ORCID Profile
0000-0003-2451-0358
Current Organisation
Flinders Medical Centre
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Publisher: Springer Science and Business Media LLC
Date: 10-07-2018
DOI: 10.1007/S00432-018-2701-X
Abstract: 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. 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. 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). 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.
Publisher: Wiley
Date: 10-2016
DOI: 10.1002/CAM4.868
Publisher: Bentham Science Publishers Ltd.
Date: 03-2013
Publisher: SAGE Publications
Date: 14-05-2015
Abstract: 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 s les are mailed. A retrospective cohort study 34,298 collection devices were sent, over five years, to screening invitees (median age 60.6). Participant demographics, temperature on s le 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. 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 s le 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). 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.
Publisher: Wiley
Date: 12-2006
Publisher: Elsevier BV
Date: 12-2004
DOI: 10.1053/J.GASTRO.2004.08.061
Abstract: Visceral mechanoreceptors are critical for perceived sensations and autonomic reflex control of gastrointestinal function. However, the molecular mechanisms underlying visceral mechanosensation remain poorly defined. Degenerin/epithelial Na+ channel (DEG/ENaC) family ion channels are candidate mechanosensory molecules, and we hypothesized that they influence visceral mechanosensation. We examined the influence of the DEG/ENaC channel ASIC1 on gastrointestinal mechanosensory function, on gastric emptying, and on fecal output. We also compared its role in gastrointestinal and somatic sensory function. To assess the role of ASIC1 we studied wild-type and ASIC1-/- mice. Reverse-transcription polymerase chain reaction (RT-PCR) and Western blot analysis determined expression of ASIC1 messenger RNA and protein in vagal and spinal sensory ganglia. Colonic, gastroesophageal, and cutaneous afferent fibers were characterized by functional subtype and their mechanical stimulus-response relationships were determined. Gastric emptying was determined by using a 13CO2 breath test. Behavioral tests assessed somatic mechanical and thermal sensitivity. ASIC1 was expressed in sensory ganglia and was lost after disruption of the ASIC1 gene. Loss of ASIC1 increased mechanosensitivity in all colonic and gastroesophageal mechanoreceptor subtypes. In addition, ASIC1-/- mice showed almost double the gastric emptying time of wild-type mice. In contrast, loss of ASIC1 did not affect function in any of the 5 types of cutaneous mechanoreceptors, nor did it affect paw withdrawal responses or fecal output. ASIC1 influences visceral but not cutaneous mechanoreceptor function, suggesting that different mechanisms underlie mechanosensory function in gut and skin. The role of ASIC1 is highlighted by prolonging gastric emptying of a meal in ASIC1-/- animals.
Publisher: Wiley
Date: 12-08-2021
DOI: 10.5694/MJA2.51222
Publisher: Hindawi Limited
Date: 24-09-2022
DOI: 10.1111/ECC.13713
Abstract: 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. Eight hundred in iduals 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. 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]). 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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2005
DOI: 10.1097/01.MPG.0000168994.29181.C4
Abstract: The gastric emptying breath test (GEBT) is now routinely used in many centers. Validation studies in adults have shown that although there is a linear correlation between the GEBT and scintigraphy, the GEBT overestimates gastric half emptying time (GEt1/2) by a constant of approximately 60 minutes because of postgastric processing. It is therefore conventional to apply a "correction factor" to the GEBT result. Because = no similar validation studies have been performed in infants, the aim of this study was to directly characterize the postgastric processing of 13C octanoic acid in infants to assess the suitability of the standard correction factor for use in infants. The pattern of breath 13CO2 excretion after separate infusion of 13C octanoic acid into either the stomach or the duodenum was measured in 13 healthy preterm infants (6 male, 7 female). The raw 13CO2 half excretion time after intragastric (GEt1/2 raw) and intraduodenal (DEt1/2 raw) administration of C octanoic acid was calculated, and the difference between GEt1/2 raw and DEt1/2 raw (i.e., GEt1/2 raw - DEt1/2 raw) was directly compared with GEt1/2 corrected, derived by applying the standard correction factor to GEt1/2 raw. Values for GEt1/2 raw - DEt1/2 raw correlated significantly with GEt1/2 corrected. Our results show that the standard correction factor is appropriate for performing the GEBT in preterm infants.
