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Background: Lynch syndrome is a hereditary cancer disease resulting in an increased risk of colorectal cancer. Herein, findings are reported from an emergency clinical service implemented during the COVID-19 pandemic utilizing faecal immunochemical testing ('FIT') in Lynch syndrome patients to prioritize colonoscopy while endoscopy services were limited. Methods: An emergency service protocol was designed to improve colonoscopic surveillance access throughout the COVID-19 pandemic in England for people with Lynch syndrome when services were extremely restricted (1 March 2020 to 31 March 2021) and promoted by the English National Health Service. Requests for faecal immunochemical testing from participating centres were sent to the National Health Service Bowel Cancer Screening South of England Hub and a faecal immunochemical testing kit, faecal immunochemical testing instructions, paper-based survey, and pre-paid return envelope were sent to patients. Reports with faecal haemoglobin results were returned electronically for clinical action. Risk stratification for colonoscopy was as follows: faecal haemoglobin less than 10 µg of haemoglobin/g of faeces (µg/g)—scheduled within 6–12 weeks; and faecal haemoglobin greater than or equal to 10 µg/g—triaged via an urgent suspected cancer clinical pathway. Primary outcomes of interest included the identification of highest-risk Lynch syndrome patients and determining the impact of faecal immunochemical testing in risk-stratified colonoscopic surveillance. Results: Fifteen centres participated from June 2020 to March 2021. Uptake was 68.8 per cent amongst 558 patients invited. For 339 eligible participants analysed, 279 (82.3 per cent) had faecal haemoglobin less than 10 µg/g and 60 (17.7 per cent) had faecal haemoglobin greater than or equal to 10 µg/g. In the latter group, the diagnostic accuracy of faecal immunochemical testing was 65.9 per cent and escalation to colonoscopy was facilitated (median 49 versus 122 days, χ2 = 0.0003, P < 0.001). Conclusion: Faecal immunochemical testing demonstrated clinical value for Lynch syndrome patients requiring colorectal cancer surveillance during the pandemic in this descriptive report of an emergency COVID-19 response service. Further longitudinal investigation on faecal immunochemical testing efficacy in Lynch syndrome is warranted and will be examined under the 'FIT for Lynch' study (ISRCTN15740250). This was an emergency service protocol designed to improve access to colonoscopy using faecal immunochemical testing for risk-stratified triage during the height of the COVID-19 pandemic for people with Lynch syndrome when endoscopy services were extremely limited. Requests for faecal immunochemical testing for eligible Lynch syndrome patients were made by participating National Health Service Trusts, which triggered the sending of a faecal immunochemical testing kit, faecal immunochemical testing instructions, a paper-based survey, and pre-paid return envelope from the National Health Service Bowel Cancer Screening South of England Hub in Surrey to said patients, and risk stratification for colonoscopy was as follows: faecal haemoglobin less than 10 µg/g—schedule colonoscopy within 6–12 weeks; and faecal haemoglobin greater than or equal to 10 µg/g—triage via an urgent suspected cancer clinical pathway. For 339 participants analysed, 279 (82.3 per cent) had faecal haemoglobin less than 10 µg/g and 60 (177.0 per cent) met criteria for urgent triage (faecal haemoglobin greater than or equal to 10 µg/g), with escalation to colonoscopy facilitated in the latter group of patients, with a median wait of 49 days (versus 122 days for f-Hb less than 10), demonstrating the clinical value of faecal immunochemical testing for patients with Lynch syndrome requiring colorectal cancer surveillance during the pandemic. [ABSTRACT FROM AUTHOR]

Background Risk evaluation of lymph node metastasis for early-stage (T1 and T2) colorectal cancers is critical for determining therapeutic strategies. Traditional methods of lymph node metastasis prediction have limited accuracy. This systematic review aimed to review the potential of artificial intelligence in predicting lymph node metastasis in early-stage colorectal cancers. Methods A comprehensive search was performed of papers that evaluated the potential of artificial intelligence in predicting lymph node metastasis in early-stage colorectal cancers. Studies were appraised using the Joanna Briggs Institute tools. The primary outcome was summarizing artificial intelligence models and their accuracy. Secondary outcomes included influential variables and strategies to address challenges. Results Of 3190 screened manuscripts, 11 were included, involving 8648 patients from 1996 to 2023. Due to diverse artificial intelligence models and varied metrics, no data synthesis was performed. Models included random forest algorithms, support vector machine, deep learning, artificial neural network, convolutional neural network and least absolute shrinkage and selection operator regression. Artificial intelligence models' area under the curve values ranged from 0.74 to 0.9993 (slide level) and 0.9476 to 0.9956 (single-node level), outperforming traditional clinical guidelines. Conclusion Artificial intelligence models show promise in predicting lymph node metastasis in early-stage colorectal cancers, potentially refining clinical decisions and improving outcomes. PROSPERO registration number CRD42023409094. [ABSTRACT FROM AUTHOR]

Studies have confirmed that the occurrence of many complex diseases in the human body is closely related to the microbial community, and microbes can affect tumorigenesis and metastasis by regulating the tumor microenvironment. However, there are still large gaps in the clinical observation of the microbiota in disease. Although biological experiments are accurate in identifying disease-associated microbes, they are also time-consuming and expensive. The computational models for effective identification of diseases related microbes can shorten this process, and reduce capital and time costs. Based on this, in the paper, a model named DSAE_RF is presented to predict latent microbe–disease associations by combining multi-source features and deep learning. DSAE_RF calculates four similarities between microbes and diseases, which are then used as feature vectors for the disease-microbe pairs. Later, reliable negative samples are screened by k -means clustering, and a deep sparse autoencoder neural network is further used to extract effective features of the disease-microbe pairs. In this foundation, a random forest classifier is presented to predict the associations between microbes and diseases. To assess the performance of the model in this paper, 10-fold cross-validation is implemented on the same dataset. As a result, the AUC and AUPR of the model are 0.9448 and 0.9431, respectively. Furthermore, we also conduct a variety of experiments, including comparison of negative sample selection methods, comparison with different models and classifiers, Kolmogorov–Smirnov test and t -test, ablation experiments, robustness analysis, and case studies on Covid-19 and colorectal cancer. The results fully demonstrate the reliability and availability of our model. [ABSTRACT FROM AUTHOR]

Background There is an increasing incidence of early-onset colorectal cancer; however, the psychosocial impacts of this disease on younger adults have been seldom explored. Methods A systematic review was conducted according to the PRISMA guidelines. The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, PubMed, and Scopus were searched, and papers were included if published in English within the last 10 years and if they reported results separately by age (including early-onset colorectal cancer, defined as colorectal cancer diagnosed before the age of 50 years). Critical appraisal of all studies was done using the Joanna Briggs Institute tools. The primary outcome of interest was the global quality of life in patients with early-onset colorectal cancer. Secondary outcomes included the effect on sexual function, body image, finances, career, emotional distress, and social and family functioning. Results The search yielded 168 manuscripts and 15 papers were included in the review after screening. All studies were observational, and included a total of 18 146 patients, of which 5015 were patients with early-onset colorectal cancer. The studies included scored highly using Joanna Briggs Institute critical appraisal tools, indicating good quality and a low risk of bias, but data synthesis was not performed due to the wide range of scoring systems that were used across the studies. Six papers reported significant negative impacts on quality of life in patients with early-onset colorectal cancer. Three of the four studies that compared the quality of life in patients with early-onset colorectal cancer with older patients found that the younger group had worse mean quality-of-life scores (P ≤ 0.05). Secondary outcomes measured in five studies in relation to sexual dysfunction, body image, financial and career impacts, and social and family impacts and in eight studies in relation to emotional distress were found to be more severely impacted in those with early-onset colorectal cancer compared with those with late-onset colorectal cancer. Conclusion Whilst data are limited, the impact of colorectal cancer is different in patients with early-onset colorectal cancer compared with older patients in relation to several aspects of the quality of life. This is particularly prominent in areas of global quality of life, sexual functioning, family concerns, and financial impacts. [ABSTRACT FROM AUTHOR]

