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Objectives: Colonoscopy surveillance reduces the incidence of colorectal cancer through the detection and endoscopic removal of adenomas. Current guidelines recommend that patients with Lynch syndrome should have colonoscopy surveillance every 1-2 years starting at the age of 20-25. However, insufficient data are available to evaluate the quality and safety of colonoscopy surveillance for patients with Lynch syndrome nationwide in Japan., Methods: Patients with Lynch syndrome ( n  = 309) from 13 institutions who underwent one or more colonoscopy procedures were enrolled in this retrospective analysis. Colonoscopy completion rate, colonoscopy-related complication rate, proportion with an adequate colonoscopy interval, and adenoma detection rate were reviewed., Results: The colonoscopy completion rate was 98.8% and a history of previous colorectal cancer surgery was significantly associated with a higher completion rate. All complications were associated with endoscopic treatment and the rate of bleeding needing hemostasis and perforation needing surgical repair were both 0.16% after colonoscopy with polypectomy. The adenoma detection rate at the first colonoscopy was 25%. Although there was no difference in the completion and complication rates based on differences in the colonoscopy experience of the endoscopist, the detection rate of adenomas and intramucosal cancers was significantly higher with more experienced endoscopists. The proportion of patients developing cancer was significantly higher with a >24 months than a ≤24 months interval., Conclusion: High-volume experienced endoscopists and appropriate surveillance intervals may minimize the risk of developing colorectal cancers in patients with Lynch syndrome., Competing Interests: The authors declare that they have no conflict of interest., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Aim: The surgical treatment of inguinal lymph node (ILN) metastases secondary to anorectal adenocarcinoma remains controversial. This study aimed to clarify the surgical treatment and management of ILN metastasis according to its classification., Methods: This retrospective, multi-centre, observational study included patients with synchronous or metachronous ILN metastases who were diagnosed with rectal or anal canal adenocarcinoma between January 1997 and December 2011. Treatment outcomes were analysed according to recurrence and prognosis., Results: Among 1181 consecutively enrolled patients who received treatment for rectal or anal canal adenocarcinoma at 20 referral hospitals, 76 (6.4%) and 65 (5.5%) had synchronous and metachronous ILN metastases, respectively. Among 141 patients with ILN metastasis, differentiated carcinoma, solitary ILN metastasis and ILN dissection were identified as independent predictive factors associated with a favourable prognosis. No significant difference was found in the frequency of recurrence after ILN dissection between patients with synchronous (80.6%) or metachronous (81.0%) ILN metastases. Patients who underwent R0 resection of the primary tumour and ILN dissection had a 5-year survival rate of 41.3% after ILN dissection (34.1% and 53.1% for patients with synchronous and metachronous ILN metastases, respectively, P = 0.55)., Conclusion: The ILN can be appropriately classified as a regional lymph node in rectal and anal canal adenocarcinoma. Moreover, aggressive ILN dissection might be effective in improving the prognosis of low rectal and anal canal adenocarcinoma with ILN metastases; thus, prophylactic ILN dissection is unnecessary., (© 2022 Association of Coloproctology of Great Britain and Ireland.)

Background and Objective: Colonoscopy is a common procedure performed by colorectal surgeons for screening, diagnosis, and surveillance of various colorectal diseases. Existing literature has conflicting data on quality outcomes of colonoscopies performed in the afternoon and the morning schedules and only includes colonoscopies performed by gastroenterologists. We sought to analyze procedural outcomes between morning and afternoon colonoscopies performed by colorectal surgeons., Data Sources and Main Outcome Measures: A retrospective chart review of colonoscopies performed by colorectal surgeons at a tertiary care center from October 2018 through July 2020 was performed. Complete colonoscopies with documented times were included. Patients with colonic resection and incomplete colonoscopy were excluded. Main outcome measures adenoma and polyp detection rates and colonoscopy time variables were compared between morning and afternoon colonoscopies., Results: A total of 781 patients were analyzed. Colonoscopies were evenly distributed during shifts (49% morning and 51% afternoon). The overall polyp and adenoma detection rates were 46% and 29%, respectively. There were no significant differences in adenoma and polyp detection rates and colonoscopy duration between morning and afternoon colonoscopies. Multivariate analysis demonstrated that history of prior polypectomy was an independent predictor of adenoma detection rate (OR: 2.17, 95% CI 1.33-3.54, p = 0.002) and was associated with significantly increased colonoscopy times in afternoon shift., Conclusion: There were no differences in quality outcomes of adenoma and polyp detection rates between morning and afternoon colonoscopies performed by colorectal surgeons. In addition to known predictors, cecal intubation time and history of polypectomy were also independent predictors of adenoma detection rate. Patients with prior polypectomy had increased colonoscopy times in afternoon shift. Since colorectal surgeons perform higher proportion of diagnostic and surveillance colonoscopies, these patients may be better suited for colonoscopies in morning shift., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Alternative splicing (AS) plays a crucial role in regulating the progression of colorectal cancer (CRC), but its distribution remains to be explored. Here, we aim to investigate the genes edited by AS which show differential expression in patients with mismatch repair deficiency (dMMR)/microsatellite instability (MSI)., Materials and Methods: We applied long-read nanopore sequencing to determine the mRNA profiles and screen AS genes using Oxford Nanopore Technologies (ONT) method in ten paired CRC tissues. CRC tissue and plasma samples were used to validate the differential genes with AS using real-time fluorescent quantitative PCR, immunohistochemistry, and enzyme-linked immunosorbent assay., Results: ONT sequencing identified 404 genes were downregulated, and 348 genes were upregulated in MSI cancer tissues compared with microsatellite stability (MSS) cancer tissues. In total, 6,200 AS events were identified in 2,728 mRNA transcripts. WGCNA revealed dMMR/MSI-correlated gene modules, including INHBA and RPL22L1, which were upregulated; conversely, HMGCS2 was downregulated in MSI cancer. Overexpression of RPL22L1, INHBA, and CAPZA1 was further confirmed in CRC tissues. INHBA was found to be associated with tumor lymphatic metastasis. Importantly, the levels of INHBA in CRC plasma were significantly increased compared with those in noncancer plasma. INHBA showed a higher level in dMMR/MSI CRC than in MSS CRC, indicating that INHBA is a useful biomarker., Conclusion: Our results showed that ONT-identified genes provide a pool to explore AS-associated markers for dMMR/MSI CRC. We demonstrated INHBA as a promising signature for clinical application in predicting tumor lymphatic metastasis and screening dMMR/MSI candidates., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Hao Qu et al.)

To explore the role of intestinal microbiota on the occurrence of depression-like behavior. Twenty male adult Wistar rats were randomly divided into control and experimental groups. Depression-like behavior of the rats was validated using sucrose preference test (SPT) and forced swimming test (FST) after chronic unpredictable mild stress (CUMS) for 3 weeks. Fecal microbiota was analyzed through 16S rRNA sequence analysis. The levels of 5-HT and inflammatory factors in the colon, brain and sera were measured using enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR) and western blotting analyses. The percentage of different types of immune cells in the peripheral blood was determined through flow cytometry. CUMS caused depression-like symptoms, including anhedonia and desperate behavior. Significant differences were found in the structure and abundance of intestinal microbiota. CUMS intervention significantly increased the levels of 5-HT and Tph1 in the colon and decreased the level of Scl6a4. The concentrations of 5-HT and Tph2 in the prefrontal and hippocampal tissues were lower, while IDO1 was higher. Certain cytokines, such as IL-6, IL-1 and TNF-ɑ, were significantly elevated in peripheral blood, while the percentage of CD3 + CD4 + double-positive cells and CD4 + /CD8 + ratio were downregulated in the CUMS group. Pearson correlation analysis showed that intestinal microbiota was significantly associated with not only the metabolism of 5-HT in intestinal and brain tissues, but also with the proportion of immune cells and certain cytokines. Stress can lead to disturbances in the intestinal microbial structure, which may contribute to depression by interfering with 5-HT metabolism and immune inflammatory responses., (© 2022 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

