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Background: Metastatic colorectal cancer (mCRC) poses a clinical challenge and requires a combination of systemic therapy and conversion surgery. Although first-line chemotherapy and targeted therapy are considered the standard treatments for mCRC, the role of primary tumor resection (PTR) in asymptomatic synchronous mCRC with unresectable metastatic lesion after initial therapy remains relatively underexplored., Materials: A retrospective review was conducted from January 2015 to January 2021, involving 74 patients with synchronous mCRC who received bevacizumab plus FOFIRI as first-line systemic therapy. All 74 patients had unresectable metastatic lesions confirmed through multidisciplinary team discussion. Patient characteristics, PTR data, and radiotherapy (RT) and overall survival (OS) outcomes were analyzed. The patients were categorized into a "PTR" group and a "No PTR" group and then further stratified into "4A," "4B," and "4C" subgroups based on the initial mCRC stage. Additionally, four subgroups-namely "PTR( +)/RT( +)," "PTR( +)/RT( -)," "PTR( -)/RT( +)," and "PTR( -)/RT( -)"-were formed to assess the combined effects of PTR and RT., Results: The median OS for all the patients was 23.8 months (20.5-27.1 months). The "PTR" group exhibited a significantly higher median OS of 25.9 months (21.3-30.5 months) compared with 21.4 months (15.8-27.1 months) in the "No PTR" group (p = 0.048). Subgroup analyses revealed a trend of improved survival with PTR in patients with stage IVA and IVB; however, the results were not statistically significant (p = 0.116 and 0.493, respectively). A subgroup analysis of PTR and RT combinations revealed no significant difference in median OS rates., Conclusion: For asymptomatic mCRC with synchronous unresectable distant metastasis, PTR following first-line therapy with bevacizumab plus FOLFIRI may provide a potential survival benefit, particularly in stage IVA/IVB patients compared with stage IVC patients. Additionally, RT for primary tumor did not provide an additional OS benefit in mCRC with unresectable metastasis. A prospective randomized trial with a larger sample size is essential to further elucidate the role of PTR in this context., (© 2024. The Author(s).)

Background: Sessile serrated lesions (SSLs) are obscured lesions predominantly in the right-sided colon and associated with interval colorectal cancer; however, their prevalence and risk factors among younger individuals remain unclear., Methods: This retrospective study enrolled individuals who underwent index colonoscopy. The primary outcome was the SSL prevalence in the younger (<50 years) and older (≥50 years) age groups, while the secondary outcomes included clinically significant serrated polyps (CSSPs). Multivariable logistic regression was employed to identify predictors., Results: Of the 9854 eligible individuals, 4712 (47.8%) were categorized into the younger age group. Individuals in the younger age group exhibited lower prevalences of adenomas (22.6% vs. 46.2%; P <0.001) and right-sided adenomas (11.2% vs. 27.2%; P <0.001) compared with their older counterparts. However, both groups exhibited a similar prevalence of SSLs (7.2% vs. 6.5%; P =0.16) and CSSPs (10.3% vs. 10.3%; P =0.96). Multivariable analysis revealed that age 40-49 years (odds ratio [OR] 1.81, 95%CI 1.01-3.23), longer withdrawal time (OR 1.17, 95%CI 1.14-1.20, per minute increment), and endoscopist performance (OR 3.35, 95%CI 2.44-4.58) were independent predictors of SSL detection in the younger age group. No significant correlation was observed between adenoma and SSL detection rates among endoscopists., Conclusion: SSLs are not uncommon among younger individuals. Moreover, diligent effort and expertise are of paramount importance in SSL detection. Future studies should explore the clinical significance of SSLs in individuals of younger age., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of immunoglobulin (Ig)A in maintaining gut homeostasis and preventing inflammation has been well established. Our earlier work demonstrated that the marginal zone and B1 cell-specific protein (MZB1) promotes gut IgA secretion and its absence results in pronounced dextran sulfate sodium salt (DSS)-induced colitis. In the present study, we explored the role of MZB1 in CRC development using the azoxymethane (AOM)/DSS-induced CRC model. We observed an increase in both the number and size of the tumor nodules in Mzb1 -/- mice compared with Mzb1 +/+ mice. The increase in CRC development and progression in Mzb1 -/- mice was associated with reduced intestinal IgA levels, altered gut flora, and more severe gut and systemic inflammation. Oral administration of the monoclonal IgA, W27, alleviated both the gut inflammation and AOM/DSS-induced CRC. Notably, cohousing Mzb1 +/+ and Mzb1 -/- mice from the 10th day after birth led to similar CRC development. Our findings underscore the pivotal role of MZB1-mediated IgA secretion in suppressing the onset and progression of CRC triggered by gut inflammation. Moreover, our study highlights the profound impact of microbiota composition, modulated by gut IgA levels, on gut inflammation. Nonetheless, establishing a direct correlation between the severity of colitis and subsequent CRC development and the presence or absence of a particular microbiota is challenging., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

RNA interactomes and their diversified functionalities have recently benefited from critical methodological advances leading to a paradigm shift from a conventional conception on the regulatory roles of RNA in pathogenesis. However, the dynamic RNA interactomes in adenoma-carcinoma sequence of human CRC remain unexplored. The coexistence of adenoma, cancer, and normal tissues in colorectal cancer (CRC) patients provides an appropriate model to address this issue. Here, we adopted an RNA in situ conformation sequencing technology for mapping RNA-RNA interactions in CRC patients. We observed large-scale paired RNA counts and identified some unique RNA complexes including multiple partners RNAs, single partner RNAs, non-overlapping single partner RNAs. We focused on the antisense RNA OIP5-AS1 and found that OIP5-AS1 could sponge different miRNA to regulate the production of metabolites including pyruvate, alanine and lactic acid. Our findings provide novel perspectives in CRC pathogenesis and suggest metabolic reprogramming of pyruvate for the early diagnosis and treatment of CRC., (© 2024. The Author(s).)

Proteins overexpressed in early-stage cancers may serve as early diagnosis and prognosis markers as well as targets for cancer therapies. In this study, we examined the expression of an essential amino acid carrier SLC7A5 (LAT1, CD98, or 4F2 light chain) in cancer tissue from two well-annotated cohorts of 575 cases of early-stage and 106 cases of late-stage colorectal cancer patients. Immunohistochemistry showed SLC7A5 overexpression in 72.0% of early-stage and 56.6% of late-stage cases. SLC7A5 expression was not influenced by patient gender, age, location, or mismatch repair status, although it appeared to be slightly less prevalent in tumors of mucinous differentiation or with lymphovascular invasion. Statistical analyses revealed a positive correlation between SLC7A5 overexpression and both overall survival and disease-free survival in early-stage but not late-stage cancers. Co-expression analyses of the TCGA and CPTAC colorectal cancer cohorts identified a network of gene transcripts positively related to SLC7A5, with its heterodimer partner SLC3A2 having the highest co-expression score. Network analysis uncovered the SLC7A network to be significantly associated with ncRNA such as tRNA processing and the mitotic cell cycle. Since SLC7A5 is also a marker of activated lymphocytes such as NK, T, and B lymphocytes, SLC7A5 overexpression in early colorectal cancers might trigger a strong anti-tumor immune response which could results in better clinical outcome. Overall, our study provides clear evidence of differential SLC7A5 expression and its prognostic value for early-stage colorectal cancer, although the understanding of its functions in colorectal tumorigenesis and cancer immunity is currently rather limited and awaits further characterization., Competing Interests: MO, AT, MM, KN, YO, and JS declare no conflicts of interest related to this study. JYW is a founder of Curandis. MHR is a member of the Scientific Advisory Boards of Azenta and Universal DX. None of these companies had any influence in support, design, execution, data analysis, or other aspects of this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Ogawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Metastatic progression of colorectal adenocarcinoma (CRC) remains poorly understood and poses significant challenges for treatment. To overcome these challenges, we performed multiomics analyses of primary CRC and liver metastases. Genomic alterations, such as structural variants or copy number alterations, were enriched in oncogenes and tumor suppressor genes and increased in metastases. Unsupervised mass spectrometry-based proteomics of 135 primary and 123 metastatic CRCs uncovered distinct proteomic subtypes, three each for primary and metastatic CRCs, respectively. Integrated analyses revealed that hypoxia, stemness, and immune signatures characterize these 6 subtypes. Hypoxic CRC harbors high epithelial-to-mesenchymal transition features and metabolic adaptation. CRC with a stemness signature shows high oncogenic pathway activation and alternative telomere lengthening (ALT) phenotype, especially in metastatic lesions. Tumor microenvironment analysis shows immune evasion via modulation of major histocompatibility complex (MHC) class I/II and antigen processing pathways. This study characterizes both primary and metastatic CRCs and provides a large proteogenomics dataset of metastatic progression., Competing Interests: Declaration of interests D.S.K. was a consultant for and is now employed by Paige.AI. P.G.B. and J.G. are employees of and hold equity interests in Genuity Science. J.Y.W. is the founder of Curandis. M.H.A.R. is a member of the scientific advisory boards of Azenta Life Sciences and Universal DX. None of these companies had any role in design, execution, data analysis, or any other aspect of this study., (Copyright © 2024. Published by Elsevier Inc.)

