-up time of 3.07 years; no significant differences in both groups. The indications for colonoscopy were screening (42.6%), alarm symptoms (38.9%), radiological findings (3.7%), prior polypectomy (9.3%), history of colorectal cancer (1.9%), and family history (3.7%). The rate of patients with endoscopic complications was 2.9% intraprocedural bleeding and 2.9% delayed bleeding.
The mean lesion size was 23.48 mm, and the most common location was the rectum.
Regarding the therapeutic approach, 63.0% of patients underwent surgery and 29.6% underwent endoscopic surveillance. Among the surgical patients, complications included suture dehiscence (6%), and hemorrhage (2%). In the surgical specimen analysis, residual lesion was found in 6 patients, and metastatic lymph nodes in 2. 5.55% required adjuvant therapy due to lymph node involvement, and 1.85% were stage IV at diagnosis, excluded from the comparative analysis.
Comparing both study groups, the surgical group had a significantly higher rate of submucosal invasion, with no differences in the remaining characteristics studied. During the study period, progression with lymph node involvement was observed in one patient who underwent surgery and two patients who underwent endoscopy treatment (average time 11 and 24.5 months, respectively). No patient has developed distant metastases to date.

Conclusion

In our study, patients who underwent endoscopic treatment did not present significant differences with respect to those who received surgery in terms of long-term tumor progression, despite having a higher rate of submucosal invasion. Further studies with larger sample sizes are needed to determine which factors and to what extent influence lymphatic and distant dissemination of pT1 adenocarcinoma.

References

1. Hassan C, Wysocki PT, Fuccio L, Seufferlein T, Dinis-Ribeiro M, Brandão C, et al. Endoscopic surveillance after surgical or endoscopic resection for colorectal cancer: European Society of Gastrointestinal Endoscopy (ESGE) and European Society of Digestive Oncology (ESDO) Guideline. Endoscopy 2019;51:266–77. https://doi.org/10.1055/a-0831-2522.
2. Ozeki T, Shimura T, Ozeki T, Ebi M, Iwasaki H, Kato H, et al. The risk analyses of lymph node metastasis and recurrence for submucosal invasive colorectal cancer: Novel criteria to skip completion surgery. Cancers (Basel) 2022;14:822. https://doi.org/10.3390/cancers14030822.
3. Zwager LW, Bastiaansen BAJ, Montazeri NSM, Hompes R, Barresi V, Ichimasa K, et al. Deep submucosal invasion is not an independent risk factor for lymph node metastasis in T1 colorectal cancer: A meta-analysis. Gastroenterology 2022;163:174–89. https://doi.org/10.1053/j.gastro.2022.04.010.

Introduction

In recent years, the number of early-onset CRC (EO-CRC) diagnosed at the age of less than 50 years has been increasing. Previous studies suggest that EO-CRC may have higher malignant potentials and a worse prognosis than late-onset CRC. However, the reason why EO-CRC is regarded as aggressive cancer and result in delayed diagnosis remains unclear. We thought that both the lack of appropriate opportunities for screening or medical examination and the bias that was caused owing to being analyzed altogether regarding the different clinical stages could affect worse prognosis of EO-CRC. In this study, we focused on T1 cancer to highlight the essential features of EO-CRC to minimize the bias caused by the time of diagnosis.

Aims & Methods

This study is a secondary analysis of the main JSCCR (The Japanese Society for Cancer of the Colon and Rectum) project, “International joint research on lymph node metastasis in CRC”. Utilizing 4673 T1 CRC cases treated between July 2009 and December 2016 at 27 facilities belonging to JSCCR, we divided the patients into 5 groups according to age at the diagnosis: 49 years or younger, 50‒59 years, 60‒69 years, 70‒79 years, and 80 years or older. To analyze the clinicopathological features including sex, tumor location, macroscopic type, tumor size, histology, submucosal invasion depth, lymphatic/venous invasion, tumor budding, lymph node metastasis, and treatment methods, the Spearman’s correlation test was used. The difference of disease-free survival (DFS) between early-onset and later-onset CRC was also examined using log-rank test and Kaplan–Meier method.

