Distal Colorectal Cancer Research Articles

Racial Disparities in the Presentation and Treatment of Colorectal Cancer: A Statewide Cross-sectional Study.

Non-Hispanic blacks (NHB) and Hispanics often present with advanced colorectal cancer (CRC). The aim of the study was to characterize CRC differences among Hispanics, NHB, and non-Hispanic whites (NHW). A cross-sectional analysis and logistic regression of 2009 Florida Agency for Healthcare Administration Hospital Admission Database data for CRC using the International Classification of Diseases, 9th Revision, Clinical Modification codes was performed. Outcomes included CRC location, frequency of metastasis and colectomy rates. Each minority group was compared with NHW. A total of 34,577 patients were NHW, 5190 were NHB, and 5033 were Hispanic. NHB had more proximal CRC [odds ratio (OR), 1.17; 95% confidence interval (CI), 1.09-1.25; P<0.0001]; Hispanics had more distal CRC (OR, 0.90; 95% CI, 0.83-0.96; P=0.0024). Hispanics had increased metastases (OR, 1.11; 95% CI, 1.02-1.22; P=0.04). NHB and Hispanics underwent fewer colectomies [(OR, 0.93; 95% CI, 0.86-0.99; P=0.03) and (OR, 0.9; 95% CI, 0.84-0.97; P=0.001), respectively]. Disparities in CRC metastases and colectomy rates exist among these racial groups in Florida. This work should serve as a foundation to study potential causes and to design culture-specific interventions.

Reduction of Colorectal Cancer Mortality and Advanced Stage Cancer Incidence After 10 Years of Fecal Immunochemical Test Screening

Background and aims: Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide, and fecal immunochemical testing (FIT) is most widely used for population-based screening. Reduced long-term CRC mortality has been reported only scarcely in response to early detection with FIT screening. We aimed to elucidate whether and how FIT screening led to overall and site-specific reduction of advanced stage CRC incidence and mortality after the first decade of Taiwan's screening program, which offers biennial FIT screening for people aged 50-69 years. Method: The study cohort comprised eligible subjects who did (screened group) and did not (unscreened group) participate in FIT screening during the inaugural 5 years (2004-2009) with follow up until 2014. FIT-positive subjects were offered colonoscopy as a confirmatory exam. The primary outcome was incidence of advanced stage CRC and CRC mortality. Results: Among 5,417,699 eligible subjects, 3,072,164 (56.6%) had at least once FIT screening, and 1,605,200 (52.3%) received 2 or more screenings during the study period. During mean follow-up of 9.78 years, 5716 screened and 20,962 unscreened subjects developed incident advanced stage cancers [adjusted relative risk (aRR) = 0.76; 95% CI, 0.72-0.79] after controlling for self-selection to attend screening and increasing CRC incidence. CRC deaths during follow-up included 3077 screened and 15,550 unscreened subjects (aRR = 0.56, 95% CI, 0.53-0.59). Effectiveness was greater for distal cancers (advanced cancer incidence aRR = 0.68, 95% CI, 0.65-0.71); mortality aRR = 0.52 95% CI, 0.49-0.55) than for proximal cancers (advanced cancer incidence aRR = 0.99 95% CI, 0.92-1.07; mortality aRR = 0.69 95% CI, 0.63-0.75). Conclusion: FIT screening effectively reduces risk of advanced stage CRC and CRC mortality, with effectiveness consistently stronger for distal CRC than proximal CRC.

Colorectal cancer resection rates in patients with inflammatory bowel disease: a population-based study.

