-
International Journal of Colorectal... Nov 2017Perianal fistulising Crohn's disease (PFCD) affects a third of Crohn's disease patients and represents a disabling phenotype with poor outcome. The anti-tumour necrosis... (Review)
Review
BACKGROUND
Perianal fistulising Crohn's disease (PFCD) affects a third of Crohn's disease patients and represents a disabling phenotype with poor outcome. The anti-tumour necrosis factor alpha (TNF) therapies have been shown to maintain clinical remission in a third of patients after 1 year of treatment. Maintenance therapy with systematic administration schedules confers greatest benefit, but exposes patients to risks/side effects of continued systemic use and led to consideration of local drug delivery (first described in 2000). In this review, we analyse all published articles on local anti-TNF therapy in the treatment of PFCD.
METHODS
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to systematically search Medline and Embase using the medical subject headings 'fistula', 'anus', 'Crohn disease', 'infliximab' and 'adalimumab'. This was combined with free text searches, e.g. 'local injection' and 'Crohn's perianal disease'. Studies/abstracts describing local injection treatment with anti-TNF were included in this review.
RESULTS
Six pilot studies including a total of 92 patients were included in this review. Outcomes reported were mostly clinical and included 'complete/partial response' to therapy and short-term results varied between 40 and 100%. There were no significant adverse events and the local injections were well tolerated.
CONCLUSIONS
There is paucity of data assessing this treatment modality. Local anti-TNF therapy appears safe, but outcome reporting is heterogeneous, subjective and long-term data are unavailable. Our review suggests a potential role may be in those in whom systemic treatment is contraindicated and calls for standardised reporting of outcomes in this field to enable better data interpretation.
Topics: Adalimumab; Crohn Disease; Gastrointestinal Agents; Humans; Infliximab; Injections, Intralesional; Rectal Fistula; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 28900730
DOI: 10.1007/s00384-017-2899-0 -
Journal of Cellular and Molecular... Mar 2019Tumour necrosis factor-α-induced protein 8-like 2 (TIPE2) is a tumour suppressor in many types of cancer. However, the mechanism of action of TIPE2 on the growth of...
Tumour necrosis factor-α-induced protein 8-like 2 (TIPE2) is a tumour suppressor in many types of cancer. However, the mechanism of action of TIPE2 on the growth of rectal adenocarcinoma is unknown. Our results showed that the expression levels of TIPE2 in human rectal adenocarcinoma tissues were higher than those in adjacent non-tumour tissues. Overexpression of TIPE2 reduced the proliferation, migration, and invasion of human rectal adenocarcinoma cells and down-regulation of TIPE2 showed reverse effects. TIPE2 overexpression increased apoptosis through down-regulating the expression levels of Wnt3a, phospho (p)-β-Catenin, and p-glycogen synthase kinase-3β in rectal adenocarcinoma cells, however, TIPE2 knockdown exhibited reverse trends. TIPE2 overexpression decreased autophagy by reducing the expression levels of p-Smad2, p-Smad3, and transforming growth factor-beta (TGF-β) in rectal adenocarcinoma cells, however, TIPE2 knockdown showed opposite effects. Furthermore, TIPE2 overexpression reduced the growth of xenografted human rectal adenocarcinoma, whereas TIPE2 knockdown promoted the growth of rectal adenocarcinoma tumours by modulating angiogenesis. In conclusion, TIPE2 could regulate the proliferation, migration, and invasion of human rectal adenocarcinoma cells through Wnt/β-Catenin and TGF-β/Smad2/3 signalling pathways. TIPE2 is a potential therapeutic target for the treatment of rectal adenocarcinoma.
Topics: Adenocarcinoma; Adult; Animals; Apoptosis; Biomarkers, Tumor; Case-Control Studies; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Invasiveness; Prognosis; Rectal Neoplasms; Smad2 Protein; Smad3 Protein; Survival Rate; Transforming Growth Factor beta; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 30637920
DOI: 10.1111/jcmm.14065 -
The Journal of Surgical Research Sep 2020In recent years, microRNA (miRNA) is considered as a potential therapy target. To study the regulatory mechanism and therapeutic effect of miRNAs on inflammatory bowel...
BACKGROUND
In recent years, microRNA (miRNA) is considered as a potential therapy target. To study the regulatory mechanism and therapeutic effect of miRNAs on inflammatory bowel disease (IBD), we investigated microRNAs that regulate apoptosis-related protein B cell lymphoma-2 (Bcl-2). We examined the role of miR-16 in IBD and the effect of inhibiting the expression of miR-16 on disease progression.
