Search

Background Objective Methods Results Conclusions Colonoscopy is a key component of surveillance after colorectal cancer (CRC) resection. Surveillance intervals for colonoscopy vary across the world, with a limited evidence‐base to support guidelines.To evaluate the timing and outcome of colonoscopies after CRC resection.Retrospective cohort study on prospectively collected data. Included adult patients under surveillance following CRC resection. Patients with organ transplant, inflammatory bowel disease or colon cancer syndromes were excluded. The outcomes of the first (up to) three follow‐up colonoscopies were audited and classified for presence of advanced neoplasia (advanced adenoma or adenocarcinoma).980 patients underwent at least one follow‐up colonoscopy with a median time to first colonoscopy of 12.4 months. The findings included 2.7% CRC and 13.2% advanced adenoma. Older age, stage IV disease, and synchronous cancers at surgery were significantly associated with a finding of advanced neoplasia at first colonoscopy. 562 patients underwent a second colonoscopy (median of 35 months after the first surveillance colonoscopy) with findings of 1.8% CRC and 11.4% advanced adenoma. Advanced adenoma on prior colonoscopy was associated with finding advanced neoplasia at the second colonoscopy. 288 patients underwent a third colonoscopy (median of 37 months from the preceding colonoscopy), with similar outcomes of advanced neoplasia being associated with advanced adenoma at the previous colonoscopy. 43 (4.4%) patients developed CRC whilst on surveillance.Timely surveillance after CRC resection is important for detecting advanced neoplasia, and prolonged intervals between colonoscopies in the early years after surgery should be avoided. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions Colorectal cancer (CRC) screening programs are most effective at reducing disease incidence and mortality through sustained screening participation. A novel blood test modality is being explored for CRC screening, but it is unclear whether it will provide sustained screening participation. This study aimed to investigate whether a circulating tumor DNA (ctDNA) blood test improved CRC screening re‐participation when compared with a fecal immunochemical test (FIT) and to define the predictors of sustained CRC screening in an Australian population.South Australians who initially participated in CRC screening using a ctDNA blood test (n = 36) or FIT (n = 547) were offered the same CRC screening test approximately 2 years later through an extended phase of a randomized controlled trial. Surveys collected demographic, psychosocial, and clinical information. Predictors of CRC screening re‐participation were explored using chi‐square, Wilcoxon tests, and logistic regression.Participants offered a second ctDNA blood test were equally likely to re‐participate in CRC screening as those who completed a FIT in the first round and who were offered the same test (61% vs 66% re‐participation respectively, P = 0.6). CRC fatalism, health activation, and self‐efficacy were associated with repeated screening participation. Test awareness was predictive of repeated FIT‐based CRC screening.Targeted interventions to improve CRC screening awareness and increase patient health activation may improve CRC screening adherence. A ctDNA blood test may be a suitable CRC screening option to maintain CRC screening adherence in people who do not participate in screening with FIT. [ABSTRACT FROM AUTHOR]

Background: The risk of recurrence after completion of curative‐intent treatment of colorectal cancer (CRC) is hard to predict. Post‐treatment assaying for circulating tumor DNA (ctDNA) is an encouraging approach for stratifying patients for therapy, but the prognostic value of this approach is less explored. This study aimed to determine if detection of methylated BCAT1 and IKZF1 following completion of initial treatment identified patients with a poorer recurrence‐free survival (RFS). Methods: 142 CRC stage I‐III cases with at least 2 years of follow up (unless recurrence was evident sooner) and a methylated BCAT1/IKZF1 test result between 2 weeks and 12 months after completion of initial treatment were eligible for study inclusion. The association between BCAT1/IKZF1 and RFS was assessed by the log‐rank (Mantel‐Cox) method. Cox proportional hazard regression analysis was used for multivariable survival analysis. Results: Thirty‐three (23.2%) had recurrence at a median 1.6y (interquartile range: 0.8–2.4). Methylated BCAT1/IKZF1 was detected in 19 of the 142 patients (13.4%) and was associated with a significant risk of recurrence (hazard ratio [HR] 5.7, 95%CI: 1.9–17.3, p = 0.002). Three‐year RFS for patients with or without detectable methylated BCAT1/IKZF1 was 56.5% and 83.3%, respectively. Multivariable analysis showed that detection of methylated BCAT1/IKZF1 (HR = 2.6, p = 0.049) and site of the primary tumor (HR = 4.2, p = 0.002) were the only significant prognostic indicators of poor RFS. Conclusions: BCAT1/IKZF1 methylation testing after curative‐intent treatment is an independent prognostic indicator for RFS and identifies a subgroup at high risk. Personalized surveillance is warranted for patients with these ctDNA biomarkers detectable after curative‐intent treatment. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is rising in incidence in young adults, and this observation is currently unexplained. We investigated whether having a personal history of type 2 diabetes mellitus (T2D) was a potential risk factor for young‐onset colorectal cancer (YOCRC). Methods: The South Australian Young Onset (SAYO) CRC study is a series of young adults with CRC below age 55. Ninety unrelated YOCRC cases were recruited to the study. Personal history and detailed family history of T2D were obtained at face‐to‐face interview and confirmed from medical records. Whole exome sequencing was conducted on germline DNA from each CRC case. Controls for personal history studies of T2D were 240 patients with proven clear colonoscopies and no known CRC predispositions. Results: The median age of YOCRC cases was 44 years (18–54) and of controls was 45 years (18–54), and 53% of both cases and controls were females (P = 0.99). Left‐sided (distal) CRC was seen in 67/89 (75%) of cases. A personal history of T2D was confirmed in 17/90 (19%) YOCRC patients compared with controls (12/240, 5%; P < 0.001; odds ratio = 4.4; 95% confidence interval, 2.0–9.7). YOCRC patients frequently reported at least one first‐degree relative with T2D (32/85, 38%). Ten of 87 (12%) of YOCRC cases had CRC‐related pathogenic germline variants, however, no pathogenic variants in familial diabetes‐associated genes were seen. Conclusions: Though the mechanism remains unclear, our observations suggest that there is enrichment for personal history of T2D in YOCRC patients. Impact: A diagnosis of T2D could therefore potentially identify a subset of young adults at increased risk for CRC and in whom early screening might be appropriate. [ABSTRACT FROM AUTHOR]

Background: Differentially-methylated regions (DMRs) are characteristic of colorectal cancer (CRC) and some occur more frequently than common mutations. This study aimed to evaluate the clinical utility of assaying circulating cell-free DNA for methylation in BCAT1, IKZF1 and IRF4 for detection of CRC. Methods: A multiplexed real-time PCR assay targeting DMRs in each of the three genes was developed. Assay accuracy was explored in plasma specimens banked from observational cross-sectional trials or from volunteers scheduled for colonoscopy or prior to CRC surgery. Results: 1620 specimens were suitable for study inclusion including 184 and 616 cases with CRC and adenomas, respectively, and 820 cases without neoplasia (overall median age, 63.0 years; 56% males). Combining the PCR signals for all targeted DMRs returned the best sensitivity for CRC (136/184, 73.9%, 95% CI 67.1–79.7), advanced adenomas (53/337, 15.7%, 95% CI 12.0–20.1) and high-grade dysplastic (HGD) adenomas (9/35, 25.7%, 95% CI 14.0–42.3) with a 90.1%, specificity for neoplasia (739/820, 95% CI 87.9–92.0, p < 0.01). Detection of methylation in all three genes were more likely in CRC cases than those without it (OR 28.5, 95% CI 7.3–121.2, p < 0.0001). Of the 81 positive cases without neoplasia, 62 (76.5%) were positive by a single PCR replicate only and predominantly due to detection of methylated BCAT1 (53.2%). Single replicate positivity was significantly higher than that in CRC (26/136, 19.1%, p < 0.0001), and single BCAT1 replicate positivity was more likely in cases without neoplasia than in CRC (OR 17.7, 95% CI 6.6–43.3, p < 0.0001). When a positive result was limited to those with ≥ 1 PCR replicate positive for either IKZF1 or IRF4, or at least two replicates positive for BCAT1, the multi-panel test maintained a high sensitivity for CRC (131/184, 71.2%, 95% CI 64.3–77.3) and HGD adenomas (8/35, 22.9%, 95% CI 11.8–39.3, p = 0.029) but improved specificity significantly (772/820, 94.1%, 95% CI 92.3–95.6, p < 0.0001 vs. any PCR replicate positive). Conclusion: The multi-panel methylation assay differentiates cases with CRC from those without it and does so with high specificity when criteria for BCAT1 detection are applied. The marker panel is flexible and studies in those at average risk for CRC are now warranted to determine which panel configuration best suits screening goals. Trial registration: ACTRN12611000318987. Registered 25 March 2011, https://www.anzctr.org.au/ ACTRN12611000318987. [ABSTRACT FROM AUTHOR]

