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It has been suggested that bile CEA levels could represent a sensitive index for the detection of occult liver metastases in colorectal cancer (CRC) patients. We measured serum and gallbladder bile CEA concentrations in a control group, in a group of patients with benign disease of the biliary tree, and in patients with CRC at different stages. Neoplastic patients without evidence of liver metastases at the time of laparotomy, but with elevated biliary CEA levels, were selected for a follow-up study. Our results indicate that (a) bile CEA levels are falsely increased in several benign biliary diseases; (b) CRC patients with detectable liver metastases have elevated biliary CEA levels; (c) high biliary CEA levels do not represent a predictive parameter for the presence of occult liver metastases in CRC patients.

Recently, a new immunometric assay (Cyfra 21–1) was developed to measure serum concentrations of a soluble fragment of cytokeratin subunit 19. With this method, supplied by Boehringer Mannheim (EIA Test Cyfra 21–1), an Italian multicenter trial was performed in patients with lung cancer. Cyfra 21–1 serum levels were determined in 568 normal subjects (blood donors), 607 patients with non-malignant diseases (491 respiratory diseases) and 730 patients with malignancies. In the latter group 584 had lung cancer. All these 584 patients had pathologically confirmed disease; 314 were epidermoid tumors, 166 adenocarcinomas, 88 small cell cancers and 16 large cell cancers. In the 568 healthy blood donors the mean Cyfra 21–1 value was 0.91 ng/ml (SD 0.47 ng/ml; range 0.05–2.90 ng/ml). A threshold of 1.9 ng/ml was chosen as the upper limit of normality. High levels of Cyfra21–1 were observed in patients with chronic hepatitis (positivity rate: 17/51–33.3%) and with pancreatitis (positivity rate 5/16 - 31.3%). In 114 out of 491 (23.2%) patients with respiratory diseases Cyfra 21–1 showed values greater than 1.9 ng/ml. The overall sensitivity (all stages) of Cyfra 21–1 in lung cancer was 65.6% (383/584). When the histology was considered the highest positivity rates were found in patients with squamous cell tumors (226/314; 72%) followed by adenocarcinomas (105/166; 63%). In patients with SCLC the global sensitivity was 52.3% (46/88). Higher sensitivity of Cyfra 21–1 was observed from stage I to stage IV (53.9% vs 85.7%; Chisquare: p < 0.01). When comparing patients in whom curative resections were possible (up to stage IIIa) with patients suffering from inoperable tumors, a significant difference in Cyfra 21–1 positivies was found (59% vs 81.5%; Chi square p < 0.01).

In this phase II study, we treated 7 patients, all males, with stage III or IV pancreatic cancer with goserelin (an LH-RH analogue). Goserelin was administered at a dose of 3.6 mg every 4 weeks. The tumour response was assessed by measuring lesions with US- or CT-scan studies, according to WHO criteria. No response was observed. The median survival was 8 months in locally unresectable tumours and 4 months in advanced disease. The accrual was actually stopped at 7 cases because there were no responses in either of our series or in those published during our study. The authors conclude that the treatment with LH-RH analogue alone cannot be recommended for further studies.

With the aim of investigating the clinical usefulness of CEA, CA 15-3, and MCA serum levels, we studied 143 women whose breast cancer was submitted to serial tumor marker determinations: 79 women had stage I-II tumors and were undergoing follow-up after local and adjuvant treatment; 64 women presented metastatic lesions. Among the stage I-II patients, 63 women remained disease-free during the observation period and 16 developed metastases. In 13 out of 16 patients, tumor markers were elevated and in 11 out of 16 patients the increased tumor markers were the first sign of disease progression. Among metastatic patients, 49 presented increased tumor markers and 15 normal value. Moreover, we observed a decrease or normalization of tumor markers in patients responding to treatment and increased values in progressive disease. No correlation was noted between site of disease and tumor markers. We concluded that tumor markers are of clinical value in the detection of metastasis and may be useful in monitoring response to treatment in metastatic patients.