Background Alcohol increases cancer risk, but less is known about public awareness of this link. This scoping review summarizes recent findings on the public awareness of alcohol as a cancer risk factor in European Union and UK. Methods Four databases (Web of Science, MEDLINE, PsycInfo, CINAHL) were searched for papers containing data on awareness of alcohol as cancer risk factor in EU or UK published between January 2017 and December 2022, and complemented with grey literature searches. Results In total, 45 studies were included covering 18 EU countries (Austria, Belgium, Cyprus, Czechia, Denmark, Finland, France, Germany, Hungary, Ireland, Italy, Netherlands, Poland, Romania, Slovakia, Slovenia, Spain, Sweden) and UK, presenting data collected between 2009 and 2022. Studies covered general population (17 studied a nationally representative sample), women, health professionals, patients and young people. Awareness of alcohol causing cancer in general was higher and studied more often than awareness of alcohol's impact on specific cancers. Among the EU general population, awareness of the link between alcohol and breast cancer ranged between 10% and 20%, head and neck cancer 15–25%, colorectal and oesophagus cancer 15–45% and liver cancer 40%. Awareness was higher among young people and specialized health professions and lower among women (the latter specifically for the breast cancer). Conclusions While awareness rates varied depending on the exact question wording, many studies showed low awareness of the alcohol-cancer link, especially for specific types such as breast and colon cancer. Public should be better informed about alcohol consumption-related cancer risk. [ABSTRACT FROM AUTHOR]

Aberrant glycosylation is a key mechanism employed by cancer cells to evade immune surveillance, induce angiogenesis and metastasis, among other hallmarks of cancer. Sialic acids, distinctive terminal glycan structures located on glycoproteins or glycolipids, are prominently upregulated across various tumor types, including colorectal cancer (CRC). Sialylated glycans modulate anti-tumor immune responses through their interactions with Siglecs, a family of glycan-binding receptors with specificity for sialic acid-containing glycoconjugates, often resulting in immunosuppression. In this paper, we investigated the immunomodulatory function of ST3Gal5, a sialyltransferase that catalyzes the addition of α2-3 sialic acids to glycosphingolipids, since lower expression of ST3Gal5 is associated with better survival of CRC patients. We employed CRISPR/Cas9 to knock out the ST3Gal5 gene in two murine CRC cell lines MC38 and CT26. Glycomics analysis confirmed the removal of sialic acids on glycolipids, with no discernible impact on glycoprotein sialylation. Although knocking out ST3Gal5 in both cell lines did not affect in vivo tumor growth, we observed enhanced levels of regulatory T cells in CT26 tumors lacking ST3Gal5. Moreover, we demonstrate that the absence of ST3Gal5 affected size and blood vessel density only in MC38 tumors. In summary, we ascertain that sialylation of glycosphingolipids has a limited influence on the anti-tumor immune response in CRC, despite detecting alterations in the tumor microenvironment, possibly due to a shift in ganglioside abundance. [ABSTRACT FROM AUTHOR]

The individualized treatment rule (ITR), which recommends an optimal treatment based on individual characteristics, has drawn considerable interest from many areas such as precision medicine, personalized education, and personalized marketing. Existing ITR estimation methods mainly adopt 1 of 2 or more treatments. However, a combination of multiple treatments could be more powerful in various areas. In this paper, we propose a novel double encoder model (DEM) to estimate the ITR for combination treatments. The proposed double encoder model is a nonparametric model which not only flexibly incorporates complex treatment effects and interaction effects among treatments but also improves estimation efficiency via the parameter-sharing feature. In addition, we tailor the estimated ITR to budget constraints through a multi-choice knapsack formulation, which enhances our proposed method under restricted-resource scenarios. In theory, we provide the value reduction bound with or without budget constraints, and an improved convergence rate with respect to the number of treatments under the DEM. Our simulation studies show that the proposed method outperforms the existing ITR estimation in various settings. We also demonstrate the superior performance of the proposed method in patient-derived xenograft data that recommends optimal combination treatments to shrink the tumour size of the colorectal cancer. [ABSTRACT FROM AUTHOR]

Metachronous colorectal cancer is relatively rare, occurring in 0.7–3.6% of patients diagnosed with colorectal adenocarcinoma. Cutaneous metastases are similarly a rare presentation, occurring in <6% of metastatic colorectal cancer patients. Even more rare are the cutaneous recurrences at the peristomal site. Clinically, it is difficult to distinguish between metachronous cancer and cutaneous metastases. This paper reports a case of an elderly woman presenting with a slowly progressing peristomal cutaneous lesion 16 years after surgical resection for colorectal cancer. Core punch biopsy revealed a cutaneous localization of an intestinal type of adenocarcinoma. A surgical resection of the peristomal area was carried out whereby a new colostomy was created on the contralateral side. Definite histopathological examination showed a superficially located intestinal type adenocarcinoma with extensive pagetoid spread in the epidermal surface. In conclusion, it is important to remain alert and strive for early detection for cutaneous abnormalities following colorectal cancer. [ABSTRACT FROM AUTHOR]

Accurate risk assessment is critical in clinical decision‐making. It entails the projected risk based on a risk prediction model agreeing with the observed risk in the target cohort. However, the model often over‐ or under‐estimates the risk. Building a new model for the target cohort would be ideal but costly. It is therefore of great interest to recalibrate an existing model for the target cohort. Existing methods have been proposed to recalibrate the model by leveraging the disease incidence rates from the target cohort. However, they assume the same covariate distribution across cohorts and when the assumption is violated, the recalibrated model can be substantially biased. Further, recalibration is also complicated by the two‐phase sampling design that is commonly used for developing risk prediction models. In this paper, we develop a weighted estimating‐equation approach accounting for the two‐phase design and combine it with a weighted empirical likelihood that leverages the summary information on both disease incidence rates and covariates from the target cohort. We provide a resampling‐based inference procedure. Our extensive simulation results show that using the summary information from the target population, the proposed recalibration method yields nearly unbiased risk estimates under a wide range of scenarios. An application to a colorectal cancer study also illustrates that the proposed method yields a well‐calibrated model in the target cohort. [ABSTRACT FROM AUTHOR]

Owing to its robustness properties, marginal interpretations, and ease of implementation, the pseudo‐partial likelihood method proposed in the seminal papers of Pepe and Cai and Lin et al. has become the default approach for analyzing recurrent event data with Cox‐type proportional rate models. However, the construction of the pseudo‐partial score function ignores the dependency among recurrent events and thus can be inefficient. An attempt to investigate the asymptotic efficiency of weighted pseudo‐partial likelihood estimation found that the optimal weight function involves the unknown variance–covariance process of the recurrent event process and may not have closed‐form expression. Thus, instead of deriving the optimal weights, we propose to combine a system of pre‐specified weighted pseudo‐partial score equations via the generalized method of moments and empirical likelihood estimation. We show that a substantial efficiency gain can be easily achieved without imposing additional model assumptions. More importantly, the proposed estimation procedures can be implemented with existing software. Theoretical and numerical analyses show that the empirical likelihood estimator is more appealing than the generalized method of moments estimator when the sample size is sufficiently large. An analysis of readmission risk in colorectal cancer patients is presented to illustrate the proposed methodology. [ABSTRACT FROM AUTHOR]

Objectives: Nowadays, one of the most common gastrointestinal cancers is colorectal cancer (CRC). Chemotherapy is still one of the main methods to treat cancer. However, the currently available synthetic chemotherapy drugs often cause serious adverse reactions. Apoptosis is generally considered as an ideal way for induction the death of tumour cells without the body's inflammatory response, and it is reported that lots of natural agents could trigger various cancer cells to apoptosis. The overarching aim of this project was to elucidate the specific mechanisms by which natural substances induce apoptosis in CRC cells and to be used as an alternative therapeutic option in the future. Key findings: The mechanisms for the pro-apoptotic effects of natural substances derived from herbs or plants include death receptor pathway, mitochondrial pathway, endoplasmic reticulum stress pathway, related signal transduction pathways (PI3K/Akt, MAPK, p53 signalling), and so on. Summary: This paper updated this information regarding the anti-tumour effects of natural agents via induction of apoptosis against CRC, which would be beneficial for future new drug research regarding natural products from herbs or plants. [ABSTRACT FROM AUTHOR]

