SpaceANOVA: Spatial Co-occurrence Analysis of Cell Types in Multiplex Imaging Data Using Point Process and Functional ANOVA.

Multiplex imaging platforms have enabled the identification of the spatial organization of different types of cells in complex tissue or the tumor microenvironment. Exploring the potential variations in the spatial co-occurrence or colocalization of different cell types across distinct tissue or disease classes can provide significant pathological insights, paving the way for intervention strategies. However, the existing methods in this context either rely on stringent statistical assumptions or suffer from a lack of generalizability. We present a highly powerful method to study differential spatial co-occurrence of cell types across multiple tissue or disease groups, based on the theories of the Poisson point process and functional analysis of variance. Notably, the method accommodates multiple images per subject and addresses the problem of missing tissue regions, commonly encountered due to data-collection complexities. We demonstrate the superior statistical power and robustness of the method in comparison with existing approaches through realistic simulation studies. Furthermore, we apply the method to three real data sets on different diseases collected using different imaging platforms. In particular, one of these data sets reveals novel insights into the spatial characteristics of various types of colorectal adenoma.

A novel index combining fecal immunochemical test, DNA test, and age improves detection of advanced colorectal adenoma.

Although the fecal immunochemical test for hemoglobin (FIT) is a widely used screening test for colorectal cancer, it is not sensitive enough to detect advanced colorectal adenoma. To address this issue, we performed this study to investigate whether combining the FIT and fecal DNA testing of methylated somatostatin (SST) could improve diagnostic performance for advanced colorectal adenoma. We collected feces from 79 healthy subjects with negative results on colonoscopy, 43 patients with non-advanced colorectal adenoma, 117 patients with advanced colorectal adenoma, and 126 patients with colorectal cancer. After fecal DNA was incubated with methylation-sensitive restriction enzymes, SST methylation levels were measured by droplet digital PCR. Using logistic multivariate analysis, we established a prediction formula for detecting colorectal neoplasia and named it the FAMS (FIT, age, methylated SST) index. The diagnostic performance of a single use of FIT for advanced colorectal adenoma showed a sensitivity of 29.1% (34/117) and specificity of 89.3% (109/122). In contrast, the FAMS index showed a sensitivity of 56.4% (66/117) at a similar specificity point of 91.0% (111/122). Furthermore, even at the higher specificity point of 94.3% (115/122), the sensitivity was still higher than that of FIT, reaching 42.7% (50/117). As the FAMS index showed better diagnostic performance for advanced colorectal adenoma than a single use of FIT, the FAMS index could be a promising tool for detecting advanced colorectal adenoma.

Snare Tip Soft Coagulation vs Argon Plasma Coagulation vs No Margin Treatment After Large Nonpedunculated Colorectal Polyp Resection: a Randomized Trial.

BACKGROUND & AIMS: Thermal treatment of the defect margin after endoscopic mucosal resection (EMR) of large nonpedunculated colorectal lesions reduces the recurrence rate. Both snare tip soft coagulation (STSC) and argon plasma coagulation (APC) have been used for thermal margin treatment, but there are few data directly comparing STSC with APC for this indication. METHODS: We performed a randomized 3-arm trial in 9 US centers comparing STSC with APC with no margin treatment (control) of defects after EMR of colorectal nonpedunculated lesions ≥15 mm. The primary end point was the presence of residual lesion at first follow-up. RESULTS: There were 384 patients and 414 lesions randomized, and 308 patients (80.2%) with 328 lesions completed ≥1 follow-up. The proportion of lesions with residual polyp at first follow-up was 4.6% with STSC, 9.3% with APC, and 21.4% with control subjects (no margin treatment). The odds of residual polyp at first follow-up were lower for STSC and APC when compared with control subjects (P = .001 and P = .01, respectively). The difference in odds was not significant between STSC and APC. STSC took less time to apply than APC (median, 3.35 vs 4.08 minutes; P = .019). Adverse event rates were low, with no difference between arms. CONCLUSIONS: In a randomized trial STSC and APC were each superior to no thermal margin treatment after EMR. STSC was faster to apply than APC. Because STSC also results in lower cost and plastic waste than APC (APC requires an additional device), our study supports STSC as the preferred thermal margin treatment after colorectal EMR. (Clinicaltrials.gov, Number NCT03654209.).

Risk of colorectal cancer and adenoma after an appendectomy: results from three large prospective cohort studies and meta-analysis.