Background and Aim: Fecal immunochemical tests (FIT) are used to screen asymptomatic individuals aged 50–74 years for colorectal cancer (CRC) within the Australian screening program. Gastrointestinal symptoms or iron deficiency anemia (IDA) may also drive primary care physicians to request a FIT. This study aimed to examine factors that may increase neoplasia risk associated with a positive FIT, specifically age, gastrointestinal symptoms, or IDA. Methods: A retrospective audit was performed on colonoscopies performed in a single hospital in South Australia for a positive FIT (from all referral sources) between 2014 and 2017. Patients aged < 50 years, or who had a colonoscopy in the preceding 5 years, were excluded. A subgroup (n = 198) was evaluated to assess whether age ≥ 75 years, symptoms, or IDA, as well as other demographics, comorbidities, and medications, were associated with risk of neoplasia. Features found to be associated with risk for CRC or high‐risk adenoma were examined in the entire cohort using multivariate analysis. Results: Colonoscopies (750/4221, 17.8%) were completed in patients ≥ 50 years for a positive FIT. Of these, 7.6% (n = 57) also had gastrointestinal symptoms, 5.5% (n = 41) IDA, and 13.1% (n = 98) were ≥ 75 years. At colonoscopy, 2.8% (n = 21) were diagnosed with CRC and 23.2% (n = 174) with high‐risk adenoma. CRC was more prevalent in ≥ 75 years compared with 50–74 years (7.1% vs 2.1%, P = 0.005), and associated with symptoms (15.8% vs 1.7%, P < 0.001), and IDA (14.6% vs 2.1%, P < 0.001). Multivariate analysis showed that IDA (odds ratio 7.68, P < 0.001) and symptoms (odds ratio 10.37, P < 0.001), but not age, were independent risk factors for CRC. Conclusion: The presence of gastrointestinal symptoms or IDA, independent of age, is associated with an increased risk for CRC following a positive FIT. [ABSTRACT FROM AUTHOR]

Background: The sensitive detection of recurrent colorectal cancer (CRC) by the measurement of circulating tumor DNA (ctDNA) might improve the chance of a cure. This study compared a quantitative methylated ctDNA test with carcinoembryonic antigen (CEA) in the setting of surveillance for recurrence.Methods: Blood samples collected either during surveillance or within 12 months of the confirmation of recurrence were assayed for ctDNA (methylated branched-chain amino acid transaminase 1 [BCAT1]/Ikaros family zinc-finger 1 protein [IKZF1]) and CEA. The optimal ctDNA threshold was determined by receiver operating characteristic analysis, and the test performance for the detection of recurrence was compared with CEA (5 ng/mL threshold).Results: The study cohort comprised 144 eligible patients and included 50 recurrence events. The sensitivity of the methylated ctDNA test for recurrence was 66.0% (95% confidence interval [CI], 57.1%-69.3%), which was significantly higher than the sensitivity of CEA (31.9%; 95% CI, 22.8%-36.6%; P < .001). The sensitivity for resectable recurrence (n = 20) was also higher (ctDNA, 60.0%; CEA, 20.0%; P = .01). The specificity did not differ between the tests (ctDNA, 97.9%; 95% CI, 93.2%-99.6%; CEA, 96.4%; 95% CI, 91.4%-99.0%). When adjustments were made for other predictors of the presence of recurrence, a positive ctDNA test was an independent predictor (odds ratio, 155.7; 95% CI, 17.9-1360.6; P < .001), whereas CEA was not (odds ratio, 2.5; 95% CI, 0.3-20.6; P = .407).Conclusions: The quantitative ctDNA test showed superior sensitivity in comparison with CEA without a difference in the specificity for detecting recurrent CRC. Longitudinal studies are warranted to further assess the utility (specifically the survival benefit) of methylated BCAT1/IKZF1 ctDNA in the surveillance of patients with CRC. [ABSTRACT FROM AUTHOR]

Purpose: Methylation in IKZF1 and BCAT1 are common events in colorectal cancer (CRC). They are often detected in blood as circulating tumor DNA (ctDNA) at diagnosis and disappear after surgery in most CRC patients. A prospective study was conducted to determine the relationship between detection of these markers following surgery and risk for residual disease and for recurrence.Methods: ctDNA status with methylated BCAT1 and IKZF1 was determined within 12 months of surgical resection of CRC, and was related to presence of or risk for residual disease (margins involved, metastases present or nature of node involvement), and to recurrence-free survival.Results: Blood was collected from 172 CRC patients after surgery and 28 (16%) were ctDNA positive. Recurrence was diagnosed in 23 of the 138 with clinical follow-up after surgery (median follow-up 23.3 months, IQR 14.3-29.5). Multivariate modeling indicated that features suggestive of residual disease were an independent predictor of post-surgery ctDNA status: cases with any of three features (close resection margins, apical node involved, or distant metastases) were 5.3 times (95% CI 1.5-18.4, p = 0.008) more likely to be ctDNA positive. Multivariate analysis showed that post-surgery ctDNA positivity was independently associated with an increased risk of recurrence (HR 3.8, 1.5-9.5, p = 0.004).Conclusions: CRC cases positive for methylated ctDNA after surgery are at increased risk of residual disease and subsequently recurrence. This could have implications for guiding recommendations for adjuvant therapy and surveillance strategies. Randomized studies are now indicated to determine if monitoring cases with these biomarkers leads to survival benefit. [ABSTRACT FROM AUTHOR]

Objectives Faecal immunochemical test accuracy may be adversely affected when samples are exposed to high temperatures. This study evaluated the effect of two sample collection buffer formulations (OC-Sensor, Eiken) and storage temperatures on faecal haemoglobin readings. Methods Faecal immunochemical test samples returned in a screening programme and with ≥10 µg Hb/g faeces in either the original or new formulation haemoglobin stabilizing buffer were stored in the freezer, refrigerator, or at room temperature (22℃–24℃), and reanalysed after 1–14 days. Samples in the new buffer were also reanalysed after storage at 35℃ and 50℃. Results were expressed as percentage of the initial concentration, and the number of days that levels were maintained to at least 80% was calculated. Results Haemoglobin concentrations were maintained above 80% of their initial concentration with both freezer and refrigerator storage, regardless of buffer formulation or storage duration. Stability at room temperature was significantly better in the new buffer, with haemoglobin remaining above 80% for 20 days compared with six days in the original buffer. Storage at 35℃ or 50℃ in the new buffer maintained haemoglobin above 80% for eight and two days, respectively. Conclusion The new formulation buffer has enhanced haemoglobin stabilizing properties when samples are exposed to temperatures greater than 22℃. [ABSTRACT FROM AUTHOR]

