Bcl-2 is a useful prognostic marker in Dukes' B colon cancer.

BACKGROUND: Currently, the use of adjuvant therapy specifically in Dukes' B colon cancers is controversial, emphasizing the importance of identifying prognostic markers to select patients for such therapy. Bcl-2 plays an important role in apoptosis regulation of solid tumors, such as colon and breast cancer, and is normally expressed in the base of the colonic crypts. The purpose of this study is to determine whether or not bcl-2 expression can be used to predict survival in Dukes' B colon cancer patients. METHODS: Charts of 76 patients operated on at the Royal Victoria Hospital from 1986 to 1992 were reviewed. Bcl-2 staining was done with the avidin-biotin-peroxidase complex method using commercially available monoclonal bcl-2 antibodies. Two pathologists graded the intensity of bcl-2 staining on a scale of 0-3 and estimated the percentage of tumor cells staining positively (T-percent). Univariate and multiple regression of factors on overall survival (OS) and disease-free survival (DFS) was done with a Cox proportional hazards model and Kaplan-Meier survival curves. RESULTS: The mean age was 71.2 years, with 41 female and 35 male patients. Mean tumor size was 5.4 cm with tumor grades of 19 well, 52 moderate, and 5 poorly differentiated. Tumors expressing bcl-2 had a similar DFS (P = .14) but a significantly improved OS (P = .04) compared with the bcl-2 negative tumors. The risk ratio for DFS was 0.49 (95% CI, 0.19-1.26) and for OS was 0.35 (95% CI, 0.13-0.94). CONCLUSIONS: These data indicate that enhanced bcl-2 expression, specifically in Dukes' B colon carcinomas, is associated with improved survival. Thus, patients whose tumors do not express bcl-2 should be considered for adjuvant therapy.

Pelvic exenteration for locally advanced rectal carcinoma: factors predicting improved survival.

BACKGROUND: The purpose of this retrospective review was to determine whether a number of clinicopathologic factors (age, gender, type of exenteration, tumor extent, adjuvant therapy, tumor DNA ploidy, and S-phase fraction) that could be determined before operation were useful in predicting survival in patients undergoing pelvic exenteration for rectal cancer. METHODS: Between 1983 and 1992, 40 patients (15 male and 25 female) at our institution underwent pelvic exenteration for rectal adenocarcinoma in which tumor-free pathologic margins were obtained. Twenty-nine patients presented with primary tumors; 11 had recurrent disease. A total exenteration was performed in 20 patients, posterior exenteration in 18 patients, and an anterior exenteration in 2 patients. RESULTS: By multivariate (Cox proportional hazards regression) analysis, age, preoperative chemoradiation therapy, and an S phase of 10% or greater were found to be significant predictors of survival. Age older than 55 years was associated with a relative risk for cancer-related death (RR) of 0.13 (p = 0.02), and chemoradiation had an RR of 0.05 (p = 0.01), indicating their beneficial effect. An S-phase fraction of 10% or greater had an RR of 16.97 (p = 0.03), indicating a poor survival. The clinicopathologic factors listed above were used to derive a prognostic index (PI). A PI of less than 1.37 was associated with a 5-year survival rate of 65% (low risk), whereas patients with a PI of 1.37 or greater had a 5-year survival rate of 20% (high risk) (p = 0.005). CONCLUSIONS: These results indicate that adjuvant chemoradiation may significantly improve survival in patients who require pelvic exenteration for resection of locally advanced rectal carcinoma. An S-phase fraction of 10% or greater is also predictive of a poor outcome. Use of these factors allowed the generation of a PI that identifies high- and low-risk patients. Consideration of the ability to deliver chemoradiation and the determinates of the tumor S-phase fraction in patients requiring pelvic exenteration for rectal cancer may be helpful in predicting outcome and planning therapy.

Apoptosis induced in human colorectal carcinoma by anti-Fas antibody.