Motivation Assessment of genetic mutations is an essential element in the modern era of personalized cancer treatment. Our strategy is focused on 'multiple network analysis' in which we try to improve cancer diagnostics by using biological networks. Genetic alterations in some important hubs or in driver genes such as BRAF and TP53 play a critical role in regulating many important molecular processes. Most of the studies are focused on the analysis of the effects of single mutations, while tumors often carry mutations of multiple driver genes. The aim of this work is to define an innovative bioinformatics pipeline focused on the design and analysis of networks (such as biomedical and molecular networks), in order to: (1) improve the disease diagnosis; (2) identify the patients that could better respond to a given drug treatment; and (3) predict what are the primary and secondary effects of gene mutations involved in human diseases. Results By using our pipeline based on a multiple network approach, it has been possible to demonstrate and validate what are the joint effects and changes of the molecular profile that occur in patients with metastatic colorectal carcinoma (mCRC) carrying mutations in multiple genes. In this way, we can identify the most suitable drugs for the therapy for the individual patient. This information is useful to improve precision medicine in cancer patients. As an application of our pipeline, the clinically significant case studies of a cohort of mCRC patients with the BRAF V600E-TP53 I195N missense combined mutation were considered. Availability The procedures used in this paper are part of the Cytoscape Core, available at (www.cytoscape.org). Data used here on mCRC patients have been published in [ 55 ]. Supplementary Information A supplementary file containing a more detailed discussion of this case study and other cases is available at the journal site as Supplementary Data. [ABSTRACT FROM AUTHOR]

Background: A novel pathway incorporating faecal immunochemical testing (FIT) for rapid colorectal cancer diagnosis (RCCD) was introduced in 2017. This paper reports on the service evaluation after 2 years of pathway implementation. Methods: The RCCD protocol was based on FIT, blood results and symptoms to stratify adult patients in primary care. Two-week-wait (2WW) investigation was indicated for patients with rectal bleeding, rectal mass and faecal haemoglobin (fHb) level of 10 µg Hb/g faeces or above or 4 µg Hb/g faeces or more in the presence of anaemia, low ferritin or thrombocytosis, in all other symptom groups. Patients with 100 µg Hb/g faeces or above had expedited investigation . A retrospective audit of colorectal cancer detected between 2017 and 2019 was conducted, fHb thresholds were reviewed and critically assessed for cancer diagnoses. Results: In 2 years, 14788 FIT tests were dispatched with 13361 (90.4 per cent) completed returns. Overall, fHb was less than 4 µg Hb/g faeces in 9208 results (68.9 per cent), 4-9.9 µg Hb/g in 1583 (11.8 per cent), 10-99.9 µg Hb/g in 1850 (13.8 per cent) and 100 µg Hb/g faeces or above in 720 (5.4 per cent). During follow-up (median 10.4 months), 227 colorectal cancers were diagnosed. The cancer detection rate was 0.1 per cent in patients with fHb below 4 µg Hb/g faeces, 0.6 per cent in those with fHb 4-9.9 µg Hb/g faeces, 3.3 per cent for fHb 10-99.9 µg Hb/g faeces and 20.7 per cent for fHb 100 µg Hb/g faeces or above. The detection rate in the cohort with 10-19.9 µg Hb/g faeces was 1.4 per cent, below the National Institute for Health and Care Excellence threshold for urgent referral. The colorectal cancer rate in patients with fHb below 20 µg Hb/g faeces was less than 0.3 per cent. Conclusion: Use of FIT to "rule out" urgent referral from primary care misses a small number of cases. The threshold for referral may be adjusted with blood results to improve stratification. [ABSTRACT FROM AUTHOR]

Motivation When phase III clinical drug trials fail their endpoint, enormous resources are wasted. Moreover, even if a clinical trial demonstrates a significant benefit, the observed effects are often small and may not outweigh the side effects of the drug. Therefore, there is a great clinical need for methods to identify genetic markers that can identify subgroups of patients which are likely to benefit from treatment as this may (i) rescue failed clinical trials and/or (ii) identify subgroups of patients which benefit more than the population as a whole. When single genetic biomarkers cannot be found, machine learning approaches that find multivariate signatures are required. For single nucleotide polymorphism (SNP) profiles, this is extremely challenging owing to the high dimensionality of the data. Here, we introduce RAINFOREST (tReAtment benefIt prediction using raNdom FOREST), which can predict treatment benefit from patient SNP profiles obtained in a clinical trial setting. Results We demonstrate the performance of RAINFOREST on the CAIRO2 dataset, a phase III clinical trial which tested the addition of cetuximab treatment for metastatic colorectal cancer and concluded there was no benefit. However, we find that RAINFOREST is able to identify a subgroup comprising 27.7% of the patients that do benefit, with a hazard ratio of 0.69 (P  = 0.04) in favor of cetuximab. The method is not specific to colorectal cancer and could aid in reanalysis of clinical trial data and provide a more personalized approach to cancer treatment, also when there is no clear link between a single variant and treatment benefit. Availability and implementation The R code used to produce the results in this paper can be found at github.com/jubels/RAINFOREST. A more configurable, user-friendly Python implementation of RAINFOREST is also provided. Due to restrictions based on privacy regulations and informed consent of participants, phenotype and genotype data of the CAIRO2 trial cannot be made freely available in a public repository. Data from this study can be obtained upon request. Requests should be directed toward Prof. Dr. H.J. Guchelaar (h.j.guchelaar@lumc.nl). Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Background For cancer screening programmes to be effective in early detection it is important that those invited can access screening services and understand the benefits of participation. A better understanding of the factors that matter to potential participants of cancer screening programmes can assist in developing strategies to increase current uptake. Methods We conducted an overview of systematic reviews to answer the question: What factors influence the uptake of cancer screening services (breast, bowel and cervical) in high-income countries? A thematic approach supported by tabular summaries and qualitative heat maps was used to categorize factors, described as 'barriers' or 'facilitators'. Results A total of 41 systematic reviews met the criteria for inclusion. The barrier with the greatest number of 'hot spots' across all three screening programmes was a fear of the unknown regarding a possible diagnosis of cancer or abnormal screening results, followed closely by a general lack of knowledge surrounding cancer screening programmes. The greatest collective facilitator to uptake was recommendation by a healthcare provider to attend screening. Conclusion Across all factors 'trust' and 'building trusted relationships' can be seen as integral to the success of cancer screening programmes and must be reflective of collaborative efforts to mitigate barriers and enhance facilitators to uptake. There is future scope to consider interventions that (i) increase demand for screening services, (ii) reduce barriers to uptake of services and/or (iii) are relevant to the healthcare system and those providing services. [ABSTRACT FROM AUTHOR]

The use of immune checkpoint inhibitors (ICIs) has revolutionized cancer care, particularly in immune-inflamed tumors and tumors with a high mutational burden, like microsatellite instable colorectal cancer (CRC). However, their effectiveness in microsatellite stable (MSS) CRC is limited. This systematic review aims to evaluate the efficacy of ICIs in MSS CRC and explore promising combination strategies. A comprehensive search from the Web of Science, Medline, and Embase databases, for studies published until 14 November 2022, identified 53 clinical trials included in the review. ICI monotherapy or ICI-ICI combinations demonstrated limited clinical activity for patients with MSS CRC, with overall response rates below (ORR) 10% in most studies. The ICI and tyrosine kinase inhibitor (TKI) garnered ORRs ranging from 10% to 40% and indicated a higher benefit for patients, particularly those without active liver metastases. The combination of ICIs with anti-VEGF agents showed modest ORRs, especially in the earlier treatment lines and in combination with chemotherapy. While these combinations could lead to modest improvements, well-defined biomarkers for long-term benefit are yet to be delineated. Combinations involving BRAF inhibitors with ICIs were studied, showing promising responses with combination approaches in molecularly defined subgroups. In conclusion, while ICI monotherapy has limited efficacy in MSS CRC, combination strategies hold promise to enhance survival outcomes. Further research is necessary to identify optimal combination approaches, predictive biomarkers for treatment response, as well as enrollment according to tumor molecular characteristics. [ABSTRACT FROM AUTHOR]

