Association of MICA-TM and MICB C1_2_A microsatellite polymorphisms with tumor progression in patients with colorectal cancer.

PURPOSE: The major histocompatibility complex class I related A (MICA) and MICB molecules are ligands of NKG2D receptors on natural killer cells, gamma/delta T cells, and CD8ass T cells that mediate host antitumor immune response. The role of MICA-TM and MICB C1_2_A alleles in patients with colorectal cancer has not yet been investigated. METHODS: We have analyzed the MICA-TM and MICB C1_2_A polymorphisms in colorectal cancer patients (n = 79) by polymerase chain reaction amplification, subsequent electrophoresis, and sequencing in comparison to a previously analyzed cohort of healthy controls (n = 306). Allele frequencies obtained for MICA-TM and MICB C1_2_A were compared to histopathological data regarding tumor invasion, disease progression, microsatellite instability, and the presence of KRAS mutations (codon 12) and analyzed for possible impact on tumor-related survival (n = 61). RESULTS: Allele frequencies of MICA-TM and MICB C1_2_A polymorphisms were not different in patients with colorectal cancer in comparison to normal controls. In colorectal cancer patients, MICA-TM A4 allele was directly and MICA-TM A5 allele was inversely associated with lymph node involvement and advanced UICC stages. Tumor-related survival in colorectal cancer patients was significantly reduced in the presence of the MICA-TM A4 allele (p = 0.015). In patients with microsatellite stable tumors, survival was reduced in association with the MICA-TM A4 allele (p = 0.006) and MICA-TM A9 allele (p = 0.034), but increased in patients showing the MICA-TM A5 allele (p = 0.042). CONCLUSIONS: Specific MICA-TM alleles seem to influence tumor progression and midterm survival of patients with colorectal cancer, indicating an important role of host innate immune predisposition involving NKG2D mediated antitumor response.

Gender differences in long-term survival of patients with colorectal cancer.

BACKGROUND: Significant differences exist in the immunological response to surgery. This raises the possibility that gender differences exist concerning the outcome after curative colorectal cancer resection. METHODS: To study this hypothesis, a database of patients with colorectal cancer was analysed prospectively. RESULTS: Some 894 patients were included, 500 (55.9 per cent) were men and 394 (44.1 per cent) were women. Median follow-up was 54.5 months for the entire group and 63.3 months for survivors. The mean(s.e.m.) patient age was 65.3(0.4) years (women 66.1(0.6), men 64.7(0.5) years; P < 0.05). Women lived significantly longer after cancer resection than men (57.8(1.5) versus 52.0(1.3) months; P < 0.05, log rank 0.009). Disease-free survival was significantly longer in women than in men (51.6(1.7) versus 46.0(1.4) months; P < 0.05). Subgroup analysis revealed significant gender differences in Union Internacional Contra la Cancrum (UICC) stages I (n = 195, log rank 0.01) and UICC IV (n = 38, log rank 0.021). Survival analysis after rectal cancer resection revealed significant advantages for women (log rank 0.02), while no gender differences were detected when comparing patients after resection for colonic cancer. Moreover, patients older than 50 years (n = 635) showed significant gender-related survival differences (log rank 0.015). CONCLUSION: Significant gender differences following curative rectal cancer resection were observed. In women disease-free and overall survival were significantly longer. Whether or not these gender differences are related to gender-specific immune functions or to other gender-related local or systemic factors remains to be determined.

The role of carcinoembryonic antigen for the detection of recurrent disease following curative resection of large-bowel cancer.

