A novel calibration framework for survival analysis when a binary covariate is measured at sparse time points.

Rates of New or Missed Colorectal Cancers After Colonoscopy and Their Risk Factors: A Population-Based Analysis

667 Background: The prognostic role of CpG Island Methylator Phenotype (CIMP) in colorectal cancer (CRC) is still controversial, especially in metastatic CRC. Methods: We retrospectively analyzed the CpG island methylator phenotype (CIMP) in stage I to IV CRC specimens, which were diagnosed during 2005-2013. CIMP status was determined using a 5- gene MethyLight-based assay ( p16, MINT1, MINT2, MINT31, and MLH1). Tumors were designated as CIMP if 3 or more of 5 genes gave percent of methylated reference value ≧ 10. The clinicopatholoical characteristics, anti-cancer therapies, and the overall survival outcome were reviewed. Overall survival (OS) was compared between patients with CIMP CRC and those with non-CIMP CRC. Results: Among 450 patients with successfully determined CIMP status, 259 (57.56%) were male, 312 (70.31%) were stages I-III, 316 (70.69%) were left-sided CRC. In the survival analyses in stages I-IV patients, there was no significant difference in OS between those with or without CIMP (long rank test, p = 0.4526). Importantly, patients with metastatic CIMP CRC had poor OS than those with metastatic non-CIMP CRC (median survival, CIMP vs. non-CIMP: 1.36 vs. 3.11 years, log rank test, p = 0.0047). In a multivariate analysis, which adjusted prognostic variables such as: KRAS and BRAF mutations, microsatellite instability status, age, sex, grade, primary site, metastatic site number, chemotherapies and targeted therapies, CIMP remained an independent poor prognostic factor for OS (HR = 6.213, 95% confidence interval: 2.443 to 15.799, p = 0.0001) in metastatic CRC. In an exploratory analysis, there were more tumors with liver metastases at diagnosis in CIMP CRC than in non-CIMP CRC (94.4% vs. 71.3%, p = 0.0416). Conclusions: Our data demonstrated CIMP might independently predict poor survival in metastatic CRC in a large East Asian cohort.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Differentiating adenomas and cancers in colorectal lesions is essential for reducing morbidity and mortality associated with CRC. Endoscopic ultrasound (EUS) is crucial in the diagnosis of CRC, and artificial intelligence (AI) offers a promising approach for identifying colorectal lesions without the need for histopathological confirmation. The objective of this study was to validate the efficacy of EUS combined with AI for the diagnosis of colorectal adenoma and cancer and to compare it with that of conventional endoscopic diagnosis. This retrospective study included 554 patients (167 with CRC, 136 with adenomas, and 251 controls) from two independent centers. The dataset was randomly divided into training and test sets in a 2:1 ratio (360 for the training dataset; 194 for the testing dataset). A model was developed using a "feature extractor + multilayer perceptron (MLP) classifier" framework, incorporating Residual Network 50 (ResNet50), EfficientNet-B0, Visual Geometry Group 11_BN (VGG_11_BN), and Vision Transformer (ViT) as feature extractors. Four AI systems were trained and validated, and the model with the highest F1 scores was subsequently compared to four endoscopists using the test dataset, and interobserver agreement measured by Fleiss' kappa. The accuracies for three-category classification (CRC, adenoma and controls) were 70.62% for ResNet50, 68.56% for EfficientNet-B0, 63.4% for ViT, and 70.10% for VGG_11_BN. ResNet50 achieved the highest F1 scores (70.37%) and diagnostic accuracy and was selected for comparison with endoscopists. For CRC diagnosis, ResNet50 outperformed endoscopists with an accuracy of 80.93%, sensitivity of 72.88%, and specificity of 84.44%, which were significantly higher than those of all endoscopists (P<0.05). For adenoma diagnosis, ResNet50 had a sensitivity of 47.92%, which was significantly higher than that of nonexpert endoscopists (P<0.05). The interobserver agreement was fair among AI systems (Fleiss' κ =0.674) and among experts (Fleiss' κ =0.557) and was slight among nonexperts (Fleiss' κ =0.284). EUS-AI has high diagnostic accuracy for CRC and adenoma as compared to non-expert endoscopists. ResNet50 is a promising tool for enhancing diagnostic accuracy in clinical practice using EUS.