Background and Objectives : Approximately 5-10% of all patients with metastatic colorectal cancer (mCRC) harbor a BRAF V600E mutation. These patients exhibit distinct metastatic patterns, poor prognosis, and heterogenous survival outcomes. The findings from the TRIBE study indicated that the administration of FOLFOXIRI plus bevacizumab as first-line treatment extended the median duration of overall survival (OS). In this study, we explored the effects of UGT1A1 polymorphism on the outcomes of irinotecan dose escalation versus FOLFOXIRI plus bevacizumab in patients with BRAF V600E -mutant mCRC. Materials and Methods : We retrospectively reviewed the medical records of 25 patients who had received a diagnosis of BRAF V600E -mutant mCRC between October 2015 and August 2022. All patients underwent UGT1A1 genotyping before receiving bevacizumab plus FOLFIRI. The primary end point was progression-free survival (PFS), and secondary endpoints were OS and adverse events (AEs). The two treatment arms were compared in terms of 6-month PFS and 12-month OS. Results : Over a median follow-up duration of 15.0 (interquartile range, 10.0-30.5) months, no significant differences were noted between the treatment arms in severe AEs (SAEs), 6-month PFS, or 12-month OS (all p < 0.05). Regarding AEs, the FOLFIRI plus bevacizumab regimen was associated with a lower incidence of anorexia than was the FOLFOXIRI plus bevacizumab regimen ( p = 0.042). Conclusions : Our findings indicate that FOLFIRI plus bevacizumab with irinotecan dose escalation is an effective first-line treatment regimen for patients with BRAF V600E -mutant mCRC. This regimen leads to acceptable clinical outcomes with manageable AEs. However, the effects on survival and safety outcomes could only be speculated, and further studies are needed because of the sample size, the follow-up for the OS evaluation, and the non-uniformity in all the variables considered in the two groups.

Background: Systemic therapy is the standard treatment for unresectable colorectal cancer with liver metastasis (CRCLM). Transarterial chemoembolization with drug-eluting beads (DEB-TACE) is considered an effective treatment option for CRCLM. Few studies have investigated the combination of DEB-TACE, chemotherapy, and targeted therapy for CRCLM. In the present study, we evaluated the disease control rate (DCR), adverse events, and survival among patients with CRCLM who underwent the combination of DEB-TACE and chemotherapy/targeted therapy., Materials: We retrospectively reviewed 35 patients with CRCLM who were treated between January 2015 and January 2021. Standard systemic chemotherapy, targeted therapy, and 66 DEB-TACE procedures were administered. Data were collected on each DEB-TACE procedure, including chemotherapy agents, tumor burden of liver metastasis, number of DEB-TACE courses, and adverse events. Patients who received DEB-TACE after failure of first-line systemic therapy were categorized into the first-line failure group. Patients who received DEB-TACE after the failure of second-line, third-line, or fourth-line therapy were categorized into the other group. Subgroup analysis was performed to compare overall survival (OS) and progression-free survival (PFS) between the two groups., Results: In total, 35 patients with CRCLM (34 patients with adenocarcinoma and 1 patient with neuroendocrine carcinoma) were enrolled. In total, 13 patients (37.1%) had extrahepatic metastases at initial diagnosis. In this study, 66 DEB-TACE procedures were performed. The DCR was 54.3%. The median OS period was 47.4 months, and the estimated 3-year OS rate was 59.5%. The median PFS period was 6.3 months, and the estimated 1-year PFS rate was 20.6%. The PFS period was longer in the first-line failure group than in the other group (7.2 vs. 6.3 months). No significant difference was observed in OS between the two groups. Four episodes (6.1%) of grade 3 intra-abdominal infection were observed., Conclusion: The combination of chemotherapy, targeted therapy, and DEB-TACE can lead to a favorable DCR and survival outcomes in patients with CRCLM. Early intervention with DEB-TACE (i.e., after the failure of first-line therapy) has the potential to extend the PFS period in patients with CRCLM. Severe adverse events were rare and manageable. Further prospective, randomized controlled studies are warranted to obtain more conclusive findings., (© 2023. The Author(s).)

Absrtact: BACKGROUND: Patients treated with anti-epidermal growth factor receptor (anti-EGFR) will ultimately develop acquired resistance promoted by clonal selection, mainly the emergence of mutations in the MAPK pathway (mostly RAS mutations). Baseline assessment of RAS mutations in the blood of patients correlates well with RAS tumour tissue testing and is currently an alternative option in routine clinical practice to guide first-line therapy. The aim of this study was the prevalence of acquired genomic alterations detected in the auxiliary tool of ctDNA testing and investigated the role of RAS ctDNA status for detecting tumour response and predicting benefit to anti-EGFR therapy., Methods: Only patients with concordant wild-type formalin-fixed, paraffin-embedded (FFPE) tumour tissue and baseline ctDNA RAS wild-type were included. RAS mutations in plasma were evaluated using MassARRAY platform. Blood samples were collected at baseline, every 3 months during first-line treatment, and at disease progression. The primary endpoint was the detection rate of RAS mutations during cetuximab treatment. The correlation between response and survival outcomes and the emergence of circulating RAS mutations was also analysed., Results: The detection rate of RAS mutations during treatment was 9.3% (10/108). RAS mutations detection occurred a median of 3 months prior to radiologic documentation. The subgroup of patients with RAS mutations exhibited significantly inferior progression-free survival and overall survival (P = 0.002 and 0.027, respectively) but the baseline characteristics, response rates, disease control rates, and metastatectomy were not significant (all P > 0.05)., Conclusions: We demonstrated that RAS ctDNA status might be a valuable biomarker for detecting early tumour response and predicting benefit to anti-EGFR therapy., Clinical Trial Registration: NCT03401957 (January 17, 2018)., (© 2023. The Author(s).)

The objectives were to identify the functional domains of a potential oncoprotein, cell migration inducing hyaluronidase 2 (CEMIP2), evaluate its expression levels and roles in colorectal cancer (CRC), and develop an aptamer-based nanoparticle for targeted therapy. Data mining on TCGA identified that CEMIP2 might play oncogenic roles in CRC. In a local cohort, CEMIP2 mRNA levels significantly stepwise increase in CRC patients with higher stages, and high CEMIP2 confers worse disease-free survival. In addition, CEMIP2 mRNA levels significantly correlated to hyaluronan levels in sera from CRC patients. Deletion mapping identified that CEMIP2 containing G8 and PANDER-like domains preserved hyaluronidase activity and oncogenic roles, including cell proliferation, anchorage-independent cell growth, cell migration and invasion, and human umbilical vein endothelial cell (HUVEC) tube formation in CRC-derived cells. A customized monoclonal mouse anti-human CEMIP2 antibody probing the PANDER-like domain (anti-289307) counteracted CEMIP2-mediated carcinogenesis in vitro. Cell-SELEX pinpointed an aptamer, aptCEMIP2(101), specifically interacted with the full-length CEMIP2, potentially involving its 3D structure. Treatments with aptCEMIP2(101) significantly reduced CEMIP2-mediated tumorigenesis in vitro. Mesoporous silica nanoparticles (MSN) carrying atpCEMIP2(101) and Dox were fabricated. Dox@MSN, MSN-aptCEMIP2(101), and Dox@MSN-aptCEMIP2(101) significantly suppressed tumorigenesis in vitro compared to the Mock, while Dox@MSN-aptCEMIP2(101) showed substantially higher effects compared to Dox@MSN and MSN-aptCEMIP2(101) in CRC-derived cells. Our study identified a novel oncogene and developed an effective aptamer-based targeted therapeutic strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Malnutrition is a common problem in patients with metastatic colorectal cancer (mCRC) receiving targeted therapy plus chemotherapy, resulting in severe toxicity and decreased survival rates. This retrospective study employing propensity score matching (PSM) examined the efficacy and safety of a supplemental home parenteral nutrition (HPN) program for patients with RAS wild-type mCRC receiving cetuximab plus chemotherapy. This retrospective nationwide registry study included data from 14 medical centers/hospitals across Taiwan, and the data period ranged from November 2016 to December 2020. Patients with RAS wild-type mCRC receiving cetuximab plus chemotherapy as their first-line therapy were included and divided into HPN and non-HPN program groups. HPN was initiated based on patient-specific factors, such as baseline nutritional status, treatment-related toxicities, and comorbidities. Clinical outcomes were evaluated using response to therapy, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). This study recruited 758 patients, of whom 110 and 648 were included in the HPN and non-HPN program groups, respectively. After 1:3 PSM, the data of 109 and 327 patients from the HPN and non-HPN program groups were analyzed, respectively. The HPN program group had a higher metastasectomy rate (33.9% vs. 20.2%, p = 0.005), and longer duration of treatment and DoR than the non-HPN program group (13.6 vs. 10.3 and 13.6 vs. 9.9 months, p = 0.001 and < 0.001, respectively). The HPN program group tended to have a longer median PFS (18.2 vs. 13.9 months, p = 0.102). Moreover, we noted a significant improvement in the median OS in the same group (53.4 vs. 34.6 months, p = 0.002). Supplemental HPN programs may be recommended for select patients with mCRC receiving targeted therapy plus chemotherapy to improve oncological outcomes.

Recent innovations within the field of robotic surgery have particular relevance to colorectal surgery. Although a robotic approach has been associated with satisfactory outcomes, there remains a wide variation in levels of adoption. In particular, this study focuses on patient positioning, docking, and table placement, with the intent of understanding the strength of opinion of colorectal surgeons in the Asia-Pacific region to the practical application of these developments to achieve optimal surgical outcomes. Using a modified Delphi methodology, a steering group of colorectal surgeons with experience in robotic surgery from across the Asia-Pacific region identified 35 consensus statements. An online 4-point Likert scale questionnaire was distributed to surgeons in the Asia-Pacific region using convenience sampling. Respondents were excluded from further analysis if they did not perform colorectal surgery or had no experience in robotic surgery. A total of 140 responses (71.8% response rate) were received between August and October 2021. 22 statements attained a very high degree of agreement (≥ 90%). High agreement (< 90% and ≥ 75%) was achieved in another 12, and one failed to meet the consensus threshold (< 75%). A set of five recommendations were developed based on these results. The high levels of agreement demonstrate recognition amongst colorectal surgeons within the Asia-Pacific region of the potential advantage of recent improvements in robotic surgery technology to further improve surgical outcomes. The recommendations may inform a set of practical principles to help standardise the use of colorectal robotic surgery, which may also be relevant to other surgical fields., (© 2022. The Author(s).)