We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil (FTD/TPI) combined with other antineoplastic agents in advanced cancers, including metastatic colorectal cancer (mCRC). We conducted a systematic search on May 29, 2021, for studies reporting one or more efficacy or safety outcome with FTD/TPI-containing combinations. Our search yielded 1378 publications, with 38 records meeting selection criteria: 35 studies of FTD/TPI-containing combinations in mCRC (31 studies second line or later) and 3 studies in other tumor types. FTD/TPI plus bevacizumab was extensively studied, including 19 studies in chemorefractory mCRC. Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory mCRC. Based on one randomized and several retrospective studies, FTD/TPI plus bevacizumab was associated with improved outcomes compared with FTD/TPI monotherapy. FTD/TPI combinations with chemotherapy or other targeted agents were reported in small early-phase studies; preliminary data indicated higher antitumor activity for certain combinations. Overall, no safety concerns existed with FTD/TPI combinations; most common grade ≥ 3 adverse event was neutropenia, ranging 5%-100% across all studies. In studies comparing FTD/TPI combinations with monotherapy, grade ≥ 3 neutropenia appeared more frequently with combinations (29%-67%) vs. monotherapy (5%-41%). Discontinuation rates due to adverse events ranged 0%-11% for FTD/TPI plus bevacizumab and 0%-17% with other combinations. This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC. Data on non-bevacizumab FTD/TPI combinations remain preliminary and need further validation. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed. Here, we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original tumors. To efficiently identify repurposed drugs for CRC, we developed a robust organoid-based drug screening system. By combining the repurposed drug library and computation-based drug prediction, 335 drugs were tested and 34 drugs with anti-CRC effects were identified. More importantly, we conducted a detailed transcriptome analysis of drug responses and divided the drug response signatures into five representative patterns: differentiation induction, growth inhibition, metabolism inhibition, immune response promotion, and cell cycle inhibition. The anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft (PDOX) system in vivo. We found that fedratinib, trametinib, and bortezomib exhibited effective anticancer effects. Furthermore, the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated. Our study offers an innovative approach for drug discovery, and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC. [ABSTRACT FROM AUTHOR]

Introduction Cancer is a major public health problem in Rwanda and other low- and middle-income countries (LMICs). While there have been some improvements in access to cancer treatment, the cost of care has increased, leading to financial toxicity and treatment barriers for many patients. This study explores the financial toxicity of cancer care in Rwanda. Methods This prospective cross-sectional study was conducted at 3 referral hospitals in Rwanda, which deliver most of the country's cancer care. Data were collected over 6 months from June 1 to December 1, 2022 by trained research assistants (RAs) using a modified validated data collection tool. RAs interviewed consecutive eligible patients with breast cancer, cervical cancer, colorectal cancer, Hodgkin's and non-Hodgkin's lymphoma who were on active systemic therapy. The study aimed to identify sources of financial burden. Data were analyzed using descriptive statistics. Results 239 patients were included; 75% (n  = 180/239) were female and mean age was 51 years. Breast, cervix, and colorectal cancers were the most common diagnoses (42%, 100/239; 24%, 58/239; and 24%, 57/239, respectively) and 54% (n  = 129/239) were diagnosed with advanced stage (stages III-IV). Financial burden was high; 44% (n  = 106/239) of respondents sold property, 29% (n  =  70/239) asked for charity from public, family, or friends, and 16% (n  = 37/239) took loans with interest to fund cancer treatment. Conclusion Despite health insurance which covers many elements of cancer care, a substantial proportion of patients on anti-cancer treatment in Rwanda experience major financial toxicity. Novel health financing solutions are needed to ensure accessible and affordable cancer care. [ABSTRACT FROM AUTHOR]

with colorectal cancer (CRC) for adjuvant therapy is to estimate the likelihood that death fromother causes will preclude cancer events from occurring. The aim of this paper is to evaluate whether comprehensive geriatric assessment (CGA) can predict survival and cancer-specific mortality in elderly CRC patients candidates for adjuvant therapy. Material and Methods. One hundred ninety-five consecutive patients aged ≥ 75 with high-risk stage II and stage III CRC were prospectively included from May 2008 to May 2015. All patients underwent CGA, which evaluated comorbidity, polypharmacy, functional status, geriatric syndromes, mood, cognition, and social support. According to CGA results, patients were classified into three groups--fit, medium-fit, and unfit--to receive standard therapy, adjusted treatment, and best supportive care, respectively. We recorded survival and cause of death and used the Fine-Gray regression model to analyze competing causes of death. Results. Following CGA, 85 (43%) participants were classified as fit, 57 (29%) as medium-fit, and 53 (28%) as unfit. The univariate 5-year survival rates were 74%, 52%, and 27%. Sixty-one (31%) patients died due to cancer progression (53%), noncancer- related cause (46%), and unknown reasons (1%); there were no toxicity-related deaths. Fit and medium-fit participants were more likely to die due to cancer progression, whereas patients classified as unfit were at significantly greater risk of non-cancer-related death. Conclusion. CGA showed efficacy in predicting survival and discriminating between causes of death in elderly patients with high-risk stage II and stage III resected CRC, with potential implications for shaping the decision-making process for adjuvant therapies. [ABSTRACT FROM AUTHOR]

Background Right-sided colon cancer (RCC) differs in mutation profile and risk of recurrence compared to distal colon cancer. Circulating tumour DNA (ctDNA) present after surgery can identify patients with residual disease after curative surgery and predict risk of early recurrence. Methods This is a prospective observational biomarker trial with exploration of ctDNA in 50 non-metastatic RCC patients for which oncological right-sided colectomy was performed. Blood samples were collected preoperatively, within 1 month post surgery, 3 months (not mandatory), 6 months and every 6 months thereafter. Plasma cell free DNA and/or tumour was investigated for cancer-related mutations by the next-generation sequencing (NGS) panel AVENIO surveillance specifically designed for ctDNA analysis. Detected mutations were quantified using digital droplet PCR (ddPCR) for follow-up. Recurrence-free survival was explored. Results 50 patients were recruited. Somatic cancer-related mutations were detected in 47/50 patients. ddPCR validated results from NGS for 27/34 (plasma) and 72/72 samples (tumour). Preoperative ctDNA was detected in 31/47 of the stage I/III patients and the majority of ctDNA positive patients showed reduction of ctDNA after surgery (27/31). ctDNA-positive patients at first postoperative sample had high recurrence risk compared to patients without measurable ctDNA (adjusted hazard ratio: 172.91; 95% c.i.: 8.70 to 3437.24; P : 0.001). Conclusion ctDNA was detectable in most patients with non-metastatic RCC before surgery. Positive postoperative ctDNA was strongly associated with early recurrence. Detectable postoperative ctDNA is a prognostic factor with high (100%) positive predictive value for recurrence in this cohort of non-metastatic RCC. Clinical Trial Registration ClinicalTrials.gov ID: NCT03776591 [ABSTRACT FROM AUTHOR]

Introduction: Primary sclerosing cholangitis (PSC) is a progressive cholestatic disorder that ultimately can lead to cirrhosis, liver failure, malignancy and death. It is strongly associated with inflammatory bowel disease (IBD), and though a rare disease, its incidence is increasing. There are no proven medical therapies for PSC. Sources of data: Ovid Medline was utilised to search for articles with keywords 'sclerosing cholangitis' and 'cholangiocarcinoma' and containing titles 'primary sclerosing cholangitis', and references of these papers were cross-referenced for further relevant manuscripts. Areas of agreement: PSC is a rare disease, and there is a strong association with risk loci within the major histocompatibility complex and other genes common to other autoimmune diseases. PSC is a premalignant condition, associated with higher rates of hepatobiliary and colorectal cancer in patients with ulcerative colitis (UC). Areas of controversy: The pathogenesis is unclear, and competing theories exist surrounding toxic bile acids, enhanced homing of particular T cells from the gut to the liver and increased passage of toxins to the liver through a permeable bowel wall. It is unclear whether the higher rate of colonic cancer in PSC/UC occurs in PSC/Crohn's disease. Ursodeoxycholic acid therapy reduces liver enzymes but has not been shown to improve survival. It may reduce the prevalence of bowel cancer. Growing points: Recent genetic studies have revealed new risk loci, pointing to the importance of the immune system and its interaction with the biome. Areas timely for developing research: On the basis of the genetic studies discussed earlier, novel agents are being developed and trialled in the treatment of PSC. [ABSTRACT FROM AUTHOR]