Background and objectiveInflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC). This study aimed to analyse the trends in rates of resection for IBD-related CRC in the USA.MethodsWe used the Nationwide Inpatient Sample from 1995 to 2012. Temporal trends in age-adjusted rates of resection for CRC in the setting of IBD were analysed using multivariate Joinpoint regression models. The primary outcome was surgical resection of CRC in the setting of IBD.ResultsWe included 3 597 168 IBD discharges in the present study, of which 275 479 underwent CRC resection between 1995 and 2012. The annual CRC resection rates among IBD population decreased significantly from 1995 to 2012. This decrease was significant in all age groups with an annual decrease of 393 (P < 0.001), 359 (P < 0.001), 293 (P < 0.001) and 159 (P < 0.001) per 100 000 IBD discharges between 1995 and 2012 for age groups 18–39, 40–49, 50–74 and >75 years, respectively. The annual IBD-CRC resection rate per 100 000 IBD discharges for proximal CRC decreased by 149 (P < 0.001), 130 (P < 0.001), 95 (P < 0.001) and 50 (P < 0.001), respectively, and the annual distal CRC resections per 100 000 IBD discharges decreased by 104 (P < 0.001), 123 (P < 0.001), 123 (P < 0.001) and 82 (P < 0.001), respectively, for age groups 18–39, 40–49, 50–74 and >75 years, between 1995 and 2012. On multivariate Poisson regression analysis, after adjustment for age and sex, CRC resections decreased by 3.9% each year from 1995 to 2012.ConclusionsCRC resection rates among IBD patients have continued to decrease annually from 1995 to 2012. There is a population-level decrease in resection of both proximal and distal CRC reflecting a decreasing incidence of IBD-related CRC incidence in the USA.

Abstract 136: T-cell clonotype convergence in colorectal cancer driven by tumor-specific neoantigens

Abstract A cornerstone of the biological process which mediates response to immunotherapy in cancer patients is the expression of neoantigens resulting from somatic mutations in cancer cells. Little attention has been paid so far to the neoantigen's immune cell counterpart, the T-cell receptor (TCR). In this study, we aimed at characterizing the tumor infiltrating T-cell repertoire in colorectal cancer (CRC), and to evaluate evidence for neoantigen driven T-cell expansion within the tumor microenvironment. To characterize the T-cell repertoire, we used the Ion AmpliSeq Immune Repertoire Assay Plus with an Ion S5 XL system. This assay works with as little as 10ng of starting total RNA, allows 400bp read length, and offers complete characterization of the CDR1, CDR2 and CDR3 regions. A cohort of 20 CRC cases was used, including microsatellite instability (MSI) positive and MSI-negative cases. Our results show a higher T-cell richness in distal CRC samples compared with proximal samples (p=0.04), and lower T-cell richness in M1 as compared with M0 cases (p=0.0001). No association was observed with MSI status, inflammatory infiltrate, tumor grade or lymph node metastasis. We observed that the T-cell repertoire in CRC samples is highly convergent compared to the peripheral blood lymphocyte repertoire of healthy donors (p&amp;lt;0.0001). In CRC samples we observed evidence of selection of TCR clonotypes coding for the same CDR3 aminoacid sequence, suggesting neoantigen-driven TCR convergence. TCR clone overlap was observed only between pairs of samples (4 pairs of primary tumor and metastasis samples available) from the same patient, and not between samples from different patients, suggesting high tumor specificity of T-cell clonotype selection. A validation cohort of CRC cases, including additional pairs of primary tumor and metastasis samples, is currently being analyzed to validate our findings. In this study we provide evidence of T-cell clonotype selection in CRC driven by tumor-specific neoantigens. The specificity of this process is further reinforced by the T-cell clonotype overlap within patients. It remains to be seen whether it is possible to map convergent T-cell clonotypes to its respective tumor neoantigens. Citation Format: Jose C. Machado, Joana Reis, Margarida Fernandes, Rafaela Silva, Luis Cirnes, Fatima Carneiro, Jose L. Costa. T-cell clonotype convergence in colorectal cancer driven by tumor-specific neoantigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 136.

