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Objective: To investigate the regulatory mechanisms of radiation-induced rectal fibrosis (RIRF) and assess the therapeutic potential of S3I-201., Methods: Sprague-Dawley rats were divided into control and radiation groups, with the latter exposed to 20 Gray pelvic X-rays. After 10 weeks, rectal tissues were analyzed using tandem mass tag (TMT) proteomics and phosphoproteomics. Pathway enrichment was performed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, with secondary annotation using Cluego. Representative proteins and their phosphorylated counterparts were validated through immunoblotting in another cohort. STAT3 levels in rectal tissues from irradiated and non-irradiated colorectal cancer patients were examined, and the effects of S3I-201 on human rectal fibroblasts were evaluated., Results: The radiation group showed significant inflammatory responses and collagen deposition in the rat rectal walls. Enrichment analysis revealed that radiation-induced proteins and phosphoproteins were primarily involved in extracellular matrix-receptor interaction and the MAPK signaling pathway. Immunoblotting indicated increased expression of p-CAMKII, p-MRACKS, p-Cfl1, p-Myl9, and p-STAT3 in the radiation group compared to the control, while p-AKT1 expression decreased. Elevated phosphorylation of STAT3 was observed in submucosal fibroblasts of the post-radiation human rectum. S3I-201 specifically inhibited STAT3 phosphorylation and suppressed activation of human rectal fibroblasts, also inhibiting the pro-fibrotic effects of the classical TGF-β/Smad/CTGF pathway., Conclusion: By integrating phosphoproteomics and proteomics, this study elucidated the protein regulatory network of RIRF and identified the potential therapeutic targets, including phosphoproteins such as STAT3 in managing RIRF., Significance: In our research, we employed TMT labeling alongside LC-MS/MS techniques to comprehensively explore the proteomic and phosphoproteomic landscapes in rat models of radiation-induced intestinal fibrosis (RIRF). Our analysis revealed the function and pathways of proteins and phosphorylated proteins triggered by radiation, as well as those with protective roles. We mapped a network of interactions among these proteins and validated key protein expression levels using quantitative methods. Furthermore, we investigated STAT3 as a potential therapeutic target, assessing the efficacy of the inhibitor S3I-201 in laboratory settings, and highlighting its potential for RIRF treatment. Overall, our findings provide groundbreaking insights into the mechanisms underlying RIRF, paving the way for the development of future antifibrotic therapies., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Despite the therapeutic benefits of insulin-pramlintide dual-hormone therapy in diabetes, its application potential has been limited due to a lack of efficient delivery routes. Here, we developed a temperature-responsive dual-hormone foam nanoengine (HormFoam) and combined it with a customized spraying device to further construct an in situ foam-generating system for improving the rectal bioavailability of dual-hormone therapy. To support rapid clinical translation, a continuous microfluidic preparation for HormFoam was proposed, including the power unit of perfluorocarbon nanodroplets and the pharmaceutical components Pluronic F127-functionalized liposomal insulin and pramlintide. We found that HormFoam could consistently generate foams to drive drugs forward after rectal administration, which enhanced intestinal distribution and mucosa absorption, leading to systemic codelivery of insulin-pramlintide. HormFoam reproduced the physiology of endocrine pancreas for glycemic control and induced body weight loss while reversing metabolic disorders in diabetic mice with good biosafety. Therefore, HormFoam represents a state-of-the-art dual-hormone regimen with the potential to address unmet needs in diabetes management.

Ozone therapy acts in the body inducing controlled oxidative stress, thereby improving the antioxidant, immune and circulatory responses. However, very little is known about how this therapy affects oxidative stress indicators in dogs. We aimed to assess the clinical, hematological, biochemical and oxidative stress parameters of healthy dogs subjected to ozone therapy and oxygen therapy by rectal insufflation. Ten healthy dogs were allocated into three experimental groups in a cross-over design: control, without intervention; ozone, which received 100 µg of O 3 /kg through rectal insufflation; and oxygen, which received an ozone-equivalent volume of medicinal O 2 through rectal insufflation. Dogs received four applications weekly and were followed up until the seventh week. Ozone therapy significantly increased the weight, mean corpuscular volume and mean platelet volume and decreased total cholesterol of treated dogs. Regarding oxidative stress, ozone therapy reduced total antioxidant capacity by ferric reduction (TAC-FRAP) in D7 compared with baseline and the control, significantly increased total antioxidant capacity by cupric reduction (TAC-CUPRAC) in D42 and D49 compared with the control group, caused an increase in uric acid compared with the oxygen group and decreased lipid peroxidation on D21 compared with the control group. In conclusion, ozone therapy through rectal insufflation causes transient oxidative stress followed by an antioxidant response and discreetly interferes with a few clinical, hematological and biochemical variables in healthy dogs, although variables still remained within the reference ranges for the species, thus proving the safety of the therapy. Furthermore, oxygen therapy causes oxidative stress without inducing a subsequent antioxidant response., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Substantial clinical and preclinical evidence indicates that transient receptor potential vanilloid 1 (TRPV1) receptors are expressed on terminals of colorectal chemoreceptors and mechanoreceptors and are involved in various rectal hypersensitivity disorders with common features of colorectal overactivity. These stimulatory properties of TRPV1 receptors on colorectal function suggested that brief stimulation of TRPV1 might provide a means of pharmacologically activating the colorectum to induce defecation in patients with an "unresponsive" colorectum. The current studies explored the basic features of TRPV1 receptor-induced contractions of the colorectum in anesthetized rats with and without acute spinal cord injury (aSCI). Cumulative concentration-response curves to intrarectal (IR) capsaicin (CAP) solutions (0.003%-3.0%) were performed in anesthetized aSCI and spinal intact rats. CAP produced an "inverted U," cumulative concentration-response curve with a threshold for inducing colorectal contractions at 0.01% and a peak response at 0.1% and slight decreases in responses up to 3%. Decreases in responses with concentrations >0.1% are due to a rapid desensitization (i.e., ≤30 minutes) of TRPV1 receptors to each successive dose. Desensitization appeared fully recovered within 24 hours in spinal intact rats. Colorectal contractions were completely blocked by atropine, indicating a reflexogenic activation of parasympathetic neurons, and responses were completely unaffected by a neurokinin 2 receptor antagonist, indicating that release of neurokinin A from afferent terminals and subsequent direct contractions of the smooth muscle was not involved. IR administration of three other TRPV1 receptor agonists produced similar results as CAP. SIGNIFICANCE STATEMENT: Individuals with spinal cord injury often lose control of defecation. Time-consuming bowel programs using digital stimulation of the rectum are used to empty the bowel. This study shows that intrarectal administration of the transient receptor potential vanilloid 1 (TRPV1) receptor agonist, capsaicin, can induce rapid-onset, short-duration colorectal contractions capable of inducing defecation in spinal cord injured and intact rats. Therefore, TRPV1 agonists show promise as potential therapeutics to induce defecation in individuals with neurogenic bowel., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Emodin, a natural anthraquinone derivative isolated from the roots of Rheum officinale Baill, has many pharmacological effects including anti-inflammatory, antioxidant, antiviral, antibacterial and anti-cancer. However, little is known about the effect of emodin on acute radiation proctitis (ARP). The present study was conducted to determine its effects and elucidate its mechanisms involving AKT/MAPK/NF-κB/VEGF pathways in ARP mice., Methods: Total 60 C57BL/6 mice were divided randomly into control group, ARP group, AKT inhibitor MK-2206 group, and different doses of emodin groups. ARP mice were induced by 27 Gy of 6 MV X-ray pelvic local irradiation. MK-2206 was given orally for 2 weeks on alternate days. Emodin was administered daily by oral gavage for 2 weeks. Subsequently, all mice were sacrificed on day 15. The rectal tissues were obtained for further tests. The general signs score and the pathological grade were used to evaluate the severity of ARP. The expression of NF-κB, VEGF and AQP1 were determined by immunohistochemistry and western blot. The expression of p-AKT, p-ERK, p-JNK, p-p38, Bcl-2 and Bax were assessed using western blot., Results: The worse general signs and damaged tissue structure of ARP mice were profoundly ameliorated by emodin. The expression of p-AKT, p-ERK, NF-κB, VEGF and AQP1 were significantly increased, resulting in the inflammation-induced angiogenesis in ARP mice. However, the expression of p-JNK and p-p38 were decreased, leading to the reduction of apoptosis in ARP mice. Excitedly, emodin reversed these changes, not only inhibited inflammation-induced angiogenesis, but also promoted apoptosis. Notably, the effects of emodin were similar to that of AKT inhibitor MK-2206, suggesting the involvement of AKT signaling in the effect of emodin., Conclusion: These results suggest that emodin attenuates ARP in mice, and the underlying mechanism might involve inhibition of the AKT/ERK/NF-κB/VEGF pathways and the induction of apoptosis mediated by JNK and p38., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

This study aims to explore and characterize the role of pediatric sedation via rectal route. A pediatric physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) model of midazolam gel was built and validated to support dose selection for pediatric clinical trials. Before developing the rectal PBPK model, an intravenous PBPK model was developed to determine drug disposition, specifically by describing the ontogeny model of the metabolic enzyme. Pediatric rectal absorption was developed based on the rectal PBPK model of adults. The improved Weibull function with permeability, surface area, and fluid volume parameters was used to extrapolate pediatric rectal absorption. A logistic regression model was used to characterize the relationship between the free concentrations of midazolam and the probability of sedation. All models successfully described the PK profiles with absolute average fold error (AAFE) < 2, especially our intravenous PBPK model that extended the predicted age to preterm. The simulation results of the PD model showed that when the free concentrations of midazolam ranged from 3.9 to 18.4 ng/mL, the probability of "Sedation" was greater than that of "Not-sedation" states. Combined with the rectal PBPK model, the recommended sedation doses were in the ranges of 0.44-2.08 mg/kg for children aged 2-3 years, 0.35-1.65 mg/kg for children aged 4-7 years, 0.24-1.27 mg/kg for children aged 8-12 years, and 0.20-1.10 mg/kg for adolescents aged 13-18 years. Overall, this model mechanistically quantified drug disposition and effect of midazolam gel in the pediatric population, accurately predicted the observed clinical data, and simulated the drug exposure for sedation that will inform dose selection for following pediatric clinical trials.

