Invasive papillary adenocarcinoma of the colon.

Colonic adenocarcinomas are among the most common type of tumors. In this report, we present the morphologic, immunohistochemical, and microsatellite findings of 2 cases with a distinct invasive papillary component. Both tumors arose from polyps in middle-aged patients, followed an aggressive course, and showed a superficial adenomatous component. The immunohistochemical stains showed that the tumor cells were negative for p27 and p53; both tumors were microsatellite stable, that is, with no microsatellite instability in the 6 markers studied, and there was no loss of the mismatch repair proteins hMSH2 or hMLH1. These findings suggest that these tumors follow the tumor-suppressor pathway and represent an aggressive subtype of colonic adenocarcinoma.

Microsatellite status and cell cycle associated markers in rectal cancer patients undergoing a combined regimen of 5-FU and CPT-11 chemotherapy and radiotherapy.

BACKGROUND: Microsatellite instability (MSI) and expression of cell cycle-related markers may predict a favorable outcome in colorectal cancer patients. The aim of this study was to elucidate the molecular profiles of patients with rectal cancers treated with neoadjuvant chemotherapy (5-Fluorouracil and CPT-11), radiotherapy and surgery that correlate with response to therapy. PATIENTS AND METHODS: Fifty-seven patients with rectal cancer were treated with the same preoperative chemotherapy regimen, radiotherapy (45 to 54 Gy) followed by surgery. The microsatellite status, the expression of the mismatch repair proteins MLH1 and MSH2 and p21WAF1/C1PI, p27, bcl-2, topoisomerase II (topo II) and Ki-67 were assessed in the pretreatment biopsies. The response to adjuvant therapy was categorized in the resected specimens as complete response (CR, no microscopic residual tumor present) and partial response (PR, tumor present). RESULTS: p21WAF1/C1PI, expression characterized the CR with 12 out of 30 tumors (40%) positive for this marker. None of the patients whose tumors did not express p21WAFI/C1PI (10 patients) was a CR (p=0.011). Overall, the tumors with CR also showed higher expression of bcl-2, Ki-67, topo II and p27. However, p53 was more frequently expressed in the PR tumors. Tumors with high microsatellite instability showed CR (3/5, 60%) more often than PR, whereas tumors with stable microsatellites showed PR (26/36, 80%) more often than CR (p=0.099). CONCLUSION: We conclude that a molecular profile characterized by high microsatellite instability with loss of mismatch repair protein expression and p21WAF1/C1PI is predictive of an improved response to neoadjuvant treatment with 5-FU, CPT-11 and radiation therapy.

Nitric oxide-donating aspirin derivatives suppress microsatellite instability in mismatch repair-deficient and hereditary nonpolyposis colorectal cancer cells.

Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are an emergent class of pharmaceutical derivatives with promising utility as cancer chemopreventive agents. Aspirin and sulindac have been shown to be effective in selecting for cells with reduced microsatellite instability (MSI) that is inherent in mismatch repair (MMR)-deficient hereditary nonpolyposis colorectal cancer (HNPCC) cells. The effect of NO-NSAIDs on MSI in MMR-deficient HNPCC cells is unknown. Here, we have examined genetically defined MMR-deficient murine embryo fibroblasts, murine colonocytes, and isogenic human HNPCC tumor cell lines treated with acetylsalicylic acid (aspirin; ASA) and three isomeric derivatives of NO-aspirin (NO-ASA). The MSI profiles were determined and compared with the Bethesda Criteria. We found that the ASA- and NO-ASA-treated MMR-deficient cell lines displayed a dose-dependent suppression of MSI that appeared as early as 8 weeks and gradually increased to include up to 67% of the microsatellite sequences examined after 19 to 20 weeks of continuous treatment. Residual resistance to microsatellite stabilization was largely confined to mononucleotide repeat sequences. Control (MMR-proficient) cells showed no changes in microsatellite status with or without treatment. The relative dose-dependent stabilization selection was: ortho-NO-ASA approximately para-NO-ASA > meta-NO-ASA >> ASA. Moreover, the doses required for stabilization by the ortho- and para-NO-ASA were 300- to 3,000-fold lower than ASA. These results suggest that NO-ASA derivatives may be more effective at suppressing MSI in MMR-deficient cell lines than ASA and should be considered for chemopreventive trials with HNPCC carriers.