MATERIALS AND METHODS
Dextran sulfate sodium was used to induce ulcerative colitis in mice. RNA and protein were extracted from the rectal mucosa of mice. Real-time quantitative polymerase chain reaction and Western blotting were used to detect the expression of miR-16 and Bcl-2. The effects of miR-16 on intestinal mucosal immunity were studied by real-time quantitative polymerase chain reaction, and inflammatory factors such as interleukin-1β, interleukin-6, and tumor necrosis factor-α were detected. The weight changes, disease activity index, length of the rectal colon, and pathological score of the mice were used to evaluate the effect of inhibiting miR-16 on disease progression. Through the establishment of overexpression and low expression cell lines of miR-16, the regulation of miR-16 on Bcl-2 was studied.
RESULTS
MiR-16 was overexpressed in the IBD model, whereas Bcl-2 had lower expression in the mucosa. Inhibiting expression of miR-16 significantly decreased the expression of interleukin-1β, interleukin-6, and tumor necrosis factor-α. In mice, the weight change, disease activity index, and pathological score decreased in the experimental group, in which miR-16 was inhibited. High expression of miR-16 can inhibit Bcl-2 expression.
CONCLUSIONS
MiR-16 plays a critical role in IBD via Bcl-2 and is a promising target in IBD therapy.
Topics: Animals; Caco-2 Cells; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Female; Humans; Interleukin-1beta; Interleukin-6; Intestinal Mucosa; Mice; MicroRNAs; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 32361613
DOI: 10.1016/j.jss.2020.03.037 -
The Korean Journal of Internal Medicine Jan 2016The objective of this study was to assess the prognostic roles of treatment response and tissue necrosis after chemoradiotherapy (CRT) in locally advanced rectal cancer. (Comparative Study)
Comparative Study
BACKGROUND/AIMS
The objective of this study was to assess the prognostic roles of treatment response and tissue necrosis after chemoradiotherapy (CRT) in locally advanced rectal cancer.
METHODS
A total of 243 patients with locally advanced rectal cancer who underwent neoadjuvant CRT were included. Three treatment response groups were classified by their pathological stage results: complete treatment response (CTR), intermediate treatment response (ITR), and poor treatment response (PTR). Three tissue necrosis groups were classified based on tissue pathological results: complete necrosis response (CNR), intermediate necrosis response (INR), and poor necrosis response (PNR).
RESULTS
Overall survival (OS) and recurrence-free survival (RFS) rate at three years were 74.5% and 61.3%, respectively. The 3-year OS rates of the CTR, ITR, and PTR groups were 83.7%, 75.9%, and 69.7%, respectively (p < 0.001); the 3-year RFS rates were 76.7%, 69.0%, and 52.1%, respectively (p < 0.001). The 3-year OS rates of the CNR, INR, and PNR groups were 83.7%, 80.6%, and 61.8%, respectively (p < 0.001); the 3-year RFS rates were 76.7%, 68.9%, and 44.3%, respectively (p < 0.001). When compared to CTR/CNR, PTR/PNR was strongly related to an increased risk of recurrence (hazard ratio [HR], 5.53; 95% confidence interval [CI], 2.01 to 15.23 vs. HR, 6.37; 95% CI, 2.29 to 17.74, respectively) in univariate Cox regression. Both PTR and PNR were strongly associated with shorter RFS and OS when compared with CTR and CNR in the multivariate Cox regression.
CONCLUSIONS
Tissue necrosis is an equally important prognostic marker as treatment response for oncologic outcomes in locally advanced rectal cancer.
Topics: Aged; Biopsy; Chemoradiotherapy, Adjuvant; Chi-Square Distribution; Disease Progression; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Laparoscopy; Male; Middle Aged; Multivariate Analysis; Necrosis; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Proportional Hazards Models; Rectal Neoplasms; Remission Induction; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome
PubMed: 26767867
DOI: 10.3904/kjim.2016.31.1.134 -
Fundamental & Clinical Pharmacology Feb 2021Ulcerative colitis (UC) is a chronic inflammatory disease characterized by diffused inflammation of the colon and rectum mucosa. The pathogenesis of UC is...
