Rare Case of Sigmoid Colon Adenocarcinoma Invading the Vermiform Appendix

Colorectal cancer (CRC) ranks third in the top of the most common neoplasms in both women and men, with a high mortality rate. In the etiopathogenesis of colorectal cancer, genetic and environmental factors play an important role. In recent years, there has been a decrease in the incidence of new cases and mortality among patients over the age of 50. This can be explained by the application of modern multimodal treatment methods as well as by increasing the use of screening methods. Particular attention should be paid to inherited syndromes such as Lynch syndrome and Familial Adenomatous Polyposis, which together account for 5% of all colorectal cancers. It was found that an accumulation of genetic mutations over a period of 10 to 15 years, leads to changes in the normal colonic epithelium, with the eventual appearance of invasive carcinoma.(1,2)

Curriculum review: serrated lesions of the colorectum

Colorectal cancer (CRC) is the second leading cause of death from cancer in the UK. Sporadic CRC evolves by the cumulative effect of genetic and epigenetic alterations. Typically, over the course of several years, this leads to the transformation of normal colonic epithelium to benign adenomatous polyp, low-grade to high-grade dysplasia and finally cancer—the adenoma-carcinoma sequence. Over the last decade, the serrated neoplasia pathway which progresses by methylation of tumour suppressing genes has been increasingly recognised as an important alternative pathway accounting for up to 30% of CRC cases. Endoscopists should be aware of the unique features of serrated lesions so that their early detection, appropriate resection and surveillance interval can be optimised.

Polyp Genetics

The genetic events involved in the transformation of normal colonic epithelium to neoplastic polyps to invasive carcinoma, as initially proposed by Fearon and Vogelstein, form the foundation of our understanding of colorectal cancer. The identification of the polyp as the precursor lesion to colorectal cancer is the basis of many of our current practices for screening, surveillance, and prevention. The last three decades have seen a veritable explosion in our understanding of the molecular events involved in the pathogenesis of colorectal cancer. It is now clear that there are multiple genetic pathways in the polyp to carcinoma sequence. Some polyps previously thought to be nonneoplastic have now been shown to have malignant potential. Finally, increased understanding of the sequence of genetic events has led to the development of targeted therapeutics. The clinical translation of these scientific advances has made a significant impact on the management of patients with colorectal cancer. Accordingly, it is imperative that all clinicians caring for these patients have an understanding of the genetics of colorectal polyps and cancer. In this article, we review the etiology and genetic pathways to carcinoma associated with a range of polyps of the colon and rectum.

CD24 can be used to isolate Lgr5+ putative colonic epithelial stem cells in mice

A growing body of evidence has implicated CD24, a cell-surface protein, as a marker of colorectal cancer stem cells and target for antitumor therapy, although its presence in normal colonic epithelium has not been fully characterized. Previously, our group showed that CD24-based cell sorting can be used to isolate a fraction of murine small intestinal epithelial cells enriched in actively cycling stem cells. Similarly, we hypothesized that CD24-based isolation of colonic epithelial cells would generate a fraction enriched in actively cycling colonic epithelial stem cells (CESCs). Immunohistochemistry performed on mouse colonic tissue showed CD24 expression in the bottom half of proximal colon crypts and the crypt base in the distal colon. This pattern of distribution was similar to enhanced green fluorescent protein (EGFP) expression in Lgr5-EGFP mice. Areas expressing CD24 contained actively proliferating cells as determined by ethynyl deoxyuridine (EdU) incorporation, with a distinct difference between the proximal colon, where EdU-labeled cells were most frequent in the midcrypt, and the distal colon, where they were primarily at the crypt base. Flow cytometric analyses of single epithelial cells, identified by epithelial cell adhesion molecule (EpCAM) positivity, from mouse colon revealed an actively cycling CD24+ fraction that contained the majority of Lgr5-EGFP+ putative CESCs. Transcript analysis by quantitative RT-PCR confirmed enrichment of active CESC markers [leucine-rich-repeat-containing G protein-coupled receptor 5 (Lgr5), ephrin type B receptor 2 (EphB2), and CD166] in the CD24+EpCAM+ fraction but also showed enrichment of quiescent CESC markers [leucine-rich repeats and immunoglobin domains (Lrig), doublecortin and calmodulin kinase-like 1 (DCAMKL-1), and murine telomerase reverse transcriptase (mTert)]. We conclude that CD24-based sorting in wild-type mice isolates a colonic epithelial fraction highly enriched in actively cycling and quiescent putative CESCs. Furthermore, the presence of CD24 expression in normal colonic epithelium may have important implications for the use of anti-CD24-based colorectal cancer therapies.

KRN330, a fully human antibody against A33, in combination with irinotecan for patients with metastatic colorectal cancer (mCRC).

534 Background: KRN330 is a recombinant, fully-human monoclonal antibody directed against A33, a surface differentiation antigen on normal colonic epithelium, which is uniformly expressed in 95% of colorectal cancers. A KRN330 monotherapy phase I study showed over 1 year of stable disease in 2 pts with refractory mCRC. We report results of the phase I part of a phase I/II trial of KRN330 in combination with irinotecan in pts with mCRC. Methods: Pts with mCRC who progressed on one or more prior therapies received weekly (QW) or biweekly (Q2W) intravenous doses of KRN330 at 0.5 or 1.0 mg/kg with Q2W irinotecan at 180 mg/m2 in a standard 3+3 dose escalation design. Results: Nineteen pts were treated. Four pts received 1.0 mg/kg of KRN330 Q2W and irinotecan treatment. Three pts developed DLTs, which included G4 febrile neutropenia and G3 colitis, prolonged G3 diarrhea, and, G4 neutropenia with prolonged G3 diarrhea. KRN330 was then deescalated to 0.5 mg/kg Q2W and 0.5 mg/kg QW. There were no DLTs in 7 of 8 pts in the Q2W cohort. The 1 DLT in this cohort was G3 colitis. None of the 7 pts in the QW cohort experienced DLT. The most common G3/4 toxicities included diarrhea (26.3%) and febrile neutropenia (15.9%), leucopenia (10.5%), neutropenia (10.5%), abdominal pain (10.5%), and colitis (10.5%). Of the 16 pts evaluable for efficacy, 2 pts had PR, 8 SD and 6 PD as best response. The 2 pts with PR had previously received an irinotecan-containing regimen, one with PD on an irinotecan-containing regimen. The responses are being confirmed by independent adjudicator. Conclusions: QW and Q2W intravenous doses of KRN330 at 0.5 mg/kg KRN330 with irinotecan were tolerable and demonstrated antitumor effect in pts who had received previous irinotecan-containing regimens. The phase II part of the phase I/II study of QW KRN330 plus irinotecan in pts with second line mCRC is ongoing. No significant financial relationships to disclose.