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Background and Aims The aim of this study was to examine clinical outcomes and adverse events (AEs) of self-expandable metal stents (SEMSs) in the management of malignant colonic obstruction (MCO). Methods Patients with SEMSs for MCO treated at our institution from 2007 to 2016 were included. Clinical success was defined as successful oral intake after the procedure and technical success as stent deployment across the stricture in the desired location. Results Of 199 patients, the mean age was 58, 54% were men, and 99% had stage IV cancer. MCO etiology was colorectal cancer in 82% and extrinsic compression in 17%. Technical success was achieved in 99.5% and clinical success in 89%. The SEMSs were palliative in 97% and were a bridge to surgery in 4%. MCO occurred in the left side of the colon in 90%, transverse in 4.5%, and ascending colon in 5.5%. SEMSs were placed in curved segments in 30% and straight segments in 70%. Tandem SEMSs were required in 27 patients. Forty-six patients had 48 AEs (24%), including 2% periprocedure, 15% postprocedure, and 83% after 72 hours. Stent-related AEs (n = 25) included persistent obstruction (n = 14), occlusion (n = 10), and failure of expansion (n = 1). Procedural AEs (n = 23) included minor bleeding (n = 2), perforations (n = 4), abdominal pain (n = 12), stent migration (n = 4), and respiratory insufficiency (n = 1). Repeat procedures were performed in 21 of 46 patients. After SEMSs, 48 patients underwent surgery, including resection with primary anastomosis (n = 8), resection with definitive stoma (n = 18), and diverting stoma without resection (n = 19). Mean time to surgery after SEMS placement was 175 days. Postsurgical AEs occurred in those with resections (leak, 2; infection, 2). Of 104 receiving bevacizumab, 22% had AEs, including 1 perforation compared with 3 in the nonbevacizumab group (P = .549). Mean overall survival was 5.6 months. Extrinsic compression and curved strictures were associated with poor clinical success by univariate analysis and etiology (noncolonic with poor outcome) by multivariate analysis. Conclusions SEMSs for MCO has high technical but suboptimal clinical success. Curved strictures and extrinsic compression are associated with poor outcomes. The perforation rate was not higher in the bevacizumab compared with the nonbevacizumab group, although this should be further validated in a larger population.

Background Gene expression-based profiling of colorectal cancer (CRC) can be used to identify four molecularly homogeneous consensus molecular subtype (CMS) groups with unique biologic features. However, its applicability to colorectal premalignant lesions remains unknown. Patients and methods We assembled the largest transcriptomic premalignancy dataset by integrating different public and proprietary cohorts of adenomatous and serrated polyps from sporadic (N = 311) and hereditary (N = 78) patient populations and carried out a comprehensive analysis of carcinogenesis pathways using the CMS random forest (RF) classifier. Results Overall, transcriptomic subtyping of sporadic and hereditary polyps revealed CMS2 and CMS1 subgroups as the predominant molecular subtypes in premalignancy. Pathway enrichment analysis showed that adenomatous polyps from sporadic or hereditary cases (including Lynch syndrome) displayed a CMS2-like phenotype with WNT and MYC activation, whereas hyperplastic and serrated polyps with CMS1-like phenotype harbored prominent immune activation. Rare adenomas with CMS4-like phenotype showed significant enrichment for stromal signatures along with transforming growth factor-β activation. There was a strong association of CMS1-like polyps with serrated pathology, right-sided anatomic location and BRAF mutations. Conclusions Based on our observations made in premalignancy, we propose a model of pathway activation associated with CMS classification in colorectal carcinogenesis. Specifically, while adenomatous polyps are largely CMS2, most hyperplastic and serrated polyps are CMS1 and may transition into other CMS groups during evolution into carcinomas. Our findings shed light on the transcriptional landscape of premalignant colonic polyps and may help guide the development of future biomarkers or preventive treatments for CRC.