BACKGROUND AND AIMS: During recent years, a discussion about cost-effectiveness and importance of follow-up evaluation after curative resection of large-bowel cancer has developed. It is not known whether the determination of carcino-embryonic antigen (CEA) plays a crucial role in the early detection of recurrent disease. PATIENTS/METHODS: We conducted an analysis of the prospective follow-up database of 1321 patients after curative resection of colorectal cancer in our institution between 1990 and 1998 to evaluate the role of CEA in the early detection of recurrent disease. RESULTS: Of the 1321 patients included in our study, 306 developed recurrent disease following curative resection (23.2%). These patients with recurrent disease were divided into: Group I. No pre-operative CEA determination/insufficient follow-up (n=47; 15.4%). Group II. No elevation of CEA with primary cancer (n=156; 51.0%): (IIa) elevation with recurrent disease (n=62); (IIb) no elevation at any time point (n=53); and (IIc) role of CEA not completely elucidated (n=41). Thirteen patients of group II underwent curative relapse surgery (8.3%). Group III. Elevated CEA with primary cancer (n=103; 33.7%): (IlIa) no increase with recurrent disease (n=21); (IIIb) increase with other symptoms of recurrent disease (n=45); and (IIIc) increased values as an early symptom of recurrent disease (n=37). Sixteen patients of group III underwent curative relapse surgery (15.5%). In patients after relapse surgery, recurrent disease developed again after a median time of 12 months (mean 17.9+/-3.8 months). CONCLUSIONS: Our findings indicate that 2.8% of all patients (12.1% of patients with recurrent disease) who underwent curative resection of colorectal cancer profit from follow-up CEA determinations. With careful observation of CEA kinetics, 6.2% (n=82) of all patients or 26.8% of patients with recurrent disease could profit from routine follow-up CEA determinations. In 9.5% of patients with recurrent disease, curative resection of relapse was achieved and these patients remained disease free for a median time of 12 months. Regular CEA measurements remain an important part of routine patient care after curative resection of colorectal cancer.

Carcinoembryonic antigen for the detection of recurrent disease following curative resection of colorectal cancer.

BACKGROUND: During recent years a discussion about cost-effectiveness and importance of follow-up determination of carcinoembryonic antigen (CEA) after curative resection of large bowel cancer has developed. PATIENTS AND METHODS: Between 1990 and 1998 follow-up CEA levels of 1,321 patients after curative colorectal cancer resection were prospectively collected in cooperation with family physicians, CEA determinations were made with different assays by various laboratories. The reported findings were adjusted for the different methods used. RESULTS: 306 patients developed recurrent disease following curative cancer resection (23.2% of all patients). Regarding the role of follow-up CEA determination, they were divided into: I. no preoperative CEA determination/insufficient follow-up (N = 47); II. no elevation of CEA with primary cancer, a) elevation with recurrent disease (N = 62), b) no elevation at any time point (N = 53), c) role of CEA not completely elucidated (N = 41); III. elevated CEA levels with primary cancer, a) no increase with recurrent disease (N = 21), b) increase with other symptoms of recurrent disease (N = 45), c) increased levels as early symptom of recurrent disease (N = 37). 30 patients (9.8% of all patients with recurrent disease; 2.3% of all patients) with increased CEA levels at the time of recurrent disease underwent surgical resection with curative intention (R0 resection). CONCLUSIONS: Our findings indicate that up to 47% of the patients with recurrent disease and 11% of all patients (N = 144, groups IIa + IIIb + IIIc) could benefit from routine follow-up CEA determinations after curative colorectal cancer resection. Nonetheless, only 2.3% of all patients with elevated CEA levels underwent R0 resection of recurrent disease. Despite these detection and R0 resectability rates, CEA plays a crucial role in the early detection of recurrent disease and remains an important part of routine patient care after curative resection of colorectal cancer.

Multivariate analysis of the prognostic value of CEA and CA 19-9 serum levels in colorectal cancer.