The tumor microenvironment (TME) plays a crucial role in tumor progression. One of its key stromal components, cancer-associated fibroblasts (CAFs), may crosstalk with cancer cells by secreting certain cytokines or chemokines. However, which important mediator(s) are released by CAFs, and the underlying molecular mechanism, remain largely unknown. In the present study, we isolated patient-derived CAFs and normal fibroblasts (NFs). Using microarray analysis, we detected chemokine ligand 11 (CCL11) overexpression in CAFs compared to NFs. CCL11 administration promoted the migration and invasion of head and neck cancer (HNC) cells with enhanced cancer stem cell-like properties and induction of epithelial-to-mesenchymal transition. Furthermore, neutralization of CCL11 activity reversed the aggressive phenotype of CAF-induced cancer cells. Confocal microscopy showed colocalization of CCL11 and CC chemokine receptor 3 (CCR3) on HNC cells. Moreover, immunohistochemical analysis of clinical samples from 104 patients with HNC showed that expression of CCL11 and CCR3 were significantly correlated with poor overall survival ( p = 0.003 and 0.044, respectively). Collectively, CCL11 expressed on CAFs promotes HNC invasiveness, and neutralization of CCL11 reverses this effect. We propose that the CCL11/CCR3 signaling circuit is a potential target for optimizing therapeutic strategies against HNC.

Background: Complex interactions among endogenous and exogenous factors influence the incidence of colorectal cancer (CRC). Germline mutations in mismatch repair (MMR) genes causing Lynch syndrome (LS) are major endogenous factors. The exogenous factor, alcohol consumption, is potentially associated with CRC incidence among patients with LS. However, insufficient data are available to determine whether alcohol consumption influences the time of the first onset of CRC associated with sex, MMR gene mutations, and anatomical tumor site., Methods: Among 316 patients with LS identified in a Japanese LS cohort, we included 288 with data on age, sex, proband status, alcohol status, smoking status, tumor location, and MMR gene mutations. Multivariable analysis assessed the association of alcohol consumption with earlier onset of the first CRC., Results: Ever drinkers were associated with higher risk of the first onset of CRC than never drinkers (HR 1.54, 95%CI 1.14-2.07, P = 0.004). The association of the first onset of CRC with alcohol consumption was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations (vs those with pathogenic MSH6, PMS2 and EPCAM mutations), and tumors in the proximal colon cancer (vs distal colon and rectal cancer)., Conclusions: Alcohol consumption was associated with earlier onset of the first CRC in Japanese LS cohort. The association was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations, and tumors located in the proximal colon. Our findings illuminate the mechanism of LS-associated carcinogenesis and serve as a recommendation for discontinuing or ceasing alcohol consumption., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Objective: This study aimed to investigate the duration of progesterone (P) therapy on clinical pregnancy rates as measured by the window of implantation (WOI) in the first cycle of frozen embryo transplantation., Methods: The study compared the pregnancy rates between 345 cleavage stage transfers and 348 blastocyte transfers of frozen embryos with modified natural cycles in patients from July 1, 2020, to November 30, 2020. Four different P durations were analyzed in the cleavage stage embryo transfer group, i.e., two, three, four, and five days. Five different P durations were analyzed in the blastocyst transfer group, i.e., three, four, five, six, and seven days., Results: The baseline demographics and clinical characteristics of the cleavage stage embryos and blastocyst transfer groups were not comparable. The clinical pregnancy rates following the cleavage stage embryo transfer after two, three, four, and five-day P administration were 45.71%, 44.60%, 38.40%, and 30.43%, respectively (the difference among the subgroups was not significant). Following the blastocyst transfer, the clinical pregnancy rates after three, four, five, six, and seven-day P administration were 50.65%, 63.51%, 60.00%, 54.55%, and 61.54%, respectively (the difference among the subgroups was not significant). In contrast, these two transfer groups showed significantly different clinical pregnancy rates following four and five-day P exposure (P < 0.05)., Conclusion: For cleavage-stage embryo transfer, the most effective WOI was found between days two and five of P administration. The effective WOI for blastocyst transfer was observed between days three and seven of P administrations., (Copyright © 2022. Published by Elsevier B.V.)

Background: There is still a lack of nomograms that can accurately predict liver metastasis and poor prognosis after neoadjuvant therapy for locally advanced rectal cancer (LARC). Effective nomograms may help clinicians better identify LARC patients with potential high-risk risks, so as to carry out more targeted monitoring, treatment and follow-up., Methods: The nomograms were based on the FOWARC trial (NCT01211210), which included 302 LARC patients who underwent neoadjuvant treatment before surgery at the Sixth Affiliated Hospital of Sun Yat-sen University from 2011 to 2014. The predictive accuracy and discriminative ability of the nomograms were determined by the concordance index (C-index) and calibration curve. The results were validated using bootstrap resampling and a prospective study on 100 patients in 2017., Results: The 3-year liver disease-free survival (LDFS) rate after neoadjuvant treatment for LARC was 91.65% (training cohort 92.22%, validation cohort 90.01%). Factors associated with LDFS were hepatitis B virus (HBV) infection, anemia, lymph node number, postoperative T stage and tumor nodule, which were all included in the nomogram for LDFS. The C-indies of the nomogram for LDFS were 0.828 and 0.845 in the training and validation cohorts. The 3-year overall survival (OS) rate was 94.14% (training cohort 94.13%, validation cohort 94.05%). Factors in the nomogram for OS were mesorectal fascia involvement (MRF), postoperative N stage, pathological differentiation, tumor nodule and neural invasion. The C-indies of the nomogram for predicting OS were 0.73 and 0.774 in the training and validation cohorts. The calibration curve for the survival probability showed good agreement between the nomogram predictions and the actual observations., Conclusions: The nomograms established in this study can effectively predict LDFS and has good clinical application potential for OS in LARC patients treated with neoadjuvant therapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-2790/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: Colorectal cancer is the second cause of death by cancer around the world. Sporadic colorectal cancer is the most frequent (75%), and it is produced by the interaction of environmental, epigenetic, and genetic factors. The accumulation of single-nucleotide variants in genes associated with cell proliferation, DNA repair, and/or apoptosis could confer a risk to cancer. The aim of this study was to analyze the gene-gene interactions among CCND2 (rs3217901), CDKN1A (rs1059234 and rs1801270), and POLD3 (rs3824999) variants in Mexican patients with colorectal cancer., Methods: We collected peripheral blood samples from 185 patients with sporadic colorectal cancer before treatment and from 185 unrelated blood donors as the reference group; all participants signed an informed consent form. DNA extraction was performed by Miller and Cetyltrimethylammonium bromide (CTAB)/ Dodecyltrimethylammonium bromide (DTAB) methods. Polymerase chain reaction- restriction fragment length polymorphism followed by polyacrylamide gel electrophoresis stained with AgNO3 methods were used to identify the variants rs3217901, rs1059234, rs1801270, and rs3824999. Odds ratio and single-nucleotide variant interaction were determined by single-locus analysis and Multifactorial Dimensionality Reduction software, respectively., Results: No association was found for CCND2 and CDKN1A variants; yet, a significant association for the GG genotype, G allele, and recessive and additive models for the POLD3 variant was observed (P < .05). The single-nucleotide variant-single-nucleotide variant interaction revealed the combination rs1059234, rs3217901, and rs3824999 as the best model and the comparison showed an increased risk (P < .05)., Conclusion: Single-locus and gene-gene interaction analyses disclosed that both the rs3824999 (POLD3) variant and the combination of rs3217901 (CCND2), rs1059234 (CDKN1A), and rs3824999 (POLD3) genotypes increase the risk for colorectal cancer in Mexican population.