Risk of Malignancy in Adenomas Detected During Screening Colonoscopy

A higher incidence of proximal interval cancers after colonoscopy has been reported in several follow-up studies. One possible explanation for this might be that proximally located adenomas have greater malignant potential. The aim of the present study was to assess the risk of malignancy in proximal versus distal adenomas in patients included in a large screening colonoscopy database; adenoma shape and the patients' age and sex distribution were also analyzed. Data for 2007-2012 from the German National Screening Colonoscopy Registry, including 594,614 adenomas identified during 2,532,298 screening colonoscopies, were analyzed retrospectively. The main outcome measure was the rate of high-grade dysplasia (HGD) in adenomas, used as a surrogate marker for the risk of malignancy. Odds ratios (ORs) for the rate of HGD found in adenomas were analyzed in relation to patient- and adenoma-related factors using multivariate analysis. HGD histology was noted in 20,873 adenomas (3.5%). Proximal adenoma locations were not associated with a higher HGD rate. The most significant risk factor for HGD was adenoma size (OR 10.36 ≥1 cm vs <1 cm), followed by patient age (OR 1.26 and 1.46 for age groups 65-74 and 75-84 vs 55-64 years) and sex (OR 1.15 male vs female). In comparison with flat adenomas as a reference lesion, sessile lesions had a similar HGD rate (OR 1.02) and pedunculated adenomas had a higher rate (OR 1.23). All associations were statistically significant (P ≤ .05). In this large screening database, it was found that the rates of adenomas with HGD are similar in the proximal and distal colon. The presence of HGD as a risk marker alone does not explain higher rates of proximal interval colorectal cancer. We suggest that certain lesions (flat, serrated lesions) may be missed in the proximal colon and may acquire a more aggressive biology over time. A combination of endoscopy-related factors and biology may therefore account for higher rates of proximal versus distal interval colorectal cancer.

High-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer consortia

Colorectal cancer (CRC) remains the third most common cancer worldwide, with a growing incidence among young adults. Multiple studies have presented associations between the gut microbiome and CRC, suggesting a link with cancer risk. Although CRC microbiome studies continue to profile larger patient cohorts with increasingly economical and rapid DNA sequencing platforms, few common associations with CRC have been identified, in part due to limitations in taxonomic resolution and differences in analysis methodologies. Complementing these taxonomic studies is the newly recognized phenomenon that bacterial organization into biofilm structures in the mucus layer of the gut is a consistent feature of right-sided (proximal), but not left-sided (distal) colorectal cancer. In the present study, we performed 16S rRNA gene amplicon sequencing and biofilm quantification in a new cohort of patients from Malaysia, followed by a meta-analysis of eleven additional publicly available data sets on stool and tissue-based CRC microbiota using Resphera Insight, a high-resolution analytical tool for species-level characterization. Results from the Malaysian cohort and the expanded meta-analysis confirm that CRC tissues are enriched for invasive biofilms (particularly on right-sided tumors), a symbiont with capacity for tumorigenesis (Bacteroides fragilis), and oral pathogens including Fusobacterium nucleatum, Parvimonas micra, and Peptostreptococcus stomatis. Considered in aggregate, species from the Human Oral Microbiome Database are highly enriched in CRC. Although no detected microbial feature was universally present, their substantial overlap and combined prevalence supports a role for the gut microbiota in a significant percentage (>80%) of CRC cases.

Is whole-colon investigation by colonoscopy, computerised tomography colonography or barium enema necessary for all patients with colorectal cancer symptoms, and for which patients would flexible sigmoidoscopy suffice? A retrospective cohort study.