Publisher: Wiley
Date: 09-03-2021
DOI: 10.1002/JGH3.12525
Abstract: The coronavirus disease 2019 (COVID‐19) global pandemic has affected elective procedures, including colonoscopy, worldwide. Delayed colorectal cancer surveillance may increase cancer risk. This study aimed to determine the impact of COVID‐19 on the proportion of surveillance colonoscopies booked and completed and the extent to which that surveillance was delayed. This was a retrospective analysis of colonoscopy data during the 3 months (April–June 2020) when clinical services were most affected by COVID‐19 in South Australia compared to the same period in 2019. Data on colonoscopies and responses to surveillance recall letters were reviewed to determine the numbers and proportions of colonoscopies that were delayed. During 2020, the total number of colonoscopies decreased by 51.1% ( n = 569) compared to 2019 ( n = 1164). In 2019, 45.5% ( n = 530) of colonoscopies were completed for surveillance, but this proportion decreased to 32.0% ( n = 182) during 2020, an overall decrease in the number of surveillance colonoscopies of 65.6%. Of surveillance colonoscopies that were due in 2020, 46.1% (134/291) were delayed months, a significant increase compared to 2019 (19.3% 59/306, P 0.001). A decrease in response to surveillance recall letters was only observed in patients ≥75 years, with more nonresponders (51.6%) in 2020 compared to that observed in 2019 (25.6%, P = 0.03). Significant delays in surveillance colonoscopies occurred during the COVID‐19 pandemic in South Australia. These effects are likely to be in areas more severely affected by the pandemic. Planning for post‐COVID‐19 colonoscopy capacity is required to avoid cancer progression due to delays in surveillance colonoscopies.
Publisher: Springer Science and Business Media LLC
Date: 05-03-2019
DOI: 10.1007/S10620-019-05569-8
Abstract: Early detection and removal of precursor lesions reduce colorectal cancer morbidity and mortality. Sessile serrated adenomas olyps (SSP) are a recognized precursor of cancer, but there are limited studies on whether current screening techniques detect this pathology. To investigate the sensitivity of fecal immunochemical tests (FIT) and epigenetic biomarkers in blood for detection of SSP. 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. 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). Sensitivity of the blood test for SSP was 8.8%, and 26.5% when combined with FIT. Both FIT and blood-based markers of DNA hypermethylation have low sensitivity for detection of SSP. Further development of sensitive screening tests is warranted.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Asian Pacific Organization for Cancer Prevention
Date: 11-01-2016
DOI: 10.7314/APJCP.2015.16.18.8455
Abstract: Poor participation rates are often observed in colorectal cancer (CRC) screening programs utilising faecal occult blood tests. This may be from dislike of faecal s ling, or having benign bleeding conditions that can interfere with test results. These barriers may be circumvented by offering a blood-based DNA test for screening. The aim was to determine if program participation could be increased by offering a blood test following faecal immunochemical test (FIT) non-participation. People were invited into a CRC screening study through their General Practice and randomised into control or intervention (n=600/group). Both groups were mailed a FIT (matching conventional screening programs). Participation was defined as FIT completion within 12wk. Intervention group non-participants were offered a screening blood test (methylated BCAT1/IKZF1). Overall participation was compared between the groups. After 12wk, FIT participation was 82% and 81% in the control and intervention groups. In the intervention 96 FIT non- participants were offered the blood test - 22 completed this test and 19 completed the FIT instead. Total screening in the intervention group was greater than the control (88% vs 82%, p<0.01). Of 12 invitees who indicated that FIT was inappropriate for them (mainly due to bleeding conditions), 10 completed the blood test (83%). Offering a blood test to FIT non-participants increased overall screening participation compared to a conventional FIT program. Blood test participation was particularly high in invitees who considered FIT to be inappropriate for them. A blood test may be a useful adjunct test within a FIT program.