Introduction: Colorectal cancer (CRC) is a leading cause of death. For three decades, chemotherapy with or without targeted therapy (provided before or after tumor resection surgery) has been the standard treatment for patients with CRC. Biomarkers are key tools for performing early detection, prognostication, and survival and treatment response predictions. Notably, immune checkpoint inhibitors (ICIs) have transformed prognoses for solid tumors (including CRC)., Area Covered: Although immunotherapy has developed considerably, it is only effective for a small number of microsatellite instability-high (MSIH) cancer cases; such cases represent only 5% of metastatic CRC (mCRC) cases, which are characterized by an immune-inflamed microenvironment that can be rewired against cancer cells through ICI administration. Immunotherapy research is gradually uncovering the mechanism underlying immune resistance in patients with CRC and discovering new biomarkers. For example, studies have clinically validated the associations of deficient mismatch repair system/microsatellite instability, tumor mutation burden, programmed death ligand 1 expression, and polymerase epsilon with CRC in patients undergoing immunotherapy., Expert Opinions: Clinical trials documenting the effect of immune checkpoints were performed to produce long-lasting effects for patients with mCRC. Consequently, therapeutic decision-making models are further refined by the inclusion of powerful molecular biomarkers in patients with CRC.

Background: Owing to the heterogeneity of microbiota among individuals and populations, only Fusobacterium nucleatum and Bacteroides fragilis have been reported to be enriched in colorectal cancer (CRC) in multiple studies. Thus, the discovery of additional bacteria contributing to CRC development in various populations can be expected. We aimed to identify bacteria associated with the progression of colorectal adenoma to carcinoma and determine the contribution of these bacteria to malignant transformation in patients of Han Chinese origin., Methods: Microbiota composition was determined through 16S rRNA V3-V4 amplicon sequencing of autologous adenocarcinomas, adenomatous polyps, and non-neoplastic colon tissue samples (referred to as "tri-part samples") in patients with CRC. Enriched taxa in adenocarcinoma tissues were identified through pairwise comparison. The abundance of candidate bacteria was quantified through genomic quantitative polymerase chain reaction (qPCR) in tissue samples from 116 patients. Associations of candidate bacteria with clinicopathological features and genomic and genetic alterations were evaluated through odds ratio tests. Additionally, the effects of candidate bacteria on CRC cell proliferation, migration, and invasion were evaluated through the co-culture of CRC cells with bacterial cells or with conditioned media from bacteria., Results: Prevotella intermedia was overrepresented in adenocarcinomas compared with paired adenomatous polyps. Furthermore, co-abundance of P. intermedia and F. nucleatum was observed in tumor tissues. More notably, the coexistence of these two bacteria in adenocarcinomas was associated with lymph node involvement and distant metastasis. These two bacteria also exerted additive effects on the enhancement of the migration and invasion abilities of CRC cells. Finally, conditioned media from P. intermedia promoted the migration and invasion of CRC cells., Conclusion: This report is the first to demonstrate that P. intermedia is enriched in colorectal adenocarcinoma tissues and enhances the migration and invasion abilities of CRC cells. Moreover, P. intermedia and F. nucleatum exert additive effects on the malignant transformation of colorectal adenomas into carcinomas. These findings can be used to identify patients at a high risk of malignant transformation of colorectal adenomas or metastasis of CRC, and they can accordingly be provided optimal clinical management., (© 2022. The Author(s).)

Objective: The UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity, which may increase the risk of severe toxicity in patients who receive standard-dose irinotecan, such as severe neutropenia and diarrhea. This real-world study assessed the optimal irinotecan dose in terms of efficacy and toxicity in metastatic colorectal cancer (mCRC) patients homozygous for the UGT1A1*28 polymorphism and receiving FOLFIRI plus bevacizumab or cetuximab as first-line therapy., Methods: We analyzed toxicity and treatment outcomes in seven mCRC patients who were homozygous for UGT1A1*28 and received FOLFIRI plus bevacizumab or cetuximab, with an initial irinotecan dose of 120 mg/m 2 ., Results: Six of the seven patients tolerated 120 mg/m 2 irinotecan without requiring dose reductions in subsequent cycles. The overall response and disease control rates were 43.0% (3/7) and 71.4% (5/7), respectively. The median progression-free survival and overall survival were 11.0 and 33.0 months, respectively. Only one severe adverse event, grade III neutropenia (2.5%), was observed., Conclusions: mCRC patients homozygous for the UGT1A1*28 allele can tolerate irinotecan at an initial dose of 120 mg/m 2 with favorable oncological outcomes and toxicity profiles. Further prospective studies are warranted to optimize irinotecan-based chemotherapy in these patients.

Icariside II, a flavonol glycoside, one of the major components of Traditional Chinese Medicine Herba epimedii. In the present study, we found that Icariside II suppressed the proliferation of CRC by inducing cell cycle arrest and apoptosis in vitro and inhibited tumor growth in vivo. The further mechanism investigation showed that Icariside II suppressed the expression of β-catenin and led to the functional inactivation of Wnt/β-catenin signaling. Circβ-catenin was considered as a promising candidate for mediating the tumorigenesis and the activation of Wnt/β-catenin signaling in CRC cells. Furthermore, Icariside II has been proven to suppress the biogenesis of circβ-catenin via epigenetically targeting DNA methyltransferases (DNMTs) to decrease global DNA methylation levels in CRC cells. Taken together, our results indicated that Icariside II suppressed tumorigenesis by epigenetically silencing the activation of circβ-catenin-Wnt/β-catenin axis in colorectal cancer. More importantly, the information gained from this study suggest that Icariside II may have great potential to be developed as a therapeutic drug for CRC patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Uridine diphosphate glucuronosyltransferase 1A1 ( UGT1A1 ) polymorphism plays a crucial role in the increased susceptibility and toxicity of patients to irinotecan. This retrospective, observational study compared the clinical outcomes and adverse events (AEs) in RAS wild-type metastatic colorectal cancer (mCRC) patients treated with cetuximab or bevacizumab plus FOLFIRI with UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. In total, 173 patients with mCRC with RAS wild-type were enrolled. Among them, 98 patients were treated with cetuximab, whereas 75 patients were treated with bevacizumab. All patients received irinotecan dose escalation based on UGT1A1 genotyping. We compared the progression-free survival (PFS), overall survival (OS), objective response rates (ORRs), disease control rates (DCRs), metastatectomy, and severe adverse events (SAEs) between the two groups. The clinical effects of primary tumor sidedness and target therapy crossover were further analyzed. Over a median follow-up of 23.0 months [interquartile range (IQR), 15.032.5 months], no significant differences were observed between the cetuximab and bevacizumab groups in PFS [18.0 months vs. 14.0 months; 95% confidence interval (CI), 0.5171.027; hazard ratio (HR), 0.729; p =0.071], OS (40.0 months vs. 30.0 months; 95% CI, 0.4101.008; HR, 0.643; p =0.054), ORR (65.3% vs. 62.7%; p =0.720), DCR (92.8% vs. 86.7%; p =0.175), metastatectomy (36.7% vs. 29.3%; p =0.307), and SAEs ( p =0.685). Regardless of primary tumor sidedness and target therapy crossover, no significant differences were noted in efficacy and safety between the two groups (all p >0.05). Our results revealed that patients with wild-type RAS mCRC, regardless of biologics, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favorable clinical outcome without significantly increased toxicity.

The bidirectional interaction between carcinogens and gut microbiota that contributes to colorectal cancer is complicated. Reactivation of carcinogen metabolites by microbial β-glucuronidase (βG) in the gut potentially plays an important role in colorectal carcinogenesis. We assessed the chemoprotective effects and associated changes in gut microbiota induced by pre-administration of bacterial-specific βG inhibitor TCH-3511 in carcinogen azoxymethane (AOM)-treated APC Min/+ mice. AOM induced intestinal βG activity, which was reflected in increases in the incidence, formation, and number of tumors in the intestine. Notably, inhibition of gut microbial βG by TCH-3511 significantly reduced AOM-induced intestinal βG activity, decreased the number of polyps in both the small and large intestine to a frequency that was similar in mice without AOM exposure. AOM also led to lower diversity and altered composition in the gut microbiota with a significant increase in mucin-degrading Akkermansia genus. Conversely, mice treated with TCH-3511 and AOM exhibited a more similar gut microbiota structure as mice without AOM administration. Importantly, TCH-3511 treatment significant decreased Akkermansia genus and produced a concomitant increase in short-chain fatty acid butyrate-producing gut commensal microbes Lachnoospiraceae NK4A136 group genus in AOM-treated mice. Taken together, our results reveal a key role of gut microbial βG in promoting AOM-induced gut microbial dysbiosis and intestinal tumorigenesis, indicating the chemoprotective benefit of gut microbial βG inhibition against carcinogens via maintaining the gut microbiota balance and preventing cancer-associated gut microbial dysbiosis. Thus, the bacterial-specific βG inhibitor TCH-3511 is a potential chemoprevention agent for colorectal cancer., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In a quest for prognostic biomarkers in early-stage colorectal cancer, we investigated NNMT (nicotinamide N-methyltransferase) in large cohorts of patients. Immunohistochemical examination of 679 patients illustrates that NNMT protein is predominantly expressed in the cancer stroma at varying levels, and about 20% of cancer tissues overexpress NNMT when compared to levels observed in normal colorectal mucosa. Clinical correlation analyses of 572 patients with early-stage cancers reveal that NNMT protein overexpression is significantly associated with shorter overall and disease-free survival, but no such correlation is found in late-stage colorectal cancer. Analyses of TCGA and CPTAC colorectal cancer cohorts show that NNMT mRNA expression is positively correlated with protein levels, is significantly higher in CIMP-high or MSI subtypes than in CIMP-low or MSS subtypes, and is positively correlated with its paralog INMT but not with its interaction partners such as PNMT, ADK, APP, ATF6, BMF, BRD4, CDC37, or CRYZ. In early-stage cancers, NNMT expression is higher in BRAF-mutated than in BRAF wild type tumors but is not affected by KRAS or PIK3CA mutation status. As a cancer stromal protein with important roles in metabolism and cancer epigenetics, NNMT is emerging as a promising biomarker for risk stratification of early-stage cancers., (© 2022. The Author(s).)