e16082 Background: OPN is a secreted adhesive glycoprotein overexpressed in human cancers. A stimulatory effect of OPN on human PCa cells in vitro has been demonstrated. This study intends to determine if measuring serum OPN and PSA levels can provide informative markers for the detection of PCa. Methods: Serum total PSA using a chemiluminescent immunoassay system (Hybritech PSA, DxI Beckman Coulter, Inc.) and plasma OPN using an ELISA technique (R&D Systems, Inc.) were measured in 263 male subjects referred for diagnostic prostate biopsy, including 167 control patients with benign prostate pathology (mean age: 65.30; median age: 66; SD: 6.80; range 46–83) and 96 PCa patients (mean age: 66.80; median age: 68; SD: 7.90; range 47–86). Sensitivity and specificity were determined for each marker. The relationship between sensitivity and specificity was profiled by receiver operating characteristic (ROC) curves of OPN and PSA. Results: Both markers levels were higher in PCa patients (OPN 51.98 ng/ml, SD 32.64, range 5.9–169.54; PSA 12.91 ng/ml, SD 14.73, range 1.69–90) than in controls (OPN 49.93 ng/m, SD 27.78, range 4.15–146.34; PSA 8.04 ng/ml, SD 5.94, range 0.46–45), although the elevation was significant (p No significant financial relationships to disclose.

18097 Background: While no previous data has so far shown any difference between the efficacy of serum platelet-derived growth factor (PDGF-AB) and serum epidermal growth factor (EGF) in distinguishing MPM from benign pleural diseases, some pilot studies have shown the potentiality of both these markers in the prognosis of MPM patients. This study investigates this capacity by analyzing survival in a series of MPM patients. Methods: Using an ELISA method, EGF (ng/ml) baseline serum was determined in 83 newly diagnosed MPM patients, and in 62 cases PDGF-AB serum levels were also measured. After a median follow-up time of 11.8 months (range 0.4–52.1 months), the log-rank test was used to compare the survival curves, and Cox’s regression analysis was also performed. Results: Median serum values were 0.56 ng/ml (range 0.09–2.05) for EGF and 43.0 ng/ml (range 0.1–145) for PDGF-AB. Patients with EGF levels higher than the median level of 0.56 ng/ml had an average survival time of 9.4 months (95%CI: 5.7–13.2), while the average survival time of patients with below-median EGF levels was 13.2 months (95%CI: 10.6–15.8); a statistically significant difference (p=0.005). For patients with PDGF-AB levels higher than an assumed cut-off of 49.8 ng/ml, (above 75th percentile of MPM marker concentration) average survival was 7.9 months (95%CI: 4.5–11.3) as against the 14.9 months (95%CI: 10.3–18.7) in patients with below cut-off marker levels, again statistically significant (p=0.02). Cox’s regression analysis was performed on 42 patients in whom data on age, sex, histology, stage and platelet count were available. EGF and PDGF-AB levels higher than the selected cut-offs were confirmed as independent predictors of poor survival (HR=1.49; 95% CI: 1.04–2.13; p=0.03 and HR=1.96; 95% CI: 1.23–3.13; p=0.005, respectively). Conclusions: Our data suggest that circulating PDGF-AB and EGF levels are promising markers for clinical monitoring of MPM patients. No significant financial relationships to disclose.

