High-Throughput Metabolic Pattern Screening Strategy for Early Colorectal and Gastric Cancers Based on Covalent Organic Frameworks-Assisted Laser Desorption/Ionization Mass Spectrometry.

Precise early diagnosis and staging are conducive to improving the prognosis of colorectal cancer (CRC) and gastric cancer (GC) patients. However, due to intrusive inspections and limited sensitivity, the prevailing diagnostic methods impede precisely large-scale screening. In this work, we reported a high-throughput serum metabolic patterns (SMP) screening strategy based on covalent organic frameworks-assisted laser desorption/ionization mass spectrometry (hf-COFsLDI-MS) for early diagnosis and staging of CRC and GC. Notably, 473 high-quality SMP were extracted without any tedious sample pretreatment and coupled with multiple machine learning algorithms; the area under the curve (AUC) value is 0.938 with 96.9% sensitivity for early CRC diagnosis, and the AUC value is 0.974 with 100% sensitivity for early GC diagnosis. Besides, the discrimination of CRC and GC is accomplished with an AUC value of 0.966 for the validation set. Also, the screened-out features were identified by MS/MS experiments, and 8 metabolites were identified as the biomarkers for CRC and GC. Finally, the corresponding disordered metabolic pathways were revealed, and the staging of CRC and GC was completed. This work provides an alternative high-throughput screening strategy for CRC and GC and highlights the potential of metabolic molecular diagnosis in clinical applications.

Temporal trends and regional variability in BRAF and KRAS genetic testing in Denmark (2010-2022): Implications for precision medicine.

OBJECTIVE: This study aims to evaluate the developments in the testing of Kirsten Rat Sarcoma viral oncogene homolog (KRAS) and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations across different cancer types and regions in Denmark from 2010 to 2022. STUDY DESIGN AND SETTING: Using comprehensive data from the Danish health registries, we linked molecular test results from the Danish Pathology Registry with cancer diagnoses from the Danish National Patient Registry between 2010 and 2022. We assessed the frequency and distribution of KRAS and BRAF mutations across all cancer types, years of testing, and the five Danish regions. RESULTS: The study included records of KRAS testing for 30 671 patients and BRAF testing for 30 860 patients. Most KRAS testing was performed in colorectal (78%) and lung cancer (18%), and BRAF testing in malignant melanoma (13%), colorectal cancer (67%), and lung cancer (12%). Testing rates and documentation mutational subtypes increased over time. Reporting of wildtype results varied between lung and colorectal cancer, with underreporting in lung cancer. Regional variations in testing and reporting were observed. CONCLUSION: Our study highlights substantial progress in KRAS and BRAF testing in Denmark from 2010 to 2022, evidenced by increased and more specific reporting of mutational test results, thereby improving the precision of cancer diagnosis and treatment. However, persistent regional variations and limited testing for cancer types beyond melanoma, colorectal, and lung cancer highlight the necessity for a nationwide assessment of the optimal testing approach.

The role of galanin in the progression and prognosis of colorectal cancer: the unfinished story.

The paper presents a summary of immunohistochemical (IHC) and biochemical investigations on the presence of galanin (Gal), one of the neuropeptides abundant in the enteric nervous systems, and three types of its receptors (GalR1-3) in colorectal cancer (CRC) tissue and non-involved colon wall and their associations with clinical-pathological data of the CRC patients. We were the first to morphologically demonstrate the presence of endogenous Gal in CRC sections and measure its content in homogenates of tumor tissue and dissected compartments of unchanged colon wall. The prominent atrophy of myenteric plexuses displaying Gal immunoreactivity (Gal-Ir) located close to the tumor invasion was found to be accompanied by higher Gal content in the tumor-adjacent muscularis externa than in tumor-distant tissue. In further studies for the first time, we demonstrated by the IHC technique the presence of the GalR1-3 receptors in the CRC tumors and the colon mucosa and found that higher GalR3-Ir in the tumor tissue correlated with longer overall survival of CRC patients. Furthermore, we discovered that lower GalR1 expression in submucosal plexuses located near the tumor correlated with a better prognosis in patients with CRC. These findings suggest that GalR1 could be considered as a novel therapeutic target in CRC. In conclusion, our morphological investigations provided novel data documenting the involvement of Gal and its receptors in the progression of CRC and showed the usefulness of the IHC technique for the prognosis of CRC patients.