PURPOSE: The relationship between appendectomy and subsequent colorectal cancer risk remains unclear, and no study has examined its association with colorectal adenoma. METHODS: We used data from three prospective cohorts: Health Professionals Follow-up Study, Nurses' Health Study (NHS), and NHSII. Appendectomy history was self-reported at baseline. Colorectal cancer risk was analyzed with Cox proportional hazard models among 224,109 participants followed up to 32 years. Colorectal adenoma risk was evaluated among 157,490 participants with at least one lower gastrointestinal endoscopy during follow-up with logistic regression models accounting for repeated observations. We also performed a meta-analysis of cohort studies that examined association between appendectomy and colorectal cancer risk. RESULTS: We documented 3,384 colorectal cancers, 13,006 conventional adenomas, and 11,519 serrated polyps during the follow-up period. Compared to participants without appendectomy, those who reported appendectomy history were not at higher risk of colorectal (HR [95% CI], 0.92 [0.84-1.00]), colon (0.92 [0.83-1.01]), or rectal (0.85 [0.70-1.03]) cancer. Similarly, appendectomy history was not associated with higher risk of conventional adenoma (OR [95% CI], 1.00 [0.97-1.02]), serrated polyp (0.97 [0.94-1.00]), or high-risk adenoma (0.96 [0.92-1.01]). The meta-analysis showed appendectomy was associated with a higher risk of colorectal cancer within a short time after the procedure (1.68 [1.01-2.81]), while the long-term risk was slightly inverse (0.94 [0.90-0.97]). CONCLUSION: We found no evidence of an association between appendectomy history and long-term risk of colorectal cancer or its precursors. The observed higher risk of colorectal cancer right after appendectomy in the first few years is likely due to reverse causation.

Multiple-matrix metabolomics analysis for the distinct detection of colorectal cancer and adenoma.

OBJECTIVES: Although colorectal cancer (CRC) is the leading cause of cancer-related morbidity and mortality, current diagnostic tests for early-stage CRC and colorectal adenoma (CRA) are suboptimal. Therefore, there is an urgent need to explore less invasive screening procedures for CRC and CRA diagnosis. METHODS: Untargeted gas chromatography-mass spectrometry (GC-MS) metabolic profiling approach was applied to identify candidate metabolites. We performed metabolomics profiling on plasma samples from 412 subjects including 200 CRC patients, 160 CRA patients and 52 normal controls (NC). Among these patients, 45 CRC patients, 152 CRA patients and 50 normal controls had their fecal samples tested simultaneously. RESULTS: Differential metabolites were screened in the adenoma-carcinoma sequence. Three diagnostic models were further developed to identify cancer group, cancer stage, and cancer microsatellite status using those significant metabolites. The three-metabolite-only classifiers used to distinguish the cancer group always keeps the area under the receiver operating characteristic curve (AUC) greater than 0.7. The AUC performance of the classifiers applied to discriminate CRC stage is generally greater than 0.8, and the classifiers used to distinguish microsatellite status of CRC is greater than 0.9. CONCLUSION: This finding highlights potential early-driver metabolites in CRA and early-stage CRC. We also find potential metabolic markers for discriminating the microsatellite state of CRC. Our study and diagnostic model have potential applications for non-invasive CRC and CRA detection.

Gut microbiota alterations in colorectal adenoma-carcinoma sequence based on 16S rRNA gene sequencing: A systematic review and meta-analysis.

