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Aim: The aim of this study was to compare the clinicopathological and oncological characteristics of sporadic colorectal cancer (CRC) between young and elderly patients without any genetic mutations that cause hereditary CRC. Method: In this cross‐sectional, retrospective study conducted at three tertiary referral hospitals, we enrolled 1599 patients with CRC who underwent surgery between January 2010 and December 2017, including 157 young patients (age ≤ 40 years; yCRC) and 1442 elderly patients (age ≥ 70 years; eCRC). The clinicopathological and oncological outcomes were compared between the two groups. Results: The median age at diagnosis was 37 years in the yCRC group (range 33.0–39.2 years) and 76 years in the eCRC group (range 72.0–79.0 years). The yCRC group did not present with advanced stages at diagnosis compared with the eCRC group, and the distribution of tumour stages was similar between the two groups. Microsatellite instability (MSI) testing revealed no difference in the frequency of tumours with high MSI (7.8% in yCRC, 5.8% in eCRC), and the frequency of mutations in the KRAS, NRAS and BRAF genes was also similar. The 3‐year overall survival was better in the yCRC group than in the eCRC group (97.4% vs. 83.5%, p < 0.001); however, no such difference was observed in cancer‐specific survival. Conclusion: Genetically proven sporadic CRCs did not differ significantly between young and elderly patients in terms of tumour stage, tumour location and various molecular features. Clinical Trial Registration Number: The study was retrospectively registered with Clinical Trials.gov (no. NCT05601609). [ABSTRACT FROM AUTHOR]

Background: Clinical diabetic traits have been reported to be associated with increased colorectal cancer (CRC) risk in observational studies. Using the Mendelian randomization (MR) analysis method, we examined the causal association between glycemic traits, such as fasting glucose (FG), fasting insulin (FI), and glycosylated hemoglobin A1c (HbA1c), and survival in a cohort of CRC patients. Methods: We conducted a two‐sample MR analysis among a cohort of patients with locally advanced CRC at Seoul National University Hospital. Single‐nucleotide polymorphisms robustly associated (p < 5 × 10−8) with the three glycemic traits were obtained from the Meta‐Analyses of Glucose and Insulin‐related traits Consortium, Asian Genetic Epidemiology Network, and Korea Biobank Array. Three‐year and 5‐year overall survival (OS) and progression‐free survival (PFS) were used as outcomes. Survival analysis was conducted using subgroup analysis by cancer stage and subsite in a multivariate Cox proportional hazards model adjusted for age and sex to examine whether glycemic traits affected survival. Results: A total of 509 patients were included in our final analysis. MR analysis showed that HbA1c levels were associated with poor 3‐year OS (β = 4.20, p = 0.02). Sensitivity analyses did not show evidence of any violations of the MR assumptions. In the cancer subgroup analysis of the Cox proportional hazards model, pooled hazard ratios for FG were significantly associated with poor 3‐year OS and PFS regardless of cancer stage. FI was not significantly associated with any 3‐year survival endpoints. Among Stage III patients, three glycemic traits were significantly associated with both 5‐year OS and PFS. Location‐specific subgroup analysis showed a significant association between three glycemic traits and 5‐year PFS in patients with left‐sided colon cancer. FG was associated with poor 3‐year survival for colon cancer but not rectal cancer. Conclusions: Our results suggest that FG and HbA1c could be used to predict prognosis in CRC patients. Lifestyle and/or pharmacological interventions targeting glycemic traits could help improve survival for CRC patients. [ABSTRACT FROM AUTHOR]

Emerging new mutations after treatment can provide clues to acquired resistant mechanisms. Circulating tumor DNA (ctDNA) sequencing has enabled noninvasive repeated tumor mutational profiling. We aimed to investigate newly emerging mutations in ctDNA after disease progression in metastatic colorectal cancer (mCRC). Blood samples were prospectively collected from mCRC patients receiving palliative chemotherapy before treatment and at radiological evaluations. ctDNA from pretreatment and progressive disease (PD) samples were sequenced with a next‐generation sequencing panel targeting 106 genes. A total of 712 samples from 326 patients were analyzed, and 381 pretreatment and PD pairs (163 first‐line, 85 second‐line and 133 later‐line [≥third‐line]) were compared. New mutations in PD samples (mean 2.75 mutations/sample) were observed in 49.6% (189/381) of treatments. ctDNA samples from later‐line had more baseline mutations (P =.002) and were more likely to have new PD mutations (adjusted odds ratio [OR] 2.27, 95% confidence interval [CI]: 1.40‐3.69) compared to first‐line. RAS/BRAF wild‐type tumors were more likely to develop PD mutations (adjusted OR 1.87, 95% CI: 1.22‐2.87), independent of cetuximab treatment. The majority of new PD mutations (68.5%) were minor clones, suggesting an increasing clonal heterogeneity after treatment. Pathways involved by PD mutations differed by the treatment received: MAPK cascade (Gene Ontology [GO]: 0000165) in cetuximab and regulation of kinase activity (GO: 0043549) in regorafenib. The number of mutations revealed by ctDNA sequencing increased during disease progression in mCRC. Clonal heterogeneity increased after chemotherapy progression, and pathways involved were affected by chemotherapy regimens. [ABSTRACT FROM AUTHOR]