Engaging with Rural Communities for Colorectal Cancer Screening Outreach Using Modified Boot Camp Translation.

BACKGROUND: Colorectal cancer (CRC) incidence and mortality are disproportionately high among rural residents and Medicaid enrollees. OBJECTIVES: To address disparities, we used a modified community engagement approach, Boot Camp Translation (BCT). Research partners, an advisory board, and the rural community informed messaging about CRC outreach and a mailed fecal immunochemical test program. METHODS: Eligible rural patients (English-speaking and ages 50-74) and clinic staff involved in patient outreach participated in a BCT conducted virtually over two months. We applied qualitative analysis to BCT transcripts and field notes. RESULTS: Key themes included: the importance of directly communicating about the seriousness of cancer, leveraging close clinic-patient relationships, and communicating the test safety, ease, and low cost. CONCLUSIONS: Using a modified version of BCT delivered in a virtual format, we were able to successfully capture community input to adapt a CRC outreach program for use in rural settings. Program materials will be tested during a pragmatic trial to address rural CRC screening disparities.

Trends in colorectal cancer screening compliance and incidence among 60- to 74-year-olds in China.

BACKGROUND: Compliance with colonoscopy among elderly individuals participating in colorectal cancer (CRC) screening programs is unsatisfactory, despite a high detection rate of bowel-related diseases. In this study, our aim was to analyze the impact of risk factors on the trends of compliance and detection rates in colonoscopy among high-risk individuals aged 60-74. METHODS: A retrospective study was conducted on the high-risk individuals aged 60-74 participating in the 2021 CRC screening program in Tianjin, China. Logistic regression analyses, including both univariate and multivariate analyses, were performed to explore the impact of different risk factors on colonoscopy compliance among the high-risk individuals. Besides, the study investigated the influence of various risk factors on the detection rates of bowel-related diseases among the high-risk individuals who underwent colonoscopy. RESULTS: A total of 24,064 high-risk individuals were included, and 5478 individuals received a free colonoscopy, with an overall compliance of 22.76%. Among them, the adenoma detection rate was 55.46%. Males and individuals with a positive FIT had high compliance and detection rates for CRC, advanced adenomas (AA), advanced colorectal neoplasia (ACN), and colorectal neoplasm (CN). Individuals aged 70-74 were associated with low compliance but high CRC, ACN, and CN detection rates. Individuals who reported a history of chronic constipation, bloody mucous, and CRC in first-degree relative showed high compliance but no significantwere associated with the detection rates of CRC, AA, and CN. CONCLUSION: This study reported several risk factors associated with the screening behaviors for CRC. Patterns and trends in CRC, AA, ACN, and CN compliance and detection rates correlate with risk factors.

Stage at diagnosis of colorectal cancer through diagnostic route: Who should be screened?