Introduction: In Japanese patients with familial adenomatous polyposis (FAP), colectomy tends to be postponed or avoided., Aim: This study aimed to clarify the current clinical practice from a Japanese multicenter cohort study database., Methods: We analyzed the records of 250 patients with non-dense FAP who did not require colorectal cancer removal. The clinical outcomes were compared between patients who received colectomy (n = 142) (Group A) and those who did not receive colectomy (n = 108) (Group B)., Results: The colectomy rate based on the age at the final follow-up examination was 46%, 60%, 54%, 65%, at ≤29, 30-39, 40-49, and ≥ 50 years, respectively ( P  = .11). The development of colorectal cancer did not differ between Groups A and B (25% vs 22% P  = .67); however, colorectal cancer was diagnosed at the Tis stage in 88% of the patients with colorectal cancer in Group B, and 34% of the patients with colorectal cancer in Group A ( P  < .01). Regarding survival, all patients in Group B were alive at the final follow-up examination. In contrast, six patients in Group A died, including three patients with desmoid tumors and one with colon cancer., Conclusion: Over one-third of patients with non-dense FAP (polyps ≤ 1000) in Japan did not receive colectomy at >30 years of age, and patients who managed without colectomy showed acceptable survival with the early diagnosis of colorectal cancer, and a very low incidence of desmoid tumor development, indicating that this approach represents a potential option for the management of selected non-dense FAP patients., (© 2022 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterology.)

Background: There are no randomized control trials comparing the efficacy of trifluridine/tipiracil and regorafenib in patients with metastatic colorectal cancer (mCRC). Herein, we conducted an observational study to compare the oncologic outcomes of trifluridine/tipiracil-containing regimen (TAS-102) and regorafenib-containing regimen (REG) in patients with mCRC., Material and Method: Patients who were diagnosed to have mCRC in 2015 to 2021 and treated with TAS-102-containing regimen or REG-containing regimen were recruited. Monotherapy or combination therapy were all allowed in this study. Oncologic outcomes were presented with progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and disease control rate (DCR)., Results: A total of 125 patients were enrolled into our study, accounting for 50 patients with TAS-102 and 75 patients with REG. Of these patients, 64% were treated with TAS-102 or REG monotherapy, while the remaining were treated with TAS-102 combination or REG combination. In general, the median PFS and OS were 3.7 versus 2.0 months ( P = 0.006) and 9.2 versus 6.8 months ( P = 0.048) in TAS-102 and REG, respectively. The ORR and DCR were 44% versus 20% ( P < 0.001) and 72% versus 43% ( P < 0.001) in TAS-102 and REG, respectively. As for treatment strategies, the survival were significantly longer in combination than in monotherapy, no matter in TAS-102 or REG group. Multivariate analysis showed TAS-102 and combination therapy were independent predictor associated with better survival., Conclusions: Our results suggested that TAS-102 had better oncologic outcomes than REG in patients with mCRC, especially in combination. Further prospective trials are warranted to confirm our results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hsieh, Rau, Lin, Liu, Chiu, Chen, Song and Chen.)

Objectives: This retrospective study was conducted to clarify the morphological characteristics of colorectal cancer (CRC) in Japanese familial adenomatous polyposis (FAP) patients., Methods: This study was carried out by the study group for FAP of the Japanese Society for Cancer of the Colon and Rectum. FAP patients who underwent surgical resection between 2000 and 2012 were included in the study., Results: Of the 303 patients enrolled, 119 patients without CRC were excluded. Of 523 lesions, 49 lesions with missing morphological information were excluded; hence, only 474 CRC lesions in 178 patients (328 superficial lesions in 122 patients and 146 non-superficial lesions in 92 patients) were included in the study. Depressed lesions accounted for 3.0% of superficial lesions and ulcerated lesions accounted for 84.9% of non-superficial lesions. The depressed superficial lesions were observed only in patients with sparse and attenuated FAP ( P = 0.003). The age of the patients at surgery differed between the two groups, with patients with depressed superficial lesions being significantly older than those with non-depressed superficial lesions ( P = 0.009). Moreover, the age of the patients at FAP diagnosis differed between the two groups, with patients with ulcerated non-superficial lesions being significantly older than those with protruded non-superficial lesions ( P = 0.006)., Conclusions: In patients with FAP, depressed superficial CRC lesions rarely developed but were detected in our study group, and ulcerated non-superficial CRC lesions were also present with similar ratios. Clinicians should pay attention to depressed superficial lesions during endoscopic surveillance of FAP patients., Competing Interests: Conflicts of Interest There are no conflicts of interest., (Copyright © 2022 by The Japan Society of Coloproctology.)

Purpose: Previous studies on the effect of hepatitis B virus (HBV) infection on colorectal liver metastasis (CRLM) are contradictory. This study revealed different, more specific impacts of HBV on CRLM., Patients and Methods: A total of 3132 colorectal cancer patients treated from 2013 to 2015 were analyzed retrospectively and followed up for five years. The patients were divided into three groups: group A (chronic HBV infection, CHB); group B, (occult HBV infection, OHB) and group C (no HBV infection, NHB). The risk factors for CRLM, 5-year overall survival (OS), and liver disease-free survival (LDFS) were analyzed., Results: A total of 905 patients (28.9%) had CRLM, with poor survival compared to those without CRLM (P < 0.01). The incidence of CRLM was 33.41% (138/413) in group A, 21.63% (138/638) in group B and 30.23% (629/2081) in group C (P < 0.05). Synchronous colorectal cancer liver metastasis (SYN-CRLM) was found in 425 patients (13.57%). CHB increased the risk of SYN-CRLM (P < 0.01), with a worse prognosis (P < 0.05). Metachronous colorectal cancer liver metastasis (MET-CRLM) was found in 480 patients (15.33%). OHB decreased the risk of MET-CRLM after surgery (P = 0.02), with a better 5-year LDFS (P = 0.01). Even without surgery, patients with OHB showed a lower incidence rate of MET-CRLM (P < 0.01)., Conclusion: The incidence of CRLM in this study was approximately 28.9%. Surgery and different HBV infection statuses affected the occurrence of CRLM. Chronic HBV infection increased the risk of SYN-CRLM with poor prognosis. Occult HBV infection reduced the risk of MET-CRLM with better LDFS after surgery., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Zhou et al.)

Background: In the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination has been effective in preventing COVID-19 infections and related mortality. The SARS-CoV-2 vaccination was also recommended by the international society for patients with inflammatory bowel disease (IBD). However, IBD patients were not recruited in prospective randomized clinical vaccine studies. To evaluate the efficacy and safety of SARS-CoV-2 vaccination in IBD patients, we conducted this systemic review and meta-analysis., Methods: We systematically searched PubMed, Medline, and the Cochrane Library for studies published between January 1, 2019, and September 9, 2021. Studies written in English reported the efficacy, seroconversion (anti-SARS-CoV-2 anti-spike (S) antibody titer beyond the threshold) rate, and adverse events after the SARS-CoV-2 vaccination in IBD patients. We extracted the author, date, study design, country, types of SARS-CoV-2 vaccination, number of IBD patients receiving SARS-CoV-2 vaccinations, and study outcomes. Published data from the enrolled studies were pooled to determine effect estimates. The study protocol was registered in PROSPERO (CRD42021264993)., Results: We analyzed findings from 27 454 IBD patients who received SARS-CoV-2 vaccinations in 11 studies that met the inclusion criteria. The post-SARS-CoV-2 vaccination COVID-19 infection rate was comparable between the IBD patients and non-IBD patients (odds ratio [OR], 1.28 [95% CI, 0.96-1.71]) and higher in nonvaccinated IBD patients compared with vaccinated IBD patients (OR, 8.63 [95% CI, 5.44-13.37]). The adverse event rate, severe adverse events, and mortality after the SARS-CoV-2 vaccination were 69%, 3%, and 0%, respectively., Conclusion: The SARS-CoV-2 vaccine is effective and tolerated in preventing COVID-19 infections in IBD patients. Over 98% of patients had seroconversion after receiving all doses of the SARS-CoV-2 vaccination, and the influence of biologics on vaccination was limited. The SARS-CoV-2 vaccination is recommended for IBD patients., Competing Interests: Conflicts of interest: Dr. Ming-Chih Hou, an editorial board member at the Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Purpose: Postoperative ileus (POI) is the most common complication of elective colon resection. Coffee or caffeine has been reported to be useful in improving gastrointestinal function after abdominal surgery. This study aimed to investigate the effect of coffee/caffeine on POI in patients undergoing elective colorectal surgery., Methods: We searched Cochrane library, Embase, PubMed, and ClinicalTrials.gov (until July 2021) to identify randomized controlled trials (RCTs) evaluating the effect of coffee or caffeine on bowel movements and POI in patients undergoing elective colorectal surgery. The mean difference (MD) for continuous outcomes and risk ratio (RR) for dichotomous outcomes were calculated and are presented with 95% confidence intervals (CIs). A random effects model was used in all meta-analyses., Results: A total of four RCTs including 312 subjects met the inclusion criteria and were included in the meta-analysis. Postoperative coffee or caffeine consumption decreased the time to first bowel movement (MD, - 10.36 h; 95% CI, - 14.61 to - 6.11), shortened the length of hospital stay (MD, - 0.95 days; 95% CI, - 1.57 to - 0.34), and was associated with a decreased risk of the use of any laxatives after the procedure (RR, 0.64; 95% CI, 0.44 to 0.92). The time to first flatus, time to tolerance of solid food, risk of any postoperative complication, postoperative reinsertion of a nasogastric (NG) tube, and anastomotic leakage showed no statistical differences between groups., Conclusion: Postoperative coffee or caffeine consumption improved bowel movement and decreased the duration of hospital stay in patients undergoing elective colorectal surgery. This method is safe and can prevent or treat POI., (© 2022. The Author(s).)

