Distal Colorectum Research Articles

Dysbiosis promotes recurrence of adenomatous polyps in the distal colorectum

BACKGROUND Colorectal polyps, which are characterized by a high recurrence rate, represent preneoplastic conditions of the intestine. Due to unclear mechanisms of pathogenesis, first-line therapies for non-hereditary recurrent colorectal polyps are limited to endoscopic resection. Although recent studies suggest a mechanistic link between intestinal dysbiosis and polyps, the exact compositions and roles of bacteria in the mucosa around the lesions, rather than feces, remain unsettled. AIM To clarify the composition and diversity of bacteria in the mucosa surrounding or 10 cm distal to recurrent intestinal polyps. METHODS Mucosal samples were collected from four patients consistently with adenomatous polyps (Ade), seven consistently with non-Ade (Pol), ten with current Pol but previous Ade, and six healthy individuals, and bacterial patterns were evaluated by 16S rDNA sequencing. Linear discriminant analysis and Student’s t -tests were used to identify the genus-level bacteria differences between groups with different colorectal polyp phenotypes. Pearson’s correlation coefficients were used to evaluate the correlation between intestinal bacteria at the genus level and clinical indicators. RESULTS The results confirmed a decreased level of probiotics and an enrichment of pathogenic bacteria in patients with all types of polyps compared to healthy individuals. These changes were not restricted to the mucosa within 0.5 cm adjacent to the polyps, but also existed in histologically normal tissue 10 cm distal from the lesions. Significant differences in bacterial diversity were observed in the mucosa from individuals with normal conditions, Pol, and Ade. Increased abundance of Gram-negative bacteria, including Klebsiella , Plesiomonas , and Cronobacter , was observed in Pol group and Ade group, suggesting that resistance to antibiotics may be one risk factor for bacterium-related harmful environment. Meanwhile, age and gender were linked to bacteria changes, indicating the potential involvement of sex hormones. CONCLUSION These preliminary results support intestinal dysbiosis as an important risk factor for recurrent polyps, especially adenoma. Targeting specific pathogenic bacteria may attenuate the recurrence of polyps.

Effect of optical diagnosis training on recognition and treatment of submucosal invasive colorectal cancer in community hospitals: a prospective multicenter intervention study.

Recognition of submucosal invasive colorectal cancer (T1 CRC) is difficult, with sensitivities of 35 %-60 % in Western countries. We evaluated the real-life effects of training in the OPTICAL model, a recently developed structured and validated prediction model, in Dutch community hospitals. In this prospective multicenter study (OPTICAL II), 383 endoscopists from 40 hospitals were invited to follow an e-learning program on the OPTICAL model, to increase sensitivity in detecting T1 CRC in nonpedunculated polyps. Real-life recognition of T1 CRC was then evaluated in 25 hospitals. Endoscopic and pathologic reports of T1 CRCs detected during the next year were collected retrospectively, with endoscopists unaware of this evaluation. Sensitivity for T1 CRC recognition, R0 resection rate, and treatment modality were compared for trained vs. untrained endoscopists. 1 year after e-learning, 528 nonpedunculated T1 CRCs were recorded for endoscopies performed by 251 endoscopists (118 [47 %] trained). Median T1 CRC size was 20 mm. Lesions were mainly located in the distal colorectum (66 %). Trained endoscopists recognized T1 CRCs more frequently than untrained endoscopists (sensitivity 74 % vs. 62 %; mixed model analysis odds ratio [OR] 2.90, 95 %CI 1.54-5.45). R0 resection rate was higher for T1 CRCs detected by trained endoscopists (69 % vs. 56 %; OR 1.73, 95 %CI 1.03-2.91). Training in optical recognition of T1 CRCs in community hospitals was associated with increased recognition of T1 CRCs, leading to higher en bloc and R0 resection rates. This may be an important step toward more organ-preserving strategies.