RESUMEN Hereditary Nonpolyposis Colorectal Cancer (HNPCC or “Lynch syndrome”), involving pathogenic variants in the Mismatch Repair (MMR) genes, is the most common inherited condition that predisposed to colorectal adenomas and colorectal cancer. In this chapter I review the history of HNPCC, from early case reports, to more systematic clinical information and clinical criteria, and finally to the discovery of the MMR genes themselves in 1993, including the key feature of microsatellite instability. This central role for microsatellite analysis of colorectal cancers involves a growing trend toward “universal testing” for evidence of MSI, whether by PCR methods or by immunohistochemistry (IHC). Even though such universal testing has not been completely adopted around the world, we are already evolving toward more routine use of multi-gene “panels” for germline MMR mutation detection. Under these circumstances, one may reasonably ask whether understanding the historical unfolding of clinical features of HNPCC is even relevant. As this chapter hopes to demonstrate, an appreciation of the landscape of HNPCC would not be complete without such a historical perspective, including the important role of Dr Henry Lynch over a lifetime of work in the field.

Nonampullary duodenal adenomas are either sporadic or associated with a hereditary syndrome such as familial adenomatous polyposis (FAP). The aim of this study is to compare characteristics and outcomes of sporadic and FAP-associated duodenal adenomas.We retrospectively collected clinical, endoscopic, and pathologic data in patients diagnosed with duodenal adenomas at our institution and included all available follow-up.Two hundred thirteen subjects were identified; 118 had FAP and 95 had sporadic adenomas. FAP subjects were more likely to have multifocal disease. Initial size was not significantly associated with dysplasia. Fourteen (12%) with FAP and 33 (35%) with sporadic adenomas underwent EMR. Among those subjects who did not undergo EMR or surgery, there was no difference between the FAP and sporadic groups with progression to new dysplasia or cancer. However, the FAP group was significantly more likely to have dysplasia at follow-up (P = .05). There was a significant difference in overall survival between the FAP and sporadic groups (log-rank test, P .001). In the subgroup of patients aged 40 years old and older who did not undergo intervention, the FAP group had a shorter time to pathology progression compared with the similar sporadic subgroup. Range of time to progression to cancer was 3 to 161 months.FAP subjects were more likely to be younger and have multifocal disease. Progression of pathology was more likely in the older FAP group compared with the sporadic group. Time to progression to cancer was widely variable and, therefore, unpredictable.

Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied, and multiple professional societies have proposed clinical management guidelines for affected individuals. Several studies have demonstrated a reduced penetrance for monoallelic carriers of PMS2 mutations compared with the other mismatch repair (MMR) genes, but clinical management guidelines have largely proposed the same screening recommendations for all MMR gene carriers. The authors considered whether enough evidence existed to propose new screening guidelines specific to PMS2 mutation carriers with regard to age at onset and frequency of colonic screening. Published reports of PMS2 germ-line mutations were combined with unpublished cases from the authors' research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued. A total of 234 monoallelic PMS2 mutation carriers from 170 families were included. Approximately 8% of those with colorectal cancer (CRC) were diagnosed before age 30, and each of these tumors presented on the left side of the colon. As it is currently unknown what causes the early onset of CRC in some families with monoallelic PMS2 germline mutations, the authors recommend against reducing cancer surveillance guidelines in families found having monoallelic PMS2 mutations in spite of the reduced penetrance.Genet Med 18 1, 13-19.