For patients referred to hospital with suspected colorectal cancer (CRC), it is current standard clinical practice to conduct an examination of the whole colon and rectum. However, studies have shown that an examination of the distal colorectum using flexible sigmoidoscopy (FS) can be a safe and clinically effective investigation for some patients. These findings require validation in a multicentre study. To investigate the links between patient symptoms at presentation and CRC risk by subsite, and to provide evidence of whether or not FS is an effective alternative to whole-colon investigation (WCI) in patients whose symptoms do not suggest proximal or obstructive disease. A multicentre retrospective study using data collected prospectively from two randomised controlled trials. Additional data were collected from trial diagnostic procedure reports and hospital records. CRC diagnoses within 3 years of referral were sourced from hospital records and national cancer registries via the Health and Social Care Information Centre. Participants were recruited to the two randomised controlled trials from 21 NHS hospitals in England between 2004 and 2007. Men and women aged ≥ 55 years referred to secondary care for the investigation of symptoms suggestive of CRC. Diagnostic yield of CRC at distal (to the splenic flexure) and proximal subsites by symptoms/clinical signs at presentation. The data set for analysis comprised 7380 patients, of whom 59% were women (median age 69 years, interquartile range 62-76 years). Change in bowel habit (CIBH) was the most frequently presenting symptom (73%), followed by rectal bleeding (38%) and abdominal pain (29%); 26% of patients had anaemia. CRC was diagnosed in 551 patients (7.5%): 424 (77%) patients with distal CRC, 122 (22%) patients with cancer proximal to the descending colon and five patients with both proximal and distal CRC. Proximal cancer was diagnosed in 96 out of 2021 (4.8%) patients with anaemia and/or an abdominal mass. The yield of proximal cancer in patients without anaemia or an abdominal mass who presented with rectal bleeding with or without a CIBH or with a CIBH to looser and/or more frequent stools as a single symptom was low (0.5%). These low-risk groups for proximal cancer accounted for 41% (3032/7380) of the cohort; only three proximal cancers were diagnosed in 814 low-risk patients examined by FS (diagnostic yield 0.4%). A limitation to this study is that changes to practice since the trial ended, such as new referral guidelines and improvements in endoscopy quality, potentially weaken the generalisability of our findings. Symptom profiles can be used to determine whether or not WCI is necessary. Most proximal cancers were diagnosed in patients who presented with anaemia and/or an abdominal mass. In patients without anaemia or an abdominal mass, proximal cancer diagnoses were rare in those with rectal bleeding with or without a CIBH or with a CIBH to looser and/or more frequent stools as a single symptom. FS alone should be a safe and clinically effective investigation in these patients. A cost-effectiveness analysis of symptom-based tailoring of diagnostic investigations for CRC is recommended. Current Controlled Trials ISRCTN95152621. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 66. See the NIHR Journals Library website for further project information.

Cystic Fibrosis & disorders of the large intestine: DIOS, constipation, and colorectal cancer

Since 1966 when the Cystic Fibrosis Foundation Patient Registry (CFFPR) was founded, clinicians have witnessed significant advances in both the quality and quantity of life for patients living with Cystic Fibrosis (CF). As patients with CF live longer and fuller lives, increasing encumbrances from gastrointestinal manifestations of CF will be observed. This article serves to discuss “below the diaphragm” concerns involving the large intestine (Distal Intestinal Obstruction Syndrome, Constipation, and Colorectal Cancer). Avenues for development and implementation of clinical care protocols, particularly regarding proactive management of known associated conditions and cancer screening, will continue to be refined in the coming years. It falls to the multidisciplinary CF care team to be actively engaged in addressing these concerns effectively as priority shifts from relative acuity (typically related to early nutrition and lung function) to the travails of longevity as the CF population continues to age.

Serrated Colorectal Neoplasia: From Sideshow to Center Stage

Serrated Colorectal Neoplasia: From Sideshow to Center Stage

Biomarker correlation network in colorectal carcinoma by tumor anatomic location

BackgroundColorectal carcinoma evolves through a multitude of molecular events including somatic mutations, epigenetic alterations, and aberrant protein expression, influenced by host immune reactions. One way to interrogate the complex carcinogenic process and interactions between aberrant events is to model a biomarker correlation network. Such a network analysis integrates multidimensional tumor biomarker data to identify key molecular events and pathways that are central to an underlying biological process. Due to embryological, physiological, and microbial differences, proximal and distal colorectal cancers have distinct sets of molecular pathological signatures. Given these differences, we hypothesized that a biomarker correlation network might vary by tumor location.ResultsWe performed network analyses of 54 biomarkers, including major mutational events, microsatellite instability (MSI), epigenetic features, protein expression status, and immune reactions using data from 1380 colorectal cancer cases: 690 cases with proximal colon cancer and 690 cases with distal colorectal cancer matched by age and sex. Edges were defined by statistically significant correlations between biomarkers using Spearman correlation analyses. We found that the proximal colon cancer network formed a denser network (total number of edges, n = 173) than the distal colorectal cancer network (n = 95) (P < 0.0001 in permutation tests). The value of the average clustering coefficient was 0.50 in the proximal colon cancer network and 0.30 in the distal colorectal cancer network, indicating the greater clustering tendency of the proximal colon cancer network. In particular, MSI was a key hub, highly connected with other biomarkers in proximal colon cancer, but not in distal colorectal cancer. Among patients with non-MSI-high cancer, BRAF mutation status emerged as a distinct marker with higher connectivity in the network of proximal colon cancer, but not in distal colorectal cancer.ConclusionIn proximal colon cancer, tumor biomarkers tended to be correlated with each other, and MSI and BRAF mutation functioned as key molecular characteristics during the carcinogenesis. Our findings highlight the importance of considering multiple correlated pathways for therapeutic targets especially in proximal colon cancer.