Background: Clinically, metastatic rectal cancer has been considered a subset of left-sided colon cancer. However, heterogeneity has been proposed to exist between high and middle/low rectal cancers. We aimed to examine the efficacy of anti-epidermal growth factor receptor (EGFR) treatment for middle/low rectal and left-sided colon cancers., Methods: This study enrolled 609 patients with metastatic colorectal cancer who were treated with anti-EGFR therapy. They were divided into groups based on primary tumour locations: the right-sided colon, the left-sided colon or the middle/low rectum. The efficacy of first-line and non-first-line anti-EGFR treatment was analysed. Genomic differences in colorectal cancer data from The Cancer Genome Atlas (TCGA) were investigated and visualised with OncoPrint and a clustered heatmap., Results: On first-line anti-EGFR treatment, patients with middle/low rectal tumours had significantly lower progression-free survival, overall survival, and overall response rates (6.8 months, 27.8 months and 43%, respectively) than those with left-sided colon cancer (10.1 months, 38.3 months and 66%, respectively). Similar outcomes were also identified on non-first-line anti-EGFR treatment. In TCGA analysis, rectal tumours displayed genetic heterogeneity and shared features with both left- and right-sided colon cancer., Conclusions: Anti-EGFR treatment has lower efficacy in metastatic middle/low rectal cancer than in left-sided colon cancer., (© 2021. The Author(s).)

Containment of the AIDS pandemic requires reducing HIV transmission. HIV infection is initiated by the fusion of the membrane between the virus and the cell membrane of the host. 2P23 is an effective HIV membrane fusion inhibitor that may be a good entry inhibitor microbicide candidate. This study evaluated the potential of using gel-formulated 2P23 as a topical microbicide to prevent sexual transmission of HIV in the rectum and vagina. Our data revealed that 2P23 formulated in gel is effective against HIV. There was no change in antiviral activity at 25°C for 4 months or 60°C for 1 week. In addition, we demonstrated that the 2P23 gel was stable and fully functional at pH 4.0-8.0 and under different concentrations of H 2 O 2 . Finally, the 2P23 gel exhibited no cytotoxicity or antimicrobial activity and did not induce inflammatory changes in the rectal or vaginal mucosal epithelium in New Zealand rabbits after 20 mg/day daily rectovaginal application for 14 consecutive days. Despite repeated tissue sampling and 2P23 gel treatment, the inflammatory cytokines and microbiota of the rectum and vagina remained stable. These results add to general knowledge on the in vivo evaluation of anti-HIV microbicide application concerning inflammatory cytokines and microbiota changes in the rectum and vagina. These findings suggest that the 2P23 gel is an excellent candidate for further development as a safe and effective pre-exposure prophylactic microbicide for the prevention of HIV transmission., 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 Gao, Fu, Li, Wang and He.)

Background: Chemotherapeutic drugs cause severe toxicities if administered unprotected, without proper targeting, and controlled release. In this study, we developed topotecan- (TPT-) loaded solid lipid nanoparticles (SLNs) for their chemotherapeutic effect against colorectal cancer. The TPT-SLNs were further incorporated into a thermoresponsive hydrogel system (TRHS) (TPT-SLNs-TRHS) to ensure control release and reduce toxicity of the drug. Microemulsion technique and cold method were, respectively, used to develop TPT-SLNs and TPT-SLNs-TRHS. Particle size, polydispersive index (PDI), and incorporation efficiency (IE) of the TPT-SLNs were determined. Similarly, gelation time, gel strength, and bioadhesive force studies of the TPT-SLNs-TRHS were performed. Additionally, in vitro release and pharmacokinetic and antitumour evaluations of the formulation were done., Results: TPT-SLNs have uniformly distributed particles with mean size in nanorange (174 nm) and IE of ~90%. TPT-SLNs-TRHS demonstrated suitable gelation properties upon administration into the rat's rectum. Moreover, drug release was exhibited in a control manner over an extended period of time for the incorporated TPT. Pharmacokinetic studies showed enhanced bioavailability of the TPT with improved plasma concentration and AUC. Further, it showed significantly enhanced antitumour effect in tumour-bearing mice as compared to the test formulations., Conclusion: It can be concluded that SLNs incorporated in TRHS could be a potential source of the antitumour drug delivery with better control of the drug release and no toxicity., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 R. Xing et al.)

Purpose: Neoadjuvant chemoradiotherapy has now become a standard treatment for rectal cancer. Recently, attempts have been made to predict the response rate to this treatment to decide whether or not it must be performed. However, tissue factors for predicting the response rate is not cohesively reviewed., Methods: Eighty-three patients with rectal cancer, all under neoadjuvant chemoradiotherapy and subsequent surgery, were examined for tissue factors in the biopsy sample. The tissue factors examined include tumor differentiation grade, lymphovascular invasion, perineural invasion, pathological stage, and lymphocytic infiltration. Lymphocytic infiltration was investigated by immunohistochemistry for CD8 T lymphocyte in biopsy samples., Results: In this study, tissue factors were found to play a decisive role in predicting response to neoadjuvant treatment. The most important factor was the pathological stage, which has the highest correlation with response to treatment. There is a significant relationship between CD8 lymphocyte infiltration and response to treatment (P value = 0.018). Primary perineural invasion and lymphovascular invasion also have a significant meaningful relationship with response to treatment (P value = 0.021 and P value = 0.036)., Conclusion: In this study, it was determined that the investigated factors have a significant relationship with response to treatment and could be used to predict the response to treatment, and if a low possibility of positive response exists, prevention of the complications of neoadjuvant chemoradiotherapy for the patients could occur.

Polyphenon E (Poly E) is a green tea polyphenol preparation whose most active component is epigallocatechin gallate (EGCG). We studied the cancer preventive efficacy and safety of Poly E in subjects with rectal aberrant crypt foci (ACF), which represent putative precursors of colorectal cancers. Eligible subjects had prior colorectal advanced adenomas or cancers, and had ≥5 rectal ACF at a preregistration chromoendoscopy. Subjects ( N = 39) were randomized to 6 months of oral Poly E (780 mg EGCG) daily or placebo. Baseline characteristics were similar by treatment arm (all P >0.41); 32 of 39 (82%) subjects completed 6 months of treatment. The primary endpoint was percent reduction in rectal ACF at chromoendoscopy comparing before and after treatment. Among 32 subjects (15 Poly E, 17 placebo), percent change in rectal ACF number (baseline vs. 6 months) did not differ significantly between study arms (3.7% difference of means; P = 0.28); total ACF burden was also similar (-2.3% difference of means; P = 0.83). Adenoma recurrence rates at 6 months were similar by arm ( P > 0.35). Total drug received did not differ significantly by study arm; 31 (79%) subjects received ≥70% of prescribed Poly E. Poly E was well tolerated and adverse events (AE) did not differ significantly by arm. One subject on placebo had two grade 3 AEs; one subject had grade 2 hepatic transaminase elevations attributed to treatment. In conclusion, Poly E for 6 months did not significantly reduce rectal ACF number relative to placebo. Poly E was well tolerated and without significant toxicity at the dose studied. PREVENTION RELEVANCE: We report a chemoprevention trial of polyphenon E in subjects at high risk of colorectal cancer. The results show that polyphenon E was well tolerated, but did not significantly reduce the number of rectal aberrant crypt foci, a surrogate endpoint biomarker of colorectal cancer., (©2021 American Association for Cancer Research.)

Defining tissue and plasma-specific prophylactic drug concentrations is central to pre-exposure prophylaxis product development for sexual transmission of HIV-1. Pharmacokinetic (PK) data from study RMP-02/MTN-006 comparing single dose oral tenofovir disoproxil fumarate with single and multiple dose rectal tenofovir (TFV) gel administration in HIV-1 seronegative adults was used to construct a multicompartment plasma-rectal tissue population PK model for TFV and tenofovir-diphosphate (TFVdp) in plasma and rectal tissue. PK data were collected in five matrices: TFV (plasma, rectal tissue homogenate), TFVdp (peripheral blood mononuclear cells, rectal mononuclear cells (MMCs), rectal tissue homogenate). A viral growth compartment and a delayed effect compartment for p24 antigen expression measured from an ex vivo explant assay described HIV-1 infection and replication. Using a linear PK/pharmacodynamic model, MMC TFVdp levels over 9,000 fmol/million cells in the explant assay provided apparent viral replication suppression down to 1%. Parameters were estimated using NONMEM version 7.4., (© 2021 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

We demonstrate the application of mixture density networks (MDNs) in the context of automated radiation therapy treatment planning. It is shown that an MDN can produce good predictions of dose distributions as well as reflect uncertain decision making associated with inherently conflicting clinical tradeoffs, in contrast to deterministic methods previously investigated in the literature. A two-component Gaussian MDN is trained on a set of treatment plans for postoperative prostate patients with varying extents to which rectum dose sparing was prioritized over target coverage. Examination on a test set of patients shows that the predicted modes follow their respective ground truths well, both spatially and in terms of their dose-volume histograms. A special dose mimicking method based on the MDN output is used to produce deliverable plans and thereby showcase the usability of voxel-wise predictive densities. Thus, this type of MDN may serve to support clinicians in managing clinical tradeoffs and has the potential to improve the quality of plans produced by an automated treatment planning pipeline.