Background: Self-expanding metallic stenting (SEMS) is usual for the temporary resolution of obstructive left-sided colorectal cancer (CRC) as a bridge to elective surgery. However, there is no consensus regarding adequate time intervals from stenting to radical surgery. The aim of this study was to identify the optimal time interval that results in favorable short- and long-term outcomes. Methods: Data on patients with obstructive left-sided CRC who underwent elective radical surgery after clinically successful SEMS deployment in five tertiary referral hospitals from 2004 to 2016 were analyzed, retrospectively. An inverse probability treatment-weighted propensity score analysis was used to minimize bias. Postoperative short- and long-term outcomes were compared between two groups: an early surgery (within 8 days) group and delayed surgery (after 8 days) group. Results: Of 311 patients, 148 (47.6%) underwent early and 163 (52.4%) underwent delayed surgery. The median surgery interval was 9.0 days. After adjustment, the groups had similar patient and tumor characteristics. In terms of short-term outcomes, there was no difference in hospitalization length or postoperative complications. No deaths were observed. With a median follow-up of 71.0 months, no significant difference was observed between the groups in 5-year overall survival (early vs. delayed surgery: 79.6% vs. 71.3%, P = 0.370) and 5-year disease-free survival (early vs. delayed surgery: 59.1% vs. 60.4%, P = 0.970). Conclusions: In obstructive left-sided CRC, the time interval between SEMS and radical surgery did not significantly influence short- and long-term outcomes. Therefore, early surgery after SEMS could be suggested if there is no reason to postpone surgery for preoperative medical optimization. [ABSTRACT FROM AUTHOR]

Aim: Carcinoembryonic antigen (CEA) is a primary prognostic marker and can detect colorectal cancer (CRC) recurrence; however, it has low sensitivity. Carbohydrate antigen 19‐9 (CA 19‐9) can be used as a supplemental tumour marker along with CEA. The purpose of this study was to determine whether preoperative CA 19‐9 added to CEA helped predict long‐term prognosis and whether follow‐up CA 19‐9 added to CEA had additional benefits in diagnosing the recurrence of CRC. Method: We retrospectively assessed patients who underwent surgery for primary CRC between January 2004 and December 2015 at Seoul National University Hospital. Data on demographics, preoperative and follow‐up CEA and CA 19‐9 levels, recurrence and survival were obtained and analysed with respect to tumour marker levels to ascertain their prognostic and diagnostic values. Results: A total of 4972 and 1530 patients were included to analyse preoperative and follow‐up tumour marker levels, respectively. The 5‐year relapse‐free survival rates were 72.2% ± 0.8%, 52.5% ± 2.2%, 55.5% ± 3.2% and 32.1% ± 2.3% in the normal CEA and CA 19‐9, high CEA, high CA 19‐9, and high CEA and high CA 19‐9 groups, respectively (all P < 0.001). Patients whose elevated CEA or CA 19‐9 levels reduced to normal levels had better survival outcomes than those with postoperatively elevated levels. Elevated follow‐up CA 19‐9 and CEA levels were related to higher incidences of distant metastasis (CA 19‐9, 14.0% vs. 23.1%, P = 0.004; CEA, 12.6% vs. 30.1%, P < 0.001) but not to local recurrence. Combined follow‐up CEA and CA 19‐9 increased the sensitivity for recurrence to 31.4%, with a 5% difference from the sensitivity of CEA alone. In the subgroup with high preoperative CA 19‐9 levels, sensitivity increased by 18.2% overall. Conclusion: CA 19‐9 is a valuable prognostic and diagnostic marker for CRC when used adjunctively with CEA and can be a supplementary marker with CEA to improve sensitivity, especially with elevated preoperative CA 19‐9. [ABSTRACT FROM AUTHOR]

