The efficacy of a leukotriene receptor antagonist in the treatment of human rectal aberrant crypt foci: a nonrandomized, open-label, controlled trial.

BACKGROUND: Leukotriene receptor antagonists (LTRAs) are broadly used for the management of allergic asthma and have recently been indicated to inhibit carcinogenesis and cancer cell growth. In colorectal cancer (CRC) chemoprevention studies, the occurrence of adenoma or CRC itself is generally set as the trial endpoint. Although the occurrence rate of CRC is the most confident endpoint, it is inappropriate for chemoprevention studies because CRC incidence rate is low in the general population and needed for long-term monitoring. Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and darker in methylene blue staining than normal crypts, are regarded to be a fine surrogate biomarker of CRC. Therefore, this prospective study was designed to explore the chemopreventive effect of LTRA on colonic ACF formation and the safety of the medicine in patients scheduled for a poly resection as a pilot trial leading the CRC chemoprevention trial. METHODS: This study is a nonrandomized, open-label, controlled trial in patients with colorectal ACF and polyps scheduled for a polypectomy. Participants meet the inclusion criteria will be recruited, and the number of ACF in the rectum will be counted at the baseline colonoscopic examination. Next, the participants will be assigned to the LTRA or no treatment group. Participants in the LTRA group will continue 10 mg of oral montelukast for 8 weeks, and those in the no treatment group will be observed without the administration of any additional drugs. At the end of the 8-week LTRA intervention period, a polypectomy will be conducted to evaluate the changes in the number of ACF, and cell proliferation in the normal colorectal epithelium will be analyzed. DISCUSSION: This will be the first study to investigate the effect of LTRAs on colorectal ACF formation in humans. TRIAL REGISTRATION: This trial has been registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000029926 . Registered 10 November 2017.

Morphological Classification of Corrupted Colonic Crypts in Ulcerative Colitis.

BACKGROUND/AIM: In ulcerative colitis (UC) the colonic mucosa shows, in addition to a high number of inflammatory cells, crypts with architectural distortions, called corrupted colonic crypts (CCC). Here we classify the histologic repertoire and assess the frequency of CCC in UC. PATIENTS AND METHODS: Five-hundred and sixteen histologic sections from 29 colectomy specimens with UC (24 having adenocarcinoma and five, high-grade dysplasia, HGD) were reviewed. RESULTS: The vast majority of the colonic mucosa portrayed countless crypts with normal shapes (CNS) lined with normal epithelium, except for 45 CNS: 28 showed inconclusive-suspected cellular changes (ISCC), and 17, high-grade dysplasia (HGD). CCC were subdivided into four groups: i) Crypts with fission distortions, ii) Crypts with length distortions, iii) Crypts with outline distortions and iv) Crypts with axial polarity distortions. The most frequent CCC group had axial polarity distortions (33.4%), and the less frequent CCC group, outline distortions (21.1%) (p<0.05). No apparent differences in frequency between groups were found in colectomies with HGD/carcinoma, or in colectomies preformed for medically-refractory UC without HGD/carcinoma. Out of the 902 CCC present in the specimens, 343 (38.0%) displayed ISCC, 186 (20.6%) HGD, and the remaining 373 (41.4%) normal epithelium. Hence, of the 203 crypts exhibiting HGD, 186 (91.6%) were CCC and the remaining 17 (8.4%) CNS (p<0.05). CONCLUSION: Based on these findings it is suggested that the microscopic search for HGD in UC colectomy-specimens should preferentially be focused on mucosal areas exhibiting CCC. This view is validated by recent findings showing that p53 overexpression (a biomarker of epithelial carcinogenesis) significantly correlated with architectural distortions of the crypts in UC.

The significance of ectopic crypt formation in the differential diagnosis of colorectal polyps.

BACKGROUND: Ectopic crypts, defined as abnormally positioned crypts that have lost their orientation toward the muscularis mucosae, have been suggested to be the best defining histologic feature of traditional serrated adenoma (TSA). However, the significance of ectopic crypt formation (ECF) in the distinction between TSA and conventional adenoma (CA) has rarely been studied. METHODS: We designed this study to determine if ECF can be found in CA and its presence is exclusive to TSA. We studied 107 TSAs and 191 CAs including 106 tubular adenomas (TAs), 66 tubulovillous adenomas (TVAs), and 19 villous adenomas (VAs). RESULTS: ECF was identified in most (79.4%) but not all TSAs. Additionally, ECF was not infrequent in CA (62 of 191, 32.5%), and its presence correlated with the presence of a villous component and larger tumor size (each p <0.001). CONCLUSIONS: Based on its strong association with the presence of a villous component and larger tumor size, ECF appears to be involved in the protuberant growth of colorectal CA. Because ECF can be found in CA, particularly in cases with a villous component, the possibility of CA should be considered before making a diagnosis of TSA when encountering colorectal polyps with ECF. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_212.

HD chromoendoscopy coupled with DNA mass spectrometry profiling identifies somatic mutations in microdissected human proximal aberrant crypt foci.

UNLABELLED: Despite increased implementation of screening colonoscopy, interval cancers in the proximal colon remain a major public health concern. This fact underscores the limitations of current screening paradigms and the need for developing advanced endoscopic techniques. The density of aberrant crypt foci (ACF), the earliest identifiable mucosal abnormality, may serve as a surrogate marker for colon cancer risk, but has rarely been studied in the proximal colon. To this end, high-definition (HD) chromoendoscopy was conducted to define the relevance of ACF in the proximal colon. In addition, due to limited ACF size, the development of a combinatorial approach was required to maximize data acquisition obtained from individual biopsy samples. Proximal and distal ACF samples were characterized for a total of 105 mutations across 22 known tumor suppressor and proto-oncogenes using high-throughput Sequenom MassARRAY analysis. From this profiling, a discrete number of somatic mutations were identified, including APC(R876*) and FLT3(I836M), as well as a deletion within the EGFR gene. Combined, these data highlight the significance of ACF within the context of colon cancer pathogenesis, particularly in the proximal colon. IMPLICATIONS: The identification of cancer-related mutations in commonly overlooked mucosal lesions underscores the preventive benefit of implementing advanced endoscopic screening to larger patient populations, particularly in the proximal colon. Visual Overview: http://mcr.aacrjournals.org/content/early/2014/05/22/1541-7786.MCR-13-0624/F1.large.jpg. Mol Cancer Res; 12(6); 823-9. ©2014 AACR.