Purpose: A systematic literature review was conducted to estimate the global prevalence of Kirsten rat sarcoma virus gene (KRAS) mutations, with an emphasis on the clinically significant KRAS G12C mutation, and to estimate the prognostic significance of these mutations in patients with colorectal cancer (CRC). Design: Relevant English-language publications in the Embase, MEDLINE, and the Cochrane Library databases (from 2009 to 2021) and congress presentations (from 2016 to 2021) were reviewed. Eligible studies were those that reported the prevalence and clinical outcomes of the KRAS G12C mutation in patients with CRC. Results: A total of 137 studies (interventional [n = 8], post hoc analyses of randomized clinical trials [n = 6], observational [n = 122], and longitudinal [n =1]) were reviewed. Sixty-eight studies reported the prevalence of KRAS mutations (KRASm) in 42 810 patients with CRC. The median global prevalence of KRASm was 38% (range, 13.3%-58.9%) and that of the KRAS G12C mutation (KRAS G12C) 3.1% (range, 0.7%-14%). Available evidence suggests that KRASm are possibly more common in tumors that develop on the right side of the colon. Limited evidence suggests a lower objective response rate and inferior disease-free/relapse-free survival in patients with KRAS G12C compared with patients with KRASwt or other KRASm. Conclusion: Our analysis reveals that KRAS G12C is prevalent in 3% of patients with CRC. Available evidence suggests a poor prognosis for patients with KRAS G12C. Right-sided tumors were more likely to harbor KRASm; however, their role in determining clinical outcomes needs to be investigated further. This review was conducted to estimate the global prevalence of KRAS mutations, with an emphasis on the clinically significant KRAS G12C mutation, and to estimate the prognostic significance of these mutations in patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Background Invasive infection with Streptococcus bovis/Streptococcus equinus complex (SBSEC) bacteria is associated with underlying colorectal neoplasia. However, the link between intestinal or fecal colonization with SBSEC isolates or antibody responses to SBSEC members and colorectal cancer is not thoroughly investigated in the literature. Methods We searched the PubMed, EMBASE, and Web of Science databases for case–control studies as well as retrospective or prospective cohort studies reporting an association between SBSEC bacteria and colorectal neoplasia. Results We identified 22 studies (15 case–control and 7 cohort) that met our inclusion criteria. Among the cohort studies, patients with SBSEC bacteremia were 3.73 times more likely to have underlying colorectal cancer compared with individuals with no bacteremia (relative risk [RR], 3.73; 95% CI, 2.79–5.01), whereas the risk of underlying colorectal adenoma in patients with SBSEC bacteremia was not significantly increased (RR, 5.00; 95% CI, 0.83–30.03). In case–control studies, patients with colorectal cancer were 2.27 times more likely to have evidence of intestinal or fecal colonization with SBSEC isolates (odds ratio [OR], 2.27; 95% CI, 1.11–4.62) and immunoglobulin G (IgG) antibody responses to SBSEC antigens (OR, 2.27; 95% CI, 1.06–4.86) compared with controls. Patients with colorectal adenoma were not more likely to be colonized with SBSEC isolates compared with controls (OR, 1.12; 95% CI, 0.55–2.25). Conclusions Apart from the well-established association of SBSEC bacteremia and underlying colorectal cancer, intestinal or fecal colonization with SBSEC isolates and IgG antibody responses to SBSEC antigens were higher in patients with colorectal cancer compared with controls. Neither bacteremia from SBSEC isolates nor colonization with SBSEC bacteria was associated with underlying colorectal adenoma. [ABSTRACT FROM AUTHOR]

Background HER2 overexpression/amplification in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) may be associated with resistance to standard-of-care anti-EGFR therapies. Given the lack of comprehensive investigations into this association, we assessed the prognostic or predictive effect of HER2 amplification/overexpression on anti-EGFR treatment outcomes. Methods A systematic review of MEDLINE, Embase, and Cochrane Library (2001-2021) identified studies evaluating progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) in HER2-positive vs. HER2-negative patients with RAS WT mCRC who received anti-EGFR treatments and whose HER2 status was known. Meta-analyses of proportions (ORR) and hazard ratios (PFS, OS) were performed using random-effect models with pre-specified sensitivity analyses. Results Five high-quality retrospective cohort studies were included in the meta-analyses representing 594 patients with mCRC. All patients received anti-EGFR treatment, either as monotherapy or in combination with chemotherapy. Meta-analysis of PFS demonstrated a 2.84-fold higher risk of death or progression (95% CI, 1.44-5.60) in patients with HER2-positive (vs. HER2-negative) RAS WT mCRC treated with anti-EGFR regimens. The odds of response to anti-EGFR treatment were 2-fold higher in HER2-negative vs. HER2-positive (odds ratio, 1.96 [95% CI, 1.10-3.48]). Differences in OS were not statistically significant. Sensitivity analyses confirmed the robustness of the base-case estimates. Conclusions While this study could not account for all confounding factors, in patients with RAS WT mCRC who received anti-EGFR therapy, HER2 overexpression/amplification was associated with worse PFS and ORR and may therefore predict poorer outcomes. HER2 testing is important to inform treatment decisions and could optimize outcomes for patients. [ABSTRACT FROM AUTHOR]

Appalachian regions of Kentucky and Ohio are hotspots for colorectal cancer (CRC) mortality in the USA. Screening reduces CRC incidence and mortality; however, screening uptake is needed, especially in these underserved geographic areas. Implementation science offers strategies to address this challenge. The aim of the current study was to conduct multi-site, transdisciplinary research to evaluate and improve CRC screening processes using implementation science strategies. The study consists of two phases (Planning and Implementation). In the Planning Phase, a multilevel assessment of 12 health centers (HC) (one HC from each of the 12 Appalachian counties) was conducted by interviewing key informants, creating community profiles, identifying HC and community champions, and performing HC data inventories. Two designated pilot HCs chose CRC evidence-based interventions to adapt and implement at each level (i.e. patient, provider, HC, and community) with evaluation relative to two matched control HCs. During the Implementation Phase, study staff will repeat the rollout process in HC and community settings in a randomized, staggered fashion in the remaining eight counties/HCs. Evaluation will include analyses of electronic health record data and provider and county surveys. Rural HCs have been reluctant to participate in research because of concerns about capacity; however, this project should demonstrate that research does not need to be burdensome and can adapt to local needs and HC abilities. If effective, this approach could be disseminated to HC and community partners throughout Appalachia to encourage the uptake of effective interventions to reduce the burden of CRC. [ABSTRACT FROM AUTHOR]

Aims: The association between heart failure (HF) patients and the incidence of cancer is not well understood, with conflicting results to date. The aim of this meta-analysis was to evaluate whether patients with HF have a higher risk of developing cancer. Methods and results: We performed a systematic literature search using PubMed, Embase, and Scopus for relevant articles from inception until 10 December 2022. The primary clinical outcome was the incidence of cancer. Secondary endpoints were the incidence of breast cancer, lung cancer, haematological cancer, colorectal cancer, and prostate cancer. A total of 9 articles with 7 329 706 (515 041 HF vs. 6 814 665 non-HF) patients were involved in the analysis. The mean age of the patients in the HF and the non-HF groups was 69.06 and 66.76 years. The median follow-up duration was 6.7 years. The most common comorbidity among both groups includes diabetes mellitus (27.58 vs. 14.49%) and hypertension (81.46 vs. 57.38%). Patients with HF were associated with a significant increase in the incidence of cancer {hazard ratio [HR], 1.43 [95% confidence interval (CI): 1.21–1.68], P < 0.001}, breast cancer [HR, 1.28 (95% CI: 1.09–1.50), P < 0.001], lung cancer [HR, 1.89 (95% CI: 1.25–2.85), P < 0.001], haematological cancer [HR, 1.63 (95% CI: 1.15–2.33), P = 0.01], and colorectal cancer [HR, 1.32 (95% CI: 1.11–1.57), P < 0.001] compared with patients without HF. However, the incidence of prostate cancer was comparable between both groups [HR, 0.97 (95% CI: 0.66–1.43), P = 0.88]. Conclusion: This meta-analysis confirms that the state of HF is associated with a higher risk for incident cancer. These data may aid in raising awareness with physicians that cancer may develop in patients with prevalent heart failure and that early screening and evaluation may be useful in an early diagnosis of cancer. Graphical Abstract Central illustration highlighting the association between heart failure and cancer incidence. [ABSTRACT FROM AUTHOR]

A correction to the article "Propofol regulates miR-1-3p/IGF1 axis to inhibit the proliferation and accelerates apoptosis of colorectal cancer cells" that was published in the October 28, 2021 issue is presented.