Mucoadhesive Nanoparticles Enhance the Therapeutic Effect of Dexamethasone on Experimental Ulcerative Colitis by the Local Administration as an Enema

As the first-line drug to treat ulcerative colitis (UC), long-term use of glucocorticoids (GCs) produces severe toxic and side effects. Local administration as enema can increase the local GCs concentrations and reduce systemic exposure to high oral doses by directly delivering GCs to the inflammation site in the distal colorectum. However, UC patients are often accompanied by diarrhea, leading to the short colonic residence time of GCs and failure to exert their function fully. A kind of mucoadhesive nanoparticles (NPs) loading different dexamethasone derivatives (DDs) were developed, which could attach to the positively charged inflammatory colonic mucosa through electrostatic adsorption after administered by enema, thereby improving the local concentration and achieving effective targeted therapy for UC. Two DDs, dexamethasone hemisuccinate and dexamethasone phosphate, were synthesized. In NPs preparation, The core PEI-DDs NPs were built by the electrostatic adsorption of DDs and the cationic polymer polyethyleneimine (PEI). Then, the natural polyanionic polysaccharide sodium alginate (SA) was electronically coated around NPs to construct the final SA-PEI-DDs NPs, followed by the in vitro stability and release tests, in vitro and in vivo colonic mucosal adhesion tests. In the in vivo anti-UC test, the experimental colitis mice were induced by 2,4,6-trinitrobenzenesulfonic acid. The body weight and disease activity index changes were measured, and the myeloperoxidase activity, pro-inflammatory cytokines concentration, and hematoxylin and eosin staining were also investigated to evaluate the therapeutic effect of NPs. The structures of two DDs were demonstrated by 1H-NMR and MS. Both NPs were negatively charged and achieved high loading efficiency of DDs, while their particle sizes were significantly different. NPs showed good stability and sustained release properties in the simulated colonic environment. Moreover, the negative charge on the of NPs surface made them easier to adhere to the positively charged inflammatory colonic mucosa, thereby enhancing the enrichment and retention of DDS in the colitis site. Furthermore, the NPs exhibited better therapeutic effects than free Dex on the experimental colitis mice induced by TNBS through the enema rectal. These results indicated the mucoadhesive NPs as a kind of novel nano-enema showed great potential to achieve efficient treatment on UC.

Significance of diagnosis and prognosis for appendiceal orifice inflammation in ulcerative colitis: a real-world study.

ObjectiveUlcerative colitis (UC) is a chronic inflammatory disease of the large intestine. At present, the significance of appendiceal orifice inflammation (AOI) in UC prognosis is still controversial. This prospective observational study investigated the importance of AOI in UC diagnosis and prognosis. Additionally, it compared the therapeutic efficacy of treatments in UC patients with or without AOI.DesignThis study was a prospective, observational, single-centre, real-world study. Patients with AOI were included in the observation group, and patients without AOI were assigned to the control group. All patients were followed up for 1 year; the disease remission and treatment efficacy were re-examined by colonoscopy. In addition, the clinical, endoscopic and pathological features were collected before and after the treatment.ResultsPatients with endoscopic diffuse inflammatory changes in the distal colorectum accompanied by AOI had a higher positive UC diagnosis rate than those without (96.5% vs 78.0%). Also, AOI had a specificity of 95.2% and a sensitivity of 28.3% for UC diagnosis. However, no difference in the modified Mayo score (p=0.881) or Baron grading was observed between the control and observation groups, indicating that AOI does not affect the treatment outcome of UC patients.ConclusionIn this study, the observation of AOI improved the UC diagnostic accuracy in patients with diffuse lesions in the distal colorectum. Furthermore, the presence of AOI does not affect the treatment efficacies of UC.Trial registration numberChiCTR1800017753.

The Histopathology of Anorectal Neisseria gonorrhoeae Infection.

Neisseria gonorrhoeae infection of the anorectal tract is often asymptomatic and infrequently biopsied, but pathologists can be tasked with identifying the histologic features of possible infection. The study was undertaken to better characterize clinical and morphologic features of confirmed anorectal gonococcal infection. From 2011 to 2020, 201 positive gonococcal nucleic acid amplification testing samples from 174 patients collected from the distal colorectum and/or anus were matched to eight patients with concurrent biopsy specimens of the distal anorectum. Complete demographic, clinical, and infectious information was collected for each biopsied patient. The histomorphologic features of each biopsy were systematically tabulated. All eight gonococcal cases were obtained from men who have sex with men. Each case showed at least mild acute inflammation with moderate activity identified in one case with concurrent cytomegalovirus infection. Intense lymphoplasmacytic infiltration was not commonly seen (two of eight). Half of the cases showed mucosal ulceration, and seven of eight cases demonstrated lymphoid aggregates. The microscopic features are mild compared with other well-described types of infectious proctitis, with most cases displaying mild acute inflammation and scattered lymphoid aggregates. These findings highlight the importance of obtaining a complete patient history and recommending additional infectious workup even when only subtle changes are present.