Targeting IL-10, ZO-1 gene expression and IL-6/STAT-3 trans-signaling by a combination of atorvastatin and mesalazine to enhance anti-inflammatory effects and attenuates progression of oxazolone-induced colitis.
Ulcerative colitis (UC) is a chronic inflammatory disease characterized by diffused inflammation of the colon and rectum mucosa. The pathogenesis of UC is multifactorial, and the exact underlying mechanisms remain poorly understood. This study aims to investigate the effect of mesalazine and atorvastatin combination in enhancing anti-inflammatory effects and attenuates progression of oxazolone colitis in rats. In the present study, male albino rats (N = 60) were divided into six groups (10 rats each), the first two groups served as normal control and a control saline group. Colitis was induced by intra-rectal administration of oxazolone in the 5th and 7th days after pre-sensitization. Then, rats were divided into untreated group, groups treated with mesalazine or atorvastatin or their combination. Colitis was assessed by colon length, body weight, and incidence of diarrhea, rectal bleeding, and histopathology of colon tissue. Colon tissues were used for measuring interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), IL-13, signal transducer and activator of transcription-3 (STAT-3), myeloperoxidase activity (MPO), reduced glutathione(GSH), and tissue expression of IL-10, tight junction protein zonula occludens (ZO-1), and caspase-3 genes. The combination therapy significantly attenuated progression of UC by decreasing incidence of diarrhea, rectal bleeding, weight loss, IL-13, IL-6, TNF-α, STAT-3, caspase-3, and MPO activity and significantly increased IL-10, ZO-1, colon length, and GSH content, and these effects were more superior to single drugs. These findings showed that combination therapy was able to ameliorate progression of UC and enhance anti-inflammatory effects possibly by restoring IL-10 and ZO-1 levels and limiting IL-6/STAT-3 trans-signaling.
Topics: Animals; Anti-Inflammatory Agents; Atorvastatin; Colitis, Ulcerative; Colon; Drug Therapy, Combination; Interleukin-10; Interleukin-13; Interleukin-6; Male; Mesalamine; Oxazolone; Rats; STAT3 Transcription Factor; Signal Transduction; Tumor Necrosis Factor-alpha; Zonula Occludens-1 Protein
PubMed: 32383169
DOI: 10.1111/fcp.12563 -
Frontiers in Oncology 2020Differential expressions and functions of various micoRNAs (miRNAs) have been intensively studied in both colon and rectal cancers. However, the importance of miRNAs on...
Expressions of miR-302a, miR-105, and miR-888 Play Critical Roles in Pathogenesis, Radiotherapy, and Prognosis on Rectal Cancer Patients: A Study From Rectal Cancer Patients in a Swedish Rectal Cancer Trial of Preoperative Radiotherapy to Big Database Analyses.
Differential expressions and functions of various micoRNAs (miRNAs) have been intensively studied in both colon and rectal cancers. However, the importance of miRNAs on radiotherapy (RT) response and clinical outcome in rectal cancer patients remains unclear. In this study, we used real-time polymerase chain reaction to examine the expressions of miR-302a, miR-105, and miR-888 in normal mucosa and cancer tissue from rectal cancer patients with and without preoperative RT. The biological function of miR-302a, miR-105, and miR-888 expression was further analyzed and identified through the public databases: TCGA (The Cancer Genome Atlas) and GEPIA (Gene Expression Profiling Interactive Analysis). The results showed that the expression of miR-105 in rectal cancer was higher than that in normal mucosa in RT ( = 0.042) and non-RT patients ( = 0.003) and was associated with mucinous histological type ( = 0.004), COX-2 ( = 0.042), and p73 expression ( = 0.030). The expression of miR-302a was shown more frequently in cancers with necrosis ( = 0.033) and with WRAP53 expression ( = 0.015), whereas miR-888 expression occurred more frequently in tumors with protein the expression of survivin ( = 0.015), AEG-1 (astrocyte elevated gene-1) ( = 0.003), and SATB1 (special AT-rich sequence binding protein 1) ( = 0.036). Moreover, TargetScan also predicted AEG-1 and SATB1 as putative targets for miR-888. The miRNA-gene network analysis showed that ABI2 was associated with all the three miRNAs, with lower expression and good diagnostic value in rectal cancers. The TCGA database demonstrated the association of miR-105 expression with high carcinoembryonic antigen level ( = 0.048). RT reduced the expressions of miR-302a, miR-105, and miR-888. Prognostic analysis showed that miR-888 expression was independently associated with worse survival of patients without RT [overall survival, = 0.001; disease-free survival, = 0.009]. Analysis of biological function revealed that the protein serine/threonine kinase activity and PI3K-AKT signaling pathway were the most significantly enriched functions and pathways, respectively. Our findings suggest that miR-105 is involved in rectal cancer pathogenesis and miR-888 is associated with prognosis. MiR-302a, miR-105, and miR-888 have potential influence on the pathogenesis, RT, and prognosis of rectal cancer.