Anastomotic leakage (AL) is a devastating complication after colorectal surgery, possibly due to the loss of stabilizing collagen fibers in the submucosa. Our aim was to assess the formation of collagen in the colon versus the rectum with or without transforming growth factor (TGF)-β1 exposure in a human cellular model of colorectal repair. Primary fibroblasts were isolated by an explant procedure from clinically resected tissue rings during anastomosis construction in 19 consecutive colorectal patients who underwent laparoscopy. The cells, identified as fibroblasts by morphologic characteristics and flow cytometry analysis (CD90 + ), were cultured for 8 days and in 12 patients in the presence of 1 ng/mL TGF-β1. Total collagen deposition was measured colorimetrically after Sirius red staining of fixed cell layers, and type I, III, and VI collagen biosynthesis and degradation were specifically determined by the biomarkers PINP, PRO-C3, PRO-C6, and C3M in conditioned media by competitive enzyme-linked immunosorbent assays. Total collagen deposition by fibroblasts from the colon and rectum did not significantly differ. TGF-β1 treatment increased PINP, PRO-C6, and total collagen deposition. Mechanistically, TGF-β1 treatment increased COL1A1 and ACTA2 (encoding α-smooth muscle actin), and decreased COL6A1 and MMP2 mRNA levels in colorectal fibroblasts. In conclusion, we found no effect of anatomic localization on collagen production by fibroblasts derived from the large intestine. TGF-β1 represents a potential therapeutic agent for the prevention of AL by increasing type I collagen synthesis and collagen deposition.

We evaluated the inter-physician variability in the target contouring of the radiotherapy for anal squamous cell carcinoma (ASCC). Clinical target volume (CTV) of three patients diagnosed with ASCC was delineated by seven experienced radiation oncologists from multi-institution. These patients were staged as pT1N1a, cT2N0, and cT4N1a, respectively, according to 8 th edition of the American Joint Committee on Cancer staging system. Expert agreement was quantified using an expectation maximization algorithm for Simultaneous Truth and Performance Level Estimation (STAPLE). The maximum distance from the boundaries of the STAPLE generated volume with confidence level of 80% to those of the contour of each CTV in 6 directions was compared. CTV of pelvis which includes primary tumor, perirectal tissue and internal/external iliac lymph node (LN) area (CTV-pelvis) and CTV of inguinal area (CTV-inguinal) were obtained from the seven radiation oncologists. One radiation oncologist did not contain inguinal LN area in the treatment target volume of patient 2 (cT2N0 stage). CTV-inguinal displayed moderate agreement for each patient (overall kappa 0.58, 0.54 and 0.6, respectively), whereas CTV-pelvis showed substantial agreement (overall kappa 0.66, 0.68 and 0.64, respectively). Largest variation among each contour was shown in the inferior margin of the CTV-inguinal. For CTV-pelvis, anterior and superior margin showed the biggest variation. Overall, moderate to substantial agreement was shown for CTV delineation. However, large variations in the anterior and cranial boarder of the CTV-pelvis and the caudal margin of the CTV-inguinal suggest that further studies are needed to establish a clearer target volume delineation guideline.

The central nervous system is involved in regulation of defaecation. It is generally considered that supraspinal regions control the spinal defaecation centre. However, signal transmission from supraspinal regions to the spinal defaecation centre is still unclear. In this study, we investigated the regulatory role of an anorexigenic neuropeptide, α-MSH, in the spinal defaecation centre in rats. Intrathecal administration of α-MSH to the L6-S1 spinal cord enhanced colorectal motility. The prokinetic effect of α-MSH was abolished by severing the pelvic nerves. In contrast, severing the colonic nerves or thoracic cord transection at the T4 level had no impact on the effect of α-MSH. RT-PCR analysis revealed MC1R mRNA and MC4R mRNA expression in the L6-S1 spinal cord. Intrathecally administered MC1R agonists, BMS470539 and SHU9119, mimicked the α-MSH effect, but a MC4R agonist, THIQ, had no effect. These results demonstrate that α-MSH binds to MC1R in the spinal defaecation centre and activates pelvic nerves, leading to enhancement of colorectal motility. This is, to our knowledge, the first report showing the functional role of α-MSH in the spinal cord. In conclusion, our findings suggest that α-MSH is a candidate for a neurotransmitter from supraspinal regions to the spinal defaecation centre.

Aspirin is one of the most commonly prescribed medications. Evidence shows that it can even treat and prevent intestinal tumors. However, it has also caused a great deal of controversy due to its intestinal side effects. We therefore explored whether aspirin was beneficial or harmful to the intestines. We used aspirin continuously interfered with C57BL/6 J mice for 48 weeks, examining their intestinal tissues at 13, 26 and 48 weeks to determine the drug's effect on the intestines. In addition, we used flow cytometry (FCM) used to detect T cells and expression of T-cell immunoreceptor with immunoglobulin (Ig)- and tyrosine-based inhibitory motif (ITIM) domain (TIGIT) on their surfaces to determine aspirin's immunomodulatory effects. The results showed that long-term aspirin intervention could reverse damage to the intestines, an effect related to the drug's significant inhibitory effect on TIGIT. The change in TIGIT level could regulate T-cell subsets, so that counts of Cluster of Differentiation 4 (CD4) + /chemokine (C-X3-C motif) receptor 3 (CXCR3) + T-helper 1 (T h 1) cells and CD4 + /interleukin-4 (IL-4) + T h 2 cells increased, while those of CD4 + /C-C chemokine receptor type 6 (CCR6) + T h 17 cells and CD4 + /CD25 + regulatory T cells (Tregs) decreased. In summary, we demonstrated that long-term aspirin intervention could inhibit TIGIT, regulating T cells to reverse damage to the intestines. Furthermore, aspirin is a potential therapy for diseases related to an increase in TIGIT., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Among bacterial metabolites, hydrogen sulfide (H 2 S) has received increasing attention. The epithelial cells of the large intestine are exposed to two sources of H 2 S. The main one is the luminal source that results from specific bacteria metabolic activity toward sulfur-containing substrates. The other source in colonocytes is from the intracellular production mainly through cystathionine β-synthase (CBS) activity. H 2 S is oxidized by the mitochondrial sulfide oxidation unit, resulting in ATP synthesis, and, thus, establishing this compound as the first mineral energy substrate in colonocytes. However, when the intracellular H 2 S concentration exceeds the colonocyte capacity for its oxidation, it inhibits the mitochondrial respiratory chain, thus affecting energy metabolism. Higher luminal H 2 S concentration affects the integrity of the mucus layer and displays proinflammatory effects. However, a low/minimal amount of endogenous H 2 S exerts an anti-inflammatory effect on the colon mucosa, pointing out the ambivalent effect of H 2 S depending on its intracellular concentration. Regarding colorectal carcinogenesis, forced CBS expression in late adenoma-like colonocytes increased their proliferative activity, bioenergetics capacity, and tumorigenicity; whereas, genetic ablation of CBS in mice resulted in a reduced number of mutagen-induced aberrant crypt foci. Activation of endogenous H 2 S production and low H 2 S extracellular concentration enhance cancerous colorectal cell proliferation. Higher exogenous H 2 S concentrations markedly reduce mitochondrial ATP synthesis and proliferative capacity in cancerous cells and enhance glycolysis but do not affect their ATP cell content or viability. Thus, it appears that, notably through an effect on colonocyte energy metabolism, endogenous and microbiota-derived H 2 S are involved in the host intestinal physiology and physiopathology.

Increased COX-2 and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 IU/day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically normal rectal mucosa from 62 paients with colorectal adenoma in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated IHC and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, because these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group ( P = 0.001), 46% in the calcium group ( P = 0.002), and 34% in the calcium + vitamin D group ( P = 0.03), relative to the placebo group. Among individuals with the functional vitamin D-binding protein isoform DBP2 ( GC rs4588*A), the COX-2/15-HPDG ratio decreased 70% ( P = 0.0006), 75% ( P = 0.0002), and 60% ( P = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD-biomarkers of inflammation that are strongly linked to colorectal carcinogenesis-in the normal-appearing colorectal mucosa of patients with colorectal adenoma (perhaps especially those with the DBP2 isoform). PREVENTION RELEVANCE: Supplemental calcium and vitamin D reduce indicators of cancer-promoting inflammation in normal colorectal tissue in humans, thus furthering our understanding of how they may help prevent colorectal cancer., (©2020 American Association for Cancer Research.)