UNLABELLED: Carcinoembrionic Antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) are the most commonly used tumor-associated antigens in the management of patients with colorectal cancer. The aim of this study was to evaluate the prognostic value of preoperative serum levels of CEA and/or CA 19-9 and the classical prognostic factors (age, sex, tumor infiltration and staging) in 495 patients. PATIENTS AND METHODS: The retrospective study was performed on frozen sera (stored at -70 degrees C) of patients with histologically proven colorectal cancer. Survival function estimates were calculated (Kaplan-Meier). The patients were separated into two groups according to the preoperative marker levels. Cut-off levels calculated at a specificity of 100% versus healthy individuals were used: < 4 ng/mL versus > or = 4 ng/mL for CEA and < 60 U/mL versus > or = 60 U/mL for CA 19-9. Survival curve differences were assessed using the log-rank-test. Mulivariate Cox's proportional hazard regression analysis was performed to examine the association between tumor marker levels and survival time. Classical prognostic factors such as age, sex, tumor infiltration, tumor stage (Dukes' classification) were included as covariants. The mantel-Haenszel method was used to assess the survival rate of patients with colorectal carcinoma and high versus low levels of tumor-associated antigens according to tumor stages. RESULTS: The Dukes' stages (log-rank chi-square = 231.9; p < 0.0001) represent the best prognostic factor besides the preoperative values of CA 19-9 (log-rank chi-square = 162.5). CEA shows a log-rank chi-square of 71.4. Thus, CEA and CA 19-9 can be used to discriminate two groups of patients with significantly different survival times (p < 0.0001). The importance of different parameters in providing additional prognostic information was evaluated by multivariate analysis. Only items of statistically significant prognostic relevance (univariate analysis) were used for this analysis. Estimated relative risks of death adjusted for tumor stage were 5.5 considering Dukes' stage A versus Dukes' stage B/C and Dukes' stage B/C versus Dukes' stage D, respectively, and an increasing relative risk of 27.5 for Dukes' stage A versus Dukes' stage D (p < 0.001). The relative risk for preoperative CA 19-9 serum concentrations (> or = 60 U/mL versus < 60 U/mL) was 2.3 (p < 0.001) and for preoperative CEA concentrations (> or = 4 ng/mL versus < 4 ng/mL) 1.4 (p < 0.07). For CEA the 2-year survival rates in the group of patients with preoperative serum concentrations > 4 ng/mL versus < 4 ng/mL and Dukes' stage D were 16% versus 38%, in Dukes' stage B/C 73% versus 91% and in Dukes' stage A 100% versus 98%. For CA 19-9 the 2-year survival rates in the group of patients with preoperative serum concentrations > or = 60 U/mL versus < 60 U/mL and Dukes' stage D were 10% versus 39%, whilst in Dukes' stage B/C 58% versus 87%. In the group of patients with Dukes' stage A with serum levels > or = 60 U/mL a 2-years survival rate of 100% was found. CONCLUSION: The postoperative Dukes' classification represents the best prognostic information besides the preoperative values of CA 19-9. The predictive information provided by preoperative CA 19-9 serum levels is independent from that obtained by the other factors investigated. Only Dukes' classification and CA 19-9 levels showed statistical significance (p < 0.001).

Preoperative serum levels of CEA and CA 19-9 and their prognostic significance in colorectal carcinoma.

UNLABELLED: The prognostic information provided by preoperative serum CEA, CA 19-9 antigen assays as compared with the classical prognostic factors (age, sex, tumor infiltration, tumor stage (Dukes') and R-classification) in 495 patients with colorectal carcinoma was analysed. PATIENTS AND METHODS: Survival function estimates were calculated according to Kaplan-Meier. The patients were separated into two groups according to the preoperative marker levels. Fixing specificity at 100% for healthy people, cut off levels were calculated. Survival curve differences were assessed using the log-rank-test. Multivariate Cox's proportional hazard regression analysis was performed. The Mantel-Haenszel method was used to assess the survival rate of patients with colorectal carcinoma and high versus low levels of tumor-associated antigens according to tumor stages. The study was performed on the frozen sera (stored at -80 degrees C) of 495 patients with histologically proven colorectal carcinoma. RESULTS: The Dukes' stages (log-rank chi-square = 231.9; P < 0.0001) represent the best prognostic factor besides the preoperative values of CA 19-9 (log-rank chi-square = 162.5). CEA shows a log-rank chi-square of 71.4. Thus, CEA and CA 19-9 can be used to discriminate two groups of patients with significantly different survival times (P < 0.0001). The importance of different parameters in providing additional prognostic information was evaluated by multivariate analysis (Cox's model). Estimated relative risks of death adjusted for tumor stage were 5.5 for Dukes' stage A versus Dukes' stage B/C and Dukes' stage B/C versus Dukes' stage D, respectively and an increasing relative risk of 27.5 for Dukes' stage A versus Dukes' stage D (P < 0.001). The relative risk for preoperative CA 19-9 serum concentrations (> or = 60 U/mL versus < 60 U/mL) was 2.3 (P < 0.001) for preoperative CEA concentrations (> or = 4 ng/mL versus < 4 ng/mL) 1.4 (P < 0.07). For CEA the 2-years survival rates in the group of patients with preoperative serum concentrations > or = 4 ng/mL versus < 4 ng/mL and Dukes' stage D were 16% versus 38%, in Dukes' stage B/C 73% versus 91% and in Dukes' stage A 100% versus 98%. For CA 19-9 the 2-years survival rates in the group of patients with preoperative serum concentrations > or = 60 U/mL versus < 60 U/mL and Dukes' stage D were 10% versus 39%, in Dukes' stage B/C 58% versus 87%. In the group of patients with Dukes' stage A with serum levels > or = 60 U/mL a 2-year survival rate of 100% was found. In the corresponding group only one patient exists. CONCLUSION: The postoperative Dukes' classification provides the best prognostic information besides the preoperative values of CA 19-9. The predictive information provided by the preoperative CA 19-9 serum level is additional to that obtained from the other factors investigated.