PubMed: 33123477
DOI: 10.3389/fonc.2020.567042 -
Artificial Organs Jul 2020While fecal incontinence (FI) is not fatal, it can dramatically decrease the patient's quality of life. An artificial anal sphincter (AAS) is an implantable device that...
While fecal incontinence (FI) is not fatal, it can dramatically decrease the patient's quality of life. An artificial anal sphincter (AAS) is an implantable device that treats FI by replacing a diseased or damaged anal sphincter, thus allowing the patient's continence to be maintained. Here, we report a novel implantable puborectalis-like artificial anal sphincter (PAAS) that replicates rectal perception and has a low risk of ischemia necrosis. Using the pressure sensors embedded in the PAAS, the relationship between the mass of feces and the pressure was determined, and a feces mass estimation model was developed based on in vitro studies. Rectal perception is provided through the real-time monitoring of rectal feces, and the feeling of defecation is quantified based on a comparison between the feces mass and a preset threshold mass. In vivo studies were performed for validation, and the accuracy of the model was determined to be as high as 90%. The performance of the PAAS in the real-time monitoring of rectal feces and its in vivo biocompatibility were also evaluated. The device should further the functionality of existing AAS systems while improving their biosafety and thus expand the applicability of implantable AAS systems in the treatment of FI.
Topics: Anal Canal; Animals; Artificial Organs; Defecation; Disease Models, Animal; Fecal Incontinence; Humans; Materials Testing; Pressure; Prosthesis Design; Prosthesis Implantation; Quality of Life; Swine; Swine, Miniature
PubMed: 31970792
DOI: 10.1111/aor.13645 -
Journal of Gastroenterology and... Feb 2024Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis. These post hoc analyses evaluated early improvement in patient-reported outcomes...
Early recapture of response with tofacitinib 10 mg twice daily in patients with ulcerative colitis in OCTAVE Open following dose reduction or treatment interruption in OCTAVE Sustain.
BACKGROUND AND AIM
Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis. These post hoc analyses evaluated early improvement in patient-reported outcomes with tofacitinib 10 mg twice daily (BID) in OCTAVE Open among patients with ulcerative colitis who experienced treatment failure with placebo (retreatment subpopulation) or tofacitinib 5 mg BID (dose escalation subpopulation) during maintenance.
METHODS
Endpoints based on Mayo subscores (rectal bleeding improvement, stool frequency improvement, and symptomatic [both rectal bleeding and stool frequency] improvement) were analyzed overall and by prior tumor necrosis factor inhibitor (TNFi) failure status from month (M)1-M6 in OCTAVE Open. Changes from baseline in partial Mayo score, rectal bleeding subscore, and stool frequency subscore at M1 were also analyzed, by M2 clinical response status.
RESULTS
At M1 of OCTAVE Open, 83.2%, 70.3%, and 64.4% of patients in the retreatment subpopulation (n = 101) had rectal bleeding improvement, stool frequency improvement, and symptomatic improvement, respectively. Corresponding values in the dose escalation subpopulation (n = 57) were 59.6%, 50.9%, and 38.6%. For both subpopulations, results were generally consistent regardless of prior TNFi failure. In the dose escalation subpopulation, mean decrease from baseline in partial Mayo score and stool frequency subscore at M1 was greater in patients with versus without a clinical response at M2.
CONCLUSIONS
Rectal bleeding improvement and stool frequency improvement were achieved by M1 in many patients receiving tofacitinib 10 mg BID in both subpopulations, with no apparent difference by prior TNFi failure. Analyses were limited by small sample sizes for some subgroups.
Topics: Humans; Colitis, Ulcerative; Remission Induction; Drug Tapering; Treatment Interruption; Treatment Outcome; Piperidines; Pyrimidines
PubMed: 37953548
DOI: 10.1111/jgh.16386 -
Cancer Management and Research 2022To determine an accurate method of inspecting low anastomotic leakages and application of transurethral prostate resection instrumentation for treating low rectal...