Background: A significant proportion of colorectal cancer (CRC) patients suffer from early recurrence and progression after surgical treatment. Although the gut microbiota is considered as a key player in the initiation and progression of CRC, most prospective studies have been focused on a particular pathobionts such as Fusobacterium nucleatum. Here, we aimed to identify novel prognostic bacteria for CRC by examining the preoperative gut microbiota through 16S ribosomal RNA gene sequencing. Results: We collected stool samples from 333 patients with primary CRC within 2 weeks before surgery and followed up the patients for a median of 27.6 months for progression and 43.6 months for survival. The sequence and prognosis data were assessed using the log-rank test and multivariate Cox proportional hazard analysis. The gut microbiota was associated with the clinical outcomes of CRC patients (Pprogress = 0.011, Pdecease = 0.007). In particular, the high abundance of Prevotella, a representative genus of human enterotypes, indicated lower risks of CRC progression (P = 0.026) and decease (P = 0.0056), while the occurrence of Alistipes assigned to Bacteroides sp., Pyramidobacter piscolens, Dialister invisus, and Fusobacterium nucleatum indicated a high risk of progression. A microbiota-derived hazard score considering the five prognostic bacteria accurately predicted CRC progression in 1000 random subsamples; it outperformed widely accepted clinical biomarkers such as carcinoembryonic antigen and lymphatic invasion, after adjustment for the clinicopathological stage (adjusted HR 2.07 [95% CI, 1.61–2.64], P = 7.8e−9, C-index = 0.78). PICRUSt2 suggested that microbial pathways pertaining to thiamine salvage and L-histidine degradation underlie the different prognoses. Conclusions: The enterotypical genus Prevotella was demonstrated to be useful in improving CRC prognosis, and combined with the four pathobionts, our hazard score based on the gut microbiota should provide an important asset in predicting medical outcomes for CRC patients. 48KLrU1kw-NevPNeR-hyqw Video Abstract [ABSTRACT FROM AUTHOR]

Background: Tumor budding is associated with lymph node (LN) metastasis in submucosal colorectal cancer (CRC). However, the rate of LN metastasis associated with the number of tumor buds is unknown. Here, we determined the optimal tumor budding cut-off number and developed a composite scoring system (CSS) for estimating LN metastasis of submucosal CRC.Methods: In total, 395 patients with histologically confirmed T1N0-2M0 CRC were evaluated. The clinicopathological characteristics were subjected to univariate and multivariate analyses. The Akaike information criterion (AIC) values of the multivariate models were evaluated to identify the optimal cut-off number. A CSS for LN metastasis was developed using independent risk factors.Results: The prevalence of LN metastasis was 13.2%. Histological differentiation, lymphatic or venous invasion, and tumor budding were associated with LN metastasis in univariate analyses. In multivariate models adjusted for histological differentiation and lymphatic or venous invasion, the AIC value was lowest for five tumor buds. Unfavorable differentiation (odds ratio [OR], 8.16; 95% confidence interval [CI], 1.80-36.89), lymphatic or venous invasion (OR, 5.91; 95% CI, 2.91-11.97), and five or more tumor buds (OR, 3.01; 95% CI, 1.21-7.69) were independent risk factors. In a CSS using these three risk factors, the rates of LN metastasis were 5.6%, 15.5%, 31.0%, and 52.4% for total composite scores of 0, 1, 2, and ≥ 3, respectively.Conclusions: For the estimation of LN metastasis in submucosal CRC, the optimal tumor budding cut-off number was five. Our CSS can be utilized to estimate LN metastasis. [ABSTRACT FROM AUTHOR]