Background and Aims The adenoma detection rate (ADR) is a quality metric tied to interval colon cancer occurrence. However, manual extraction of data to calculate and track the ADR in clinical practice is labor-intensive. To overcome this difficulty, we developed a natural language processing (NLP) method to identify adenomas and sessile serrated adenomas (SSAs) in patients undergoing their first screening colonoscopy. We compared the NLP-generated results with that of manual data extraction to test the accuracy of NLP and report on colonoscopy quality metrics using NLP. Methods Identification of screening colonoscopies using NLP was compared with that using the manual method for 12,748 patients who underwent colonoscopies from July 2010 to February 2013. Also, identification of adenomas and SSAs using NLP was compared with that using the manual method with 2259 matched patient records. Colonoscopy ADRs using these methods were generated for each physician. Results NLP correctly identified 91.3% of the screening examinations, whereas the manual method identified 87.8% of them. Both the manual method and NLP correctly identified examinations of patients with adenomas and SSAs in the matched records almost perfectly. Both NLP and the manual method produced comparable values for ADRs for each endoscopist and for the group as a whole. Conclusions NLP can correctly identify screening colonoscopies, accurately identify adenomas and SSAs in a pathology database, and provide real-time quality metrics for colonoscopy.

Background Standards for the detection of adenomas during screening colonoscopy are widely used to measure examination quality. No such standards exist for sessile serrated adenomas (SSAs). Objective To measure both the adenoma detection rate (ADR) and SSA detection rate (SSADR) during screening colonoscopy before and after quality improvement/financial incentive measures. Design Retrospective determination of baseline ADR/SSADR by the endoscopist, followed by prospective collection of data after informing physicians of baseline detection rates. Setting Tertiary cancer center with a large cancer screening program. Patients A total of 2833 average-risk colorectal cancer screening patients 50 to 75 years of age undergoing initial colonoscopy. Data Collection Electronic medical records for indication and demographics, endoscopy report, and pathology report. Main Outcome Measurements Detection rates of adenomas and SSAs by sex. Results The overall ADR in male and female patients was 50.6% and 36.6%, respectively. The overall detection rate of advanced adenomas in male and female patients was 12.4% and 6.5%, respectively. The overall SSADR in male and female patients was 10.1% and 7.1%, respectively. In 108 patients (3.8% of entire group), SSAs were the only premalignant lesions found. Detection rates of both types of premalignant polyps improved over time but did not reach statistical significance. Limitations Single-center experience with limited sample size and small group of endoscopists. Conclusion ADRs far in excess of current standards are achievable. Cecal withdrawal time is associated with the ADR. Prevalence of SSA rivals that of advanced adenomas and is greater than current medical literature suggests. The combination of monitoring and financial incentives did not result in statistically significant improvement in ADRs.

Endometrial biopsy (EMBx) and colonoscopy performed under the same sedation is termed combined screening and has been shown to be feasible and to provide a less painful and more satisfactory experience for women with Lynch syndrome (LS). However, clinical results of these screening efforts have not been reported. The purpose of this study was to evaluate the long-term clinical outcomes and patient compliance with serial screenings over the last 10.5 years.We retrospectively analyzed the data for 55 women with LS who underwent combined screening every 1-2 years between 2002 and 2013. Colonoscopy and endometrial biopsy were performed by a gastroenterologist and a gynecologist, with the patient under conscious sedation.Out of 111 screening visits in these 55 patients, endometrial biopsies detected one simple hyperplasia, three complex hyperplasia, and one endometrioid adenocarcinoma (FIGO Stage 1A). Seventy-one colorectal polyps were removed in 29 patients, of which 29 were tubular adenomas. EMBx in our study detected endometrial cancer in 0.9% (1/111) of surveillance visits, and premalignant hyperplasia in 3.6% (4/111) of screening visits. No interval endometrial or colorectal cancers were detected.Combined screening under sedation is feasible and less painful than EMBx alone. Our endometrial pathology detection rates were comparable to yearly screening studies. Our results indicate that screening of asymptomatic LS women with EMBx every 1-2 years, rather than annually, is effective in the early detection of (pre)cancerous lesions, leading to their prompt definitive management, and potential reduction in endometrial cancer.