PURPOSE
To determine an accurate method of inspecting low anastomotic leakages and application of transurethral prostate resection instrumentation for treating low rectal anastomotic leakage.
PATIENTS AND METHODS
Clinical data of eight patients treated for anastomotic leakage after rectal cancer surgery at Zhangye People's Hospital (affiliated to Hexi University), from August 2019 to November 2021, were retrospectively analyzed. Transanal prostate resection instrumentation was used to assess the leakage and surrounding conditions. Using prostate resection instrumentation, the presacral and perirectal residual cavities were washed and removed, and indwelling suprapubic presacral, transanal presacral, and rectal drainage tubes were placed. Continuous presacral saline irrigation and drainage and open negative-pressure suction in the rectal cavity were performed until the patients' fistula healed.
RESULTS
Of the eight patients with anastomotic leakages, one had grade B and seven had grade C International Study Group of Rectal Cancer anastomotic leakage classifications following Dixon operation. Transanal prostate resection instrumentation showed that the leakage of the one patient with grade B was less than a third of the circumference of the anastomosis. Among the seven patients with grade C, one leakage was less than a third of the anastomotic circumference. One patient had complete separation of the anastomosis and one distal colon necrosis, which necessitated immediate descending colostomy. Conservative treatment was successful in six patients; the conservative overall cure rate was 75%, and the median healing time was 43 (21-68) days.
CONCLUSION
Transanal examination of rectal anastomotic leakage using prostate resection instrumentation is comprehensive, easy to perform, provides clear visualization, accurately guides catheter placement, and can be combined with continuous open negative-pressure drainage, which is a safe, convenient, and effective method for treating low rectal leakage.
PubMed: 35733511
DOI: 10.2147/CMAR.S367039 -
Clinical Gastroenterology and... Jan 2019Vedolizumab, a humanized monoclonal antibody against α4β7 integrin, is used to treat adults with moderately to severely active ulcerative colitis (UC) and Crohn's...
BACKGROUND & AIMS
Vedolizumab, a humanized monoclonal antibody against α4β7 integrin, is used to treat adults with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). We investigated the time course of clinical response to vedolizumab in patients who were and were not previously treated with tumor necrosis factor (TNF) antagonists.
METHODS
We performed a post-hoc analysis of data from phase 3, randomized, controlled trials of vedolizumab vs placebo in adult patients with UC (N = 374) or CD (N = 784). We collected data on patient-reported symptoms (rectal bleeding and stool frequency for patients with UC, abdominal pain and loose stool frequency for patients with CD) reported at weeks 2, 4, and 6 of treatment. We reported mean percentage score changes from baseline and proportions of patients who achieved predefined scores. We performed multivariate logistic regression analysis to identify factors associated with an early response (at week 2).
RESULTS
In patients with UC (overall or naive to TNF antagonist therapy), a significantly greater percentage of patients given vedolizumab achieved the predefined composite symptom score at weeks 2, 4, and 6 compared to those given placebo. In patients with CD who were naive to TNF antagonists, a significantly greater percentage of patients given vedolizumab achieved the predefined score at weeks 2 and 4 compared to those given placebo. Among patients with UC given vedolizumab, 19.1% (overall) and 22.3% (TNF antagonist naive) achieved a composite score of rectal bleeding of 0 and stool frequency ≤1 at week 2 compared to 10% (overall) and 6.6% (TNF antagonist naive) of those receiving placebo. Among TNF antagonist-naive patients with CD, 15.0% of those given vedolizumab achieved an average daily composite score of abdominal pain ≤1 and loose stool frequency ≤3 at week 2 (compared to 7.9% given placebo), and 23.8% of those given vedolizumab achieved these by week 4 (compared to 10.3% given placebo).
CONCLUSIONS
In a post-hoc analysis of data from phase 3 clinical trials, vedolizumab significantly improved patient-reported symptoms of UC and CD as early as week 2 of treatment, continuing through the first 6 weeks-especially when given as first-line biologic therapy. ClinicalTrials.gov no: NCT00783718, NCT00783692, NCT01224171.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Clinical Trials, Phase III as Topic; Female; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Patient Reported Outcome Measures; Placebos; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Young Adult
PubMed: 29857145
DOI: 10.1016/j.cgh.2018.05.026