Circulating tumor DNA (ctDNA) may reveal dynamic tumor status during therapy. We conducted serial ctDNA analysis to investigate potential association with clinical outcome in metastatic colorectal cancer (mCRC) patients receiving chemotherapy. Tissue KRAS/NRAS wild-type mCRC patients were enrolled and treated with first-line cetuximab-containing chemotherapy. ctDNA isolated from plasma were analyzed by next generation sequencing (NGS) with 16 targeted gene panel. Among 93 patients, 84 (90.3%) had at least 1 somatic mutation in baseline ctDNA samples (average 2.74). Five patients with KRAS or NRAS hotspot mutation in the ctDNA showed significantly worse progression-free survival (PFS) (p = 0.029). Changes in average variant allele frequency (VAF) in ctDNA showed significant correlation with tumor size change at the time of first response evaluation (p = 0.020) and progressive disease (PD) (p = 0.042). Patients whose average VAF decreased below cutoff (< 1%) at the first evaluation showed significantly better PFS (p < 0.001), and the average VAF change further discriminated the PFS in the patients in partial response (p = 0.018). At the time of PD, 54 new mutations including KRAS and MAP2K1 emerged in ctDNA. ctDNA sequencing can provide mutation profile that could better reflect tumor mutation status and predict treatment outcome. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the prevalence of preoperative anemia and impacts of anemia and transfusion on survival in patients undergoing surgery for colorectal cancer. Methods: This study included patients who underwent surgery for primary colorectal cancer between 2011 and 2012. The influence of preoperative anemia and postoperative transfusion on recurrence-free survival and overall survival were retrospectively investigated. Anemia was defined as hemoglobin level < 13 g/dL in males and < 12 g/dL in females. The primary outcome was the prevalence of preoperative anemia in patients with colorectal cancer. Secondary outcomes included preoperative anemia management, postoperative 30-day mortality and morbidity, tumor recurrence, and overall survival. Results: Among a total of 1899 patients, 823 patients (43.3%) were anemic preoperatively, and 264 patients (13.9%) received postoperative transfusions. Postoperative transfusion was associated with 30-day postoperative complications (OR = 1.514, 95% CI = 1.020 ~ 2.247) but not preoperative anemia (OR = 1.143, 95% CI, 0.811 ~ 1.611). Preoperative anemia (HR = 1.459, 95% CI = 1.104 ~ 1.929) and postoperative transfusion (HR = 1.566, 95% CI = 1.089 ~ 2.252) were significantly associated with worse recurrence-free survival in multivariable analysis. Preoperative anemia (HR = 1.572, 95% CI = 1.274 ~ 1.940) and postoperative transfusion (HR = 1.381, 95% CI = 1.076 ~ 1.773) were significant independent risk factors for worse overall survival. Conclusions: Preoperative anemia and postoperative transfusion were associated with worse survival in patients undergoing surgery for colorectal cancer. An alternative therapy to treat anemia and reduce transfusions should be introduced to improve oncologic outcomes. [ABSTRACT FROM AUTHOR]

Background: The present study aimed to compare the surgical and oncological outcomes between young and older women with colorectal cancer (CRC). Materials and Methods: This retrospective study included 1815 women with CRC between 2010 and 2014. Participants were divided into a young group (under the age of 65 years) and an old group (65 years and older). The surgical and oncological outcomes were compared between the two groups using univariate and multivariate analyses. Results: Around 45.1% (N = 819) patients were the older group. The old group had a higher comorbidity rate and a lower proportion of receiving postoperative chemotherapy. The old group also had a significantly higher blood loss (190 ± 611 mL vs. 145 ± 200 mL, p = 0.027) and a higher rate of intraoperative transfusion (5.4% vs. 3.0%, p = 0.011). They were found to develop more complications after surgery (11.7% vs. 7.8%, p = 0.015). The overall survival (OS) of the old group was lower than that of the young group (5-year OS rates: 72.8% vs. 83.8%, p < 0.001; adjusted hazard ratio: 1.86, 95% confidence interval: 1.49–2.33). However, the cancer-specific survival (CSS) was not significantly different between the old and young groups (5-year CSS rates: 84.7% vs. 84.9%, p = 0.076). Conclusions: Older women with CRC had poorer OS than young women with CRC, but had similar CSS. Therefore, the management of comorbidities along with cancer treatment may be important in older women with CRC. [ABSTRACT FROM AUTHOR]

The management of colorectal cancer in patients with liver cirrhosis requires a thorough understanding of both diseases. This study evaluated the effect of liver cirrhosis on oncologic and surgical outcomes and prognostic factors in colorectal cancer patients. Fifty-five consecutive colorectal cancer patients with liver cirrhosis underwent colorectal resection (LC group). Using a prospectively maintained database, these patients were matched 1:4 using propensity scoring with R programming language, package "MatchIt" and "optmatch" by sex, age, cancer location, and tumor stage with 220 patients without liver cirrhosis (non-LC group), resulting in 275 patients. The 5-year overall survival (OS) was significantly worse in the LC group than in the non-LC group (46.7% vs. 76.2% respectively, P < 0.001); however, the 5-year proportion of recurrence free (PRF) rates were similar (73.1% vs. 84.5% respectively, P = 0.094). On multivariate analysis of the LC group, tumor-node-metastasis (TNM) stage ≥III disease, venous invasion, and a model for end-stage liver disease plus serum sodium (MELD-Na) score >10 were prognostic factors for OS. However, the OS was not different between the LC group with MELD-Na score ≤10 and the non-LC group (5-year OS rate, TNM stage ≤II, 85.7 vs 89.5%, p = 0.356; TNM stage ≥III, 41.1 vs 66.2%, p = 0.061). Colorectal cancer patients with liver cirrhosis have poorer OS compared to those without liver cirrhosis; however, the PRF rates are similar. It might be due to the mortality from the liver, and surgical treatment should be actively considered for patients with MELD-Na score <10. [ABSTRACT FROM AUTHOR]