Publisher: Springer Science and Business Media LLC
Date: 05-04-2007
Publisher: Wiley
Date: 24-01-2022
Abstract: Failure of colorectal cancer (CRC) treatment is due to residual disease, and its timely identification is critical for patient survival. Detecting CRC‐associated mutations in patient circulating cell‐free DNA is confounded by tumor mutation heterogeneity, requiring primary tumor sequencing to identify relevant mutations. In this study, we assessed BCAT1 and IKZF1 methylation levels to quantify circulating tumor DNA (ctDNA) and investigated whether this method can be used to assess tumor burden and efficacy of therapy. In 175 patients with CRC who were ctDNA‐positive pretreatment, ctDNA levels were higher with advancing stage ( P 0.05) and correlated with tumor diameter ( r = 0.35, P 0.001) and volume ( r = 0.58, P 0.01). After completion of treatment (median of 70 days [IQR 49‐109] after surgery, +/− radiotherapy, +/− chemotherapy), ctDNA levels were reduced in 98% (47/48) and were undetectable in 88% (42/48) of patients tested. For those with incomplete adjuvant chemotherapy after surgery, roughly half remained ctDNA‐positive (11/21, 52.4%). The presence of ctDNA after treatment was associated with disease progression (HR 9.7, 95%CI 2.5‐37.6) compared to no ctDNA. Assaying blood for ctDNA methylated in BCAT1/IKZF1 has the potential for identifying residual disease due to treatment failure, informing a potential need for therapy adjustment in advanced disease.
Publisher: American Chemical Society (ACS)
Date: 10-03-2023
DOI: 10.1021/JACS.2C11446
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1940-6207.22534507.V1
Abstract: Supplementary Tables 1 and 2, and Supplementary Figure 1
Publisher: Wiley
Date: 26-01-2023
DOI: 10.1111/AOGS.14508
Abstract: Interventional radiology (IR) is a technique for controlling hemorrhage and preserving fertility for women with serious obstetric conditions such as placenta accreta spectrum (PAS) or postpartum hemorrhage. This study examined maternal, pregnancy and hospital characteristics and outcomes for women receiving IR in pregnancy and postpartum. A population‐based record linkage study was conducted, including all women who gave birth in hospital in New South Wales or the major tertiary hospital in the neighboring Australian Capital Territory, Australia, between 2003 and 2019. Data were obtained from birth and hospital records. Characteristics and outcomes of women who underwent IR in pregnancy or postpartum are described. Outcomes following IR were compared in a high‐risk cohort of women: those with PAS who had a planned cesarean with hysterectomy. Women were grouped by those who did and those who did did not have IR and were matched using propensity score and other factors. We identified IR in 236 pregnancies of 1 584 708 (15.0 per 100 000), including 208 in the delivery and 26 in a postpartum admission. Two‐thirds of women receiving IR in the birth admission received a transfusion of red cells or blood products, 28% underwent hysterectomy and 12.5% were readmitted within 6 weeks. Other complications included: severe maternal morbidity (29.8%), genitourinary tract trauma/repair (17.3%) and deep vein thrombosis ulmonary embolism (4.3%). Outcomes for women with PAS who underwent planned cesarean with hysterectomy were similar for those who did and did not receive IR, with a small reduction in transfusion requirement for those who received IR. Interventional radiology is infrequently used in pregnant women. In our study it was performed at a limited number of hospitals, largely tertiary centers, with the level of adverse outcomes reflecting use in a high‐risk population. For women with PAS undergoing planned cesarean with hysterectomy, most outcomes were similar for those receiving IR and those not receiving IR, but IR may reduce bleeding.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2015
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1940-6207.22533860.V1
Abstract: Demographics of study invitees who requested information about the blood test and who did and did not participate in screening.