Adenoma characteristics associated with post-polypectomy proximal colon cancer incidence: a retrospective cohort study

BackgroundColorectal cancer (CRC) screening is less effective at reducing cancer incidence in the proximal colon compared to the distal colorectum. We aimed to identify adenoma characteristics associated with proximal colon cancer (PCC).MethodsEndoscopy and pathology data for patients with ≥1 adenoma detected at baseline colonoscopy were obtained from 17 UK hospitals between 2001 and 2010. Multivariable Cox regression models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for PCC, and, for comparison, distal CRC incidence, by adenoma characteristics.ResultsAmong 18,431 patients, 152 and 105 developed PCC and distal CRC, respectively, over a median follow-up of 9.8 years. Baseline adenoma characteristics positively associated with PCC incidence included number (≥3 vs. < 3: aHR 2.10, 95% CI: 1.42–3.09), histology (tubulovillous/villous vs. tubular: aHR 1.61, 95% CI: 1.10–2.35) and location (any proximal vs. distal only: aHR 1.70, 95% CI: 1.20–2.42), for which there was borderline evidence of heterogeneity by subsite (p = 0.055). Adenoma dysplasia (high vs. low grade) was associated with distal CRC (aHR 2.42, 95% CI: 1.44–4.04), but not PCC (p-heterogeneity = 0.023).ConclusionsBaseline adenoma number, histology and proximal location were independently associated with PCC and may be important to identify patients at higher risk for post-polypectomy PCC.

A Fiber-Rich Diet and Radiation-Induced Injury in the Murine Intestinal Mucosa.

Dietary fiber is considered a strong intestinal protector, but we do not know whether dietary fiber protects against the long-lasting mucosal damage caused by ionizing radiation. To evaluate whether a fiber-rich diet can ameliorate the long-lasting pathophysiological hallmarks of the irradiated mucosa, C57BL/6J mice on a fiber-rich bioprocessed oat bran diet or a fiber-free diet received 32 Gray in four fractions to the distal colorectum using a linear accelerator and continued on the diets for one, six or 18 weeks. We quantified degenerating crypts, crypt fission, cell proliferation, crypt survival, macrophage density and bacterial infiltration. Crypt loss through crypt degeneration only occurred in the irradiated mice. Initially, it was most frequent in the fiber-deprived group but declined to levels similar to the fiber-consuming group by 18 weeks. The fiber-consuming group had a fast response to irradiation, with crypt fission for growth or healing peaking already at one week post-irradiation, while crypt fission in the fiber-deprived group peaked at six weeks. A fiber-rich diet allowed for a more intense crypt cell proliferation, but the recovery of crypts was eventually lost by 18 weeks. Bacterial infiltration was a late phenomenon, evident in the fiber-deprived animals and intensified manyfold after irradiation. Bacterial infiltration also coincided with a specific pro-inflammatory serum cytokine profile. In contrast, mice on a fiber-rich diet were completely protected from irradiation-induced bacterial infiltration and exhibited a similar serum cytokine profile as sham-irradiated mice on a fiber-rich diet. Our findings provide ample evidence that dietary fiber consumption modifies the onset, timing and intensity of radiation-induced pathophysiological processes in the intestinal mucosa. However, we need more knowledge, not least from clinical studies, before this finding can be introduced to a new and refined clinical practice.

Tumor-Associated Microbiota in Proximal and Distal Colorectal Cancer and Their Relationships With Clinical Outcomes.

The proximal and distal subsites of colorectal cancer (CRC) have distinct differences in their embryonic origin, epidemiology, and prognosis. Therefore, they are not considered as the same disease. However, the possible difference in microbial characterization of the two subsites of CRC is still unclear. In this study, we explored tumor microbiota diversity and composition difference in patients with proximal (N = 187) and distal CRCs (N = 142). This was carried out on cancer tissues and adjacent tissues using bacterial 16S rRNA sequencing. The Kaplan–Meier method was used to analyze the correlation between differential flora and overall survival rate of the patients. It was found that there were significant differences in tumor microbial characteristics between the proximal and distal CRC tissues. The microbiota communities were distinctly richer in the proximal colon tumor tissues than in the distal CRC tissues. Microbial diversity and structure were relatively constant in the paracancerous normal tissues of the proximal and distal colorectum. Generally, microbial communities of CRC tumor tissues were composed of Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Alpha diversity in the proximal and distal CRC tumor tissues was closely related to specific microflora. The abundance of Fusobacteria was associated with age of patient, tumor diameter, and tumor microsatellite instability (MSI) status of the patients. Moreover, Fusobacteria enrichment was associated with poor prognosis especially in patients with proximal colon cancers, but not in patients with distal CRC. In conclusion, proximal and distal subsites of the CRC present distinct microbiota diversity and community structures. The differences indicate that there are different risk factors across anatomical subsites of CRC, which may provide a new strategy for precise prevention and treatment of CRC in the future.