BACKGROUND: Most sporadic colorectal cancers (CRC) develop through the adenoma-carcinoma sequence. While dysbiosis of the intestinal flora contributes to CRC's pathogenesis, precise microbial taxa closely associated with the colorectal adenoma-carcinoma sequence remain elusive. This meta-analysis aimed to summarize the features of intestinal flora in patients with AD and CRC. METHODS: PubMed, Embase, Cochrane Library, and Web of Science were searched for case-control studies comparing the relative abundance of gut microbiota in the feces of patients with AD, CRC, and healthy controls (HC) from inception to January 2024. The weighted mean difference (WMD) with a 95 % confidence interval (CI) was used to display the results. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the entailed literature. Publication bias was evaluated with the Egger's and Begg's tests. RESULTS: Eleven studies were included, involving 477 CRC patients, 628 AD patients, and 864 healthy controls. Compared with HC, the patients with AD had a significantly lower Chao 1 index (WMD = -30.17, 95 % CI [-41.10, -19.23], P < 0.001) and Shannon index (WMD = -0.11 95 % CI [-0.18, -0.04], P = 0.002). Compared with AD, the CRC patients had a significantly higher Chao1 index (WMD = 22.09, 95 % CI [7.59, 36.00], P = 0.003) and Shannon index (WMD = 0.08, 95 % CI [0.00, 0.15], P = 0.037). Enterobacteriaceae (WMD = 0.03 95 % CI [0.00,0.05], P = 0.047; WMD = 0.02 95 % CI [0.00,0.04], P = 0.027) significantly increased in the order of Control-AD-CRC, while that of Blautia (WMD = -0.00 95 % CI [-0.01, -0.00], P = 0.001; WMD = -0.00 95 % CI [-0.00, -0.00], P = 0.002) was reduced. Compared with HC, the relative abundance of Proteobacteria (WMD = 0.05 95 % CI [0.03,0.07], P < 0.001), Fusobacteria (WMD = 0.02 95 % CI [0.00,0.03], P = 0.042), Streptococcaceae (WMD = 0.03 95 % CI [0.01,0.05], P = 0.017), Prevotellaceae (WMD = 0.02 95 % CI [0.00,0.04], P = 0.040), and Escherichia-Shigella (WMD = 0.06 95 % CI [0.01, 0.11], P = 0.021) was enriched in the CRC group. The relative abundance of Alistipes (WMD = 0.00 95 % CI [0.00,0.01], P = 0.032) and Streptococcus (WMD = 0.00 95 % CI [0.00,0.00], P = 0.001) was increased in the AD vs HC. The relative abundance of Firmicutes (WMD = -0.07 95 % CI [-0.12, -0.03], P = 0.003), Bifidobacteria (WMD = -0.03 95 % CI [-0.05, -0.01], P = 0.016), and Klebsiella (WMD = -0.01 95 % CI [-0.01, -0.00], P = 0.001) was decreased in the CRC vs HC. Compared with AD, the relative abundance of Firmicutes (WMD = -0.04 95 % CI [-0.07, -0.02], P = 0.002), Peptostreptococcaceae (WMD = -0.03 95 % CI [-0.05, -0.00], P = 0.021), Lachnospiraceae (WMD = -0.04 95 % CI [-0.08,-0.00], P = 0.037), Ruminococcaceae (WMD = -0.06 95 % CI [-0.09,-0.03], P < 0.001), Faecalibacterium (WMD = -0.01 95 % CI [-0.02, -0.01], P = 0.001), and Lachnoclostridium (WMD = -0.02 95 % CI [-0.03, -0.00], P = 0.040) was decreased in the CRC group, while Proteobacteria (WMD = 0.04 95 % CI [0.02,0.05], P < 0.001) was increased. CONCLUSIONS: The dysbiosis characterized by reduced levels of short-chain fatty acid (SCFA)-producing bacteria, decreased anti-inflammatory bacteria, increased pro-inflammatory bacteria, and an elevation of bacteria with cytotoxic effects damaging to DNA may represent the specific microbial signature of colorectal adenoma/carcinoma. Further research is required to elucidate the mechanisms by which gut dysbiosis leads to the progression from AD to CRC and to explore the potential of specific microbiota markers in clinical treatment and non-invasive screening.

Intestinal metabolite xylulose inhibits colorectal cancer by inducing apoptosis through the MAPK signalling pathway.

BACKGROUND: The intestinal metabolites are involved in the initiation, progression and metastasis of colorectal cancer (CRC). They are a potential source of agents for cancer therapy. Our previous study identified altered faecal metabolites between CRC patients and healthy volunteers. However, no specific metabolite was clearly illustrated for CRC therapy. RESULTS: We found that the level of xylulose was lower in the stools of CRC patients than in those of healthy volunteers. Xylulose inhibited cell growth without affecting the cell cycle by inducing apoptosis in CRC cells, which was evidenced by increased expression of the proapoptotic proteins C-PARP and C-Caspase3 and decreased expression of the antiapoptotic protein BCL-2 in CRC cells. Mechanistically, xylulose reduced the activity of the MAPK signalling pathway, represented by reduced phosphorylation of JNK, ERK, and P38. Furthermore, an ALI model was used to show the tumour killing ability of xylulose on human CRC spheres, as well as human colorectal adenoma (AD) spheres. CONCLUSION: Xylulose inhibits CRC growth by inducing apoptosis through attenuation of the MAPK signalling pathway. These results suggest that xylulose may serve as an effective agent for CRC therapy.