Background: With the growth of the aging population, the need for colonoscopies in nonagenarians is rising. However, few data on colonoscopies in extremely elderly individuals are available. To better acknowledge the role of colonoscopies in this specific group of patients, we conducted this study to evaluate the safety and clinical impact of colonoscopy in nonagenarian patients., Methods: We performed a retrospective cohort study comparing nonagenarians who received colonoscopy in a tertiary medical center in Taiwan in 2016 with 76- to 80-year-old patients (relatively elderly patients) who were 1:1 propensity score matched by sex as the control subjects. The postcolonoscopy 30-day adverse events, mortality, and long-term survival were recorded., Results: A total of 137 nonagenarians and 137 relatively elderly patients were included. The nonagenarians receiving colonoscopy were more likely to be hospitalized (40.1% vs 19.7%, p < 0.001), and the adjusted colonoscopy completion rates were comparable in both groups (92.0% vs 97.1%, p = 0.063). The overall adverse event rate and postcolonoscopy 30-day mortality rates were low in both groups (2.9% vs 1.5%, p = 0.409 and 2.2% vs 1.5%, p = 0.652, respectively). A total of 18.2% of the nonagenarians were diagnosed with advanced neoplasia. Among the nonagenarians diagnosed with colorectal cancer, the patients receiving surgery had a significantly lower risk of death than the patients receiving conservative management (hazards ratio 0.1044, 0.01275-0.8529, p = 0.0352)., Conclusion: Colonoscopy in patients older than 90 years is generally safe. Colonoscopy findings that led to surgery in nonagenarians diagnosed with colorectal cancer were associated with survival benefits., Competing Interests: Conflicts of interest: Dr. Fa-Yauh Lee and Dr. Ming-Chih Hou, Editorial board members at Journal of the Chinese Medical Association, have no roles in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Patients with peritoneal metastasis (PM) of colorectal cancer (CRC) have poorer overall survival outcomes than those without PM. Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and mediate CRC progression and PM. It is imperative to identify and develop novel therapeutic targets for PM-CRC driven by CAFs. Using lipidomics, we reveal that the abundance of phosphatidylcholine (PC) with unsaturated acyl chains was increased in clinical PM-CRC specimens. Additionally, we found that CAFs were present at a higher relative abundance in primary PM-CRC tumors and that membrane fluidity in CRC cells was increased after incubation with CAF-conditioned medium (CM) through three independent methods: lipidomics, fluorescence recovery after photobleaching (FRAP), and generalized polarization. Then, we found that increased membrane fluidity can enhance glucose uptake and metabolism, as supported by real-time bioenergetics analysis and U- 13 C glucose labeling. Interestingly, stearoyl-CoA desaturase 1 (SCD), the rate-limiting enzyme in the biosynthesis of unsaturated fatty acids (uS-FAs), was expressed at low levels in PM and associated with poor prognosis in CRC patients. Importantly, by untargeted metabolomics analysis and fatty acid ([U- 13 C]-stearic acid) tracing analyses, we found that CRC cells take up lipids and lipid-like metabolites secreted from CAFs, which may compensate for low SCD expression. Both in vitro and in vivo experiments demonstrated that sodium palmitate (C16:0) treatment could decrease the CAF-induced change in cell membrane fluidity, limit glucose metabolism, suppress cell invasiveness, and impair tumor growth and intraperitoneal dissemination. An increased C16:0 concentration was shown to induce apoptosis linked to lipotoxicity. Furthermore, C16:0 effectively enhanced the antitumor activity of 5-fluorouracil (5-FU) in vitro and was well tolerated in vivo . Taken together, these findings suggest that adding the saturated fatty acid (S-FA) C16:0 to neoadjuvant chemotherapy may open new opportunities for treating PM-CRC in the future., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: Computer-aided diagnosis (CAD)-based artificial intelligence (AI) has been shown to be highly accurate for detecting and characterizing colon polyps. However, the application of AI to identify normal colon landmarks and differentiate multiple colon diseases has not yet been established. We aimed to develop a convolutional neural network (CNN)-based algorithm (GUTAID) to recognize different colon lesions and anatomical landmarks., Methods: Colonoscopic images were obtained to train and validate the AI classifiers. An independent dataset was collected for verification. The architecture of GUTAID contains two major sub-models: the Normal, Polyp, Diverticulum, Cecum and CAncer (NPDCCA) and Narrow-Band Imaging for Adenomatous/Hyperplastic polyps (NBI-AH) models. The development of GUTAID was based on the 16-layer Visual Geometry Group (VGG16) architecture and implemented on Google Cloud Platform., Results: In total, 7838 colonoscopy images were used for developing and validating the AI model. An additional 1273 images were independently applied to verify the GUTAID. The accuracy for GUTAID in detecting various colon lesions/landmarks is 93.3% for polyps, 93.9% for diverticula, 91.7% for cecum, 97.5% for cancer, and 83.5% for adenomatous/hyperplastic polyps., Conclusions: A CNN-based algorithm (GUTAID) to identify colonic abnormalities and landmarks was successfully established with high accuracy. This GUTAID system can further characterize polyps for optical diagnosis. We demonstrated that AI classification methodology is feasible to identify multiple and different colon diseases., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: In 2019, the Enhanced Recovery After Surgery (ERAS) protocol for colorectal cancer surgery was adopted by a minority of hospitals in Piemonte (4.3 million inhabitants, north-west Italy). The present analysis aims to compare the level of application of the ERAS protocol between hospitals already adopting it (ERAS, N = 3) with the rest of the regional hospitals (non-ERAS, N = 28) and to identify possible obstacles to its application., Methods: All patients surgically treated for a newly diagnosed colorectal cancer during September-November 2019, representing the baseline period of a randomized controlled trial with a cluster stepped-wedge design, were included. Indicators of compliance to the ERAS items were calculated overall and for groups of items (preoperative, intraoperative and postoperative) and analyzed with a multilevel linear model adjusting for patients' characteristics, considering centers as random effects., Results: Overall, the average level of compliance to the ERAS protocol was 56% among non-ERAS centers (N = 364 patients) and 80% among ERAS ones (N = 79), with a difference of 24% (95% CI: -41.4; -7.3, p = 0.0053). For both groups of centers, the lowest level of compliance was recorded for postoperative items (42% and 66%). Sex, age, presence of comorbidities and American Society of Anesthesiologists (ASA) score were not associated with a different probability of compliance to the ERAS protocol., Conclusions: Several items of the ERAS protocol were poorly adopted in colorectal surgery units in the Piemonte region in the baseline period of the ERAS Colon-Rectum Piemonte study and in the ERAS group. No relevant obstacles to the ERAS protocol implementation were identified at patient level.

