Aspirin chemoprevention in colorectal cancer: network meta-analysis of low, moderate, and high doses.

BACKGROUND: Colorectal cancer is the third most common cancer, with nearly 2 million cases worldwide and just under 1 million deaths in 2020. Several trials have demonstrated that aspirin has the potential to reduce the incidence and/or recurrence of colorectal cancer; however, the optimal aspirin dose is unclear. METHODS: Relevant studies were identified by searching MEDLINE, Embase and the Cochrane Library from database inception to 2 February 2022. Data from RCTs in which the incidence of colorectal cancer in patients without active colorectal cancer assigned to aspirin versus control were included. Two investigators independently identified studies and abstracted data. Study quality was assessed using Cochrane Collaboration risk-of-bias 2 tool. The study was performed according to PRISMA guidelines. Aspirin dose was stratified into low (50-163 mg/day), mid (164-325 mg/day), and high (500-1200 mg/day). RESULTS: Thirteen articles representing 11 RCTs (92 550 participants) were included, with studies assessing aspirin as primary prophylaxis in general or high-risk populations, and as secondary prophylaxis for metachronous colorectal cancer. There was a statistically significant reduction in colorectal cancer incidence in the high-dose aspirin group compared with the group that received no aspirin or placebo (OR 0.69, 95 per cent credible interval 0.50 to 0.96; surface under the cumulative ranking 0.82). There was no statistically significant difference between mid- and low-dose aspirin versus no aspirin/placebo. CONCLUSION: In this network meta-analysis of RCTs, high-dose aspirin was associated with a reduction in colorectal cancer incidence. However, this was based on a limited number of trials. This study did not show a statistically significant risk reduction in colorectal cancer incidence with mid- or low-dose aspirin.

Rate of dissemination and prognosis in early and advanced stage colorectal cancer based on microsatellite instability status: systematic review and meta-analysis.

INTRODUCTION: For the past two decades, microsatellite instability (MSI) has been reported as a robust clinical biomarker associated with survival advantage attributed to its immunogenicity. However, MSI is also associated with high-risk adverse pathological features (poorly differentiated, mucinous, signet cell, higher grade) and exhibits a double-edged sword phenomenon. We performed a systematic review and meta-analysis to evaluate the rate of dissemination and the prognosis of early and advanced stage colorectal cancer based on MSI status. METHODS: A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, Clinical Trials databases from inception of database to June 2019. Colorectal cancer, microsatellite instability, genomic instability and DNA mismatch repair were used as key words or MeSH terms. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were pooled using a random-effects model with odds ratio (OR) as the effect size. Statistical analysis was performed using RevMan ver 5.3 Cochrane Collaboration. RESULTS: From 5288 studies, 136 met the inclusion criteria (n = 92,035; MSI-H 11,746 (13%)). Overall, MSI-H was associated with improved OS (OR, 0.81; 95% CI 0.73-0.90), DFS (OR, 0.73; 95% CI 0.66-0.81) and DSS (OR, 0.69; 95% CI 0.52-0.90). Importantly, MSI-H had a protective effect against dissemination with a significantly lower rate of lymph node and distant metastases. By stage, the protective effect of MSI-H in terms of OS and DFS was observed clearly in stage II and stage III. Survival in stage I CRC was excellent irrespective of MSI status. In stage IV CRC, without immunotherapy, MSI-H was not associated with any survival benefit. CONCLUSIONS: MSI-H CRC was associated with an overall survival benefit with a lower rate of dissemination. Survival benefit was clearly evident in both stage II and III CRC, but MSI-H was neither a robust prognostic marker in stage I nor stage IV CRC without immunotherapy.

Pathways of Gastric Carcinogenesis, Helicobacter pylori Virulence and Interactions with Antioxidant Systems, Vitamin C and Phytochemicals.