Objectives Positive rates in faecal immunochemical test (FIT)-based colorectal cancer screening programmes vary, suggesting that differences between programmes may affect test results. We examined whether demographic, pathological, behavioural, and environmental factors affected haemoglobin concentration and positive rates where samples are mailed. Methods A retrospective cohort study; 34,298 collection devices were sent, over five years, to screening invitees (median age 60.6). Participant demographics, temperature on sample postage day, and previous screening were recorded. Outcomes from colonoscopy performed within a year following FIT were collected. Multivariate logistic regression identified significant predictors of test positivity. Results Higher positive rate was independently associated with male gender, older age, lower socioeconomic status, and distally located neoplasia, and negatively associated with previous screening (p < 0.05). Older males had higher faecal haemoglobin concentrations and were less likely to have a false positive result at colonoscopy (p < 0.05). High temperature on the sample postage day was associated with reduced haemoglobin concentration and positivity rate (26–35℃: Odds ratio 0.78, 95% confidence interval 0.66–0.93), but was not associated with missed significant neoplasia at colonoscopy (p > 0.05). Conclusions Haemoglobin concentrations, and therefore FIT positivity, were affected by factors that vary between screening programmes. Participant demographics and high temperature at postage had significant effects. The impact of temperature could be reduced by seasonal scheduling of invitations. The importance of screening, and following up positive test results, particularly in older males, should be promoted. [ABSTRACT FROM AUTHOR]

Background: Specific genes, such as BCAT1 and IKZF1, are methylated with high frequency in colorectal cancer (CRC) tissue compared to normal colon tissue specimens. Such DNA may leak into blood and be present as cell-free circulating DNA. We have evaluated the accuracy of a novel blood test for these two markers across the spectrum of benign and neoplastic conditions encountered in the colon and rectum.Methods: Circulating DNA was extracted from plasma obtained from volunteers scheduled for colonoscopy for any reason, or for colonic surgery, at Australian and Dutch hospitals. The extracted DNA was bisulphite converted and analysed by methylation specific real-time quantitative PCR (qPCR). A specimen was deemed positive if one or more qPCR replicates were positive for either methylated BCAT1 or IKZF1 DNA. Sensitivity and specificity for CRC were estimated as the primary outcome measures.Results: Plasma samples were collected from 2105 enrolled volunteers (mean age 62 years, 54 % male), including 26 additional samples taken after surgical removal of cancers. The two-marker blood test was run successfully on 2127 samples. The test identified 85 of 129 CRC cases (sensitivity of 66 %, 95 % CI: 57-74). For CRC stages I-IV, respective positivity rates were 38 % (95 % CI: 21-58), 69 % (95 % CI: 53-82), 73 % (95 % CI: 56-85) and 94 % (95 % CI: 70-100). A positive trend was observed between positivity rate and degree of invasiveness. The colonic location of cancer did not influence assay positivity rates. Gender, age, smoking and family history were not significant predictors of marker positivity. Twelve methylation-positive cancer cases with paired pre- and post-surgery plasma showed reduction in methylation signal after surgery, with complete disappearance of signal in 10 subjects. Sensitivity for advanced adenoma (n = 338) was 6 % (95 % CI: 4-9). Specificity was 94 % (95 % CI: 92-95) in all 838 non-neoplastic pathology cases and 95 % (95 % CI: 92-97) in those with no colonic pathology detected (n = 450).Conclusions: The sensitivity for cancer of this two-marker blood test justifies prospective evaluation in a true screening population relative to a proven screening test. Given the high rate of marker disappearance after cancer resection, this blood test might also be useful to monitor tumour recurrence.Trial Registration: ACTRN12611000318987 . [ABSTRACT FROM AUTHOR]

Objective Inhibition of food intake and glucose homeostasis are both promoted when nutrients stimulate enteroendocrine cells (EEC) to release gut hormones. Several specific nutrient receptors may be located on EEC that respond to dietary sugars, amino acids and fatty acids. Bypass surgery for obesity and type II diabetes works by shunting nutrients to the distal gut, where it increases activation of nutrient receptors and mediator release, but cellular mechanisms of activation are largely unknown. We determined which nutrient receptors are expressed in which gut regions and in which cells in mouse and human, how they are associated with different types of EEC, how they are activated leading to hormone and 5-HT release. Design and results mRNA expression of 17 nutrient receptors and EEC mediators was assessed by quantitative PCR and found throughout mouse and human gut epithelium. Many species similarities emerged, in particular the dense expression of several receptors in the distal gut. Immunolabelling showed specific colocalisation of receptors with EEC mediators PYY and GLP-1 (L-cells) or 5-HT (enterochromaffin cells). We exposed isolated proximal colonic mucosa to specific nutrients, which recruited signalling pathways within specific EEC extracellular receptor-regulated kinase (p-ERK) and calmodulin kinase II (pCAMKII), as shown by subsequent immunolabelling, and activated release of these mediators. Aromatic amino acids activated both pathways in mouse, but in humans they induced only pCAMKII, which was colocalised mainly with 5-HT expression. Activation was pertussis toxin-sensitive. Fatty acid (C12) potently activated p-ERK in human in all EEC types and evoked potent release of all three mediators. Conclusions Specific nutrient receptors associate with distinct activation pathways within EEC. These may provide discrete, complementary pharmacological targets for intervention in obesity and type II diabetes. [ABSTRACT FROM AUTHOR]

Helicobacter pylori infection and gastritis can cause symptoms suggestive of altered gastrointestinal function; however, it is unclear if H. pylori influences gastric motility. This study assessed gastric emptying rates in mouse models of gastritis. Gastritis was induced in C57BL/6 mice via ethanol treatment or via challenge with H. pylori or H. felis. Gastric emptying rates of nutrient and non-nutrient liquids were assessed with the non-invasive (13)C-breath test, and the results were compared to healthy mice. Gastric emptying of the non-nutrient liquid was unaltered with the presence of gastritis; however, gastric emptying of the nutrient liquid was accelerated after a 4-week infection with H. pylori. H. felis infection and ethanol treatment caused a more severe gastritis and disruptions to the normal gastric emptying. Changes to gastric emptying in mouse models of gastritis are associated with the presence of nutrients. Altered gastric emptying may contribute to symptoms commonly reported in humans with gastritis. [ABSTRACT FROM AUTHOR]

Background The role of Helicobacter pylori infection in iron deficiency during pregnancy is limited. The aim of the present study was to assess the relationship between Helicobacter infection and levels of iron stores in pregnant mice. Materials and Methods Female C57BL/6 mice were either inoculated with 108  H. pylori, Helicobacter felis or water. In the nonpregnant study, 15 mice from each group were sacrificed after 4 and 20 weeks of infection. In the pregnancy study, after 6 weeks of infection all female mice were mated and approximately 2 weeks after mating, half of the pregnant mice (n = 9/group) from each group were sacrificed. The remaining mice were allowed to give birth, and approximately 4 weeks after birth, mice were asphyxiated with CO2, followed by heart puncture, and killed by cervical dislocation. Serum ferritin and iron were determined with a micro-particle enzyme immunoassay method and by a timed-endpoint method. Results Serum iron levels in mice infected with H. felis were significantly ( p < .05) lowered compared to control (24%) and H. pylori (27%)-infected mice at 4 weeks of infection. Serum iron in the control, H. pylori and H. felis groups were significantly ( p < .05) elevated at 20 weeks by 39, 26 and 77%, respectively, compared to 4 weeks of infection. H. felis-infected mice had a significantly ( p < .05) decreased serum ferritin level during pregnancy (61%) compared to H. pylori-infected mice. Conclusion These results suggest that H. felis but not H. pylori infection causes an acute iron deficiency in normal and pregnant mice. [ABSTRACT FROM AUTHOR]