Colorectal cancer (CRC) is the third most common cancer worldwide. The incidence and mortality rates of CRC are significantly higher in Taiwan than in other developed countries. Genes involved in CRC tumorigenesis differ depending on whether the tumor occurs on the left or right side of the colon, and genomic analysis is a keystone in the study and treatment of CRC subtypes. However, few studies have focused on the genetic landscape of Taiwanese patients with CRC. This study comprehensively analyzed the genomes of 141 Taiwanese patients with CRC through whole-exome sequencing. Significant genomic differences related to the site of CRC development were observed. Blood metabolomic profiling and polygenic risk score analysis were performed to identify potential biomarkers for the early identification and prevention of CRC in the Taiwanese population. Our findings provide vital clues for establishing population-specific treatments and health policies for CRC prevention in Taiwan.

Objective: To investigate the role of ubiquitin-specific peptidase 22 (USP22) in colorectal cancer multidrug resistance and its correlation with multidrug resistance genes P-gp and MRP1, and to preliminarily explore the mechanism of USP22 affecting colorectal cancer resistance. Methods: USP22 over-expression plasmid was transfected into colorectal cancer cells (RKO, SW480)with low expression of USP22. Cell counting kit (CCK-8) assay was used to detect the effect of USP22 on oxaliplatin resistance in colorectal cancer cells. The cells were treated with oxaliplatin of the same concentration. Western blot method was used to detect the expression of apoptosis-related proteins cleaved-caspase3, Bcl-2, and drug resistance proteins MRP1, P-gp in the cells. The cell efflux test was used to detect the effect of up-regulated USP22 on Calcein-AM and rhodamine123. Immunohistochemical methods were used to detect the expressions of USP22 and P-gp in the oxaliplatin chemotherapy-sensitive group and the drug-resistant group and to analyze the correlation between USP22 and MRP1, P-gp. Results: CCK-8 assay showed that the IC 50 values of SW480-USP22 (SW480 cells overexpressing USP22) treated with oxaliplatin for 24 h and 48 h was (4.62±0.05)μmol/L and (2.32±0.04)μmol/L respectively; which was 2.7 times and 3.0 times higher than that in control cells, respectively. After treating with 1.25 μmol/L oxaliplatin for 48 h, USP22 overexpression can inhibit SW480 cells apoptosis. The fluorescence intensity of calcein-AM and rhodamine123 in the SW480-USP22 group were significantly increased when compared with that in the control cells (both P <0.01). The protein expression levels of MRP1 and P-gp in SW480-USP22 cells were significantly increased when compared with that in the control cells(both P <0.01). Immunohistochemistry showed that the positive expression rates of USP22, MRP1, and P-gp in the oxaliplatin chemotherapy-sensitive group were significantly lower than those in the chemotherapy-resistant group, the difference was statistically significant (all P <0.05), and USP22 was positively correlated with the expressions of MRP1 and P-gp in colorectal cancer tissues ( r 1 =0.377, r 2 =0.423, both P <0.05). Conclusions: The up-regulation of USP22 is related to the acquired resistance of colorectal cancer cells to oxaliplatin. USP22 may be involved in the process of platinum-based chemotherapy resistance of colorectal cancer by regulating the expressions of P-gp and MRP1.

Background and objectives : Patients with BRAF -mutated metastatic colorectal cancer have considerably poorer responses to conventional systemic treatment. The real-world effects of triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in Asia have not been well-reported. Materials and Methods : This single-center case series included patients with BRAF -mutated metastatic colorectal cancer undergoing triplet therapy after failure of prior systemic treatment from 2016 to 2020. The primary outcome was progression-free survival, and secondary outcomes were overall survival, response rate, disease control rate, and adverse events. Results : Nine eligible patients with BRAF -mutated metastatic colorectal cancer receiving triplet therapy were enrolled, with a median follow-up time of 14.5 months (range, 1-26). Most patients (88.8%) had two or more prior systemic treatments, and the triplet regimen was mainly dabrafenib, trametinib, and panitumumab. The overall response rate and disease control rate were 11.1% and 33.3%, respectively. Median progression-free survival and overall survival were 2.9 and 7.4 months, respectively, and a trend toward better overall survival was found with left-sided metastatic colorectal cancer compared with right-sided disease (9.2 vs. 6.9 months, p = 0.093). Adverse events were mostly Grade 1-2, including nausea, hypertension, gastrointestinal symptoms, and skin disorders. Conclusions : In this single-center case series, triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in BRAF -mutated metastatic colorectal cancer had an acceptable safety profile and reasonable efficacy.

Background/purpose: This analysis reports safety and effectiveness data from the Taiwanese cohort of the CORRELATE study., Methods: CORRELATE was a prospective, observational study to assess the safety and effectiveness of regorafenib for the treatment of metastatic colorectal cancer (CRC) in real-world clinical practice that was conducted in 13 different countries in Asia, Europe and Latin America. The primary endpoint of the study was incidence of all treatment-emergent AEs (TEAEs), and secondary endpoints included overall survival (OS), progression-free survival (PFS), and disease control rate (DCR)., Results: The global study population (N = 1037) included 128 Taiwanese patients with a median age of 64 years, median weight of 62.02 kg and 66.41% were male. Reduced initiating doses of regorafenib and dose interruptions were common in Taiwanese patients (71.87% and 50.00%, respectively). The safety profile of regorafenib was consistent with that seen in Asian patients in the clinical development trials, including the CORRECT and CONCUR studies, with hand-foot-skin reactions (HFSR) of any grade occurring in 33.59% of patients. Median OS was 11.64 months in the Taiwanese patients (95% confidence interval [CI], 8.36-13.82) and median PFS was 2.17 months (95% CI, 1.97-2.89)., Conclusion: The safety and effectiveness of regorafenib in this real-world study was generally consistent with the known efficacy and safety profile in Asian patients in clinical trials., Trial Registration: NCT02042144., Competing Interests: Declaration of competing interest K-HY has received honoraria from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, and Takeda. C-WD and Y-SL are full-time employees of Bayer. SF-B is a full-time employee of Bayer and owns stock in Bayer; MD has received grants/research support from Merck Serono and Roche; has participated on advisory boards for Amgen, Bayer, Celgene, Ipsen, Merck Serono, Roche and Servier; has received honoraria from Amgen, Bayer, Ipsen, Lilly, Merck Serono, Novartis, Roche and Servier; and has received travel/accommodations/expenses from Amgen, Ipsen, Lilly, Merck Serono, Merck Sharp & Dohme, and Roche. T-SY, T-CH, WT-LC, H-HC, H-WT, B-WL, F-CK, F-FC and J-YW have no conflicts of interest to report., (Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

This study evaluated the survival effects of metronomic maintenance therapy with oral fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy with oral capecitabine (daily dose of 850 mg/m², twice daily, on days 114 every 3 weeks for 6 months) on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockout of the EGFR gene, we analyzed the capacities of cell proliferation and migration. Relapse and survival were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent associated factor of relapse and survival as well as a prognostic factor of disease-free survival and overall survival. Significant intergroup differences in survival were only observed in patients with positive EGFR expression. Thus, our findings suggest EGFR expression is a prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. Analysis of EGFR expression in these patients helps identify potential candidates who may receive the optimal survival benefit from metronomic maintenance therapy.

Irinotecan, a topoisomerase inhibitor, is a common cytotoxic agent prescribed for metastatic colorectal cancer (mCRC) patients. Diarrhea is the most common adverse event (AE). The underlying mechanism of irinotecan-induced diarrhea is intestinal mucosal damage caused by SN-38 (active metabolite of irinotecan) hydrolyzed from SN-38G (inactive metabolite) by bacterial -glucuronidase (G). According to an animal study, silymarin reduces the activity of bacterial G without impairing antitumor efficacy. We conducted a prospective open-label pilot study to evaluate the effect of silymarin as supplementation in reducing toxicities of mCRC patients undergoing irinotecan-based chemotherapy. We enrolled and randomized 70 mCRC patients receiving first-line FOLFIRI (5-fluorouracil/leucovorin/irinotecan) plus bevacizumab. In each treatment cycle, the study group was administered silymarin capsules (150 mg) three times daily for 7 days. The study group experienced less AEs in diarrhea (5.7% vs. 14.6%, p =0.002) and nausea (27.0% vs. 40.2%, p =0.005) in comparison with the control group, but no significant differences in hepatic toxicities were observed. In conclusion, simultaneous administration of silymarin is a potential effective supplementation for reducing toxicities in mCRC patients undergoing first-line FOLFIRI plus bevacizumab, especially in diarrhea and nausea.