Publisher: Cambridge University Press (CUP)
Date: 08-01-2008
DOI: 10.1017/S002211200700941X
Abstract: The theory of turbulent resistivity in ‘wavy’ magnetohydrodynamic turbulence in two dimensions is presented. The goal is to explore the theory of quenching of turbulent resistivity in a regime for which the mean field theory can be rigorously constructed at large magnetic Reynolds number Rm . This is achieved by extending the simple two-dimensional problem to include body forces, such as buoyancy or the Coriolis force, which convert large-scale eddies into weakly interacting dispersive waves. The turbulence-driven spatial flux of magnetic potential is calculated to fourth order in wave slope – the same order to which one usually works in wave kinetics. However, spatial transport, rather than spectral transfer, is the object here. Remarkably, adding an additional restoring force to the already tightly constrained system of high Rm magnetohydrodynamic turbulence in two dimensions can actually increase the turbulent resistivity, by admitting a spatial flux of magnetic potential which is not quenched at large Rm , although it is restricted by the conditions of applicability of weak turbulence theory. The absence of Rm -dependent quenching in this wave-interaction-driven flux is a consequence of the presence of irreversibility due to resonant nonlinear three-wave interactions, which are independent of collisional resistivity. The broader implications of this result for the theory of mean field electrodynamics are discussed.
Publisher: Wiley
Date: 07-01-2020
DOI: 10.1002/CNCR.32695
Publisher: Frontiers Media SA
Date: 24-07-2018
Publisher: Wiley
Date: 15-03-2022
DOI: 10.1002/CNCR.34159
Abstract: 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). 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). A methylation level of 0.07%, corresponding to the 98 th 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). 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.
Publisher: Wiley
Date: 16-03-2022
DOI: 10.1111/JGH.15823
Abstract: 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. A retrospective cohort study of in iduals 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.” In iduals 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. 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. 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.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2019
DOI: 10.1158/1940-6207.CAPR-19-0089
Abstract: Suboptimal participation is commonly observed in colorectal cancer screening programs utilizing fecal tests. This randomized controlled trial tested whether the offer of a blood test as either a “rescue” strategy for fecal test nonparticipants or an upfront choice, could improve participation. A total of 1,800 people (50–74 years) were randomized to control, rescue, or choice groups (n = 600/group). All were mailed a fecal immunochemical test (FIT, OC-Sensor, Eiken Chemical Company) and a survey assessing awareness of the screening tests. The rescue group was offered a blood test 12 weeks after FIT nonparticipation. The choice group was given the opportunity to choose to do a blood test (Colvera, Clinical Genomics) instead of FIT at baseline. Participation with any test after 24 weeks was not significantly different between groups (control, 37.8% rescue, 36.9% choice, 33.8% P & 0.05). When the rescue strategy was offered after 12 weeks, an additional 6.5% participated with the blood test, which was greater than the blood test participation when offered as an upfront choice (1.5% P & 0.001). Awareness of the tests was greater for FIT than for blood (96.2% vs. 23.1% P & 0.0001). In a population familiar with FIT screening, provision of a blood test either as a rescue of FIT nonparticipants or as an upfront choice did not increase overall participation. This might reflect a lack of awareness of the blood test for screening compared with FIT.
Publisher: American Association for Cancer Research (AACR)
Date: 14-06-2021
DOI: 10.1158/1940-6207.CAPR-21-0080
Abstract: This trial of screening for those at average risk for colorectal cancer targeted past fecal-test nonparticipants and compared participation rates for mailed invitations offering a fecal test, blood test, or choice of either. Although there was no clear advantage between strategies, factors associated with participation differed between each strategy.
Publisher: Springer Science and Business Media LLC
Date: 03-04-2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2012
DOI: 10.1038/CTG.2012.9
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1940-6207.C.6547277.V1
Abstract: Abstract Suboptimal participation is commonly observed in colorectal cancer screening programs utilizing fecal tests. This randomized controlled trial tested whether the offer of a blood test as either a “rescue” strategy for fecal test nonparticipants or an upfront choice, could improve participation. A total of 1,800 people (50–74 years) were randomized to control, rescue, or choice groups ( i n /i = 600/group). All were mailed a fecal immunochemical test (FIT, OC-Sensor, Eiken Chemical Company) and a survey assessing awareness of the screening tests. The rescue group was offered a blood test 12 weeks after FIT nonparticipation. The choice group was given the opportunity to choose to do a blood test (Colvera, Clinical Genomics) instead of FIT at baseline. Participation with any test after 24 weeks was not significantly different between groups (control, 37.8% rescue, 36.9% choice, 33.8% i P /i 0.05). When the rescue strategy was offered after 12 weeks, an additional 6.5% participated with the blood test, which was greater than the blood test participation when offered as an upfront choice (1.5% i P /i 0.001). Awareness of the tests was greater for FIT than for blood (96.2% vs. 23.1% i P /i 0.0001). In a population familiar with FIT screening, provision of a blood test either as a rescue of FIT nonparticipants or as an upfront choice did not increase overall participation. This might reflect a lack of awareness of the blood test for screening compared with FIT. /
Publisher: Springer Science and Business Media LLC
Date: 31-08-2008
DOI: 10.1007/S10620-007-9928-8
Abstract: 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.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2007
Publisher: BMJ
Date: 11-07-2015
Publisher: Wiley
Date: 21-06-2012
Publisher: Wiley
Date: 13-07-2022
DOI: 10.1002/CAM4.5008
Abstract: 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). 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. 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. 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.
