Sialyl Lewisa expression as a predictor of the prognosis of colon carcinoma patients in a prospective randomized clinical trial

BACKGROUND: The metastatic potential of tumors is dependent on the cell to cell adhesion by cell surface carbohydrate antigens. Thus, expression of sialyl Lewis(a), which is one of the important molecules of cell surface carbohydrates, may serve as a prognostic marker of aggressive and metastasizing tumor growth. However, the prognostic value of sialyl Lewis(a) expression in colon cancer is still controversial. METHODS: In this study, we investigated the expression of sialyl Lewis(a) antigen in 233 colon cancer specimens from patients who were registered in a prospective adjuvant immunochemotherapy clinical trial. The clinical course and the prognosis of the patients were evaluated after all the immunohistochemical analyses had been performed. RESULTS: Sialyl Lewis(a) expression levels were correlated with both overall survival (P = 0.0006) and disease-free survival (P = 0.004) in all patients with the log-rank test. This result could be assumed to have been influenced by the difference in the metastatic preponderance in a high versus low sialyl Lewis(a) expression in the tumor cells. CONCLUSION: This prospective study in a randomized controlled trial suggests that sialyl Lewis(a) expression levels may serve as an indicator of the metastatic potential of colon cancer cells, which would strongly predict the prognosis.     

Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01.

PURPOSE: Adjuvant postoperative treatment with fluorouracil (5-FU) and levamisole in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrence and improves survival. Biochemical modulation of 5-FU with leucovorin has resulted in increased remission rates in metastatic colorectal cancer, thus reflecting an increased tumor-cell kill. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in comparison with the effects of 5-FU plus levamisole in the prospective multicentric trial adjCCA-01. PATIENTS AND METHODS: Patients with a curatively resected International Union Against Cancer stage III colon cancer were stratified according to T, N, and G category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m(2) body-surface area intravenously in the first chemotherapy course, then 450 mg/m(2) x 5 days; 12 cycles, plus leucovorin 100 mg/m(2) (arm A), or 5-FU plus levamisole (Moertel scheme; arm B). RESULTS: Six hundred eighty (96.9%) of 702 patients enrolled onto this study were eligible. After a median follow-up time of 46.5 months, the 5-FU plus leucovorin combination significantly improved disease-free survival (P =.037) and significantly decreased overall mortality (P =.0089) in comparison with 5-FU plus levamisole. In a multivariate proportional hazards model, adjuvant chemotherapy emerged as a significant prognostic factor for survival (P =.0059) and disease-free survival (P =.03). Adjuvant treatment with 5-FU plus levamisole as well as with 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities. CONCLUSION: After a curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated and significantly more effective than 5-FU plus levamisole in reducing tumor relapse and improving survival.     

An individual patient data meta-analysis of adjuvant therapy with carmofur in patients with curatively resected colon cancer

BACKGROUND: Oral carmofur, either as a single or in combination with other chemotherapeutic agents, has been used as adjuvant chemotherapy for curatively resected colon cancer patients. Past trials and meta-analyses indicate that it is somewhat effective in extending survival of patients with this cancer. The objective of this study was to perform a reappraisal of randomized clinical trials conducted in this regard. METHODS: We designed an individual patient-based meta-analysis of relevant clinical trials to examine the benefit of oral carmofur for curatively resected colon cancer in terms of overall survival (OS) and disease-free survival (DFS). RESULTS: We analyzed individual patient data of three randomized clinical trials, which met the predetermined inclusion criteria. These three trials had a combined total of 2152 patients, carmofur as adjuvant chemotherapy compared with surgery-alone, 5 years follow-up, intention-to-treat-based analytic strategy and similar end points (OS and DFS). In a pooled analysis, 5 year OS rates were 80.4 and 76.4%, and 5 year DFS rates 76.9 and 71.0%, respectively, in carmofur and surgery-alone group. Oral carmofur had significant advantage over surgery-alone in terms of both OS [pooled hazard ratio, 0.82; 95% confidence interval (CI) = 0.68-0.99; P = 0.043] and DFS (pooled hazard ratio, 0.77; 95% CI = 0.65-0.91; P = 0.003). CONCLUSIONS: This individual patient-based meta-analysis demonstrated that oral carmofur significantly improves both OS and DFS in patients with curatively resected colon cancers.     

The Rhesus D-negative phenotype is an independent predictor of poor prognosis in curatively (RO) resected gastric cancer patients.