Before embarking on an individual participant data meta‐analysis (IPDMA) project, researchers should consider the power of their planned IPDMA conditional on the studies promising their IPD and their characteristics. Such power estimates help inform whether the IPDMA project is worth the time and funding investment, before IPD are collected. Here, we suggest how to estimate the power of a planned IPDMA of randomised trials aiming to examine treatment‐covariate interactions at the participant‐level (i.e., treatment effect modifiers). We focus on a time‐to‐event (survival) outcome with a binary or continuous covariate, and propose an approximate analytic power calculation that conditions on the actual characteristics of trials, for example, in terms of sample sizes and covariate distributions. The proposed method has five steps: (i) extracting the following aggregate data for each group in each trial—the number of participants and events, the mean and SD for each continuous covariate, and the proportion of participants in each category for each binary covariate; (ii) specifying a minimally important interaction size; (iii) deriving an approximate estimate of Fisher's information matrix for each trial and the corresponding variance of the interaction estimate per trial, based on assuming an exponential survival distribution; (iv) deriving the estimated variance of the summary interaction estimate from the planned IPDMA, under a common‐effect assumption, and (v) calculating the power of the IPDMA based on a two‐sided Wald test. Stata and R code are provided and a real example provided for illustration. Further evaluation in real examples and simulations is needed.

This post is not about quackery, nor university politics. It is about inference, How do we know what we should eat? The question interests everyone, but what do we actually know? Not as much as you might think from the number of column-inches devoted to the topic. The discussion below is a synopsis of parts of an article called "In praise of randomisation", written as a contribution to a forthcoming book, Evidence, Inference and Enquiry. About a year ago just about every newspaper carried a story much like this one in the Daily Telegraph, What, I wondered, was the evidence behind these dire warnings. They did not come from a lifestyle guru, a diet faddist or a supplement salesman. This is nothing to do with quackery. The numbers come from the 2007 report of the World Cancer Research Fund and American Institute for Cancer Research, with the title ' Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective'. This is a 537 page report with over 4,400 references. Its panel was chaired by Professor Sir Michael Marmot, UCL's professor of Epidemiology and Public Health. He is a distinguished epidemiologist, renowned for his work on the relation between poverty and health. Nevertheless there has never been a randomised trial to test the carcinogenicity of bacon, so it seems reasonable to ask how strong is the evidence that you shouldn't eat it? It turns out to be surprisingly flimsy. In praise of randomisation Everyone knows about the problem of causality in principle. Post hoc ergo propter hoc; confusion of sequence and consequence; confusion of correlation and cause. This is not a trivial problem. It is probably the main reason why ineffective treatments often appear to work. It is traded on by the vast and unscrupulous alternative medicine industry. It is, very probably, the reason why we are bombarded every day with conflicting advice on what to eat. This is a bad thing, for two reasons. First, we end up confused about what we should eat. But worse still, the conflicting nature of the advice gives science as a whole a bad reputation. Every time a white-coated scientist appears in the media to tell us that a glass of wine per day is good/bad for us (delete according to the phase of the moon) the general public just laugh. In the case of sausages and bacon, suppose that there is a correlation between eating them and developing colorectal cancer. How do we know that it was eating the bacon that caused the cancer - that the relationship is causal? The answer is that there is no way to be sure if we have simply observed the association. It could always be that the sort of people who eat bacon are also the sort of people who get colorectal cancer. But the question of causality is absolutely crucial, because if it is not causal, then stopping eating bacon won't reduce your risk of cancer. The recommendation to avoid all processed meat in the WCRF report (2007) is sensible only if the relationship is causal. Barker Bausell said: [Page39] "But why should nonscientists care one iota about something as esoteric as causal inference? I believe that the answer to this question is because the making of causal inferences is part of our job description as Homo Sapiens." That should be the mantra of every health journalist, and every newspaper reader. Briefly, a lady claims to be able to tell whether the milk was put in the cup before or after the tea was poured. Fisher points out that to test this you need to present the lady with an equal number of cups that are 'milk first' or 'tea first' (but otherwise indistinguishable) in random order, and count how many she gets right. There is a beautiful analysis of it in Stephen Senn's book, Dicing with Death: Chance, Risk and Health. As it happens, Google books has the whole of the relevant section Fisher's tea test (geddit?), but buy the book anyway. Such is the fame of this example that it was used as the title of a book, The Lady Tasting Tea was published by David Salsburg (my