Role of MEK1 and DIAPH3 expression in colorectal adenoma-carcinoma sequence.

BACKGROUND: It is well established that most colorectal carcinomas arise from conventional adenomas through the adenoma-carcinoma sequence (ACS) model. mitogen-activated protein kinases (MAPKs) pathway has been reported as a crucial player in tumorigenesis. The MAPK signaling pathway is activated by different extracellular signals involving the "mitogen-activated/extracellular signal-regulated kinase 1 (MEK1)", and this induces the expression of genes involved in proliferation and cellular transformation. Diaphanous-related formin-3 (DIAPH3) acts as a potential metastasis regulator through inhibiting the cellular transition to amoeboid behavior in different cancer types. OBJECTIVE: The aim of the study was to investigate the pattern of immunohistochemical expression of MEK1 and DIAPH3 in colorectal adenoma (CRA) and corresponding colorectal carcinoma (CRC) specimens. METHODS: The immunohistochemical expression of DIAPH3 and MEK1 was examined in 43 cases of CRC and their associated adenomas using tissue microarray technique. RESULTS: MEK1 was overexpressed in 23 CRC cases (53.5%) and in 20 CRA cases (46.5%). DIAPH3 was overexpressed in 11 CRA cases (about 29%) which were significantly lower than CRC (22 cases; 58%) (P = 0.011). Both MEK1 and DIAPH3 overexpression were significantly correlated in CRC (P = 0.009) and CRA cases (P = 0.002). Tumors with MEK1 overexpression had a significantly higher tumor grade (P = 0.050) and perineural invasion (P = 0.017). CONCLUSIONS: Both MEK1 and DIAPH3 are overexpressed across colorectal ACS with strong correlation between them. This co- expression suggests a possible synergistic effect of MEK1 and DIAPH-3 in colorectal ACS. Further large-scale studies are required to investigate the potential functional aspects of MEK1 and DIAPH3 in ACS and their involvement in tumor initiation and the metastatic process.

Association between colonic adenoma size and proliferative zone in the crypt.

BACKGROUND: We previously reported unusual adenomas with proliferative zones confined to the lower two-thirds of the crypt. The proliferative zones of colorectal adenomas have three patterns: 'lower,' 'superficial' and 'entire'. This study aimed to clarify the characteristics of each adenoma pattern. METHODS: We investigated 2925 consecutive patients who underwent colonoscopy at our institute. All polyps that were removed were histologically examined using hematoxylin and eosin staining. The location of the proliferative zone was assessed for adenomas. Data were compared using Dunn's and Kruskal-Wallis tests. RESULTS: Colorectal adenomas with 'lower' proliferative zone often appeared similar to hyperplastic polyps (42.8%), and the frequency was significantly higher than that of adenomas with 'superficial' and 'entire' proliferative zones (p < 0.001). The mean sizes of adenomas were 2.4, 3.0 and 3.9 mm for 'lower,' 'superficial' and 'entire' proliferative zones, respectively. A significant gradual increase was observed. Regarding morphology, the proportion of type 0-I in adenomas with an 'entire' proliferative zone was significantly higher than that in adenomas with 'superficial' proliferative zone (p < 0.001). CONCLUSION: While colorectal adenomas develop and increase in size, the proliferative zone appears to shift upward and become scattered.

MAFLD with central obesity is associated with increased risk of colorectal adenoma and high-risk adenoma.

OBJECTIVE: To analyze the risk factors associated with colorectal adenoma and to investigate the associations of metabolism-related fatty liver disease (MAFLD) with obesity, colorectal adenoma and high-risk adenoma. METHODS: A total of 1395 subjects were enrolled and divided into a colorectal adenoma group (593 subjects) and a control group (802 subjects) according to the inclusion and exclusion criteria. The characteristics of patients in the colorectal adenoma group and the control group were compared by the chi-square test. Univariate and multivariate logistic analyses were used to analyze independent risk factors and associations with different MAFLD subtypes. Colorectal adenoma characteristics and the proportion of patients with high-risk colorectal adenoma were also compared. RESULTS: High-density lipoprotein (HDL-C) was significantly lower in patients in the colorectal adenoma group than in those in the control group (P < 0.001). Logistic regression analysis revealed that age, obesity status, central obesity status, hypertension status, diabetes status, fatty liver status, smoking history, BMI, waist circumference, triglyceride level, HDL-C level, fasting blood glucose level and degree of hepatic steatosis were all independent risk factors for colorectal adenoma. Notably, MAFLD was associated with a significantly increased risk of colorectal adenoma in patients with central obesity (P < 0.001). In addition, obesity, central obesity, diabetes, fatty liver and degree of hepatic steatosis were all shown to be independent risk factors for high-risk colorectal adenoma. In addition, a greater proportion of MAFLD patients with central obesity than those without central obesity had high-risk colorectal adenoma. CONCLUSION: MAFLD and central obesity are independently associated with the development of colorectal adenoma. MAFLD with central obesity is associated with an increased risk of colorectal adenoma and high-risk adenoma.

