Hypermethylation in the promoter region of the p16 gene was suspected to be involved in the tumorigenesis of colorectal cancers, although its clinical and biological significance remains obscure. In this study, we collected 84 T3N0M0 stage primary colorectal cancers that were curatively resected. The clinicopathologic data were reviewed. p16 hypermethylation was determined by a methylation-specific polymerase chain reaction (PCR). p53 overexpression was detected by immunocytochemistry (ICC). The point mutations in the 12 and 13 codons of the K-ras gene were screened by restriction enzyme analysis. Loss of heterozygosity (LOH) of the DCC (Deleted in Colorectal cancer) gene was examined by PCR using primers of the DCC (18q21) microsatellite marker. The DNA replication error (RER) was examined using 7 microsatellite markers at distinct chromosomal loci. p16 hypermethylation, regarded as an indication of p16 inactivation, was evident in 24 (28.6%) of the tumors. No correlation was found between p16 hypermethylation and various clinicopathologic factors, includinig age, sex, tumor location, tumor size, growth pattern, tumor differentiation, mucin production, vascular and/or lymphatic invasion, lymphocyte infiltration of the tumor, and serum level of carcinoembryonic antigen. There was no association between p16 hypermethylation of K-ras gene mutation, p53 overexpression and LOH of the DCC gene. However, p16 hypermethylation was significantly associated with DNA RER (p = 0.01). Survival analysis revealed a significant survival disadvantage of p16-hypermethylated versus non-p16-hypermethylated tumors (p = 0.0001). These findings indicate that p16 hypermethylation plays a role in the carcinogenesis of a subset of colorectal cancers; and the presence of p16 hypermethylation predicts shorter survival in T3N0M0 stage colorectal cancers.

The influence of MSI on treatment outcome of colorectal cancers remains unclear and deserves further investigation. We recruited 244 patients with stage IV sporadic colorectal cancers for our study, based on appropriate eligibility criteria. Patients were nonrandomly allocated to 2 treatment groups of either with or without high-dose 5-FU plus leucovorin chemotherapy (HDFL, 5-FU 2,600 mg/m 2 leucovorin 300 mg/m 2 maximum 500 mg). Each treatment group was further divided into 2 subgroups according to high-frequency MSI (MSI-H) status. MSI-H was defined as the appearance of MSI in at least 2 of the 5 examined chromosomal loci (BAT-25, BAT-26, D5S346, D2S123, D17S250 8 -10 The inconsistency of the clinical relevance of MSI in different studies might result from different methodology and interpretation criteria used for the assessment of MSI, 11 different clinical treatment modalities used for patients and variations in the clinicopathologic characteristics of the included patients, particularly with regard to pTNM, stage grouping and residual tumor (R) classification. 12 Furthermore, biologically, tumor prognosis is determined by intrinsic aggressiveness and/or potential sensitivity to chemotherapy. However, currently, although some authors strongly advocate that colorectal cancers with MSI benefit from adjuvant chemotherapy, [13][14][15][16][17][18][19] we are not fully convinced that this is due to better chemosensitivity and/or lower biologic invasiveness. In vitro studies have provided conflicting results as to whether colorectal cancer cells with deficient MMR genes are more resistant to 5-FU-based treatment. 20,21 Therefore, the clinical implications of MSI remain obscure and deserve further investigation. Clarification of the prognostic significance of MSI status will rely on the implementation of large, populationbased studies and prospective clinical trials. [22][23][24][25] In our study, we determined the clinical relevance of MSI-H in stage IV sporadic colorectal cancer, based on a nonrandomized, prospective study. We explored whether MSI-H was associated with chemosensitivity and/or biologic aggressiveness in predicting the clinical outcome of stage IV sporadic colorectal cancer. MATERIAL AND METHODS PatientsPatients met the following eligibility criteria: (i) the sporadic primary colorectal cancer could be palliatively resected and pathologically confirmed as adenocarcinoma; (ii) metastatic lesions were measurable but unresectable; (iii) Karnofsky performance status was Ն50%; (iv) life expectancy was Ͼ12 weeks; (v) WBC