This study investigated the roles of low-molecular-weight fucoidan (LMWF) in enhancing the anti-cancer effects of fluoropyrimidine-based chemotherapy. HCT116 and Caco-2 cells were treated with LMWF and 5-FU. Cell viability, cell cycle, apoptosis, and migration were analyzed in both cell types. Potential mechanisms underlying how LMWF enhances the anti-cancer effects of fluoropyrimidine-based chemotherapy were also explored. The cell viability of HCT116 and Caco-2 cells was significantly reduced after treatment with a LMWF--5FU combination. In HCT116 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through the (1) induction of cell cycle arrest in the S phase and (2) late apoptosis mediated by the Jun-N-terminal kinase (JNK) signaling pathway. In Caco-2 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through both the c-mesenchymal-epithelial transition (MET)/Kirsten rat sarcoma virus (KRAS)/extracellular signal-regulated kinase (ERK) and the c-MET/phosphatidyl-inositol 3-kinases (PI3K)/protein kinase B (AKT) signaling pathways. Moreover, LMWF enhanced the suppressive effects of 5-FU on tumor cell migration through the c-MET/matrix metalloproteinase (MMP)-2 signaling pathway in both HCT116 and Caco-2 cells. Our results demonstrated that LMWF is a potential complementary therapy for enhancing the efficacies of fluoropyrimidine-based chemotherapy in colorectal cancers (CRCs) with the wild-type or mutated KRAS gene through different mechanisms. However, in vivo studies and in clinical trials are required in order to validate the results of the present study.

Colorectal cancer (CRC) is the third leading cause of cancer death in Taiwan. A recent study suggested a link between exposure to endocrine-disrupting chemicals (EDCs) and increased susceptibility to pathology. Exposure to di-(2-ethylhexyl) phthalate (DEHP), an EDC and plasticizer widely used in consumer products, has been reported to be significantly positively correlated with increased risks of various cancers. We explored this connection of DEHP exposure with the development of CRC through the detection of urinary monoethylhexyl phthalate (MEHP), a potent metabolite of DEHP. Participants comprised 221 individuals recruited between October 2016 and November 2019 from a single institution. Overall, urinary MEHP concentrations were significantly higher in patients with CRC than in the patients with adenoma or healthy participants (both P < 0.001). Higher exposure to DEHP may contribute to the occurrence of CRC. Urinary MEHP detection may serve as a beneficial noninvasive indicator of increased CRC risk.

Background: Taiwan has witnessed a surge in the incidence of colorectal cancer (CRC), of which 40-60% metastasize. Continuous updating of cytoreductive strategies in metastatic CRC (mCRC) has contributed to median overall survival reaching 40 months. In this changing scenario, to standardize the approaches across Taiwan, a group of experts from the Taiwan Society of Colon and Rectal Surgeons (TSCRS) convened to establish evidence- and opinion-based recommendations for defining the criteria of "resectability" in mCRC., Methods: Over the course of one-on-one consultations, lasting 30-40 min each, with 30 medical specialists (19 colorectal surgeons, 4 general surgeons, and 7 medical oncologists) from 16 hospitals in Taiwan followed by a 2-h meeting with 8 physician experts (3 general surgeons, 4 colorectal surgeons, and 1 thoracic surgeon), 12 key questions on cytoreduction were addressed. This was further contextualized based on published literature., Results: The final consensus includes eight recommendations regarding the criteria for metastasis resection, role of local control treatment in liver potentially resectable patients, management of synchronous liver metastases, approach for peritoneal metastasis, place for resection in multiple-organ metastasis, and general criteria for resectability., Conclusions: mCRC patients undergoing R0 resection have the greatest survival advantage following surgery. Our role as a multidisciplinary team (MDT) should be to treat potentially resectable mCRC patients as rapidly and safely as possible, and achieve R0 resection as far as possible and for as long as possible (continuum of care). This TSCRS consensus statement aims to help build clinical capacity within the MDTs, while making better use of existing healthcare resources.

Introduction: The incidence of early-onset colorectal cancer is increasing. This study explored the feasibility of fecal immunochemical test (FIT) and risk factors for predicting colorectal neoplasm in younger adults., Methods: This single-center study included 6,457 participants who underwent health examination from 2013 to 2016 including index colonoscopy (3,307 individuals aged 30-49 years as the younger adult group and 3,150 aged ≥50 years as the average-risk group). Primary outcomes were adenoma detection rate (ADR) and advanced ADR (AADR). Findings of younger participants were stratified by the results of FIT and clinical risk factors and were compared with those of the average-risk group., Results: Among participants aged 30-49 years, a positive FIT was associated with significantly higher ADR (28.5% vs 15.5, P < 0.001) and AADR (14.5% vs 3.7%, P < 0.001) than a negative FIT. Moreover, a positive FIT was associated with higher AADR in younger participants than in average-risk counterparts (14.5% vs 9.8%, P = 0.028). Although no single risk factor predicted FIT positivity in younger participants, nonalcoholic fatty liver disease was independently associated with higher ADR (odds ratio = 2.60, 95% confidence interval = 1.27-5.34, P = 0.001), and metabolic syndrome was independently predictive of higher AADR in younger participants than in average-risk participants (odds ratio = 3.46, 95% confidence interval = 1.66-7.21, P = 0.001)., Discussion: A positive FIT in people aged 30-49 years implies a higher risk of colorectal neoplasm, particularly among patients with nonalcoholic fatty liver disease and metabolic syndrome., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Despite the steadily increasing worldwide incidence of colorectal cancer (CRC), an effective noninvasive approach for early detection of CRC is still under investigation. The guaiac-based fecal occult blood test (FOBT) and fecal immunochemical test (FIT) have gained popularity as noninvasive CRC screening tests owing to their convenience and relatively low costs. However, the FOBT and FIT have limited sensitivity and specificity. To develop a noninvasive tool for the detection of CRC, we investigated the sensitivity, specificity, and accuracy of a stool DNA test targeting methylated syndecan-2 (SDC2), which is frequently methylated in patients with CRC. The present study enrolled 62 patients diagnosed as having stage 0-IV CRC and 76 healthy participants between July 2018 and June 2019 from two institutions. Approximately 4.5 g of stool sample was collected from each participant for detection of human methylated SDC2 gene. In total, 48 of 62 (77.4%) patients with CRC showed positive results, whereas 67 out of 76 (88.2%) healthy participants showed negative results. The area under the curve of the receiver operating characteristic curve constructed was 0.872 for discrimination between patients with CRC and healthy individuals. The present study highlights the potential of the fecal methylated SDC2 test as a noninvasive detection method for CRC screening with a relatively favorable sensitivity of 77.4%, a specificity of 88.2% and a positive predictive value of 84.2% compared with other available fecal tests. Further multicenter clinical trials comprising subjects of varied ethnicities are required to validate this test for the mass screening of patients with CRC., (© 2021 The Author(s).)

DEAD-box RNA helicase DDX21 (also named nucleolar RNA helicase 2) is a nuclear autoantigen with undefined roles in cancer. To explore possible roles of autoimmune recognition in cancer immunity, we examined DDX21 protein expression in colorectal cancer tissue and its association with patient clinical outcomes. Unbiased deep proteomic profiling of two independent colorectal cancer cohorts using mass spectrometry showed that DDX21 protein was significantly upregulated in cancer relative to benign mucosa. We then examined DDX21 protein expression in a validation group of 710 patients, 619 of whom with early stage and 91 with late stage colorectal cancers. DDX21 was detected mostly in the tumor cell nuclei, with high expression in some mitotic cells. High levels of DDX21 protein were found in 28% of stage I, 21% of stage II, 30% of stage III, and 32% of stage IV colorectal cancer cases. DDX21 expression levels correlated with non-mucinous histology in early stage cancers but not with other clinicopathological features such as patient gender, age, tumor location, tumor grade, or mismatch repair status in any cancer stage. Kaplan-Meier analyses revealed that high DDX21 protein levels was associated with longer survival in patients with early stage colorectal cancer, especially longer disease-free survival in patients with microsatellite instability (MSI) cancers, but no such correlations were found for the microsatellite stable subtype or late stage colorectal cancer. Univariate and multivariate analyses also identified high DDX21 protein expression as an independent favorable prognostic marker for early stage MSI colorectal cancer.