Ingestion of starch from corn (naturally enriched with (13)C) should produce (13)CO(2) after small intestinal digestion and (13)CO(2) and H(2) from colonic fermentation. This study used a combined (13)CO(2)/H(2) breath test to assess the digestion and fermentation of resistant starch and to show that the test could detect changes in digestibility due to cooking. Volunteers consumed 40 g digestible cornstarch with water (n = 8), or 40 g resistant cornstarch in liquid (n = 12) or cooked into a pancake (n = 4). Interval breath sampling was performed and analyzed for (13)CO(2) and H(2). Ingestion of resistant starch produced a double-peaked (13)CO(2) excretion curve. The first increase in (13)CO(2) occurred at the same time as excretion from digestible starch (55 +/- 9 and 68 +/- 9 min, respectively), which was due to small intestinal digestion. The second increase in (13)CO(2) was accompanied by an increase in H(2) excretion (432 +/- 15 and 428 +/- 48 min, respectively), which was indicative of colonic bacterial fermentation. Cooking resistant starch increased its degree of digestion from 36 to 72%. The (13)CO(2)/H(2) breath test can be used to estimate digestion and fermentation of starches in different physiologic and pathologic conditions. [ABSTRACT FROM AUTHOR]

Assesses the liquid and solid gastric emptying in the mouse using the octanoic acid breath test. Examination of gastric emptying rates of intralipid and liquid meals; Details on the intragastric separation of octanoic acid and natural enrichment of the pellet; Measurement of gastric emptying based on the ingestion of substrate.

Methylated circulating tumour DNA (ctDNA) blood tests for BCAT1/IKZF1 (COLVERA) and SEPT9 (Epi proColon) are used to detect colorectal cancer (CRC). However, there are no ctDNA assays approved for other gastrointestinal adenocarcinomas. We aimed to characterize BCAT1, IKZF1 and SEPT9 methylation in different gastrointestinal adenocarcinoma and non-gastrointestinal tumours to determine if these validated CRC biomarkers might be useful for pan-gastrointestinal adenocarcinoma detection. Tissue DNA methylation data from colorectal (COAD, READ), gastroesophageal (ESCA, STAD), pancreatic (PAAD) and cholangiocarcinoma (CHOL) adenocarcinoma cohorts within The Cancer Genome Atlas were used for differential methylation analyses. Clinicodemographic predictors of BCAT1, IKZF1 and SEPT9 methylation, and the selectivity of hypermethylated BCAT1, IKZF1 and SEPT9 for colorectal adenocarcinomas in comparison to other cancers were each explored with beta regression. Hypermethylated BCAT1, IKZF1 and SEPT9 were each differentially methylated in colorectal and gastroesophageal adenocarcinomas. IKZF1 was differentially methylated in pancreatic adenocarcinoma. Hypermethylated DNA biomarkers BCAT1, IKZF1 and SEPT9 were largely stable across different stages of disease and were highly selective for gastrointestinal adenocarcinomas relative to other cancer types. Existing CRC methylated ctDNA blood tests for BCAT1/IKZF1 and SEPT9 might be usefully repurposed for use in other gastrointestinal adenocarcinomas and warrant further prospective ctDNA studies. [ABSTRACT FROM AUTHOR]

The APCmin/+ mouse is commonly used in cancer research and is just one of many genetically altered models that is currently being developed. With high numbers of breeding programs, it is important to have a simple method that can be used to genotype the mice non-invasively. Here we report a reproducible method for genotyping mice with DNA extracted from fecal samples. Comparison of fecal results with those obtained from intestinal tissue DNA and clinical outcome (presence/absence of tumors) showed this technique to have 100% accuracy. This noninvasive method of genotyping may be applied to other transgenic mouse models. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) has a high rate of recurrence, in particular for advanced disease, but prognosis based on staging and pathology at surgery can have limited efficacy. The presence of circulating tumor DNA (ctDNA) at diagnosis could be used to improve the prediction for disease recurrence. Objectives: To assess the impact of detecting methylated BCAT1/IKZF1 ctDNA at diagnosis in combination with demographic, lifestyle, clinical factors and tumor pathology, to assess predictive value for recurrence. Design: A retrospective cohort study. Methods: The cohort included 180 patients (36 with recurrent CRC), who had undergone complete treatment and surveillance for a minimum of 3 years. Participant clinical details and ctDNA methylated BCAT1 / IKZF1 results were compared between those with and without recurrence, and cox regression analysis assessed each factor on disease-free survival. Results: Clinical factors independently associated with reduced disease-free survival included nodal involvement (HR = 3.83, 95% CI 1.56-9.43, P =.003), M1 stage (HR = 4.41, 95% CI 1.18-16.45, P =.027), a resection margin less than 2 mm (HR = 4.60, 95% CI 1.19-17.76, P =.027), perineural involvement (HR = 2.50, 95% CI 1.01-6.17, P =.047) and distal tumors (HR = 3.13, 95% CI 1.07-9.18, P =.037). Methylated BCAT1 / IKZF1 was detected in 51.7% (93/180) of pre-treatment plasma samples. When a positive ctDNA finding was considered in combination with these clinical prognostic factors, there was improved predictive power of recurrence for patients with perineural involvement (HR = 4.44, 95% CI 1.92-10.26, P <.001), and it marginally improved the predictive factor for M1 stage (HR = 7.59, 95% CI 2.30-25.07, P =.001) and distal tumors (HR = 5.04, 95% CI 1.88-13.49, P =.001). Conclusions: Nodal invasion, metastatic disease, distal tumor site, low resection margins and perineural invasion were associated with disease recurrence. Pre-treatment methylated ctDNA measurement can improve the predictive value for recurrence in a subset of patients, particularly those with perineural involvement. Registration: Australian and New Zealand Clinical Trials Registry #12611000318987. [ABSTRACT FROM AUTHOR]

Background. Iron deficiency (ID) is a common micronutrient deficiency and the leading cause of anemia worldwide. ID can be caused by chronic occult blood loss from colorectal neoplasia including colorectal cancer (CRC) and advanced precancerous colorectal lesions. Current guidelines recommend colonoscopy in both men and postmenopausal women presenting with ID anemia (IDA). However, there is controversy on the investigation of patients presenting with a lower risk of CRC including younger women with ID and those with nonanemic ID (NAID). There is a need for a triaging tool to identify which ID patients may benefit from colonoscopy. The fecal immunochemical test (FIT) is sensitive for CRC screening in an asymptomatic population, but its role in ID patients is unclear. The aim of this study is to conduct a systematic review to determine the diagnostic accuracy of FIT for detecting CRC and advanced precancerous neoplasia in individuals presenting with ID with or without anemia. Methods and Analysis. This protocol conforms with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols and Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. A comprehensive search of the MEDLINE, Embase, and Web of Science databases will be undertaken for studies published after 2010 which involve patients with ID, who completed a FIT in the 6 months prior to colonoscopy, with FIT sensitivity and specificity calculated against the reference standard colonoscopy. The search will be limited to studies conducted after 2010 to reduce variability in colonoscopy quality. Risk of bias assessment will be conducted using the Quality Assessment of Diagnostic Accuracy Studies version 2. FIT sensitivity and specificity will be the primary measure of diagnostic accuracy, and data will be analysed using a random effects meta-analysis. Discussion. This review and meta-analysis will be the first to systematically explore the value of the FIT as a triaging tool for patients with ID. This trial is registered with CRD42022367162. [ABSTRACT FROM AUTHOR]