Among gastric cancer patients, the Rhesus D-negative phenotype correlated with increased tumour recurrence [all patients, n = 83, P = 0.026; curatively (R0) resected patients, n = 51, P = 0.093] and reduced overall survival time (all patients, log-rank P = 0.0028; R0 patients, log-rank P = 0.0003) and was identified in multivariate analysis as the most important independent prognostic marker in the R0 patient group (relative risk 9.1, P = 0.0013).     

5-Fluorouracil plus leucovorin is an effective adjuvant chemotherapy in curatively resected stage III colon cancer: long-term follow-up results of the adjCCA-01 trial.

BACKGROUND: Adjuvant postoperative treatment with 5-fluorouracil (5-FU) and leucovorin in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrences and improves survival. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in a long-term follow-up study in comparison with the effects of 5-FU plus levamisole in the prospective multicenter trial adjCCA-01. PATIENTS AND METHODS: Patients with a curatively resected stage III (International Union Against Cancer) colon cancer were stratified according to tumor, node and grading category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m2 body surface area intravenously in the first chemotherapy course, then 450 mg/m2 x 5 days, plus leucovorin 100 mg/m2, 12 cycles (arm A), or 5-FU plus levamisole (Moertel scheme; arm B). RESULTS: Six hundred and eighty (96.9%) of 702 patients enrolled into this study were eligible. To date, 261 patients have died, 117 on arm A and 144 on arm B (P = 0.007). After a median follow-up time of 82 months, the 5-FU plus leucovorin combination significantly improved disease-free survival [79.8 months in arm A versus 69.3 months in arm B (P = 0.012)] and significantly increased median overall survival (88.9 months in arm A versus 78.6 months in arm B; P = 0.003). Adjuvant treatment with 5-FU plus levamisole as well as 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities. CONCLUSIONS: After curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated. This long-term follow-up study demonstrates that adjuvant treatment with 5-FU plus leucovorin given for 12 cycles is significantly more effective than 5-FU plus levamisole (Moertel scheme) in reducing tumor relapse and improving survival.     

Thymidylate Synthase expression as a predictor of clinical response to fluoropyrimidine-based chemotherapy in advanced colorectal cancer

Thymidylate Synthase (TS) is a rate-limiting enzyme in the DNA synthetic pathway and represents the cellular target of the antimetabolite drug 5-fluorouracil (FUra). Both preclinical and clinical studies have shown that the level of expression of this enzyme and the ability to achieve its inhibition are the major determinants of sensitivity and resistance to fluoropyrimidines (FP). In particular, five recent studies have consistently demonstrated an inverse correlation between the level of TS gene or protein expression measured in colorectal cancer metastases and the clinical response to either FUra or 5-fluorodeoxyuridine (FUdR). Patients with low levels of TS expression in their metastases have indeed shown response rates that are three to ten times higher compared to those obtained in patients with high TS levels. The independent predictive value demonstrated in a logistic regression model, the longer survival shown by patients with low TS levels in three of five studies and the consistency of the results obtained by independent groups using different techniques to quantitate TS expression, strengthen the predictive role of TS. Targeted treatment of colorectal cancer based on TS quantitation has thus been hypothesized similar to the use of hormone receptor in breast cancer. In this review preclinical and clinical data supporting the use of TS quantitation to predict for the clinical response to FUra will be described and unresolved problems including assays standardization, response prediction based on TS levels measured in primary tumors, intrapatient variations in TS levels and biological/biochemical limitations of this strategy will be discussed.     

Clinical results of a randomized controlled trial on the effect of adjuvant immunochemotherapy using Esquinon and Krestin in patients with curatively resected gastric cancer. Cooperative Study Group of Cancer Immunochemotherapy, Tokai Gastrointestinal Oncology Group

From July 1977, a controlled clinical trial in 168 patients who received curative surgery for stomach cancer and 111 similarly treated for colorectal cancer was conducted in the form of a cooperative study involving 22 institutions. One week after surgery, carboquon (CQ) was given at a dose of 2 mg/m2 once a week, followed by PSK at a dose of 2 g/m2 every day for 4 weeks. This regimen was repeated 9 times for 55 weeks. For stomach cancer, patients were divided into 3 groups; Group A: CQ intermittently, Group B: CQ PSK in alternate doses, Group C: controls. For colorectal cancer, the patients were divided into 2 groups; Group D: CQ + PSK in alternate doses, Group E: controls. Survival rate of stage III stomach cancer patients in Group B was higher than that in Group A, the difference being statistically significant between 20 and 24 months after surgery. For colorectal cancer, the survival rate of patients with Dukes C in Group D was statistically superior to that in Group E. These differences were much more apparent among patients who received more than 6 courses of the regimen.     