Helicobacter pylori is a class one carcinogen which causes chronic atrophic gastritis, gastric intestinal metaplasia, dysplasia and adenocarcinoma. The mechanisms by which H. pylori interacts with other risk and protective factors, particularly vitamin C in gastric carcinogenesis are complex. Gastric carcinogenesis includes metabolic, environmental, epigenetic, genomic, infective, inflammatory and oncogenic pathways. The molecular classification of gastric cancer subtypes has revolutionized the understanding of gastric carcinogenesis. This includes the tumour microenvironment, germline mutations, and the role of Helicobacter pylori bacteria, Epstein Barr virus and epigenetics in somatic mutations. There is evidence that ascorbic acid, phytochemicals and endogenous antioxidant systems can modify the risk of gastric cancer. Gastric juice ascorbate levels depend on dietary intake of ascorbic acid but can also be decreased by H. pylori infection, H. pylori CagA secretion, tobacco smoking, achlorhydria and chronic atrophic gastritis. Ascorbic acid may be protective against gastric cancer by its antioxidant effect in gastric cytoprotection, regenerating active vitamin E and glutathione, inhibiting endogenous N-nitrosation, reducing toxic effects of ingested nitrosodimethylamines and heterocyclic amines, and preventing H. pylori infection. The effectiveness of such cytoprotection is related to H. pylori strain virulence, particularly CagA expression. The role of vitamin C in epigenetic reprogramming in gastric cancer is still evolving. Other factors in conjunction with vitamin C also play a role in gastric carcinogenesis. Eradication of H. pylori may lead to recovery of vitamin C secretion by gastric epithelium and enable regression of premalignant gastric lesions, thereby interrupting the Correa cascade of gastric carcinogenesis.

Major Abdominal and Perianal Surgery in Crohn's Disease: Long-term Follow-up of Australian Patients With Crohn's Disease.

BACKGROUND: Most patients with Crohn's disease still require surgery despite significant advances in medical therapy, surveillance, and management strategies. OBJECTIVE: The purpose of this study was to assess surgical strategies and outcomes in Crohn's disease, including surgical recurrence and emergency surgery. DESIGN: This was a multicenter, retrospective review of a prospectively collected database. SETTINGS: A specialist-referred cohort of patients with Crohn's disease between 1970 and 2009 was studied. PATIENTS: Included were 972 patients with Crohn's disease who were referred to the Sydney Inflammatory Bowel Disease cohort database. MAIN OUTCOME MEASURES: Main outcomes of interest were the rates of major abdominal and perianal surgery between decades (1970-1979, 1980-1989, 1990-1999, and 2000-2009), indications for surgery, types of procedure performed, rate of elective and emergency surgery, risk of surgical recurrence, and predictive factors for surgery. RESULTS: Between 1970 and 2009, the overall risks of surgery within 5, 10, and 15 years of diagnosis were 31.7%, 43.3%, and 48.4%. The median time to first surgery from time of diagnosis was 2 years (range, 0-31 years). A total of 6.7% of patients required emergency surgery within 5 years of diagnosis. In total, 8.8% of patients required emergency surgery within 15 years. The overall risk of surgical recurrence was 35.9%. The risk of major abdominal surgery significantly decreased between 2000 and 2009 when compared with the 1970 to 1979 period (OR = 0.49 (95% CI, 0.34-0.70). However, the rate of perianal surgery significantly increased (OR = 5.76 (95% CI, 2.54-13.06)). The main indications for surgery were enteric stricture or obstruction, perianal disease, and intra-abdominal fistulas/abscess. Of the 972 patients over 4 decades, only 11 patients (1.1%) were diagnosed with colorectal cancer. LIMITATIONS: This was a specialist-referred cohort, not a population-based study. CONCLUSIONS: The rate of major abdominal surgery has decreased, with surgery reserved for more severe and complicated disease. The natural history of patients with more complicated Crohn's disease and severe phenotypes puts them at higher risk of surgical recurrence and emergency surgery. There has been no reduction in emergency surgery rates and there has been an increase in surgical recurrence despite the reduction in surgical rate morbidity. See Video Abstract at http://links.lww.com/DCR/A483.

Improved short-term outcomes of laparoscopic versus open resection for colon and rectal cancer in an area health service: a multicenter study.

