The diagnosis of colorectal cancer in patients with symptoms: finding a needle in a haystack

Patients often see primary care physicians with symptoms that might signal colorectal cancer but are also common in adults without cancer. Physicians and patients must then make a difficult decision about whether and how aggressively to evaluate the symptom. Favoring referral is that missed diagnoses lead to unnecessary testing, prolonged uncertainty, and continuing symptoms; also, the physician will suffer chagrin. It is not clear that diagnostic delay leads to progression to a more advanced stage. Against referral is that proper evaluation includes colonoscopy, with attendant inconvenience, discomfort, cost, and risk. The article by Hamilton et al, published this month in BMC Medicine, provides strong estimates of the predictive value of the various symptoms and signs of colorectal cancer and show how much higher predictive values are with increasing age and male sex. Unfortunately, their results also make clear that most colorectal cancers present with symptoms with low predictive values, < 1.2%. Models that include a set of predictive variables, that is, risk factors, age, sex, screening history, and symptoms, have been developed to guide primary prevention and clinical decision-making and are more powerful than individual symptoms and signs alone. Although screening for colorectal cancer is increasing in many countries, cancers will still be found outside screening programs so primary care physicians will remain at the front line in the difficult task of distinguishing everyday symptoms from life-threatening cancer

The bioenergetic signature of isogenic colon cancer cells predicts the cell death response to treatment with 3-bromopyruvate, iodoacetate or 5-fluorouracil

<p>Abstract</p> <p>Background</p> <p>Metabolic reprogramming resulting in enhanced glycolysis is a phenotypic trait of cancer cells, which is imposed by the tumor microenvironment and is linked to the down-regulation of the catalytic subunit of the mitochondrial H⁺-ATPase (β-F1-ATPase). The <it>bioenergetic signature </it>is a protein ratio (β-F1-ATPase/GAPDH), which provides an estimate of glucose metabolism in tumors and serves as a prognostic indicator for cancer patients. Targeting energetic metabolism could be a viable alternative to conventional anticancer chemotherapies. Herein, we document that the <it>bioenergetic signature </it>of isogenic colon cancer cells provides a gauge to predict the cell-death response to the metabolic inhibitors, 3-bromopyruvate (3BrP) and iodoacetate (IA), and the anti-metabolite, 5-fluorouracil (5-FU).</p> <p>Methods</p> <p>The <it>bioenergetic signature </it>of the cells was determined by western blotting. Aerobic glycolysis was determined from lactate production rates. The cell death was analyzed by fluorescence microscopy and flow cytometry. Cellular ATP concentrations were determined using bioluminiscence. Pearson's correlation coefficient was applied to assess the relationship between the <it>bioenergetic signature </it>and the cell death response. <it>In vivo </it>tumor regression activities of the compounds were assessed using a xenograft mouse model injected with the highly glycolytic HCT116 colocarcinoma cells.</p> <p>Results</p> <p>We demonstrate that the <it>bioenergetic signature </it>of isogenic HCT116 cancer cells inversely correlates with the potential to execute necrosis in response to 3BrP or IA treatment. Conversely, the <it>bioenergetic signature </it>directly correlates with the potential to execute apoptosis in response to 5-FU treatment in the same cells. However, despite the large differences observed in the <it>in vitro </it>cell-death responses associated with 3BrP, IA and 5-FU, the <it>in vivo </it>tumor regression activities of these agents were comparable.</p> <p>Conclusions</p> <p>Overall, we suggest that the determination of the <it>bioenergetic signature </it>of colon carcinomas could provide a tool for predicting the therapeutic response to various chemotherapeutic strategies aimed at combating tumor progression.</p

TRAPPC4-ERK2 Interaction Activates ERK1/2, Modulates Its Nuclear Localization and Regulates Proliferation and Apoptosis of Colorectal Cancer Cells

The trafficking protein particle complex 4 (TRAPPC4) is implicated in vesicle-mediated transport, but its association with disease has rarely been reported. We explored its potential interaction with ERK2, part of the ERK1/2 complex in the Extracellular Signal-regulated Kinase/ Mitogen-activated Protein Kinase (ERK-MAPK) pathway, by a yeast two-hybrid screen and confirmed by co-immunoprecipitation (Co-IP) and glutathione S-transferase (GST) pull-down. Further investigation found that when TRAPPC4 was depleted, activated ERK1/2 specifically decreased in the nucleus, which was accompanied with cell growth suppression and apoptosis in colorectal cancer (CRC) cells. Overexpression of TRAPPC4 promoted cell viability and caused activated ERK1/2 to increase overall, but especially in the nucleus. TRAPPC4 was expressed more highly in the nucleus of CRC cells than in normal colonic epithelium or adenoma which corresponded with nuclear staining of pERK1/2. We demonstrate here that TRAPPC4 may regulate cell proliferation and apoptosis in CRC by interaction with ERK2 and subsequently phosphorylating ERK1/2 as well as modulating the subcellular location of pERK1/2 to activate the relevant signaling pathway