Discovery and Features of an Alkylating Signature in Colorectal Cancer.

Several risk factors have been established for colorectal cancer, yet their direct mutagenic effects in patients' tumors remain to be elucidated. Here, we leveraged whole-exome sequencing data from 900 colorectal cancer cases that had occurred in three U.S.-wide prospective studies with extensive dietary and lifestyle information. We found an alkylating signature that was previously undescribed in colorectal cancer and then showed the existence of a similar mutational process in normal colonic crypts. This alkylating signature is associated with high intakes of processed and unprocessed red meat prior to diagnosis. In addition, this signature was more abundant in the distal colorectum, predicted to target cancer driver mutations KRAS p.G12D, KRAS p.G13D, and PIK3CA p.E545K, and associated with poor survival. Together, these results link for the first time a colorectal mutational signature to a component of diet and further implicate the role of red meat in colorectal cancer initiation and progression. SIGNIFICANCE: Colorectal cancer has several lifestyle risk factors, but the underlying mutations for most have not been observed directly in tumors. Analysis of 900 colorectal cancers with whole-exome sequencing and epidemiologic annotations revealed an alkylating mutational signature that was associated with red meat consumption and distal tumor location, as well as predicted to target KRAS p.G12D/p.G13D.This article is highlighted in the In This Issue feature, p. 2355.

Idiopathic Myointimal Hyperplasia of Mesenteric Veins (IMHMV) with two spontaneous bowel perforations: A case report and literature review.

Introduction and importanceIdiopathic myointimal hyperplasia of the mesenteric veins (IMHMV) is a poorly understood disorder which poses a diagnostic challenge to clinicians and pathologists. Here we have described the case of a male patient with IMHMV along with a presumed history of ulcerative colitis for 1 year.Case presentationA 55-year-old male presented to the OPD with history of chronic abdominal pain. Clinical and radiological examination coupled with endoscopic findings resulted in the patient being wrongly diagnosed to be a case of ulcerative colitis and was managed accordingly. Throughout his multiple hospital visits following treatment for ulcerative colitis, the patient was persistently symptomatic. He presented with 10 days history of increasing abdominal pain and constipation following which he developed spontaneous colonic perforation for which he underwent exploratory laparotomy left colectomy and Hartman's procedure. The final pathology of the resected colon found to be consistent of Idiopathic myointimal hyperplasia of the mesenteric veins and ischemic bowel changes.Clinical discussionThe absence of clear-cut endoscopic biopsy findings of ulcerative colitis made radiological picture to be the mainstay for diagnosis, which was inaccurate and exposed the patient to unnecessary treatment with immuno-modulators thus resulting in poor response to treatment. As the disease progressed, further narrowing of the vessels made the clinical picture to look closer to ischemic bowel pathology as the patient developed a top surgical emergency (i.e. bowel perforation). Such pathological finding (IMHMV) can only be diagnosed in a fully prepared tissue histology, but rather be considered when no other consistent alternative diagnosis was found.ConclusionThe treating physicians must definitely consider the possibility of idiopathic myointimal hyperplasia of mesenteric veins when similar manifestations are encountered in biopsy specimens of old cases with suspected inflammatory bowel disease or non-occlusive ischemia of the distal colorectum.

Lymphogranuloma venereum (LGV) of the anorectum: evaluation of clinicopathological associations and the utility of a novel RNA in-situ hybridisation stain.

Recent studies from multiple global regions have reported a resurgence of lymphogranuloma venereum (LGV) proctitis, which is caused by Chlamydia trachomatis (CT). LGV proctitis is histologically indistinguishable from other forms of sexually transmitted proctitis and is difficult to differentiate from inflammatory bowel disease. While immunohistochemical stains are available for syphilis, there is no commonly available stain for the tissue identification of CT. From 200 positive CT nucleic acid tests (NAT) from anorectal swabs, we identified 12 patients with biopsies collected from the distal colorectum or anus within 90days of the positive NAT. We collected basic demographic information and tabulated clinical and histological findings. We examined the performance of a novel RNA in-situ hybridisation (ISH) stain targeting CT 23s rRNA on these 12 cases and 10 controls from the anorectum. All 12 patients were male; nine were HIV+, two had concurrent gonococcal infection, one had concurrent syphilis and one had cytomegalovirus co-infection. The majority of biopsies (11 of 12) showed mild or moderate acute inflammation, had a prominent lymphoplasmacytic infiltrate (eight of 11) and lacked marked crypt distortion (10 of 10). The RNA ISH stain was positive in 10 of 12 cases (sensitivity 83%). One case showed equivocal staining. No controls showed definitive positive staining (specificity 100%). One had equivocal staining. Our series showed that anorectal LGV had similar histological findings to those of prior STI proctitis series predominantly comprised of syphilis. The novel RNA ISH stain was sensitive and specific and may show utility in differentiating types of STI proctitis.