Aim: Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility of patients to irinotecan and its toxicity. This study is a multicenter, randomised clinical trial comparing the clinical outcomes and adverse events (AEs) in metastatic colorectal cancer (mCRC) patients treated with bevacizumab plus FOLFIRI with or without UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy., Methods: The control group received conventional biweekly FOLFIRI plus bevacizumab without UGT1A1 genotyping, whereas the study group received the same regimen with irinotecan dose escalation based on UGT1A1 genotyping. The primary end-point was progression-free survival (PFS), and secondary end-points were overall response rate (ORR), disease control rate (DCR), overall survival (OS), AEs and metastasectomy rate., Results: Over a median follow-up of 26.0 months (IQR, 17.0-35.0 months), study group (n = 107) was superior to the control group (n = 106) in PFS, OS, ORR, DCR, and metastasectomy rate (all P < 0.05). Furthermore, there were no significant differences in AEs ≥ grade III between the two groups, even with the 1.36-fold increase in the relative dose intensity of irinotecan in the study group. Dose escalation of irinotecan, an independent factor of ORR (P < 0.001) and DCR (P = 0.006), improved PFS in mCRC patients with wild-type and mutant KRAS (P = 0.007 and P = 0.019, respectively)., Conclusion: The current study revealed that mCRC patients, regardless of KRAS gene status, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favourable clinical outcome without significantly increased toxicities., Clinical Trial Registration: NCT02256800., Competing Interests: Conflict of interest statement The authors have declared that no conflicts of interest exist., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Proteomic analyses indicate that STAT1 protein (signal transducer and activator of transcription 1 or transcription factor ISGF-3 components p91/p84) is upregulated in some colorectal cancers. This study examined 736 colorectal cancer patients for the expression of STAT1 protein in tissue specimens, including 614 early stage patients and 122 advanced stage patients. Tissue microarrays were constructed, and STAT1 expression was examined by immunohistochemistry and scored semi-quantitatively. Among all cases, 9% of cases displayed high levels of cytoplasmic expression of STAT1 and 15% of cases had positive nuclear expression. Based on statistical analyses of a cohort of 559 early stage patients with survival data and no neoadjuvant therapy, we found that high levels of cytoplasmic expression of STAT1 correlated with shorter survival time in early stage colorectal cancer, particularly of the microsatellite instability (MSI) subtype. Additional analysis of a 244-case cohort of colorectal cancers from the Cancer Genome Atlas found that STAT1 gene expression correlated positively with PD-L1 (CD274) and PD-1 (PDCD1) but had no correlation with KRAS or BRAF mutation status. STAT1 expression showed no clear correlation with any of the 4 clinical diagnostic markers of mismatch repair, MLH1, MSH2, MSH6, and PMS2, suggesting its potential as an independent outcome marker for MSI cancers. Our findings suggest that STAT1 may be used as a potential prognostic protein marker for stratifying the outcome risk of early stage MSI colorectal cancer., Competing Interests: Atsushi Tanaka, Yihua Zhou, Makiko Ogawa, and Jinru Shia declare no competing interests related to this study. David S. Klimstra is a consultant for and equity holder in Paige.AI and a consultant for Merck. Julia Y. Wang is founder, CEO, and equity holder of Curandis. Michael H. Roehrl is member of the Scientific Advisory Boards of Proscia and Trans-Hit. None of these companies had any influence in support, design, execution, data analysis, or any other aspect of this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Aberrant activation of STAT3 is frequently encountered and promotes survival, cellular proliferation, migration, invasion and angiogenesis in tumor cell. Convallatoxin, triterpenoid ingredient, exhibits anticancer pharmacological properties., Purpose: In this work, we investigated the anticancer potential of convallatoxin and explored whether convallatoxin mediates its effect through interference with the STAT3 activation in colorectal cancer cells., Methods: In vitro, the underlying mechanisms of convallatoxin at inhibiting STAT3 activation were investigated by homology modeling and molecular docking, luciferase reporter assay, MTT assay, RT-PCR, Western blotting and immunofluorescence assays. Changes in cellular proliferation, apoptosis, migration, invasion and angiogenesis were analyzed by EdU labeling assay, colony formation assay, flow cytometry assay, wound-healing assay, matrigel transwell invasion assay and tube formation assays. And in vivo, antitumor activity of convallatoxin was assessed in a murine xenograft model of HCT116 cells., Results: Convallatoxin decreased the viability of colorectal cancer lines. Moreover, convallatoxin reduced the P-STAT3 (T705) via the JAK1, JAK2, and Src pathways and inhibited serine-727 phosphorylation of STAT3 via the PI3K-AKT-mTOR-STAT3 pathways in colorectal cancer cells. Interestingly, we discovered the crosstalk between mTOR and JAK2 in mTOR/STAT3 and JAK/STAT3 pathways, which collaboratively regulated STAT3 activation and convallatoxin play a role in it. Convallatoxin also downregulated the expression of target genes involved cell survival (e.g., Survivin, Bcl-xl, Bcl-2), proliferation (e.g., Cyclin D1), metastasis (e.g., MMP-9), and angiogenesis (e.g., VEGF). Indeed, we found that convallatoxin inhibited tube formation, migration, and invasion of endothelial cells, and inhibited the proliferation. Finally, in vivo observations were confirmed by showing antitumor activity of convallatoxin in a murine xenograft model., Conclusion: The result of the current study show that convallatoxin promotes apoptosis and inhibits proliferation and angiogenesis through crosstalk between JAK2/STAT3 (T705) and mTOR/STAT3 (S727) signaling pathways in colorectal cancer cells and indicate that convallatoxin could be a valuable candidate for the development of colorectal cancer therapeutic., Competing Interests: Declaration of Competing Interest The authors declare that there are no financial conflicts of interest in regard to this work., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Background: Colorectal cancer (CRC) is the third most common cancer in the world. Genome-wide association studies are a powerful method to analyze the status of single-nucleotide polymorphisms (SNPs) in specific genes. Heat shock proteins (HSPs) were found to be involved in the cancer progression and chemoresistance. However, there is still no further study about polymorphisms of HSP beta-1 (HSPB1) in colorectal cancer. We proposed the SNP of HSPB1 may be correlated with the progression and metastasis in colon cancer., Methods: We recruited 379 colorectal cancer patients and categorized as four stages following the UICC TNM system. Then, we selected tagging SNPs of HSPB1 by 10% minimum allelic frequency in Han Chinese population from the HapMap database and analyze with the Chi-square test., Results: We demonstrated the association of HSPB1 genetic polymorphisms rs2070804 with tumor depth with colorectal cancer. But, there is a lack of association between HSPB1 genetic polymorphisms and colorectal cancer invasion, recurrence or metastasis., Conclusions: The polymorphisms of HSPB1 seemed to change the tumor behavior of colorectal cancer. HSPB1 rs2070804 polymorphism is associated with the depth of the primary tumor. But, there is no further correlation with other to the clinical parameters such as cancer invasiveness, local recurrence, or distant metastasis., (© 2018 Wiley Periodicals, Inc.)

Background: Regorafenib is an oral multikinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor, and monoclonal antibodies targeting epidermal growth factor receptor. A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in a 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) regimen on the basis of an individual uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. The aim of this study is to address the efficacy and safety of a dose-adjusted combination of regorafenib and FOLFIRI for patients with mCRC., Methods: A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose-escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with mCRC. The primary endpoint is progression-free survival, and the secondary endpoints are overall survival, disease control rate, time to progression, and duration of treatment. Safety assessments will also be recorded., Discussion: Dose adjustment for regorafenib and irinotecan makes treatment-related AEs tolerable and makes the concomitant treatment practicable. This study will provide initial evidence regarding the efficacy and safety of a new combination of chemotherapy and a targeted agent for mCRC., Trial Registration: ClinicalTrials.gov, NCT03880877. Prospectively registered on 19 March 2019.

Background: The impact of dual-ring wound protectors (DRWPs) on the long-term outcomes of patients with colorectal cancer (CRC) undergoing elective surgery remains unclear. The aim of this cohort study was to compare short- and long-term outcomes after CRC resection with or without use of a DRWP., Methods: This study enrolled 625 patients with stage I-III CRC undergoing curative resection and divided them into DRWP (n = 348) and control (n = 277) groups. Primary endpoints were postoperative short- and long-term complications. Secondary endpoints were oncological outcomes including wound recurrence, disease-free survival, and overall survival., Results: Rates of postoperative complications (P = 0.004) and laparotomy wound infection (LWI) (P < 0.001) were markedly lower in the DRWP group. Operation quality, as per the number of lymph nodes harvested and rate of R0 resection, did not differ between the groups (all P > 0.05). The DRWP group exhibited significantly lower rates of incisional hernia occurrence (5.3% versus 9.5%, P = 0.045) compared with the control group. Multivariable analyses demonstrated an increased risk of LWI with no wound protector in colorectal surgery (odds ratio, 3.778; P = 0.001), and patients who developed LWI after surgery were more than 4 times more likely to develop an incisional hernia during outpatient follow-up (odds ratio, 4.333; P = 0.001). One patient in the control group (0.36%) had isolated wound recurrence at 12 mo postoperatively., Conclusions: Fewer postoperative and late complications, comparable oncological safety, and similar long-term clinical outcomes confirmed the benefits of DRWP use for patients with CRC undergoing elective surgery. Therefore, the use of DRWP may be considered in curative CRC resection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Regorafenib prolonged overall survival (OS) versus placebo in patients with treatment-refractory metastatic colorectal cancer (mCRC) in phase III trials. We conducted an observational study of regorafenib for patients with mCRC in real-world clinical practice., Methods: The international, prospective, CORRELATE study recruited patients with mCRC previously treated with approved therapies, for whom the decision to treat with regorafenib was made by the treating physician according to the local health authority approved label. The primary objective was safety, assessed by treatment-emergent adverse events (TEAEs; National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03)., Results: A total of 1037 patients were treated. The median age was 65 years (range: 24-93); 87% of patients had Eastern Cooperative Oncology Group performance status 0-1, 56% of patients had KRAS, 7% had NRAS and 4% had BRAF mutations. The initial regorafenib dose was 160 mg/day in 57% of patients. The most common grade III or IV drug-related TEAEs were fatigue (9%), hand-foot skin reaction (7%) and hypertension (6%). Drug-related grade V (fatal) TEAEs occurred in 1% of patients. Dose reductions for drug-related TEAEs occurred in 24% of patients. Median OS was 7.7 months (95% confidence interval [CI]: 7.2-8.3), and median progression-free survival (PFS) was 2.9 months (95% CI: 2.8-3.0)., Conclusions: In this real-world, observational study of patients with mCRC, the regorafenib toxicity profile was similar to that reported in phase III trials. The starting dose for almost half of patients was less than the approved 160-mg dose, and the median OS and PFS were in the range observed in phase III trials., Trial Registration: NCT02042144., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The aim of the study was to assess apical lymph nodes (APNs) for predicting distant metastases in patients with stage III colorectal cancer (CRC) curatively treated with FOLFOX adjuvant chemotherapy and adequate lymph node retrieval. We investigated the correlation between APN metastasis and clinical outcomes. This retrospective study examined 97 patients. All patients were followed until death, loss to follow-up, or May 2017. Clinicopathological variables, including the APN status, were assessed. Multivariate logistic regression model was used to identify the independent risk factors for APN and distant metastases, and Cox proportional regression model was used to evaluate the association between APN metastasis and oncologic outcomes. Multivariate analyses revealed the N2 stage as an independent predictor of APN metastasis [P = 0.036; odds ratio (OR): 3.016; 95% confidence interval (CI): 1.076-8.499], while APN metastasis was an independent risk factor for distant metastases (P < 0.001; OR: 13.876; 95% CI: 3.815-50.475). Furthermore, APN metastasis was an independent risk factor for poorer disease-free survival (DFS) and overall survival (OS) (P < 0.001 and P = 0.005, respectively). The liver (31.6%) was the most common site of distant metastases in patients with APN metastases. APN metastasis is an important prognostic factor for node-positive CRC; it enhanced the distant metastases in patients with stage III CRC curatively treated with adequate lymph node retrieval following FOLFOX adjuvant chemotherapy. Therefore, for patients with stage III CRC involving APN metastasis, prospectively randomized trials are mandatory to investigate different therapeutic strategies in addition to conventional FOLFOX adjuvant chemotherapy.