BACKGROUND: Apoptosis or programmed cell death has been shown to play an important role in the progression from polyps to carcinomas. Fas/APO-1 is a cell surface protein that can induce apoptosis in a variety of cell types upon specific binding. In this study seven human colorectal carcinoma (HCRC) cell lines of varying differentiation were analyzed for cell surface Fas expression. Fas-mediated apoptosis, and correlation of apoptosis with bcl-2 expression. METHODS AND RESULTS: Using flow cytometry, all seven lines expressed varying amounts of cell surface Fas antigen. Exposure to anti-Fas antibody induced cell death in all the cell lines, albeit to varying degrees. The rate of apoptosis was quantitated using flow cytometry with propidium iodide staining of nuclear DNA. The poorly differentiated cell lines had a significantly decreased (p < 0.05) anti-Fas sensitivity as compared with the well-differentiated lines. Measurement of bcl-2 expression by flow cytometry showed an inverse correlation with anti-Fas sensitivity. CONCLUSIONS: This study confirms that HCRC cell lines express Fas antigen and, more importantly, provides the first evidence that exposure to anti-Fas antibody can induce apoptosis. Fas-mediated apoptosis in HCRC cell lines may be regulated by bcl-2 and may correlate with the degree of differentiation.

Small-bowel resection for metastatic melanoma.

OBJECTIVE: To determine whether complete resection of small-bowel metastases from melanoma improves patient survival. DESIGN: A computer-aided chart review. SETTING: Hospitals associated with McGill University. PATIENTS: Twenty patients (17 men, 3 women), identified from 1524 patients with melanoma, who underwent surgery to the small bowel for metastases. Patient age and clinical presentation, tumour site and stage were recorded. INTERVENTION: Exploratory laparotomy with complete or partial resection of involved small bowel. MAIN OUTCOME MEASURES: Operative morbidity, mortality and length of survival related to the extent of small-bowel resection. RESULTS: Eleven patients had complete resection, 8 patients had partial resection and 1 patient had a palliative bypass only. Long-term survival (ranging from 2 to 10 years) was 36% in those who had complete resection and 0% in those who had partial resection; operative morbidity and mortality were 20% and 15% respectively. CONCLUSION: Complete resection of small-bowel metastases in patients with metastatic melanoma can result in long-term survival.

Soft-tissue sarcomas of the shoulder girdle: factors influencing local recurrence distant metastases, and survival.

BACKGROUND: Prognostic factors and the role of radiotherapy have not been well characterized for soft-tissue sarcomas (STS) of the shoulder girdle. METHODS: The cases of 70 patients with primary shoulder STS were reviewed for the following information: size, grade and histology of tumors, extent of resection, and use of adjuvant radiotherapy. The influence of these factors on local disease-free survival (LDFS), distant disease-free survival (DDFS), and overall survival (OS) rates was analyzed using univariate analysis. RESULTS: With a median follow-up of 108 months, the overall 5- and 10-year survival rates for patients with shoulder girdle STS were 82% and 80%, respectively, whereas the 5-year disease-free survival rate was 63%. There were 25 (35%) tumor recurrences: 12 (17%) distant and 13 (18%) local regional. Tumors > 5 cm in size were associated with a significantly decreased 5-year OS rate compared with lesions < 5 cm, and high-grade tumors were associated with significantly decreased DDFS and OS rates. Because most of the patients who underwent amputation had large, high-grade tumors, they had significantly decreased 5-year DDFS and OS rates compared with wide local excision. Radiotherapy produced a significant improvement in LDFS rates, particularly in patients with tumors > 5 cm in size. CONCLUSIONS: The results indicate that both tumor size and grade are important prognostic factors in shoulder girdle STS. Adjuvant radiotherapy should be considered in large tumors to improve the LDFS and to decrease the need for radical ablative surgery.

Preoperative infusional chemoradiation therapy for stage T3 rectal cancer.