Computational Modeling of Mouse Colorectum Capturing Longitudinal and Through-thickness Biomechanical Heterogeneity

Mechanotransduction, the encoding of local mechanical stresses and strains at sensory endings into neural action potentials at the viscera, plays a critical role in evoking visceral pain, e.g., in the distal colon and rectum (colorectum). The wall of the colorectum is structurally heterogeneous, including two major composites: the inner consists of muscular and submucosal layers, and the outer consists of circular muscular, intermuscular, longitudinal muscular, and serosal layers. In fact the colorectum presents biomechanical heterogenity across both the longitudinal and through-thickness directions thus highlighting the differential roles of sensory nerve endings within different regions of the colorectum in visceral mechanotransduction. We determined constitutive models and model parameters for individual layers of the colorectum from three longitudinal locations (colonic, intermediate, and distal) using nonlinear optimization to fit our experimental results from biaxial extension tests on layer-separated colorectal tissues (mouse model, 7×7 mm2, Siri et al., Am. J. Physiol. Gastrointest. Liver Physiol. 316, G473-G481 and 317, G349-G358), and quantified the thicknesses of the layers. In this study we also quantified the residual stretches stemming from separating colorectal specimens into inner and outer composites and we completed new pressure-diameter mechanical testing to provide an additional validation case. We implemented the constitutive equations and created two-layered, 3-D finite element models using FEBio (University of Utah), and incorporated the residual stretches. We validated the modeling framework by comparing FE-predicted results for both biaxial extension testing of bulk specimens of colorectum and pressure-diameter testing of bulk segments against corresponding experimental results independent of those used in our model fitting. We present the first theoretical framework to simulate the biomechanics of distal colorectum, including both longitudinal and through-thickness heterogeneity, based on constitutive modeling of biaxial extension tests of colon tissues from mice. Our constitutive models and modeling framework facilitate analyses of both fundamental questions (e.g., the impact of organ/tissue biomechanics on mechanotransduction of the sensory nerve endings, structure-function relationships, and growth and remodeling in health and disease) and specific applications (e.g., device design, minimally invasive surgery, and biomedical research).

SPARC: Determine the topology and function of DRG neurons innervating mouse colon and rectum.

Visceral pain is the major complaint of patients with irritable bowel syndrome (IBS) that affects ~15% of the U.S. population, and satisfactory management of IBS pain remains an unmet clinical challenge. Neuromodulation targeting afferent somata in dorsal root ganglions (DRG) has emerged as a new and effective therapy for many types of chronic pain. To advance neuromodulation for treating IBS‐related visceral pain, new knowledge is needed regarding the topological distribution and neural encoding functions of lumbosacral DRG neurons that innervate distal colon and rectum (colorectum). Here, we implemented GCaMP6f to conduct high‐throughput optical recordings of colorectal afferent activities in lumbosacral DRG. By establishing this optical approach with single‐spike resolution, the current study characterizes the neural encoding from hundreds of colorectal afferents in the DRG, which are sparsely distributed and difficult to study with conventional methods. Using a mouse ex vivo preparation with distal colorectum and L5‐S1 DRG in continuity, we recorded 791 colorectal afferents’ responses to graded colorectal distension (15, 30, 40, 60 mmHg) and/or luminal shear flow (20–30 mL/min), then functionally classified them into four mechanosensitive classes, and determined the topological distribution of their somata in the DRG. Of the 791 colorectal afferents, 90.8% were in the L6 DRG, 8.3% in the S1 DRG, and only 0.9% in the L5 DRG. L6 afferents had all four classes: 29% mucosal, 18.4% muscular‐mucosal, 34% low‐threshold (LT) muscular and 18.2% high‐threshold (HT) muscular afferents. S1 afferents only had three classes: 19.7% mucosal, 34.8% LT muscular and 45.5% HT muscular afferents. All seven L5 afferents were HT muscular. In L6 DRG, somata of HT muscular afferents, i.e., putative colorectal mechano‐nociceptors were clustered in the caudal region whereas somata of the other classes did not cluster in specific regions. Outcomes of this study can directly inform the design and improvement of next‐generation neuromodulation devices that likely implement spatially selective DRG modulation to alleviate visceral pain in IBS patients.Support or Funding InformationSupported by NIH SPARC grant U01 NS113873 (BF and GZ)