Background: Family history of colorectal cancer (CRC) is used to stratify individuals into risk categories which determine timing of initial screening and ongoing CRC surveillance. Evidence for long-term CRC risk following a normal index colonoscopy in family history populations is limited. Aims: To assess the incidence of advanced neoplasia and associated risk factors in a population undergoing surveillance colonoscopies due to family history of CRC. Methods: Surveillance colonoscopy findings were examined in 425 individuals with a family history of CRC, a normal index colonoscopy and a minimum of 10 years of follow-up colonoscopies. Advanced neoplasia risk was determined for three CRC family history categories (near-average, medium and high-risk), accounting for demographics and time after the first colonoscopy. Results: The median follow-up was 13.5 years (IQR 11.5–16.0), with an incidence of advanced neoplasia of 14.35% (61/425). The number of affected relatives and age of CRC diagnosis in the youngest relative did not predict the risk of advanced neoplasia (p > 0.05), with no significant differences in advanced neoplasia incidence between the family history categories (p = 0.16). Patients ≥ 60 years showed a fourfold (HR 4.14, 95% CI 1.33–12.89) higher advanced neoplasia risk during surveillance than those < 40 years at index colonoscopy. With each subsequent negative colonoscopy, the risk of advanced neoplasia at ongoing surveillance was reduced. Conclusions: The incidence of advanced neoplasia was low (14.35%), regardless of the family history risk category, with older age being the main risk for advanced neoplasia. Delaying onset of colonoscopy or lengthening surveillance intervals could be a more efficient use of resources in this population. [ABSTRACT FROM AUTHOR]

Background: Cell-free circulating tumour-derived DNA (ctDNA) can be detected by testing for methylated BCAT1 and IKZF1 DNA, which has proven sensitivity for colorectal cancer (CRC). A prospective correlative biomarker study between presence of methylated BCAT1 and IKZF1 in tissue and blood was conducted in cases with CRC to explore how detection of such ctDNA biomarkers relates to cancer characteristics, methylation in tissue and surgical resection of the primary cancer. Methods: Enrolled patients with invasive CRC had blood collected at diagnosis, prior to any treatment or surgery (peri-diagnostic sample). A subgroup of patients also had cancer and adjacent non-neoplastic tissue collected at surgical resection, as well as a second blood sample collected within 12 months of surgery (post-surgery sample). DNA was extracted from all samples and assayed for methylated BCAT1 and IKZF1 to determine the degree of methylation in tissue and the presence of ctDNA in blood. Results: Of 187 cases providing peri-diagnostic blood samples, tissue was available in 91, and 93 provided at least one post-surgery blood sample for marker analysis. Significant methylation of either BCAT1 or IKZF1 was seen in 86/91 (94.5%) cancer tissues, with levels independent of stage and higher than that observed in adjacent non-neoplastic specimens (P < 0.001). ctDNA methylated in BCAT1 or IKZF1 was detected in 116 (62.0%) cases at diagnosis and was significantly more likely to be detected with later stage (P < 0.001) and distal tumour location (P = 0.004). Of the 91 patients who provided pre-and post-surgery blood samples, 47 patients were ctDNA-positive at diagnosis and 35 (74.5%) became negative after tumour resection. Conclusion: This study has shown that BCAT1 and IKZF1 methylation are common events in CRC with almost all cancer tissues showing significant levels of methylation in the two genes. The presence of ctDNA in blood is stage-related and show rapid reversion to negative following surgical resection. Monitoring methylated BCAT1 and IKZF1 levels could therefore inform adequacy of surgical resection. Trial registration: Australian New Zealand Clinical Trial Registry number 12611000318987. Registered 25 March 2011. [ABSTRACT FROM AUTHOR]

The article explores the effect of gender on faecal haemoglobin levels by analyzing these concentrations in single sample faecal immunochemical tests completed within 2 week before scheduled colonoscopy. It investigated the baseline faecal haemoglobin level of males and females found to have a normal colon and the sensitivity of the same haemoglobin cut-off in males and females to detect advanced neoplasia. It notes that a statistically significant difference between sexes was evident.

1. The nutrient content of meals can affect the rate of gastric emptying. The aim of the present study was to assess whether the gastric emptying breath test could detect nutrient-induced delays in gastric emptying. 2. Following ingestion of a non-nutrient, carbohydrate- or lipid-containing liquid, mice were placed into chambers and breath samples were collected at intervals. Analysis of the rate of 13CO2 excretion allowed the calculation of gastric half-excretion time. 3. Gastric half-excretion time was significantly delayed by the incorporation of carbohydrate or lipid into the test liquid. 4. The present study has shown that the breath test is sensitive enough to detect changes induced by altering the nutrient and caloric content of test meals. [ABSTRACT FROM AUTHOR]

Purpose: There is increasing demand for colorectal cancer (CRC) surveillance, but healthcare capacity is limited. The burden on colonoscopy resources could be reduced by personalizing surveillance frequency using the fecal immunochemical test (FIT). This study will determine the safety, cost-effectiveness, and patient acceptance of using FIT to extend surveillance colonoscopy intervals for individuals at elevated risk of CRC. Methods: This multicenter, prospective, randomized controlled trial will invite participants who are scheduled for surveillance colonoscopy (due to a personal history of adenomas or a family history of CRC) and who have returned a low fecal hemoglobin (< 2 μg Hb/g feces; F-Hb) using a two-sample FIT (OC Sensor, Eiken Chemical Company) in the prior 3 years. A total of 1344 individuals will be randomized to either surveillance colonoscopy as scheduled or delayed by 1 or 2 years for individuals originally recommended a 3- or 5-year surveillance interval, respectively. The primary endpoint is incidence of advanced neoplasia (advanced adenoma and/or CRC). Secondary endpoints include cost-effectiveness and consumer acceptability of extending surveillance intervals, determined using surveys and discrete choice experiments. Conclusion: This study will establish the safety, cost-effectiveness, and acceptability of utilizing a low FIT Hb result to extend colonoscopy surveillance intervals in a cohort at elevated risk for CRC. This personalized approach to CRC surveillance will lead to a reduction in unnecessary colonoscopies, increases in healthcare savings, and a better patient experience. Trial registration: Registration was approved on December 9, 2019 with the Australian New Zealand Clinical Trials Registry ANZCTR 12619001743156. [ABSTRACT FROM AUTHOR]

Objective: This is to determine whether health beliefs regarding colorectal cancer (CRC) screening could predict discomfort with a change to CRC surveillance proposing regular faecal immunochemical tests (FIT) instead of colonoscopy. Methods: Eight hundred individuals enrolled in a South Australian colonoscopy surveillance programme were invited to complete a survey on surveillance preferences. Responses were analysed using binary logistic regression predicting discomfort with a hypothetical FIT‐based surveillance change. Predictor variables included constructs based on the Health Belief Model: perceived threat of CRC, perceived confidence to complete FIT and colonoscopy (self‐efficacy), perceived benefits from current surveillance and perceived barriers to FIT and colonoscopy. Results: A total of 408 participants (51%) returned the survey (complete data n = 303; mean age 62 years, 52% male). Most participants (72%) were uncomfortable with FIT‐based surveillance reducing colonoscopy frequency. This attitude was predicted by a higher perceived threat of CRC (OR = 1.03 [95% CI 1.01–1.04]), higher colonoscopy self‐efficacy (OR = 1.34 [95% CI 1.13–1.59]) and lower perceived barriers to colonoscopy (OR = 0.92 [95% CI 0.86–0.99]). Conclusions: Health beliefs regarding colonoscopy and perceived threat of CRC may be important to consider when changing CRC surveillance protocols. If guideline changes were introduced, these factors should be addressed to provide patients reassurance concerning the efficacy of the alternative protocol. [ABSTRACT FROM AUTHOR]