BACKGROUND: Colorectal cancer (CRC) is a global health concern, with advanced-stage diagnoses contributing to poor prognoses. The efficacy of CRC screening has been well-established; nevertheless, a significant proportion of patients remain unscreened, with > 70% of cases diagnosed outside screening. Although identifying specific subgroups for whom CRC screening should be particularly recommended is crucial owing to limited resources, the association between the diagnostic routes and identification of these subgroups has been less appreciated. In the Japanese cancer registry, the diagnostic routes for groups discovered outside of screening are primarily categorized into those with comorbidities found during hospital visits and those with CRC-related symptoms. AIM: To clarify the stage at CRC diagnosis based on diagnostic routes. METHODS: We conducted a retrospective observational study using a cancer registry of patients with CRC between January 2016 and December 2019 at two hospitals. The diagnostic routes were primarily classified into three groups: Cancer screening, follow-up, and symptomatic. The early-stage was defined as Stages 0 or I. Multivariate and univariate logistic regressions were exploited to determine the odds of early-stage diagnosis in the symptomatic and cancer screening groups, referencing the follow-up group. The adjusted covariates were age, sex, and tumor location. RESULTS: Of the 2083 patients, 715 (34.4%), 1064 (51.1%), and 304 (14.6%) belonged to the follow-up, symptomatic, and cancer screening groups, respectively. Among the 2083 patients, CRCs diagnosed at an early stage were 57.3% (410 of 715), 23.9% (254 of 1064), and 59.5% (181 of 304) in the follow-up, symptomatic, and cancer screening groups, respectively. The symptomatic group exhibited a lower likelihood of early-stage diagnosis than the follow-up group [P < 0.001, adjusted odds ratio (aOR), 0.23; 95% confidence interval (95%CI): 0.19-0.29]. The likelihood of diagnosis at an early stage was similar between the follow-up and cancer screening groups (P = 0.493, aOR for early-stage diagnosis in the cancer screening group vs follow-up group = 1.11; 95%CI = 0.82-1.49). CONCLUSION: CRCs detected during hospital visits for comorbidities were diagnosed earlier, similar to cancer screening. CRC screening should be recommended, particularly for patients without periodical hospital visits for comorbidities.

Real-world data evaluating Guy's rapid diagnostic clinic as an alternate pathway for patients with FIT levels below 10.

OBJECTIVE: To analyse the effectiveness of rapid diagnostic clinics (RDCs) as an alternative pathway for patients with concerning symptoms and a faecal immunochemical test (FIT) result <10. Our primary endpoint was rate of colorectal cancer (CRC) detection. Second endpoints were rates of other cancers and gastrointestinal (GI) serious benign conditions. Finally, we analysed the specific pathway followed by FIT <10 patients with cancer at Guy's and St Thomas NHS Foundation Trust (GSTT) RDC. DESIGN: A retrospective and prospective cohort study. SETTING: GSTT RDC, one of England's largest single-centre RDCs. Sociodemographic and clinical characteristics of FIT <10 patients were analysed descriptively. PARTICIPANTS: Patients with an FIT result <10, seen at GSTT RDC between 1 January 2020 and 5 May 2023. RESULTS: A total of 1299 patients with an FIT<10 were seen at GSTT RDC between January 2020 and May 2023. Of these, 66% (n=861) reported weight loss, 62% (n=805) pain, 37% (n=481) fatigue, 34% (n=444) were anaemic and 23% (n=301) had nausea and vomiting. Among these patients, 7% (n=88) received a cancer diagnosis, 36% (n=462) were identified as having a serious benign condition. Within the patients with cancer, 9% (n=8) were diagnosed with CRC. Among patients with serious benign conditions, 7% (n=31) were referred to colorectal, hepatopancreatobiliary, or upper GI specialists. CONCLUSION: This study demonstrates the effectiveness of RDCs as an alternate pathway for FIT <10 patients with ongoing clinical concerns. These results contribute to enhancing patient care and optimising resource allocation within the healthcare system.

Symptom Burden and Time from Symptom Onset to Cancer Diagnosis in Patients with Early-Onset Colorectal Cancer: A Multicenter Retrospective Analysis.