review of it is here) Most studies of diet and health fall into one of three types, case-control studies, cohort (or prospective) studies, or randomised controlled trials (RCTs). Case-control studies are the least satisfactory: they look at people who already have the disease and look back to see how they differ from similar people who don't have the disease. They are retrospective. Cohort studies are better because they are prospective: a large group of people is followed for a long period and their health and diet is recorded and later their disease and death is recorded. But in both sorts of studies,each person decides for him/herself what to eat or what drugs to take. Such studies can never demonstrate causality, though if the effect is really big (like cigarette-smoking and lung cancer) they can give a very good indication. The difference in an RCT is that each person does not choose what to eat, but their diet is allocated randomly to them by someone else. This means that, on average, all other factors that might influence the response are balanced equally between the two groups. Only RCTs can demonstrate causality. Randomisation is a rather beautiful idea. It allows one to remove, in a statistical sense, bias that might result from all the sources that you hadn't realised were there. If you are aware of a source of bias, then measure it. The danger arises from the things you don't know about, or can't measure ( Senn, 2004; Senn, 2003). Although it guarantees freedom from bias only in a long run statistical sense, that is the best that can be done. Everything else is worse. Ben Goldacre has referred memorably to the newspapers' ongoing "Sisyphean task of dividing all the inanimate objects in the world into the ones that either cause or cure cancer" ( Goldacre, 2008). This has even given rise to a blog. " The Daily Mail Oncological Ontology Project ". The problem arises in assessing causality. It wouldn't be so bad if the problem were restricted to the media. It is much more worrying that the problem of establishing causality often seems to be underestimated by the authors of papers themselves. It is a matter of speculation why this happens. Part of the reason is, no doubt, a genuine wish to discover something that will benefit mankind. But it is hard not to think that hubris and self-promotion may also play a role. Anything whatsoever that purports to relate diet to health is guaranteed to get uncritical newspaper headlines. At the heart of the problem lies the great difficulty in doing randomised studies of the effect of diet and health. There can be no better illustration of the vital importance of randomisation than in this field. And, notwithstanding the generally uncritical reporting of stories about diet and health, one of the best accounts of the need for randomisation was written by a journalist, Gary Taubes, and it appeared in the New York Times ( Taubes, 2007). The case of hormone replacement therapy In the 1990s hormone replacement therapy (HRT) was recommended not only to relieve the unpleasant symptoms of the menopause, but also because cohort studies suggested that HRT would reduce heart disease and osteoporosis in older women. For these reasons, by 2001, 15 million US women (perhaps 5 million older women) were taking HRT ( Taubes, 2007). These recommendations were based largely on the Harvard Nurses' Study. This was a prospective cohort study in which 122,000 nurses were followed over time, starting in 1976 (these are the ones who responded out of the 170,000 requests sent out). In 1994, it was said ( Manson, 1994) that nearly all of the more than 30 observational studies suggested a reduced risk of coronary heart disease (CHD) among women receiving oestrogen therapy. A meta-analysis gave an estimated 44% reduction of CHD. Although warnings were given about the lack of randomised studies, the results were nevertheless acted upon as though they were true. But they were wrong. When proper randomised studies were done, not only did it turn out that CHD was not reduced: it was actually increased. The Women's Health Initiative Study ( Rossouw et al., 2002) was a randomized double blind trial on 16,608 postmenopausal women aged 50-79 years and its results contradicted the conclusions from all the earlier cohort studies. HRT increased risks of heart disease, stroke, blood clots, breast cancer (though possibly helped with osteoporosis and perhaps colorectal cancer). After an average 5.2 years of follow-up, the trial was stopped because of the apparent increase in breast cancer in the HRT group. The relative risk (HRT relative to placebo) of CHD was 1.29 (95% confidence interval 1.02 to 1.63) (286 cases altogether) and for breast cancer 1.26 (1.00 -1.59) (290 cases). Rather than there being a 44% reduction of risk, it seems that there was actually a 30% increase in risk. Notice that these are actually quite small risks, and on the margin of statistical significance. For the purposes of communicating the nature of the risk to an individual person it is usually better to specify the absolute risk rather than relative risk. The absolute number of CHD cases per 10,000 person-years is about 29 on placebo and 36 on HRT, so the increased risk of any individual is quite small. Multiplied over the whole population though, the number is no longer small. Several plausible reasons for these contradictory results are discussed by Taubes,(2007): it seems that women who choose to take HRT are healthier than those who don't. In fact the story has become a bit more complicated since then: the effect of HRT depends on when it is started and on how long it is taken ( Vandenbroucke, 2009). This is perhaps one of the most dramatic illustrations of the value of randomised controlled trials (RCTs). Reliance on observations of correlations suggested a 44% reduction in CHD, the randomised trial gave a 30% increase in CHD. Insistence on randomisation is not just pedantry. It is essential if you want to get the right answer. Having dealt with the cautionary tale of HRT, we can now get back to the 'Sisyphean task of dividing all the inanimate objects in the world into the ones that either cause or cure cancer'. The case of processed meat The WCRF report (2007) makes some pretty firm recommendations. Don't get overweight Be moderately physically active, equivalent to brisk walking for at least 30 minutes every day Consume energy-dense foods sparingly. Avoid sugary drinks. Consume 'fast foods' sparingly, if at all Eat at least five portions/servings (at least 400 g or 14 oz) of a variety of non-starchy vegetables and of fruits every day. Eat relatively unprocessed cereals (grains) and/or pulses (legumes) with every meal. Limit refined starchy foods People who eat red meat to consume less than 500 g (18 oz) a week, very little if any to be processed. If alcoholic drinks are consumed, limit consumption to no more than two drinks a day for men and one drink a day for women. Avoid salt-preserved, salted, or salty foods; preserve foods without using salt. Limit consumption of processed foods with added salt to ensure an intake of less than 6 g (2.4 g sodium) a day. Dietary supplements are not recommended for cancer prevention. These all sound pretty sensible but they are very prescriptive. And of course the recommendations make sense only insofar as the various dietary factors cause cancer. If the association is not causal, changing your diet won't help. Note that dietary supplements are NOT recommended. I'll concentrate on the evidence that lies behind "People who . . . very little if any to be processed." The problem of establishing causality is dicussed in the report in detail. In section 3.4 the report says " . . . causal relationships between food and nutrition, and physical activity can be confidently inferred when epidemiological evidence, and experimental and other biological findings, are consistent, unbiased, strong, graded, coherent, repeated, and plausible." The case of processed meat is dealt with in chapter 4.3 (p. 148) of the report. "Processed meats" include sausages and frankfurters, and 'hot dogs', to which nitrates/nitrites or other preservatives are added, are also processed meats. Minced meats sometimes, but not always, fall inside this definition if they are preserved chemically. The same point applies to 'hamburgers'. The evidence for harmfulness of processed meat was described as "convincing", and this is the highest level of confidence in the report, though this conclusion has been challenged ( Truswell, 2009) . How well does the evidence obey the criteria for the relationship being causal? Twelve prospective cohort studies showed increased risk for the highest intake group when compared to the lowest, though this was statistically significant in only three of them. One study reported non-significant decreased risk and one study reported that there was no effect on risk. These results are summarised in this forest plot (see also Lewis &amp; Clark, 2001) Each line represents a separate study. The size of the square represents the precision (weight) for each. The horizontal bars show the 95% confidence intervals. If it were possible to repeat the observations many times on the same population, the 95% CL would be different on each repeat experiment, but 19 out of 20 (95%) of the intervals would contain the true value (and 1 in 20 would not contain the true value). If the bar does not overlap the vertical line at relative risk = 1 (i.e. no effect) this is equivalent to saying that there is a statistically significant difference from 1 with P &lt; 0.05. That means, very roughly, that there is a 1 in 20 chance of making a fool of yourself if you claim that the association is real, rather than being a result of chance ( more detail here), There is certainly a tendency for the relative risks to be above one, though not by much, Pooling the results sounds like a good idea. The method for doing this is called meta-analysis . Meta-analysis was possible on five studies, shown below. The outcome is shown by the red diamond at the bottom, labelled "summary effect", and the width of the diamond indicates the 95% confidence interval. In this case the final result for association between processed meat intake and colorectal cancer was a relative risk of 1.21 (95% CI 1.04-1.42) per 50 g/day. This is presumably where the headline value of a 20% increase in risk came from. Support came from a meta-analysis of 14 cohort studies, which reported a relative risk for processed meat of 1.09 (95% CI 1.05 - 1.13) per 30 g/day ( Larsson &amp; Wolk, 2006). Since then another study has come up with similar numbers ( Sinha etal. , 2009). This consistency suggests a real association, but it cannot be taken as evidence for causality. Observational studies on HRT were just as consistent, but they were wrong. The accompanying editorial ( Popkin, 2009) points out that there are rather more important reasons to limit meat consumption, like the environmental footprint of most meat production, water supply, deforestation and so on. So the outcome from vast numbers of observations is an association that only just reaches the P = 0.05 level of statistical significance. But even if the association is real, not a result of chance sampling error, that doesn't help