Our study aims to further clarify the prognostic significance of p53 overexpression in stage IV colorectal cancer. Between January 1994 and June 1997, we recruited 144 patients with stage IV colorectal cancers for our study, based on appropriate eligibility criteria. The patients were nonrandomly allocated to 2 treatment groups of either with or without high-dose 5-fluorouracil plus leucovorin chemotherapy (HDFL: 5-Fu: 2,600 mg/m 2 leucovorin 300 mg/m maximum 500 mg). Each treatment group was further divided into 2 subgroups according to the status of p53 overexpression. Therefore, 4 subgroups were allocated in our study and were designated as p53 (overexpression) HDFL (؉), n ‫؍‬ 65; p53 (normal) HDFL (؉), n ‫؍‬ 37; p53 (overexpression) HDFL (؊), n ‫؍‬ 27; and p53 (normal) HDFL (؊), n ‫؍‬ 15, respectively. All patients were prospectively followed until April 2001. There was no significant difference of the background clinicopathologic data of these 4 allocated subgroups of patients (p > 0.05). Multivariate analysis of various clinicopathologic factors of the whole group of patients indicated that age >60 years, poor differentiation, mucin production, CEA >100 ng/ml, p53 overexpression and without chemotherapy were the significant independent poor prognostic factors (p < There is generally acceptance of the important role of p53 as "guardian of genome," i.e., as regulator of cell proliferation, differentiation, DNA repair (response to DNA damage) and apoptosis. 1-8 Moreover, according to the "molecular paradigm" of colorectal carcinogenesis, as pointed out by Fearon and Vogelstein, p53 mutation is involved in the later stage of adenoma-carcinoma sequence. 9 Therefore, we have good reasons to speculate that colorectal cancers with p53 mutations might be more aggressive in biologic behavior. In fact, numerous investigators have attempted to correlate this important molecular marker with the clinical outcome of colorectal cancers. 10 -12 However, results reported to date have been controversial. [13][14][15][16][17][18][19] The inconsistency of the clinical relevance of p53 mutations in different studies resulted from different methodology and interpretation criteria used for the assessment of p53 status, 20 -26 different clinical treatment modalities used for patients 27,28 and the variations in clinicopathologic characteristics of the included patients, in particular in regard to pTNM, staging grouping and residual tumor (R) classification. 29 -32 Furthermore, theoretically, tumor prognosis is determined by intrinsic aggressiveness and/or potential sensitivity to chemotherapy. However, although some authors strongly advocate that colorectal cancers with p53 mutations are associated with poor clinical prognosis, we are not fully convinced whether it is due to their chemotherapeutic insensitivity and/or more biologic invasiveness. [33][34][35][36][37][38][39][40][41][42][43] Therefore, the clinical implications of p53 alterations remain obscure and deserve further investigation. Further clarification of the progno...

Marked eIF4E overexpression in gastric cancer was found to be associated with vascular invasion. The prognosis for gastric cancer patients with marked overexpression of eIF4E was worse than those with underexpression. It may serve as an additional prognostic and therapeutic factor in gastric cancer, and deserves further investigation.

ObjectiveThe purpose of this study was to investigate the clinical usefulness of microvessel density (MVD) and an in vivo angiogenesis parameter, color Doppler vascularity index (CDVI), in patients with gastric cancer. Summary Background DataMany studies have reported a significant association between the degree of MVD-evaluated angiogenesis with the clinicopathologic factors and prognosis of patients with various solid tumors. All these studies were accomplished on tissue sections retrospectively obtained from surgical specimens. However, an in vivo method to assess tumor angiogenesis for human malignancies is highly desirable for diagnostic purpose, treatment planning, and follow-up. The CDVI is a new ultrasound parameter for evaluating in vivo angiogenesis, has a good correlation with status of lymph node metastasis in cervical carcinoma, and can predict distant metastasis and survival in colon cancer patients. Therefore, the CDVI may also be useful to assess in vivo angiogenesis in human gastric cancer. MethodsA total of 79 patients with gastric cancer were enrolled in this study, and microvessel density was evaluated by using immunohistochemical staining of surgical specimens with anti-CD-34 antibody. Tumors were sonographically visible in 31 patients. The CDVI of each tumor was determined using transabdominal color Doppler ultrasound. The CDVI was defined as the ratio of the number of the colored pixels within a tumor section to the number of total pixels in that specific tumor section, and was calculated by using Encomate software (Electronic Business Machine Co. Ltd., Taipei, Taiwan). Correlation between MVD, CDVI and clinicopathologic factors and patient survival was studied. ResultsThe MVD was significantly correlated with vascular invasion by multiple linear regression analysis. Although the survival of patients with high MVD (Ͼ 32) was significantly worse than those with low MVD (Ͻ 32) by univariate analysis, vascular invasion was an independent prognostic factor by Cox proportional hazard model. There was a linear correlation between CDVI and MVD (r ϭ .495, P ϭ .005). Moreover, in patients with a high CDVI (Ͼ 11%), the survival rate was significantly lower than that in those with low CDVI (Յ 11%, P ϭ .005). None of the patients with high CDVI (Ͼ 11%) survived 2 years after curative resection. In addition to vascular invasion, the CDVI was another independent prognostic factor in the patients with stage III gastric cancer. ConclusionsVascular invasion was an important prognostic indicator in gastric cancer. The high CDVI was a good preoperative indicator of early death in stage III gastric cancer patients. Thus, the CDVI may be helpful in selecting patients with gastric cancer for neoadjuvant chemotherapy and/or anti-angiogenic therapy.Angiogenesis is a very complex phenomenon and essential for the growth of solid tumors measuring more than a few millimeters.1 It permits rapid tumor growth and potential presence of tumor metastasis.2,3 It is not easy to develop a single method capable of detecting su...