BACKGROUND: Evidence demonstrates short-term benefits of laparoscopic surgery for colon cancer. The situation for rectal cancer is less clear. OBJECTIVES: This review assessed the use and short-term outcomes of elective open and laparoscopic colon and rectal cancer resections within an area health service. DESIGN: This was a multicenter, retrospective review of a prospective database. SETTINGS: All elective colon and rectal cancer resections in the western zone of Sydney South West Area Health Service from 2001 until 2008 were included. PATIENTS: Included were 1721 patients who underwent either a laparoscopic colon (n = 434) or rectal (n = 157) resection or an open colon (n = 742) or rectal (n = 388) resection. MAIN OUTCOME MEASURES: : Outcome measures included operating time, blood loss, adequacy of resection, conversion rate, intensive care unit admission, length of stay, and 26 acute postoperative complications. RESULTS: Patients were matched for age, sex, ASA, BMI, and tumor stage. Laparoscopic surgery increased in frequency. Fewer patients experienced a complication in both the laparoscopic colon (28.8 vs 54.4%; p < 0.0001) and rectal (41.4 vs 60.3%; p < 0.0001) group irrespective of age. Laparoscopic operating time for colon and rectal cancer was 24.1 minutes (p < 0.0001) and 25.8 minutes (p < 0.0001) longer, with a low conversion-to-open rate (6.5% and 8.3%; p = 0.44). Laparoscopic surgery resulted in fewer transfusions (0.4 vs 0.7 units; p = 0.0028) and length of stay (7 vs 10 days; p = 0.0011) for colon cancers, and reduced intraoperative hemoglobin drop (20.5 vs 24.8; p = 0.029) and intensive care unit admissions (26.8 vs 36.3%; p = 0.032) for rectal cancers. LIMITATIONS: : This was a nonrandomized study with rectal cancers more often resected with the open technique (71.2 vs 28.8%; p < 0.001). CONCLUSIONS: Within an area health service, elective laparoscopic resection for colon and rectal cancer had improved short-term outcomes in comparison with open surgery.

Current status on microsatellite instability, prognosis and adjuvant therapy in colon cancer: A nationwide survey of medical oncologists, colorectal surgeons and gastrointestinal pathologists.

BACKGROUND: There is significant variation in attitude both towards the role of microsatellite instability (MSI) in predicting prognosis, and towards its role in guiding which Stage II colon cancer patients may benefit from adjuvant chemotherapy. AIM: To examine the current status of specialist attitudes towards MSI in guiding prognosis and adjuvant therapy in stage II colon cancer. METHODS: The Pathology in Colon Cancer, Prognosis and Uptake of Adjuvant Therapy (PiCC UP) Australia and New Zealand questionnaire was distributed to colorectal surgeons, medical oncologists and pathologists after institutional board approval. A 5-scale Likert score was used to assess attitudes towards 23 pathological features for prognosis and 18 features for adjuvant therapy. Data were analysed using a rating scale and graded response model in item response theory (IRT) on STATA (Stata MP, version 15; StataCorp LP). RESULTS: 164 specialists (45 oncologists, 86 surgeons and 33 pathologists) participated. 80.5% regularly attended colorectal multidisciplinary team (MDT) meetings. 89.63% and 59.26% of specialists reported that MSI status was likely or definitely to influence prognosis in colon cancer and recommendations for adjuvant therapy in Stage II colon cancer respectively. IRT modelling was achieved in 17 pathological features for prognosis. MSI IRT score was 4.47 (95% CI: 4.05-4.68). IRT modelling was achieved in 10 pathological features for adjuvant therapy. MSI IRT score was 3.62 (2.89-4.15). MSI ranked 10 (of 17) in order of importance in determining prognosis and ranked three (of 10) in guiding adjuvant therapy. CONCLUSION: MSI status is considered an important biomarker when selecting patients for adjuvant therapy in Stage II colon cancer. MSI is also considered useful in prognostication of colon cancer. MSI status was ranked similar to the tumour grade of differentiation and the presence of perineural invasion.

Optimal Isolation Protocols for Examining and Interrogating Mononuclear Phagocytes From Human Intestinal Tissue.

The human intestine contains numerous mononuclear phagocytes (MNP), including subsets of conventional dendritic cells (cDC), macrophages (Mf) and monocytes, each playing their own unique role within the intestinal immune system and homeostasis. The ability to isolate and interrogate MNPs from fresh human tissue is crucial if we are to understand the role of these cells in homeostasis, disease settings and immunotherapies. However, liberating these cells from tissue is problematic as many of the key surface identification markers they express are susceptible to enzymatic cleavage and they are highly susceptible to cell death. In addition, the extraction process triggers immunological activation/maturation which alters their functional phenotype. Identifying the evolving, complex and highly heterogenous repertoire of MNPs by flow cytometry therefore requires careful selection of digestive enzyme blends that liberate viable cells and preserve recognition epitopes involving careful selection of antibody clones to enable analysis and sorting for functional assays. Here we describe a method for the anatomical separation of mucosa and submucosa as well as isolating lymphoid follicles from human jejunum, ileum and colon. We also describe in detail the optimised enzyme digestion methods needed to acquire functionally immature and biologically functional intestinal MNPs. A comprehensive list of screened antibody clones is also presented which allows for the development of high parameter flow cytometry panels to discriminate all currently identified human tissue MNP subsets including pDCs, cDC1, cDC2 (langerin+ and langerin-), newly described DC3, monocytes, Mf1, Mf2, Mf3 and Mf4. We also present a novel method to account for autofluorescent signal from tissue macrophages. Finally, we demonstrate that these methods can successfully be used to sort functional, immature intestinal DCs that can be used for functional assays such as cytokine production assays.