Diagnostic performance of flexible sigmoidoscopy combined with fecal immunochemical test in colorectal cancer screening: meta-analysis and modeling.

Once-only flexible sigmoidoscopy (FS), which reliably detects neoplasms in the distal colon and rectum but not in the proximal colon, has been shown to reduce incidence and mortality of distal colorectal cancer (CRC). Fecal immunochemical tests (FITs) detect the majority of CRCs and some proportion of adenomas also in the proximal colon. We assessed the expected diagnostic performance of combined application of FS and FIT. We systematically reviewed screening studies conducted in an average risk population that reported specificities and site-specific sensitivities of FITs for detection of CRC or advanced adenoma (AA). Only studies that conducted colonoscopy in all subjects were included. PubMed and Web of Science were searched until May 13, 2016. Reference lists of eligible studies were also screened. Sensitivity of FS was derived from colonoscopy results, assuming the same sensitivity as colonoscopy for left-sided neoplasms and follow-up colonoscopy after detection of distal adenomas. Bivariate meta-analyses were used to derive summary estimates of overall sensitivity and specificity of individual and joint application of both tests. Ten eligible studies were identified. Summary estimates (95% confidence intervals) of overall sensitivity for detecting CRC and AA were 65% (56-74%) and 27% (23-31%) for FIT alone, 67% (58-75%) and 67% (59-75%) for FS alone, and 89% (83-92%) and 75% (68-80%), respectively, for the combination of both tests. The pooled specificity (95% CI) of FIT was 92% (90-95%). Adding a FIT to a once-only screening FS would substantially increase sensitivity of CRC screening at a modest loss in specificity.

One-Time Flexible Sigmoidoscopy at Age 60 Yields Long-Term Benefits

In the UK Flexible Sigmoidoscopy Screening Trial (UKFSST), 170,000 patients (age range, 55–64) were randomized to once-only flexible sigmoidoscopy or no colorectal cancer (CRC) screening; 71% of those assigned to sigmoidoscopy actually underwent screening. After 11 years of follow-up, participants who underwent sigmoidoscopy had significant relative reductions in distal and total CRC (hazard ratios, 0.50 and 0.67, respectively) and CRC-related mortality (HR, 0.57) compared with participants randomized to no screening (NEJM JW …

Strong subsite-specific variation in detecting advanced adenomas by fecal immunochemical testing for hemoglobin.