This study investigated stress and other factors associated with colorectal cancer (CRC) outpatients with temporary colostomies in Taiwan. Temporary colostomies have been incorporated as a defecation alternative to maintain physical function and are accompanied by chemotherapy/radiotherapy in CRC patients. A cross-sectional study was conducted, and a convenience sampling approach was adopted to recruit 110 discharged CRC patients with temporary colostomies from a medical centre in southern Taiwan. The mean score of the Stress of Colostomy Patients Scale was 66.49 (out of 120). Demographic attributes were found to have an impact on different stress types. Stress of changes in familial and social interaction was affected by age, employment status, educational level and colostomy assistant caregiver. The stress of colostomy care was impacted by the factor of employment status, and the stress of changes of self-concept was impacted by the factors of educational level and self-perception of disease. The results provide post-operative information regarding stress and stress types among CRC patients with temporary colostomies, serve as a reference for clinical assessment, practice and care, and generate up-to-date knowledge and comprehension of learning how to live with a temporary colostomy., (© 2019 John Wiley & Sons Ltd.)

Background: In the management of patients with RAS wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) therapies have demonstrated a clinical benefit, with longer survival. However, the correlation between the emergence of circulating RAS mutations and secondary resistance to anti-EGFR therapies requires further elucidation. In this study, we aim to examine evolutionary changes in RAS mutations through liquid biopsy in patients with mCRC during and after anti-EGFR therapy., Methods: A total of 120 patients diagnosed with RAS wild-type mCRC will be enrolled in this study. Patients will receive a cetuximab-based infusional 5-fluorouracil regimen as first-line treatment. Cetuximab-based treatment is expected to continue until disease progression, intolerable toxic effects, or withdrawal of consent. Blood samples from enrolled patients will be collected before and then every 3 months during cetuximab-based treatment and also at disease progression. These blood samples will be evaluated for RAS resistance mutations by using the MassARRAY platform. The primary endpoint is the percentage of RAS mutations detected in circulating DNA from patients during cetuximab treatment. The correlation between the tumor response and survival outcomes of these patients and the emergence of circulating RAS mutations will be further analyzed., Discussion: Liquid biopsy is a powerful technology that can represent tumor heterogeneity in a relatively noninvasive manner. Because RAS mutations play a major role in resistance to anti-EGFR therapy for mCRC, examining evolutionary changes in these mutations during such treatment through liquid biopsy would be useful. After comprehensively analyzing the emergence of circulating RAS mutations and its clinical relevance in this study, our results should provide practical guidance on anti-EGFR therapy for mCRC., Trial Registration: The date of trial registration ( NCT03401957 ) in this study was January 17, 2018.

Vascular endothelial growth factor (VEGF) is correlated with angiogenesis and early relapse of colorectal cancer (CRC). This study investigated the role of miR-148a in the regulation of VEGF/angiogenesis and early relapse of CRC. We established a stable clone with miR-148a expression in HCT116 and HT29 cell lines and created a hypoxic condition by using CoCl 2 to determine the underlying mechanism of miR-148a. The effects of miR-148a on the phosphoryl-ERK (pERK)/hypoxia-inducible factor-1α (HIF-1α)/VEGF pathway were evaluated through Western blotting and the inhibitory effect of miR-148a on angiogenesis was demonstrated through a tube formation assay. Sixty-three CRC tissues (28 early relapse and 35 non-early relapse) were analysed to assess the relationship between miR-148a and HIF-1α/VEGF. The protein expression of pERK/HIF-1α/VEGF in HCT116 and HT29 cells was significantly decreased by miR-148a (all P < 0.05). The protein expression of VEGF/HIF-1α was strongly inversely associated with the expression of miR-148a in the 63 CRC tissue samples (all P < 0.05). Tube formation assay demonstrated that miR-148a significantly obliterated angiogenesis. miR-148a suppresses VEGF through down-regulation of the pERK/HIF-1α/VEGF pathway and might lead to the inhibition of angiogenesis; miR-148a down-regulation increased the early relapse rate of CRC. This demonstrates that miR-148a is a potential diagnostic and therapeutic target., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: In colorectal cancer (CRC) patients, pulmonary nodules are usually considered lung metastases (LM). However, approximately 10% of LM is presented as a solitary pulmonary nodule which mimics primary lung cancer (PLC). This study aims to determine the distinguishing characteristics of the two pulmonary nodule types during postoperative surveillance of CRC patients., Methods: Between March 2009 and February 2018, 47 CRC patients with pulmonary nodules from a single institution were retrospectively analyzed. They were divided into two groups, namely CRC with second PLC (CSPLC) and CRC with LM (CRCLM), and their demographic data and clinicopathological features were analyzed., Results: When pulmonary nodules are presented, multiple lesions and serum carcinoembryonic antigen (CEA) level >5 ng/mL indicated a higher probability of CRCLM (p < 0.001 and p = 0.028, respectively). A CK7 - /CK20 + /CDX2 + /TTF-1 - phenotype on immunohistochemistry (IHC) stain suggested CRCLM. Other clinicopathological features showed no significant between-group differences. The median overall survival was considerably longer in the CSPLC group (not reached) than in the CRCLM group (45.41 months, p = 0.064)., Conclusions: The detection of a suspicious isolated pulmonary nodule in CRC patients warrants further workup to distinguish between SPLC and LM. Multiple lesions, serum CEA >5 ng/mL when an isolated pulmonary nodule detected, and initial TNM stage IV CRC are more likely related to LM rather than SPLC. Image-guided needle biopsy and IHC stain can reduce the probability of misdiagnosis and rule out LM. CSPLC may have a favorable prognosis owing to early detection and receiving appropriate treatment., (Copyright © 2018. Published by Elsevier Taiwan LLC.)

Objective: Surgical technique process innovations are expected to generally incur no additional cost but gain better quality. Whether a mini-laparotomy surgery (MLS) in the treatment of colorectal cancer (CRC) is more cost effective than conventional open surgery had not been well examined. The objective of this study was to apply cost-effectiveness approaches to investigate the cost effectiveness of adopting MLS compared with open surgery 1 year following resection in CRC patients., Research Design: A prospective non-randomized cohort study design., Setting: An academic medical center., Participants: A total of 224 patients who received elective MLS and 339 who received conventional surgery; after propensity score matching, 212 pairs were included for analysis., Intervention: None., Main Outcome Measures: Cost measures were hospital-index cost and outpatient and inpatient costs within 1 year after discharge. Effectiveness measures were life-years (LYs) gained and quality-adjusted life-year (QALYs) gained., Statistical Methods: We calculated incremental costs and effectiveness by differences in these values between MLS and conventional surgery using adjusted predicted estimates., Results: MLS patients had lower rates of blood transfusions, less complication, and shorter post-surgical lengths of stay and more medical cost savings. One-year overall medical costs for MLS patients were TWD 748,269 (USD 24,942) per QALY gained, significant lower than for the comparison group (p-value = 0.045)., Conclusion: Our findings supported that the less invasive surgical process through MLS not only saved medical costs, but also increased QALYs for surgical treatment in CRC patients., Competing Interests: The authors have declared that no competing interests exist.

Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer that is widely used in many consumer products and medical devices. Humans can be exposed to DEHP through ingestion, inhalation, or dermal absorption. Previous studies on DEHP have focused on its role as an endocrine-disrupting chemical leading to endocrine-related diseases. However, the correlation between DEHP exposure and the progression of colorectal cancer (CRC) is largely unknown. The aim of this study was to investigate the effects of mono(2-ethylhexyl) phthalate (MEHP), an active metabolite of DEHP, on the progression of CRC. Our results showed that treatment with MEHP enriched the population of cancer-stem-cell (CSC)-like cells and upregulated IL-8 expression by inducing the AKT-β-catenin-TCF4 signaling pathway. Blocking β-catenin-TCF4-mediated IL-8 expression reversed the MEHP-induced migration and enrichment of CSC-like cells. Consistent with the in vitro data, DEHP treatment increased the levels of nuclear β-catenin, polyp formation, and invasive adenocarcinoma in a mouse model. Our results suggest that MEHP facilitates the progression of CRC through AKT-β-catenin signaling.