in the least in establishing causality. There are two more criteria that might help, a good relationship between dose and response, and a plausible mechanism. Dose - response relationship Doll &amp; Peto, 1978 There have been six studies that relate consumption of processed meat to incidence of colorectal cancer. All six dose-response relationships are shown in the WCRG report. Here they are. This Figure was later revised to This is the point where my credulity begins to get strained. Dose - response curves are part of the stock in trade of pharmacologists. The technical description of these six curves is, roughly, 'bloody horizontal'. The report says "A dose-response relationship was also apparent from cohort studies that consumption in I simply cannot that any relationship whatsoever is They are certainly the least dose-response relationships I have Nevertheless a meta-analysis came up with a for response that just the level of statistical significance. The conclusion of the report for processed meat and colorectal cancer was as is a of evidence, with a dose-response relationship apparent from cohort studies. There is strong evidence for plausible in meat is a cause of colorectal But the dose-response curves look and it is reasonable to ask whether public should be based on a 1 in 20 chance of being quite in 20 at best Senn, 2008). I certainly wouldn't want to risk my on like that, never it as a for public So we are with as the bit of evidence for causality. who has much experimental work knows that it is possible to up a plausible of any result Most are and so is a pretty play is of the fact that meats contain and but there is no real evidence that the they contain is The main source of in the diet is not from meat but from vegetables vegetables like and which - of The in processed meat is - but - 400 with a limit of - 400 Dietary intake was not with risk for colorectal cancer in two cohort 2004; for Research on 2006). to the another cohort study on over people compared and from and from all were not different between and meat ( et al., more the incidence of all was among than among meat the was colorectal cancer which a incidence in than in meat ( et al., et compared cohort studies and RCTs for of diet on risk of coronary heart disease. for was for intake of and and of intake of and foods with a There was also a bit less strong evidence for of and for intake of whole dietary and and But RCTs showed evidence only for and for of the As a final in the of case studies, to &amp; from a of case studies in association was between consumption (at least one of per and the risk of of the with relative risks of for and for for for and for on is one to make of should be on the Health to a reduction in As the authors may simply a general and of a It is observations like this that to make a of making causal inferences from studies. They are simply the observed association even The most about the of red meat and processed meat is not only that they are small but also that they only just the 5 level of statistical significance. It has been in these real are to be in size ( Senn, 2008). still, there as some good reasons to think that many (perhaps even of the that are in this sort of study are not real ( The of the of is to be in small studies, so it is that the large meta-analysis by Larsson &amp; Wolk, "In the present the of the relationship of processed meat consumption with colorectal cancer risk was than in the earlier This is all with the well tendency of randomized trials to show a good effect of but trials to show The reasons, and the for this worrying problem are discussed by ( &amp; &amp; 2009) do randomized studies tell The only of evidence for causality from randomised controlled The in people to over long of time are and that is no one reason why there are RCTs than there are observational studies. But when they have been the results often those from cohort studies. The RCTs of hormone replacement therapy above contradicted the cohort studies and the advice given to women about more illustrations of how plausible about diet can be by RCTs supplements and RCTs have shown that various of supplement do no good and may even do (see At least we now know that per do you no The that might be good for you was never more than a plausible and like so many plausible it has out to be a The is now no more than a though it very for unscrupulous The randomised Women's Health Initiative Dietary ( et al., showed of dietary on though the conclusion has been challenged on the of the possible of reported diet ( et al., 2006). to much about ( et al., 2009) no in over two years between very different They randomly overweight to one of The of from and in the were and and and and and difference could be between the different all that for was the number of It should be added, though, that there were some reasons to think that the may not have to their very well ( 2009). The one gets from RCTs is that the of diet are not like as important as has been inferred from observational studies. So does processed meat give you After all we can to the sausages or bacon give you colorectal The is that really I do know that, on the of the evidence, it seems to to be an to that evidence is that processed meat is a cause of In the there were 5 cases of colorectal cancer per 10,000 population in so a 20% even if it were real, and would result in 6 rather than 5 cases per 10,000 That makes the risk sound trivial for any the other there were cases of colorectal cancer in the in A 20% increase would if the association were causal, about cases as a result of eating processed but no cases if the association