Enhancing the radioresponsiveness of colorectal cancer (CRC) is essential for local control and prognosis. However, consequent damage to surrounding healthy cells can lead to treatment failure. We hypothesized that short‑chain fatty acids (SCFAs) could act as radiosensitizers for cancer cells, allowing the administration of a lower and safer dose of radiation. To test this hypothesis, the responses of three‑dimensional‑cultured organoids, derived from CRC patients, to radiotherapy, as well as the effects of combined radiotherapy with the SCFAs butyrate, propionate and acetate as candidate radiosensitizers, were evaluated via reverse transcription‑quantitative polymerase chain reaction, immunohistochemistry and organoid viability assay. Of the three SCFAs tested, only butyrate suppressed the proliferation of the organoids. Moreover, butyrate significantly enhanced radiation‑induced cell death and enhanced treatment effects compared with administration of radiation alone. The radiation‑butyrate combination reduced the proportion of Ki‑67 (proliferation marker)‑positive cells and decreased the number of S phase cells via FOXO3A. Meanwhile, 3/8 CRC organoids were found to be non‑responsive to butyrate with lower expression levels of FOXO3A compared with the responsive cases. Notably, butyrate did not increase radiation‑induced cell death and improved regeneration capacity after irradiation in normal organoids. These results suggest that butyrate could enhance the efficacy of radiotherapy while protecting the normal mucosa, thus highlighting a potential strategy for minimizing the associated toxicity of radiotherapy.

Background: Although many patients with locally advanced rectal cancer undergo restaging imaging after neoadjuvant chemoradiotherapy and before surgery, the benefit of this practice is unclear. The purpose of this study was to examine the impact of reimaging on outcomes., Materials and Methods: We performed a retrospective analysis of consecutive patients with stage 2 and 3 rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy between May 2005 and April 2018. Patient and disease characteristics, imaging, treatment, and oncologic outcomes were compared between those who underwent restaging and those who went directly to surgery. Predictors of outcomes and cost effectiveness of restaging were determined., Results: Of 224 patients, 146 underwent restaging. Six restaged patients had findings leading to a change in management. There was no difference in freedom from recurrence (P = 0.807) and overall survival (P = 0.684) based on restaging. Pretreatment carcinoembryonic antigen level >3 ng/mL (P = 0.010), clinical T stage 4 (P = 0.016), and pathologic T4 (P = 0.047) and N2 (P = 0.002) disease increased the risk of death, whereas adjuvant chemotherapy decreased the risk of death (P < 0.001) on multivariate analysis. Disease recurrence was lower with pelvic exenteration (P = 0.005) and in females (P = 0.039) and higher with pathologic N2 (P = 0.003) and N3 (P = 0.002) disease. The average cost of reimaging is $40,309 per change in management; however, $45 is saved per patient when downstream surgical costs are considered., Conclusions: Imaging restaging after neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer rarely changes treatment and does not improve survival. In a subset of patients at higher risk for worse outcome, reimaging may be beneficial., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: In patients with locally advanced rectal cancer, restaging pelvis magnetic resonance imaging (MRI) after neoadjuvant concurrent chemoradiotherapy is recommended despite its limited accuracy in predicting pathologic T (ypT) and N (ypN) stage. Neoadjuvant rectal (NAR) score is a novel short-term surrogate endpoint for disease-free survival (DFS) and overall survival (OS). We tested the agreement between restaging MRI T (yT) and N (yN) with ypT and ypN stages, respectively, and explored the prognostic significance of restaging MRI NAR (mNAR) score., Patients and Methods: Between 2014 and 2018, 43 patients with locally advanced rectal cancer completed neoadjuvant concurrent chemoradiotherapy, had a restaging MRI, and underwent surgery. Weighted kappa was used to test the agreement between yT and yN with ypT and ypN, respectively. A kappa value of less than 0.5 was deemed unacceptable. Paired t test was used to compare NAR and mNAR mean scores. Survival was estimated by Kaplan-Meier curves., Results: Restaging MRI could not predict ypT stage (slight agreement, κ = 0.111) or ypN stage (fair agreement, κ = 0.278). The mean mNAR score was higher than the mean NAR score (20 vs. 16, P = .0079). The median DFS for patients with low-intermediate NAR and high NAR was not reached vs. 30 months (P = .0063). The median OS for patients with low-intermediate NAR and high NAR was not reached vs. 40 months (P = .0056). There was a trend for longer DFS and OS in patients with low-intermediate mNAR scores (not reached in both groups, P = .058) compared to patients with high mNAR scores (not reached in both groups, P = .15)., Conclusion: Restaging MRI could not predict ypT and ypN stage. The mean mNAR score was higher than the mean NAR score. There was a trend for longer DFS and OS in patients with low-intermediate mNAR scores compared to patients with high mNAR scores., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The modern study of the traditional Chinese medicine (TCM) compound recipes is a complex issue because of the large number of components in the recipes that would produce several metabolites after entering the body. The TCM compound recipes are known to have the advantage of synergistic treatment by multiple targets due to diverse components. Therefore, a research method that can reflect the overall effect of compounds with multi-components is essential. The pharmacological studies of the classic TCM compound recipes mainly use the sero-pharmacological method. It is a semi-in vivo study method, and the drug to be tested in the in vitro experiment is the drug-containing serum from the model animals (the drug to be tested is a mixed drug system containing the prototype drugs in animal bodies that have pharmacodynamic effects and the metabolites). Herein, a safe and effective external TCM recipe was used to develop another semi-in vivo experimental method to reflect the overall effects of TCM., Aim: To observe the effects of in-vitro intestinal absorption liquid of aqueous extracts of the TCM compound recipe-Guangtongxiao foam aerosol (Guangtongxiao)-on the tension of isolated rectal rings of mouse and investigate the underlying mechanisms of antispasmodic and amelioration of muscular spasm-induced pain., Methods: Intestinal absorption liquid of the Guangtongxiao aqueous extract at the five time points (30, 45, 75, 105, and 120 min) was prepared using a non-everted gut sac method. The isolated rectal rings of mice were prepared by pre-contraction using potassium chloride (KCl) or acetylcholine chloride (ACh) to make steady contraction. The intestinal absorption liquid were added cumulatively to the sink with the constricted rectal rings. The effects of the five groups of the intestinal absorption liquid with different drug concentration were observed on the tension of the isolated rectal rings. Then the ex vivo perfusion of the mouse rectal ring was performed as same as Guangtongxiao intestinal absorption liquid experiments, and the effects of two major components of Guangtongxiao, paeoniflorin (Pae) and tetrahydropalmatine (THP), on the rectal ring pre-treated with high concentration of KCl and ACh to induce contraction were studied., Results: The relaxation rate of the five groups of the intestinal canals increased significantly with 3200 μL cumulative sample volume as compared to the blank group (P < 0.01). It suggested that the relaxation activity of the intestinal absorption liquid enhanced significantly with the prolongation of the interaction between isolated rectal rings and intestinal absorption liquid in a time-dependent manner. Also, significant differences were detected while comparing between the 120-min intestinal absorption liquid group and the blank group with respect to various cumulative sampling volumes (P < 0.01). In addition, the intestinal relaxation rate elevated gradually with the increase in sampling volume, indicating that the concentrations of active substances in the intestinal absorption liquid prepared by the non-everted gut sac model increased and the intestinal relaxation activity was enhanced with the prolongation of the absorption time in a dose-dependent manner. And Pae and THP in a concentration-dependent manner caused relaxation of the rectal ring, which is pretreated with high K + (KCl) and ACh to induce contraction. The EC 50 of Pae and THP was 8.67 × 10 -5  M (6.68 × 10 -5 -1.13 × 10 -4 ) and 1.41 × 10 -4  M (1.24 × 10 -4 -1.61 × 10 -4 ) in the contraction model induced by KCl, and was 6.15 × 10 -5  M (4.47 × 10 -5 -8.45 × 10 -5 ), and 1.31 × 10 -4  M(1.22 × 10 -4 -1.42 × 10 -4 ) in the model induced by ACh, respectively., Conclusion: The intestinal absorption liquid of Guangtongxiao exerted a remarkable relaxation activity for the rectal rings, and relaxation of the smooth muscle tension might be one of the antispasmodic mechanisms of Guangtongxiao compound recipe. Also, adopting a semi-in-vivo experimental method to study the efficacy of topical external TCM recipe medicine is optimal., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Long-term outcomes of patients with ulcerative proctitis (UP) have been poorly investigated, since these patients are excluded from participation in randomized controlled clinical trials., Objective: The aim of this study was to investigate the prognostic and therapeutic long-term outcomes of patients with UP., Methods: A retrospective study of patients with UP followed at our referral centre between 1 January 1998 and 1 January 2019 was performed. Treatment success was defined as clinical response (significant improvement in UP-related symptoms) and endoscopic response (mayo endoscopic sub-score of 0 or 1) if available at last follow-up., Results: From a total of 1561 patients with ulcerative colitis, 118 patients with UP were identified. A total of 36 (31%) patients were refractory to rectal and oral therapy with 5-ASA and corticosteroids, necessitating azathioprine as monotherapy in 19 (16%) patients and/or biological therapies in 33 (28%) patients. After a median follow-up of 71 months (interquartile range 29-149 months), treatment success was observed in 103/118 (87%) UP patients and in 25/36 (69%) patients with refractory UP. Clinical response rates were significantly higher for refractory UP patients treated with biologicals (23/33; 70%) compared to ones treated with azathioprine (2/19; 11%; p   =  0.001)., Conclusion: Good clinical outcomes were recorded in UP, with treatment success in 87% of patients. Nevertheless, 28% needed escalation to biologicals. Long-term outcome in patients on biologicals was superior to azathioprine.