Development and Validation of the Asia-Pacific Proximal Colon Neoplasia Risk Score

Patients found to be at high risk of advanced proximal neoplasia (APN) after flexible sigmoidoscopy screening should be considered for colonoscopy examination. We developed and validated a scoring system to identify persons at risk for APN. We collected data from 7954 asymptomatic subjects (age, 50-75 y) who received screening colonoscopy examinations at 14 sites in Asia. We randomly assigned 5303 subjects to the derivation cohort and the remaining 2651 to the validation cohort. We collected data from the derivation cohort on age, sex, family history of colorectal cancer, smoking, drinking, body mass index, medical conditions, and use of nonsteroidal anti-inflammatory drugs or aspirin. Associations between the colonoscopic findings of APN and each risk factor were examined using the Pearson χ2 test, and we assigned each participant a risk score (0-15), with scores of 0 to 3 as average risk and scores of 4 or higher as high risk. The scoring system was tested in the validation cohort. We used the Cochran-Armitage test of trend to compare the prevalence of APN among subjects in each group. In the validation cohort, 79.5% of patients were classified as average risk and 20.5% were classified as high risk. The prevalence of APN in the average-risk group was 1.9% and in the high-risk group was 9.4% (adjusted relative risk, 5.08; 95% CI, 3.38-7.62; P < .001). The score included age (61-70 y, 3; ≥70 y, 4), smoking habits (current/past, 2), family history of colorectal cancer (present in a first-degree relative, 2), and the presence of neoplasia in the distal colorectum (nonadvanced adenoma 5-9 mm, 2; advanced neoplasia, 7). The c-statistic of the score was 0.74 (95% CI, 0.68-0.79), and for distal findings alone was 0.67 (95% CI, 0.60-0.74). The Hosmer-Lemeshow goodness-of-fit test statistic was greater than 0.05, indicating the reliability of the validation set. The number needed to refer was 11 (95% CI, 10-13), and the number needed to screen was 15 (95% CI, 12-17). We developed and validated a scoring system to identify persons at risk for APN. Screening participants who undergo flexible sigmoidoscopy screening with a score of 4 points or higher should undergo colonoscopy evaluation.

Location of colorectal adenomas and serrated polyps in patients under age 50.

The incidence of colorectal cancer, especially located in distal colorectum, is rising markedly in young patients. Conventional adenomas and serrated polyps have been widely recognized as precursors of colorectal cancer. To investigate the correlation of polyp feature with polyp location in patients under age 50. Patients under age 50 who had received colonoscopy were included from 2010 to 2018. Clinical data including number, location, size, and histopathology of polyps were collected. Odd ratios and 95% confidence interval of adenomas with their location were calculated. In total, 25,636 patients aged 18-49 were enrolled, among which 4485 patients had polyps, with polyp detection rate of 17.5%. A total of 2484 and 2387 patients had conventional adenomas and serrated polyps, respectively. 76.0% advanced adenomas and 69.5% ≥ 10-mm serrated polyps were located in the distal colorectum. The detection rate of advanced adenomas was higher in patients aged 45-49. Patients with adenomas especially advanced adenomas in the distal colorectum were more likely to have advanced adenoma in the proximal colon. Among patients under age 50, advanced adenomas and ≥ 10-mm serrated polyps were predominantly in the distal colorectum. Advanced adenomas tended to be found in patients aged 45-49. Our results might explain the rising trend of distal colorectal cancer and emphasize the necessity for colonoscopy screening among these populations.

Sugar-sweetened beverages and colorectal cancer risk in the California Teachers Study.