Association Between Microsatellite Instability Status and Peri-Operative Release of Circulating Tumour Cells in Colorectal Cancer.

Microsatellite instability (MSI) in colorectal cancer (CRC) is a marker of immunogenicity and is associated with an increased abundance of tumour infiltrating lymphocytes (TILs). In this subgroup of colorectal cancer, it is unknown if these characteristics translate into a measurable difference in circulating tumour cell (CTC) release into peripheral circulation. This is the first study to compare MSI status with the prevalence of circulating CTCs in the peri-operative colorectal surgery setting. For this purpose, 20 patients who underwent CRC surgery with curative intent were enrolled in the study, and peripheral venous blood was collected at pre- (t1), intra- (t2), immediately post-operative (t3), and 14-16 h post-operative (t4) time points. Of these, one patient was excluded due to insufficient blood sample. CTCs were isolated from 19 patients using the IsofluxTM system, and the data were analysed using the STATA statistical package. CTC number was presented as the mean values, and comparisons were made using the Student t-test. There was a trend toward increased CTC presence in the MSI-high (H) CRC group, but this was not statistically significant. In addition, a Poisson regression was performed adjusting for stage (I-IV). This demonstrated no significant difference between the two MSI groups for pre-operative time point t1. However, time points t2, t3, and t4 were associated with increased CTC presence for MSI-H CRCs. In conclusion, there was a trend toward increased CTC release pre-, intra-, and post-operatively in MSI-H CRCs, but this was only statistically significant intra-operatively. When adjusting for stage, MSI-H was associated with an increase in CTC numbers intra-operatively and post-operatively, but not pre-operatively.

Robotic colorectal surgery: more than a fantastic toy?

There has been a rapid rise in the number of robotic colorectal procedures worldwide since the da Vinci Surgical System robotic technology was approved for surgical procedures in the year 2000. Several recent meta-analyses and systematic reviews have shown a significant difference in outcomes between robotic and laparoscopic rectal cancer surgery. However, these results from pooled data have not been supported by the initial results reported from the Robotic assisted versus laparoscopic assisted resection for rectal cancer trial. In this article, we examine the current evidence for robotic colorectal surgery, assess its features and functionality, evaluate its learning curve and provide our perspective on its future.

Peristomal pyoderma gangrenosum: 12-year experience in a single tertiary referral centre.

BACKGROUND: Peristomal pyoderma gangrenosum (PPG) is an unusual but potentially devastating condition that is difficult to diagnose and manage. METHODS: This was a single centre, retrospective review of a prospectively collected database. Included were consecutive patients referred to a stoma therapy clinic at a single institution between 2005 and 2016. Main outcomes of interest were management strategies and outcome of patients with PPG including time to healing and recurrence. RESULTS: Of 1295 consecutive patients who underwent stoma formation, 12 patients with PPG were identified. The mean age at the time of diagnosis of PPG was 43.5 years (range 19-72 years). Five cases (41.7%) were associated with Crohn's disease and five cases (41.7%) with ulcerative colitis. The median duration of days between stoma formation and PPG diagnosis was 101.5 days (mean duration was 670 days (range 14-2641 days)). Nearly all patients (91.7%) were referred to a dermatologist. Majority (66.7%) were managed in an outpatient setting. For those requiring inpatient management, the mean length of stay was 13.5 days (range 3-31 days). Five patients had a biopsy and seven patients were diagnosed with PPG by dermatologist without biopsy. A range of oral and topical steroids, steroid injections, dressings, anti-inflammatories, antibiotics, tacrolimus and analgesia was used in the management of PPG. All patients achieved complete healing of PPG, with only one patient developing a recurrence of PPG. The mean duration of time to achieve complete healing of PPG was 282 days (range 28-1751 days). DISCUSSION: Medical management of PPG was effective with complete healing and low recurrence. The average duration to complete healing of PPG was approximately 9 months.

Association of Mechanical Bowel Preparation and Oral Antibiotics Before Elective Colorectal Surgery With Surgical Site Infection: A Network Meta-analysis.