Publisher: Informa UK Limited
Date: 04-11-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2018
Publisher: Elsevier BV
Date: 05-2003
DOI: 10.1016/S0014-2999(03)01779-5
Abstract: The effect of the GABA(B) receptor agonist baclofen, a potential treatment for gastroesophageal reflux, on gastric emptying has not been determined. The effect of 1-4 mg/kg baclofen on liquid and solid gastric emptying in mice was evaluated by noninvasive [13C] breath tests. Baclofen accelerated gastric emptying of solids but delayed emptying of liquid, suggesting that it may have differential effects on proximal and distal stomach emptying.
Publisher: Wiley
Date: 14-09-2000
DOI: 10.1046/J.1440-1681.2000.03318.X
Abstract: 1. Gastric emptying studies in small laboratory animals are h ered by the deficiency of a technique that is non-invasive and repeatable. The aim of the present study was to adapt the non-invasive [13C]-octanoic acid breath test, which has been validated in humans, to assess both liquid and solid gastric emptying in the mouse. 2. Gastric emptying rates were investigated for a liquid meal (Intralipid Kabi Pharmacia AB, Stockholm, Sweden n = 7) and two solid meals (egg yolk and mouse chow n = 7) incorporating [13C]-octanoic acid. All meals were analysed for natural enrichment of [13C]. Mathematical analysis of the 13CO2 excretion rate allowed the determination of gastric emptying parameters. 3. Gastric emptying of Intralipid was more rapid than egg yolk (P < 0.0001). Gastric emptying of mouse chow could not be assessed due to intragastric separation of [13C]-octanoic acid and natural [13C] enrichment of the pellet. 4. The [13C]-octanoic acid breath test can reproducibly assess both liquid and solid gastric emptying non-invasively in the mouse. This method can now be used to assess gastric emptying in drug studies and disease studies for which there are established mouse models.
Publisher: Elsevier BV
Date: 12-2022
Publisher: Oxford University Press (OUP)
Date: 25-03-2009
DOI: 10.1111/J.1365-2249.2009.03934.X
Abstract: Citrobacter rodentium is a murine pathogen that transiently colonizes the lumen of the large intestine. C. rodentium induces colitis, but the relative importance and temporal induction of the T helper type 17 (Th17) and regulatory T cell (Treg) pathways in protection from the infection and inflammation have not been assessed. Our aim was to investigate the key immunological signalling events associated with successful clearance of C. rodentium. Mice were challenged with luminescent-tagged C. rodentium and killed at days 3 (early infection), 10 (peak infection) and 21 (late infection) post-infection. Bioluminescent imaging and bacterial culture determined levels of C. rodentium. Distal colon mRNA expression of interleukin (IL)-17, IL-6, IL-1β, tumour necrosis factor (TNF)-α, forkhead box P3 (FoxP3) and ghrelin were assessed using real-time polymerase chain reaction. Results were compared with age-matched non-infected mice. Low levels of C. rodentium were found at day 3, high levels at day 10, with clearance from the majority of the mice by day 21. In the distal colon, there was up-regulation of TNF-α and FoxP3 throughout the study and increases in IL-6 and IL-17 during the peak and late stages of infection. Ghrelin expression was increased at the peak and late stages of infection. This study has characterized changes to the T helper cell pathways, following the course of C. rodentium infection in mice. There were significant immunological changes, with up-regulation of the Th17 and Treg pathways in the distal colon and an increase in ghrelin expression compared with non-infected control mice. These changes may play a role in the pathology and clearance of C. rodentium.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2015
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1940-6207.C.6547525.V1