Background: The fecal immunochemical test (FIT) is widely used in colorectal cancer (CRC) screening, but limited data exist for its application in individuals at above-average risk for CRC who complete surveillance colonoscopies.To assess the accuracy, acceptability, and effectiveness of FIT in the interval between surveillance colonoscopies, for predicting advanced neoplasia (advanced adenoma or CRC) at the next colonoscopy.Individuals enrolled in an Australian surveillance program were included. Diagnostic accuracy was determined for 614 individuals completing a two-sample FIT (OC-Sensor) ≤ 3 months preceding surveillance colonoscopy. 386 Individuals were surveyed to assess acceptability of interval FIT. Additionally, a retrospective analysis was performed on 7331 individuals offered interval FIT between colonoscopies, where a positive FIT (≥ 20 µg hemoglobin/g feces) triggered an early colonoscopy. Associations between interval FIT results and advanced neoplasia were determined using regression analysis.FIT detected CRC and advanced adenoma with sensitivities of 60.0% (3/5) and 27.1% (35/129), respectively. Most (89.1%, 344/386) survey respondents preferred completing interval FIT every 1–2 years. The detection rate of interval FIT for advanced neoplasia decreased with increasing FIT completion. Individuals returning a positive FIT had a higher risk of advanced neoplasia than those who did not complete FIT. Positive interval FIT reduced time-to-diagnosis for CRC and advanced adenoma by a median of 30 and 20 months, respectively.Interval FIT was well accepted and enabled earlier detection of advanced neoplasia in individuals at above-average risk of CRC. Given that interval FIT predicts advanced neoplasia, it may be used to personalize surveillance colonoscopy intervals.Aim: The fecal immunochemical test (FIT) is widely used in colorectal cancer (CRC) screening, but limited data exist for its application in individuals at above-average risk for CRC who complete surveillance colonoscopies.To assess the accuracy, acceptability, and effectiveness of FIT in the interval between surveillance colonoscopies, for predicting advanced neoplasia (advanced adenoma or CRC) at the next colonoscopy.Individuals enrolled in an Australian surveillance program were included. Diagnostic accuracy was determined for 614 individuals completing a two-sample FIT (OC-Sensor) ≤ 3 months preceding surveillance colonoscopy. 386 Individuals were surveyed to assess acceptability of interval FIT. Additionally, a retrospective analysis was performed on 7331 individuals offered interval FIT between colonoscopies, where a positive FIT (≥ 20 µg hemoglobin/g feces) triggered an early colonoscopy. Associations between interval FIT results and advanced neoplasia were determined using regression analysis.FIT detected CRC and advanced adenoma with sensitivities of 60.0% (3/5) and 27.1% (35/129), respectively. Most (89.1%, 344/386) survey respondents preferred completing interval FIT every 1–2 years. The detection rate of interval FIT for advanced neoplasia decreased with increasing FIT completion. Individuals returning a positive FIT had a higher risk of advanced neoplasia than those who did not complete FIT. Positive interval FIT reduced time-to-diagnosis for CRC and advanced adenoma by a median of 30 and 20 months, respectively.Interval FIT was well accepted and enabled earlier detection of advanced neoplasia in individuals at above-average risk of CRC. Given that interval FIT predicts advanced neoplasia, it may be used to personalize surveillance colonoscopy intervals.Methods: The fecal immunochemical test (FIT) is widely used in colorectal cancer (CRC) screening, but limited data exist for its application in individuals at above-average risk for CRC who complete surveillance colonoscopies.To assess the accuracy, acceptability, and effectiveness of FIT in the interval between surveillance colonoscopies, for predicting advanced neoplasia (advanced adenoma or CRC) at the next colonoscopy.Individuals enrolled in an Australian surveillance program were included. Diagnostic accuracy was determined for 614 individuals completing a two-sample FIT (OC-Sensor) ≤ 3 months preceding surveillance colonoscopy. 386 Individuals were surveyed to assess acceptability of interval FIT. Additionally, a retrospective analysis was performed on 7331 individuals offered interval FIT between colonoscopies, where a positive FIT (≥ 20 µg hemoglobin/g feces) triggered an early colonoscopy. Associations between interval FIT results and advanced neoplasia were determined using regression analysis.FIT detected CRC and advanced adenoma with sensitivities of 60.0% (3/5) and 27.1% (35/129), respectively. Most (89.1%, 344/386) survey respondents preferred completing interval FIT every 1–2 years. The detection rate of interval FIT for advanced neoplasia decreased with increasing FIT completion. Individuals returning a positive FIT had a higher risk of advanced neoplasia than those who did not complete FIT. Positive interval FIT reduced time-to-diagnosis for CRC and advanced adenoma by a median of 30 and 20 months, respectively.Interval FIT was well accepted and enabled earlier detection of advanced neoplasia in individuals at above-average risk of CRC. Given that interval FIT predicts advanced neoplasia, it may be used to personalize surveillance colonoscopy intervals.Results: The fecal immunochemical test (FIT) is widely used in colorectal cancer (CRC) screening, but limited data exist for its application in individuals at above-average risk for CRC who complete surveillance colonoscopies.To assess the accuracy, acceptability, and effectiveness of FIT in the interval between surveillance colonoscopies, for predicting advanced neoplasia (advanced adenoma or CRC) at the next colonoscopy.Individuals enrolled in an Australian surveillance program were included. Diagnostic accuracy was determined for 614 individuals completing a two-sample FIT (OC-Sensor) ≤ 3 months preceding surveillance colonoscopy. 386 Individuals were surveyed to assess acceptability of interval FIT. Additionally, a retrospective analysis was performed on 7331 individuals offered interval FIT between colonoscopies, where a positive FIT (≥ 20 µg hemoglobin/g feces) triggered an early colonoscopy. Associations between interval FIT results and advanced neoplasia were determined using regression analysis.FIT detected CRC and advanced adenoma with sensitivities of 60.0% (3/5) and 27.1% (35/129), respectively. Most (89.1%, 344/386) survey respondents preferred completing interval FIT every 1–2 years. The detection rate of interval FIT for advanced neoplasia decreased with increasing FIT completion. Individuals returning a positive FIT had a higher risk of advanced neoplasia than those who did not complete FIT. Positive interval FIT reduced time-to-diagnosis for CRC and advanced adenoma by a median of 30 and 20 months, respectively.Interval FIT was well accepted and enabled earlier detection of advanced neoplasia in individuals at above-average risk of CRC. Given that interval FIT predicts advanced neoplasia, it may be used to personalize surveillance colonoscopy intervals.Conclusion: The fecal immunochemical test (FIT) is widely used in colorectal cancer (CRC) screening, but limited data exist for its application in individuals at above-average risk for CRC who complete surveillance colonoscopies.To assess the accuracy, acceptability, and effectiveness of FIT in the interval between surveillance colonoscopies, for predicting advanced neoplasia (advanced adenoma or CRC) at the next colonoscopy.Individuals enrolled in an Australian surveillance program were included. Diagnostic accuracy was determined for 614 individuals completing a two-sample FIT (OC-Sensor) ≤ 3 months preceding surveillance colonoscopy. 386 Individuals were surveyed to assess acceptability of interval FIT. Additionally, a retrospective analysis was performed on 7331 individuals offered interval FIT between colonoscopies, where a positive FIT (≥ 20 µg hemoglobin/g feces) triggered an early colonoscopy. Associations between interval FIT results and advanced neoplasia were determined using regression analysis.FIT detected CRC and advanced adenoma with sensitivities of 60.0% (3/5) and 27.1% (35/129), respectively. Most (89.1%, 344/386) survey respondents preferred completing interval FIT every 1–2 years. The detection rate of interval FIT for advanced neoplasia decreased with increasing FIT completion. Individuals returning a positive FIT had a higher risk of advanced neoplasia than those who did not complete FIT. Positive interval FIT reduced time-to-diagnosis for CRC and advanced adenoma by a median of 30 and 20 months, respectively.Interval FIT was well accepted and enabled earlier detection of advanced neoplasia in individuals at above-average risk of CRC. Given that interval FIT predicts advanced neoplasia, it may be used to personalize surveillance colonoscopy intervals. [ABSTRACT FROM AUTHOR]