DNA ploidy is a valuable predictor for prognosis of patients with resected renal cell carcinoma.

BACKGROUND: Renal cell carcinomas (RCCs) are heterogeneous and include several distinct entities with a range of biologic and clinical behaviors from relatively favorable to extremely aggressive. The heterogeneity leads to unpredictable outcome and survival. DNA ploidy is a relatively new predictor differentiating diploid from aneuploid tumor cells according to regular or irregular DNA content. The authors evaluated the predictive value of DNA ploidy in patients who underwent resection because of RCC. METHODS: In a prospective study, 180 patients who underwent resection because of RCC were investigated. DNA cytometry was conducted on each resected tumor to determine DNA ploidy. Patients were completely followed up until death or up to 12 years. RESULTS: Survival analysis showed that patients who underwent resection because of RCC in tumor classifications pT1, pT2, and pT3 survived 10 years in 85%, 53%, and 8% of cases, respectively. Patients suffering from small tumors (pT1 and pT2, n = 44) with diploid nuclei survived 10 years in 94% but only in 8% if the tumor was aneuploid (n = 55). In addition, 91% of patients who underwent resection of large tumors (pT3, n = 12) with diploid nuclei survived 10 years, but no patient with large and aneuploid tumor (n = 51) survived more than 3 years. Furthermore, 92% of all patients afflicted from diploid RCC survived 10 years. This finding was independent of tumor stage. CONCLUSIONS: The results of this study suggest that DNA ploidy is a significant and independent predictor for survival of patients afflicted from RCC and superior to tumor classification and grade. DNA ploidy is a reliable prognostic factor for RCC and yields considerable information for patient management and predicting clinical outcome.     

Clinical results of a randomized controlled trial on the effect of adjuvant immunochemotherapy using Esquinon and Krestin in patients with curatively resected gastric cancer--7-year survival--Cooperative Study Group for Cancer Immunochemotherapy, Tokai Gastrointestinal Oncology Group

A randomized controlled study was carried out on curatively resected gastric cancer patients in a cooperative study involving 16 institutions in order to evaluate the effect of an alternative long-term adjuvant immunochemotherapy using Esquinon (CQ) and Krestin (PSK). One week after surgery, CQ was given at a dose of 2mg/m2 once a week for 3 weeks and this was repeated every 6 weeks. CQ was administered intravenously in the 1st course and thereafter orally up to 9 courses. Three postoperative week, immunotherapy was then started in which PSK was given orally in 3 divided doses of 2g/m2/day from the day when CQ therapy ended for 4 consecutive weeks, and this performed for every course. Estimated survival rate and cumulative survival curves were compared utilizing the data up to 7 years after surgery in the chemotherapy group given CQ alone and in the immunochemotherapy group given CQ + PSK. The survival curve in all cases showed a favorable form in the CQ + PSK group for up to 36 months, and thereafter it crossed with that of the CQ group for up to 68 months. Both curves twisted at 68 months and then deviated from each other, showing that the effect in the CQ + PSK group beneficial. The curve showed a twisting configuration throughout the treatment period. There was no statistically significant difference between the survival curves of the two groups. Retrospective survival analysis was then performed on separate subgroups classified into the category of S1, S2, N1, and N2. The CQ + PSK group was better than the CQ alone group in its survival rate for the S1 + S2 (N1-2) group, the percentage being 11.5%, and a statistically significant difference was observed between the two groups (p = 0.089).     

Low thymidylate synthase expression in the primary tumor predicts favorable clinical outcome in resected gastric cancer patients treated with adjuvant tegafur