Fecal immunochemical tests (FITs) for hemoglobin are increasingly recommended and used in colorectal cancer (CRC) screening. We aimed to provide a detailed assessment of the sensitivity of FIT according to type and subsite of neoplasms in a true screening setting. A quantitative FIT (FOB Gold, Sentinel Diagnostics, Milano, Italy) was applied prior to colonoscopy by 3,466 participants of the German screening colonoscopy program. Subsite specific sensitivity for various types of colorectal neoplasms was derived by comparing FIT results with findings at screening colonoscopy. The most advanced finding at colonoscopy was CRC, advanced adenoma, and nonadvanced adenoma in 29, 354 and 686 cases, respectively. Per-adenoma sensitivity for large advanced adenomas (>1 cm) strongly varied by location (p < 0.001): cecum: 0/14 (0%), ascending colon and right flexure: 11/43 (26%), transverse colon and left flexure: 2/14 (14%), descending colon: 7/12 (58%), sigmoid colon: 47/92 (51%), rectum: 14/39 (36%). By contrast, the FIT detected all of 5 proximal CRC and 23 out of 24 (96%) distal CRCs, whereas per-adenoma sensitivity of both proximal (17/259, 7%) and distal nonadvanced adenomas (20/237, 8%) essentially equaled the false positivity rate among those without neoplasms (152/2,397, 6%). In conclusion, we found a very large gradient of subsite specific FIT sensitivity for detecting large advanced adenomas ranging from 0% for advanced adenomas located in the cecum to >50% for those located in the descending or sigmoid colon. By contrast, FIT sensitivity was uniformly excellent for CRC and uniformly poor for nonadvanced adenomas, regardless of their location.

Topographical incidence and survival analysis of gastrointestinal tract cancer in adolescent and young adults compared with older adults in the United States.

545 Background: Adolescent and young adults (AYAs) who develop gastrointestinal (GI) cancer are rare and have unique needs. There is limited literature defining the epidemiology of malignant disease across the entire GI tract in this age group. The objective of this study was to explore incidence and survival trends in the United States for all types of GI cancers in AYAs compared to older adults. Methods: We analyzed all incident cases of GI tract cancers in AYAs aged 15 to 39 and older adults aged 40 to 64 in the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) program 2000-2013 database. For each age group and sex, we determined incidence rates, temporal changes in incidence, overall prognosis and stage-based prognosis for all primary tumor sites throughout the GI tract. Results: The incidence of colorectal cancer (CRC) distal to the splenic flexure has increased in AYAs whereas all CRC has decreased in older adults. We found that compared to older adults, AYAs have experienced better survival for most cancers arising at or proximal to the cecum regardless of stage. Conversely, more distal tumors were associated with worse prognosis in AYAs for regional or distant-stage disease. For distal CRC, the greatest age-based discrepancy in survival occurred for regional disease. Despite decreasing incidence of anal cancer in AYAs, young females have experienced worse survival with this disease compared to AYA males and older adults. Conclusions: We have identified age and gender-based disparities in survival relating to GI cancers. Rising rates of distal CRC in AYAs highlight the need for further exploration of molecular mechanisms and potential therapeutic targets for these malignancies which are also associated with worse survival in the younger population.

LDB1 overexpression is a negative prognostic factor in colorectal cancer.

BackgroundColorectal cancer (CRC) is the third most common cancer in western countries and is driven by the Wnt signaling pathway. LIM-domain-binding protein 1 (LDB1) interacts with the Wnt signaling pathway and has been connected to malignant diseases. We therefore aimed to evaluate the role of LDB1 in CRC.ResultsOverexpression of LDB1 in CRC is associated with strikingly reduced overall and metastasis free survival in all three independent patient cohorts. The expression of LDB1 positively correlates with genes involved in the Wnt signaling pathway (CTNNB1, AXIN2, MYC and CCND1). Overexpression of LDB1 in CRC cell lines induced Wnt pathway upregulation as well as increased invasivity and proliferation. Upon separate analysis, the role of LDB1 proved to be more prominent in proximal CRC, whereas distal CRC seems to be less influenced by LDB1.Materials and MethodsThe expression of LDB1 was measured via RT-qPCR in 59 clinical tumor and normal mucosa samples and correlated to clinical end-points. The role of LDB1 was examined in two additional large patient cohorts from publicly available microarray and RNAseq datasets. Functional characterization was done by lentiviral overexpression of LDB1 in CRC cell lines and TOP/FOP, proliferation and scratch assays.ConclusionsLDB1 has a strong role in CRC progression, confirmed in three large, independent patient cohorts. The in vitro data confirm an influence of LDB1 on the Wnt signaling pathway and tumor cell proliferation. LDB1 seems to have a more prominent role in proximal CRC, which confirms the different biology of proximal and distal CRC.