Background: The incidence of colorectal cancer (CRC) is decreasing in individuals >50 years due to organised screening but has increased for younger individuals. We characterized symptoms and their timing before diagnosis in young individuals. Methods: We identified all patients diagnosed with CRC between 1990-2017 in British Columbia, Canada. Individuals <50 years (n = 2544, EoCRC) and a matched cohort >50 (n = 2570, LoCRC) underwent chart review to identify CRC related symptoms at diagnosis and determine time from symptom onset to diagnosis. Results: Across all stages of CRC, EoCRC presented with significantly more symptoms than LoCRC (Stage 1 mean ± SD: 1.3 ± 0.9 vs. 0.7 ± 0.9, p = 0.0008; Stage 4: 3.3 ± 1.5 vs. 2.3 ± 1.7, p < 0.0001). Greater symptom burden at diagnosis was associated with worse survival in both EoCRC (p < 0.0001) and LoCRC (p < 0.0001). When controlling for cancer stage, both age (HR 0.87, 95% CI 0.8-1.0, p = 0.008) and increasing symptom number were independently associated with worse survival in multivariate models. Conclusions: Patients with EoCRC present with a greater number of symptoms of longer duration than LoCRC; however, time from patient reported symptom onset was not associated with worse outcomes.

Screening for Colorectal Cancer.

Colorectal cancer (CRC) is the second leading cause of cancer death. Screening has been proven to reduce both cancer incidence and cancer-related mortality. Various screening tests are available, each with their own advantages and disadvantages and varying levels of evidence to support their use. Clinicians should offer CRC screening to average-risk persons aged 50 to 75 years; starting screening at age 45 years remains controversial. Screening may be beneficial in select persons aged 76 to 85 years, based on their overall health and screening history. Offering a choice of screening tests or sequentially offering an alternate test for those who do not complete screening can significantly increase participation.

Colorectal Cancer Screening After Sequential Outreach Components in a Demographically Diverse Cohort.

Importance: Organized screening outreach can reduce differences in colorectal cancer (CRC) incidence and mortality between demographic subgroups. Outcomes associated with additional outreach, beyond universal outreach, are not well known. Objective: To compare CRC screening completion by race and ethnicity, age, and sex after universal automated outreach and additional personalized outreach. Design, Setting, and Participants: This observational cohort study included screening-eligible individuals aged 50 to 75 years assessed during 2019 in a community-based organized CRC screening program within the Kaiser Permanente Northern California (KPNC) integrated health care delivery setting. For KPNC members who are not up to date with screening by colonoscopy, each year the program first uses automated outreach (mailed prescreening notification postcards and fecal immunochemical test [FIT] kits, automated telephone calls, and postcard reminders), followed by personalized components for nonresponders (telephone calls, electronic messaging, and screening offers during office visits). Data analyses were performed between November 2021 and February 2023 and completed on February 5, 2023. Exposures: Completed CRC screening via colonoscopy, sigmoidoscopy, or FIT. Main Outcomes and Measures: The primary outcome was the proportion of participants completing an FIT or colonoscopy after each component of the screening process. Differences across subgroups were assessed using the χ2 test. Results: This study included 1 046 745 KPNC members. Their mean (SD) age was 61.1 (6.9) years, and more than half (53.2%) were women. A total of 0.4% of members were American Indian or Alaska Native, 18.5% were Asian, 7.2% were Black, 16.2% were Hispanic, 0.8% were Native Hawaiian or Other Pacific Islander, and 56.5% were White. Automated outreach significantly increased screening participation by 31.1%, 38.1%, 29.5%, 31.9%, 31.8%, and 34.5% among these groups, respectively; follow-up personalized outreach further significantly increased participation by absolute additional increases of 12.5%, 12.4%, 13.3%, 14.4%, 14.7%, and 11.2%, respectively (all differences P < .05 compared with White members). Overall screening coverage at the end of the yearly program differed significantly among members who were American Indian or Alaska Native (74.1%), Asian (83.5%), Black (77.7%), Hispanic (76.4%), or Native Hawaiian or Other Pacific Islander (74.4%) compared with White members (82.2%) (all differences P < .05 compared with White members). Screening completion was similar by sex; older members were substantially more likely to be up to date with CRC screening both before and at the end of the screening process. Conclusions and Relevance: In this cohort study of a CRC screening program, sequential automated and personalized strategies each contributed to substantial increases in screening completion in all demographic groups. These findings suggest that such programs may potentially reduce differences in CRC screening completion across demographic groups.