Onset Time and Characteristics of Postprocedural Bleeding after Endoscopic Resection of Colorectal Lesions: A Multicenter Retrospective Study.

INTRODUCTION: Postprocedural bleeding is a major adverse event after endoscopic resection of colorectal lesions, but the optimal surveillance time after endoscopy is unclear. In this study, we determined onset time and characteristics of postprocedural bleeding events. METHODS: We retrospectively screened patients who underwent endoscopic resection of colorectal lesions at three German hospitals between 2010 and 2019 for postprocedural bleeding events using billing codes. Only patients who required re-endoscopy were included for analysis. For identified patients, we collected demographic data, clinical courses, characteristics of colorectal lesions, and procedure-related variables. Factors associated with late-onset bleeding were determined by univariate and multivariate logistic regression analysis. RESULTS: From a total of 6,820 patients with eligible billing codes, we identified 113 cases with postprocedural bleeding after endoscopic mucosal (61.9%) or snare resection (38.1%) that required re-endoscopy. The median size of the culprit lesion was 20 mm (interquartile range 14-30 mm). The median onset time of postprocedural bleeding was day 3 (interquartile range: 1-6.5 days), with 48.7% of events occurring within 48 h. Multivariate logistic regression analysis demonstrates that a continued intake of antiplatelet drugs (OR: 3.98, 95% CI: 0.89-10.12, p = 0.025) and a flat morphology of the colorectal lesion (OR: 2.98, 95% CI: 1.08-8.01, p = 0.031) were associated with an increased risk for late postprocedural bleeding (>48 h), whereas intraprocedural bleeding was associated with a decreased risk (OR: 0.12, 95% CI: 0.04-0.50, p = 0.001). CONCLUSION: Significant postprocedural bleeding can occur up to 18 days after endoscopic resection of colorectal lesions, but was predominantly observed within 48 h. Continued intake of antiplatelet drugs and a flat polyp morphology are associated with risk for late postprocedural bleeding.

MIST: multiple instance learning network based on Swin Transformer for whole slide image classification of colorectal adenomas.

Colorectal adenoma is a recognized precancerous lesion of colorectal cancer (CRC), and at least 80% of colorectal cancers are malignantly transformed from it. Therefore, it is essential to distinguish benign from malignant adenomas in the early screening of colorectal cancer. Many deep learning computational pathology studies based on whole slide images (WSIs) have been proposed. Most approaches require manual annotation of lesion regions on WSIs, which is time-consuming and labor-intensive. This study proposes a new approach, MIST - Multiple Instance learning network based on the Swin Transformer, which can accurately classify colorectal adenoma WSIs only with slide-level labels. MIST uses the Swin Transformer as the backbone to extract features of images through self-supervised contrastive learning and uses a dual-stream multiple instance learning network to predict the class of slides. We trained and validated MIST on 666 WSIs collected from 480 colorectal adenoma patients in the Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School. These slides contained six common types of colorectal adenomas. The accuracy of external validation on 273 newly collected WSIs from Nanjing First Hospital was 0.784, which was superior to the existing methods and reached a level comparable to that of the local pathologist's accuracy of 0.806. Finally, we analyzed the interpretability of MIST and observed that the lesion areas of interest in MIST were generally consistent with those of interest to local pathologists. In conclusion, MIST is a low-burden, interpretable, and effective approach that can be used in colorectal cancer screening and may lead to a potential reduction in the mortality of CRC patients by assisting clinicians in the decision-making process. © 2022 The Pathological Society of Great Britain and Ireland.

Risk of advanced neoplasia after removal of colorectal adenomas with high-grade dysplasia.

