Satoshi Okabe

T1 Adenocarcinoma of the Rectum: Transanal Excision or Radical Surgery?

Background:Recent studies suggest local excision may be acceptable treatment of T1 adenocarcinoma of the rectum, but there is little comparative data with radical surgery to assess outcomes and quantify risk. We performed a retrospective evaluation of patients with T1 rectal cancers treated by either transanal excision or radical resection at our institution to assess patient selection, cancer recurrence, and survival. Methods:All patients who underwent surgery for T1 adenocarcinomas of the rectum (0–15 cm from anal verge) by either transanal excision (TAE) or radical resection (RAD) between January 1987 and January 2004 were identified from a prospective database. Data were analyzed using Fisher exact test, Kaplan-Meier method, and log-rank test. Results:Three hundred nineteen consecutive patients with T1 lesions were treated by transanal excision (n = 151) or radical surgery (n = 168) over the 17-year period. RAD surgery was associated with higher tumor location in the rectum, slightly larger tumor size, a similar rate of adverse histology, and a lymph node metastasis rate of 18%. Despite these features, patients who underwent RAD surgery had fewer local recurrences, fewer distant recurrences, and significantly better recurrence-free survival (P = 0.0001). Overall and disease-specific survival was similar for RAD and TAE groups. Conclusion:Despite a similar risk profile in the 2 surgical groups, patients with T1 rectal cancer treated by local excision were observed to have a 3- to 5-fold higher risk of tumor recurrence compared with patients treated by radical surgery. Local excision should be reserved for low-risk cancers in patients who will accept an increased risk of tumor recurrence, prolonged surveillance, and possible need for aggressive salvage surgery. Radical resection is the more definitive surgical treatment of T1 rectal cancers.

Lymph node metastasis in T1 adenocarcinoma of the colon and rectum.

The biology of colorectal cancer differs according to location within the large intestine. To evaluate the clinical significance of tumor location as a risk factor for lymph node metastasis (LNM), we performed a detailed pathological review of T1 adenocarcinomas of the colon and rectum. T1 adenocarcinomas of the colon and rectum treated by radical resection (n = 428) were identified from prospective clinical databases at two institutions. Tumor location was assigned as right colon (cecum to transverse), left colon (splenic flexure to sigmoid), or rectum (0–18 cm from AV). Pathology slides were reviewed, extent of submucosal invasion (sm width, sm depth) was quantified using an optical micrometer, and morphologic features of the cancer and its infiltrating margin were recorded. The overall rate of LNM was 10%. On univariate analysis, LNM was significantly more common in the rectum (27/176, 15%) compared to the left colon (13/160, 8%, p = .04) or right colon (3/92, 3%, p = .003). However, on multivariate analysis, deep submucosal invasion and lymphovascular invasion were independent and significant risk factors, whereas tumor location was not. T1 colorectal cancers have a progressively higher risk of LNM as their location becomes more distal. However, the increasing rate of LNM observed in cancers of the left colon and rectum is explained by a higher prevalence of high-risk pathologic features. In early colorectal cancers, tumor morphology is the strongest clinical predictor of metastatic behavior.

Genomic structure of the human Smad3 gene and its infrequent alterations in colorectal cancers

The Smad3 gene is a member of the Smad family, vertebrate homologues of Drosophila Mad, and its gene product is a cytoplasmic element in the TGF-beta signaling pathway. Smad2 and Smad4/DPC4, other members of the Smad family, are possibly tumor suppressor genes because alterations of these genes occurred in various carcinomas. We determined the genomic structure of human Smad3 which consists of nine exons. Then we examined whether or not Smad3 gene mutations exist in sporadic and hereditary non-polyposis colorectal cancers and found no mutations in the entire coding region in 50 cancers. Loss of heterozygosity of Smad3 was observed in two of the 17 (11.8%) informative cases using a polymorphism found in intron 2. These findings suggest that the Smad3 gene may not play an important role in the tumorigenesis of colorectal cancers.