OBJECTIVE: To assess the thymidylate synthase protein (TS) in tumor cells of resected gastric cancer patients treated with adjuvant tegafur (TG), we reviewed the outcome of 94 randomized patients treated either with adjuvant TG plus mitomycin C (MMC) or MMC alone. METHODS: TS was determined in 76 out of 94 patients, previously randomized to receive adjuvant TG, 500 mg/m(2)/day p.o. for 6 months plus four courses of MMC, 10- 20 mg/m(2) i.v. every 6 weeks or MMC alone. An immunohistochemical assessment with the monoclonal antibody TS-106 was performed. RESULTS: Low TS was observed in 38 patients (20 treated with TG-MMC and 18 with MMC) and high TS in the other 38 patients (21 treated with TG-MMC and 17 with MMC). After 10 years' median follow-up time, 61% of adjuvant TG-MMC patients and 43% of MMC patients were alive and disease-free. Disease-free survival and overall survival were significantly better for patients treated with TG-MMC compared to MMC adjuvant (p = 0.0277 and p = 0.05), and low-TS compared to high-TS patients (p = 0.0184 and p = 0.0198). In 38 low-TS patients we observed an 83% chance to be disease-free in TG-MMC-treated patients and 55% in MMC-treated patients (p = 0.04). CONCLUSIONS: A low TS level determines a subset of patients that may benefit from adjuvant oral TG when added to MMC showing a 5-year cure rate of more than 80%.     

Thymidylate synthase expression in stage II and III colon cancer: a retrospective review.

This study is a retrospective analysis of thymidylate synthase (TS) levels in patients with stage II (T3 or T4) and III colon cancer. Two groups of patients were identified: one undergoing surgery alone (98 patients) and the second receiving adjuvant 5-fluorouracil chemotherapy (112 patients). TS analyses were carried out using the 106 monoclonal antibody and a published grading system dividing staining into high and low intensity. The distribution of patients with low versus high TS levels was similar in the two groups. There was no association between TS staining intensity and grade, stage or location of primary. Seventy-nine patients have relapsed: 46 (48%) in the surgery only group, 33 (30%) in the adjuvant therapy group (median follow-up: 51 and 61 months). Similar proportions relapsed when analyzed according to TS: in the surgery only group, 41% of patients with low TS, 48% with high TS; in the adjuvant group, 31% with low TS, 30% with high TS. In the surgery only group, a trend toward improved disease-free survival (DFS) was seen in the low TS group (84 versus 63% at 2 years, p = 0.08). No difference was seen in overall survival. There were no differences in DFS or overall survival in patients receiving adjuvant therapy according to TS intensity. The trend for worse outcome in patients with high TS is consistent with previous reports. The lack of difference in outcome for patients with low and high TS receiving chemotherapy suggests that high TS levels may predict greater benefit from adjuvant treatment.     

The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial

The effect of an adjuvant mistletoe extract treatment was tested in a prospective, randomised controlled clinical trial involving 477 patients with head and neck squamous cell carcinoma. The patients were stratified into two treatment groups that underwent surgery or surgery followed by radiotherapy and both groups were randomised for additional treatment with mistletoe extract. Patients treated with a mistletoe lectin-1 (ML-1) standardised mistletoe preparation had no lower risk of local/locoregional recurrences, distant metastases or second primaries. In the main analysis based on 202 patients treated with surgery and 275 patients treated with surgery and radiotherapy the adjusted hazard ratio for the disease-free survival (DFS) was 0.959 (95% confidence interval (CI) 0.725-1.268). The 5-year survival rates of patients from the mistletoe group were no better than the survival rates of patients from the control group. Furthermore, no significant changes in the cellular immune reaction or in quality of life could be detected. We conclude that the used mistletoe preparation has no indication in the adjuvant treatment of patients with head and neck cancer.     

Phase II clinical trial using novel peptide cocktail vaccine as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients

We investigated peptide cocktail vaccine OCV‐C01 containing epitope peptides derived from KIF20A, vascular endothelial growth factor receptor (VEGFR)1 and VEGFR2 combined with gemcitabine in the adjuvant treatment for resected pancreatic cancer patients. A single‐arm multicenter phase II study was performed on 30 patients with pancreatic ductal carcinoma who underwent pancreatectomy. At each 28‐day treatment cycle, patients received weekly subcutaneous injection of OCV‐C01 for 48 weeks and gemcitabine was administered intravenously at 1,000 mg/m² on days 1, 8 and 15 for 24 weeks. Patients were followed for 18 months. The primary endpoint was disease‐free survival (DFS) and secondary endpoints included safety, overall survival (OS) and immunological assays on peptide‐specific cytotoxic T lymphocyte (CTL) activity and KIF20A expression in resected pancreatic cancer. The median DFS was 15.8 months [95% confidence interval (CI), 11.1–20.6] and the DFS rate at 18 months was 34.6% (95% CI, 18.3–51.6). The median OS was not reached and the OS rate at 18 months was 69.0% (95% CI, 48.8–82.5). The administration of OCV‐C01 was well tolerated. In the per protocol set, there were significant differences in DFS between patients with KIF20A‐specific CTL responses and without (p = 0.027), and between patients with KIF20A expression and without (p = 0.014). In addition, all four patients who underwent R0 resection with KIF20A expression had no recurrence of pancreatic cancer with KIF20A‐specific CTL responses. OCV‐C01 combined with gemcitabine was tolerable with a median DFS of 15.8 months, which was favorable compared with previous data for resected pancreatic cancer.     

Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis.

PURPOSE: A number of studies have investigated the relationship between thymidylate synthase (TS) expression and survival in colorectal cancer (CRC) patients. Although most have reported poorer overall and progression-free survival with high TS expression, estimates of the hazard ratio (HR) between studies differ wildly. To derive a more precise estimate of the prognostic significance of TS expression, we have reviewed published studies and carried out a meta-analysis. MATERIALS AND METHODS: Twenty studies stratifying overall survival and/or progression-free survival in CRC patients by TS expression status were eligible for analysis. The principal outcome measure was the HR. Data from these studies were pooled using standard meta-analysis techniques. RESULTS: Thirteen studies investigated outcome in a total of 887 cases with advanced CRC, and seven studies investigated outcome in a total of 2,610 patients with localized CRC. A number of methods were used both to assess TS expression and to assign TS status. Sample sizes varied greatly, small sample sizes being a feature of the advanced disease studies. The combined HR estimate for overall survival (OS) was 1.74 (95% CI, 1.34 to 2.26) and 1.35 (95% CI, 1.07 to 1.80) in the advanced and adjuvant settings, respectively, but there was evidence of heterogeneity and possible publication bias. CONCLUSION: Tumors expressing high levels of TS appeared to have a poorer OS compared with tumors expressing low levels. Additional studies with consistent methodology are needed to define the precise prognostic value of TS.     

Thymidylate synthase expression predicts the response to 5-fluorouracil-based adjuvant therapy in pancreatic cancer.

PURPOSE: Thymidylate synthase (TS) is the target enzyme for 5-fluorouracil (5-FU), and TS expression may determine clinical response and survival after therapy with 5-FU in colorectal cancer. 5-FU is also widely used in the adjuvant therapy of pancreatic cancer. Therefore, we explored the hypothesis that TS expression was associated with patient prognosis and the response to adjuvant therapy in pancreatic cancer. EXPERIMENTAL DESIGN: Cylindrical tissue cores from a large retrospective, nonrandomized series covering 132 resected patients were used to build a pancreatic cancer tissue microarray. TS expression was determined using immunohistochemistry. RESULTS: High intratumoral TS expression and low intratumoral TS expression were present in 83 of 132 (63%) and 49 of 132 (37%) tumors, respectively. Median survival among patients with low intratumoral TS expression (18 months) was longer than that among patients with high TS expression (12 months). In multivariate analysis, more advanced pathological stage [risk ratio (RR) = 1.70; P = 0.015], poorly differentiated histology (RR = 1.71; P = 0.015), management with adjuvant therapy (RR = 0.49; P = 0.011), and high TS expression [RR = 1.66; 95% confidence interval (CI) = 1.05-2.63; P = 0.029] were independent predictors of mortality. The risk of death was significantly reduced by any adjuvant therapy (RR = 0.40; 95% CI = 0.18-0.90; P = 0.001) among patients with high TS expression. This difference in survival among patients with low- and high-TS-expressing tumors became more significant when the analysis was restricted to the 73 patients receiving 5-FU-based adjuvant therapy (RR = 0.37; 95% CI = 0.16-0.86; P = 0.0006). In contrast, 5-FU-based adjuvant therapy did not influence survival among patients with low-TS-expressing pancreatic cancer. CONCLUSIONS: High TS expression is a marker of poor prognosis in resected pancreatic cancer. Patients with high intratumoral TS expression benefit from adjuvant therapy.     

Thymidylate synthase expression in hepatic tumors is a predictor of survival and progression in patients with resectable metastatic colorectal cancer.