13049 Background: The irinotecan active metabolite, SN38, is inactivated through glucuronidation mainly by uridine diphosphate glucuronosyltransferase (UGT) 1A1. The (TA)7 allele of a polymorphism in UGT1A1 promoter has been associated with reduced SN38-glucuronidation rate and more severe toxicity. Since other UGT1A family isoforms, the extrahepatic UGT1A7 and the hepatic UGT1A9, are involved in SN38 glucuronidation, it has been suggested that also polymorphic variants of these genes may affect irinotecan toxicity. Methods: 84 patients with advanced colorectal cancer received an irinotecan-based (180 mg/m2 q.2wks) combination treatment. Polymorphisms of UGT1A1 [(TA)6>7], UGT1A7 [387T > G, 391–2CG > AA, 622T > C] and UGT1A9 [-118(T)9>10, -87G > A, 98T > C, I152G > A] were identified by sequencing on DNA from blood samples obtained under an IRB approved protocol. Toxicity has been graded according to NCI-CT criteria. Results: Patient median age was 64 y (range: 31–82); median PS was 0 (range: 0–2). Severe toxicity (diarrhea or/and neutropenia ≥G3) has been observed in 32 patients: diarrhea in 11, neutropenia in 25 (4 patients had both). The estimated allele frequencies were as follows: UGT1A1, (TA)7 (0.35); UGT1A7, 387T and the completely linked 391–2CG (0.39), 622C (0.39); UGT1A9, -118(T)10 (0.39), -87A (0.05), T98C (0.02), I152A (0.21). Severe toxicity was significantly associated only with: (a) the UGT1A1 (TA)7 allele [severe toxicity in 25% of (TA) 6/6, in 46% of (TA) 6/7, in 55% of (TA) 7/7 (Mantel-Haenszel trend test, P < 0.03)]; and (b) the low activity UGT1A7 622C allele [severe toxicity in 26% of 622 T/T, in 39% of 622 T/C, in 67% of 622 C/C (Mantel-Haenszel, P < 0.02)]. In addition, the analysis of the combined genotypes [(TA)6>7 and 622T > C] has shown severe toxicity in 21% of patients with none of (TA)7 and of 622C alleles, in 43% of patients in which the sum of the number of (TA)7 and of 622C alleles is 1 or 2, in 57% of patients in which this sum is ≥3 (the latter includes all patients with both toxicities) (Mantel-Haenszel, P < 0.02). Conclusions: These data show that both the low activity UGT1A1 (TA)7 and UGT1A7 622C alleles are significantly associated with irinotecan severe toxicity. It is to evaluate if their combined genotype may be a better predictor of toxicity. No significant financial relationships to disclose.

10080 Background: MPM is an uncommon but extremely aggressive tumor of the serosal surfaces, which has been closely linked to asbestos exposure. Several in-vitro studies have demonstrated that HGF enhances MPM cell proliferation, migration, and invasiveness and the presence of EGF is closely related to the process of cell differentiation and the synthesis of glycosaminoglycans in MPM cells. Few studies have measured the blood levels of these growth factors in tumor patients and assessed their correlation with clinical outcome. This pilot study was designed to investigate the potential value of serum EGF and HGF measurements for the diagnosis and the prediction of survival in MPM patients. Methods: Baseline serum EGF and HGF levels (ng/ml) were determined using an ELISA method in 81 newly diagnosed MPM patients (mean age 67.5±11.0 years) and 48 patients with benign respiratory diseases (BRD; mean age 64.3±13.5 years). Results: HGF and EGF median concentrations in MPM (1.6 ng/ml and 0.5 ng/ml, respectively) were not statistically different from concentrations in BRD (1.2 ng/ml and 0.4 ng/ml). Median follow-up for MPM patients was 27 months, while overall median survival was 11.8 months. At univariate analysis, only high EGF serum levels were associated with an unfavorable survival outcome. Using a cut-off point for EGF of 0.5 ng/ml (corresponding to the median of marker concentration in MPM), the survival rate in patients with higher serum EGF was significantly worse than that in patients with lower levels (median 10.7 vs. 13.0 months, p=0.01). Multivariate analysis, after adjusting for age, sex, histology and platelet count, confirmed the independent predictive value of serum EGF concentration as a negative prognostic factor (p=0.01). Conclusions: High pre-treatment levels of serum EGF are associated with an adverse prognostic impact on survival in MPM patients. No significant financial relationships to disclose.