This article presents a study that aimed to replicate previous research on the relationship between a genetic polymorphism in the COX-2 gene promoter and peritoneal infection after colorectal cancer surgery. However, the study found that the previous findings could not be replicated, and there was a non-significant reverse association between the genetic polymorphism and peritoneal infection. The study suggests that factors such as sample size, analytic differences, outcome definition, and allele frequencies may have contributed to the differences in results. The study concludes that more research is needed to gain a better understanding of the relationship between the genetic polymorphism and peritoneal infection. [Extracted from the article]

The primary purpose of this paper is to present the available evidence for the administration of cetuximab on an every-2-weeks basis in combination with irinotecan in metastatic colorectal cancer (mCRC). Cetuximab is an epidermal growth factor receptor--targeted IgG1 monoclonal antibody that is approved for use in combination with irinotecan or as monotherapy in the treatment of mCRC. The currently approved dosing regimen for cetuximab is a 400-mg/m² initial dose followed by 250 mg/m² weekly. Many commonly used chemotherapy agents for mCRC (including irinotecan alone or in combination with 5-fluorouracil [5-FU]/ folinic acid [FA] and oxaliplatin plus 5-FU/FA) are administered on an every-2-weeks basis. The ability to synchronize the administration of cetuximab and concomitant chemotherapy is desirable for both patients and health care workers. A cetuximab dose of 500 mg/m² every 2 weeks exhibited predictable pharmacokinetics, which were similar to those of the approved weekly dosing regimen. Active serum concentrations of cetuximab were maintained throughout the 2-week dosing period with this regimen. There was no difference between the dosing regimens on pharmacodynamic parameters in skin. The efficacy and safety of the every-2- weeks dosing regimen were similar to those reported for the approved weekly dosing regimen. The indication from these preliminary findings is that every-2-weeks administration of cetuximab (500 mg/m²1) may be a potentially convenient alternative to the approved weekly dosing regimen of 250 mg/m² (following an initial dose of 400 mg/m²) in the treatment of mCRC. [ABSTRACT FROM AUTHOR]

Background Previous meta-analyses reporting significant associations between perioperative allogeneic blood transfusions and poor prognosis in gastric cancer or colorectal cancer had a high risk of confounding bias. This meta-analysis explored this issue using observational studies that applied propensity score analysis. Methods PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for manuscripts published between 2013 and 2022. Studies applying propensity score analysis were included to investigate the association between perioperative allogeneic blood transfusions and prognosis in gastric cancer or colorectal cancer after radical surgery. Pooled HRs for overall survival and disease-free survival were calculated using a fixed-effect model or random-effect model according to heterogeneity. Results Twelve retrospective cohort studies with 17 607 patients reported were included. Ten studies applied propensity score matching and two applied inverse probability of treatment weighting using propensity score. A total of 5962 patients were analysed after propensity score adjustment. After propensity score adjustment, perioperative allogeneic blood transfusions did not correlate with disease-free survival in gastric cancer (HR 1.16; 95 per cent c.i. 0.96–1.39; heterogeneity was assessed by the chi-squared test and inconsistency index (I 2) = 57 per cent) or colorectal cancer (HR 1.12; 95 per cent c.i. 0.84–1.49; I 2 = 54 per cent). However, after propensity score adjustment, perioperative allogeneic blood transfusions were significantly associated with worse overall survival in gastric cancer (HR 1.20; 95 per cent c.i. 1.08–1.32; I 2 = 25 per cent) and colorectal cancer (HR 1.40; 95 per cent c.i. 1.06–1.85; I 2 = 52 per cent). Subgroup analyses showed that perioperative allogeneic blood transfusions did not correlate with overall survival in colorectal cancer when major postoperative complications were balanced after propensity score. Conclusion Perioperative allogeneic blood transfusion is not correlated with recurrence of gastric cancer and colorectal cancer. Perioperative allogeneic blood transfusions are significantly associated with worse overall survival in gastric cancer and colorectal cancer, which may be attributable to unbalanced major postoperative complications after propensity score adjustment. [ABSTRACT FROM AUTHOR]

Chemoresistance is an obstacle for colorectal cancer (CRC) treatment. This study investigates the role of the ubiquitin E3 ligase MDM2 in affecting cell growth and chemosensitivity in CRC cells by modifying the transcription factor inhibitor of growth protein 3 (ING3). The expression of MDM2 and ING3 in CRC tissues was predicted by bioinformatics analysis, followed by expression validation and their interaction in CRC HCT116 and LS180 cells. Ectopic overexpression or knockdown of MDM2/ING3 was performed to test their effect on proliferation and apotptosis as well as chemosensitivity of CRC cells. Finally, the effect of MDM2/ING3 expression on the in vivo tumorigenesis of CRC cells was examined through subcutaneous tumor xenograft experiment in nude mice. MDM2 promoted ubiquitin-proteasome pathway degradation of ING3 through ubiquitination and diminished its protein stability. Overexpression of MDM2 downregulated ING3 expression, which promoted CRC cell proliferation and inhibited the apoptosis. The enhancing role of MDM2 in tumorigenesis and resistance to chemotherapeutic drugs was also confirmed in vivo. Our findings highlight that MDM2 modifies the transcription factor ING3 by ubiquitination-proteasome pathway degradation, thus reducing ING3 protein stability, which finally promotes CRC cell growth and chemoresistance. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the efficacy and safety of particle beam therapy (PBT) with proton or carbon ion beam for pelvic recurrence of colorectal cancer (PRCC) by comparing the clinical outcomes of a dataset of prospectively enrolled patients for PBT with those from the literature, which were collected by a systematic review of external X-ray radiotherapy (XRT) and PBT. Patients with PRCC treated at 14 domestic facilities between May 2016 and June 2019 and entered the database for prospective observational follow-up were analyzed. The registry data analyzed included 159 PRCC patients treated with PBT of whom 126 (79%) were treated with carbon ion radiation therapy (CIRT). The 3-year overall survival and local control rate were 81.8 and 76.4%, respectively. Among these PRCC patients, 5.7% had Grade 3 or higher toxicity. Systematic search of PubMed and Cochrane databases published from January 2000 to September 2020 resulted in 409 abstracts for the primary selection. Twelve studies fulfilled the inclusion criteria. With one additional publication, 13 studies were selected for qualitative analysis, including 9 on XRT and 4 on PBT. There were nine XRT studies, which included six on 3D conformal radiotherapy and three on stereotactic body radiation therapy, and four PBT studies included three on CIRT and one on proton therapy. A pilot meta-analysis using literatures with median survival time extractable over a 20-month observation period suggested that PBT, especially CIRT, may be a promising treatment option for PRCC not amenable to curative resection. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) have been accepted to play key roles in the development and progression of mutiple cancers including colorectal cancer (CRC). Here, we identified circ-METTL9, derived from 2 to 4 exons of METTL9 gene, may promote CRC progression by accelerating cell cycle progression. However, the role and mechanism of circ-METTL9 in CRC remains unclear. Based on our data, the expression of circ-METTL9 was significantly upregulated in CRC tissues and markedly increased in advanced tumors in CRC patients. Functional experiments demonstrated that circ-METTL9 overexpression promoted CRC cells proliferation and migration in vitro , and simultaneously enhanced CRC tumor growth and metastasis in vivo. Mechanistically, RNA immunoprecipitation (RIP) assays proved that circ-METTL9 might be a miRNA sponge, and RNA pulldown assays showed the interaction between circ-METTL9 and miR-551b-5p. Notably, cyclin-dependent kinase 6 (CDK6), a key regulator in cell cycle, is a conserved downstream target of miR-551b-5p. Taken together, our findings highlight a novel oncogenic function of circ-METTL9 in CRC progression via circ-METTL9/miR-551b-5p/CDK6 axis, which may serve as a prognostic biomarker and therapeutic target for CRC patients. [ABSTRACT FROM AUTHOR]

Introduction With increasing interest in income-related differences in cancer outcomes, accurate measurement of income is imperative. Misclassification of income can result in wrong conclusions as to the presence of income inequalities. We determined misclassification between individual- and neighborhood-level income and their association with overall survival among colorectal cancer (CRC) patients. Methods The Canadian Census Health and Environment Cohorts were used to identify CRC patients diagnosed from 1992 to 2017. We used neighborhood income quintiles from Statistics Canada and created individual income quintiles from the same data sources to be as similar as possible. Agreement between individual and neighborhood income quintiles was measured using cross-tabulations and weighted kappa statistics. Cox proportional hazards and Lin semiparametric hazards models were used to determine the effects of individual and neighborhood income independently and jointly on survival. Analyses were also stratified by rural residence. Results A total of 103 530 CRC patients were included in the cohort. There was poor agreement between individual and neighborhood income with only 17% of respondents assigned to the same quintile (weighted kappa = 0.18). Individual income had a greater effect on relative and additive survival than neighborhood income when modeled separately. The interaction between individual and neighborhood income demonstrated that the most at risk for poor survival were those in the lowest individual and neighborhood income quintiles. Misclassification was more likely to occur for patients residing in rural areas. Conclusion Cancer researchers should avoid using neighborhood income as a proxy for individual income, especially among patients with cancers with demonstrated inequalities by income. [ABSTRACT FROM AUTHOR]