Lynch syndrome is a hereditary disease characterized by an increased risk of colorectal and other cancers. Germline variants in the mismatch repair (MMR) genes are responsible for this disease. Previously, we screened the MMR genes in colorectal cancer patients who fulfilled modified Amsterdam II criteria, and multiplex ligation-dependent probe amplification (MPLA) identified 11 structural variants (SVs) of MLH1 and MSH2 in 17 patients. In this study, we have tested the efficacy of long read-sequencing coupled with target enrichment for the determination of SVs and their breakpoints. DNA was captured by array probes designed to hybridize with target regions including four MMR genes and then sequenced using MinION, a nanopore sequencing platform. Approximately, 1000-fold coverage was obtained in the target regions compared with other regions. Application of this system to four test cases among the 17 patients correctly mapped the breakpoints. In addition, we newly found a deletion across an 84 kb region of MSH2 in a case without the pathogenic single nucleotide variants. These data suggest that long read-sequencing combined with hybridization-based enrichment is an efficient method to identify both SVs and their breakpoints. This strategy might replace MLPA for the screening of SVs in hereditary diseases., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Objectives: This study aimed to explore the risk factors associated with cancer cell exfoliation in Stage II and III colorectal cancer (CRC)., Methods: This multicenter, prospective, observational study targeted 1,698 patients with cStage II and III CRC who underwent R0 resection between 2013 and 2017. Clinicopathological variables were analyzed for correlations with positive peritoneal lavage cytology (PLC)., Results: The positive PLC rate was 2.7% (46/1,694 cases) at laparotomy and 1.6% (25/1,590 cases) after tumor resection. Logistic regression analyses identified that undifferentiated histologies diagnosed by preoperative biopsy specimen, cT4, and pN+ were independent factors that affected the positive PLC at laparotomy. The positive PLC rate at laparotomy was 4.5% (33/736 cases) among the patients with undifferentiated histology and/or cT4. Logistic regression analyses revealed that the presence of ascites and undifferentiated histology by biopsy independently affected positive PLC after tumor resection., Conclusions: The undifferentiated histology and/or T4 indicated by preoperative diagnosis were identified as factors affecting PLC at laparotomy. Furthermore, ascites and preoperative histological type were identified as factors affecting positive PLC after tumor resection. As factors affecting positive PLC, these preoperative findings were found to be equivalent to pathological findings., Competing Interests: Conflicts of Interest There are no conflicts of interest., (Copyright © 2021 by The Japan Society of Coloproctology.)

Objective: To observe the clinical effect of high suspension and low incision (HSLI) surgery on mixed haemorrhoids, compared with Milligan-Morgan haemorrhoidectomy., Methods: A multi-centre, randomized, single-blind, non-inferiority clinical trial was performed. Participants with mixed haemorrhoids from Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing Rectum Hospital, Air Force Medical Center of People's Liberation Army of China, and Puyang Hospital of Traditional Chinese Medicine were enrolled from September 2016 to March 2018. By using a blocked randomization scheme, participants were assigned to two groups. The experimental group was treated with HSLI, while the control group was treated with Milligan-Morgan haemorrhoidectomy. The primary outcome was the clinical effect evaluated at 12 weeks after operation. The secondary outcomes included the number of haemorrhoids treated during the operation, pain scores, use of analgesics, postoperative oedema, wound healing, incidence of anal stenosis, anorectal manometry after operation, as well as surgical duration, length of stay and total hospitalization expenses. A safety evaluation was also conducted., Results: In total, 246 eligible participants were enrolled, with 123 cases in each group. There was no significant difference in the clinical effect between the two groups (100.00% vs. 99.19%, P>0.05). Compared with the control group, the number of external haemorrhoids treated during the operation and the pain scores after operation were significantly reduced in the experimental group (P<0.05 or P<0.01); the patient number with wound healing at 2 weeks after operation and the functional length of anal canal at 12 weeks after operation were significantly increased in the experimental group (P<0.05). There was no significant difference in the incidence of anal stenosis, the numbers of patients using analgesics and patients with postoperative oedema between the two groups after operation (P>0.05). The surgical duration and length of stay in the experimental group were significantly longer than those in the control group, and the total hospitalization expense was significantly higher than that in the control group (all P<0.05). No adverse events were reported in either group during the whole trial or follow-up period., Conclusion: HSLI had the advantages of preserving the skin of anal canal completely, alleviating postsurgical pain and promoting rapid recovery after operation. (Registration No. ChiCTR1900022883)., (© 2021. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To describe patient characteristics associated with preoperative anxiety and subsequently assess the relationship between preoperative anxiety and postoperative anxiety, pain, sleep quality, nausea and vomiting., Methods: The study collected data from patients undergoing elective operation from 12 hospitals in China. The State-Trait Anxiety Inventory (STAI) and the Athens Insomnia Scale (AIS) were used to assess anxiety and sleep quality before surgery. Evaluations of anxiety, pain, sleep quality, nausea and vomiting were quantified using the Visual Analogue Scale on postoperative days 1 and 2., Results: Data from 997 patients were analyzed. Preoperatively, 258 (25.9%) patients had high anxiety (STAI-State>44). Multivariate analyses showed a significant relationship between high anxiety and female gender (OR: 1.66, 95% CI: 1.08-2.57, p = 0.02), highly invasive surgery (OR: 2.29, 95% CI: 1.29-4.06, p = 0.005), higher trait anxiety (OR: 1.24, 95% CI: 1.20-1.28, p < 0.001) and insomnia (AIS ≥ 6, OR: 1.79, 95% CI: 1.17-2.76, p = 0.008). Preoperative anxiety demonstrated a negative correlation with postoperative anxiety following highly invasive surgery; this became a positive relationship following less invasive surgery. Preoperative anxiety was also positively related to postoperative pain and poor sleep quality. The correlation between preoperative anxiety and postoperative nausea and vomiting was not statistically significant., Conclusion: Female gender, highly invasive surgery, higher trait anxiety and insomnia are independent risk factors for high preoperative anxiety. Surgical invasiveness influences association between pre- and postoperative anxiety. Higher preoperative anxiety is related to poorer sleep quality and more severe pain postoperatively., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Despite recent advances, treatment for head and neck squamous cell carcinoma (HNSCC) has limited efficacy in preventing tumor progression. We confirmed previously that carcinoma-associated fibroblasts (CAF)-induced interleukin-33 (IL-33) contributed to cancer progression. However, the molecular mechanisms underlying the complex communication network of the tumor microenvironment merited further evaluation. To simulate the IL-33-induced autocrine signaling, stable clones of IL-33-overexpressing HNSCC cells were established. Besides well-established IL-33/ST2 and SDF1/CXCR4 (stromal-derived factor 1/C-X-C motif chemokine receptor 4) signaling, the CAF-induced IL-33 upregulated CXCR4 via cancer cell induction of IL-33 self-production. The IL-33-enhanced-CXCR4 regulatory circuit involves SDF1/CXCR4 signaling activation and modulates tumor behavior. An in vivo study confirmed the functional role of IL-33/CXCR4 in tumor initiation and metastasis. The CXCR4 and/or IL-33 blockade reduced HNSCC cell aggressiveness, with attenuated invasions and metastases. Immunohistochemistry confirmed that IL-33 and CXCR4 expression correlated significantly with disease-free survival and IL-33-CXCR4 co-expression predicted a poor outcome. Besides paracrine signaling, the CAF-induced IL-33 reciprocally enhanced the autocrine cancer-cell self-production of IL-33 and the corresponding CXCR4 upregulation, leading to the activation of SDF1/CXCR4 signaling subsequent to cancer progression. Thus, targeting the IL-33-enhanced-CXCR4 regulatory circuit attenuates tumor aggressiveness and provides a potential therapeutic option for improving the prognosis in HNSCC patients.