PURPOSE: To investigate the role of thymidylate synthase (TS),p53, and epidermal growth factor receptor (EGF-R) expressions in hepatic tumors in predicting overall survival (OS), progression-free survival (PFS), and hepatic progression-free survival (HPFS) in patients with resectable metastatic colorectal cancer who were randomly assigned to receive either systemic chemotherapy (SYS) alone or systemic and hepatic arterial infusion (HAI+SYS) chemotherapy following liver surgery. PATIENTS AND METHODS: Tissues from metastatic tumors were collected during liver resection from 156 patients, and marker expressions were determined using immunohistochemistry on frozen samples. Univariate associations between marker expressions and baseline variables with OS, PFS, and HPFS were examined. Independent predictors of outcome were determined using a multivariate Cox model. RESULTS: In multivariate analyses, TS overexpression was found to be an independent factor of poor prognosis in OS (P <.01), PFS (P =.06), and HPFS (P <.01). In addition, resection margin was a significant independent factor for all three outcomes. Patients who received HAI+SYS experienced delayed progression in general, and in the liver, specifically. Increased levels of serum alkaline phosphatase correlated with hepatic progression. We also found a significant TS-treatment interaction for OS (P =.01) in multivariate analysis. In particular, TS+ patients receiving HAI+SYS had significantly higher survival than those receiving SYS (64 month sv 21 months; P =.01). CONCLUSION: TS levels in hepatic tumors and resection margin are independent predictors of survival and progression in patients with metastatic colorectal cancer, whereas p53 and EGFR are not independent predictors. Treatment with HAI + SYS significantly improved the survival profile of TS+ patients.     

Aurora-A is a novel predictor of poor prognosis in patients with resected lung adenocarcinoma

Background： The Aurora-A （AurA） gene, a key regulator of mitosis, has been proved as an oncogene in a variety of cancers. The Aur-A overexpression has been proved correlated with aggressiveness of cancer cells. However, the frequency of Aur-A protein overexpression, as well as its association with clinicopathologic parameters and prognosis remain unclear in lung adenocarcinoma （ADC）. This study tried to clarify the clinical significance of Aur-A in patients with resected lung ADC. Patients and methods： A total of 142 informative patients with surgically resected lung ADC and 20 normal lung tissues were enrolled. Western blot and immunohistochemistry （IHC） were utilized to assess protein expression of Aur-A. Result： The expression of Aur-A was elevated in most of tumor tissues compared with the adjacent tissues by western blot. The IHC results showed that Aur-A protein was over-expressed in 98 of 142 （69.0%） tumor sections, while Aur-A was low-expressed in all normal lung sections. A positive correlation between Aur-A overexpression rate and ascending pathologic stages was observed （P〈0.05）. Kaplan-Meier analysis demonstrated that patients with Aur-A high expression had significantly inferior survival compared to those with Aur-A low expression. Both overall survival （OS） and disease-free survival （DFS） of positive overexpression patients were shorter than the negative group （P=0.036, P=0.041, respectively）. Multivariate analysis confirmed that Aur-A expression, as an independent and significant factor for both DFS and OS, could predict a poor prognosis in patients with resected lung ADC （P=0.022, P=0.049, respectively）. Conclusions： Aur-A was overexpressed in lung ADC and overexpression of Aur-A might be a novel predictor for poor prognosis and potential therapeutic target in lung ADC.     

Thymidylate synthase expression in normal colonic mucosa: a predictive marker of toxicity in colorectal cancer patients receiving 5-fluorouracil-based adjuvant chemotherapy

OBJECTIVES: We retrospectively evaluated the relevance of thymidylate synthase (TS) expression in normal colonic mucosa as a predictive factor of toxicity in colorectal cancer patients receiving adjuvant fluorouracil (5-FU)-based chemotherapy. METHODS: TS expression was immunohistochemically assessed on normal colonic mucosa from 50 patients with colorectal cancer Dukes' stages B (15 patients) and C (35 patients) treated with 5-FU-based adjuvant chemotherapy. RESULTS: The incidence of grade 2-3 diarrhea and stomatitis (according to WHO) was demonstrated to be significantly higher in patients with low nuclear TS expression in normal mucosa than in those with high TS expression (p < 0.0001). Moreover, patients with low TS expression in normal colonic mucosa developed weight loss and worsening of the performance status (according to ECOG score) more commonly than patients with high TS expression (p = 0.005 and p = 0.02, respectively). Furthermore, low TS expression in normal colonic mucosa significantly correlated with a higher rate of a delay of chemotherapy courses, dose reduction and treatment discontinuation. CONCLUSIONS: Immunohistochemical TS expression in normal colonic mucosa may represent an important predictive parameter for identifying a subset of patients with a high risk of developing severe 5-FU-related toxicities.