Background and purpose: The discovery of chemical substances with carcinogenic properties has allowed the development of several experimental models of colorectal cancer (CRC). Classically, experimental models of CRC in mice have been evaluated through clinical or serial euthanasia. The present study aims to investigate the role of low endoscopy in the analysis of carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Methods: Thirty C57BL6 mice were divided into two groups: a control group with fifteen animals that underwent rectal instillation of saline solution on day 0 and a carcinogen group with fifteen animals that underwent a 100 mg/kg MNNG rectal instillation on day 0. In both groups, low endoscopies were performed on weeks 4 and 8. We used a validated endoscopic scoring system to evaluate the severity of colitis and colorectal tumor. Euthanasia was carried out at week 12. Results: We observed higher inflammation scores (p <0.001) and a higher number of tumors (p <0.05) in the MNNG group than the control group, both at weeks 4 and 8. A worsening of inflammation scores from the first to the second endoscopy was also noticeable in the MNNG group. There were no bowel perforations related to the procedure, and there was one death in the control group. Conclusion: Low endoscopy in experimental animals allows safe macroscopic evaluation of colorectal carcinogenesis without the need for euthanasia., Competing Interests: COMPETING INTERESTS: The authors have declared that no competing interest exists., (© The author(s).)

Background: Leukotriene receptor antagonists (LTRAs) are broadly used for the management of allergic asthma and have recently been indicated to inhibit carcinogenesis and cancer cell growth. In colorectal cancer (CRC) chemoprevention studies, the occurrence of adenoma or CRC itself is generally set as the trial endpoint. Although the occurrence rate of CRC is the most confident endpoint, it is inappropriate for chemoprevention studies because CRC incidence rate is low in the general population and needed for long-term monitoring. Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and darker in methylene blue staining than normal crypts, are regarded to be a fine surrogate biomarker of CRC. Therefore, this prospective study was designed to explore the chemopreventive effect of LTRA on colonic ACF formation and the safety of the medicine in patients scheduled for a poly resection as a pilot trial leading the CRC chemoprevention trial., Methods: This study is a nonrandomized, open-label, controlled trial in patients with colorectal ACF and polyps scheduled for a polypectomy. Participants meet the inclusion criteria will be recruited, and the number of ACF in the rectum will be counted at the baseline colonoscopic examination. Next, the participants will be assigned to the LTRA or no treatment group. Participants in the LTRA group will continue 10 mg of oral montelukast for 8 weeks, and those in the no treatment group will be observed without the administration of any additional drugs. At the end of the 8-week LTRA intervention period, a polypectomy will be conducted to evaluate the changes in the number of ACF, and cell proliferation in the normal colorectal epithelium will be analyzed., Discussion: This will be the first study to investigate the effect of LTRAs on colorectal ACF formation in humans., Trial Registration: This trial has been registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000029926 . Registered 10 November 2017.

In this study we investigated the use of cancer cell protein expression of ABCG2 to predict efficacy of systemic first-line irinotecan containing therapy in patients with metastatic colorectal cancer (mCRC). From a Danish national cohort, we identified 119 mCRC patients treated with irinotecan containing therapy in first-line setting. Among these, 108 were eligible for analyses. Immunohistochemistry (IHC) analyses were performed on the primary tumor tissue in order to classify samples as high or low presence of ABCG2 protein. Data were then associated with patient outcome (objective response (OR), progression free survival (PFS) and overall survival (OS)). ABCG2 protein expression in the basolateral membrane was high (score 3+) in 33% of the patients. Exploratory analyses revealed a significant interaction between ABCG2 score, adjuvant treatment and OR ( p = 0.041) in the 101 patients with evaluable disease. Patients with low ABCG2 (score 0-2) and no prior adjuvant therapy had a significantly higher odds ratio of 5.6 (Confidence Interval (CI) 1.68-18.7; p = 0.005) for obtaining OR. In contrast, no significant associations between ABCG2 expression and PFS or OS were found. These results suggest that measurement of the ABCG2 drug efflux pump might be used to select patients with mCRC for irinotecan treatment. However, additional studies are warranted before conclusions regarding a clinical use can be made. Moreover, patients with high ABCG2 immunoreactivity could be candidates for specific ABCG2 inhibition treatment in combination with irinotecan.

Background: Addition of oxaliplatin to capecitabine remains controversial for locally advanced rectal cancer (LARC). And cumulative oxaliplatin dose (COD) varied among clinical trials showing different therapeutic effects of this regimen. The objective of this study was to explore how COD affected tumor metastasis and patient survival., Methods: Totally 388 patients diagnosed with stage cII-III rectal cancer and treated with neoadjuvant chemoradiotherapy followed by radical surgery plus adjuvant chemotherapy were consecutively enrolled into this study and retrospectively reviewed. After grouping by total chemotherapy cycle (TCC), influences of COD on adverse effects and patients' survivals were analyzed in each group. Univariate and multivariate survival analyses were performed through Kaplan-Meier approach and COX proportional hazards model, respectively. Age, gender, anemia, differentiation, carcinoembryonic antigen, carbohydrate antigen 19-9, pretreatment clinical stage and postsurgical pathologic stage were used as covariates., Results: COD < 460 mg/m 2 emerged as an independent predictor of poorer overall, metastasis-free and disease-free survivals, in patients treated with TCC ≤ 7. The hazard ratios were 1.972, 1.763 and 1.637 (P values were 0.021, 0.028 and 0.041), respectively. But it was note-worthy that COD ≥460 mg/m 2 increased incidence of acute toxicities from 38.4 to 70.8% (P < 0.001). And in patients treated with TCC ≥ 8, COD failed to be a prognosticator., Conclusions: For LARC patients treated with insufficient TCC (≤ 7), oxaliplatin of ≥460 mg/m 2 might be needed to improve survival, though it might resulted in more acute toxicities.

Background: Linaclotide, a guanylate cyclase C agonist relieves irritable bowel syndrome with predominant constipation (IBS-C) symptoms, but how it improves pain in humans is unknown., Aims: To investigate the effects of linaclotide and placebo on the afferent and efferent gut-brain-gut signalling in IBS-C patients, in a randomised clinical trial., Methods: Patients with IBS-C (Rome III) and rectal hypersensitivity were randomised (2:1) to receive linaclotide (290 µg) or placebo for 10 weeks and undergo bi-directional gut and brain axis assessment using anorectal electrical stimulations and transcranial/transspinal-anorectal magnetic stimulations. Rectal sensations were examined by balloon distention. Assessments included abdominal pain, bowel symptoms and quality of life (QOL) scores. Primary outcomes were latencies of recto-cortical and cortico-rectal evoked potentials., Results: Thirty-nine patients participated; 26 received linaclotide and 13 received placebo. Rectal cortical evoked potentials latencies (milliseconds) were significantly prolonged with linaclotide compared to baseline (P1:Δ 19 ± 6, P < 0.005; N1:Δ 20 ± 7, P < 0.02) but not with placebo (P1:Δ 3 ± 5; N1:Δ 4.7 ± 5,P = 0.3) or between groups. The efferent cortico-anorectal and spino-anorectal latencies were unchanged. The maximum tolerable rectal volume (cc) increased significantly with linaclotide compared to baseline (P < 0.001) and placebo (Δ 29 ± 10 vs 4 ± 20, (P < 0.03). Abdominal pain decreased (P < 0.001) with linaclotide but not between groups. Complete spontaneous bowel movement frequency increased (P < 0.001), and IBS-QOL scores improved (P = 0.01) with linaclotide compared to baseline and placebo. There was no difference in overall responders between linaclotide and placebo (54% vs 23%, P = 0.13)., Conclusions: Linaclotide prolongs afferent gut-brain signalling from baseline but both afferent and efferent signalling were unaffected compared to placebo. Linaclotide significantly improves rectal hypersensitivity, IBS-C symptoms and QOL compared to placebo. These mechanisms may explain the effects of linaclotide on pain relief in IBS-C patients. ClinicalTrials.Gov: Registered at Clinical trials.gov no NCT02078323., (© 2020 John Wiley & Sons Ltd.)