Background Accurate measures of the total polyp burden in familial adenomatous polyposis (FAP) are lacking. Current assessment tools include polyp quantitation in limited-field photographs and qualitative total colorectal polyp burden by video. Objective To develop global quantitative tools of the FAP colorectal adenoma burden. Design A single-arm, phase II trial. Patients Twenty-seven patients with FAP. Intervention Treatment with celecoxib for 6 months, with before-treatment and after-treatment videos posted to an intranet with an interactive site for scoring. Main Outcome Measurements Global adenoma counts and sizes (grouped into categories: 4 mm) were scored from videos by using a novel Web-based tool. Baseline and end-of-study adenoma burden results were summarized by using 5 models. Correlations between pairs of reviewers were analyzed for each model. Results Interobserver agreement was high for all 5 measures of polyp burden. Measures that used both polyp count and polyp size had better interobserver agreement than measures based only on polyp count. The measure in which polyp counts were weighted according to diameter, calculated as (1) × (no. of polyps 4 mm) had the highest interobserver agreement (Pearson r = 0.978 for two gastroenterologists, 0.786 and 0.846 for the surgeon vs each gastroenterologist). Treatment reduced the polyp burden by these measurements in 70% to 89% of patients (P Limitations Phase II study. Conclusion This novel, Web-based polyp scoring method provides a convenient and reproducible way to quantify the global colorectal adenoma burden in FAP patients and a framework for developing a clinical staging system for FAP.

Hereditary colorectal cancer syndromes are increasingly being recognized. Genetic mutation testing affords the possibility of pinpointing patients who are and are not carriers of susceptibility. The genetic testing process is, however, technically complex and time consuming. Published professional practice guidelines have been produced by an array of professional organizations. These provide for clinical recognition for subjects who may have FAP, HNPCC, and related conditions. More or less directed genetic workup of suspected patients are included. Detailed algorithms for endoscopic surveillance and management exist and should be familiar to GI endoscopists. Practice guidelines may be considered to codify standards of care, deviation from which may carry risk of medical malpractice litigation. Detailed consideration of these issues and related matters are discussed.

Purpose: To assess pelvic chemoradiotherapy (CXRT) without colostomy as a component of the multidisciplinary management of patients presenting with metastatic rectal cancer. Methods and Materials: Eighty patients with synchronous distant metastases from rectal cancer were treated with initial CXRT. Hypofractionated radiotherapy was administered usually with concurrent 5-FU (92%, 300 mg/m2/day, M–F). Three-field belly-board technique was used in 89%. Group 1 had CXRT alone (n = 55). Group 2 (n = 25) patients were selected for primary disease resection, and sometimes HAI chemotherapy (n = 10) or hepatic resection (n = 5). Subsequently, 78% received systemic chemotherapy. Results: Symptoms from primary tumor resolved in 94%. Endoscopic complete clinical response rate was 36%. Two-year survival (11% vs. 46%, p < 0.0001) and symptomatic pelvic control (PC, 81% vs. 91%, p = 0.111) were higher in Group 2, but colostomy-free rate (CFR) was lower (79% vs. 51% p = 0.02). CFR was 87% in Group 1 patients managed initially without fecal diversion (n = 50). Examining all patients using multivariate analysis, pelvic pain at presentation (p < 0.00001), BED (biologic equivalent dose at 2 Gy/fraction) < 35 Gy (p = 0.077), and poor differentiation (0.079) predicted worse PC. Poor differentiation (p = 0.017) and selection for CXRT alone (p < 0.0001) predicted worse survival. There were 4 RTOG of Grade 3 or greater acute complications, 5 severe perioperative complications, and no significant late treatment-related complications. Conclusions: Durable PC can be safely achieved without colostomy in most patients presenting with primary rectal cancer and synchronous systemic metastases using hypofractionated pelvic chemoradiation. A BED greater than 35 Gy is recommended. Selected patients appear to benefit from resection of primary disease. Higher doses should be investigated in patients with pelvic pain.