2016 Background: Inherited variation in the activity of enzymes involved in drug metabolism are likely to be responsible for most inter-individual variability in the toxicity and the efficacy of the drugs themselves. The topoisomerase-I inhibitor irinotecan may have unpredictable severe toxicity: mainly diarrhea and myelosuppression. Its active metabolite, SN38, is inactivated through glucuronidation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). The UGT1A1 promoter includes, in the TATA box region, a well known polymorphism containing either 7 or, more commonly, 6 TA repeats. The (TA)7 allele has been associated with a reduced rate of SN-38 glucuronidation and more severe toxicity in patients treated with irinotecan. Methods: UGT1A1 was genotyped by PCR on samples obtained under an institutional review board-approved protocol from 66 patients with advanced colorectal cancer treated, 24 in first and 42 in second line, with irinotecan-containing chemotherapy. Toxicity has been graded accordin...

7315 Background: Diffuse malignant pleural mesothelioma (DMPM) is an aggressive and highly lethal tumor. Its incidence is increasing and is sensibly higher in some Italian areas, due to occupationa...

The presence of the Ca-125 antigen was tested in the serum of 46 patients with ovarian cancer in order to determine the prognostic value of preoperative levels and its usefulness for monitoring the clinical response in longitudinal studies; survival (S) and progression-free survival (PFS) were also evaluated. In our series, the specificity of the assay in normal subjects and in patients with benign gynecological diseases is 99.3 and 73.2% respectively, and the sensitivity is 91.9%. Preoperative Ca-125 levels are not correlated with S and PFS, whereas an advantage in S and PFS is clearly shown for patients in whom the marker level decreases after treatment. Serial determinations of Ca-125 serum levels provide a reliable test to assess response to therapy and to predict disease progression.

The relationship between preoperative CEA, Dukes staging and disease recurrence, was analyzed in 92 patients with colon-rectal cancer, all who underwent curative surgery. Sixty-five of the 92 patients were followed for 36 months. A significant increase in disease recurrence risk is observable starting from a preoperative CEA value of greater than 7.5 ng/ml; corresponding values as such are verified by a significant fall in the actuarial survival curve in comparison to the progress of the curves of the other two groups with lower CEA values. A statistically significant correlation between preoperative CEA and staging was not observed, while both parameters result statistically very reliable (p less than 0.001) for prognosis; preoperative CEA values, less or greater than 7.5 ng/ml can help to stratify the Dukes tumours with respect to the probability of recurrence.

During the cooking process of meat, mutagenic and/or carcinogenic substances can be formed that can induce tumours of the gastro-intestinal tract or of other organs in the rat. The formation of these substances is proportionate to the cooking time, the cooking surface and the quantity of fats contained in meat. A comparison is made between beef cooked on a grid where the temperature reaches 200 degrees C, and cooked in a microwave oven (Cuocorapido Candy 500 CL, frequency 2450 Mhz) where the temperature does not exceed 100 degrees C. Mutagenic substances were extracted by the Commoner technique and mutagenic activity was assayed with the Ames test.no mutagenic activity was demonstrated in the extracts of meat cooked in microwave ovens, while mutagenic activity was clearly demonstrated in the extracts of meat cooked on a grid.

The potential synergism of sequential combinations of tamoxifen (TMX) or estradiol benzoate (E2B) with medroxyprogesterone acetate (MPA) in inhibiting the growth of 7.12-dimethylbenz(a)anthracene(DMBA) - induced rat mammary tumors has been investigated. In addition, the effect of TMX and E2B on estrogen and progesterone receptors' (ERs and PgRs) synthesis has been evaluated in the attempt to elucidate possible mechanisms involved. Previous treatment both with TMX and E2B has been shown to strongly enhance the antitumor activity of MPA. A priming on PgR synthesis has been observed only after E2B administration, TMX producing a sharp decrease in PgR levels. It is concluded that, while the priming action exerted by E2B on PgRs might explain the potentiating effect shown by E2B on MPA activity, the synergism observed between TMX and MPA should be explained on an extrareceptorial basis, an induction on PgR synthesis by TMX not being evident at the dosage and priming time employed in this study.