PURPOSE: To evaluate preoperative infusional chemoradiation for patients with operable rectal cancer. METHODS AND MATERIALS: Preoperative chemoradiation therapy using infusional 5-fluorouracil (5-FU), (300 mg/m2/day) together with daily irradiation (45 Gy/25 fractions/5 weeks) was administered to 77 patients with clinically Stage T3 rectal cancer. Endoscopic ultrasound confirmed the digital rectal exam in 63 patients. Surgery was performed approximately 6 weeks after the completion of chemoradiation therapy and included 25 abdominoperineal resections and 52 anal-sphincter-preserving procedures. RESULTS: Posttreatment tumor stages were T1-2, N0 in 35%, T3 N0 in 25%, and T1-3, N1 in 11%; 29% had no evidence of tumor. Local tumor control after chemoradiation was seen in 96% (74 out of 77); 2 patients had recurrent disease at the anastomosis site and were treated successfully with abdominoperineal resection. Overall, pelvic control was obtained in 99% (76 out of 77). The survival after chemoradiation was higher in patients without node involvement than in those having node involvement (p = n.s.). More patients with pathologic complete responses or only microscopic foci survived than did patients who had gross residual tumor (p = 0.07). The actuarial survival rate was 83% at 3 years; the median follow-up was 27 months, with a range of 3 to 68 months. Acute, perioperative, and late complications were not more numerous or more severe with chemoradiation therapy than with traditional radiation therapy (XRT) alone. CONCLUSIONS: Excellent treatment response allowed two-thirds of the patients to have an anal-sphincter-sparing procedure. Gross residual disease in the resected specimen indicates a poor prognosis, and therapies specifically targeting these patients may improve survival further.

Effect of membrane free fatty acid alterations on the adhesion of human colorectal carcinoma cells to liver macrophages and extracellular matrix proteins.

Epidemiologic studies have linked diets high in animal fat with colon carcinogenesis. A number of animal tumor models have shown that diets rich in omega-3 fatty acids inhibit colon carcinogenesis while diets rich in omega-6 fatty acids promote tumor growth. This study examines whether modification of the membrane fatty acid composition of both moderately (CX-1) and poorly differentiated (MIP-101 and Clone A) human colorectal carcinoma cells alters their interaction with Kupffer cells and extracellular matrix proteins (collagen type IV, fibronectin and laminin). The cells were treated with 15-16 micrograms/ml of docosahexanoic acid (22:6, omega 3) or linoleic acid (18:2,omega 6). Gas chromatography showed significant alterations in the membrane fatty acid composition of the human colorectal cancer cell lines. Binding assays were performed by measuring adherence of 51Cr-labelled tumor cells to Kupffer cell monolayers or to immobilized proteins. Omega-3 treatment significantly decreased the Kupffer cell binding of only the CX-1 line while omega-6 treatment decreased binding of all three cell lines. In contrast both omega-3 and omega-6 treatment of MIP-101 cells decreased binding to the extracellular matrix proteins with the omega-6 effect being more pronounced. These results indicate that the binding characteristics of the colon cancer cells to both Kupffer cells and extracellular matrix proteins may be determined in part by the membrane fatty acid composition. Decreased adherence to extracellular matrix proteins may lead to increased cell motility and invasiveness. Since Kupffer cell binding precedes tumor cell phagocytosis and killing, decreased binding may improve tumor cell survival.

Kupffer cell/tumor cell interactions and hepatic metastasis in colorectal cancer.

The degree of interaction with Kupffer cells of two moderately well differentiated cell lines, CX-1 and CCl-188 of high metastatic potential (61%) were compared to two poorly differentiated cell lines, MIP-101 and Clone A of low metastatic potential (6%) in the intrasplenic injection model for liver metastasis. MIP-101 and Clone A bound significantly better to mouse Kupffer cells in vitro than either CX-1 or CCL-188. We also identified specific cell surface proteins mediating attachment of colorectal carcinoma cells to murine Kupffer cells. Kupffer cells were radiolabelled and their surface proteins incubated with MIP-101 and CX-1. Two radiolabelled proteins from murine Kupffer cells of 14 and 34 kDa were identified consistently binding to the tumor cells. Binding of both proteins was inhibited by asialofetuin but not by fetuin. This suggests that the major binding proteins between Kupffer cells and colorectal cancer cells are galactose binding lectins.