Colorectal cancer health services research study protocol: the CCR-CARESS observational prospective cohort project

BACKGROUND: Colorectal cancers are one of the most common forms of malignancy worldwide. But two significant areas of research less studied deserve attention: health services use and development of patient stratification risk tools for these patients. METHODS:DESIGN: a prospective multicenter cohort study with a follow up period of up to 5 years after surgical intervention. Participant centers: 22 hospitals representing six autonomous communities of Spain. Participants/Study population: Patients diagnosed with colorectal cancer that have undergone surgical intervention and have consented to participate in the study between June 2010 and December 2012. Variables collected include pre-intervention background, sociodemographic parameters, hospital admission records, biological and clinical parameters, treatment information, and outcomes up to 5 years after surgical intervention. Patients completed the following questionnaires prior to surgery and in the follow up period: EuroQol-5D, EORTC QLQ-C30 (The European Organization for Research and Treatment of Cancer quality of life questionnaire) and QLQ-CR29 (module for colorectal cancer), the Duke Functional Social Support Questionnaire, the Hospital Anxiety and Depression Scale, and the Barthel Index. The main endpoints of the study are mortality, tumor recurrence, major complications, readmissions, and changes in health-related quality of life at 30 days and at 1, 2, 3 and 5 years after surgical intervention. STATISTICAL ANALYSIS: In relation to the different endpoints, predictive models will be used by means of multivariate logistic models, Cox or linear mixed-effects regression models. Simulation models for the prediction of discrete events in the long term will also be used, and an economic evaluation of different treatment strategies will be performed through the use of generalized linear models. DISCUSSION: The identification of potential risk factors for adverse events may help clinicians in the clinical decision making process. Also, the follow up by 5 years of this large cohort of patients may provide useful information to answer different health services research questions

Adherence to colorectal cancer screening: Four rounds of faecal immunochemical test-based screening

Background:The effectiveness of faecal immunochemical test (FIT)-based screening programs is highly dependent on consistent participation over multiple rounds. We evaluated adherence to FIT screening over four rounds and aimed to identify determinants of participation behaviour.Methods:A total of 23 339 randomly selected asymptomatic persons aged 50-74 years were invited for biennial FIT-based colorectal cancer screening between 2006 and 2014. All were invited for every consecutive round, except for those who had moved out of the area, passed the upper age limit, or had tested positive in a previous screening round. A reminder letter was sent to non-responders. We calculated participation rates per round, response rates to a reminder letter, and differences in participation between subgroups defined by age, sex, and socioeconomic status (SES).Results:Over the four rounds, participation rates increased significantly, from 60% (95% CI 60-61), 60% (95% CI 59-60), 62% (95% CI 61-63) to 63% (95% CI 62-64; P for trend&lt;0.001) with significantly higher participation rates in women in all rounds (P&lt;0.001). Of the 17 312 invitees eligible for at least two rounds of FIT screening, 12 455 (72%) participated at least once, whereas 4857 (28%) never participated; 8271 (48%) attended all rounds when eligible. Consistent participation was associated with older age, female sex, and higher SES. Offering a reminder letter after the initial invite in the first round increased uptake with 12%; in subsequent screening rounds this resulted in an additional uptake of up to 10%.Conclusions:In four rounds of a pilot biennial FIT-screening program, we observed a consistently high and increasing participation rate, whereas sending reminders remain effective. The substantial proportion of inconsistent participants suggests the existence of incidental barriers to participation, which, if possible, should be identified and removed

Behavioural and demographic predictors of adherence to three consecutive faecal occult blood test screening opportunities: a population study

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background Social cognitive variables are often examined for their association with initial participation in colorectal cancer screening. Few studies have examined the association of these variables with adherence to multiple screening offers i.e., rescreening. This study aimed to describe patterns of participatory behaviour after three rounds of screening using faecal immunochemical tests (FIT) and to determine social cognitive, demographic and background variables predictive of variations in adherence. Methods Participants were 1,540 men and women aged 50 to 75 living in South Australia who completed a behavioural survey measuring demographic (for example, age, gender) and social cognitive variables relevant to FIT screening (for example, perceived barriers, benefits, self-efficacy). The survey was followed by three, free FIT screening offers mailed on an annual basis from 2008 to 2010. Patterns of participation after three screening rounds were described as one of five screening behaviours; 1) consistent re-participation (adherent with all screening rounds), 2) consistent refusal (adherent with no screening rounds), 3) drop out (adherent with earlier but not later rounds), 4) intermittent re-participation (adherent with alternate rounds) and 5) delayed entry (adherent with later but not initial round(s)). Univariate (Chi Square and Analysis of Variance) and multivariate (Generalised Estimating Equations) analyses were conducted to determine variables predictive of each category of non-adherence (those that did not participate in every screening offer, groups 2, 3, 4 and 5) relative to consistent re-participation. Results Significant social cognitive predictors of non-adherence were; less self-efficacy (drop out and consistent refusal), greater perceived barriers (drop out) and lower levels of response efficacy (consistent refusal). Demographic predictors of non-adherence included; male gender (delayed entry), younger age (intermittent, delayed and consistent refusal), less frequent GP visits (intermittent re-participation) and lack of adequate health insurance (drop out). Less satisfaction with screening at baseline predicted drop out, consistent refusal and delayed entry. Conclusions Different combinations of demographic and behavioural variables predicted different patterns of rescreening adherence. Rescreening interventions may benefit from a targeted approach that considers the different needs of the population subgroups. Satisfaction with past FOBT screening measured prior to the study screening offers was an important predictor of adherence