BACKGROUND: Many studies reported the presence of adenomas with high-grade dysplasia (HGD) at index colonoscopy increased the incidence of advanced neoplasia (AN) and colorectal cancer (CRC) following. However, the conclusion remains obscure due to lack of studies on the specific population of adenomas with HGD. This study aimed to assess the long-term risk of AN and CRC after removal of adenomas with HGD. METHODS: A total of 814 patients who underwent adenomas with HGD removal between 2010 and 2019 were retrospectively analyzed. The outcomes were the incidences of AN and CRC during surveillance colonoscopy. Cox proportional hazards models were utilized to identify risk factors associated with AN and CRC. RESULTS: During more than 2000 person-years of follow-up, we found that AN and CRC incidence densities were 44.3 and 4.4 per 1000 person-years, respectively. The 10-year cumulative incidence of AN and CRC were 39.1% and 5.5%, respectively. In the multivariate model, synchronous low-risk polyps (HR 1.80, 95% CI 1.10-2.93) and synchronous high-risk polyps (HR 3.99, 95% CI 2.37-6.72) were risk factors for AN, whereas participation in surveillance colonoscopy visits (HR 0.56, 95% CI 0.36-0.88 for 1 visit; HR 0.10, 95% CI 0.06-0.19 for ≥ 2 visits) were associated with decreased AN incidence. Additionally, elevated baseline carcinoembryonic antigen (CEA) level (HR 10.19, 95% CI 1.77-58.59) was a risk factor for CRC, while participation in ≥ 2 surveillance colonoscopy visits (HR 0.11, 95% CI 0.02-0.56) were associated with decreased CRC incidence. Interestingly, for 11 patients who developed CRC after removal of adenomas with HGD, immunohistochemistry revealed that 8 cases (73%) were deficient mismatch repair CRCs. CONCLUSIONS: Patients who have undergone adenoma with HGD removal are at higher risk of developing AN and CRC, while surveillance colonoscopy can reduce the risk. Patients with synchronous polyps, or with elevated baseline CEA level are considered high-risk populations and require more frequent surveillance.

Association of the triglyceride-glucose index with the occurrence and recurrence of colorectal adenomas: a retrospective study from China.

BACKGROUND: Resection of colorectal adenoma (CRA) prevents colorectal cancer; however, recurrence is common. We aimed to assess the association of the triglyceride-glucose (TyG) index with CRA occurrence and recurrence. METHODS: Data from 3392 participants at a hospital in China from 2020 to 2022 were analyzed. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A restricted cubic spline was used to fit TyG index dose‒response curves to recurrent adenomas. The discriminatory power of TyG index for predicting later recurrence was assessed with the area under the receiver operating characteristic (ROC) curve in 170 patients with a TyG index at initial adenoma diagnosis. RESULTS: One thousand five hundred ninety-six adenoma and 1465 normal participants were included in the occurrence analysis, and 179 recurrent and 152 nonrecurrent participants were included in the recurrence analysis. The TyG mutation was an independent risk factor for CRA occurrence and recurrence. After adjusting for confounders, the risk of adenoma in the participants in Q2, Q3, and Q4 groups of TyG was 1.324 (95% CI 1.020-1.718), 1.349 (95% CI 1.030-1.765), and 1.445 (95% CI 1.055-1.980) times higher than that of the Q1, respectively, and the risk of recurrence in the Q3 and Q4 groups was 2.267 (95% CI 1.096-4.691) and 2.824 (95% CI 1.199-6.648) times in Q1 group. Multiple logistic regression showed that the highest quartile of the TyG index was associated with a greater risk of advanced adenoma recurrence (OR 4.456, 95% CI 1.157-17.164), two or more adenomas (OR 5.079, 95% CI 1.136-22.714 [after removal of TyG index extreme values]), and proximal colon or both adenomas (OR 3.043, 95% CI 1.186-7.810). Subgroup analysis revealed that the association was found to be present only in participants of all age groups who were either male or without obesity, hyperglycemia, hypertension, or dyslipidemia (p < 0.05). ROC curves illustrated that the TyG index had good predictive efficacy for identifying recurrence, especially for patients with two or more adenomas (AUC 0.777, 95% CI 0.648-0.907). CONCLUSIONS: An increase in the TyG index is associated with an increased risk of adenoma occurrence and recurrence, with a stronger association with the latter.

Clinical significance of colonoscopy before laparoscopic bariatric/metabolic surgery in Japanese patients.