Importance: There has been a resurgence of interest in the use of mechanical bowel preparation (MBP) and oral antibiotics (OAB) before elective colorectal surgery. Until now, clinical trials and meta-analyses have not compared all 4 approaches (MBP with OAB, OAB only, MBP only, or no preparation) simultaneously. Objective: To perform a network meta-analysis to clarify which approach in colorectal surgery is associated with the lowest rate of surgical site infection (SSI). Data Sources: Five electronic databases were searched, including PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ACP Journal Club. and Database of Abstracts of Review of Effectiveness from database inception to November 27, 2017. Study Selection: Only data from randomized clinical trials were included. Inclusion criteria were RCTs that reported on SSI rates or other complications based on MBP or OAB status. Quality of studies was appraised by the Cochrane Collaboration risk of bias tool. Data Extraction and Synthesis: The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Main Outcomes and Measures: Total, incisional, and organ/space SSI rates. Secondary outcomes included rates of anastomotic leak, mortality, readmissions/reoperations, urinary tract infection, and pulmonary complications. Results: Thirty-eight randomized clinical trials among 8458 patients (52.1% male) were included, providing 4 direct comparisons and 2 indirect comparisons for 8 outcome measures. On Bayesian analysis, MBP with OAB vs MBP only was associated with reduced SSI (odds ratio [OR], 0.71; 95% equal-tail credible interval [CrI], 0.57-0.88). There was no significant difference between MBP with OAB vs OAB only (OR, 0.95; 95% CrI, 0.56-1.62). Oral antibiotics without MBP was not associated with a statistically significant reduction in SSI compared with any other group (except for a risk reduction in organ/space SSI when indirectly compared with no preparation) (OR, 0.13; 95% CrI, 0.02-0.55). There was no difference in SSI between MBP only vs no preparation (OR, 0.84; 95% CrI, 0.69-1.02). Conclusions and Relevance: In this network meta-analysis of randomized clinical trials, MBP with OAB was associated with the lowest risk of SSI. Oral antibiotics only was ranked as second best, but the data available on this approach were limited. There was no difference between MBP only vs no preparation. In addition, there was no difference in rates of anastomotic leak, readmissions, or reoperations between any groups.

The Potential Value of Immunotherapy in Colorectal Cancers: Review of the Evidence for Programmed Death-1 Inhibitor Therapy.

Colorectal cancers (CRCs) have been identified as potential targets for immunotherapy with programmed cell death (PD)-1 inhibitors. English-language publications from MedLine and Embase that evaluated PD-1/PD ligand 1 (PD-L1) in the CRC tumor microenvironment and clinical trials that assessed PD-1 inhibitors were included. Sixteen abstracts were screened. Fifteen met the inclusion criteria. After review of the full texts, this resulted in a final reference list of 8 studies eligible for review. Five studies that assessed PD-1/PD-L1 in CRC and 3 trials that assessed PD-1 inhibitors were included. PD-1-positive (PD-1+) tumor-infiltrating lymphocytes and PD-L1+ cancer cells featured more prominently in high-level microsatellite instability (MSI-H) CRCs compared with microsatellite stable (MSS) CRCs, except in 1 study in which PD-L1 expression was higher in MSS CRCs. In the 3 trials that assessed PD-1 inhibitor, all 3 studies recruited patients with metastatic CRC (mCRC). One study also included patients with recurrent CRC. The objective response according to the Response Evaluation Criteria in Solid Tumors criteria was 0% (19 CRC patients with unknown microsatellite instability status) in the nivolumab study. In the pembrolizumab study, the objective response to PD-1 inhibitor was 40% and 0% in patients with MSI-H and MSS mCRC, respectively (10 patients in the MSI-H group, 18 patients in the MSS group). Seventy-eight percent of the patients in the MSI-H mCRC group compared with 11% in the MSS mCRC group (P < .005) showed no further disease progression at 12 weeks. In the nivolumab with or without ipilimumab study, objective partial response at 12 weeks to PD-1 inhibitor with or without cytotoxic T-lymphocyte-associated protein 4 inhibitor was 25.5% to 33.3% and 5% in the MSI-H and MSS groups, respectively (100 patients in the MSI-H group, 20 patients in the MSS group). Clinical trials that assessed PD-1 inhibitor immunotherapy in patients with CRC have recruited only small cohorts of patients with mCRC. Studies on the tumor microenvironment have been on the basis of archival specimens with different antibody PD-1 and PD-L1 preparations for immunohistochemistry, independent from immunotherapy trials. Immunotherapy with PD-1 therapy has potential benefit for immunogenic MSI-H CRCs whereas there is no evidence to date to suggest immunotherapy benefit in MSS CRCs. The available data are limited, and there is no information on non-mCRCs. Future trials are under way to determine its benefits.