Background: The role of neoadjuvant short-course radiation therapy (SCRT) in treating rectal adenocarcinoma is a topic of ongoing debate. Growing interest in total neoadjuvant therapy has spurred discussion on the optimal sequence of preoperative SCRT and chemotherapy., Patients and Methods: All patients receiving SCRT (5 Gy × 5 fractions) were identified. Details about preoperative treatments, radiation toxicities, and postoperative complications were collected. Patients were divided into 2 groups: those who underwent surgery within 14 days of completing SCRT and those with a longer delay. Outcomes compared included extent of pathologic response, margin-negative resection rate, acute radiation toxicities, and postoperative complications., Results: Fifty-seven patients with locally advanced or metastatic rectal cancer received SCRT between 2008 and 2018. Thirty-nine of 57 patients underwent definitive pelvic surgery with total mesorectal excision. There were no significant differences in tumor downstaging, radial margin status, or percent tumor viability between patients with immediate surgery versus delayed surgery. The delay group had higher rates of nodal downstaging (64.7% vs. 18.2%; P = .003). There were no differences in total or grade 3+ gastrointestinal radiation toxicity, postoperative complications, reoperation, readmission, and mortality between the 2 groups., Conclusions: Though not yet common in the United States, SCRT has compared favorably with long course chemoradiation in multiple trials. Moreover, it is associated with greater efficiency and less disruption to chemotherapy. Our data show similar response and toxicity outcomes between the immediate and delay groups, suggesting SCRT is well-tolerated regardless of treatment sequence. Recently completed prospective trials may reveal the optimal preoperative treatment sequence., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Arsenic and copper, two toxic pollutants, are powerful inducers of oxidative stress. Exposure to copper and arsenic can cause intestinal injury in cockerel. This study was carried out to investigate the effects of these two pollutants on the gastrointestinal tract of cockerels. Experimental results showed that the activity of antioxidant enzymes (catalase and glutathione peroxidase) was inhibited and the ionic balance was destroyed after exposure to copper sulfate (300 mg/kg) and/or arsenic trioxide (30 mg/kg). However, the expression of pro-inflammatory cytokines (nuclear factor kappa-B, cyclooxygenase-2, tumor necrosis factor-α, and prostaglandin E2 synthases) increased markedly. Damages to the biofilm structure and inflammatory cell infiltration were simultaneously observed during histological examination. Heat-shock proteins were also expressed in large quantities after exposure to the poisons. Collectively, exposure to arsenite and/or Cu 2+ can cause rectal damage in cockerels, inducing inflammation and an imbalance in immune system responses. Sometimes, exposure to both pollutants can produce even more toxic effects. Heat-shock proteins can protect the tissue from the exotoxins but the specific mechanisms require exploration. After oral ingestion of toxins, the rectum can still be damaged, necessitating attention to the safety of poultry breeding, human food safety, and environmental protection.

Background: This study explored the impact of chemotherapy completion on irinotecan efficacy in preoperative chemoradiotherapy in patients with locally advanced rectal cancer., Patients and Methods: Patients with locally advanced rectal cancer (T3/4 and/or LN+) receiving neoadjuvant chemoradiotherapy were enrolled. All received preoperative pelvic radiotherapy concurrently with capecitabine and irinotecan, followed by a course of XELIRI and surgery. Patients were divided into low- and high-completion groups based on their cycles of concurrent irinotecan (1-3 or 4-5). Tumor response was compared. Significant risk factors for low completion were investigated by logistic regression modeling then a predictive nomogram was built., Results: Overall, 371 patients were enrolled, with 102 patients from CinClare phase III trial (NCT02605265). Proportions of patients with low and high completion were 38.8% and 61.2%, respectively. In the general population, the complete tumor response rates (combining sustained clinical complete response and pathologic complete response) were 21.5% and 33.6% in the low- and high-completion groups, respectively (P = .02), which were 24.2% versus 43.5% in the CinClare group (P = .08). The pathologic complete response rates were 19.4% and 26.1%, respectively (P = .19). A predictive nomogram was established and 3 different risk groups (low, intermediate, and high risk) were identified, with high completion rates of 29.2%, 50.0%, and 68.9%, respectively (P < .0001)., Conclusion: Our analysis suggested higher completion of concurrent irinotecan was associated with better tumor response for patients with locally advanced rectal cancer with UGT1A1∗1∗1 or UGT1A1∗1∗28 phenotypes in the neoadjuvant setting, and at least 4 cycles was recommended., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Preoperative radiochemotherapy (RCT) is recommended in France prior to total mesorectal excision in patients with mid or low locally advanced rectal cancer (LARC) (cT3/T4 and/or N+) because it has been shown to improve local control. Preoperative RCT has also disadvantages including the absence of proven impact on metastatic recurrence and the risk of late side effects on bowel and genitourinary function. In patients with primarily resectable LARC, preoperative systemic chemotherapy without pelvic irradiation could be used as an alternative to RCT., Methods: This study is a multicenter, open-label randomized, 2-arm phase III non-inferiority trial. Patients with mid or low resectable LARC (cT3N0 or cT1-T3N+ with circumferential resection margin [CRM] > 2 mm on pretreatment MRI) will be randomized to either modified FOLFIRINOX for 3 months or RCT (Cap50 intensified-modulated radiotherapy). All patients have restaging MRI after preoperative treatment. The primary endpoint is 3-year progression-free survival (PFS) from the time to randomization including progression during preoperative treatment. Secondary endpoints are treatment related toxicity, treatment compliance, R0 resection rate, sphincter saving surgery rate, postoperative morbidity and mortality rates, loco-regional recurrence free survival, overall survival, bowel and sexual functions at diagnosis, quality of life, radiologic and pathologic response after preoperative treatment. The number of patients required is 574., Discussion: The choice of modified FOLFIRINOX for preoperative chemotherapy is supported by recent and consistent data on safety and efficacy of this regimen on rectal cancer. The use of preoperative chemotherapy instead of RCT could be associated with pronounced advantages in terms of functional results and quality of life in cancer survivors. However and first of all, the non-inferiority of preoperative chemotherapy compared to RCT on oncologic outcome has to be validated. If this study demonstrates the non-inferiority of chemotherapy compared to RCT, this can lead to a crucial change in clinical practice in a large subset of rectal cancer patients., Trial Registration: ClinicalTrials.gov NCT03875781 (March 15, 2019). Version 1.1.

Background: Neoadjuvant chemotherapy is currently recommended as preoperative treatment for locally advanced rectal cancer (LARC); however, evaluation of treatment response to neoadjuvant chemotherapy is still challenging., Aim: To create a multi-modal radiomics model to assess therapeutic response after neoadjuvant chemotherapy for LARC., Methods: This retrospective study consecutively included 118 patients with LARC who underwent both computed tomography (CT) and magnetic resonance imaging (MRI) before neoadjuvant chemotherapy between October 2016 and June 2019. Histopathological findings were used as the reference standard for pathological response. Patients were randomly divided into a training set ( n = 70) and a validation set ( n = 48). The performance of different models based on CT and MRI, including apparent diffusion coefficient (ADC), dynamic contrast enhanced T1 images (DCE-T1), high resolution T2-weighted imaging (HR-T2WI), and imaging features, was assessed by using the receiver operating characteristic curve analysis. This was demonstrated as area under the curve (AUC) and accuracy (ACC). Calibration plots with Hosmer-Lemeshow tests were used to investigate the agreement and performance characteristics of the nomogram., Results: Eighty out of 118 patients (68%) achieved a pathological response. For an individual radiomics model, HR-T2WI performed better (AUC = 0.859, ACC = 0.896) than CT (AUC = 0.766, ACC = 0.792), DCE-T1 (AUC = 0.812, ACC = 0.854), and ADC (AUC = 0.828, ACC = 0.833) in the validation set. The imaging performance for extramural venous invasion detection was relatively low in both the training (AUC = 0.73, ACC = 0.714) and validation (AUC = 0.578, ACC = 0.583) sets. The multi-modal radiomics model reached an AUC of 0.925 and ACC of 0.886 in the training set, and an AUC of 0.93 and ACC of 0.875 in the validation set. For the clinical radiomics nomogram, good agreement was found between the nomogram prediction and actual observation., Conclusion: A multi-modal nomogram using traditional imaging features and radiomics of preoperative CT and MRI adds accuracy to the prediction of treatment outcome, and thus contributes to the personalized selection of neoadjuvant chemotherapy for LARC., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts-of-interest related to this article., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Epigallocatechin gallate (EGCG) is a polyhydroxy phenolic compound extracted from tea and its antitumor effect has received widespread attention. We explored the inhibitory effect of EGCG on dimethylhydrazine (DMH)-induced colorectal cancer (CRC) using a rat model, predicted the interaction between EGCG and CRC target genes using a database, and explained the EGCG associated target pathways and mechanisms in CRC., Aim: To understand the inhibitory mechanisms of EGCG on CRC cell proliferation and identify its pharmacological targets by network pharmacology analysis., Methods: DMH (40 mg/kg, s.c., twice weekly for eight weeks) was used to induce CRC in rats. After model establishment, the rats were administered with EGCG (50, 100, or 200 mg/kg, p.o., once daily for eight weeks) and killed 12 and 20 wk after the start of the experiment. Formation of aberrant crypt foci and tumor was studied by histological analysis. Using network pharmacology analysis, candidate and collective targets of EGCG and CRC were identified, and Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were used to predict the pathways altered by EGCG., Results: At week 12, high-dose EGCG treatment significantly reduced the tumor formation rate, total number of tumors, cancerous and non-cancerous tumors, tumor volume, ascites formation, and aberrant crypt foci count. At week 20, all three doses of EGCG were effective. Seventy-eight collective targets of EGCG and CRC were identified, of which 28 genes were dysregulated in CRC. Kyoto Encyclopedia of Genes and Genomes and GO analyses showed that the dysregulated genes were enriched in hsa05210 (CRC), hsa04115 (p53 signaling pathway), and hsa04151 (PI3K-Akt signaling pathway), GO:0043124 (negative regulation of I-kappaB kinase/NF-kappaB signaling pathway), GO:0043409 (negative regulation of mitogen-activated protein kinase cascade), and GO:2001244 (positive regulation of intrinsic apoptotic signaling pathway) respectively., Conclusion: EGCG inhibits the formation of DMH-induced CRC by regulating key pathways involved in tumorigenesis., Competing Interests: Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: There is no clear consensus on the use of re-irradiation (reRT) in the management of locally recurrent rectal cancer (LRRC). The aim of the present study was to investigate all reRT administered for rectal cancer at a large referral institution and to evaluate patient outcomes and toxicity. Material and methods: All patients with rectal cancer were identified who had received previous pelvic radiotherapy (RT) and underwent reRT during 2006-2016. Medical records and RT details of the primary tumor treatments and rectal cancer recurrence treatments were registered, including details on reRT, chemotherapy, surgery, adverse events, and long-term outcomes. Results: Of 77 patients who received ReRT, 67 had previously received pelvic RT for rectal cancer and were administered reRT for LRRC. Re-irradiation doses were 30.0-45.0 Gy, most often given as hyperfractionated RT in 1.2-1.5 Gy fractions twice daily with concomitant capecitabine. The median time since initial RT was 29 months (range, 13-174 months). Of 36 patients considered as potentially resectable, 20 underwent surgery for LRRC within 3 months after reRT. Operated patients had better 3-year overall survival (OS) (62%) compared to those who were not operated (16%; HR 0.32, p  = .001). The median gross tumor volume (GTV) was 107 cm 3 , and 3-year OS was significantly better in patients with GTV <107 cm 3 (44%) compared to patients with GTV ≥107 cm 3 (21%; HR 0.52, p  = .03). Conclusion: Three-year survival was significantly better for patients who underwent surgery after reRT or who had small tumor volume. Prospective clinical trials are recommended for further improvements in patient selection, outcomes, and toxicity assessment.