On repeated diagnostic testing in screening for a medical condition: How often should the diagnostic test be repeated?

In screening large populations a diagnostic test is frequently used repeatedly. An example is screening for bowel cancer using the fecal occult blood test (FOBT) on several occasions such as at 3 or 6 days. The question that is addressed here is how often should we repeat a diagnostic test when screening for a specific medical condition. Sensitivity is often used as a performance measure of a diagnostic test and is considered here for the individual application of the diagnostic test as well as for the overall screening procedure. The latter can involve an increasingly large number of repeated applications, but how many are sufficient? We demonstrate the issues involved in answering this question using real data on bowel cancer at St Vincents Hospital in Sydney. As data are only available for those testing positive at least once, an appropriate modeling technique is developed on the basis of the zero-truncated binomial distribution which allows for population heterogeneity. The latter is modeled using discrete nonparametric maximum likelihood. If we wish to achieve an overall sensitivity of 90%, the FOBT should be repeated for 2 weeks instead of the 1 week that was used at the time of the survey. A simulation study also shows consistency in the sense that bias and standard deviation for the estimated sensitivity decrease with an increasing number of repeated occasions as well as with increasing sample size.

COVID-related disruptions to colorectal cancer screening, diagnosis, and treatment could increase cancer Burden in Australia and Canada: A modelling study.

COVID-19 disrupted cancer control worldwide, impacting preventative screening, diagnoses, and treatment services. This modelling study estimates the impact of disruptions on colorectal cancer cases and deaths in Canada and Australia, informed by data on screening, diagnosis, and treatment procedures. Modelling was used to estimate short- and long-term effects on colorectal cancer incidence and mortality, including ongoing impact of patient backlogs. A hypothetical mitigation strategy was simulated, with diagnostic and treatment capacities increased by 5% from 2022 to address backlogs. Colorectal cancer screening dropped by 40% in Canada and 6.3% in Australia in 2020. Significant decreases to diagnostic and treatment procedures were also observed in Australia and Canada, which were estimated to lead to additional patient wait times. These changes would lead to an estimated increase of 255 colorectal cancer cases and 1,820 colorectal cancer deaths in Canada and 234 cases and 1,186 deaths in Australia over 2020-2030; a 1.9% and 2.4% increase in mortality, respectively, vs a scenario with no screening disruption or diagnostic/treatment delays. Diagnostic and treatment capacity mitigation would avert 789 and 350 deaths in Canada and Australia, respectively. COVID-related disruptions had a significant impact on colorectal cancer screening, diagnostic, and treatment procedures in Canada and Australia. Modelling demonstrates that downstream effects on disease burden could be substantial. However, backlogs can be managed and deaths averted with even small increases to diagnostic and treatment capacity. Careful management of resources can improve patient outcomes after any temporary disruption, and these results can inform targeted approaches early detection of cancers.

Surveillance Colonoscopy Findings in Older Adults With a History of Colorectal Adenomas.