Patterns and outcomes of colorectal cancer in adolescents and young adults

BackgroundThe incidence of colorectal cancer (CRC) in the adolescent and young adult (AYA) population (aged 15-39 y) is rising. Materials and methodsWe used the Surveillance, Epidemiology, and End Results Database to study CRC in the AYA population. We studied clinical and socioeconomic factors associated with survival. ResultsOf the 11,071 cases of CRC, the most common site of the primary tumor was the rectum (25%), whereas 66.6% of the diseases were left sided. Most of the patients (72%) presented with regional or metastatic disease. However, the disease-specific survival (DSS) and the overall survival of the AYA population were comparable to those of the general population (DSS; 5- and 10-y: 64.8%, 57.3%; overall survival; 5- and 10-y: 61.5% and 52.4%). On multivariate analysis, disease stage at the time of the diagnosis was the strongest predictor of mortality. After controlling for disease stage, male gender, black race, and higher grade tumors were associated with worse survival. ConclusionsThe AYA population presents with advanced distal CRC but have similar survival compared with the general population.

Invasive Fusobacterium nucleatum may play a role in the carcinogenesis of proximal colon cancer through the serrated neoplasia pathway

The prevalence of invasive Fusobacterium nucleatum (Fn) within the serrated neoplasia pathway of the proximal colon has seldom been investigated. We examined the invasive Fn and bacterial biofilms in 35 proximal hyperplastic polyps (HPs), 33 sessile serrated adenomas (SSAs), 48 proximal colorectal cancers (CRCs) and 10 matched metastatic lymph nodes using 16S rRNA fluorescence in situ hybridization (FISH). Samples of normal mucosa, traditional adenomas (TAs), distal HPs, distal CRCs and matched lymph nodes with or without metastases were used as controls. The prevalence of invasive Fn within proximal HPs (65.7%) and SSAs (78.8%) were significantly higher than that of proximal TAs (28.9%) and distal TAs (24.4%; p < 0.05). Invasive Fn was detected in markedly more proximal CRCs (89.6%) than in distal CRCs (42.2%; p < 0.05). Moreover, invasive Fn was detected in a significantly higher proportion of matched metastatic lymph nodes (100%) than that within nonmetastatic lymph nodes (40.0%; p < 0.001). Bacterial biofilms were found on 52.1% of proximal CRCs, 55.6% of distal CRCs and 48.5% of SSAs. Biofilms were positive for Fn in 47.9% of proximal CRCs, 48.9% of distal CRCs and 27.3% of SSAs. However, the presence of Fn in biofilms was not related to invasive Fn within colorectal tissues (p = 0.415). Invasive Fn may play a role in the carcinogenesis of proximal colon developing via the serrated neoplasia pathway, but might have a less important role in the TA-carcinoma sequence. Bacterial biofilms may not contribute to the invasion of Fn into tumor tissues.

Systematic review with meta-analysis: faecal occult blood tests show lower colorectal cancer detection rates in the proximal colon in colonoscopy-verified diagnostic studies.

The performance of faecal occult blood tests (FOBTs) to screen proximally located colorectal cancer (CRC) has produced inconsistent results. To assess in a meta-analysis, the diagnostic accuracy of FOBTs for relative detection of CRC according to anatomical location of CRC. Diagnostic studies including both symptomatic and asymptomatic cohorts assessing performance of FOBTs for CRC were searched from MEDINE and EMBASE. Primary outcome was accuracy of FOBTs according to the anatomical location of CRC. Bivariate random-effects model was used. Subgroup analyses were performed to evaluate test performance of guaiac-based FOBT (gFOBT) and immunochemical-based FOBT (iFOBT). Thirteen studies, with 17 cohorts, reporting performance of FOBT were included; a total of 26 342 patients (mean age 58.9 years; 58.1% male) underwent both colonoscopy and FOBT. Pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of FOBTs for CRC detection in the proximal colon were 71.2% (95% CI 61.3-79.4%), 93.6% (95% CI 90.7-95.7%), 11.1 (95% CI 7.8-15.8) and 0.3 (95% CI 0.2-0.4) respectively. Corresponding findings for CRC detection in distal colon were 80.1% (95% CI 70.9-87.0%), 93.6% (95% CI 90.7-95.7%), 12.6 (95% CI 8.8-18.1) and 0.2 (95% CI 0.1-0.3). The area-under-curve for FOBT detection for proximal and distal CRC were 90% vs. 94% (P = 0.0143). Both gFOBT and iFOBT showed significantly lower sensitivity but comparable specificity for the detection of proximally located CRC compared with distal CRC. Faecal occult blood tests, both guaiac- and immunochemical-based, show better diagnostic performance for the relative detection of colorectal cancer in the distal colon than in the proximal bowel.