Budesonide is a glucocorticoid for the treatment of ulcerative colitis (UC). The current study aims to develop a thermosensitive in situ and adhesive gel for rectal delivery of budesonide. HPMC K4M was selected as the adhesive agent based on the adhesive force and the effect on gel performance. The formulation of gel was optimized by using the central composite design-response surface methodology (CCD-RSM); a mathematical model was successfully developed to predict desired formulations as well as to analyze relationships between the amount of Pluronic F-127, Pluronic F-68, and HPMC K4M and the performances of gel. Based on CCD-RSM, a thermosensitive in situ and adhesive gel consisting of 0.002% budesonide, 0.74% HPMC, 4.87% F-68, and 19.0% F-127 was developed. Furthermore, the in vivo behavior of gel was evaluated in Sprague-Dawley rats. In comparison with budesonide solution, rectal administration of budesonide gel at 0.1 mg/kg in rats showed relative bioavailability of 230% with significant increase in rectum uptake.

Intestinal microflora plays a key role in maintaining the homeostasis between immune and host health. Here, we reported the fluoride-induced changes of rectal structure and microflora in mice. The morphology of rectal tissue was observed by hematoxylin and eosin staining. The rectal development parameters (the thickness of mucosa, intestinal gland and muscle layer) were evaluated. The proliferation of rectal epithelial cells was evaluated via BrdU labeling. The distribution of goblet, glycoprotein and mast cell were evaluated by specific staining. Rectal microflora was detected using 16S rRNA high-throughput sequencing. The results showed that the rectal structure was seriously damaged and the proliferation of rectal epithelial cells was significantly inhibited by fluoride. The distribution of goblet cells, glycoprotein and mast cells decreased significantly after fluoride exposure. The relative richness of microfloras was changed after fluoride treatment, such as increased Bacteroidetes and decreased Firmicutes. In summary, this study indicated that excessive fluoride damages the intestinal structure, disturbs the intestinal micro-ecology and causes intestinal microflora disorder in mice. Findings mentioned in the present study enrich a new scope for elucidating fluoride toxicity from intestinal homeostasis.

Background: Electromyographic studies have shown that external anal sphincter activity is modified in response to distension in animals with spinal cord injury. Gonadotropin-releasing hormone and its agonist leuprolide acetate have neurotrophic properties in animals with spinal cord injury., Aim: This study was to determine the effects of leuprolide acetate treatment on electromyographic activity of the external anal sphincter and anorectal manometry in ovariectomized rats with spinal cord injury., Methods: Adult ovariectomized rats were divided in three groups: (a) sham of spinal cord injury, (b) spinal cord injury treated with saline solution, and (c) spinal cord injury treated with leuprolide acetate. The spinal cord injury was induced by clamping at level T9. Leuprolide acetate dosage of 10 μg/kg was proctored intramuscular for 5 weeks, commencing the day after the lesion. Electromyography of the external anal sphincter, anorectal manometry, and volume of the cecum were evaluated in all groups., Results: The electromyographic study of the external anal sphincter activity showed a significant improvement in injured rats treated with leuprolide acetate. Manometric analysis and cecum volume data obtained in animals with leuprolide acetate were very similar to those found in the sham group., Conclusions: These results demonstrate that leuprolide acetate treatment improves the neurogenic colon in ovariectomized rats with spinal cord injury.

Obesity is associated with risk of colorectal adenoma (CRA) and colorectal cancer. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in Apc Min/+ mice via metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPK, decreased pmTOR/mTOR ratio, and decreased pS6 Ser235 /S6 Ser235 ratio in polyps. We hypothesized that metformin would affect colorectal tissue S6 Ser235 among obese patients with recent history of CRA. A phase IIa clinical biomarker trial was conducted via the U.S. National Cancer Institute-Chemoprevention Consortium. Nondiabetic, obese subjects (BMI ≥30) ages 35 to 80 with recent history of CRA were included. Subjects received 12 weeks of oral metformin 1,000 mg twice every day. Rectal mucosa biopsies were obtained at baseline and end-of-treatment (EOT) endoscopy. Tissue S6 Ser235 and Ki-67 immunostaining were analyzed in a blinded fashion using Histo score (Hscore) analysis. Among 32 eligible subjects, the mean baseline BMI was 34.9. Comparing EOT to baseline tissue S6 Ser235 by IHC, no significant differences were observed. Mean (SD) Hscore at baseline was 1.1 (0.57) and 1.1 (0.51) at EOT; median Hscore change was 0.034 ( P = 0.77). Similarly, Ki-67 levels were unaffected by the intervention. The adverse events were consistent with metformin's known side-effect profile. Among obese patients with CRA, 12 weeks of oral metformin does not reduce rectal mucosa pS6 or Ki-67 levels. Further research is needed to determine what effects metformin has on the target tissue of origin as metformin continues to be pursued as a colorectal cancer chemopreventive agent., (©2019 American Association for Cancer Research.)

The aim of the present study was to investigate the effects of high concentrations of copper (Cu) on the cecum and rectum of intestinal microbiota in female mice. Twenty-four Kunming mice were weighed and randomly divided into two groups (n = 12 per group) including the control group and Cu group. Cu group was given drinking water with 5 mg/kg-bw copper chloride (CuCl 2 ), while the control group was treated with drinking water without CuCl 2 . At the 90th day, results showed that compared with the control group, mice in the treatment group had a lower body weight, and the feces turned yellow and had a lower pH value. Histopathological lesions showed that the intestinal tissue from the treatment group had increased thickness of outer muscularis and smoothed muscle fiber, widened submucosa, decreased goblet cells, and showed blunting of intestinal villi and severe atrophy of central lacteal. In addition, at the genus level, 16S rRNA gene sequencing from the Cu group showed that Corynebacterium were significantly increased whereas Staphylococcaceae, Odoribacter, Rikenella, and Jeotgalicoccus were significantly decreased in the cecum. Dehalobacterium, Coprococcus, and Spirochaetales increased significantly whereas Salinicoccus, Bacillales, Staphylococcus, and Lactobacillales decreased sharply in the rectum. This study demonstrated that high concentrations of Cu could induce tissue injury and interrupt the homeostasis of microbiota.

HIV topical microbicides are products with anti-HIV activity, generally incorporating a direct-acting antiretroviral agent, that when applied to the vagina or rectum have the potential to prevent the sexual acquisition of HIV in women and men. Topical microbicides may meet the prevention needs of individuals and groups for whom oral daily forms of pre-exposure prophylaxis (PrEP) have not been acceptable. Microbicides can provide personal control over HIV prevention and offer the possibility of discreet use, qualities that may be particularly important for receptive partners in sexual relationships such as women and transgender women and men, who together account for the clear majority of new HIV infections worldwide. Although the promise of such a product emerged nearly three decades ago, proof of concept has been demonstrated only within the last decade. A robust pipeline of microbicidal gels, films, inserts, and rings has been evaluated in multiple studies among at-risk women and men, and refinement of products for ease of use, reversibility, and high safety is the priority for the field.