were not causal. For the purposes of public health about the question of causality is One has for the that they have to because they are to on the of If it were not already the discussed above make it very that the only sound to causality is a randomised The only to that are when are really The relative risk of lung cancer for a is 20 times that of a and there is a very relationship between dose per and response cancer as shown That is a increase in risk, very different from the 20% for processed meat (and many other dietary could the causality in that The about whether to eat bacon and sausages has to be a It depends on your to the principle. The observations do in my strong evidence for causality, but they are certainly with causality. It could be true so if you want to be on the then avoid course would not be much if your were based on things that just could be true. would be to any relative risk based on observational if it was less than about The Cancer Institute ( 2002) that relative risks less than should be with but to what with means in so the advice very In fact any of the relative risks reported in the WCRF report (2007) this all relative risks are less than (or than for it is best to worrying and get on with your At some point it to to diet on the of There is a to for being It the risk of making people that has a sound It the risk of of And it science into when people at the contradictory of observational The question of how diet and other health is to There is reason to think that it For example one study that breast cancer incidence increased in women who to and up to in the Since then has been put into out The great was but that is the only similar have come to after of and or and cancer count as The WCRF report (2007) has 537 and over and we don't I think we should don't rather more to Ben The of the Part 1 and Part and at Risk The and of about diet and supplements up the of seems to like the line at according to his blog. of the The report has been in Project This studies up to The result of of the was to reduce the apparent risk from eating processed meat from 1.21 (95% CI = 1.04-1.42) in the study to (95% CI = in the The is small to much, though it is in for the that the dose-response curves are The evidence for causality is by of the of processed meat and colorectal cancer

This review summarizes the evidence regarding physical activity and diet after colorectal cancer diagnosis in relation to quality of life, disease recurrence, and survival. There have been extensive reports on adiposity, inactivity, and certain diets, particularly those high in red and processed meats, and increased risk of colorectal cancer. Only in the past decade have data emerged on how such lifestyle factors are associated with outcomes in colorectal cancer survivors. Prospective observational studies have consistently reported that physical activity after colorectal cancer diagnosis reduces mortality. A meta-analysis estimated that each 15 metabolic equivalent task-hour per week increase in physical activity after colorectal cancer diagnosis was associated with a 38% lower risk of mortality. No randomized controlled trials have been completed to confirm that physical activity lowers risk of mortality among colorectal cancer survivors; however, trials have shown that physical activity, including structured exercise, is safe for colorectal cancer survivors (localized to metastatic stage, during and after treatment) and improves cardiorespiratory fitness and physical function. In addition, prospective observational studies have suggested that a Western dietary pattern, high carbohydrate intake, and consuming sugar-sweetened beverages after diagnosis may increase risk of colorectal cancer recurrence and mortality, but these data are limited to single analyses from one of two US cohorts. Additional data from prospective studies and randomized controlled trials are needed. Nonetheless, on the basis of the available evidence, it is reasonable to counsel colorectal cancer survivors to engage in regular physical activity and limit consumption of refined carbohydrates, red and processed meats, and sugar-sweetened beverages.

Guidelines on genetic evaluation and management of Lynch syndrome: A consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer

Acute Leukemias Following a Diagnosis of Colorectal Cancer: Are They Therapy-Related?

BackgroundHigh quality evidence indicates that aspirin is effective in reducing colorectal polyps; and numerous epidemiological studies point towards an ability to prevent colorectal cancer. However the role of Aspirin as an adjuvant agent in patients with established cancers remains to be defined. Recently a nested case-control study within the Nurses Health cohort suggested that the initiation of Aspirin after the diagnosis of colon cancer reduced overall colorectal cancer specific mortality. Although this data is supportive of Aspirin's biological activity in this disease and possible role in adjuvant therapy, it needs to be confirmed in a randomized prospective trial.Methods/DesignWe hypothesize through this randomized, placebo-controlled adjuvant study, that Aspirin in patients with dukes C or high risk dukes B colorectal cancer (ASCOLT) can improve survival in this patient population over placebo control. The primary endpoint of this study is Disease Free Survival and the secondary Endpoint is 5 yr Overall Survival. This study will randomize eligible patients with Dukes C or high risk Dukes B colorectal cancer, after completion of surgery and standard adjuvant chemotherapy (+/- radiation therapy for rectal cancer patients) to 200 mg Aspirin or Placebo for 3 years. Stratification factors include study centre, rectal or colon cancer stage, and type of adjuvant chemotherapy (exposed/not exposed to oxaliplatin). After randomization, patient will be followed up with 3 monthly assessments whilst on study drug and for a total of 5 years. Patients with active peptic ulcer disease, bleeding diathesis or on treatment with aspirin or anti-platelet agents will be excluded from the study.DiscussionThis study aims to evaluate Aspirin's role as an adjuvant treatment in colorectal cancer. If indeed found to be beneficial, because aspirin is cheap, accessible and easy to administer, it will positively impact the lives of many individuals in Asia and globally.Trials RegistrationClinicaltrials.gov: NCT00565708