Segmental distribution of some common molecular markers for colorectal cancer (CRC): influencing factors and potential implications.

Proximal and distal colorectal cancers (CRCs) are regarded as distinct disease entities, evolving through different genetic pathways and showing multiple clinicopathological and molecular differences. Segmental distribution of some common markers (e.g., KRAS, EGFR, Ki-67, Bcl-2, COX-2) is clinically important, potentially affecting their prognostic or predictive value. However, this distribution is influenced by a variety of factors such as the anatomical overlap of tumorigenic molecular events, associations of some markers with other clinicopathological features (stage and/or grade), and wide methodological variability in markers' assessment. All these factors represent principal influences followed by intratumoral heterogeneity and geographic variation in the frequency of detection of particular markers, whereas the role of other potential influences (e.g., pre-adjuvant treatment, interaction between markers) remains rather unclear. Better understanding and elucidation of the various influences may provide a more accurate picture of the segmental distribution of molecular markers in CRC, potentially allowing the application of a novel patient stratification for treatment, based on particular molecular profiles in combination with tumor location.

Tumor site, clinicopathological characteristics, and survival of patients undergoing primary elective colorectal cancer resection.

585 Background: Cancers arising in the proximal and distal colorectum differ in embryological origin, predisposing genetic and epigenetic mutations, clinicopathological characteristics and survival. However, the effect of tumor site on the prognostic value of clinicopathological characteristics and systemic inflammatory responses (SIR) is not known. The present study aims to examine the relationship between tumor site, clinicopathological characteristics and cancer-specific survival (CSS) in patients undergoing elective colorectal cancer (CRC) resection. Methods: Patients who had undergone elective, primary resection of stage I-III CRC (1997-2013) were included. Tumors were categorized as proximal (cecum to splenic flexure) or distal (splenic flexure to rectum) based on pathological reports. SIR was assessed using modified Glasgow Prognostic Score (mGPS; 0-CRP &lt; 10mg/L, 1-CRP &gt; 10mg/L, 2-CRP &gt; 10mg/L and albumin &lt; 35g/L). Results: 796 patients were included; 302 tumors were proximal and 494 were distal to the splenic flexure. Proximal location was associated with advanced age, T stage, poor differentiation, greater lymph node yield, peritoneal involvement and an increased mGPS (all P&lt; 0.01). In all patients, on multivariate survival analysis, distal tumor site, advanced age, T stage, N stage, venous invasion, margin involvement and mGPS were independently associated with reduced CSS (all P&lt; 0.05). In patients with proximal cancer, only age (HR 1.8, P= 0.001), T stage (HR 1.9, P= 0.009), N stage (HR 1.9, P&lt; 0.001) and mGPS (HR 1.6, P= 0.004) were associated with CSS, whereas in patients with distal CRC, T stage (HR 1.4, P= 0.024), N stage (HR 1.5, P= 0.001), venous invasion (HR 1.5, P= 0.038), margin involvement (HR 4.1, P&lt; 0.001) and mGPS (HR 1.5, P= 0.003) were associated with survival. Conclusions: In the present study, tumor site was associated with distinct clinicopathological characteristics. Furthermore, the prognostic value of pathological characteristics currently employed in tumor staging, such as venous invasion and margin involvement, differed with tumor site, whereas evaluation of the SIR was similarly prognostic in patients with proximal and distal CRC.