For the purpose of demonstrating the clinical value and unraveling the molecular mechanisms of micro RNA (miR)-1-3p in colorectal carcinoma (CRC), the present study collected expression and diagnostic data from Gene Expression Omnibus (GEO), ArrayExpress and existing literature to conduct meta‑analyses and diagnostic tests. Furthermore, the potential targets of miR‑1‑3p were attained from datasets that transfected miR‑1‑3p into CRC cells, online prediction databases and differentially expressed genes from The Cancer Genome Atlas and literature. Subsequently, bioinformatics analysis was conducted based on the aforementioned selected target genes. As a result, downregulation of miR‑1‑3p was observed. The combined standardized mean difference was ‑0.51 with 95% confidence interval (CI) of ‑0.68 to ‑0.33 using a fixed effect model, which demonstrated a significant downregulation of miR‑1‑3p in CRC. The combined sensitivity, specificity, positive likelihood ratio, negative likelihood ratio diagnostic score and odds ratio were 0.74 (95%CI: 0.48, 0.90), 0.75 (95%CI: 0.35, 0.94), 2.94 (95%CI: 1.01, 8.55), 0.34 (95%CI: 0.19, 0.60), 2.15 (95%CI: 1.06, 3.23) and 8.57 (95%CI: 2.89, 25.36). The summarized receiver operating characteristic curve demonstrated that the area under the curve was 0.81. In bioinformatics analyses based on 30 promising targets, the most enriched terms in Gene Ontology were positive regulation of transcription from RNA polymerase II promoter, extracellular region and transcription factor binding. Kyoto Encyclopedia of Genes and Genomes pathway analysis highlighted the pathway termed cytokine‑cytokine receptor interaction. In protein‑protein interaction analysis, platelet factor 4 was selected as the hub gene. To conclude, miR‑1‑3p is downregulated in CRC and likely suppresses CRC via multiple biological approaches, which indicates the diagnostic potential and tumor suppressive efficacy.

Aim: This phase II, open-label study evaluated the efficacy and safety of neoadjuvant therapy with bevacizumab plus XELOX (capecitabine and oxaliplatin) for untreated metastatic colorectal cancer with unresectable liver metastases and assessed conversion of unresectable to resectable metastases after neoadjuvant treatment., Methods: Patients received bevacizumab 5 mg/kg and oxaliplatin 85 mg/m 2 on day 1, and capecitabine 1000 mg/m 2 twice daily on days 1-5 followed by 2 days of rest in a 14-day cycle for 12 cycles; bevacizumab was excluded in cycles 6 and 7. Patients were later divided into resected and unresected groups, depending upon whether they underwent curative resection after chemotherapy. Efficacy and safety were evaluated., Results: Of 45 patients enrolled, 17.8% completed the study. The resection rate of liver metastases after neoadjuvant therapy was 42.2%. The median time to disease progression was 10.1 and 8.7 months in the resected and unresected groups, respectively (P = 0.1341). Response rate was significantly higher in the resected (47.4%) versus the unresected group (34.6%; P = 0.0010), and seven patients achieved complete response (resected group). Overall, 94.3% of adverse events were of mild or moderate severity, and grade ≥3 adverse events occurred in 4.3% and 7.3% of patients in the resected and unresected groups, respectively. The most common adverse events in both groups were palmar-plantar erythrodysesthesia syndrome, decreased appetite, thrombocytopenia, peripheral neuropathy, fatigue, diarrhea, vomiting, proteinuria and nausea., Conclusion: Neoadjuvant therapy with bevacizumab plus XELOX was well tolerated and effective in previously untreated metastatic colorectal cancer patients with initially unresectable liver metastases., (© 2017 John Wiley & Sons Australia, Ltd.)

Objective: To analyze the effect to the prognosis of tumor site on the patients of colorectal cancer after curative resection with different stage. Methods: Clinicopathological and follow-up data of 2 097 colorectal carcinoma cases undergoing resection at Fourth Hospital of Hebei Medical University from January 2008 to March 2015 were retrospectively analyzed. There were 421 patients in left-sided colorectal cancer (LCC) group (including carcinoma in cecum, ascending colon , hepatic flexure, and transvers colon) , 386 in right-sided colorectal cancer (RCC) group (including carcinoma in splenic flexure, descending colon and sigmoid colon) and 1 290 in rectal cancer (RECC) group. Clinicopathologic features in patients with different tumor location were compared. 5-year overall survival rate were compared among the 3 groups. Patients were stratified by different stage to analyze the effect of tumor location on the prognosis. χ(2)test and Kruskal-Wallis rank-sum test were used to compare the clinicopathological features among the 3 groups, Kaplan-Meier curve and Log-rank test were used to analyze prognosis, respectively. Results: No significant differences were identified between the three groups in age, family history, N stage and intestinal obstruction. Significant difference were found in gender among LCC, RCC and RECC group (male were 62.5% vs . 54.9% vs .56.3%, χ(2)=6.040, P =0.049) . Compared with LCC group and RCC group, RECC group had more well and moderately differentiated adenocarcinoma patients (89.7% vs . 86.0% vs. 82.4%, χ(2)=10.712 and 17.385, P =0.013 and 0.001) , more stage Ⅰ patients (17.1% vs . 6.9% vs. 6.5%, χ(2)=37.459 and 37.208, P =0.000 and 0.000) , and less likely to be stage T4 (44.7% vs . 76.7% vs .78.5%, χ(2)=128.015 and 133.704, P =0.000 and 0.000), metastasis (2.6% vs . 5.7% vs . 3.6%, χ(2)=1 417.167 and 1 424.217, P =0.000 and 0.000) and intestinal obstruction (11.3% vs . 21.1% vs . 24.4%, χ(2)=25.846 and 41.141, P =0.000 and 0.000). Five-year survival rate reduced in turn in the patients with RECC, LCC and RCC(70.9%, 59.8%, 58.9%, χ(2)=11.577, P =0.009). In the subgroup of stage Ⅲ, patients with different tumor location had different overall survival (χ(2)=9.878, P =0.007). Compared to right-sided colon cancer patients, rectal ones had significantly better overall survival (χ(2)=9.271, P =0.002); but in the subgroup of stage Ⅰ, Ⅱ and stage Ⅳ, patients with different tumor location had similar overall survival ( P were 0.124, 0.888, 0.263, respectively). Conclusions: Colorectal cancer patients with tumor location had different clinicopathologic features. Patients with rectal cancer had better five-year survival rate than those with left located and right located colon cancer. Tumor location had different effects on the prognosis according to the different TNM stage-subgroups.

Background: Colorectal carcinoma (CRC) is one of the most common causes of cancer-related deaths. The mean age of patients with CRC ranges from 49 to 60 years. Pediatric CRC is unusual, which often escapes early diagnosis because of a lack of awareness of its occurrence in children. The association between the mutation of APC and the occurrence of CRC in the first decade of life remains unknown., Case Presentation: We report a 10-year-old child with CRC; he was diagnosed with stage IIIB advanced transverse colon cancer without distal metastases. We detected a heterozygous germline mutation at c.5465 T > A in both blood and tissue samples and a heterozygous somatic mutation at c.7397C > T in the tissue sample. Both of these mutations can cause CRC tumorigenesis in the first decade of life., Conclusions: The rare genetic features of this 10-year-old patient might be the predisposing cause of pediatric CRC. Therefore, screening patients with early-onset CRC through clinical and genetic characterizations is suggested.

Background: With the recent development of molecular markers, strategies for identifying patients with colorectal cancer (CRC) having a high risk of postoperative early relapse (within 1 y) and relapse have been improved. We previously constructed a multigene biochip with 19 candidate genes. The objective of the present study was to optimize a multigene biochip for detecting the risk of postoperative early relapse and relapse in patients with CRC., Methods: We included 357 patients with stage I-III CRC who underwent curative resection at a single institution between June 2010 and May 2015. During each follow-up, a postoperative surveillance strategy including the National Comprehensive Cancer Network recommendations and a multigene biochip was used. A statistical algorithm was developed to select candidate biomarkers for an optimal combination., Results: After a 30.9-mo median follow-up, 67 patients (18.8%) had postoperative relapse, of whom 25 (7.0%) relapsed within 1 y after operation and accounted for 37.3% of all relapsed patients. Of the 19 circulating biomarkers, ELAVL4, PTTG1, BIRC5, PDE6D, CHRNB1, MMP13, and PSG2, which presented significant predictive validity, were selected for combination. The expression of the seven-biomarker biochip resulted in area under the receiver operating characteristic curve values of 0.854 (95% confidence interval: 0.756-0.952) for early relapse and 0.884 (95% confidence interval: 0.830-0.939) for relapse. Moreover, the sensitivity, specificity, and predictive accuracy levels were 84.0%, 83.1%, and 83.2% for early relapse and 76.1%, 91.0%, and 88.2% for relapse (P = 0.415, 0.006, and 0.054, respectively). The median lead times before the detection of postoperative early relapse and relapse were 3.8 and 10.4 mo, respectively., Conclusions: From 19 circulating biomarkers, we optimized seven contemporary circulating biomarkers. The prediction model used for the early and accurate identification of Taiwanese patients with CRC having a high risk of postoperative early relapse and relapse seems to be feasible and comparable., (Copyright © 2017 Elsevier Inc. All rights reserved.)