Colonic mucosal resection using a transparent cap-fitted endoscope

Recently, we have had increased chances of f inding flat lesions in the colon as the resu l t of improved technology for colonoscopy. These lesions include ear ly colon cancers t ha t can be completely removed by endoscopic mucosal resection. 14 However , it is not always easy to remove large flat lesions by endoscopic mucosectomy. We have been performing endoscopic mucosal resect ion us ing a t r a n s p a r e n t cap for flat lesions of the colon and found t ha t this me thod enabled us to per form a safe and easy mucosal resection. 5, 6

Genomic organization and mutation analyses of the DR5/TRAIL receptor 2 gene in colorectal carcinomas.

The DR5/TRAIL receptor 2 gene is a novel TNF receptor family member and induces apoptosis by overexpression of its product. DR5 is located on chromosome 8p21, where allelic deletions are often observed in advanced colorectal cancers. This evidence led us to examine whether or not mutations of the DR5 gene exist in these tumors. We determined the genomic structure of DR5, which consists of nine exons. DR5 has two alternatively spliced isoforms. All seven colorectal cancer (CRC) cell lines examined expressed the longer isoform predominantly. No somatic mutation was found in 41 CRC cases. Loss of heterozygosity of DR5 was found in nine (52.9%) of the 17 informative cases, which is similar to the previously reported frequencies observed for 8p21-22 in colorectal cancers. These findings suggest that inactivation of the DR5 gene may play only a small role, if any, in colorectal tumorigenesis.

Involvement of cyclin D3 in liver metastasis of colorectal cancer, revealed by genome-wide copy-number analysis.

The question of whether any genetic differences exist between primary and colorectal cancers (CRCs) and their metastatic foci is controversial. To look for genetic aberrations involved in metastasis of CRCs to the liver, we performed subtractive comparative genomic hybridization (CGH) experiments using paired samples from 20 CRC patients with primary tumors and synchronous or metachronous liver metastases. Relatively frequent gains in DNA copy number were detected at 6p, suggesting the presence of one or more metastasis-related genes in the region. Analysis of 11 CRC cell lines using array-based CGH (CGH-array) revealed one 6p candidate gene, CCND3. Quantitative reverse transcriptase-polymerase chain reaction experiments showed that CCND3 was significantly upregulated in liver-metastatic lesions compared with primary lesions (P<0.0152). In addition, immunohistochemical analysis of 120 primary CRC tumors demonstrated that cyclin D3 expression in the region of rolled edge was significantly associated with total recurrence, especially hematogenous recurrence (P=0.0307). The results implied involvement of cyclin D3 in liver metastasis of CRC, and the data may contribute to the development of a novel therapy or diagnostic agent for this currently intractable disease. Our experiments also confirmed the power of subtractive CGH and CGH-array analysis for identifying cancer-related genes.

Increased expression of CEA and MHC class I in colorectal cancer cell lines exposed to chemotherapy drugs

PurposeCancer-specific immunotherapy holds great promise as an emerging treatment for advanced colorectal cancer and may be combined with standard chemotherapy to provide a synergistic inhibitory action against tumor cells. To examine the interrelationship between the immune system and chemotherapy, we studied the induction of both CEA, a tumor-associated antigen, and MHC class I, a major component of the antigen presenting system, in response to a number of chemotherapeutic agents.MethodsThe effect of a selection of standard chemotherapeutics on MHC class I and CEA expression in human colorectal cancer cell lines was determined by flow cytometry and semi-quantitative RT-PCR. In addition, studies using mice bearing tumors derived from an injected murine colon cancer cell line were performed to determine if alteration in MHC class I expression occurs in vivo following continuous infusion of chemotherapeutic agents into the peritoneal cavity, as well as to facilitate correlations between expression of this factor and therapeutic effectiveness.ResultsAll anti-cancer drugs examined, when given at IC50 values, induced expression of MHC class I protein in the human colon cancer cell line, COLO201. However, expression of CEA mRNA was only induced upon exposure to 5-FU, in contrast to obscure induction following CDDP and SN-38 treatment. Combined treatment with 5-FU and CDDP gave additional effect on CEA expression in COLO201 cells. Regarding the in vivo studies in mice, the size of the murine colon cancer cell-derived tumors was reduced only in response to treatment with CDDP, which also mediated the highest induction of MHC class I expression.ConclusionThese results suggest that chemotherapeutic agents trigger the immune system and cancer-specific immunotherapy may be effective when used in combination with systemic chemotherapy.