Background/Aims: Although there are guidelines for colonoscopic surveillance after colorectal cancer (CRC) surgery, the data evaluating the effectiveness of these guidelines are limited. We determined the risk factors for metachronous neoplasia (MN) by performing annual colonoscopy examinations after curative resection. Methods: We performed annual colonoscopic surveillance on stage I-III CRC patients after curative resection. We stratified the patients based on the advanced neoplasia risk during the surveillance. Results: Advanced MN detected was in 59 (13.1%) of 451 patients. Overall, the cumulative incidence of advanced MN was 17.3% at 5 years. By the multivariate analysis, the risk factors for advanced MN were male gender, age >65, left-sided index cancer and being in the high-risk group. The cumulative incidence of advanced MN was 38.9% at 5 years in the high-risk group. Among the patients who had advanced MN, secondary advanced MN was detected in 13 patients (22.0%) with a subsequent colonoscopy. The 2-year cumulative incidence of secondary advanced MN was 16.9%. Four (0.88%) patients had metachronous CRC during the surveillance and the interval from the index CRC was a median of 58.5 months. Conclusions: Although the current follow-up guidelines for colonoscopic surveillance after CRC are well established, the high-risk group calls for more meticulous follow-up, which should be continued for a sufficient time. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Simple Summary: We analyzed the data from 1952 patients with stage I colorectal cancer to evaluate the risk factors for recurrence and survival rates. In the entire cohort, the recurrence rate was 4.6%. There were some differences in the risk factors for recurrence between colon and rectal cancer in stage I colorectal cancer. Left-sided tumors, T2, tumor size >5 cm, and lymphovascular invasion were independent risk factors of colon cancer recurrence. Male, preoperative carcinoembryonic antigen (CEA) ≥2.5 ng/mL, and harvested lymph nodes (LNs) <12 were independently associated with recurrence of rectal cancer. Even though patients with early-stage CRC underwent curative resection, survival sharply decreased in cases of recurrence. Our findings could suggest more aggressive surveillance for patients with an increased risk of recurrence. Recurrence can still occur even after radical resection of stage I colorectal cancer (CRC). This study aimed to identify subgroups with a high risk for recurrence in the stage I CRC. We retrospectively reviewed prospectively collected data of 1952 patients with stage I CRC after radical resection between 2002 and 2017 at our institute. 1398 (colon, 903 (64.6%), rectum, 495 (35.4%)) were eligible for analysis. We analyzed the risk factors for recurrence and survival. During the follow-up period (median: 59 months), 63 (4.6%) had a recurrence. The recurrence rate of rectal cancer was significantly higher than that of colon cancer (8.5% vs. 2.3%). Left-sided tumors, T2, tumor size >5 cm, and lymphovascular invasion were independent risk factors of colon cancer recurrence. Male, preoperative carcinoembryonic antigen (CEA) ≥2.5 ng/mL, and harvested lymph nodes (LNs) <12 were independently associated with recurrence of rectal cancer. Recurrence affected OS (5-year OS: 97.1% vs. 67.6%). Despite curative resection, survival sharply decreased with recurrence. The risk factors for recurrence were different between colon and rectal cancer. Patients with a higher risk for recurrence should be candidates for more aggressive surveillance, even in early-stage CRC. [ABSTRACT FROM AUTHOR]

B Background: b The aim of this study was to investigate the association and prognostic impact of tumor immune microenvironment and systemic inflammatory markers in colorectal cancer. According to the results of survival analysis, colorectal cancers were classified into low T-cell density (0) or high T-cell density (1-4). This study suggests that both tumor immune microenvironment (T-cell density) and systemic inflammatory marker (prognostic nutritional index) provide prognostic information in colorectal cancer. [Extracted from the article]