Purpose : Evaluate the efficacy of hydroxytyrosol in the local treatment of inflammatory colitis. Currently, the existing treatments for inflammatory bowel diseases does not cure the disease and it is associated with high rates of side effects and complications. Hydroxytyrosol is a phenyl-ethyl-alcohol derived from the hydrolysis of oleuropein and present in olive oil, previous studies have demonstrated the anti-inflammatory effect of dietary hydroxytyrosol supplement, with no toxicity. Materials & Methods: C olitis has been induced by using Trinitrobenzene Sulfonic Acid at 40 rats. They were divided into four groups randomly: 10 rats without treatment; 10 rats with pectin/alginate mixture; 10 rats treated with pectin/alginate + olive oil; 10 rats treated with pectin/alginate + olive oil + hydroxytyrosol. Animals were sacrificed 10 days after induction of trinitrobenzene sulfonic acid, receiving 5 days of continuous treatment. Samples of the rectal area were studied and observed under a microscope to determine the damage by Hunter scoring modified, assessing inflammatory infiltration, number of intestinal walls involved, damage to the mucosal architecture, and edema. Results : When the rectum was analyzed in a global way, nonsignificant differences were observed; however, when performing an individualized analysis, statistically significant differences in the inflammatory infiltrate are present in the samples, which were evaluated using the ANOVA and Student-T statistics. Conclusions : Local treatment with the natural antioxidant hydroxytyrosol combined with pectin/alginate and olive oil of inflammatory bowel disease has been shown to be effective against inflammatory infiltration of TNBS-induced colitis.

Background: Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision surgery is a standard treatment for locally advanced rectal cancer (LARC). Tumor-infiltrating lymphocytes (TILs) have been reported to be associated with tumor response; however, this remains to be established. We previously reported that histological changes on biopsy specimens obtained 7 days after starting nCRT are strong predictors of response to nCRT., Methods: The subjects were 208 patients with LARC who received nCRT. TILs on hematoxylin-eosin staining together with immunohistochemical staining of lymphocyte surface markers including CD3, CD4, CD8, and FoxP3 were performed both on the biopsy specimens before and 7 days after starting nCRT., Results: The proportions of patients with high densities of CD3+, CD4+, CD8+, and FoxP3+ cells 7 days after starting CRT were significantly lower than the respective values before starting nCRT (p < 0.0001, p < 0.0001, p = 0.0023, and p = 0.0046). In biopsy specimens obtained before treatment, high-density CD4+ cells and FOXP3+ cells were significantly associated with tumor shrinkage rate. High-density FOXP3+ cells were significantly associated with marked tumor regression. In biopsy specimens obtained 7 days after starting treatment, high-density CD4+ cells were significantly associated with marked tumor regression, tumor regression grade 1, and tumor shrinkage rate. High-density FoxP3+ cells were significantly associated with marked tumor regression and tumor shrinkage rate., Conclusions: In patients who received nCRT for LARC, the evaluations of immunohistochemical staining for CD4+ and FOXP3+ TILs were more intimately related to histological response to CRT and tumor shrinkage rates in biopsy specimens obtained 7 days after starting treatment than in biopsy specimens obtained before CRT., (© 2020 The Author(s)Published by S. Karger AG, Basel.)

The Chinese natural product, berberine, has biological properties that support its potential efficacy as a colon cancer prevention agent. Its longstanding use in China to treat gastrointestinal tract and rheumatologic disorders is generally regarded as safe, supporting initial investigations in an at-risk population, such as individuals with ulcerative colitis. However, the safety of berberine in this population is not established. Individuals living in China with biopsy-proven ulcerative colitis, ≤grade 2 dysplasia, and with a ulcerative colitis disease activity index (UCDAI) score ≤1 on mesalamine, were randomized 3:1 in a double-blind phase I trial to berberine 900 mg/day or placebo for 3 months, with the primary objective of assessing safety. Blood samples and biopsies of the colorectum, from prespecified locations, were collected prior to and following therapy. Secondary endpoints included changes in UCDAI score, and in tissue and plasma markers of inflammation. Of toxicities at least possibly related, one episode of grade 3 elevation in transaminases and one episode of grade 1 nausea were observed among 12 individuals on berberine, and none were observed among 4 on placebo. The mean plasma berberine concentration was 3.5 nmol/L after berberine treatment, significantly higher than 0.5 nmol/L with placebo. Berberine significantly decreased the Geboes grade in colonic tissue, but had a nonsignificant effect on other tissue or blood biomarkers related to cell growth and inflammation. The combination of berberine and mesalamine is well tolerated in Chinese with ulcerative colitis and may enhance mesalamine's anti-inflammatory effects in colonic tissue., (©2019 American Association for Cancer Research.)

Natural-product derived lectins can function as potent viral inhibitors with minimal toxicity as shown in vitro and in small animal models. We here assessed the effect of rectal application of an anti-HIV lectin-based microbicide Q-Griffithsin (Q-GRFT) in rectal tissue samples from rhesus macaques. E-cadherin + cells, CD4 + cells and total mucosal cells were assessed using in situ staining combined with a novel customized digital image analysis platform. Variations in cell numbers between baseline, placebo and Q-GRFT treated samples were analyzed using random intercept linear mixed effect models. The frequencies of rectal E-cadherin + cells remained stable despite multiple tissue samplings and Q-GRFT gel (0.1%, 0.3% and 1%, respectively) treatment. Whereas single dose application of Q-GRFT did not affect the frequencies of rectal CD4 + cells, multi-dose Q-GRFT caused a small, but significant increase of the frequencies of intra-epithelial CD4 + cells (placebo: median 4%; 1% Q-GRFT: median 7%) and of the CD4 + lamina propria cells (placebo: median 30%; 0.1-1% Q-GRFT: median 36-39%). The resting time between sampling points were further associated with minor changes in the total and CD4 + rectal mucosal cell levels. The results add to general knowledge of in vivo evaluation of anti-HIV microbicide application concerning cellular effects in rectal mucosa.

We present a rare case report of a bilateral avascular necrosis of lateral sacral masses in a patient who developed a sustainable complete clinical and radiological response after chemoradiotherapy for locally advanced rectal cancer. It is shown that despite the standardized and precise planning and fractioning for neoadjuvant chemoradiation therapy for locally advanced rectal cancer, the biological effects of ionizing radiation on critical organs can be va- ried both in time of occurrence and in structure. Evaluating the effect of neoadjuvant chemoradiation therapy, one should take into account the possibility of the development of even very rare effects of ionizing radiation on criti- cal organs and include their early detection in the diagnostic algorithm., (V. V. Zvirych, D. E. Makhmudov, M. I. Paliiy, A. V. Ashykhmin, O. O. Kolesnik.)

Introduction: Currently, neoadjuvant fluoropyrimidine-based chemoradiation followed by surgery is considered the standard of care for locally advanced rectal cancer. The current study aimed to investigate the predictive significance of mucinous histology on the pathologic complete response rate following neoadjuvant chemoradiation in locally advanced rectal cancer and to propose potential new treatment protocol for this specific histology., Material and Method: This retrospective study was conducted on 403 patients with locally advanced (clinically T3-4 and/or N1-2) rectal adenocarcinoma who had been treated at three tertiary academic hospitals between 2010 and 2015. Among those 403 patients, 46 (11%) had mucinous rectal cancer (MRC) and 358 (89%) had non-mucinous rectal cancer (NMRC). All patients underwent neoadjuvant chemoradiation with capecitabine followed by low anterior or abdominoperineal resection., Results: There were 268 men and 135 women with a median age of 55 years (range, 26-82 years). Patients with MRC were younger (p = 0.002) and presented with a larger tumor size (p < 0.001) and a more advanced tumor stage (p = 0.033) compared to the ones with MNRC. In the univariate analysis, female gender (p = 0.009), distal tumor location (p = 0.035), higher tumor stage (p = 0.049), node positivity (p = 0.001), MRC histology (p = 0.017), and high pretreatment CEA level (p = 0.013) were observed to be predictive of a poor pathologic complete response. However, in the multivariate analysis, tumor stage was the single most predictive factor of response to neoadjuvant chemoradiation., Conclusion: Mucinous adenocarcinoma is a significant predictive factor for poor pathologic complete response to neoadjuvant capecitabine-based chemoradiation in patients with locally advanced rectal cancer. New treatment modality based on biomarkers may be considered in future prospective studies because of MRC poor prognosis. Immunotherapy combined with chemotherapy and/or radiotherapy may be an attractive option because of the tumor microsatellite instability-high status.

Background: With the aging of the population and rising incidence of thromboembolic events, the clinical use of antithrombotic agents is also increasing. There are few reports yet on the management of antithrombotic agent use in patients undergoing cold snare polypectomy (CSP)., Aims: The aim of this study was to evaluate whether continued administration of antithrombotic agents in patients undergoing CSP would be associated with an increased rate of delayed post-polypectomy bleeding (DPPB)., Methods: A total of 1177 colorectal polyps in 501 patients were resected at Omori Red Cross Hospital between October 2017 and March 2018. The polyps were divided into two groups depending on whether the patients received antithrombotic agent treatment or not: the antithrombotic group (911 polyps) and the no-antithrombotic group (266 polyps)., Results: Among the 1177 polyp resections, there was no case of DPPB, including in the antithrombotic group. Immediate bleeding occurred in a total of 63 (5.4%) cases. Polyp location in the rectum (OR (95% CI) 2.64 (1.223-5.679); p = 0.013), polyp size ≥ 6 mm (OR (95% CI) 4.64 (2.719-7.933); p < 0.001), polypoid growth pattern (OR (95% CI) 2.78 (1.607-4.793); p < 0.001), and antithrombotic agent use (OR (95% CI) 2.98 (1.715-5.183); p < 0.001) were identified as significant risk factors of immediate bleeding., Conclusions: Continued use of antithrombotic agents does not increase the risk of DPPB, even in those receiving multiple antithrombotic agents. Thus, it is safe to perform CSP even in multiple agent users. Prospective, randomized studies are necessary to confirm our results.