Endosonography during endoscopic mucosal resection to enhance its safety : A new technique

AbstractBackground: We have performed endoscopic mucosal resection of the esophagus (172 cases), stomach (102 cases), and colon (28 cases) using a transparent plastic cap. Because the lesion-bearing mucosa is suctioned up inside the cap under endoscopic suction, the mucosa should be dissected sufficiently from the proper muscle layer to prevent perforation. Methods: To avert the risk of perforation, we introduced endosonographic assessment of submucosal dissection (47 cases). In all cases, just keeping the ultrasonic probe on the surface of the mucosa allowed us to evaluate whether the mucosal lesion was lifted up sufficiently from the proper muscle layer after local saline injection. Results: It was possible to confirm that the muscle layer was kept outside the strangulating snare by the same procedure (32 of 37 cases, 86.5%). Conclusions: We experienced five muscular resections in cases without the ultrasonic probe and no muscular resection with the ultrasonic probe. Thus we recommend endosonographic assessment during endoscopic mucosal resection to enhance its safety.

Allelotype analysis of early colorectal cancers with lymph node metastasis

Several studies have indicated that frequent allelic losses in some specific chromosomal regions occur during colorectal cancer (CRC) progression. To clarify the correlation between such allelic losses and metastatic potential, the allelotype of lymph node‐positive early CRCs, which are small but extremely malignant cancers consisting of metastatically competent cells, were investigated. Nineteen paraffin‐embedded specimens of early CRC (pT1 tumors according to TNM classification) with positive lymph nodes were collected. The tumor tissues were examined for loss of heterozygosity (LOH), using microsatellite markers on chromosomes 1p34–36, 8p21–22, 14q32, 18q21 and 22q12–13. The relationship between p53 protein expression and the metastatic status was also investigated by immunohistochemical staining. A group of 20 early CRCs with negative lymph nodes having a similar distribution of macroscopic appearance were used as controls. Among the 19 node‐positive tumors, LOH at 8p21–22 and 18q21 was detected in 11 cases (57.9%) and 17 cases (89.4%), respectively. Allelic losses within these 2 regions in node‐positive tumors were significantly more frequent than that in node‐negative ones (p< 0.01). No significant correlation was found between LOH at 1p34–36, 14q32 or 22q12–13 and lymph node metastasis. p53 protein expression was not significantly associated with lymph node metastasis. Our results suggest that putative tumor suppressor genes, which may be involved in the metastatic process of CRC, are located on chromosomes 8p21–22 and 18q21. Allelic losses in these regions are possible risk factors for lymph node metastasis of early CRC. Int. J. Cancer (Pred. Oncol.) 79:418–423, 1998.

Cyclooxygenase-2 expression in colorectal adenomas.

AbstractPURPOSE: Cyclooxygenase-2 is an important target for nonsteroidal anti-inflammatory drugs in suppressing colorectal tumorigenesis. To evaluate the role of cyclooxygenase-2 in sporadic colorectal adenoma, we correlated cyclooxygenase-2 expression in adenomas with other adenoma characteristics. METHODS: Cyclooxygenase-2 expression was evaluated immunohistochemically in 95 endoscopically resected colorectal adenomas. RESULTS: Cyclooxygenase-2 was expressed mainly in the cytoplasm of adenoma cells, where it was seen in 74 percent (70/95) of adenomas. Expression was related significantly to grade of dysplasia (P < 0.001) and tumor size (P = 0.028). Multivariate logistic regression analysis showed cyclooxygenase-2 expression in adenoma cells to be independently associated with grade of dysplasia (P = 0.001). CONCLUSION: Observed associations suggest that cyclooxygenase-2 plays an important role in progression of the adenoma-to-carcinoma sequence.