Germline mutations of the adenomatous polyposis coli ( APC ) tumor-suppressor gene result in familial adenomatous polyposis (FAP). Patients with FAP typically develop hundreds to thousands of benign colorectal tumors and early-onset colorectal cancer. A subset of germline APC mutations results in an attenuated FAP (AFAP) phenotype, in which patients develop fewer tumors and develop them at an older age. Although a genotype-phenotype correlation between the locations of APC germline mutations and the development of AFAP has been well documented, the mechanism for AFAP has not been well defined. We investigated the mechanism for AFAP in patients carrying a mutant APC allele ( APC AS9 ) that has a mutation in the alternatively spliced region of exon 9. APC AS9 was found to down-regulate β-catenin–regulated transcription, the major tumor-suppressor function of APC, as did the wild-type APC. Mutation analysis showed that both APC AS9 and the wild-type APC alleles were somatically mutated in most colorectal tumors from these patients. Functional analysis showed that 4666insA, a common somatic mutation in APC AS9 in these tumors, did not inactivate the wild-type APC. Our results indicate that carriers of APC AS9 develop fewer colorectal tumors than do typical patients with FAP because somatic inactivation of both APC alleles is necessary for colorectal tumorigenesis. However, these patients develop colorectal tumors more frequently than does the general population because APC AS9 is inactivated by mutations that do not inactivate the wild-type APC.

Background & Aims: Cyclooxygenase (COX) enzymes catalyze the conversion of arachidonic acid to prostaglandins. Evidence suggests that nonsteroidal anti-inflammatory drugs reduce the risk of colorectal cancer (CRC) and that this effect is mediated through COX inhibition. We analyzed and compared expression of the inducible COX-2 isoform in colorectal neoplasms from patients with hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), and sporadic CRC. Given that COX-2 is induced by transforming growth factor (TGF)-β and that TGF-β type II receptor ( RII ) mutations are found in HNPCCs, we determined the relationship between RII status and COX-2 expression. Methods: COX-2 protein expression was determined in colorectal epithelia using immunohistochemistry and Western blotting. Patients with HNPCC had known mutations in hMLH1 or hMSH2 genes and/or met the Amsterdam criteria. In CRCs from HNPCC cases, mutations were sought in the coding region of the RII gene using the polymerase chain reaction. Results: COX-2 was detected in adenomas from 2 of 3 HNPCC, 6 of 7 FAP, and 5 of 8 sporadic cases. In CRCs, COX-2 staining was found in 16 of 24 (67 %) HNPCC vs. 24 of 26 (92%) sporadic cases ( P = 0.035) and in 2 of 2 FAP cases. Staining intensity was reduced in HNPCCs compared with sporadic CRCs ( P = 0.035). Staining localized to the cytoplasm of neoplastic cells; normal epithelial cells were negative for COX-2. Overexpression of COX-2 in CRCs relative to normal mucosa was confirmed by Western blotting. TGF-β RII mutations were detected in 12 of 14 HNPCCs examined, including 3 of 4 COX-2–negative and 9 of 10 COX-2–positive cancers. Conclusions: The frequency and intensity of COX-2 expression was significantly reduced in HNPCCs relative to sporadic CRCs, and was not a consequence of RII mutations. Given that many HNPCCs express COX-2, inhibition of this enzyme may be an important strategy to prevent CRC in these patients.