Background: People with type 2 diabetes mellitus (T2DM) have a higher risk of developing breast and bowel cancers but are less likely to participate in cancer screening. Purpose: Two interlinked studies examined public awareness of the fact that T2DM increases breast and bowel cancer risk, and provision of this information on diabetes websites. Methods: Study-1: phase-1 surveyed awareness of T2DM-increased cancer risk in a nationally-representative British sample aged 50–74 (N = 1,458) and compared respondents with and without T2DM (n = 125 vs. n = 1,305); phase-2 surveyed an additional exclusively T2DM sample (N = 319). Study-2: High-ranking diabetes websites (N = 25) were reviewed to determine the rate of inclusion of cancer risk and cancer screening information in evident sections about diabetes-related health conditions. Results: A low proportion of respondents were aware that T2DM increases risk of breast (13.7%) and bowel (27.6%) cancers, compared to much higher awareness of other diabetes-related conditions such as sight loss (82.2%) and foot problems (81.8%). Respondents with T2DM were significantly more likely than those without T2DM to be aware of all the surveyed diabetes-related health conditions (e.g., sight loss, OR: 3.14, 95%CI: 1.61–6.15; foot problems, OR: 2.58, 95%CI: 1.38–4.81), except breast (OR: 0.82, 95%CI: 0.46–1.45) and bowel (OR: 0.95, 95%CI: 0.63–1.45) cancer, for which awareness was equally low among people with and without T2DM. Few diabetes websites with a section on diabetes-related health conditions included cancer in this section (n = 4/19), and fewer still included cancer screening among any noted cancer-protective behaviors (n = 2/4). Conclusions: There is low public awareness that T2DM increases the risk of developing breast and bowel cancers, even among people with T2DM, which may be partly due to limited information provision regarding T2DM-increased cancer risk from diabetes care providers and organizations. Most people are not aware that Type 2 diabetes increases the risk of breast and bowel cancers. Awareness is low even among people who have Type 2 diabetes. This may be partly because little information about cancer risk is being provided by diabetes care organisations. Lay Summary: People with type 2 diabetes (T2D) have a higher risk of developing breast and bowel cancers. Despite this, they are less likely to participate in cancer screening, which can improve survival from cancer. We addressed two questions. Are people aware that T2D increases the risk of breast and bowel cancer? Are people being told about this by diabetes care providers and organizations? We surveyed a large representative sample of the British public (aged 50–74). We also reviewed key information about diabetes-related health problems provided on 25 top-ranking diabetes websites. There were three main findings. (1) Relatively few people knew that T2D increases the risk of breast and bowel cancer. In contrast, many people knew that T2D increases the risk of other conditions like sight loss, foot problems, and heart disease. (2) Awareness of higher cancer risk was equally low among people with T2D and those without. In contrast, knowledge of other diabetes-related conditions (e.g., sight loss, foot problems) was higher among people with T2D than those without. (3) Few websites included cancer in their key information about diabetes-related health problems. In contrast, nearly all the diabetes websites listed the more well-known risks of sight loss, foot problems, and heart disease. [ABSTRACT FROM AUTHOR]

Background Colorectal cancer (CRC) screening using faecal tests reduces disease-specific mortality. To investigate mortality and its association with sex, rates in women and men, and in different age ranges, were examined, before and after screening began in Scotland. Methods From 1990–99, no structured screening existed. Three pilots ran from 2000 to 2007 and subsequent full roll-out completed in 2009. Crude mortality rates for 1990–2020 were calculated relative to Scottish population estimates, and age–sex standardized rates calculated for all, pre-screening (<50 years), screening (5–74 years) and post-screening (>74 years) age ranges. Results CRC mortality declined from 1990 to 2020, but not linearly, and differed between sexes. In women, 1990–99 showed a steady decline [average annual percentage change (AAPC): −2.1%, 95% confidence interval (CI): −2.8% to −1.4%], but a less marked decline after 2000 (AAPC: −0.7%, 95% CI: −0.9% to −0.4%). In men, no clear decline was seen from 1990 to 1999 (AAPC: −0.4%, 95% CI: −1.1% to 0.4%), but mortality declined from 2000 to 2020 (AAPC: −1.7%, 95% CI: −1.9% to −1.5%). This pattern was exaggerated in the screening age ranges. For 2000–20, the overall reduction in mortality was less in women and in the screening age range. In the post-screening age range, reductions were smaller, but an increase was seen in the pre-screening age range, greater in women. Conclusions CRC mortality fell during 1990–2020, but the decline differed markedly between sexes, indicating a larger beneficial effect of screening on CRC mortality in men compared to women: use of different thresholds for the sexes might lead to equality. [ABSTRACT FROM AUTHOR]

Background: Measurement of faecal haemoglobin using faecal immunochemistry testing is recommended in patients presenting with symptoms suspicious for colorectal cancer, to aid in triage and prioritization of definitive investigations. While its role in colorectal cancer has been extensively investigated, the ability of faecal immunochemistry testing to detect adenomas in symptomatic patients is unclear. Methods: A multicentre prospective observational study was conducted between April 2017 and March 2019, recruiting adults from 24 hospitals across England and 59 general practices in London who had been urgently referred with suspected colorectal cancer symptoms. Each patient provided a stool sample for faecal immunochemistry testing, in parallel with definitive investigation. A final diagnosis for each patient was recorded, including the presence, size, histology, and risk type of colonic polyps. The outcome of interest was the sensitivity of faecal immunochemistry testing in detecting the presence of adenomas. Results: Of 3496 patients included in the analysis, 553 (15.8 per cent) had polyps diagnosed. Sensitivity of faecal immunochemistry testing for polyp detection was low across all ranges; with a cut-off for faecal haemoglobin of 4 µg/g or lower, sensitivity was 34.9 per cent and 46.8 per cent for all polyp types and high-risk polyps respectively. The area under the receiver operating characteristic curve in detection probability was relatively low for both intermediate-risk (0.63) and high-risk polyps (0.63). Conclusion: While faecal immunochemistry testing may be useful in prioritizing investigations to diagnose colorectal cancer, if used as a sole test, the majority of polyps would be missed and the opportunity to prevent progression to colorectal cancer may be lost. Faecal immunochemistry testing (FIT) is currently used in the UK to triage patients referred with symptoms suggestive of colorectal cancer; however, the role of FIT in the detection of adenomatous polyps, a known precursor to colorectal cancer, in symptomatic patients is unknown. Our study demonstrates that if FIT were used as a triage for further investigations in symptomatic patients, more than half of all high-risk adenomas would be missed, therefore current endoscopic investigations in symptomatic patients must remain to ensure that all adenomas can be identified and removed. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the second leading cause of cancer-induced death in the world. Cancer-associated fibroblasts (CAFs) released exosomes that contributed to cancer progression. This research was carried out to study the influence of CRC-associated fibroblasts-derived exosomes on the phenotype of CRC cells and the underlying mechanism. CAFs-derived exosomes (CAFs-exo) and normal fibroblasts (NFs)-derived exosomes (NFs-exo) were recognized by transmission electronic microscopy, nanoparticle tracking analysis and western blot analysis. Cell counting kit-8, flow cytometry analysis, colony formation assay, Transwell, qRT-PCR, immunofluorescence, immunohistochemistry staining and xenografts model were carried out to proceed with function studies in vitro and in vivo. The results showed that CAFs-exo induced cell proliferation, migration and invasion, while NFs-exo did not influence the tumor biological properties of CRC cells. Using qRT-PCR, miR-345-5p was observed to be a notably up-regulated miRNA in CAFs-exo compared to NFs-exo. CAFs-exo could mediate the transfer of miR-345-5p to CRC cells, and downregulation of miR-345-5p in CAFs notably reversed the pro-tumoral effect of CAFs-exo on CRC cells. Based on online prediction database, CDKN1A was proved as a direct downstream target of miR-345-5p in CRC cells, which was lowly expressed and negatively associated with miR-345-5p in CRC tumors. Furthermore, miR-345-5p upregulation-mediated tumor biological behaviors were abrogated by exogenous CDKN1A. In CRC cells-beared tumor xenograft, CAFs-exo administration promoted tumor growth and decreased CDKN1A expression, whereas miR-345-5p inhibition reversed these effects. The present study revealed that by interacting with CDKN1A, CAF-derived exosomal miR-345-5p promotes CRC progression and metastasis. [ABSTRACT FROM AUTHOR]