Objective: The primary aim was to create a patient-centered definition of core symptoms that should be included in future studies of pouch function., Background: Functional outcomes after ileoanal pouch creation have been studied; however, there is great variability in how relevant outcomes are defined and reported. More importantly, the perspective of patients has not been represented in deciding which outcomes should be the focus of research., Methods: Expert stakeholders were chosen to correlate with the clinical scenario of the multidisciplinary team that cares for pouch patients: patients, colorectal surgeons, gastroenterologists/other clinicians. Three rounds of surveys were employed to select high-priority items. Survey voting was followed by a series of online patient consultation meetings used to clarify voting trends. A final online consensus meeting with representation from all 3 expert panels was held to finalize a consensus statement., Results: One hundred ninety-five patients, 62 colorectal surgeons, and 48 gastroenterologists/nurse specialists completed all 3 Delphi rounds. Fifty-three patients participated in online focus groups. One hundred sixty-one stakeholders participated in the final consensus meeting. On conclusion of the consensus meeting, 7 bowel symptoms and 7 consequences of undergoing ileoanal pouch surgery were included in the final consensus statement., Conclusions: This study is the first to identify key functional outcomes after pouch surgery with direct input from a large panel of ileoanal pouch patients. The inclusion of patients in all stages of the consensus process allowed for a true patient-centered approach in defining the core domains that should be focused on in future studies of pouch function., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Functional outcomes after ileoanal pouch creation have been studied; however, there is great variability in how relevant outcomes are defined and reported. More importantly, the perspective of patients has not been represented in deciding which outcomes should be the focus of research., Objective: The primary aim was to create a patient-centered definition of core symptoms that should be included in future studies of pouch function., Design: This was a Delphi consensus study., Setting: Three rounds of surveys were used to select high-priority items. Survey voting was followed by a series of online patient consultation meetings used to clarify voting trends. A final online consensus meeting with representation from all 3 expert panels was held to finalize a consensus statement., Patients: Expert stakeholders were chosen to correlate with the clinical scenario of the multidisciplinary team that cares for pouch patients, including patients, colorectal surgeons, and gastroenterologists or other clinicians., Main Outcome Measures: A consensus statement was the main outcome., Results: patients, 62 colorectal surgeons, and 48 gastroenterologists or nurse specialists completed all 3 Delphi rounds. Fifty-three patients participated in online focus groups. One hundred sixty-one stakeholders participated in the final consensus meeting. On conclusion of the consensus meeting, 7 bowel symptoms and 7 consequences of undergoing ileoanal pouch surgery were included in the final consensus statement., Limitations: The study was limited by online recruitment bias., Conclusions: This study is the first to identify key functional outcomes after pouch surgery with direct input from a large panel of ileoanal pouch patients. The inclusion of patients in all stages of the consensus process allowed for a true patient-centered approach in defining the core domains that should be focused on in future studies of pouch function. See Video Abstract at http://links.lww.com/DCR/B571., Los Pacientes Sometidos a Ciruga De Reservorio Ileoanal Experimentan Una Constelacin De Sntomas Y Consecuencias Que Representan Un Sndrome Unico: Un Informe de los Resultados Reportados por los Pacientes Posterior a la Cirugía de Reservorio (PROPS) Estudio de Consenso DelphiANTECEDENTES:Los resultados funcionales después de la creación del reservorio ileoanal han sido estudiados; sin embargo, existe una gran variabilidad en la forma en que se definen y reportan los resultados relevantes. Más importante aún, la perspectiva de los pacientes no se ha representado a la hora de decidir qué resultados deberían ser el foco de investigación.OBJETIVO:El objetivo principal era crear en el paciente una definición centrada de los síntomas principales que debería incluirse en los estudios futuros de la función del reservorio.DISEÑO:Estudio de consenso Delphi.ENTORNO CLINICO:Se emplearon tres rondas de encuestas para seleccionar elementos de alta prioridad. La votación de la encuesta fue seguida por una serie de reuniones de consulta de pacientes en línea que se utilizan para aclarar las tendencias de votación. Se realizo una reunión de consenso final en línea con representación de los tres paneles de expertos para finalizar una declaración de consenso.PACIENTES:Se eligieron partes interesadas expertas para correlacionar con el escenario clínico del equipo multidisciplinario que atiende a los pacientes con reservorio: pacientes, cirujanos colorrectales, gastroenterólogos / otros médicos.PRINCIPALES MEDIDAS DE VALORACION:Declaración de consenso.RESULTADOS:Ciento noventa y cinco pacientes, 62 cirujanos colorrectales y 48 gastroenterólogos / enfermeras especialistas completaron las tres rondas Delphi. 53 pacientes participaron en grupos focales en línea. 161 interesados participaron en la reunión de consenso final. Al concluir la reunión de consenso, siete síntomas intestinales y siete consecuencias de someterse a una cirugía de reservorio ileoanal se incluyeron en la declaración de consenso final.LIMITACIONES:Sesgo de reclutamiento en línea.CONCLUSIONES:Este estudio es el primero en identificar resultados funcionales claves después de la cirugía de reservorio con información directa de un gran panel de pacientes con reservorio ileoanal. La inclusión de pacientes en todas las etapas del proceso de consenso permitió un verdadero enfoque centrado en el paciente para definir los dominios principales en los que debería centrarse los estudios futuros de la función del reservorio. Consulte Video Resumen en http://links.lww.com/DCR/B571., (Copyright © The ASCRS 2021.)

Ferroptosis is a recently recognized type of regulated cell death characterized by iron- and lipid peroxidation-mediated nonapoptotic cell death. However, whether ferroptosis is involved in severe acute pancreatitis- (SAP-) induced intestinal barrier injury is unknown. The aim of this study was to investigate whether ferroptosis is involved in SAP-induced intestinal barrier injury, particularly intestinal epithelial cell (IEC) death, and determine whether the inhibition of ferroptosis would ameliorate intestinal barrier injury and prevent bacterial translocation (BT). Sodium taurocholate (5%) was retrogradely perfused into the biliopancreatic duct to establish a rat model of SAP. The rats were divided into three groups: sham operation (SO), SAP-induced intestinal barrier injury (SAP), and ferroptosis inhibitor liproxstatin-1 (SAP + Lip). Serum indexes were measured in the rats. In addition, the biochemical and morphological changes associated with ferroptosis were observed, including iron accumulation in intestinal tissue, lipid peroxidation levels, and mitochondrial shrinkage. Hematoxylin staining and eosin staining were used to assess histological tissue changes. Western blot, RT-PCR, and immunofluorescent staining were performed to analyze the expression of ferroptosis-related proteins and genes as well as tight junction. BT was detected by 16S rDNA sequencing analysis. The results indicated that ferroptosis was significantly induced in the IECs from rats with SAP and ferroptosis was mediated by lipid peroxidation. The specific lipid peroxidation of IECs clearly upregulated ferroptosis and exacerbated intestinal barrier injury. Furthermore, treatment with liproxstatin-1 lowered the levels of serum damage markers, decreased lipid peroxidation, and alleviated intestinal and acute remote organ injury in SAP rats. In addition, inhibition of ferroptosis reduced BT. Our findings are the first to demonstrate that ferroptosis contributes to SAP-induced intestinal barrier injury via lipid peroxidation-mediated IEC death. These results suggest that ferroptosis is a potential therapeutic target for SAP-induced intestinal barrier injury., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Deliang Ma et al.)

Colorectal cancer (CRC) is one of the most well-known malignancies with high prevalence and poor 5-year survival. Previous studies have demonstrated that a high-fat diet (HFD) is capable of increasing the odds of developing CRC. Acrolein, an IARC group 2A carcinogen, can be formed from carbohydrates, vegetable oils, animal fats, and amino acids through the Maillard reaction during the preparation of foods. Consequently, humans are at risk of acrolein exposure through the consumption of foods rich in fat. However, whether acrolein contributes to HFD-induced CRC has not been determined. In this study, we found that acrolein induced oncogenic transformation, including faster cell cycling, proliferation, soft agar formation, sphere formation and cell migration, in NIH/3T3 cells. Using xenograft tumorigenicity assays, the acrolein-transformed NIH/3T3 clone formed tumors. In addition, cDNA microarray and bioinformatics studies by Ingenuity Pathway Analysis pointed to the fact that RAS/MAPK pathway was activated in acrolein-transformed clones that contributed to colon tumorigenesis. Furthermore, acrolein-induced DNA damages (Acr-dG adducts) were higher in CRC tumor tissues than in normal epithelial cells in CRC patients. Notably, CRC patients with higher levels of Acr-dG adducts appeared to have better prognosis. The results of this study demonstrate for the first time that acrolein is important in oncogenic transformation through activation of the RAS/MAPK signaling pathway, contributing to colon tumorigenesis.