PURPOSE: Obesity is known to be associated with colorectal adenoma (CRA) and colorectal cancer (CRC); yet colonoscopy is not considered an essential preoperative evaluation before bariatric/metabolic surgery. The aim of this study was to clarify the clinical significance of preoperative colonoscopy for obese Japanese patients. METHODS: The subjects of this retrospective study were 114 patients who underwent screening colonoscopy before bariatric/metabolic surgery. Multivariate analyses were performed to evaluate the independent predictors of CRA/CRC among the characteristics identified as significant or nearly significant by univariate analyses. RESULTS: Colonoscopy revealed abnormal findings indicating the need for biopsy or polypectomy in 20 of the 114 patients (17.5%), and CRA was diagnosed in 13 patients (11.4%). Three patients (2.6%), who were all ≥ 56 years old, had a CRA ≥ 10 mm in diameter. The multivariate analysis showed that older age and male sex were significant predictors of CRA/CRC, which was identified in 46.2% of the male patients aged ≥ 46 years. CONCLUSION: Our findings suggest that older age and male sex may be risk factors for CRA/CRC in obese Japanese candidates for bariatric/metabolic surgery; thus, preoperative colonoscopy should be considered for these high-risk patients.

Role of Vitamin D Receptor (BsmI-VDR) and Insulin Receptor (NsiI-A/G) Gene Polymorphisms in Colorectal Adenoma Susceptibility.

Vitamin D deficiency and type 2 diabetes mellitus are risk factors for colorectal cancer, suggesting a role for vitamin D receptor (VDR) and insulin receptor (INSR) gene polymorphisms. We investigated the prevalence of the VDR-BsmI (rs1544410) and NsiI A/G-INSR (rs2059806) polymorphisms and their associations with colorectal adenoma (CRA) in a Romanian population. A case-control study was conducted with 110 participants (67 with CRA and 43 controls) who underwent colonoscopy. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to determine the genotype and allele frequencies of the two polymorphisms. Regarding rs1544410 and CRA patients, genotype distribution was 35% B/B, 47% B/b, and 19% b/b. In the controls, the distribution was 21% B/B, 45% B/b, and 34% b/b. For rs2059806, 12% of CRA patients had A/A, 30% A/G, and 58% G/G, while 8% of the controls had A/A, 40% A/G, and 52% G/G. The recessive model showed an odds ratio of 2.84 (95% CI: 1.04-7.72, p = 0.033) for the b/b genotype. CRA patients with b/b or G/G genotypes were diagnosed at a younger age. The b allele of the rs1544410 was a risk factor for CRA. Patients with the b/b and G/G genotypes were diagnosed earlier.

MicroRNA-193a-3p as a Valuable Biomarker for Discriminating between Colorectal Cancer and Colorectal Adenoma Patients.

Specific markers for colorectal cancer (CRC), preceded by colorectal adenoma (pre-CRC), are lacking. This study aimed to investigate whether microRNAs (miR-19a-3p, miR-92a-3p, miR-193a-3p, and miR-210-3p) from tissues and exosomes are potential CRC biomarkers and compare them to existing biomarkers, namely carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9. MiRNA was isolated in the samples of 52 CRC and 76 pre-CRC patients. Expression levels were analyzed by RT-qPCR. When comparing pre-CRC and CRC tissue expression levels, only miR-193a-3p showed statistically significant result (p < 0.0001). When comparing the tissues and exosomes of CRC samples, a statistically significant difference was found for miR-193a-3p (p < 0.0001), miR-19a-3p (p < 0.0001), miR-92a-3p (p = 0.0212), and miR-210-3p (p < 0.0001). A receiver-operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to evaluate the diagnostic value of CEA, CA 19-9, and miRNAs. CEA and CA 19-9 had good diagnostic values (AUCs of 0.798 and 0.668). The diagnostic value only of miR-193a-3p was highlighted (AUC = 0.725). The final logistic regression model, in which we put a combination of CEA concentration and the miR-193a-3p expression level in tissues, showed that using these two markers can distinguish CRC and pre-CRC in 71.3% of cases (AUC = 0.823). MiR-193a-3p from tissues could be a potential CRC biomarker.

Aspirin and nonaspirin nonsteroidal antiinflammatory drug use and occurrence of colorectal adenoma in Black American women.