Abstract: Abstract Few studies have directly targeted nonparticipants in colorectal cancer screening to identify effective engagement strategies. We undertook a randomized controlled trial that targeted nonparticipants in a previous trial of average-risk subjects which compared participation rates for mailed invitations offering a fecal test, a blood test or a choice of either. Nonparticipants ( i n /i = 899) were randomized to be offered a kit containing a fecal immunochemical test (FIT), directions on how to arrange a blood DNA test, or the option of doing either. Screening participation was assessed 12 weeks after the offer. To assess the cognitive and attitudinal variables related to participation and invitee choice, invitees were surveyed after 12 weeks, and associations were investigated using multinomial logistic regression. Participation rates were similar between groups ( i P /i = 0.88): 12.0% for FIT (35/292), 13.3% for the blood test (39/293), and 13.4% for choice (39/290). Within the choice group, participation was significantly higher with FIT (9.7%, 28/290) compared with the blood test (3.8%, 11/290, i P /i = 0.005). The only variable significantly associated with participation was socioeconomic status when offered FIT, and age when offered choice but there was none when offered the blood test. Survey respondents indicated that convenience, time-saving, comfort, and familiarity were major influences on participation. There was no clear advantage between a fecal test, blood test, or choice of test although, when given a choice, the fecal test was preferred. Differences in variables associated with participation according to invitation strategy warrant consideration when deciding upon an invitation strategy for screening nonparticipants. Prevention Relevance: This trial of screening for those at average risk for colorectal cancer targeted past fecal-test nonparticipants and compared participation rates for mailed invitations offering a fecal test, blood test, or choice of either. Although there was no clear advantage between strategies, factors associated with participation differed between each strategy. /
Publisher: BMJ
Date: 18-07-2023
DOI: 10.1136/GUTJNL-2023-329701
Abstract: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test’s ability to discriminate between CRC and non-cancer states ( phase I ), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations ( phase II ). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.
Publisher: Cambridge University Press (CUP)
Date: 15-10-2013
DOI: 10.1017/S0007114512004333
Abstract: Fruit antioxidants have many health benefits including prevention of cancer development. The native Australian bush fruit Illawarra plum ( Podocarpus elatus Endl., Podocarpaceae) has a high content of anthocyanin-rich phenolics, with an antioxidant capacity at levels higher than most fruits. In the present study the molecular mechanisms of the anti-proliferative activity of Illawarra plum on colorectal cancer cells were investigated. Non-tumorigenic young adult mouse colonic (YAMC) cells and tumorigenic human colonic (HT-29) cells were treated with a polyphenolic-rich Illawarra plum extract (0–1000 μg/ml). Illawarra plum had anti-proliferative properties in only the cancer cells, with growth suppressed in a dose- and time-dependent manner. Treatment of HT-29 cells with Illawarra plum extract (500 μg/ml 24 h) was also associated with a 2-fold increase in apoptosis, and a cell cycle delay in the S phase ( P 0·01). Assessment of biomarkers for DNA damage revealed that plum treatment caused a 93 % down-regulation of telomerase activity ( P 0·001) and a decrease in telomere length (up to 75 % P 0·01). Treatment with Illawarra plum extract also induced morphological alterations to HT-29 cells that were suggestive of induction of autophagy, as the formation of cytoplasmic vacuoles was observed in many cells. This could be induced by the increased (6-fold) histone deacetylase (HDAC) activity ( P 0·001) and the trend for increased expression of the class III HDAC sirtuin 1. The present study has shown that Illawarra plum extract is able to reduce the proliferation of colon cancer cells by altering the cell cycle, increasing apoptosis and possibly inducing autophagy. The active ingredients in Illawarra plum may provide an alternative chemoprevention strategy to conventional chemotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 16-01-2021