Importance: Postpolypectomy surveillance is a common colonoscopy indication in older adults; however, guidelines provide little direction on when to stop surveillance in this population. Objective: To estimate surveillance colonoscopy yields in older adults. Design, Setting, and Participants: This population-based cross-sectional study included individuals 70 to 85 years of age who received surveillance colonoscopy at a large, community-based US health care system between January 1, 2017, and December 31, 2019; had an adenoma detected 12 or more months previously; and had at least 1 year of health plan enrollment before surveillance. Individuals were excluded due to prior colorectal cancer (CRC), hereditary CRC syndrome, inflammatory bowel disease, or prior colectomy or if the surveillance colonoscopy had an inadequate bowel preparation or was incomplete. Data were analyzed from September 1, 2022, to February 22, 2024. Exposures: Age (70-74, 75-79, or 80-85 years) at surveillance colonoscopy and prior adenoma finding (ie, advanced adenoma vs nonadvanced adenoma). Main Outcomes and Measures: The main outcomes were yields of CRC, advanced adenoma, and advanced neoplasia overall (all ages) by age group and by both age group and prior adenoma finding. Multivariable logistic regression was used to identify factors associated with advanced neoplasia detection at surveillance. Results: Of 9740 surveillance colonoscopies among 9601 patients, 5895 (60.5%) were in men, and 5738 (58.9%), 3225 (33.1%), and 777 (8.0%) were performed in those aged 70-74, 75-79, and 80-85 years, respectively. Overall, CRC yields were found in 28 procedures (0.3%), advanced adenoma in 1141 (11.7%), and advanced neoplasia in 1169 (12.0%); yields did not differ significantly across age groups. Overall, CRC yields were higher for colonoscopies among patients with a prior advanced adenoma vs nonadvanced adenoma (12 of 2305 [0.5%] vs 16 of 7435 [0.2%]; P = .02), and the same was observed for advanced neoplasia (380 of 2305 [16.5%] vs 789 of 7435 [10.6%]; P < .001). Factors associated with advanced neoplasia at surveillance were prior advanced adenoma (adjusted odds ratio [AOR], 1.65; 95% CI, 1.44-1.88), body mass index of 30 or greater vs less than 25 (AOR, 1.21; 95% CI, 1.03-1.44), and having ever smoked tobacco (AOR, 1.14; 95% CI, 1.01-1.30). Asian or Pacific Islander race was inversely associated with advanced neoplasia (AOR, 0.81; 95% CI, 0.67-0.99). Conclusions and Relevance: In this cross-sectional study of surveillance colonoscopy yield in older adults, CRC detection was rare regardless of prior adenoma finding, whereas the advanced neoplasia yield was 12.0% overall. Yields were higher among those with a prior advanced adenoma than among those with prior nonadvanced adenoma and did not increase significantly with age. These findings can help inform whether to continue surveillance colonoscopy in older adults.

Investigation of long non-coding RNAs in extracellular vesicles from low-volume blood serum specimens of colorectal cancer patients.

Colorectal cancer (CRC) is the second most prevalent cancer type worldwide, which highlights the urgent need for non-invasive biomarkers for its early detection and improved prognosis. We aimed to investigate the patterns of long non-coding RNAs (lncRNAs) in small extracellular vesicles (sEVs) collected from low-volume blood serum specimens of CRC patients, focusing on their potential as diagnostic biomarkers. Our research comprised two phases: an initial exploratory phase involving RNA sequencing of sEVs from 76 CRC patients and 29 healthy controls, and a subsequent validation phase with a larger cohort of 159 CRC patients and 138 healthy controls. Techniques such as dynamic light scattering, transmission electron microscopy, and Western blotting were utilized for sEV characterization. Optimized protocol for sEV purification, RNA isolation and preamplification was applied to successfully sequence the RNA content of sEVs and validate the results by RT-qPCR. We successfully isolated sEVs from blood serum and prepared sequencing libraries from a low amount of RNA. High-throughput sequencing identified differential levels of 460 transcripts between CRC patients and healthy controls, including mRNAs, lncRNAs, and pseudogenes, with approximately 20% being lncRNAs, highlighting several tumor-specific lncRNAs that have not been associated with CRC development and progression. The validation phase confirmed the upregulation of three lncRNAs (NALT1, AL096828, and LINC01637) in blood serum of CRC patients. This study not only identified lncRNA profiles in a population of sEVs from low-volume blood serum specimens of CRC patients but also highlights the value of innovative techniques in biomolecular research, particularly for the detection and analysis of low-abundance biomolecules in clinical samples. The identification of specific lncRNAs associated with CRC provides a foundation for future research into their functional roles in cancer development and potential clinical applications.