BackgroundThe association between sugar-sweetened beverage (SSB) consumption and colorectal cancer (CRC) risk remains unclear and published data are limited.MethodsThe analytic cohort included 99,798 women, free of cancer at baseline, from the California Teachers Study, a longitudinal cohort comprised of 133,477 female teachers and administrators who were active or recently retired members of the California State Teachers Retirement System in 1995. SSB consumption constituted caloric soft drinks, sweetened bottled waters and teas, and fruit drinks, derived from a self-administered food frequency questionnaire. Consumption was divided into four categories: Rare or never, >rare/never to <1 serving/week, ≥1 serving/week to <1 serving/day, and ≥1 serving/day. CRC endpoints were based on annual linkage with California Cancer Registry, defined as first diagnosis of CRC, and classified following the Surveillance, Epidemiology, and End Results Program coding system. Multivariable-adjusted Cox proportional hazards models were used to generate hazard ratios (HR) and 95% confidence intervals (CI) for assessing the association between SSB consumption and incident CRC.ResultsA total of 1,318 incident CRC cases were identified over 20 years of follow-up (54.5% proximal colon and 45.5% distal colorectum). Compared with rare/never consumers, the multivariable-adjusted HRs (95% CI) were 1.14 (0.86, 1.53) for total CRC; 1.11 (0.73, 1.68) for proximal colon; and 1.22 (0.80, 1.86) for distal colorectum cancers among women consuming ≥ 1 serving/day of SSBs.ConclusionSSBs were not significantly associated with CRC risk. The biological effects of high SSB consumption make it important to continue to evaluate whether SSBs are associated with CRC. Additionally, future studies should further assess SSBs in large, racial/ethnically diverse cohorts of males and females, and, if feasible, address changes in SSB consumption over time.

Clinicopathologic Characterization of Early Onset Endoscopically Unresectable Adenomas (EOEUAs)

Abstract Objectives Early onset colorectal carcinoma (CRC), defined as CRC detected in patients ≤50 years old, are frequently located in the distal colorectum and are associated with risk factors that are common to adenoma. We examined the risk factors, pathologic features, and clinical implications associated with EOEUA. Methods A retrospective cohort of 154 patients with EOEUA was retrieved. Clinical data were obtained from electronic medical records. A minimum of 12 months follow-up was considered valid follow-up data. Archived pathology slides were evaluated for the presence of high-grade dysplasia (HGD) and Paneth cells (PCs) in adenomatous crypts. Additional pathologic data were retrieved from pathology reports. The patients were stratified into age &gt;50 vs ≤50 years. Fisher’s exact test and Student t test were performed when indicated (P &lt; .05 was considered statistically significant). Results In the ≤50-year group, EOEUAs were common in the rectosigmoid colon compared to &gt;50-year group (41.2% vs 16.8%; P = .025). The association with diabetes, obesity, and alcohol consumption was similar in the two groups, whereas the incidences of hypertension, hyperlipidemia, and smoking were significantly lower in the ≤50-year group. No significant differences in gender distribution, adenoma size, HGD, PC presence, and future adenoma burden were observed between the two groups. Conclusion The association with established risk factors of adenoma to include diabetes, obesity, and alcohol consumption in EOEUA is comparable to that of older patients. In contrast, hypertension, hyperlipidemia, and smoking do not appear to be associated with an increased risk of endoscopically unresectable adenoma in this age group. Similar to early onset CRC, EOEUAs are common in the rectosigmoid, supporting the premise that flexible sigmoidoscopy may be a viable screening alternative in this age group, especially for patients with diabetes, obesity, or alcohol history.

Endoscopically Unresectable Paneth Cell (PC)–Containing Adenomas and the Risk of Developing Colorectal Neoplasia

Abstract Objectives Whether the presence of Paneth cells (PCs) in colorectal adenomas indicates an increased risk of colorectal neoplasia or not is controversial. We examined the clinicopathologic features of PC-containing adenomas (PCAs) that were surgically removed, focusing on the risk of developing subsequent colorectal neoplasia on follow-up. Methods A retrospective cohort of 154 patients with endoscopically unresectable colorectal adenomas who underwent surgical removal was retrieved. Archived pathology slides were evaluated for the presence of PC, villous features, and high-grade dysplasia. Demographic and clinical data were obtained by reviewing electronic medical records. A minimum 12 months of follow-up was considered valid follow-up data. Fisher’s exact test and Student t test were performed when indicated (P &lt; .05 was considered statistically significant). Results PCAs were identified in 84 out of 154 cases (54.5%), commonly in the proximal as compared to distal colorectum (60.7% vs 38.1%, P = .018). There was no significant difference in patient age (mean, 66.0 vs 63.8), gender (M:F, 42:42 vs 35:35), adenoma size (mean, 3.18 cm vs 2.78 cm), villous features (69.0% vs 68.6%), and high-grade dysplasia (44.0% vs 35.7%) between PCA and non-PCA groups. After the mean follow-up duration of 65.8 months (range 12-169), 11 out of 30 patients (36.7%) had recurrent colorectal neoplasia, including 2 adenocarcinomas in the PCA group, as compared to 8 out of 27 (29.6%) in non-PCA group with no adenocarcinoma (P &gt; .05). No statistical difference in the risk of developing colorectal neoplasia was noted between proximal PCA (24%), distal PCA (33.3%), and non-PCA (29.6%) groups. Conclusion PCAs are more common in the proximal colon, consistent with normal anatomic distribution of PC in the colon. No association was observed between PCA and high-grade dysplasia or colorectal neoplasia risk in endoscopically unresectable adenomas. PCA location was not a significant marker for future adverse outcomes.