DOI: 10.1158/1055-9965.EPI-20-0984
Abstract: Fecal immunochemical test (FIT) performance can be affected by post-collection variables. Collection technique might also affect fecal hemoglobin concentration (f-Hb). Variation in quantity of feces collected in s les returned in a colorectal cancer detection program, and the effects of under-s ling, were assessed. Collection devices obtained from patients undergoing FIT were assessed for the color (in five classes) of the feces in buffer, mass, and f-Hb. Associations between these were examined in an in vitro study on Hb-spiked feces. Variables possibly associated with under-s ling were investigated using multivariable logistic regression. The effect of low s le mass on clinical performance (false-negative results) was determined. Of 6,898 s les collected by 3,449 in iduals (46.9% male, median age: 65.3 years), the buffer was lightest in color in 362 (5.2%), and darkest in 420 (6.1%). S les with the lightest color had a significantly lower f-Hb compared with all darker classes (P & 0.001). Mass was recorded for 650 devices: The lightest colored s les had significantly lower mass (P & 0.05). The correlation between mass and f-Hb was confirmed in vitro (r = 0.897, P & 0.001). Low mass was not associated with age, sex, or technical factors (P & 0.05). Under-s ling related to the lightest color was not associated with false-negative results for colorectal cancer and advanced adenoma, but was for all neoplasia and inflammatory bowel disease. Wide variation existed in the amount of feces collected. Under-s ling results in lower measured f-Hb and may increase false-negative results. Color of s le buffer could be used to identify inadequate s ling.
Publisher: Wiley
Date: 05-2002
DOI: 10.1046/J.1365-2362.2002.00991.X
Abstract: Noninvasive breath tests may have significant utility for the measurement of gastric emptying in mice, but the tests' sensitivity for detection of changes in gastric emptying has not been evaluated. Hydroxypropyl methyl cellulose was incorporated into a liquid meal to delay gastric emptying, and mice were injected with erythromycin to accelerate emptying of a liquid or solid meal. All test meals were labelled with (13)C-acetic acid or (13)C-octanoic acid. Breath s les collected at intervals were analysed for (13)CO(2) content, and gastric emptying rates were calculated from the resultant (13)CO(2) excretion curves. As predicted, hydroxypropyl methyl cellulose slowed emptying compared with water (14.21 +/- 0.94 min vs. 9.17 +/- 0.47 min, P < 0.001), while erythromycin treatment accelerated emptying of liquids (10.96 +/- 0.78 min vs. 16.41 +/- 1.94 min, P < 0.05) and solids (108.81 +/- 18.06 vs. 157.95 +/- 12.01 min, P < 0.05) compared with the saline injected controls. These data indicate that in mice the breath test is sensitive enough to detect differences in gastric emptying induced by meal composition and pharmacological agents. Noninvasive measurement of gastric emptying in mice will be useful as a method to evaluate the effect of nutrients or drugs on the motility of the gastrointestinal tract.
Publisher: SAGE Publications
Date: 2018
Abstract: 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.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2017
Publisher: Springer Science and Business Media LLC
Date: 16-05-2018
Publisher: SAGE Publications
Date: 16-12-2015
Abstract: 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). 13 C-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.