Part II, Provider perspectives: should patients be activated to request evidence-based medicine? a qualitative study of the VA project to implement diuretics (VAPID)

<p>Abstract</p> <p>Background</p> <p>Hypertension guidelines recommend the use of thiazide diuretics as first-line therapy for uncomplicated hypertension, yet diuretics are under-prescribed, and hypertension is frequently inadequately treated. This qualitative evaluation of provider attitudes follows a randomized controlled trial of a patient activation strategy in which hypertensive patients received letters and incentives to discuss thiazides with their provider. The strategy prompted high discussion rates and enhanced thiazide-prescribing rates. Our objective was to interview providers to understand the effectiveness and acceptability of the intervention from their perspective, as well as the suitability of patient activation for more widespread guideline implementation.</p> <p>Methods</p> <p>Semi-structured phone interviews were conducted with 21 primary care providers. Interviews were transcribed verbatim and reviewed by the interviewer before being analyzed for content. Interviews were coded, and relevant themes and specific responses were identified, grouped, and compared.</p> <p>Results</p> <p>Of the 21 providers interviewed, 20 (95%) had a positive opinion of the intervention, and 18 of 20 (90%) thought the strategy was suitable for wider use. In explaining their opinions of the intervention, many providers discussed a positive effect on treatment, but they more often focused on the process of patient activation itself, describing how the intervention facilitated discussions by informing patients and making them more pro-active. Regarding effectiveness, providers suggested the intervention worked like a reminder, highlighted oversights, or changed their approach to hypertension management. Many providers also explained that the intervention 'aligned' patients' objectives with theirs, or made patients more likely to accept a change in medications. Negative aspects were mentioned infrequently, but concerns about the use of financial incentives were most common. Relevant barriers to initiating thiazide treatment included a hesitancy to switch medications if the patient was at or near goal blood pressure on a different anti-hypertensive.</p> <p>Conclusions</p> <p>Patient activation was acceptable to providers as a guideline implementation strategy, with considerable value placed on the activation process itself. By 'aligning' patients' objectives with those of their providers, this process also facilitated part of the effectiveness of the intervention. Patient activation shows promise for wider use as an implementation strategy, and should be tested in other areas of evidence-based medicine.</p> <p>Trial registration</p> <p>National Clinical Trial Registry number NCT00265538</p

Partner randomized controlled trial: study protocol and coaching intervention

<p>Abstract</p> <p>Background</p> <p>Many children with asthma live with frequent symptoms and activity limitations, and visits for urgent care are common. Many pediatricians do not regularly meet with families to monitor asthma control, identify concerns or problems with management, or provide self-management education. Effective interventions to improve asthma care such as small group training and care redesign have been difficult to disseminate into office practice.</p> <p>Methods and design</p> <p>This paper describes the protocol for a randomized controlled trial (RCT) to evaluate a 12-month telephone-coaching program designed to support primary care management of children with persistent asthma and subsequently to improve asthma control and disease-related quality of life and reduce urgent care events for asthma care. Randomization occurred at the practice level with eligible families within a practice having access to the coaching program or to usual care. The coaching intervention was based on the transtheoretical model of behavior change. Targeted behaviors included 1) effective use of controller medications, 2) effective use of rescue medications and 3) monitoring to ensure optimal control. Trained lay coaches provided parents with education and support for asthma care, tailoring the information provided and frequency of contact to the parent's readiness to change their child's day-to-day asthma management. Coaching calls varied in frequency from weekly to monthly. For each participating family, follow-up measurements were obtained at 12- and 24-months after enrollment in the study during a telephone interview.</p> <p>The primary outcomes were the mean change in 1) the child's asthma control score, 2) the parent's quality of life score, and 3) the number of urgent care events assessed at 12 and 24 months. Secondary outcomes reflected adherence to guideline recommendations by the primary care pediatricians and included the proportion of children prescribed controller medications, having maintenance care visits at least twice a year, and an asthma action plan. Cost-effectiveness of the intervention was also measured.</p> <p>Discussion</p> <p>Twenty-two practices (66 physicians) were randomized (11 per treatment group), and 950 families with a child 3-12 years old with persistent asthma were enrolled. A description of the coaching intervention is presented.</p> <p>Trial registration</p> <p>ClinicalTrials.gov identifier <a href="http://www.clinicaltrials.gov/ct2/show/NCT00860834">NCT00860834</a>.</p