Most cancer-related deaths result from the progressive growth of metastases. Patients with peritoneal metastatic (PM) colorectal cancer have reduced overall survival. Currently, it is still unclear why colorectal cancer (CRC) cells home to and proliferate inside the peritoneal cavity, and there is no effective consolidation therapy for improved survival. Using a proteomic approach, we found that key enzymes of fatty acid oxidation (FAO) were decreased in patients with PM colorectal cancer. Furthermore, we confirmed that carnitine palmitoyltransferase IA (CPT1A), a rate-limiting enzyme of FAO, was expressed at significantly low levels in patients with PM colorectal cancer, as determined by RT-qPCR, IHC, and GEO dataset analysis. However, lipidomics revealed no difference in FFA levels between PM and non-PM primary tumors. Here, we showed that cancer-associated fibroblasts (CAFs) promote the proliferation, migration, and invasion of colon cancer cells via upregulating CPT1A to actively oxidize FAs and conduct minimal glycolysis. In addition, coculture-induced glycolysis increased in cancer cells while fatty acid catabolism decreased with lower adiponectin levels. Importantly, inhibition of glycolysis significantly reduced the survival of CRC cells after incubation with conditioned medium from CAFs CPT1A -OE in vitro and impaired the survival and growth of organoids derived from CRC-PM. Finally, we found that directly blocking FAO in CAFs CPT1A -OE with etomoxir inhibits migration and invasion in vitro and decreases tumor growth and intraperitoneal dissemination in vivo, revealing a role for CAF CPT1A in promoting tumor growth and invasion. In conclusion, our results suggest the possibility of testing FAO inhibition as a novel approach and clinical strategy against CAF-induced colorectal cancer with peritoneal dissemination/metastases., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined., Materials and Methods: This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model., Results: The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1-3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate., Conclusion: AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC., Implications for Practice: The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1-3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer., (© 2021 AlphaMed Press.)

Colorectal cancer (CRC) is a leading cause of cancer-related deaths. Because of the lack of reliable prognostic and predictive biomarkers for CRC, most patients are often diagnosed at a late stage. The tryptophan-kynurenine pathway plays a crucial role in promoting cancer progression. Kynurenine is considered an oncometabolite in colon cancer, and its downstream metabolites are also associated with CRC. Kynurenine 3-monooxygenase (KMO), a pivotal enzyme that catalyzes kynurenine metabolism, is essential for several cellular processes. In the current study, we explored the role of KMO in CRC. Immunohistochemical results showed that KMO was upregulated in CRC tissues relative to paired healthy tissue and polyps. Moreover, CRC patients with higher KMO expression were associated with higher metastasis and poorer survival rates. Knockdown of KMO decreased the expression of cancer stem cell markers, as well as the sphere-forming, migration, and invasion abilities of CRC cells. Additionally, blockade of the enzymatic activity of KMO using an inhibitor suppressed sphere formation and cell motility in CRC cells. These findings suggest the clinical relevance of KMO in CRC tumorigenesis and aggressiveness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Huang, Chen, Chu, Lee, Lee, Lee, Chang, Yang, Jiang, Chen, Chao and Teng.)

Background: Transverse colon cancers show behavioral differences in terms of the involvement of extramesocolic lymph nodes since they are closely related to all three embryological planes. These tumors have also been observed in the gastroepiploic-omental (GEOM) region, outside their usual regional areas. We will evaluate this new metastatic route in our own cases., Methods: Thirty-four patients (16 female, 18 male) that presented to our clinic with hepatic flexure, transverse colon, and splenic flexure cancer between October 2011 and May 2017 were included in the study. Type of surgery, histopathology, and factors causing metastasis, morbidity, and mortality were evaluated., Results: Cancer was located in the transverse colon in 20 patients (58.8%), hepatic flexure in 10 (29.4%), and splenic flexure in four (11.7%). Lymph node positivity in the GEOM region was present in four patients: in the infrapyloric region and pancreatic head, close to the hepatic flexure in three patients; and the midline of GEOM, close to the inferior body of the pancreas in one patient. Perineural invasion ( p  < .05) and N stage ( p  < .05) were associated with GEOM region metastasis. Tumor localization and age significantly increased pleural effusion., Conclusions: In transverse colon and both flexural tumors, we recommend planning the surgery according to the localization of the tumor and including the GEOM, infrapyloric and infrapancreatic areas. It is possible to discuss whether to perform extended excision for all or only selected patients. The best approach seems to be to evaluate the co-factors to manage these patients.

Diverticulitis manifestations may cover a spectrum of mild local inflammation to diffuse feculent peritonitis. Up to 35% of patients presenting with diverticulitis will have purulent (Hinchey grade III) or feculent (Hinchey grade IV) contamination of the abdomen, with a high-associated morbidity and mortality. Surgical management may involve segmental resection with or without restoration of bowel continuity. However, emergency resection for diverticulitis can be associated with high mortality rates, as well as low stoma reversal rates at 1 year. Therefore, laparoscopic peritoneal lavage has been proposed for use in selected patients with purulent peritonitis. The topic of laparoscopic peritoneal lavage for the treatment of perforated diverticulitis in the literature has been controversial. Our review of the recent data show that laparoscopic lavage may be safe and feasible in select patients with similar rates of mortality and major morbidity. There is, however, a concern regarding an associated higher rate of postoperative abscess and early reintervention risk., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Background: The effects of primary tumor location on colorectal liver metastasis (CRLM) and post-hepatic-metastasectomy overall survival (OS) are controversial. This study evaluated the difference in post-hepatic-metastasectomy OS among right-sided colon, left-sided colon, and rectal cancer groups., Methods: In total, 381 patients who underwent curative-intent CRLM resection were enrolled. Patients were grouped based on the primary tumor location (right-sided, left-sided, and rectum). The Kaplan-Meier analysis and log-rank test were performed for survival analysis. The univariate and multivariate analyses of clinical and pathological factors were performed using the Cox proportional hazards model., Results: Significant OS difference was noted among the three groups (log-rank, p = 0.014). The multivariate analysis revealed a 32% lower death risk in left-sided colon cancer compared with right-sided colon cancer (hazard ratio [HR] 0.68, p = 0.042), whereas no OS difference was noted between the rectal cancer and right-sided colon cancer groups. The left- versus right-sided OS advantage was noted only in the KRAS wild-type subgroup (HR 0.46, p = 0.002), and a rectal versus right-sided OS disadvantage was noted in the KRAS mutant subgroup (HR 1.78, p = 0.03)., Conclusions: The CRLM post-hepatic-metastasectomy OS was superior in left-sided colon cancer than in right-sided colon cancer and was similar in rectal and right-sided colon cancer. The OS difference in different primary tumor locations is dependent on KRAS mutation status, with a decreased left- versus right-sided death risk noted only in KRAS wild-type colon cancer and an increased rectal versus right-sided death risk noted only in KRAS mutant colon cancer.