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.EJCA.2022.06.028
Abstract: Diffuse-type tenosynovial giant cell tumour (D-TGCT) is a non-malignant but locally aggressive tumour driven by overexpression of colony-stimulating factor-1 (CSF1). CSF1R inhibitors are potential therapeutic strategies for patients not amenable to surgery. We report here the long-term outcome of nilotinib in patients with advanced D-TGCT treated within a phase II prospective international study (ClinicalTrials.gov: NCT01261429). Patients were enrolled between December 2010-September 2012 at 11 cancer centres. Eligible patients had histologically confirmed D-TGCT, not amenable to surgery. Patients received nilotinib until evidence of progression, toxicity or a maximum of one year. Long-term data were retrospectively collected after the completion of the phase II trial. Patients with nilotinib treatment ≥12 weeks and follow-up ≥12 months were included for long-term analysis. Forty-eight of 56 enrolled patients were included. Median treatment duration was 11 months 31 (65%) patients completed the treatment protocol. After 102 months of follow-up (median range 12-129), 25 patients (52%) had progression. The median progression-free survival (PFS) was 77 months. The five-year PFS rate was 53%. Fifteen patients (n = 15/46 33%) experienced clinical worsening after 11 months (median). Twenty-seven patients (58%) received additional treatment, after which eleven patients (n = 11/27 41%) had a second relapse. Nine patients required a subsequent treatment, primarily other CSF1R inhibitors (n = 6/9 67%). No unfavourable long-term effects were observed. This long-term analysis of nilotinib for advanced D-TGCT showed that about half of the patients had progression and underwent additional treatment after 8.5 years follow-up. Contrarily, several patients had ongoing disease control after limited treatment duration, demonstrating the mixed effect of nilotinib.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1940-6207.22533860
Abstract: Demographics of study invitees who requested information about the blood test and who did and did not participate in screening.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Wiley
Date: 12-11-2020
DOI: 10.1111/JGH.15328
Abstract: 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. 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. 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. 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 years and an index high‐risk SSP.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2016
DOI: 10.1038/CTG.2015.67
Publisher: American Association for Cancer Research (AACR)
Date: 26-01-2021
DOI: 10.1158/1055-9965.EPI-20-1609
Abstract: DNA methylated in BCAT1 and IKZF1 are promising circulating tumor DNA (ctDNA) biomarkers for colorectal cancer detection. This study tested for variables that might be associated with their detection in patients without colonoscopically evident colorectal cancer so-called false positives. A retrospective review of demographic and clinical variables was conducted on patients who were assayed for these biomarkers prior to a colonoscopy for any indication. Potential relationships between detection of these biomarkers and patient variables in patients without colorectal cancer were identified by logistic regression. An age- and sex-matched case–control study was undertaken to identify additional associations. A total of 196 of 1,593 patients undergoing colonoscopy were positive for BCAT1 and/or IKZF1 methylation 70 (35.7%) had confirmed diagnosis of colorectal cancer. Of the 126 false positives, biomarker levels were significantly lower than in those with colorectal cancer (P & 0.05), with the total cell-free circulating DNA concentration associated with biomarker detection (OR, 1.16 95% CI, 1.10–1.22), and 83 (65.9%) of the non-colorectal cancer cases positive for methylated BCAT1 only. Age ≥70 years was the only demographic variable associated with biomarker detection (OR, 4.31 95% CI, 1.50–12.41). No significant associations were seen with medications or comorbidities (P & 0.05). Four cases without colonoscopically evident colorectal cancer but with biomarker levels above the median for patients with colorectal cancer were diagnosed with metastatic adenocarcinoma within 1 year. False-positive results were most commonly associated with detection of methylated BCAT1 only, as well as age ≥70 years. In the absence of colonoscopically evident colorectal cancer, a high level of circulating methylated DNA warrants investigations for cancers at other sites.
Publisher: Springer Science and Business Media LLC
Date: 30-01-2012
Publisher: Elsevier BV
Date: 10-2020
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1940-6207.22534507
Abstract: Supplementary Tables 1 and 2, and Supplementary Figure 1
Publisher: SAGE Publications
Date: 10-01-2017
Abstract: Faecal immunochemical test accuracy may be adversely affected when s les are exposed to high temperatures. This study evaluated the effect of two s le collection buffer formulations (OC-Sensor, Eiken) and storage temperatures on faecal haemoglobin readings. Faecal immunochemical test s les 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. S les 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. 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. The new formulation buffer has enhanced haemoglobin stabilizing properties when s les are exposed to temperatures greater than 22℃.
Publisher: BMJ
Date: 26-02-2019
Publisher: Elsevier BV
Date: 07-2012
Publisher: Wiley
Date: 13-12-2007
DOI: 10.1111/J.1440-1681.2007.04546.X
Abstract: 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 s les were collected at intervals. Analysis of the rate of (13)CO(2) 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.
Publisher: Springer Science and Business Media LLC
Date: 10-12-2014
Publisher: SAGE Publications
Date: 20-07-2015
Publisher: Elsevier BV
Date: 12-2003
No related grants have been discovered for Erin Symonds.