168 Background: There are over 1.3 million colorectal cancer (CRC) survivors in the United States, and many of whom suffer from lower health-related quality-of-life (HRQoL) years after diagnosis and treatment. Physical activity may improve survival outcomes and HRQoL for CRC survivors. Feasible interventions to support physical activity after CRC diagnosis are needed. Methods: We conducted a two-arm randomized controlled trial of 41 men and women who had completed treatment for CRC. Participants in the intervention arm were given a Fitbit Flex™ and received daily text messages for 12 weeks. HRQoL was assessed in both arms at baseline and 12 weeks using the RAND Short Form Survey (SF-36) and the Functional Assessment of Cancer Treatment – Colorectal (FACT-C). Survey score changes from baseline to 12 weeks were compared between the two arms using independent t-tests, and scores at baseline and 12 weeks were compared using paired t-tests. SAS was used for analysis, and statistical significance was declared at p &lt; 0.05. Results: We observed a statistically significant increase in the FACT-C functional well-being sub-scale in individuals in the intervention arm pre- and post- intervention (mean ∆ 1.81 ± 2.76; p: 0.02). There was no change in functional well-being in the control arm (mean ∆ -0.35 ± 4.12; p: 0.71). The between-arm comparison of change from baseline to 12 weeks was not statistically significantly ( p: 0.08). There was a statistically significant increase in the FACT-C emotional well-being sub-scale in the control arm (mean ∆ 1.20 ± 2.48; p: 0.04) and in the SF-36 role physical sub-scale in the control arm (mean ∆ 22.5 ± 38.8; p: 0.02). No other measures of HRQoL were statistically significantly different within groups, across time points, or between groups. Conclusions: A 12-week physical activity intervention using a Fitbit Flex and daily text messages may improve functional well-being among CRC survivors. Larger randomized studies are needed to definitively determine if a digital physical activity intervention improves functional well-being among CRC survivors, and if the improvement can be sustained over time. Clinical trial information: NCT02966054.

Introduction: The outbreak of coronavirus disease 2019 (COVID-19) had affected clinical practice in several ways, including the restriction of nonessential endoscopic procedures. Therefore, our aim was to evaluate how colorectal cancer (CRC) diagnosis and management was affected during the first year of pandemics in Portugal. Methods: This is a Portuguese substudy of the French retrospective multicentric study ETICC (Etude de l’Impact de la pandémie COVID-19 sur le diagnostic et la prise en charge du Cancer Colorectal). We compared patients’ characteristics, clinical manifestations, CRC staging at diagnosis, delay to first medical appointment, histological diagnosis, surgical and medical treatments between the year previous to the pandemics (control) and the first year of pandemics. Results: We included 766 patients: 496 in the control group and 270 in the COVID group. There was no significant difference in CRC staging at diagnosis between both groups, with 21% being diagnosed as metastatic in the control group and 22% in the first year of pandemics (p = 0.770). Contrary to what happened in France, there was a significant decrease in CRC diagnosis in asymptomatic patients (25–8.4%; p < 0.001) and after a positive fecal immunochemical test (20.8–11.3%; p = 0.002) during the pandemics. Although the increase in the overall complication rate at diagnosis was nonsignificant, in Portugal, there was a significant increase in diagnosis of abdominal occlusion (12.1–18.1%; p = 0.033). In Portugal, time between the beginning of symptoms and the first medical appointment significantly increased from a median of 50 days to 64 days during COVID (p < 0.001). On the contrary, time between histological diagnosis and tumor resection had significantly decreased from a median of 65 to 39 days (p < 0.001). Time between histological diagnosis and neoadjuvant treatment was not statistically different (median of 64–67 days; p = 0.590), as was time between histological diagnosis and palliative chemotherapy (median of 50–51 days; p = 1.000). Time from CRC resection and adjuvant treatment has significantly decreased from a median of 54 to 43 days (p = 0.001). Discussion: We found a significant impact in CRC diagnosis in the first year of pandemics, more pronounced than what was found in France. These are likely related not only with the closing of endoscopy units but also with the difficulties patients had in finding an appointment with their general practitioners. On the other hand, both in France and Portugal, the first year of pandemics did not worsen CRC staging at diagnosis and did not significantly affect medical and surgical treatments once the diagnosis was made.