Assessing causal treatment effect on a time‐to‐event outcome is of key interest in many scientific investigations. Instrumental variable (IV) is a useful tool to mitigate the impact of endogenous treatment selection to attain unbiased estimation of causal treatment effect. Existing development of IV methodology, however, has not attended to outcomes subject to interval censoring, which are ubiquitously present in studies with intermittent follow‐up but are challenging to handle in terms of both theory and computation. In this work, we fill in this important gap by studying a general class of causal semiparametric transformation models with interval‐censored data. We propose a nonparametric maximum likelihood estimator of the complier causal treatment effect. Moreover, we design a reliable and computationally stable expectation–maximization (EM) algorithm, which has a tractable objective function in the maximization step via the use of Poisson latent variables. The asymptotic properties of the proposed estimators, including the consistency, asymptotic normality, and semiparametric efficiency, are established with empirical process techniques. We conduct extensive simulation studies and an application to a colorectal cancer screening data set, showing satisfactory finite‐sample performance of the proposed method as well as its prominent advantages over naive methods. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES We seek to identify preoperative prognostic factors and measure their effect on 5-year survival following pulmonary metastasectomy (PM) for Colorectal Cancer (CRC). METHODS We systematically reviewed the databases of Cochrane Library, MEDLINE, Embase and Google Scholar from January 2000 to April 2021 to identify preoperative factors that have been investigated for their prognostic effect on survival following PM. Quality assessment was performed using the QUIPS tool. The prognostic effect of each identified factor on 5-year survival post-PM was estimated using random-effects meta-analyses. RESULTS We identified 115 eligible articles which included 13 294 patients who underwent PM from CRC. The overall 5-year survival after resection of the lung metastasis was 54.1%. The risk of bias of the included studies was at least moderate in 93% (107/115). Seventy-seven preoperative factors had been investigated for their prognostic effect. Our analysis showed that 11 factors had favourable and statistically significant prognostic effect on 5-year survival post-PM. These included solitary metastasis, size <2 cm, unilateral location, N0 thoracic disease, no history of extra-thoracic or liver metastasis, normal carcinoembryonic antigen levels both before PM and CRC excision, no neo-adjuvant chemotherapy before PM, CRC T-stage < T4 and no p53 mutations on CRC. Disease-free interval at 24 months did not appear to affect 5-year survival. CONCLUSIONS Despite the considerable risk of bias in the literature, our study consolidates the available evidence on preoperative prognostic factors for PM from CRC. These findings can complement both clinical practice and the design of future research on the field of PM. [ABSTRACT FROM AUTHOR]

The article comments on a paper by A. R. Parikh and colleagues on the effectiveness and safety of cetuximab dosage in patients with colorectal, head and neck cancer. Topics mentioned include the comparison of weekly and biweekly dosage of cetuximab in patients with metastatic colororectal and squamous cell carcinoma of the head and neck cancer, the cost-effectiveness of biweekly dosing to reduce hospital visits and infusion times, and the improvement in patients' quality of life.

Background Incidence of colorectal cancer (CRC) in younger adults is increasing in many countries. Smoking is an established risk factor of CRC risk, but evidence on its impact on early-onset CRC (EOCRC) risk is limited. We aimed to evaluate the association of smoking exposure with EOCRC and compare it with late-onset CRC (LOCRC). Methods Smoking history and other known or suspected CRC risk factors were ascertained in detail in personal interviews among 6264 CRC patients and 6866 controls (frequency matched for age, sex, and county of residence) who were recruited in 2003-2020 in the DACHS study (Darmkrebs: Chancen der Verhütung durch Screening [German]; Colorectal Cancer: Chances for Prevention Through Screening [English]), a population-based case-control study from Germany. Associations of smoking with EOCRC (<55 years, 724 cases, 787 controls) and LOCRC (≥55years, 5540 cases, 6079 controls) were estimated using multiple logistic regression. Results Smoking exposure was much higher among EOCRC cases than among controls, and strong associations of smoking were observed for both EOCRC and LOCR. Adjusted odds ratios for EOCRC and LOCRC were as follows: current smoking: 1.57 (95% confidence interval [CI] = 1.20 to 2.04, P  < .001) and 1.46 (95% CI = 1.28 to 1.67, P  < .001); former smoking: 1.39 (95% CI = 1.07 to 1.81, P  = .01) and 1.24 (95% CI = 1.13 to 1.36, P  < .001); per 10 pack-years: 1.15 (95% CI = 1.05 to 1.27, P  < .001) and 1.05 (95% CI = 1.03 to 1.08, P  < .001). These patterns were similar for colon and rectum cancer and for early- and late-stage CRC. Conclusion Smoking is a strong risk factor for both EOCRC and LOCRC. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) incidence rates have decreased among adults aged 50 years or older while increasing in adults under age 50 years. Understanding these trends is challenging because of the multiple related time scales of age, diagnosis period, and birth cohort. We analyzed incidence rates of rectal, distal colon, and proximal colon cancer for individuals aged 20 years or more from the Surveillance, Epidemiology, and End Results Program for diagnosis years 1978–2017. We used a 2-stage generalized linear model to determine age, period, and cohort effects for CRC incidence. We first estimated birth cohort effects among people under age 45 years. We used these results to specify prior distributions for cohort effects in a Bayesian model to estimate period effects among people aged 45 years or more. There was no evidence of period effects for people under age 45 years. Risks of rectal and distal colon cancer increased for later birth cohorts. Compared with the 1943–1952 birth cohort, the 1983–1992 birth cohort had 2.2 times the risk of rectal cancer, 1.9 times the risk of distal colon cancer, and 1.3 times the risk of proximal colon cancer. For people aged ≥45 years, period effects showed declines in CRC risk that were attributable to screening. [ABSTRACT FROM AUTHOR]

Background: Although colorectal cancer (CRC) incidence is declining among adults aged ≥65 years, CRC incidence in younger adults has been rising. The protective role of calcium in colorectal carcinogenesis has been well established, but evidence is lacking on whether the association varies by age at diagnosis. We investigated the association between total calcium intake and risk of overall CRC and CRC before age 55 years.Methods: In the Nurses' Health Study II (1991-2015), 94 205 women aged 25-42 years at baseline were included in the analysis. Diet was assessed every 4 years through validated food frequency questionnaires. Multivariable-adjusted hazard ratios (HRs) and 95% CIs for CRC were estimated using the Cox proportional hazards model.Results: We documented 349 incident CRC cases during 2 202 604 person-years of follow-up. Higher total calcium intake was associated with a reduced risk of CRC. Compared with those with <750 mg/day of total calcium intake, the HR of CRC was 0.61 (95% CI, 0.38-0.97) for those who consumed ≥1500 mg/day (P for trend = 0.01). The HR per 300 mg/day increase was 0.85 (95% CI, 0.76-0.95). There was a suggestive inverse association between total calcium intake and CRC before age 55 years (HR per 300 mg/day increase, 0.87; 95% CI, 0.75-1.00), suggesting the importance of calcium intake in the younger population.Conclusions: In a cohort of younger women, which reflects the birth cohorts, time periods and age ranges paralleling the recent rise in CRC, higher calcium intake was associated with a decreased risk of CRC. [ABSTRACT FROM AUTHOR]

Aim Fusobacterium nucleatum (F. nucleatum) is associated with the initiation, development, and metastasis of colorectal cancer. However, it is difficult to isolate F. nucleatum from clinical specimens. In this study, we aimed to develop an effective and rapid method for isolating F. nucleatum from human feces using polyclonal antibody (PAB)-coated immunomagnetic beads (IMBs) with selective media. Methods and results IMBs conjugated with PAB were prepared and used to isolate F. nucleatum from human feces, and the bacteria were cultured with selective culture media (fastidious anaerobe agar + nalidixic acid + vancomycin). Under optimized experimental conditions, IMBs could selectively recover F. nucleatum from fecal microbiota samples spiked with Peptostreptococcus or Bacteroides fragilis. In artificial fecal samples, the detection sensitivity of IMBs for F. nucleatum was 103 CFU mL−1. In addition, IMBs combined with selective media could rapidly isolate F. nucleatum from human feces. Conclusions This study successfully established an effective method for the rapid isolation of F. nucleatum from human feces by IMBs. The whole procedure requires 2–3 days, and has a sensitivity of 103 CFU mL−1 feces. [ABSTRACT FROM AUTHOR]