Background: Endoscopic ultrasonography (EUS) is an imaging modality that is now widely used to stage gastrointestinal malignancies. Few studies have addressed the issue of interobserver variability in the interpretation of EUS, particularly as it pertains to the staging of rectal carcinoma. Methods: Twenty-six patients with a diagnosis of rectal carcinoma were evaluated prospectively by three endoscopists. One performed sigmoidoscopy, the second (primary endosonographer) performed an EUS staging examination with full knowledge of the patient history and sigmoidoscopic appearance of the lesion, and the third endoscopist (secondary endosonographer) performed EUS blinded to this information. The results of the respective examinations were then compared. Results: When the EUS findings of the endosonographers were compared, T stage agreed in 88% of patients, with the following kappa coefficients: T1 (κ = 0.00); T2 (κ = -0.04); T3 (κ = -0.05); T4 (κ = 0.00). Interrator N stage agreed in 73% of patients (κ = 0.42). Conclusion: Our study prospectively evaluated interobserver variation in staging rectal carcinoma by EUS. The protocol that was followed provides a useful template that eliminated potential observer bias. Fair agreement was demonstrated regarding lymph node assessment. Although the raters agreed in 88% of the patients, kappa statistic analysis did not reach significant agreement, due to this institution's preponderence of UT3 lesions. Thus, validation of our findings in a setting where a broader spectrum of disease is encountered is required. (Gastrointest Endosc 1996;44:573-7.)

Colorectal cancer surveillance based on a positive family history is gaining widespread acceptance. Because subjects with a positive family history are a heterogeneous group, critical assessment of the history should be made so that a clinical likelihood of hereditary nonpolyposis colorectal cancer (HNPCC) can be established. Findings from surveillance of asymptomatic subjects with HNPCC, and more modest family histories, are contrasted in this article. The threshold for colonoscopic surveillance should be low in subjects with any immediate family history of early-onset colorectal cancer, and in subjects with multiple relatives affected at any age.

An attenuated form of familial adenomatous polyposis coli, AAPC, causes relatively few colonic polyps, but still carries a significant risk of colon cancer. The mutant alleles responsible for this attenuated phenotype have been mapped in several families to the adenomatous polyposis coli ( APC ) locus on human chromosome 5q. Four distinct mutations in the APC gene have now been identified in seven AAPC families. These mutations that predict truncation products, either by single base pair changes or frameshifts, are similar to mutations identified in families with classical APC. However, they differ in that the four mutated sites are located very close to one another and nearer the 5′ end of the APC gene than any base substitutions or small deletions yet discovered in patients with classical APC.

Hereditary nonpolyposis colorectal cancer (HNPCC) dates to Warthin's description of family G, which he began studying in 1895. Warthin's observations were not fully appreciated until 1966 when two families with an autosomal dominant inheritance pattern of nonpolyposis colorectal cancer (CRC) and endometrial cancer were described. This condition was first termed the "cancer family syndrome" and was later renamed HNPCC. Some have proposed that HNPCC consists of at least two syndromes: Lynch syndrome I, with hereditary predisposition for CRC having early (approximately 44 years) age of onset, a proclivity (70%) for the proximal colon, and an excess of synchronous and metachronous colonic cancers and Lynch syndrome II, featuring a similar colonic phenotype accompanied by a high risk for carcinoma of the endometrium. Transitional cell carcinoma of the ureter and renal pelvis and carcinomas of the stomach, small bowel, ovary, and pancreas also afflict some families. Current estimates indicate that HNPCC may account for as much as 6% of the total CRC burden. There are no known premonitory phenotypic signs or biomarkers of cancer susceptibility in the Lynch syndromes. This report will summarize current knowledge, with emphasis on the manner in which this knowledge can be employed effectively for diagnosis and management of HNPCC.

A substantive amount of evidence from animal models supports the hypothesis that dietary fat is an etiological factor in colon cancer. Although various theories account for possible mechanisms, it is clear that under the influence of a basic colonic pH, fatty acids and bile acids may become highly surfactant in the colon, causing cell loss and compensatory hyperproliferation. Calcium likely reduces lipid damage in the colon by complexing with fat to form mineral-fat complexes or soaps. It has been shown in an increasing number of animal experiments that calcium has the ability to inhibit colon cancer. In limited studies in man, the colonic hyperproliferation associated with increased risk for colon cancer has been reversed for short periods by administration of supplemental dietary calcium. Taken together the available evidence suggests that increases in the daily intake of calcium in the diet may provide a means of colorectal-cancer control.