BackgroundVitamin D supplementation improves colorectal cancer (CRC) survival outcomes in randomized trials. The aim of this study was to test the feasibility, safety and efficacy of vitamin D supplementation in the pre- and perioperative period in patients undergoing CRC surgery.MethodsPatients were given 3200IU oral cholecalciferol (D3) per day perioperatively. Serial serum 25-hydroxyvitamin (25OHD) was measured by liquid chromatography tandem mass spectrometry and compared to untreated CRC controls. 25OHD and C-reactive protein (CRP) levels were compared using adjusted generalized linear mixed-effects models.ResultsA total of 122 patients underwent serial perioperative sampling, including 41 patients given high-dose perioperative supplementation. Supplementation was well-tolerated with no adverse or serious adverse events related to supplementation reported. Pre-operative supplementation increased 25OHD levels on the day of surgery (103.9 vs. 42.5 nmol/l, P = 8.2E–12). Supplementation increased 25OHD levels at all post-operative timepoints (P < 0.001) and attenuated the post-operative drop in 25OHD (46 vs. 24% drop, P = 3.0E–4). Rate of vitamin D peri-operative insufficiency was significantly less in those on supplementation (e.g., day 3–5, 14 vs. 84%, P = 1.41E–08), with multivariate modeling across all timepoints indicating a ∼59 nmol/l higher 25OHD compared to control patients (P = 3.7E–21). Post-operative CRP was lower in patients taking supplementation (e.g., day 3–5 timepoint; 129 vs. 81 mg/l, P = 0.04).ConclusionHigh dose pre-operative vitamin D supplementation is associated with higher perioperative 25OHD levels, lower rates of vitamin D insufficiency and reduced early post-operative CRP. Alongside published evidence for a beneficial effect of vitamin D on CRC survival outcomes, these novel findings provide strong rationale for early initiation of vitamin D supplementation after a diagnosis of CRC.

BackgroundThe application of circulating, cell-free, methylated Septin9 (mSEPT9) DNA in screening and recurrence monitoring is highly promising. CpG island methylator phenotype (CIMP) is associated with microsatellite instability (MSI). The present study was performed to determine the diagnostic accuracy of mSEPT9 for colorectal cancer (CRC) and to evaluate its utility in CRC screening and recurrence monitoring.MethodsFor screening and diagnosis of CRC, peripheral mSEPT9 detection and fecal occult blood test (FOBT) were performed in 650 subjects, then the level of CEA, CA19–9 and CA724 was quantified in 173 subjects. Clinicopathological parameters and mismatch repair protein were detected among subjects with CRC. For recurrence monitoring of CRC, the sensitivity of mSEPT9 of 70 subjects was compared with tumor markers and contrast enhanced computed tomography (CECT).ResultsSeventy-three percent of CRC patients were mSEPT9-positive at 94.5% specificity, and 17.1% of patients with intestinal polyps and adenoma were mSEPT9-positive at 94.5% specificity, which were higher than FOBT for the screening of CRC. The sensitivity and specificity of mSEPT9 for diagnosis and recurrence monitoring were higher than that of CEA, CA19–9 and CA724. The combined detection of mSEPT9 and CECT enhanced the sensitivity for recurrence monitoring. Pre-therapeutic levels of mSEPT9 were strongly associated with TNM stage, Dukes stages and mismatch repair deficiency (dMMR).ConclusionsmSEPT9 analysis might be popularized as a routine biomarker for CRC screening. The combined detection of mSEPT9 and CECT can play an important role for recurrence monitoring. CIMP was highly associated with the pathological stage of CRC and dMMR.

Accurate diagnostic activity in general practice before colorectal cancer (CRC) diagnosis is crucial for an early detection of CRC. This study aimed to investigate the rates of daytime consultations, hemoglobin (Hb) measurements and medicine prescriptions for hemorrhoids in general practice in the year preceding CRC diagnosis. Using Danish registries, we conducted a population-based matched cohort study including CRC patients aged 40-80 years (n = 19,209) and matched references (n = 192,090). We calculated odds ratios (ORs) using a conditional logistical regression model and incidence rate ratios (IRRs) using a negative binomial regression model. The CRC patients had significantly more consultations from 9 months before diagnosis and significantly increased rates of Hb measurements from up to 17 months before diagnosis compared with references. Furthermore, up to 18 months before diagnosis, CRC patients had significantly higher rates of prescriptions for hemorrhoids; and 2 months before diagnosis, the IRR was 12.24 (95% confidence interval (CI): 10.29-14.55) for men. The positive predictive value (PPV) of CRC for having a first-time prescription for hemorrhoids was highest among men aged 70-80 years [PPV = 3.2% (95% CI: 2.8-3.7)]. High prescription rates were predominantly seen among rectal cancer patients, whereas colon cancer patients had higher rates of consultations and Hb measurements. This study revealed a significant increase in healthcare seeking and diagnostic activity in general practice in the year prior to CRC diagnosis, which indicates the presence of a "diagnostic time window" and a potential for earlier diagnosis of CRC based on clinical signs and symptoms.

IntroductionColonoscopy is the modality of choice for bowel cancer screening and investigation of iron deficiency anaemia. Hence colonoscopists are most likely to diagnose colorectal cancer (CRC). It is desirable to...