Results

The cases of EO-CRC were 349 (7.5%). Among age groups, the proportion of rectum (from 49 years or younger to 80 years or older;44.1%, 42.0%, 36.6%, 29.0%, and 12.0%, respectively; P <0.05), protruded type (62.2%, 59.1%, 54.9%, 48.4%, 45.9%; P <0.05), and frequency of lymph node metastasis (10.0%, 7%, 8.0%, 7.0%, 4.6%; P <0.05) were decreased as the age group increased. In terms of sex, the proportion of male tends to decrease as the age group increased (57.9%, 60.8%, 63.5%, 57.0%, 52.7%, respectively; P <0.05). No significant differences were found among the five age groups for tumor size, histology, submucosal invasion depth, vascular invasion, tumor budding, recurrence rate, and treatment. No significant difference was observed regarding DFS between the two groups (5-year DFS; 98.7% for EO-CRC and 94.3% for late-onset CRC).

Conclusion

This study showed that the frequency of lymph node metastasis of T1 CRC decreased according to the increase of age at diagnosis, suggesting that EO-CRC may have a greater biological malignant potential compared to late-onset CRC. As far as we know, this is also the first study to report that “protruded type” would be one of the features of EO-CRC. Although no difference was observed as for DFS between two groups, it was plausible considering that only T1 stage CRC was enrolled in this study. Further studies are warranted to evaluate the clinicopathological features characterizing early stage EO-CRC.

Introduction

Irritable bowel syndrome (IBS) is a common disorder rooted in a disruption of the gut-brain-axis, characterized by abdominal pain and altered bowel habits. Altered gut microbiota is reported in IBS, with microbial metabolites, including bile acids, recognized to be potentially involved in the generation of IBS symptoms.

Aims & Methods

This study aims to clarify the potential link between the gut microbiota composition, fecal bile acid levels, colonic gene expression, and IBS symptoms. In patients with IBS (n = 152), and healthy controls without gastrointestinal symptoms (n = 32), we measured fecal bile acids using targeted metabolomics. We profiled the fecal microbiota by whole-genome metagenomics, and analyzed colonic gene expression patterns by RNA sequencing transcriptomics of mucosal biopsies. All individuals completed self-reported questionnaires on GI symptom severity and patterns (GSRS-IBS, Bristol Stool Form Scale-based stool diary). Spearman’s correlation with Benjamini-Hochberg multiple testing adjustment was used for correlation analyses, permutational ANOVA for analysis of gut microbial composition on Bray-Curtis dissimilarity, and the Wald test for analysis of differences in colonic gene expression. Differences in bile acid levels were tested with Kruskal-Wallis and post hoc Conover-Iman tests, with Benjamini-Hochberg adjustment.

Results

The levels of the hepatically synthesized primary bile acids, chenodeoxycholic acid and cholic acid, were lower in IBS-C (constipation-predominant IBS) compared to IBS-D (diarrhea-predominant IBS, p = 2.31e^-7), IBS-M (mixed type IBS, p = 0.002) and healthy controls (p = 2.57e^-6, Table 1). In IBS patients, levels of primary bile acids correlated with perceived symptom severity of constipation (negatively, rho = -0.3, p = 0.0002) and diarrhea (positively, rho = 0.26, p = 0.00106). When dividing IBS patients into quartiles by primary bile acid levels, 95 genes in the lowest quartile showed altered colonic expression. Gene-set enrichment analysis revealed enrichment of immune response-related genes, including those involved in chemokine and cytokine activity. Permutational ANOVA tests revealed altered gut microbiota composition in the two lowest quartiles of primary bile acid levels compared to healthy controls (p = 0.0001, p = 0.0003).

Conclusion

Alterations in fecal primary bile acid levels were associated with stool consistency in IBS, and lower levels of primary bile acids were linked with altered gut microbiota composition and expression of colonic immune-related genes, suggesting involvement of gut microbiota-bile acid-host crosstalk in symptom generation in IBS.