Evidence suggests that aspirin use reduces the occurrence of colorectal neoplasia. Few studies have investigated the association among Black Americans, who are disproportionately burdened by the disease. We assessed aspirin use in relation to colorectal adenoma among Black women. The Black Women's Health Study is a prospective cohort of self-identified Black American women established in 1995. Participants reported regular aspirin use on baseline and follow-up questionnaires. Beginning in 1999, participants reported undergoing a colonoscopy or sigmoidoscopy, the only procedures through which colorectal adenomas can be diagnosed. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between aspirin use and colorectal adenoma among 34 397 women who reported at least 1 colonoscopy or sigmoidoscopy. From 1997 through 2018, 1913 women were diagnosed with an adenoma. Compared to nonaspirin users, regular users had 14% (OR = 0.86, 95% CI: 0.78-0.95) lower odds of adenoma. The odds of adenoma decreased with increasing duration of aspirin use (≥10 years: OR = 0.80, 95% CI: 0.66-0.96). Initiating aspirin at a younger age was associated with a reduced adenoma occurrence (age < 40 years at initiation: OR = 0.69, 95% CI: 0.55-0.86). Regular aspirin use was associated with a decreased odds of colorectal adenoma in our study of Black women. These findings support evidence demonstrating a chemopreventive impact of aspirin on colorectal neoplasia and suggest that aspirin may be a useful prevention strategy among US Black women.

Establishment of a large-scale patient-derived high-risk colorectal adenoma organoid biobank for high-throughput and high-content drug screening.

BACKGROUND: Colorectal adenoma (CA), especially high-risk CA (HRCA), is a precancerous lesion with high prevalence and recurrence rate and accounts for about 90% incidence of sporadic colorectal cancer cases worldwide. Currently, recurrent CA can only be treated with repeated invasive polypectomies, while safe and promising pharmaceutical invention strategies are still missing due to the lack of reliable in vitro model for CA-related drug screening. METHODS: We have established a large-scale patient-derived high-risk colorectal adenoma organoid (HRCA-PDO) biobank containing 37 PDO lines derived from 33 patients and then conducted a series of high-throughput and high-content HRCA drug screening. RESULTS: We established the primary culture system with the non-WNT3a medium which highly improved the purity while maintained the viability of HRCA-PDOs. We also proved that the HRCA-PDOs replicated the histological features, cellular diversity, genetic mutations, and molecular characteristics of the primary adenomas. Especially, we identified the dysregulated stem genes including LGR5, c-Myc, and OLFM4 as the markers of adenoma, which are well preserved in HRCA-PDOs. Based on the HRCA-PDO biobank, a customized 139 compound library was applied for drug screening. Four drugs including metformin, BMS754807, panobinostat and AT9283 were screened out as potential hits with generally consistent inhibitory efficacy on HRCA-PDOs. As a representative, metformin was discovered to hinder HRCA-PDO growth in vitro and in vivo by restricting the stemness maintenance. CONCLUSIONS: This study established a promising HRCA-PDO biobank and conducted the first high-throughput and high-content HRCA drug screening in order to shed light on the prevention of colorectal cancer.

Identification and clinical validation of key genes as the potential biomarkers in colorectal adenoma.

BACKGROUND: Colorectal cancer (CRC), ranking third in cancer prevalence and second in mortality worldwide, is mainly derived from colorectal adenoma (CRA). CRA is a common benign disease in the intestine with rapidly increasing incidence and malignant potential. Therefore, this study aimed to recognize significant biomarkers and original pathogenesis in CRA. METHODS: Transcriptome data of GSE8671, GSE37364, and GSE15960 were downloaded from the Gene Expression Omnibus (GEO) datasets, and differentially expressed genes (DEGs) were screened. Functional pathways enrichment, protein-protein interaction (PPI) network, stem-correlation analysis, CIBERSORT, risk score and survival analyses were performed. RT-qPCR and immunohistochemical staining were applied to verify our results.  RESULTS: Screening for significant DEGs in each dataset, we identified 230 robust DEGs, including 127 upregulated and 103 downregulated genes. Functional pathways enrichment showed that these DEGs were distinctly enriched in various tumor-associated pathways, such as growth factor activity, extracellular structure organization, neutrophil activation, and inflammatory response. We filtered out two hub genes via STRING and Modules analysis, including CA2 and HSD11B2. Stem-correlation analysis displayed that hub genes were negatively associated with stem-related genes (Olfm4, CD44, CCND1 and MYC). The CIBERSORT algorithm indicated that Macrophage2, activated mast cells, and Neutrophils promoted CRA progression through inflammation. Survival analysis showed that CA2 and HSD11B2 were positively associated with survival outcomes in CRC. CONCLUSION: Our study has successfully identified the critical role of two core genes in the development and oncogenesis of CRA, which provides novel insight into the underlying pathogenesis, potential biomarkers and therapeutic targets.