Background: Acute kidney injury (AKI) is a frequent complication of severe acute pancreatitis (SAP). Ferroptosis is involved in a range of diseases. However, the role of ferroptosis in SAP-induced AKI has yet to be elucidated., Aims: We aimed to investigate whether ferroptosis is induced in the kidney after SAP and whether inhibition of ferroptosis ameliorates AKI in a rat model of SAP., Methods: Sodium taurocholate (5%) was retrogradely perfused into the biliopancreatic duct to establish a model of SAP with AKI in rats. The levels of serum amylase, lipase, tumor necrosis factor (TNF)-α, interleukin (IL)-6, creatinine (Cr) and blood urea nitrogen (BUN) in rats were measured. We also determined the biochemical and morphological changes associated with ferroptosis in renal tissue, including iron accumulation, lipid peroxidation assays, and mitochondrial shrinkage. H&E staining was used to assess pancreatic and renal histological changes. Western blot analysis, RT-PCR, and immunofluorescence staining were performed to analyze the expression of ferroptosis-related proteins and genes., Results: SAP-induced AKI was followed by iron accumulation, increased lipid peroxidation, and upregulation of ferroptosis-related proteins and genes. Twenty-four hours after SAP, TEM confirmed the presence of typical shrunken mitochondria. Furthermore, treatment with liproxstatin-1 lowered the levels of serum amylase, TNF-α, IL-6, Cr and BUN, decreased kidney lipid peroxidation and alleviated pancreatic and renal histopathology injury in SAP rats., Conclusion: Our findings are the first to demonstrate the involvement of ferroptosis in SAP-associated renal damage and present ferroptosis as a therapeutic target for effective treatment of SAP-induced AKI.

Background: Matrix metalloproteinases (MMPs) are involved in tumor invasion and progression in colorectal cancer (CRC). Variants rs11568818, rs11225395, rs2276109 and rs2252070 have been associated with this neoplasm., Objective: To evaluate MMPs 7, 8, 12, and 13 haplotypes and their association with CRC., Material and Methods: One-hundred and four patients and 112 healthy individuals were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). For the association analysis, odds ratio and confidence interval values were calculated. Haplotype and linkage disequilibrium (LD) analysis was performed with Arlequin software, v3.5., Results: LD was present between rs2276109 and rs2252070. Haplotypes rs11568818(A)-rs11225395(T)-rs2276109(A)-rs2252070(A) and rs11568818(A)-rs11225395(C)-rs2276109(A)-rs2252070(G) were associated with CRC risk, and haplotypes rs11568818(G)-rs11225395(C)-rs2276109(A)-rs2252070(A) and rs11568818(A)-rs11225395(T)-rs2276109(A)-rs2252070(G), with protection., Conclusion: Variants rs2276109 and rs2252070 showed genetic linkage. Two haplotypes were associated with the development of CRC (ATAA and ACAG) and two were associated with protection (GCAA and ATAG). This study represents the first report on variants rs11225395 and rs2276109 frequency in a Mexican population., (Copyright: © 2021 Permanyer.)

Patients with ulcerative colitis (UC) have a high prevalence of mental disorders, such as depression and anxiety. Gut microbiota imbalance and disturbed metabolism have been suggested to play an important role in either UC or mental disorders. However, little is known about their detailed multi-omics characteristics in patients with UC and depression/anxiety. In this prospective observational study, 240 Chinese patients were enrolled, including 129 patients with active UC (69 in Phase 1 and 60 in Phase 2; divided into depression/non-depression or anxiety/non-anxiety groups), 49 patients with depression and anxiety (non-UC), and 62 healthy people. The gut microbiota of all subjects was analyzed using 16S rRNA sequencing. The serum metabolome and proteome of patients with UC in Phase 2 were analyzed using liquid chromatography/mass spectrometry. Associations between multi-omics were evaluated by correlation analysis. The prophylactic effect of candidate metabolites on the depressive-like behavior of mice with colitis was investigated. In total, 58% of patients with active UC had depression, while 50% had anxiety. Compared to patients with UC without depression/anxiety, patients with UC and depression/anxiety had lower fecal microbial community richness and diversity, with more Lactobacillales, Sellimonas, Streptococcus , and Enterococcus but less Prevotella&#95;9 and Lachnospira . Most metabolites (e.g., glycochenodeoxycholate) were increased in the serum, while few metabolites, including 2'-deoxy-D-ribose and L-pipecolic acid, were decreased, accompanied by a general reduction in immunoglobulin proteins. These related bacteria, metabolites, and proteins were highly connected. A prophylactic administration of 2'-deoxy-D-ribose and L-pipecolic acid significantly reduced the depressive-like behaviors in mice with colitis and alleviated the inflammatory cytokine levels in their colon, blood and brain. This study has identified a comprehensive multi-omics network related to depression and anxiety in active UC. It is composed of a certain set of gut microbiota, metabolites, and proteins, which are potential targets for clinical intervention for patients with UC and depression/anxiety.

Introduction: Several genes determine the development of colorectal cancer (CRC), such as MLH1, which encodes a protein that participates in DNA repair. MLH1 hypermethylation has been associated with gene silencing., Objective: To analyze the methylation of five regions of MLH1 CpG island in colorectal tumors from Mexican patients., Materials and Methods: One hundred and one tumor tissue samples were obtained from Mexican patients with CRC who provided informed consent. DNA was subjected to bisulfite conversion. Methylation of all five regions of the CpG island was evaluated using methylation-specific PCR., Results: The frequency of methylation in Mexican patients with CRC was 25%. Regions A and B methylation was the main observed pattern (60%). Female patients showed a higher frequency of methylation (71%; OR 3.085; CI: 1.85-8.03; p = 0.02), and out of total methylated samples, 80% corresponded to individuals older than 45 years (p < 0.05)., Conclusion: We calculated a methylation frequency for the MLH1 gene of 25% in Mexican patients with CRC, with this being the first report for this population. Female patients and patients older than 45 years showed a higher frequency of methylation., (Copyright: © 2021 Permanyer.)

Background: There is still a need for progress in the treatment of transsphincteric anal fistulae and the use of herbal medicines seems promising., Aim: To evaluate the efficacy of Stryphnodendron adstringens associated with fistulotomy and primary sphincteroplasty in the treatment of transsphincteric fistulae in rats., Methods: Thirty Wistar rats were used, which were submitted to transsphincteric fistulas with steel wire 0; after 30 days a treatment was performed according to the group. Group A (n=10) was submitted to fistulotomy; group B (n=10), fistulotomy followed by primary sphincteroplasty with "U" stitch with polyglactin 911 4-0; group C(n=10) , similar to group B, but with the interposition between the muscular stumps of hemostatic sponge soaked in Stryphnodendron adstringens extract. Euthanasia was performed after 14 days, resecting a segment of the anal canal for histological analysis, which aimed to evaluate the closure of the fistula, the area of separation of the muscle cables, the inflammatory process and the degree of fibrosis., Results: No animal had a remaining fistulous tract. About the spacing between the muscle cables, an average of 106.3 µm2 was observed in group A, 82.8 µm2 in group B and 51.8 µm2 in group C (p<0.05). There was no difference between the groups regarding the inflammatory process and, in relation to fibrosis, in group A there was a mean of 0.6, in group B 0.7 and in group C 0.2 (p<0.05)., Conclusions: Stryphnodendron adstringens extract was able to allow less spacing between muscle cables in rats submitted to fistulotomy followed by primary sphincteroplasty, in addition to providing less local fibrosis.

Purpose: To analyze whether HBV infection can reduce the risk of colorectal liver metastasis (CRLM) in stage 2 colorectal cancer (CRC)., Methods: The data of postoperative pathological stage 2 CRC patients treated at the Sixth Affiliated Hospital of Sun Yat-sen University between 2013 and 2015 were analyzed. The patients were divided into an infection group (group A) and a non-infection group (group B). The correlations between HBV infection and CRLM, 5-year liver disease-free survival, and 5-year overall survival were compared., Results: A total of 884 patients who met the inclusion criteria were included in the study. Group A included 297 patients (33.60%), and 5 patients (1.68%) had CRLM. Group B included 587 patients (66.40%), and 31 patients (5.28%) had CRLM. The results of correlation analysis and logistic regression analysis showed that HBV infection (P = 0.013, HR = 0.29, 95% CI 0.11-0.77) was a protective factor for CRLM, while CEA > 5 ng/ml (P = 0.002, HR = 3.12, 95% CI 1.51-6.47) and hypertension (P = 0.010, HR = 3.50, 95% CI 1.34-9.09) were risk factors for CRLM. Group A had a significantly better 5-year liver disease-free survival than group B (P = 0.011, HR = 0.31, 95% CI 0.16-0.63), but there was no significant difference in the 5-year overall survival (P = 0.433)., Conclusion: HBV infection may reduce the risk of metachronous liver metastasis in stage 2 colorectal cancer.