Background and Aim: Surveillance colonoscopies may be delayed because of pressure on resources, such as the COVID‐19 pandemic. This study aimed to determine whether delayed surveillance colonoscopy increases the risk for advanced neoplasia and whether interval screening with faecal immunochemical tests (FITs) and other known risk factors can mitigate this risk. Methods: A retrospective cohort study of individuals undergoing surveillance colonoscopy for personal or family history of colorectal neoplasia was being provided with FIT between colonoscopies. Colonoscopy ≥ 6 months after the guideline‐recommended interval was considered "delayed." Individuals were stratified based on prime colonoscopy findings to nonneoplastic findings, non‐advanced adenoma, and advanced adenoma. The relative risk (RR) for developing advanced neoplasia was determined using a robust multivariable modified Poisson regression. Results: Of 2548 surveillance colonoscopies, 1457 (57.18%) were delayed. Prior advanced adenoma, older age (> 60 years) and nonparticipation in interval FIT were associated with increased risk for advanced neoplasia (P < 0.05). There was a trend to increased risk in those with prior advanced adenoma with an increasing colonoscopy delay (P trend = 0.01). In participants who did not complete interval FIT and having advanced adenoma in the prime colonoscopy, risk of advanced neoplasia was 2.48 times higher (RR = 2.48, 95% confidence interval: 1.20–5.13) in participants who had beyond 2 years of delayed colonoscopy compared with those with on‐time colonoscopy. Colonoscopy delay did not increase the risk of advanced neoplasia in participants with negative interval FIT results. Conclusion: Surveillance colonoscopy can be safely extended beyond 6 months in elevated colorectal cancer risk patients who do not have prior advanced adenoma diagnosis, particularly if interval FIT is negative. [ABSTRACT FROM AUTHOR]

Background: A blood assay measuring methylated BCAT1 and IKZF1 can detect recurrent colorectal cancer (CRC) with high sensitivity but suboptimal specificity. This study aimed to establish an upper reference limit (URL) of these biomarkers in a reference population without CRC, apply that threshold to detecting clinical recurrence in patients who had undergone definitive therapy for CRC, and compare the performance of the biomarkers with carcinoembryonic antigen (CEA). Methods: The level of methylation was reported as the aggregate methylated BCAT1 and IKZF1 expressed as a percentage of total plasma DNA. A reference population of patients confirmed to have no colorectal neoplasia (n = 857) was used to determine the URL. Test accuracy for clinical recurrence was determined in a post‐treatment surveillance population (n = 549; 77 recurrence cases). Results: A methylation level of 0.07%, corresponding to the 98th percentile in the reference population, was set as the URL. In the surveillance population, 60 patients had methylation levels above 0.07%, and 81.7% of these had recurrence. In comparison with no minimum threshold being applied, assay sensitivity with a URL of 0.07% yielded similar sensitivity (63.6% [CI, 51.9%‐74.3%] vs 64.9% [CI, 53.8%‐74.7%]; P =.87) and higher specificity (97.7% [CI, 95.9%‐98.8%] vs 91.3% [CI, 88.4%‐93.5%]; P <.001). The BCAT1/IKZF1 test was 2.5‐fold more sensitive than CEA for detecting recurrences considered amenable to surgery with curative intent (50.0% vs 20.8%; P =.016). Conclusions: Applying a threshold for positivity to the methylated BCAT1/IKZF1 blood assay improved the specificity for CRC recurrence without compromising sensitivity. Both the sensitivity and the specificity were superior to those of CEA. Applying a threshold for positivity to the methylated BCAT1/IKZF1 blood assay improves the specificity for colorectal cancer recurrence without compromising sensitivity. Higher specificity may reduce unnecessary follow‐up procedures and minimize patient anxiety. [ABSTRACT FROM AUTHOR]

Background: Rectal Cancer is a common malignancy. The current treatment approach for patients with locally advanced rectal cancer involves neoadjuvant chemoradiotherapy followed by surgical resection of the rectum. The resection can lead to complications and long-term consequences. A clinical complete response is observed in some patients after chemoradiotherapy. A number of recent studies have shown that patients can be observed safely after completing chemoradiotherapy (without surgery), provided clinical complete response has been achieved. In this approach, resection is reserved for cases of regrowth. This is called the watch and wait approach. This approach potentially avoids unnecessary surgical resection of the rectum and the resulting complications. In this study, we will prospectively investigate this approach.Methods: Adult patients with a diagnosis of rectal cancer planned to receive neoadjuvant long course chemoradiotherapy (± subsequent combination chemotherapy) will be consented into the study prior to commencing treatment. After completing the chemoradiotherapy (± subsequent combination chemotherapy), based on the clinical response, subjects will be allocated to one of the following arms: subjects who achieved a clinical complete response will be allocated to the watch and wait arm and others to the standard management arm (which includes resection). The aim of the study is to determine the rate of local failure and other safety and efficacy outcomes in the watch and wait arm. Patient reported outcome measures and the use of biomarkers as part of the clinical monitoring will be studied in both arms of the study.Discussion: This study will prospectively investigate the safety of the watch and wait approach. We will investigate predictive biomarkers (molecular biomarkers and imaging biomarkers) and patient reported outcome measures in the study population and the cost effectiveness of the watch and wait approach. This study will also help evaluate a defined monitoring schedule for patients managed with the watch and wait approach. This protocol covers the first two years of follow up, we are planning a subsequent study which covers year 3-5 follow up for the study population.Trial Registration: Name of the registry: Australia and New Zealand Clinical Trials Registry (ANZCTR).Trial Registration Number: Trial ID: ACTRN12619000207112 Registered 13 February 2019, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376810. [ABSTRACT FROM AUTHOR]

BACKGROUND: Detection of circulating cell-free DNA (ccfDNA) methylated in BCAT1 and IKZF1 is sensitive for detection of colorectal cancer (CRC), but it is not known if these biomarkers are present in other common adenocarcinomas. OBJECTIVE: Compare methylation levels of BCAT1 and IKZF1 in tissue and plasma from breast, prostate, and colorectal cancer patients. METHODS: Blood was collected from 290 CRC, 32 breast and 101 prostate cancer patients, and 606 cancer-free controls. Tumor and matched normal tissues were collected at surgery: 26 breast, 9 prostate and 15 CRC. DNA methylation in BCAT1 and IKZF1 was measured in blood and tissues. RESULTS: Either biomarker was detected in blood from 175/290 (60.3%) of CRC patients. The detection rate was higher than that measured in controls (48/606 (8.1%), OR = 18.2, 95%CI: 11.1–29.0). The test positivity rates in breast and prostate cancer patients were 9.4% (3/32) and 6.9% (7/101), respectively, and not significantly different to that measured in gender-matched controls (8.0% (33/382) females (OR = 0.84, 95%CI: 0.23–3.1) and 7.6% (26/318) males (OR = 0.86, 95%CI: 0.65–2.1). In tumor and non-neoplastic tissues, 93.5% (14/15) of CRC tumors were methylated in BCAT1 and/or IKZF1 (p < 0.004). Only 11.5% (3/26) and 44.4% (4/9) (p = 0.083) of breast and prostate tumors were hypermethylated in these two genes. CONCLUSIONS: Detection of circulating DNA methylated in BCAT1 and IKZF1 is sensitive and specific for CRC but not breast or prostate cancer. [ABSTRACT FROM AUTHOR]