Load-bearing function of the colorectal submucosa and its relevance to visceral nociception elicited by mechanical stretch.

Mechanical distension beyond a particular threshold evokes visceral pain from distal colon and rectum (colorectum), and thus biomechanics plays a central role in visceral nociception. In this study we focused on the layered structure of the colorectum through the wall thickness and determined the biomechanical properties of layer-separated colorectal tissue. We harvested the distal 30 mm of mouse colorectum and dissected this tissue into inner and outer composite layers. The inner composite consists of the mucosa and submucosa, whereas the outer composite includes the muscular layers and serosa. We divided each composite axially into three 10-mm-long segments and conducted biaxial mechanical extension tests and opening-angle measurements for each tissue segment. In addition, we quantified the thickness of the rich collagen network in the submucosa by nonlinear imaging via second-harmonic generation (SHG). Our results reveal that the inner composite is slightly stiffer in the axial direction, whereas the outer composite is stiffer circumferentially. The stiffness of the inner composite in the axial direction is about twice that in the circumferential direction, consistent with the orientations of collagen fibers in the submucosa approximately ±30° to the axial direction. Submucosal thickness measured by SHG showed no difference from proximal to distal colorectum under the load-free condition, which likely contributes to the comparable tension stiffness of the inner composite along the colorectum. This, in turn, strongly indicates the submucosa as the load-bearing structure of the colorectum. This further implies nociceptive roles for the colorectal afferent endings in the submucosa, which likely encode tissue-injurious mechanical distension.NEW & NOTEWORTHY Visceral pain from distal colon and rectum (colorectum) is usually elicited from mechanical distension/stretch, rather than from heating, cutting, or pinching, which usually evoke pain from the skin. We conducted layer-separated biomechanical tests on mouse colorectum and identified an unexpected role of submucosa as the load-bearing structure of the colorectum. Outcomes of this study will focus attention on sensory nerve endings in the submucosa that likely encode tissue-injurious distension/stretch to cause visceral pain.

Optical recording reveals topological distribution of functionally classified colorectal afferent neurons in intact lumbosacral DRG.

Neuromodulation as a non‐drug alternative for managing visceral pain in irritable bowel syndrome (IBS) may target sensitized afferents of distal colon and rectum (colorectum), especially their somata in the dorsal root ganglion (DRG). Developing selective DRG stimulation to manage visceral pain requires knowledge of the topological distribution of colorectal afferent somata which are sparsely distributed in the DRG. Here, we implemented GCaMP6f to conduct high‐throughput optical recordings of colorectal afferent activities in lumbosacral DRG, that is, optical electrophysiology. Using a mouse ex vivo preparation with distal colorectum and L5‐S1 DRG in continuity, we recorded 791 colorectal afferents' responses to graded colorectal distension (15, 30, 40, and 60 mmHg) and/or luminal shear flow (20–30 mL/min), then functionally classified them into four mechanosensitive classes, and determined the topological distribution of their somata in the DRG. Of the 791 colorectal afferents, 90.8% were in the L6 DRG, 8.3% in the S1 DRG, and only 0.9% in the L5 DRG. L6 afferents had all four classes: 29% mucosal, 18.4% muscular‐mucosal, 34% low‐threshold (LT) muscular, and 18.2% high‐threshold (HT) muscular afferents. S1 afferents only had three classes: 19.7% mucosal, 34.8% LT muscular, and 45.5% HT muscular afferents. All seven L5 afferents were HT muscular. In L6 DRG, somata of HT muscular afferents were clustered in the caudal region whereas somata of the other classes did not cluster in specific regions. Outcomes of this study can directly inform the design and improvement of next‐generation neuromodulation devices that target the DRG to alleviate visceral pain in IBS patients.