Background and Aim: Clinically significant serrated polyps are precursors of colorectal cancers, with features considered high risk including size ≥10 mm, dysplasia, and presence of synchronous conventional adenoma. While these features have been described in cohorts undergoing screening colonoscopy, there is little information regarding the prevalence and patient characteristics associated with high‐risk sessile serrated polyps (SSPs) in those undergoing surveillance colonoscopy. Methods: Polyp pathology at the index and first follow‐up colonoscopy performed between 2004 and 2019 were examined in patients enrolled in a surveillance program because of an index finding of adenoma and/or SSP. Demographics and pathology features for SSP were compared between the colonoscopies. Results: Of 6297 patients undergoing index colonoscopy, 2035 underwent follow‐up colonoscopy after 3.3 years (interquartile range 2.1–4.8 years). The proportion with SSP decreased from 7.6% at index to 5.0% at follow‐up (P < 0.001); however, the proportion of SSPs that were considered high risk was not different between the colonoscopies (62.8% vs 62.4%). Female gender was associated with the presence of high‐risk SSP at index colonoscopy (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.28–2.06), while age ≥75 years (OR 3.38, 95% CI 1.67–6.81) and previous high‐risk SSP (OR 9.40, 95% CI 4.23–20.88) were independently associated with high‐risk SSP at follow‐up. Conclusions: The prevalence of SSP falls by one‐third at first follow‐up colonoscopy although the proportion of SSP with high‐risk features remains the same. While females were more likely to have a high‐risk SSP at the index colonoscopy, those at greatest risk for high‐risk SSP at follow‐up colonoscopy were age >75 years and an index high‐risk SSP. [ABSTRACT FROM AUTHOR]

Background: Early detection and removal of precursor lesions reduce colorectal cancer morbidity and mortality. Sessile serrated adenomas/polyps (SSP) are a recognized precursor of cancer, but there are limited studies on whether current screening techniques detect this pathology.Aims: To investigate the sensitivity of fecal immunochemical tests (FIT) and epigenetic biomarkers in blood for detection of SSP.Methods: A prospective study offered FIT and a blood test (Colvera for methylated BCAT1 and IKZF1) to adults referred for colonoscopy. Sensitivity of FIT and the blood test were determined for four types of pathology: low-risk conventional adenoma, high-risk adenoma, SSP, and absence of neoplasia. Comparisons were made for FIT positivity at 10 and 20 μg hemoglobin (Hb)/g feces.Results: One thousand eight hundred and eighty-two subjects completed FIT and underwent colonoscopy. One thousand four hundred and three were also tested for methylated BCAT1/IKZF1. The sensitivity of FIT (20 μg Hb/g feces) for SSP was 16.3%. This was lower than the sensitivity for high-risk adenomas (28.7%, p < 0.05), but no different to that for low-risk adenomas (13.1%) or no neoplasia (8.4%). A positive FIT result for SSP was not associated with demographics, morphology, concurrent pathology or intake of medications that increase bleeding risk. FIT sensitivity for SSP did not significantly increase through lowering the positivity threshold to 10 μg Hb/g feces (20.4%, p > 0.05). Sensitivity of the blood test for SSP was 8.8%, and 26.5% when combined with FIT.Conclusions: Both FIT and blood-based markers of DNA hypermethylation have low sensitivity for detection of SSP. Further development of sensitive screening tests is warranted. [ABSTRACT FROM AUTHOR]

Recurrence will develop in 30-50% of colorectal cancer ( CRC) cases despite apparent clearance following treatment. Carcinoembryonic antigen ( CEA) is the only guideline-recommended blood test for monitoring cases for recurrence, but its sensitivity and specificity are suboptimal. This observational study compared a novel 2-gene (methylated BCAT1 and IKZF1 DNA) blood test with CEA for detection of recurrent CRC. We conducted a paired comparison of the BCAT1/ IKZF1 test with CEA (cut-off 5 ng/ mL) in blood from patients in remission after treatment for primary CRC and undergoing surveillance. Blood collected in the 12 months prior to or 3 months after complete investigational assessment of recurrence status were assayed and the results compared by McNemar's test. Of 397 patients enrolled, 220 underwent satisfactory assessment for recurrence and 122 had blood testing performed within the prescribed period. In 28 cases with recurrent CRC, CEA was positive in 9 (32%; 95% CI 16-52%) compared to 19 (68%; 95% CI 48-84%) positive for methylated BCAT1/ IKZF1 ( P = 0.002). All samples that were CEA positive were also BCAT1/ IKZF1 positive. In 94 patients without clinically detectable recurrence, CEA was positive in 6 (6%, 95% CI 2-13%) and BCAT1/ IKZF1 in 12 (13%, 95% CI 7-21%), P = 0.210. The odds ratio of a positive CEA test for recurrence was 6.9 (95% CI 2-22) compared to 14.4 (5-39) for BCAT1/ IKZF1. The BCAT1/ IKZF1 test was more sensitive for recurrence than CEA and the odds of recurrence given a positive test was twice that of CEA. The BCAT1/ IKZF1 test should be further considered for monitoring cases for recurrence. [ABSTRACT FROM AUTHOR]

A randomized double-blind placebo-controlled study was conducted in children admitted to hospital with gastroenteritis (≥3 loose stools per day). All were treated for 5 days following admission with either zinc (Zn, 3 mg) or without Zn-fortified rice-based oral rehydration solution (ORS). 13C-sucrose breath test (SBT) and intestinal permeability (lactulose/rhamnose or L/R ratio) were performed concurrently prior to commencement of ORS with or without Zn and at day 5 post-admission. There was a significant improvement in the SBT results in both the Zn-fortified group, median (5th-95th percentile) 2.1% (0.4% to 8.3%) versus 4.4% (0.4% to 10.4%), P < .05, and control group, 1.4% (0.1% to 5.4%) versus 4.3% (0.4% to 11.4%), P < .05, between the day of admission and day 5 post-admission. In the Zn-fortified group, there was also a significant improvement in L/R ratio between the day of admission and day 5 post-admission, 53.0 (19.5-90.6) versus 17.7 (13.4-83.2), P < .05. Low levels of Zn improved intestinal permeability but did not enhance short-term recovery following diarrheal illness. [ABSTRACT FROM PUBLISHER]

The genes BCAT1 and IKZF1 are hypermethylated in colorectal cancer (CRC), but little is known about how this relates to gene expression. This study assessed the relationship between methylation and gene expression of BCAT1 and IKZF1 in CRC and adjacent non-neoplastic tissues. The tissues were obtained at surgery from 36 patients diagnosed with different stages of CRC (stage I n = 8, stage II n = 13, stage III n = 10, stage IV n = 5). Methylated BCAT1 and IKZF1 were detected in 92% and 72% CRC tissues, respectively, with levels independent of stage (P > .05). In contrast, only 31% and 3% of non-neoplastic tissues were methylated for BCAT1 and IKZF1, respectively (P < .001). The IKZF1 messenger RNA (mRNA) expression was significantly lower in the cancer tissues compared with that of non-neoplastic tissues, whereas the BCAT1 mRNA levels were similar. The latter may be due to the BCAT1 polymerase chain reaction assay detecting more than 1 mRNA transcript. Further studies are warranted to establish the role of the epigenetic silencing of IKZF1 in colorectal oncogenesis. [ABSTRACT FROM AUTHOR]